Effects O
of O
docosahexaenoic B
acid I
and O
methylmercury B
on O
child O
' O
s O
brain O
development O
due O
to O
consumption O
of O
fish O
by O
Finnish O
mother O
during O
pregnancy O
: O
a O
probabilistic O
modeling O
approach O
. O

Fish O
contains O
both O
beneficial O
substances O
e O
. O
g O
. O
docosahexaenoic B
acids I
but O
also O
harmful O
compounds O
e O
. O
g O
. O
methylmercury B
. O

Importantly O
, O
the O
health O
effects O
caused O
by O
these O
two O
substances O
can O
be O
evaluated O
in O
one O
common O
end O
point O
, O
intelligence O
quotient O
( O
IQ O
) O
, O
providing O
a O
more O
transparent O
analysis O
. O

We O
estimated O
health O
effects O
of O
maternal O
fish O
consumption O
on O
child O
' O
s O
central O
nervous O
system O
by O
creating O
a O
model O
with O
three O
alternative O
maternal O
fish O
consumption O
scenarios O
( O
lean O
fish O
, O
fatty O
fish O
, O
and O
current O
fish O
consumption O
) O
. O

Additionally O
, O
we O
analyzed O
impacts O
of O
both O
regular O
fish O
consumption O
and O
extreme O
fish O
consumption O
habits O
. O

At O
the O
individual O
level O
, O
the O
simulated O
net O
effects O
were O
small O
, O
encompassing O
a O
range O
of O
one O
IQ O
point O
in O
all O
scenarios O
. O

Fatty O
fish O
consumption O
, O
however O
, O
clearly O
generated O
a O
beneficial O
net O
IQ O
effect O
, O
and O
lean O
fish O
consumption O
evoked O
an O
adverse O
net O
IQ O
effect O
. O

In O
view O
of O
the O
current O
fish O
consumption O
pattern O
of O
Finnish O
mothers O
the O
benefits O
and O
risks O
seem O
to O
more O
or O
less O
compensate O
each O
other O
. O

This O
study O
clearly O
shows O
the O
significance O
of O
which O
fish O
species O
are O
consumed O
during O
pregnancy O
and O
lactation O
, O
and O
the O
results O
can O
be O
generalized O
to O
apply O
to O
typical O
western O
population O
fish O
consumption O
habits O
. O

The O
mechanisms O
responsible O
for O
garlic O
- O
drug O
interactions O
and O
their O
in O
vivo O
relevance O
. O

Garlic O
phytochemicals O
and O
garlic O
supplements O
influence O
the O
pharmacokinetic O
and O
pharmacodynamic O
behavior O
of O
concomitantly O
ingested O
drugs O
. O

In O
this O
paper O
we O
have O
summarized O
the O
mechanisms O
responsible O
for O
first O
- O
pass O
intestinal O
pharmacokinetic O
interactions O
by O
investigating O
the O
intestinal O
permeability O
of O
some O
cardiovascular O
, O
antiviral O
drugs O
, O
their O
transport O
with O
hepatic O
transporters O
and O
CYP3A4 O
metabolism O
. O

Transporter O
- O
enzyme O
interplay O
was O
studied O
with O
several O
in O
vitro O
models O
of O
varying O
complexity O
: O
rat O
small O
intestine O
and O
Caco O
- O
2 O
cell O
monolayers O
were O
used O
in O
studies O
of O
intestinal O
processes O
, O
and O
hepatic O
pharmacokinetics O
was O
monitored O
in O
HepG2 O
cells O
, O
isolated O
rat O
hepatocytes O
and O
rat O
liver O
slices O
. O

Garlic O
phytochemicals O
from O
aged O
garlic O
extract O
modified O
the O
activities O
of O
secretory O
and O
absorptive O
transporters O
in O
both O
intestine O
and O
liver O
and O
competitively O
inhibited O
CYP3A4 O
enzyme O
. O

The O
increased O
activities O
of O
the O
most O
important O
intestinal O
efflux O
( O
P O
- O
glycoprotein O
- O
Pgp O
, O
Multidrug O
Resistance O
Associated O
Protein O
2 O
- O
MRP O
- O
2 O
, O
Breast O
Cancer O
Resistance O
Protein O
- O
BCRP O
) O
and O
uptake O
( O
MonoCarboxylate B
Transporter O
1 O
- O
MCT1 O
, O
Organic O
Anion O
Transporting O
Polypeptide O
- O
OATP O
, O
Peptide O
transporter O
1 O
- O
PepT1 O
) O
transporters O
were O
caused O
by O
changes O
in O
electrophysiological O
membrane O
properties O
and O
by O
allosteric O
modifications O
. O

Because O
clinical O
studies O
investigating O
interactions O
between O
garlic O
and O
human O
immunodeficiency O
virus O
protease O
inhibitors O
saquinavir B
and O
ritonavir B
have O
already O
been O
performed O
, O
we O
used O
these O
in O
vivo O
data O
to O
evaluate O
the O
in O
vitro O
results O
and O
the O
reliability O
of O
the O
models O
employed O
as O
screening O
tools O
for O
forecasting O
the O
potential O
of O
first O
- O
pass O
intestinal O
metabolism O
changes O
. O

We O
also O
assessed O
the O
probability O
of O
pharmacokinetic O
interactions O
with O
garlic O
of O
the O
novel O
drug O
darunavir B
and O
other O
cardiovascular O
drugs O
. O

Finally O
, O
selected O
garlic O
phytochemicals O
were O
tested O
for O
their O
ability O
to O
influence O
P O
- O
glycoprotein O
and O
CYP3A4 O
activities O
. O

Endothelial O
nitric B
oxide I
synthase O
genotypes O
and O
haplotypes O
modify O
the O
responses O
to O
sildenafil B
in O
patients O
with O
erectile O
dysfunction O
. O

Erectile O
dysfunction O
( O
ED O
) O
is O
usually O
treated O
with O
sildenafil B
. O

Although O
genetic O
polymorphisms O
in O
the O
endothelial O
nitric B
oxide I
synthase O
( O
eNOS O
) O
gene O
may O
impair O
endogenous O
NO B
formation O
, O
there O
is O
little O
information O
about O
how O
eNOS O
polymorphisms O
and O
haplotypes O
affect O
the O
responses O
to O
sildenafil B
. O

We O
studied O
118 O
patients O
; O
63 O
patients O
had O
ED O
secondary O
to O
radical O
prostatectomy O
( O
PED O
) O
and O
55 O
had O
organic O
, O
clinical O
ED O
. O

eNOS O
genotypes O
for O
three O
eNOS O
polymorphisms O
( O
T O
( O
- O
786 O
) O
C O
, O
rs2070744 O
; O
a O
variable O
number O
of O
tandem O
repeats O
( O
VNTR O
) O
in O
intron O
4 O
; O
and O
Glu298Asp O
, O
rs1799983 O
) O
were O
determined O
, O
and O
eNOS O
haplotypes O
were O
estimated O
using O
PHASE O
2 O
. O
1 O
. O

The O
clinical O
responses O
to O
sildenafil B
were O
evaluated O
and O
the O
patients O
were O
classified O
as O
good O
responders O
( O
GR O
) O
or O
poor O
responders O
( O
PR O
) O
when O
their O
changes O
in O
five O
- O
item O
version O
of O
International O
Index O
for O
Erectile O
Function O
questionnaire O
were O
above O
or O
below O
the O
median O
value O
. O

The O
TC O
/ O
CC O
genotypes O
and O
the O
C O
allele O
for O
the O
T O
( O
- O
786 O
) O
C O
polymorphism O
were O
more O
common O
in O
GR O
, O
compared O
with O
PR O
patients O
with O
PED O
. O

However O
, O
the O
4b4a O
/ O
4a4a O
genotypes O
and O
the O
4a O
allele O
for O
the O
VNTR O
polymorphism O
in O
intron O
4 O
were O
more O
common O
in O
GR O
, O
compared O
with O
PR O
patients O
with O
clinical O
ED O
. O

The O
C O
- O
4a O
- O
Glu O
haplotype O
was O
more O
common O
in O
GR O
than O
in O
PR O
patients O
with O
PED O
. O

Conversely O
, O
the O
T O
- O
4b O
- O
Asp O
haplotype O
was O
less O
common O
in O
GR O
than O
in O
PR O
patients O
with O
PED O
. O

No O
other O
significant O
differences O
were O
found O
. O

Our O
findings O
show O
evidence O
that O
eNOS O
polymorphisms O
affect O
the O
responses O
of O
PED O
and O
clinical O
ED O
patients O
to O
sildenafil B
. O

On O
the O
benefit O
of O
magnetic O
magnesium B
nanocarrier O
in O
cardiovascular O
toxicity O
of O
aluminum B
phosphide I
. O

The O
present O
study O
was O
designed O
to O
determine O
the O
effect O
of O
a O
new O
( B
25 I
) I
Mg I
( I
2 I
+ I
) I
- O
carrying O
nanoparticle O
( O
( B
25 I
) I
MgPMC16 I
) O
on O
energy O
depletion O
, O
oxidative O
stress O
, O
and O
electrocardiographic O
( O
ECG O
) O
parameters O
on O
heart O
tissue O
of O
the O
rats O
poisoned O
by O
aluminum B
phosphide I
( O
AlP B
) O
. O

( O
25 O
) O
MgPMC16 O
at O
doses O
of O
0 O
. O
025 O
, O
0 O
. O
05 O
, O
and O
0 O
. O
1 O
median O
lethal O
dose O
( O
LD50 O
= O
896 O
mg O
/ O
kg O
) O
was O
administered O
intravenously O
( O
iv O
) O
30 O
min O
after O
a O
single O
intragastric O
administration O
of O
AlP O
( O
0 O
. O
25 O
LD50 O
) O
. O

Sodium B
bicarbonate I
( O
Bicarb B
; O
2 O
mEq O
/ O
kg O
, O
iv O
) O
was O
used O
as O
the O
standard O
therapy O
. O

After O
anesthesia O
, O
the O
animals O
were O
rapidly O
connected O
to O
an O
electronic O
cardiovascular O
monitoring O
device O
for O
monitoring O
of O
ECG O
, O
blood O
pressure O
( O
BP O
) O
, O
and O
heart O
rate O
( O
HR O
) O
. O

Later O
lipid O
peroxidation O
, O
antioxidant O
power O
, O
ATP B
/ O
ADP B
ratio O
, O
and O
Mg B
concentration O
in O
the O
heart O
were O
evaluated O
. O

Results O
indicated O
that O
after O
AlP O
administration O
, O
BP O
and O
HR O
decreased O
while O
R O
- O
R O
duration O
increased O
. O

( O
25 O
) O
MgPMC16 O
significantly O
increased O
the O
BP O
and O
HR O
at O
all O
doses O
used O
. O

We O
found O
a O
considerable O
increase O
in O
antioxidant O
power O
, O
Mg B
level O
in O
the O
plasma O
and O
the O
heart O
and O
a O
reduction O
in O
lipid O
peroxidation O
and O
ADP B
/ O
ATP B
ratio O
at O
various O
doses O
of O
( O
25 O
) O
MgPMC16 B
, O
but O
( O
25 O
) O
MgPMC16 B
- O
0 O
. O
025 O
+ O
Bicarb B
was O
the O
most O
effective O
combination O
therapy O
. O

The O
results O
of O
this O
study O
support O
that O
( B
25 I
) I
MgPMC16 I
can O
increase O
heart O
energy O
by O
active O
transport O
of O
Mg B
inside O
the O
cardiac O
cells O
. O
( B
25 I
) I
MgPMC16 I
seems O
ameliorating O
AlP O
- O
induced O
toxicity O
and O
cardiac O
failure O
necessitating O
further O
studies O
. O

Ventilatory O
functions O
in O
cotton O
textile O
workers O
and O
the O
role O
of O
some O
inflammatory O
cytokines O
. O

Exposure O
to O
cotton O
dust O
in O
industrial O
environments O
causes O
inflammation O
in O
the O
airways O
of O
the O
exposed O
workers O
. O

This O
may O
manifest O
as O
respiratory O
complaints O
and O
changes O
in O
the O
respiratory O
functions O
after O
work O
shift O
and O
in O
the O
baseline O
of O
their O
ventilatory O
functions O
. O

The O
study O
aimed O
to O
investigate O
the O
effect O
of O
occupational O
exposure O
to O
cotton O
dust O
on O
respiratory O
symptoms O
, O
ventilatory O
functions O
and O
pro O
- O
inflammatory O
cytokine O
levels O
( O
tumor O
necrosis O
factor O
alpha O
, O
interleukin O
6 O
and O
interleukin O
1 O
beta O
) O
. O

The O
study O
was O
conducted O
on O
63 O
textile O
workers O
and O
65 O
nonexposed O
subjects O
. O

Both O
groups O
were O
matched O
for O
age O
, O
socioeconomic O
status O
and O
smoking O
habit O
. O

The O
respirable O
dust O
measured O
in O
the O
workplace O
did O
not O
exceed O
the O
permissible O
values O
of O
the O
Egyptian O
law O
1994 O
. O

The O
bacterial O
counts O
detected O
were O
within O
the O
occupational O
exposure O
limits O
of O
the O
industrial O
settings O
. O

The O
results O
revealed O
that O
the O
percentage O
of O
respiratory O
symptoms O
was O
higher O
in O
textile O
workers O
. O

Respiratory O
complaints O
were O
chronic O
cough O
( O
33 O
. O
2 O
% O
) O
, O
chronic O
bronchitis O
( O
39 O
. O
7 O
% O
) O
and O
dyspnea O
( O
23 O
. O
8 O
% O
) O
in O
textile O
workers O
compared O
to O
( O
6 O
. O
2 O
% O
, O
6 O
. O
2 O
% O
and O
1 O
. O
5 O
% O
) O
, O
respectively O
, O
in O
controls O
. O

There O
was O
a O
marked O
reduction O
in O
the O
ventilatory O
functions O
( O
forced O
vital O
capacity O
and O
forced O
expiratory O
volume O
in O
1 O
s O
) O
in O
the O
textile O
workers O
compared O
to O
the O
controls O
. O

The O
additive O
effect O
of O
smoking O
on O
the O
ventilatory O
functions O
was O
not O
apparent O
. O

The O
ventilatory O
functions O
of O
the O
workers O
were O
significantly O
positively O
correlated O
with O
the O
duration O
of O
exposure O
. O

The O
cytokines O
were O
insignificantly O
higher O
in O
the O
textile O
workers O
compared O
to O
their O
controls O
. O

The O
textile O
workers O
with O
respiratory O
complaints O
showed O
significant O
decline O
in O
ventilatory O
functions O
and O
elevation O
in O
the O
cytokine O
levels O
compared O
to O
the O
nonsymtomatizing O
workers O
with O
significant O
difference O
in O
interleukin O
1 O
beta O
and O
interleukin O
6 O
. O

In O
conclusion O
, O
the O
results O
supported O
the O
fact O
that O
exposure O
to O
cotton O
dust O
deteriorates O
ventilatory O
functions O
and O
elevates O
proinflammatory O
cytokine O
levels O
. O

Analysis O
of O
the O
release O
of O
cytokines O
can O
be O
used O
to O
evaluate O
the O
immune O
responses O
to O
organic O
dust O
- O
induced O
airway O
inflammation O
. O

Heat O
stress O
decreases O
testicular O
germ O
cell O
proliferation O
and O
increases O
apoptosis O
in O
short O
term O
: O
an O
immunohistochemical O
and O
ultrastructural O
study O
. O

Scrotal O
hyperthermia O
has O
been O
known O
as O
a O
cause O
of O
male O
infertility O
but O
the O
exact O
mechanism O
leading O
to O
impaired O
spermatogenesis O
is O
unknown O
. O

This O
work O
was O
aimed O
to O
investigate O
the O
role O
of O
scrotal O
hyperthermia O
on O
cell O
proliferation O
and O
apoptosis O
in O
testes O
. O

The O
rats O
were O
randomly O
allotted O
into O
one O
of O
the O
four O
experimental O
groups O
: O
A O
( O
control O
) O
, O
B O
( O
1 O
day O
after O
scrotal O
hyperthermia O
) O
, O
C O
( O
14 O
days O
after O
scrotal O
hyperthermia O
) O
, O
and O
D O
( O
35 O
days O
after O
scrotal O
hyperthermia O
) O
; O
each O
group O
comprised O
7 O
animals O
. O

Scrotal O
hyperthermia O
was O
carried O
out O
in O
a O
thermostatically O
controlled O
water O
bath O
at O
43 O
degrees O
C O
for O
30 O
min O
once O
daily O
for O
6 O
consecutive O
days O
. O

Control O
rats O
were O
treated O
in O
the O
same O
way O
, O
except O
the O
testes O
were O
immersed O
in O
a O
water O
bath O
maintained O
at O
22 O
degrees O
C O
. O

Hyperthermia O
- O
exposed O
rats O
were O
killed O
under O
50 O
mg O
/ O
kg O
ketamine B
anaesthesia O
and O
tissue O
samples O
were O
obtained O
for O
biochemical O
and O
histopathological O
investigations O
. O

Hyperthermia O
treatment O
significantly O
decreased O
the O
testicular O
antioxidant O
system O
, O
including O
decreases O
in O
the O
glutathione B
level O
, O
superoxide B
dismutase O
, O
and O
glutathione B
peroxidase O
activities O
. O

Moreover O
, O
exposure O
to O
hyperthermia O
resulted O
in O
lipid O
peroxidation O
increase O
in O
testes O
. O

Our O
data O
indicate O
a O
significant O
reduction O
in O
the O
expression O
of O
proliferating O
cell O
nuclear O
antigen O
and O
an O
enhancement O
in O
the O
activity O
of O
terminal O
deoxynucleotidyl O
transferase O
dUTP B
nick O
end O
labelling O
after O
scrotal O
hyperthermia O
. O

In O
scrotal O
hyperthermia O
, O
the O
mitochondrial O
degeneration O
, O
dilatation O
of O
smooth O
endoplasmic O
reticulum O
, O
and O
enlarged O
intercellular O
spaces O
were O
observed O
in O
both O
Sertoli O
and O
spermatid O
cells O
. O

Scrotal O
hyperthermia O
is O
one O
of O
the O
major O
factors O
that O
impair O
spermatogenesis O
in O
testis O
. O

This O
heat O
stress O
is O
shown O
to O
be O
closely O
associated O
with O
oxidative O
stress O
, O
followed O
by O
apoptosis O
of O
germ O
cells O
. O

A O
genomic O
approach O
to O
predict O
synergistic O
combinations O
for O
breast O
cancer O
treatment O
. O

We O
leverage O
genomic O
and O
biochemical O
data O
to O
identify O
synergistic O
drug O
regimens O
for O
breast O
cancer O
. O

In O
order O
to O
study O
the O
mechanism O
of O
the O
histone O
deacetylase O
( O
HDAC O
) O
inhibitors O
valproic B
acid I
( O
VPA B
) O
and O
suberoylanilide B
hydroxamic I
acid I
( O
SAHA B
) O
in O
breast O
cancer O
, O
we O
generated O
and O
validated O
genomic O
profiles O
of O
drug O
response O
using O
a O
series O
of O
breast O
cancer O
cell O
lines O
sensitive O
to O
each O
drug O
. O

These O
genomic O
profiles O
were O
then O
used O
to O
model O
drug O
response O
in O
human O
breast O
tumors O
and O
show O
significant O
correlation O
between O
VPA B
and O
SAHA B
response O
profiles O
in O
multiple O
breast O
tumor O
data O
sets O
, O
highlighting O
their O
similar O
mechanism O
of O
action O
. O

The O
genes O
deregulated O
by O
VPA B
and O
SAHA B
converge O
on O
the O
cell O
cycle O
pathway O
( O
Bayes O
factor O
5 O
. O
21 O
and O
5 O
. O
94 O
, O
respectively O
; O
P O
- O
value O
10 O
( O
- O
8 O
. O
6 O
) O
and O
10 O
( O
- O
9 O
) O
, O
respectively O
) O
. O

In O
particular O
, O
VPA B
and O
SAHA B
upregulate O
key O
cyclin O
- O
dependent O
kinase O
( O
CDK O
) O
inhibitors O
. O

In O
two O
independent O
datasets O
, O
cancer O
cells O
treated O
with O
CDK O
inhibitors O
have O
similar O
gene O
expression O
profile O
changes O
to O
the O
cellular O
response O
to O
HDAC O
inhibitors O
. O

Together O
, O
these O
results O
led O
us O
to O
hypothesize O
that O
VPA B
and O
SAHA B
may O
interact O
synergistically O
with O
CDK O
inhibitors O
such O
as O
PD B
- I
033299 I
. O

Experiments O
show O
that O
HDAC O
and O
CDK O
inhibitors O
have O
statistically O
significant O
synergy O
in O
both O
breast O
cancer O
cell O
lines O
and O
primary O
3 O
- O
dimensional O
cultures O
of O
cells O
from O
pleural O
effusions O
of O
patients O
. O

Therefore O
, O
synergistic O
relationships O
between O
HDAC O
and O
CDK O
inhibitors O
may O
provide O
an O
effective O
combinatorial O
regimen O
for O
breast O
cancer O
. O

Importantly O
, O
these O
studies O
provide O
an O
example O
of O
how O
genomic O
analysis O
of O
drug O
- O
response O
profiles O
can O
be O
used O
to O
design O
rational O
drug O
combinations O
for O
cancer O
treatment O
. O

Chemical O
constituents O
and O
allelopathic O
and O
antioxidant O
activities O
of O
Alchorneopsis O
floribunda O
M O
u O
ll O
. O

Arg O
. O

( O
Euphorbiaceae O
) O
. O

Chemical O
investigation O
of O
extracts O
from O
the O
stems O
and O
leaves O
of O
Alchorneopsis O
floribunda O
M O
u O
ll O
. O

Arg O
. O
, O
collected O
in O
the O
Amazon O
region O
, O
was O
performed O
. O

The O
main O
isolated O
compounds O
were O
triterpenes B
( O
alpha B
- I
amyrin I
, O
beta B
- I
amyrin I
, O
lupeol B
, O
betulin B
, O
betulinic B
acid I
, O
uvaol B
, O
erythrodiol B
and O
oleanolic B
acid I
) O
and O
phenolic B
acid I
derivatives O
from O
4 B
- I
hydroxybenzoic I
acid I
( O
gallic B
and I
protocatechuic I
acids I
and O
isocorilagin B
) O
. O

In O
the O
germination O
assays O
, O
high O
inhibitory O
allelopathic O
effects O
of O
the O
extracts O
and O
isocorilagin B
were O
observed O
and O
2 B
, I
2 I
- I
diphenyl I
- I
1 I
- I
picrylhydrazyl I
radical O
scavenging O
activity O
of O
isocorilagin B
was O
higher O
than O
those O
of O
the O
standards O
used O
( O
Trolox B
and O
butylated B
hydroxyanisole I
) O
. O

This O
is O
the O
first O
chemical O
study O
of O
the O
genus O
Alchorneopsis O
( O
Euphorbiaceae O
) O
. O

Evaluation O
of O
total O
oxidative O
status O
and O
total O
antioxidant O
capacity O
in O
patients O
with O
endemic O
fluorosis O
. O

The O
objective O
of O
the O
present O
study O
was O
to O
determine O
the O
plasma O
total O
oxidative O
status O
( O
TOS O
) O
and O
total O
antioxidant O
capacity O
( O
TAC O
) O
in O
patients O
with O
endemic O
fluorosis O
. O

A O
total O
of O
79 O
( O
35 O
males O
and O
44 O
females O
; O
mean O
age O
44 O
. O
0 O
+ O
/ O
- O
11 O
. O
9 O
years O
) O
patients O
with O
endemic O
fluorosis O
and O
55 O
( O
23 O
males O
and O
32 O
females O
; O
mean O
age O
48 O
. O
3 O
+ O
/ O
- O
8 O
. O
5 O
years O
) O
age O
- O
, O
sex O
- O
and O
body O
mass O
index O
- O
matched O
healthy O
controls O
were O
included O
in O
this O
study O
. O

The O
urine O
fluoride B
levels O
and O
plasma O
TOS O
and O
TAC O
levels O
were O
measured O
. O

The O
urine O
fluoride B
levels O
of O
fluorosis O
patients O
were O
significantly O
higher O
than O
control O
subjects O
as O
expected O
( O
1 O
. O
91 O
+ O
/ O
- O
0 O
. O
15 O
vs O
. O
0 O
. O
49 O
+ O
/ O
- O
0 O
. O
13 O
mg O
/ O
L O
, O
respectively O
; O
p O
< O
0 O
. O
001 O
) O
. O

TOS O
was O
significantly O
higher O
in O
fluorosis O
group O
than O
in O
control O
group O
( O
17 O
. O
55 O
+ O
/ O
- O
3 O
. O
82 O
vs O
. O
15 O
. O
06 O
+ O
/ O
- O
4 O
. O
31 O
mu O
mol O
H B
( I
2 I
) I
O I
( I
2 I
) I
Eq O
/ O
L O
, O
respectively O
; O
p O
= O
0 O
. O
001 O
) O
. O

TAC O
was O
significantly O
lower O
in O
fluorosis O
group O
than O
in O
control O
group O
( O
1 O
. O
60 O
+ O
/ O
- O
0 O
. O
36 O
vs O
. O
1 O
. O
82 O
+ O
/ O
- O
0 O
. O
51 O
mmol O
Trolox B
Eq O
/ O
L O
, O
respectively O
; O
p O
= O
0 O
. O
004 O
) O
. O

Oxidative O
stress O
index O
( O
OSI O
) O
was O
significantly O
higher O
in O
fluorosis O
group O
than O
in O
control O
group O
( O
11 O
. O
5 O
+ O
/ O
- O
3 O
. O
8 O
vs O
. O
8 O
. O
8 O
+ O
/ O
- O
3 O
. O
7 O
, O
respectively O
; O
p O
< O
0 O
. O
001 O
) O
. O

Correlation O
analysis O
in O
all O
the O
groups O
indicated O
that O
TAC O
was O
negatively O
correlated O
with O
urine O
fluoride B
( O
r O
= O
- O
0 O
. O
25 O
, O
p O
= O
0 O
. O
003 O
) O
, O
TOS O
was O
positively O
correlated O
with O
urine O
fluoride B
( O
r O
= O
0 O
. O
34 O
, O
p O
< O
0 O
. O
001 O
) O
and O
OSI O
was O
positively O
correlated O
with O
urine O
fluoride B
( O
r O
= O
0 O
. O
36 O
, O
p O
< O
0 O
. O
001 O
) O
. O

The O
results O
of O
our O
study O
demonstrate O
that O
oxidative O
stress O
plays O
an O
important O
role O
in O
the O
pathogenesis O
of O
the O
endemic O
fluorosis O
. O

Impact O
of O
aqueous O
doash O
extract O
on O
urinary O
mutagenicity O
in O
rats O
exposed O
to O
heterocyclic O
amines O
. O

Doash O
( O
Origanum O
majorana O
) O
is O
an O
herbaceous O
plant O
found O
commonly O
in O
Saudi O
Arabia O
. O

It O
is O
used O
as O
a O
food O
flavor O
and O
a O
folk O
remedy O
to O
treat O
a O
number O
of O
diseases O
. O

The O
2 B
- I
amino I
- I
3 I
- I
methylimidazo I
[ I
4 I
, I
5 I
- I
f I
] I
quinoline I
( O
IQ O
) O
and O
2 B
- I
amino I
- I
1 I
- I
methyl I
- I
6 I
- I
phenylimidazo I
[ I
4 I
, I
5 I
- I
b I
] I
pyridine I
( O
PhIP B
) O
are O
the O
most O
abundant O
of O
the O
heterocyclic B
amine I
carcinogens O
present O
in O
cooked O
food O
. O

In O
the O
present O
study O
, O
the O
potential O
of O
doash O
tea O
to O
influence O
carcinogen O
metabolism O
was O
investigated O
indirectly O
using O
heterocyclic B
amines I
as O
model O
mutagens O
, O
IQ O
and O
PhIP B
. O

Results O
obtained O
showed O
that O
doash O
tea O
had O
no O
influence O
on O
body O
weight O
in O
both O
the O
studies O
. O

Rats O
were O
treated O
with O
different O
doses O
of O
IQ O
( O
1 O
, O
3 O
, O
5 O
and O
10 O
mg O
/ O
kg O
) O
or O
PhIP B
( O
1 O
, O
5 O
, O
10 O
and O
20 O
mg O
/ O
kg O
) O
. O

The O
selected O
dosage O
was O
5 O
mg O
/ O
kg O
for O
both O
heterocyclic B
amines I
. O

Results O
obtained O
revealed O
that O
rats O
treated O
with O
doash O
tea O
and O
given O
a O
single O
dose O
of O
the O
heterocyclic B
amines I
, O
whether O
for O
1 O
day O
( O
short O
- O
term O
) O
or O
for O
1 O
month O
( O
long O
term O
) O
, O
showed O
a O
statistically O
significant O
decrease O
in O
their O
excretion O
of O
indirect O
mutagens O
( O
IQ O
or O
PhIP B
) O
. O

Following O
treatment O
of O
the O
rats O
with O
a O
single O
oral O
dose O
of O
IQ O
or O
PhIP B
, O
the O
highest O
mutagenic O
activity O
determined O
in O
the O
presence O
of O
an O
activation O
system O
was O
excreted O
in O
the O
urine O
after O
24 O
h O
, O
with O
much O
lower O
levels O
of O
mutagencity O
being O
excreted O
during O
subsequent O
elimination O
from O
the O
body O
. O

No O
mutagenicity O
was O
observed O
in O
the O
absence O
of O
an O
activation O
system O
that O
is O
direct O
- O
acting O
mutagenicity O
using O
( O
IQ O
and O
PhIP B
) O
. O

Statistical O
analysis O
revealed O
that O
, O
in O
comparison O
with O
the O
control O
group O
, O
the O
aqueous O
doash O
extract O
significantly O
reduced O
the O
mutagenic O
response O
after O
24 O
h O
. O

It O
was O
concluded O
that O
doash O
extract O
significantly O
decreased O
the O
excretion O
of O
mutagens O
in O
comparison O
with O
the O
control O
group O
( O
water O
only O
) O
. O

Genetic O
and O
epigenetic O
regulation O
of O
the O
organic O
cation O
transporter O
3 O
, O
SLC22A3 O
. O

Human O
organic O
cation O
transporter O
3 O
( O
OCT3 O
and O
SLC22A3 O
) O
mediates O
the O
uptake O
of O
many O
important O
endogenous O
amines B
and O
basic O
drugs O
in O
a O
variety O
of O
tissues O
. O

OCT3 O
is O
identified O
as O
one O
of O
the O
important O
risk O
loci O
for O
prostate O
cancer O
, O
and O
is O
markedly O
underexpressed O
in O
aggressive O
prostate O
cancers O
. O

The O
goal O
of O
this O
study O
was O
to O
identify O
genetic O
and O
epigenetic O
factors O
in O
the O
promoter O
region O
that O
influence O
the O
expression O
level O
of O
OCT3 O
. O

Haplotypes O
that O
contained O
the O
common O
variants O
, O
g O
. O
- O
81G O
> O
delGA O
( O
rs60515630 O
) O
( O
minor O
allele O
frequency O
11 O
. O
5 O
% O
in O
African O
American O
) O
and O
g O
. O
- O
2G O
> O
A O
( O
rs555754 O
) O
( O
minor O
allele O
frequency O
> O
30 O
% O
in O
all O
ethnic O
groups O
) O
showed O
significant O
increases O
in O
luciferase O
reporter O
activities O
and O
exhibited O
stronger O
transcription O
factor O
- O
binding O
affinity O
than O
the O
haplotypes O
that O
contained O
the O
major O
alleles O
. O

Consistent O
with O
the O
reporter O
assays O
, O
OCT3 O
messenger O
RNA O
expression O
levels O
were O
significantly O
higher O
in O
Asian O
( O
P O
< O
0 O
. O
001 O
) O
and O
Caucasian O
( O
P O
< O
0 O
. O
05 O
) O
liver O
samples O
from O
individuals O
who O
were O
homozygous O
for O
g O
. O
- O
2A O
/ O
A O
in O
comparison O
with O
those O
homozygous O
for O
the O
g O
. O
- O
2G O
/ O
G O
allele O
. O

Studies O
revealed O
that O
the O
methylation O
level O
in O
the O
basal O
promoter O
region O
of O
OCT3 O
was O
associated O
with O
OCT3 O
expression O
level O
and O
tumorigenesis O
capability O
in O
various O
prostate O
cancer O
cell O
lines O
. O

The O
methylation O
level O
of O
the O
OCT3 O
promoter O
was O
higher O
in O
62 O
% O
of O
prostate O
tumor O
samples O
compared O
with O
matched O
normal O
samples O
. O

Our O
studies O
demonstrate O
that O
genetic O
polymorphisms O
in O
the O
proximal O
promoter O
region O
of O
OCT3 O
alter O
the O
transcription O
rate O
of O
the O
gene O
and O
may O
be O
associated O
with O
altered O
expression O
levels O
of O
OCT3 O
in O
human O
liver O
. O

Aberrant O
methylation O
contributes O
to O
the O
reduced O
expression O
of O
OCT3 O
in O
prostate O
cancer O
. O

Accumulation O
patterns O
of O
some O
seed O
oil O
components O
from O
wild O
sources O
of O
Turkey O
. O

Accumulation O
profiles O
of O
fatty B
acids I
and O
alpha B
- I
tocopherol I
were O
analysed O
at O
three O
ripening O
stages O
in O
the O
seed O
oils O
of O
Primula O
and O
Echium O
species O
. O

Total O
seed O
oils O
were O
increased O
considerably O
with O
maturation O
, O
while O
alpha B
- I
tocopherol I
contents O
decreased O
in O
both O
species O
. O

Increased O
levels O
of O
ALA B
and O
oleic B
acid I
, O
and O
decrease O
in O
linoleic B
and I
palmitic I
acids I
at O
late O
ripening O
stages O
of O
Primula O
sibthorpii O
, O
and O
slightly O
fluctuations O
of O
all O
examined O
fatty B
acids I
in O
Echium O
italicum O
were O
observed O
. O

Considerable O
amounts O
of O
alpha B
- I
tocopherol I
( O
27 O
. O
4 O
mg O
/ O
100 O
g O
) O
, O
linoleic B
acid I
( O
42 O
. O
76 O
% O
) O
and O
ALA B
( O
25 O
. O
46 O
% O
) O
and O
GLA B
( O
4 O
. O
11 O
% O
) O
were O
detected O
in O
Ribes O
alpinum O
. O

Typical O
accumulation O
patterns O
of O
the O
examined O
parameters O
may O
be O
useful O
for O
species O
characterisation O
and O
biochemical O
monitoring O
of O
seed O
development O
in O
natural O
conditions O
. O

Mucopolysaccharidosi O
: O
cardiologic O
features O
and O
effects O
of O
enzyme O
- O
replacement O
therapy O
in O
24 O
children O
with O
MPS O
I O
, O
II O
and O
VI O
. O

We O
determined O
the O
cardiologic O
features O
of O
children O
with O
MPS O
I O
, O
II O
and O
VI O
, O
and O
evaluated O
the O
effect O
of O
enzyme O
- O
replacement O
therapy O
( O
ERT O
) O
on O
cardiac O
disease O
. O

Twenty O
- O
four O
children O
aged O
1 O
- O
18 O
years O
with O
MPS O
I O
, O
II O
or O
VI O
were O
prospectively O
evaluated O
with O
echocardiogram O
and O
electrocardiogram O
from O
the O
start O
of O
enzyme O
- O
replacement O
therapy O
up O
to O
6 O
years O
of O
treatment O
. O

At O
start O
of O
therapy O
, O
66 O
% O
had O
abnormal O
cardiac O
geometric O
features O
. O

Left O
- O
ventricular O
mass O
index O
( O
LVMI O
) O
was O
increased O
in O
half O
of O
the O
patients O
, O
due O
mainly O
to O
concentric O
hypertrophy O
in O
MPS O
I O
and O
II O
and O
to O
eccentric O
hypertrophy O
in O
MPS O
VI O
. O

Regurgitation O
was O
most O
severe O
in O
a O
subgroup O
of O
young O
MPS O
VI O
patients O
( O
< O
5 O
years O
) O
at O
the O
mitral O
valve O
. O

At O
baseline O
, O
all O
patients O
had O
abnormal O
valves O
. O

The O
ECG O
showed O
no O
clear O
rhythm O
or O
conduction O
abnormalities O
; O
neither O
, O
in O
most O
patients O
, O
did O
it O
reflect O
the O
hypertrophy O
. O

After O
ERT O
, O
the O
LVMI O
Z O
- O
score O
normalized O
in O
70 O
% O
of O
the O
patients O
who O
had O
a O
Z O
- O
score O
> O
2 O
. O

LVMI O
Z O
- O
scores O
decreased O
significantly O
in O
patients O
with O
MPS O
I O
and O
MPS O
II O
( O
p O
= O
0 O
. O
04 O
and O
p O
= O
0 O
. O
032 O
) O
. O

Despite O
ERT O
, O
valve O
regurgitation O
increased O
in O
60 O
% O
of O
the O
patients O
. O

We O
conclude O
that O
all O
our O
MPS O
patients O
have O
cardiac O
abnormalities O
. O

The O
most O
severe O
cardiac O
disease O
was O
observed O
in O
a O
subgroup O
of O
young O
MPS O
VI O
patients O
. O

While O
ERT O
had O
an O
effect O
on O
LVMI O
and O
IVSd O
, O
it O
apparently O
had O
little O
or O
none O
on O
valve O
regurgitation O
. O

Structural O
basis O
for O
protein O
phosphatase O
1 O
regulation O
and O
specificity O
. O

The O
ubiquitous O
serine B
/ O
threonine B
protein O
phosphatase O
1 O
( O
PP1 O
) O
regulates O
diverse O
, O
essential O
cellular O
processes O
such O
as O
cell O
cycle O
progression O
, O
protein O
synthesis O
, O
muscle O
contraction O
, O
carbohydrate B
metabolism O
, O
transcription O
and O
neuronal O
signaling O
. O

However O
, O
the O
free O
catalytic O
subunit O
of O
PP1 O
, O
while O
an O
effective O
enzyme O
, O
lacks O
substrate O
specificity O
. O

Instead O
, O
it O
depends O
on O
a O
diverse O
set O
of O
regulatory O
proteins O
( O
> O
= O
200 O
) O
to O
confer O
specificity O
towards O
distinct O
substrates O
. O

Here O
, O
we O
discuss O
recent O
advances O
in O
structural O
studies O
of O
PP1 O
holoenzyme O
complexes O
and O
summarize O
the O
new O
insights O
these O
studies O
have O
provided O
into O
the O
molecular O
basis O
of O
PP1 O
regulation O
and O
specificity O
. O

Protective O
effect O
of O
vitamin B
E I
and O
epicatechin B
against O
nicotine B
- O
induced O
oxidative O
stress O
in O
rats O
. O

Nicotine B
is O
a O
major O
pharmacologically O
active O
and O
addictive O
component O
of O
tobacco O
smoke O
, O
which O
is O
regarded O
to O
be O
a O
primary O
risk O
factor O
in O
the O
development O
of O
cardiovascular O
and O
pulmonary O
diseases O
. O

Epicatechin B
is O
one O
of O
the O
most O
potent O
antioxidants O
present O
in O
the O
human O
diet O
. O

Particularly O
high O
levels O
of O
this O
compound O
are O
found O
in O
tea O
, O
apples O
and O
chocolate O
. O

It O
has O
been O
reported O
that O
tea O
extracts O
and O
/ O
or O
its O
constituents O
have O
antibacterial O
, O
antiviral O
, O
antioxidative O
, O
antitumor O
and O
antimutagenic O
activities O
. O

Vitamin B
E I
is O
a O
major O
lipid O
- O
soluble O
antioxidant O
vitamin O
and O
free O
radical O
scavenger O
, O
presents O
as O
an O
integral O
component O
of O
cellular O
membranes O
and O
has O
important O
biological O
functions O
. O

The O
primary O
mechanism O
by O
which O
vitamin B
E I
is O
proposed O
to O
prevent O
cancer O
is O
through O
their O
antioxidant O
properties O
. O

The O
goal O
of O
this O
study O
is O
to O
evaluate O
the O
effect O
of O
epicatechin B
alone O
or O
combined O
with O
vitamin B
E I
in O
inhibiting O
the O
oxidative O
stress O
induced O
by O
nicotine B
in O
rats O
. O

Results O
obtained O
indicated O
that O
there O
was O
a O
significant O
elevation O
in O
the O
levels O
of O
malondialdhyde B
( O
MDA B
) O
in O
nicotine B
injected O
rats O
. O

The O
combined O
treatment O
( O
epicatechin B
+ O
Vit B
E I
) O
group O
showed O
a O
potential O
reduction O
of O
these O
parameters O
more O
than O
individual O
treatment O
. O

The O
activities O
of O
superoxide B
dismutase O
, O
catalase O
and O
glutathione B
peroxidase O
were O
found O
significantly O
higher O
in O
combined O
treated O
than O
untreated O
rats O
. O

In O
nicotine B
group O
, O
a O
negative O
significant O
correlation O
between O
reduced B
glutathione I
and O
MDA B
( O
r O
= O
- O
0 O
. O
92 O
) O
was O
observed O
. O

In O
conclusion O
, O
these O
results O
suggested O
that O
the O
supplementation O
of O
diet O
with O
epicatechin B
and O
vitamin B
E I
provided O
antioxidant O
defense O
with O
strong O
chemopreventive O
activity O
against O
nicotine B
- O
induced O
carcinogenesis O
. O

Prevention O
of O
cytotoxicity O
of O
nickel B
by O
quercetin B
: O
the O
role O
of O
reactive O
oxygen B
species O
and O
histone O
acetylation O
. O

Excessive O
exposure O
to O
nickel B
may O
cause O
health O
effects O
on O
the O
blood O
, O
lung O
, O
nose O
, O
kidney O
, O
reproductive O
system O
, O
skin O
and O
the O
unborn O
child O
. O

In O
the O
present O
study O
, O
we O
found O
that O
Ni B
( I
2 I
+ I
) I
exposure O
led O
to O
a O
time O
- O
and O
dose O
- O
dependent O
proliferation O
arrest O
and O
death O
in O
human O
leukemia O
HL O
- O
60 O
cells O
. O

In O
the O
presence O
of O
1 O
mM O
Ni B
( I
2 I
+ I
) I
, O
reactive O
oxygen B
species O
( O
ROS O
) O
generation O
( O
indicated O
by O
the O
level O
of O
malondialdehyde B
) O
increased O
to O
323 O
% O
and O
histone O
acetylation O
decreased O
to O
32 O
% O
. O

Interestingly O
, O
quercetin B
( O
QU O
) O
dose O
dependently O
prevented O
Ni B
( I
2 I
+ I
) I
- O
induced O
cell O
proliferation O
arrest O
and O
death O
from O
0 O
to O
80 O
mu O
M O
but O
showed O
similar O
activity O
of O
scavenging O
ROS O
at O
the O
concentrations O
of O
20 O
, O
40 O
and O
80 O
micro O
M O
. O

When O
the O
effect O
of O
QU O
on O
histone O
acetylation O
was O
studied O
, O
QU O
significantly O
prevented O
Ni B
( I
2 I
+ I
) I
- O
induced O
histone O
hypoacetylation O
at O
40 O
or O
80 O
micro O
M O
. O

Moreover O
, O
increase O
in O
histone O
acetylation O
by O
trichostatin B
A I
could O
also O
significantly O
enhance O
the O
protection O
effect O
of O
QU O
at O
10 O
or O
20 O
micro O
M O
but O
not O
at O
higher O
concentrations O
. O

Thus O
, O
our O
results O
further O
confirmed O
the O
critical O
role O
of O
ROS O
and O
histone O
hypoacetylation O
in O
the O
cytotoxicity O
of O
Ni B
( I
2 I
+ I
) I
exposure O
and O
proved O
that O
QU O
is O
a O
potentially O
useful O
native O
dietary O
compound O
to O
efficiently O
prevent O
Ni B
( I
2 I
+ I
) I
- O
caused O
cytotoxicity O
through O
both O
diminishing O
ROS O
generation O
and O
increasing O
histone O
acetylation O
. O

Cadmium B
concentrations O
in O
shrimp O
( O
Penaeus O
semisulcatus O
and O
Penaeus O
monodon O
) O
caught O
from O
the O
coastal O
areas O
in O
Southern O
Iran O
. O

This O
study O
was O
undertaken O
to O
determine O
the O
concentration O
of O
cadmium B
in O
two O
shrimp O
species O
, O
namely O
, O
Penaeus O
semisulcatus O
and O
Penaeus O
monodon O
caught O
from O
the O
coastal O
areas O
in O
southern O
Iran O
. O

Cadmium B
concentration O
was O
determined O
by O
graphite B
furnace O
atomic O
absorption O
spectrophotometry O
in O
91 O
shrimp O
samples O
after O
nitric B
acid I
/ O
perchloric B
acid I
digestion O
. O

Accuracy O
of O
the O
analysis O
was O
checked O
by O
various O
methods O
including O
the O
use O
of O
reference O
material O
. O

The O
mean O
+ O
/ O
- O
SD O
of O
cadmium B
concentrations O
in O
shrimp O
samples O
were O
0 O
. O
128 O
+ O
/ O
- O
0 O
. O
144 O
( O
mu O
g O
/ O
g O
) O
. O

The O
cadmium B
concentrations O
ranged O
from O
0 O
. O
010 O
to O
0 O
. O
96 O
mu O
g O
/ O
g O
of O
the O
muscle O
tissues O
of O
shrimp O
. O

Higher O
cadmium B
concentration O
in O
shrimp O
samples O
was O
found O
in O
summer O
( O
significant O
p O
< O
0 O
. O
05 O
) O
. O

The O
results O
show O
that O
the O
mean O
concentration O
of O
cadmium B
in O
shrimp O
is O
lower O
than O
the O
maximum O
allowed O
levels O
according O
to O
International O
standards O
, O
although O
the O
concentration O
of O
cadmium B
in O
only O
one O
sample O
was O
more O
than O
the O
amount O
recommended O
by O
Food O
and O
Agriculture O
Organization O
. O

Therefore O
, O
no O
risk O
to O
the O
consumer O
arises O
from O
the O
cadmium B
contents O
of O
the O
shrimp O
caught O
in O
these O
areas O
. O

Selective O
separation O
of O
patchouli B
alcohol I
from O
the O
essential O
oil O
of O
Cablin O
potchouli O
by O
inclusion O
crystalline O
method O
. O

In O
this O
article O
, O
we O
have O
focused O
on O
the O
application O
of O
non O
- O
traditional O
separation O
approach O
, O
the O
host O
- O
guest O
inclusion O
method O
, O
into O
the O
separation O
of O
the O
active O
component O
patchouli B
alcohol I
from O
the O
essential O
oil O
of O
Cablin O
potchouli O
Herb O
. O

The O
host O
molecule O
1 B
, I
1 I
, I
6 I
, I
6 I
- I
tetraphenylhexa I
- I
2 I
, I
4 I
- I
diyne I
- I
1 I
, I
6 I
- I
diol I
( O
A O
) O
was O
used O
to O
selectively O
recognise O
the O
guest O
molecule O
patchouli B
alcohol I
( O
B O
) O
in O
the O
essential O
oil O
of O
Pogostemon O
cablin O
( O
Blanco O
) O
Benth O
through O
two O
strong O
hydrogen B
bonding O
. O

The O
inclusion O
compound O
was O
structurally O
determined O
by O
the O
single O
crystal O
X O
- O
ray O
diffraction O
. O

The O
separation O
effect O
was O
examined O
by O
gas O
chromatography O
for O
the O
whole O
essential O
oil O
and O
the O
inclusion O
compound O
, O
showing O
that O
the O
inclusion O
crystalline O
method O
is O
simple O
, O
rapid O
and O
effective O
for O
the O
separation O
of O
patchouli B
alcohol I
from O
the O
essential O
oil O
of O
C O
. O
potchouli O
Herb O
. O

Toxic O
effects O
of O
some O
synthetic O
food O
colorants O
and O
/ O
or O
flavor O
additives O
on O
male O
rats O
. O

The O
objective O
of O
the O
present O
work O
was O
to O
evaluate O
the O
broadest O
toxic O
effect O
of O
some O
synthetic O
additives O
of O
colorants O
and O
/ O
or O
flavors O
on O
different O
body O
organs O
and O
metabolic O
aspects O
in O
rats O
. O

A O
number O
of O
chemical O
food O
color O
and O
flavor O
additives O
are O
routinely O
added O
during O
processing O
to O
improve O
the O
aesthetic O
appearance O
of O
the O
dietary O
items O
. O

However O
, O
many O
of O
them O
are O
toxic O
after O
prolonged O
use O
. O

In O
this O
experiment O
, O
a O
total O
of O
100 O
male O
albino O
rats O
of O
Spargue O
Dawley O
strain O
were O
divided O
into O
10 O
groups O
: O
G O
( O
1 O
) O
was O
fed O
basal O
diet O
and O
served O
as O
control O
, O
G O
( O
2 O
) O
: O
basal O
diet O
+ O
Brilliant B
blue I
( O
blue O
dye O
, O
No O
. O
2 O
, O
124 O
mg O
/ O
kg O
diet O
) O
, O
G O
( O
3 O
) O
: O
basal O
diet O
+ O
carmoisine B
( O
red O
dye O
, O
No O
. O
3 O
, O
70 O
mg O
/ O
kg O
diet O
) O
, O
G O
( O
4 O
) O
: O
basal O
diet O
+ O
tartrazine B
( O
yellow O
dye O
, O
FD O
& O
C O
yellow O
No O
. O
5 O
, O
75 O
mg O
/ O
kg O
diet O
) O
, O
G O
( O

5 O
) O
: O
basal O
diet O
+ O
trans B
- I
anethole I
( O
4 O
. O
5 O
g O
/ O
kg O
diet O
) O
G O
( O
6 O
) O
: O
basal O
diet O
+ O
propylene B
glycol I
( O
0 O
. O
25 O
g O
/ O
kg O
diet O
) O
, O
G O
( O
7 O
) O
: O
basal O
diet O
+ O
vanillin B
( O
1 O
. O
25 O
g O
/ O
kg O
diet O
) O
, O
G O
( O
8 O
) O
: O
basal O
diet O
+ O
Brilliant B
blue I
+ O
propylene B
glycol I
, O
G O
( O
9 O
) O
: O
basal O
diet O
+ O
carmoisine B
+ O
trans B
- I
anethole I
, O
G O
( O
10 O
) O
: O
basal O
diet O
+ O
tartrazine B
+ O
vanillin B
for O
42 O
successive O
days O

. O

All O
food O
colorants O
mixed O
with O
or O
without O
flavor O
additives O
induced O
a O
significant O
decrease O
in O
body O
weight O
, O
hemoglobin O
concentration O
and O
red O
blood O
cell O
count O
. O

Also O
there O
was O
a O
significant O
decrease O
in O
reduced B
glutathione I
content O
; O
glutathione B
- O
S B
- O
transferase O
and O
superoxide B
dismutase O
activities O
in O
both O
blood O
and O
liver O
compared O
to O
control O
group O
. O

On O
the O
other O
hand O
, O
a O
significant O
increase O
in O
serum O
alanine B
aminotransferase O
, O
aspartate B
aminotransferase O
, O
alkaline O
phosphatase O
activities O
, O
bilirubin B
, O
urea B
, O
creatinine B
, O
total O
protein O
and O
albumin O
were O
observed O
in O
all O
test O
groups O
when O
compared O
to O
control O
group O
. O

Finally O
, O
it O
is O
advisable O
to O
limit O
the O
uses O
of O
these O
food O
colorants O
and O
/ O
or O
food O
flavor O
additives O
especially O
those O
used O
by O
children O
. O

Steroids B
and O
phenolic B
constituents O
from O
the O
fruiting O
bodies O
of O
the O
basidiomycete O
Sarcodon O
joedes O
. O

Nine O
secondary O
metabolites O
, O
including O
four O
steroids B
, O
four O
phenolics B
and O
one O
cerebroside B
, O
were O
isolated O
from O
the O
methanol B
extract O
of O
the O
fruiting O
bodies O
of O
the O
basidiomycete O
Sarcodon O
joedes O
. O

The O
isolated O
compounds O
were O
identified O
by O
spectroscopic O
analyses O
as O
( B
22E I
, I
24R I
) I
- I
6 I
beta I
- I
methoxyergosta I
- I
7 I
, I
22 I
- I
diene I
- I
3 I
beta I
, I
5 I
alpha I
- I
diol I
( O
1 O
) O
, O
2 B
' I
, I
3 I
' I
- I
diacetoxy I
- I
3 I
, I
4 I
, I
5 I
' I
, I
6 I
' I
, I
4 I
' I
' I
- I
pentahydroxy I
- I
p I
- I
terphenyl I
( O
2 O
) O
, O
cerebroside B
B I
( O
3 O
) O
, O
ergosta B
- I
7 I
, I
22 I
- I
dien I
- I
3 I
beta I
- I
ol I
( O
4 O
) O
, O
ergosterol B
peroxide I
( O
5 O

) O
, O
( B
22E I
, I
24R I
) I
- I
3 I
beta I
- I
hydroxy I
- I
ergosta I
- I
5 I
, I
22 I
- I
dien I
- I
7 I
- I
one I
( O
6 O
) O
, O
benzoic B
acid I
( O
7 O
) O
, O
methyl B
p I
- I
hydroxybenzoate I
( O
8 O
) O
and O
3 B
, I
4 I
- I
dihydroxybenzoic I
acid I
( O
9 O
) O
. O

The O
cytotoxic O
activities O
of O
these O
compounds O
were O
evaluated O
. O

All O
these O
compounds O
were O
isolated O
from O
this O
fungus O
for O
the O
first O
time O
. O

In O
vitro O
evaluation O
of O
the O
protective O
effects O
of O
4 B
- I
thujanol I
against O
mitomycin B
- I
C I
and O
cyclophosphamide B
- O
induced O
genotoxic O
damage O
in O
human O
peripheral O
lymphocytes O
. O

4 B
- I
Thujanol I
( O
sabinene B
hydrate I
) O
, O
a O
bicyclic B
monoterpene I
alcohol I
, O
is O
found O
in O
the O
essential O
oils O
of O
many O
aromatic O
and O
medicinal O
plants O
and O
is O
widely O
used O
as O
a O
fragrance O
and O
flavouring O
agent O
in O
many O
different O
products O
. O

The O
aim O
of O
this O
study O
was O
to O
evaluate O
the O
protective O
effects O
of O
4 B
- I
thujanol I
against O
the O
genotoxic O
effects O
induced O
by O
mitomycin B
C I
( O
MMC B
) O
and O
cyclophosphamide B
( O
CP O
) O
in O
human O
lymphocytes O
, O
using O
the O
chromosome O
aberrations O
, O
sister O
chromatid O
exchanges O
, O
and O
micronucleus O
tests O
, O
in O
the O
absence O
and O
in O
the O
presence O
of O
S9 O
mix O
, O
respectively O
. O

The O
cells O
were O
treated O
with O
0 O
. O
25 O
micro O
g O
/ O
mL O
MMC B
and O
28 O
micro O
g O
/ O
mL O
CP O
as O
alone O
and O
cotreated O
with O
13 O
+ O
0 O
. O
25 O
, O
26 O
+ O
0 O
. O
25 O
, O
and O
52 O
+ O
0 O
. O
25 O
micro O
g O
/ O
mL O
4 B
- I
thujanol I
+ O
MMC B
and O
with O
13 O
+ O
28 O
, O
26 O
+ O
28 O
, O
and O
52 O
+ O
28 O
micro O
g O
/ O
mL O
4 B
- I
thujanol I
+ O
CP O
as O
a O
mixture O
. O

The O
present O
study O
showed O
that O
4 B
- I
thujanol I
was O
unable O
to O
reduce O
the O
genetic O
damage O
induced O
by O
MMC B
, O
in O
the O
absence O
of O
S9 O
mix O
. O

On O
the O
other O
hand O
, O
probably O
the O
metabolites O
of O
4 B
- I
thujanol I
act O
as O
an O
antagonist O
and O
markedly O
antagonize O
CP O
- O
induced O
genotoxicity O
, O
in O
the O
presence O
of O
S9 O
mix O
. O

In O
general O
, O
4 B
- I
thujanol I
+ O
MMC B
and O
4 B
- I
thujanol I
+ O
CP O
decreased O
the O
mitotic O
index O
, O
proliferation O
index O
and O
nuclear O
division O
index O
to O
the O
same O
extent O
or O
more O
than O
those O
of O
individual O
exposure O
of O
MMC B
or O
CP O
. O

In O
conclusion O
, O
4 B
- I
thujanol I
significantly O
reduced O
( O
p O
< O
0 O
. O
001 O
) O
the O
genotoxic O
damage O
induced O
by O
CP O
but O
not O
MMC B
when O
compared O
with O
the O
respective O
positive O
control O
alone O
. O

We O
can O
suggest O
that O
4 B
- I
thujanol I
may O
improve O
the O
chemopreventive O
effects O
and O
may O
also O
reduce O
the O
harmful O
side O
effects O
of O
CP O
, O
which O
is O
widely O
used O
in O
chemotherapy O
against O
cancer O
, O
without O
reducing O
its O
antiproliferative O
activities O
. O

Chlorogenic B
acid I
, O
rutin B
and O
hyperoside B
content O
in O
Fragaria O
vesca O
, O
F O
. O
viridis O
and O
F O
. O
moschata O
in O
Lithuania O
. O

In O
Lithuania O
, O
two O
species O
of O
the O
genus O
Fragaria O
L O
. O

( O
Rosaceae O
) O
, O
F O
. O
vesca O
L O
. O
and O
F O
. O
viridis O
Weston O
, O
occur O
naturally O
in O
the O
wild O
and O
two O
others O
, O
F O
. O
moschata O
Weston O
and O
F O
. O

x O
ananassa O
Duchesne O
ex O
Rozier O
are O
found O
escaped O
from O
cultivation O
. O

The O
main O
objective O
of O
this O
study O
was O
to O
establish O
the O
variation O
pattern O
in O
the O
content O
of O
chlorogenic B
acid I
, O
rutin B
and O
hyperoside B
in O
leaves O
and O
fruits O
of O
the O
native O
Lithuanian O
species O
. O

In O
this O
work O
, O
the O
chemical O
polymorphisms O
of O
different O
Fragaria O
species O
were O
studied O
by O
growing O
plants O
side O
by O
side O
under O
the O
same O
cultivated O
field O
conditions O
. O

F O
. O
vesca O
fruits O
had O
the O
highest O
rutin B
( O
1 O
. O
38 O
+ O
/ O
- O
0 O
. O
19 O
mg O
g O
( O
- O
1 O
) O
DM O
) O
, O
hyperoside B
( O
0 O
. O
69 O
+ O
/ O
- O
0 O
. O
10 O
mg O
g O
( O
- O
1 O
) O
DM O
) O
and O
chlorogenic B
acid I
( O
2 O
. O
25 O
+ O
/ O
- O
0 O
. O
34 O
mg O
g O
( O
- O
1 O
) O
DM O
) O
content O
, O
followed O
by O
F O
. O
viridis O
and O
F O
. O
moschata O
. O

Our O
results O
showed O
that O
the O
leaves O
should O
be O
taken O
into O
account O
as O
important O
rutin B
and O
hyperoside B
contributors O
for O
strawberries O
. O

Bromotheoynic B
acid I
, O
a O
brominated B
acetylenic I
acid I
from O
the O
marine O
sponge O
Theonella O
swinhoei O
. O

A O
new O
brominated B
C I
( I
17 I
) I
acetylenic I
acid I
( O
1 O
) O
designated O
as O
bromotheoynic B
acid I
has O
been O
isolated O
from O
the O
marine O
sponge O
Theonella O
swinhoei O
, O
collected O
off O
the O
coast O
of O
Tanegashima O
, O
Kagoshima O
Prefecture O
, O
Japan O
. O

The O
structure O
was O
determined O
on O
the O
basis O
of O
the O
analysis O
of O
its O
extensive O
2D O
NMR O
spectroscopic O
data O
as O
well O
as O
HRMS O
. O

Bromotheoynic B
acid I
( O
1 O
) O
inhibited O
maturation O
of O
starfish O
oocytes O
and O
cell O
division O
of O
fertilised O
starfish O
eggs O
. O

Bromotheoynic B
acid I
( O
1 O
) O
also O
inhibited O
proliferation O
of O
human O
leukaemia O
U937 O
and O
HL60 O
cells O
, O
human O
lung O
cancer O
A549 O
and O
H1299 O
cells O
, O
and O
human O
embryonic O
kidney O
293 O
( O
HEK293 O
) O
cells O
. O

Aromatic O
profiling O
of O
wild O
and O
rare O
species O
growing O
in O
Turkey O
: O
hypericum O
aviculariifolium O
Jaub O
. O
and O
Spach O
subsp O
. O
depilatum O
( O
Freyn O
and O
Bornm O
. O
) O
Robson O
var O
. O
depilatum O
and O
Hypericum O
pruinatum O
Boiss O
. O
and O
Bal O
. O

The O
volatile O
constituents O
of O
the O
rare O
species O
of O
Hypericum O
, O
namely O
Hypericum O
pruinatum O
( O
as O
one O
population O
) O
and O
Hypericum O
aviculariifolium O
subp O
. O
depilatum O
var O
. O
depilatum O
( O
endemic O
, O
as O
two O
populations O
namely O
' O
G O
u O
m O
u O
s O
' O
and O
' O
Yenik O
o O
y O
' O
) O
growing O
wild O
in O
the O
mountainous O
parts O
of O
Northern O
Turkey O
were O
studied O
for O
the O
first O
time O
. O

The O
essential O
oils O
( O
EOs O
) O
were O
extracted O
by O
hydrodistillation O
of O
the O
air O
- O
dried O
aerial O
parts O
and O
analysed O
by O
GC O
- O
FID O
and O
GC O
- O
MS O
. O

A O
total O
of O
56 O
, O
49 O
and O
50 O
EO O
components O
representing O
98 O
. O
2 O
% O
, O
96 O
. O
9 O
% O
and O
99 O
. O
4 O
% O
of O
the O
total O
composition O
were O
identified O
respectively O
from O
one O
population O
for O
H O
. O
pruinatum O
and O
two O
populations O
for O
Hypericum O
aviculariifolium O
subp O
. O
depilatum O
var O
. O
depilatum O
. O

GC O
- O
MS O
profiles O
showed O
significant O
compositional O
variations O
not O
only O
between O
the O
two O
Turkish O
species O
, O
but O
also O
between O
the O
two O
populations O
of O
the O
same O
species O
highlighting O
the O
importance O
of O
genetic O
factors O
affecting O
secondary O
metabolite O
profile O
. O

Cyclo B
- I
( I
His I
, I
Leu I
) I
: O
a O
new O
microbial O
diketopiperazine B
from O
a O
terrestrial O
Bacillus O
subtilis O
strain O
B38 O
. O

In O
continuation O
of O
our O
search O
for O
bioactive O
secondary O
metabolites O
from O
terrestrial O
Bacillus O
spp O
. O
, O
a O
new O
microbial O
diketopiperazine B
, O
cis B
- I
cyclo I
- I
( I
His I
, I
Leu I
) I
( O
1 O
) O
was O
isolated O
from O
the O
ethyl B
acetate I
extract O
of O
a O
strain O
B O
. O
subtilis O
B38 O
, O
together O
with O
cis B
- I
cyclo I
- I
( I
Phe I
, I
Phe I
) I
( O
2 O
) O
, O
tryptophane B
( O
3 O
) O
, O
cis B
- I
cyclo I
- I
( I
Leu I
, I
Tyr I
) I
( O
4 O
) O
, O
cis B
- I
cyclo I
- I
( I

Trp B
, O
Tyr B
) O
( O
5 O
) O
and O
macrolactin B
A I
( O
6 O
) O
. O

The O
chemical O
structures O
of O
the O
isolated O
compounds O
were O
identified O
by O
comparison O
of O
their O
1D O
, O
2D O
NMR O
and O
HRESIMS O
data O
with O
authentic O
spectra O
and O
literatures O
. O

To O
the O
best O
of O
our O
knowledge O
, O
this O
is O
the O
first O
time O
that O
cyclo B
- I
( I
His I
, I
Leu I
) I
has O
been O
isolated O
from O
natural O
products O
. O

Suppression O
of O
survival O
signalling O
pathways O
by O
the O
phosphatase O
PHLPP O
. O

The O
recently O
discovered O
pleckstrin O
homology O
( O
PH O
) O
domain O
leucine B
- O
rich O
repeat O
protein O
phosphatase O
( O
PHLPP O
) O
family O
is O
emerging O
as O
a O
central O
component O
in O
suppressing O
cell O
survival O
pathways O
. O

Originally O
discovered O
in O
a O
rational O
search O
for O
a O
phosphatase O
that O
directly O
dephosphorylates O
and O
inactivates O
Akt O
, O
PHLPP O
is O
now O
known O
to O
potently O
suppress O
cell O
survival O
both O
by O
inhibiting O
proliferative O
pathways O
and O
by O
promoting O
apoptotic O
pathways O
. O

In O
the O
first O
instance O
, O
PHLPP O
directly O
dephosphorylates O
a O
conserved O
regulatory O
site O
( O
termed O
the O
hydrophobic O
motif O
) O
on O
Akt O
, O
protein O
kinase O
C O
and O
S6 O
kinase O
, O
thereby O
terminating O
signalling O
by O
these O
pro O
- O
survival O
kinases O
. O

In O
the O
second O
instance O
, O
PHLPP O
dephosphorylates O
and O
thus O
activates O
the O
pro O
- O
apoptotic O
kinase O
Mst1 O
, O
thereby O
promoting O
apoptosis O
. O

PHLPP O
is O
deleted O
in O
a O
large O
number O
of O
cancers O
and O
the O
genetic O
deletion O
of O
one O
isozyme O
in O
a O
PTEN O
( O
phosphatase O
and O
tensin O
homologue O
located O
on O
chromosome O
1 O
) O
+ O
/ O
- O
( O
or O
heterozygous O
) O
prostate O
cancer O
model O
results O
in O
increased O
tumourigenesis O
, O
underscoring O
the O
role O
of O
PHLPP O
as O
a O
tumour O
suppressor O
. O

This O
review O
summarizes O
the O
targets O
and O
cellular O
actions O
of O
PHLPP O
, O
with O
emphasis O
on O
its O
role O
as O
a O
tumour O
suppressor O
in O
the O
oncogenic O
phosphoinositide O
3 O
- O
kinase O
( O
PI3K O
) O
/ O
Akt O
signalling O
cascade O
. O

Chemical O
composition O
and O
antifungal O
activity O
of O
Artemisia O
nilagirica O
essential O
oil O
growing O
in O
northern O
hilly O
areas O
of O
India O
. O

Essential O
oil O
extracted O
from O
aerial O
parts O
of O
Artemisia O
nilagirica O
was O
analysed O
by O
gas O
chromatography O
- O
mass O
spectroscopy O
. O

Forty O
- O
three O
constituents O
amounting O
to O
98 O
. O
16 O
% O
of O
the O
total O
essential O
oil O
contents O
were O
identified O
. O

The O
essential O
oil O
contained O
approximately O
79 O
. O
91 O
% O
monoterpenoids B
and O
18 O
. O
25 O
% O
sesquiterpenoids B
. O

alpha B
- I
Thujone I
( O
36 O
. O
35 O
% O
) O
, O
beta B
- I
thujone I
( O
9 O
. O
37 O
% O
) O
, O
germacrene B
D I
( O
6 O
. O
32 O
% O
) O
, O
4 B
- I
terpineol I
( O
6 O
. O
31 O
% O
) O
, O
beta B
- I
caryophyllene I
( O
5 O
. O
43 O
% O
) O
, O
camphene B
( O
5 O
. O
47 O
% O
) O
and O
borneol B
( O
4 O
. O
12 O
% O
) O
were O
identified O
as O
the O
major O
constituents O
. O

The O
essential O
oil O
exhibited O
significant O
antifungal O
activity O
against O
Rhizoctonia O
solani O
( O
ED O
( O
50 O
) O
, O
85 O
. O
75 O
mg O
L O
( O
- O
1 O
) O
) O
, O
Sclerotium O
rolfsii O
( O
ED O
( O
50 O
) O
, O
87 O
. O
63 O
mg O
L O
( O
- O
1 O
) O
) O
and O
Macrophomina O
phaseolina O
( O
ED O
( O
50 O
) O
, O
93 O
. O
23 O
mg O
L O
( O
- O
1 O
) O
) O
. O

This O
study O
indicated O
that O
A O
. O
nilagirica O
essential O
oil O
can O
be O
used O
to O
control O
phytopathogenic O
fungi O
infesting O
agricultural O
crops O
and O
commodities O
. O

Structural O
basis O
for O
the O
altered O
drug O
sensitivities O
of O
non O
- O
small O
cell O
lung O
cancer O
- O
associated O
mutants O
of O
human O
epidermal O
growth O
factor O
receptor O
. O

The O
epidermal O
growth O
factor O
receptor O
( O
EGFR O
) O
has O
an O
essential O
role O
in O
multiple O
signaling O
pathways O
, O
including O
cell O
proliferation O
and O
migration O
, O
through O
extracellular O
ligand O
binding O
and O
subsequent O
activation O
of O
its O
intracellular O
tyrosine B
kinase O
( O
TK O
) O
domain O
. O

The O
non O
- O
small O
cell O
lung O
cancer O
( O
NSCLC O
) O
- O
associated O
EGFR O
mutants O
, O
L858R O
and O
G719S O
, O
are O
constitutively O
active O
and O
oncogenic O
. O

They O
display O
sensitivity O
to O
TK O
inhibitors O
, O
including O
gefitinib B
and O
erlotinib B
. O

In O
contrast O
, O
the O
secondary O
mutation O
of O
the O
gatekeeper O
residue O
, O
T790M O
, O
reportedly O
confers O
inhibitor O
resistance O
on O
the O
oncogenic O
EGFR O
mutants O
. O

In O
this O
study O
, O
our O
biochemical O
analyses O
revealed O
that O
the O
introduction O
of O
the O
T790M O
mutation O
confers O
gefitinib B
resistance O
on O
the O
G719S O
mutant O
. O

The O
G719S O
/ O
T790M O
double O
mutant O
has O
enhanced O
activity O
and O
retains O
high O
gefitinib B
- O
binding O
affinity O
. O

The O
T790M O
mutation O
increases O
the O
ATP B
affinity O
of O
the O
G719S O
mutant O
, O
explaining O
the O
acquired O
drug O
resistance O
of O
the O
double O
mutant O
. O

Structural O
analyses O
of O
the O
G719S O
/ O
T790M O
double O
mutant O
, O
as O
well O
as O
the O
wild O
type O
and O
the O
G719S O
and O
L858R O
mutants O
, O
revealed O
that O
the O
T790M O
mutation O
stabilizes O
the O
hydrophobic O
spine O
of O
the O
active O
EGFR O
- O
TK O
conformation O
. O

The O
Met790 O
side O
chain O
of O
the O
G719S O
/ O
T790M O
double O
mutant O
, O
in O
the O
apo O
form O
and O
gefitinib B
- O
and O
AMPPNP O
- O
bound O
forms O
, O
adopts O
different O
conformations O
that O
explain O
the O
accommodation O
of O
these O
ligands O
. O

In O
the O
L858R O
mutant O
structure O
, O
the O
active O
- O
site O
cleft O
is O
expanded O
by O
the O
repositioning O
of O
Phe723 B
within O
the O
P O
- O
loop O
. O

Notably O
, O
the O
introduction O
of O
the O
F723A O
mutation O
greatly O
enhanced O
the O
gefitinib B
sensitivity O
of O
the O
wild O
- O
type O
EGFR O
in O
vivo O
, O
supporting O
our O
hypothesis O
that O
the O
expansion O
of O
the O
active O
- O
site O
cleft O
results O
in O
enhanced O
gefitinib B
sensitivity O
. O

Taken O
together O
, O
our O
results O
provide O
a O
structural O
basis O
for O
the O
altered O
drug O
sensitivities O
caused O
by O
distinct O
NSCLC O
- O
associated O
EGFR O
mutations O
. O

TGF O
- O
beta O
1 O
- O
dependent O
L1CAM O
expression O
has O
an O
essential O
role O
in O
macrophage O
- O
induced O
apoptosis O
resistance O
and O
cell O
migration O
of O
human O
intestinal O
epithelial O
cells O
. O

Patients O
with O
chronic O
inflammatory O
bowel O
disease O
( O
IBD O
) O
have O
an O
increased O
risk O
to O
develop O
colorectal O
cancer O
( O
CRC O
) O
particularly O
after O
long O
duration O
of O
the O
disease O
. O

Chronic O
inflammation O
of O
the O
intestinal O
mucosa O
is O
characterized O
by O
a O
marked O
enrichment O
of O
immune O
cells O
such O
as O
macrophages O
as O
well O
as O
by O
high O
expression O
of O
cytokines O
and O
growth O
factors O
including O
transforming O
growth O
factor O
- O
beta O
1 O
( O
TGF O
- O
beta O
1 O
) O
. O

The O
adhesion O
molecule O
L1CAM O
mediates O
chemoresistance O
and O
migration O
of O
tumor O
cells O
and O
is O
elevated O
in O
CRC O
tissues O
being O
associated O
with O
metastatic O
spread O
and O
poor O
prognosis O
for O
the O
patients O
. O

In O
this O
study O
, O
we O
examine O
the O
role O
of O
TGF O
- O
beta O
1 O
- O
induced O
L1CAM O
expression O
and O
macrophages O
in O
malignant O
transformation O
of O
intestinal O
epithelial O
cells O
. O

We O
demonstrate O
that O
TGF O
- O
beta O
1 O
stimulation O
leads O
to O
a O
Slug O
- O
dependent O
upregulation O
of O
L1CAM O
expression O
already O
in O
the O
colonic O
intestinal O
epithelial O
cell O
line O
NCM460 O
thereby O
enhancing O
cell O
motility O
and O
apoptosis O
resistance O
. O

Accordingly O
, O
NCM460 O
cells O
acquired O
a O
migratory O
and O
apoptosis O
- O
resistant O
phenotype O
if O
transfected O
with O
L1CAM O
. O

Immunohistochemistry O
of O
colonic O
biopsies O
revealed O
considerable O
L1CAM O
expression O
in O
intestinal O
epithelial O
cells O
in O
tissues O
from O
IBD O
patients O
but O
not O
in O
normal O
colonic O
tissues O
. O

Moreover O
, O
L1CAM O
expression O
increased O
with O
duration O
of O
disease O
being O
associated O
with O
the O
presence O
of O
CD33 O
+ O
macrophages O
. O

Coculture O
with O
macrophages O
generated O
from O
monocyte O
colony O
- O
stimulating O
factor O
( O
MCSF O
) O
- O
treated O
monocytes O
led O
to O
the O
upregulation O
of O
Slug O
and O
L1CAM O
in O
NCM460 O
cells O
thereby O
elevating O
cell O
motility O
and O
apoptosis O
resistance O
. O

Pharmacological O
inhibition O
of O
TGF O
- O
beta O
1 O
signalling O
abolished O
expression O
of O
Slug O
and O
L1CAM O
in O
cocultured O
NCM460 O
cells O
resulting O
in O
decreased O
cell O
migration O
and O
apoptosis O
resistance O
. O

In O
conclusion O
, O
these O
data O
provide O
new O
insights O
into O
the O
mechanisms O
by O
which O
IBD O
promotes O
malignant O
transformation O
of O
intestinal O
epithelial O
cells O
and O
underscore O
the O
role O
of O
L1CAM O
and O
macrophages O
in O
this O
scenario O
. O

Modulated O
release O
of O
5 B
- I
fluorouracil I
from O
pH O
- O
sensitive O
and O
colon O
targeted O
pellets O
: O
an O
industrially O
feasible O
approach O
. O

Pellets O
, O
reliant O
on O
pH O
- O
sensitivity O
and O
time O
- O
dependency O
for O
drug O
delivery O
, O
provide O
one O
of O
the O
most O
versatile O
opportunities O
for O
targeting O
colon O
. O

5 B
- I
Fluorouracil I
( O
5 B
- I
FU I
) O
loaded O
pellets O
were O
prepared O
by O
extrusion O
- O
spheronization O
using O
Avicel O
( O
( O
R O
) O
) O
PH101 O
as O
a O
spheronization O
aid O
and O
hydroxypropylmethylc O
K4M O
( O
HPMC O
K4M O
) O
solution O
as O
a O
binder O
. O

A O
3 O
( O
2 O
) O
full O
factorial O
design O
was O
employed O
to O
optimize O
spheronization O
speed O
and O
time O
. O

Obtained O
pellets O
were O
evaluated O
for O
flow O
properties O
, O
pellet O
size O
, O
roundness O
and O
aspect O
ratio O
. O

Optimized O
batch O
was O
coated O
in O
a O
bottom O
- O
spray O
fluidized O
bed O
processor O
( O
FBP O
) O
with O
an O
inner O
coat O
of O
sustained O
release O
polymer O
Eudragit B
NE30D I
and O
an O
outer O
coat O
of O
pH O
- O
sensitive O
polymer O
Eudragit B
FS30D I
. O

The O
coating O
levels O
were O
statistically O
optimized O
and O
in O
vitro O
drug O
release O
was O
monitored O
by O
changing O
pH O
media O
method O
. O

Optimized O
system O
with O
15 O
% O
inner O
and O
outer O
coating O
levels O
revealed O
t O
( O
50 O
% O
) O
( O
time O
required O
for O
50 O
% O
drug O
release O
) O
to O
be O
about O
9 O
h O
while O
almost O
complete O
drug O
was O
released O
in O
24 O
h O
( O
98 O
. O
71 O
+ O
/ O
- O
1 O
. O
33 O
% O
) O
with O
highest O
dissolution O
efficiency O
( O
DE O
( O
24h O
) O
) O
of O
58 O
. O
71 O
% O
. O

The O
optimization O
model O
was O
validated O
; O
the O
predicted O
and O
experimental O
/ O
actual O
values O
for O
validation O
batch O
( O
M1 O
) O
were O
in O
close O
tolerance O
and O
the O
standard O
error O
( O
SE O
) O
was O
also O
small O
. O

Drug O
release O
was O
also O
studied O
at O
pH O
7 O
. O
4 O
. O

Scanning O
electron O
microscopy O
( O
SEM O
) O
demonstrated O
average O
coating O
thickness O
to O
be O
32 O
. O
50 O
+ O
/ O
- O
3 O
. O
0 O
micro O
m O
. O

Hence O
, O
the O
present O
study O
provides O
constructive O
results O
for O
colon O
targeting O
of O
5 B
- I
FU I
pellets O
with O
industrially O
feasible O
processes O
. O

Conditional O
activation O
of O
Pik3ca O
( O
H1047R O
) O
in O
a O
knock O
- O
in O
mouse O
model O
promotes O
mammary O
tumorigenesis O
and O
emergence O
of O
mutations O
. O

Oncogenic O
mutations O
in O
PIK3CA O
, O
which O
encodes O
the O
phosphoinositide O
- O
3 O
- O
kinase O
( O
PI3K O
) O
catalytic O
subunit O
p110 O
alpha O
, O
occur O
in O
~ O
25 O
% O
of O
human O
breast O
cancers O
. O

In O
this O
study O
, O
we O
report O
the O
development O
of O
a O
knock O
- O
in O
mouse O
model O
for O
breast O
cancer O
where O
the O
endogenous O
Pik3ca O
allele O
was O
modified O
to O
allow O
tissue O
- O
specific O
conditional O
expression O
of O
a O
frequently O
found O
Pik3ca O
( O
H1047R O
) O
( O
Pik3ca O
( O
e20H1047R O
) O
) O
mutant O
allele O
. O

We O
found O
that O
activation O
of O
the O
latent O
Pik3ca O
( O
H1047R O
) O
allele O
resulted O
in O
breast O
tumors O
with O
multiple O
histological O
types O
. O

Whole O
- O
exome O
analysis O
of O
the O
Pik3ca O
( O
H1047R O
) O
- O
driven O
mammary O
tumors O
identified O
multiple O
mutations O
, O
including O
Trp53 B
mutations O
that O
appeared O
spontaneously O
during O
the O
development O
of O
adenocarinoma O
and O
spindle O
cell O
tumors O
. O

Further O
, O
we O
used O
this O
model O
to O
test O
the O
efficacy O
of O
GDC B
- I
0941 I
, O
a O
PI3K O
inhibitor O
, O
in O
clinical O
development O
, O
and O
showed O
that O
the O
tumors O
respond O
to O
PI3K O
inhibition O
. O

WNT6 O
is O
a O
novel O
target O
gene O
of O
caveolin O
- O
1 O
promoting O
chemoresistance O
to O
epirubicin B
in O
human O
gastric O
cancer O
cells O
. O

Resistance O
to O
chemotherapy O
is O
a O
major O
obstacle O
for O
curative O
treatment O
of O
human O
gastric O
cancer O
( O
GC O
) O
. O

However O
, O
the O
underlying O
molecular O
mechanisms O
are O
largely O
unknown O
. O

Wingless O
- O
type O
MMTV O
integration O
site O
family O
members O
( O
WNTs O
) O
are O
secreted O
glycoproteins O
involved O
in O
embryogenesis O
and O
, O
on O
inappropriate O
expression O
in O
the O
adult O
, O
in O
cancer O
. O

Here O
, O
we O
show O
expression O
of O
WNT6 O
in O
GC O
patient O
specimens O
, O
human O
GC O
cell O
lines O
and O
in O
a O
mouse O
model O
of O
GC O
. O

In O
human O
GC O
cells O
, O
WNT6 O
expression O
was O
enhanced O
by O
caveolin O
- O
1 O
( O
Cav1 O
) O
, O
a O
scaffold O
protein O
of O
plasma O
membrane O
caveolae O
. O

WNT6 O
knock O
- O
down O
and O
overexpression O
experiments O
demonstrated O
that O
WNT6 O
increased O
the O
resistance O
to O
apoptotic O
cell O
death O
induced O
by O
the O
anthracycline B
chemotherapeutics O
epirubicin B
( O
Epi B
) O
and O
doxorubicin B
( O
Dox B
) O
. O

Epi B
increased O
the O
activity O
of O
the O
human O
WNT6 O
promoter O
through O
Cav1 O
- O
dependent O
binding O
of O
beta O
- O
catenin O
to O
the O
proximal O
WNT6 O
promoter O
. O

Epi B
increased O
both O
WNT6 O
/ O
Wnt6 O
and O
Cav1 O
expression O
in O
human O
GC O
cells O
and O
within O
the O
tumor O
area O
of O
a O
murine O
model O
of O
GC O
( O
CEA424 O
- O
SV40 O
TAg O
) O
. O

In O
GC O
patients O
, O
WNT6 O
expression O
was O
positively O
associated O
with O
the O
tumor O
stage O
and O
the O
nodal O
status O
, O
and O
inversely O
correlated O
with O
the O
response O
to O
ECF B
( O
Epi B
, O
cisplatin B
, O
5 B
- I
fluorouracil I
) O
chemotherapy O
. O

These O
results O
showed O
that O
WNT6 O
and O
Cav1 O
are O
upregulated O
by O
chemotherapeutics O
and O
enhance O
the O
resistance O
of O
GC O
cells O
to O
anthracycline B
drugs O
. O

Understanding O
the O
molecular O
mechanisms O
driving O
WNT6 O
/ O
Cav1 O
- O
induced O
drug O
resistance O
will O
provide O
benefits O
in O
developing O
new O
therapies O
for O
GC O
. O

Three O
new O
alpha O
- O
glucosidase O
inhibitors O
from O
guggul O
, O
the O
oleogum O
resin O
of O
Commiphora O
wightii O
. O

Three O
new O
compounds O
; O
epi B
- I
mukulin I
, O
( B
Z I
) I
- I
Delta I
( I
1 I
, I
2 I
) I
dehydroguggulsterone I
and O
Delta B
( I
6 I
, I
7 I
) I
dehydro I
- I
20 I
- I
hydroxygugglsterone I
were O
isolated O
from O
the O
n B
- I
hexane I
- O
soluble O
fraction O
( O
HSF O
) O
of O
the O
methanol B
extract O
of O
guggul O
, O
the O
oleogum O
resin O
of O
Commiphora O
wightii O
together O
with O
six O
known O
compounds O
: O
diasesartemin B
, O
( B
+ I
) I
- I
epi I
- I
magnolin I
, O
( B
+ I
) I
- I
diayangambin I
, O

gugglsterol B
I I
, O
( B
E I
) I
- I
guggulsterone I
and O
( B
Z I
) I
- I
guggulsterone I
. O

Their O
structures O
were O
elucidated O
on O
the O
basis O
of O
different O
spectroscopic O
data O
. O

alpha O
- O
Glucosidase O
inhibitory O
effects O
of O
HSF O
and O
the O
isolated O
compounds O
were O
evaluated O
calorimetrically O
. O

The O
HSF O
showed O
significant O
alpha O
- O
glucosidase O
inhibitory O
effect O
[ O
IC O
( O
50 O
) O
value O
of O
140 O
micro O
g O
mL O
( O
- O
1 O
) O
( O
p O
< O
0 O
. O
05 O
) O
] O
. O

Under O
the O
assay O
conditions O
, O
diasesartemin B
( O
IC O
( O
50 O
) O
= O
60 O
. O
6 O
+ O
/ O
- O
0 O
. O
01 O
micro O
M O
) O
was O
found O
to O
be O
more O
potent O
than O
the O
positive O
control O
, O
acarbose B
( O
IC O
( O
50 O
) O
= O
92 O
. O
94 O
+ O
/ O
- O
0 O
. O
01 O
micro O
M O
) O
; O
a O
known O
alpha O
- O
glucosidase O
inhibitor O
( O
p O
< O
0 O
. O
05 O
) O
. O

The O
IC O
( O
50 O
) O
values O
of O
epi B
- I
mukulin I
and O
( B
Z I
) I
- I
guggulsterone I
were O
found O
to O
be O
159 O
. O
33 O
and O
132 O
. O
14 O
micro O
M O
, O
respectively O
. O

Other O
compounds O
showed O
weak O
alpha O
- O
glucosidase O
inhibitory O
effects O
, O
< O
30 O
% O
inhibition O
of O
the O
enzyme O
activity O
at O
0 O
. O
1 O
mg O
mL O
( O
- O
1 O
) O
. O

Chemical O
constituents O
of O
Indonesian O
plant O
Protium O
javanicum O
Burm O
. O

f O
. O
and O
their O
antifeedant O
activities O
against O
Coptotermes O
formosanus O
Shiraki O
. O

In O
the O
continuing O
study O
of O
antifeedant O
compounds O
in O
Protium O
javanicum O
Burm O
. O

f O
. O
against O
Coptotermes O
formosanus O
Shiraki O
, O
6 B
- I
desacetylnimbin I
( O
1 O
) O
, O
quercitrin B
( O
2 O
) O
and O
myricitrin B
( O
3 O
) O
were O
isolated O
from O
P O
. O
javanicum O
extract O
. O

All O
compounds O
were O
characterised O
by O
NMR O
and O
MS O
. O

Furthermore O
, O
the O
structure O
of O
6 B
- I
desacetylnimbin I
was O
confirmed O
by O
X O
- O
ray O
crystallography O
. O

The O
antifeedant O
activity O
was O
evaluated O
with O
no O
- O
choice O
feeding O
tests O
. O

At O
a O
dose O
of O
0 O
. O
5 O
mg O
, O
6 B
- I
desacetylnimbin I
exhibited O
the O
highest O
antifeedant O
activity O
among O
the O
isolates O
. O

Tumor O
angiogenesis O
is O
enforced O
by O
autocrine O
regulation O
of O
high O
- O
mobility O
group O
box O
1 O
. O

The O
endothelium O
plays O
a O
pivotal O
role O
in O
the O
progression O
of O
solid O
tumors O
and O
is O
considered O
a O
highly O
relevant O
target O
for O
therapy O
. O

However O
, O
it O
emerges O
that O
current O
clinical O
angiogenesis O
inhibitors O
that O
act O
through O
inhibition O
of O
tumor O
- O
derived O
growth O
factors O
are O
prone O
to O
inducing O
drug O
resistance O
. O

Therefore O
, O
markers O
of O
tumor O
endothelial O
cells O
( O
ECs O
) O
themselves O
provide O
attractive O
novel O
therapeutic O
targets O
. O

In O
a O
screen O
for O
markers O
of O
tumor O
angiogenesis O
, O
we O
recently O
identified O
high O
- O
mobility O
group O
box O
1 O
( O
HMGB1 O
) O
, O
known O
to O
act O
as O
proinflammatory O
cytokine O
and O
chromatin O
- O
binding O
molecule O
. O

Here O
we O
report O
on O
the O
role O
of O
HMGB1 O
in O
angiogenesis O
by O
showing O
that O
its O
overexpression O
is O
associated O
with O
an O
increased O
angiogenic O
potential O
of O
ECs O
. O

HMGB1 O
stimulates O
the O
expression O
of O
players O
in O
vascular O
endothelial O
growth O
factor O
and O
platelet O
- O
derived O
growth O
factor O
signaling O
, O
both O
in O
vitro O
and O
in O
vivo O
. O

Importantly O
, O
we O
show O
that O
HMGB1 O
triggers O
and O
helps O
to O
sustain O
this O
proangiogenic O
gene O
expression O
program O
in O
ECs O
, O
additionally O
characterized O
by O
increased O
activity O
of O
matrix O
metalloproteinases O
, O
integrins O
and O
nuclear O
factor O
- O
kappa O
B O
. O

Moreover O
, O
we O
found O
that O
HMGB1 O
is O
involved O
in O
several O
autocrine O
and O
/ O
or O
paracrine O
feedback O
mechanisms O
resulting O
in O
positive O
enforcement O
of O
HMGB1 O
expression O
, O
and O
that O
of O
its O
receptors O
, O
RAGE O
( O
receptor O
for O
advanced O
glycation O
end O
products O
) O
and O
Toll O
- O
like O
receptor O
4 O
( O
TLR4 O
) O
. O

Interference O
in O
HMGB1 O
expression O
and O
/ O
or O
function O
using O
knockdown O
approaches O
and O
antibody O
- O
mediated O
targeting O
to O
break O
this O
vicious O
circle O
resulted O
in O
inhibited O
migration O
and O
sprouting O
of O
ECs O
. O

Using O
different O
in O
vivo O
models O
, O
therapeutic O
efficacy O
of O
HMGB1 O
targeting O
was O
confirmed O
. O

First O
, O
we O
demonstrated O
induction O
of O
HMGB1 O
expression O
in O
the O
chicken O
embryo O
chorioallantoic O
membrane O
( O
CAM O
) O
neovasculature O
following O
both O
photodynamic O
therapy O
and O
tumor O
challenge O
. O

We O
subsequently O
showed O
that O
anti O
- O
HMGB1 O
antibodies O
inhibited O
vessel O
density O
in O
both O
models O
, O
accompanied O
by O
a O
reduced O
vascular O
expression O
of O
angiogenic O
growth O
factor O
receptors O
. O

Collectively O
, O
these O
data O
identify O
HMGB1 O
as O
an O
important O
modulator O
of O
tumor O
angiogenesis O
and O
suggest O
the O
feasibility O
of O
targeting O
HMGB1 O
for O
multi O
- O
level O
cancer O
treatment O
. O

Histone O
deacetylase O
inhibitors O
suppress O
mutant O
p53 O
transcription O
via O
histone O
deacetylase O
8 O
. O

Mutation O
of O
the O
p53 O
gene O
is O
the O
most O
common O
genetic O
alteration O
in O
human O
cancer O
and O
contributes O
to O
malignant O
process O
by O
enhancing O
transformed O
properties O
of O
cells O
and O
resistance O
to O
anticancer O
therapy O
. O

Mutant O
p53 O
is O
often O
highly O
expressed O
in O
tumor O
cells O
at O
least O
, O
in O
part O
, O
due O
to O
its O
increased O
half O
- O
life O
. O

However O
, O
whether O
mutant O
p53 O
expression O
is O
regulated O
by O
other O
mechanisms O
in O
tumors O
is O
unclear O
. O

Here O
we O
found O
that O
histone O
deacetylase O
( O
HDAC O
) O
inhibitors O
suppress O
both O
wild O
- O
type O
and O
mutant O
p53 O
transcription O
in O
time O
- O
and O
dose O
- O
dependent O
manners O
. O

Consistent O
with O
this O
, O
the O
levels O
of O
wild O
- O
type O
and O
mutant O
p53 O
proteins O
are O
decreased O
upon O
treatment O
with O
HDAC O
inhibitors O
. O

Importantly O
, O
we O
found O
that O
upon O
knockdown O
of O
each O
class O
I O
HDAC O
, O
only O
HDAC8 O
knockdown O
leads O
to O
decreased O
expression O
of O
wild O
- O
type O
and O
mutant O
p53 O
proteins O
and O
transcripts O
. O

Conversely O
, O
we O
found O
that O
ectopic O
expression O
of O
wild O
- O
type O
, O
but O
not O
mutant O
HDAC8 O
, O
leads O
to O
increased O
transcription O
of O
p53 O
. O

Furthermore O
, O
we O
found O
that O
knockdown O
of O
HDAC8 O
results O
in O
reduced O
expression O
of O
HoxA5 O
and O
consequently O
, O
attenuated O
ability O
of O
HoxA5 O
to O
activate O
p53 O
transcription O
, O
which O
can O
be O
rescued O
by O
ectopic O
expression O
of O
HoxA5 O
. O

Because O
of O
the O
fact O
that O
HDAC8 O
is O
required O
for O
expression O
of O
both O
wild O
- O
type O
and O
mutant O
p53 O
, O
we O
found O
that O
targeted O
disruption O
of O
HDAC8 O
expression O
remarkably O
triggers O
proliferative O
defect O
in O
cells O
with O
a O
mutant O
, O
but O
not O
wild O
- O
type O
, O
p53 O
. O

Together O
, O
our O
data O
uncover O
a O
regulatory O
mechanism O
of O
mutant O
p53 O
transcription O
via O
HDAC8 O
and O
suggest O
that O
HDAC O
inhibitors O
and O
especially O
HDAC8 O
- O
targeting O
agents O
might O
be O
explored O
as O
an O
adjuvant O
for O
tumors O
carrying O
a O
mutant O
p53 O
. O

microRNA O
- O
125b O
inhibits O
tube O
formation O
of O
blood O
vessels O
through O
translational O
suppression O
of O
VE O
- O
cadherin O
. O

Angiogenesis O
is O
controlled O
positively O
or O
negatively O
by O
extrinsic O
and O
intrinsic O
molecular O
cues O
in O
endothelial O
cells O
( O
ECs O
) O
; O
in O
the O
tumor O
microenvironment O
, O
the O
action O
of O
positive O
regulators O
exceeds O
that O
of O
negative O
regulators O
. O

Thus O
, O
overinduction O
of O
negative O
regulators O
may O
inhibit O
tumor O
angiogenesis O
. O

MicroRNAs O
( O
miRNAs O
or O
miRs O
) O
are O
endogenous O
short O
noncoding O
RNAs O
regulating O
gene O
expression O
either O
through O
translational O
inhibition O
or O
destabilization O
of O
target O
mRNA O
. O

Here O
, O
we O
show O
that O
miR O
- O
125b O
expression O
is O
transiently O
induced O
in O
ECs O
on O
stimulation O
with O
vascular O
endothelial O
growth O
factor O
or O
by O
ischemia O
. O

miR O
- O
125b O
inhibits O
translation O
of O
vascular O
endothelial O
( O
VE O
) O
- O
cadherin O
mRNA O
and O
in O
vitro O
tube O
formation O
by O
ECs O
. O

Injection O
of O
miR O
- O
125b O
into O
the O
tumor O
inhibited O
VE O
- O
cadherin O
expression O
by O
ECs O
and O
induced O
nonfunctional O
blood O
vessel O
formation O
, O
resulting O
in O
inhibition O
of O
tumor O
growth O
. O

It O
has O
been O
suggested O
that O
pro O
- O
angiogenic O
signals O
in O
ECs O
also O
upregulate O
anti O
- O
angiogenic O
molecules O
simultaneously O
via O
negative O
feedback O
. O

Because O
miR O
- O
125b O
induction O
in O
ECs O
is O
transient O
after O
pro O
- O
angiogenic O
stimulation O
, O
prolonged O
overexpression O
of O
miR O
- O
125b O
could O
result O
in O
blood O
vessel O
regression O
. O

Thus O
, O
miR O
- O
125b O
may O
be O
useful O
in O
cancer O
therapy O
by O
causing O
the O
collapse O
of O
the O
lumen O
of O
ECs O
. O

Chemical O
constituents O
comparison O
between O
Rhizoma O
Smilacis O
Glabrae O
and O
Rhizoma O
Smilacis O
Chinae O
by O
HPLC O
- O
DAD O
- O
MS O
/ O
MS O
. O

Rhizoma O
Smilacis O
Glabrae O
( O
RSG O
) O
and O
Rhizoma O
Smilacis O
Chinae O
( O
RSC O
) O
are O
two O
herbal O
materials O
that O
belong O
to O
the O
same O
genera O
and O
are O
both O
listed O
in O
the O
Chinese O
Pharmacopoeia O
. O

Chemical O
constituents O
in O
the O
two O
species O
were O
compared O
by O
HPLC O
- O
DAD O
- O
MS O
/ O
MS O
. O

Many O
common O
constituents O
were O
found O
in O
both O
species O
, O
including O
shikimic B
acid I
, O
5 B
- I
O I
- I
caffeoylshikimic I
acid I
, O
trans B
- I
resveratrol I
, O
taxifolin B
, O
astilbin B
and O
its O
three O
stereoisomers O
, O
engeletin B
and O
isoengeletin B
. O

However O
, O
syringic B
acid I
was O
found O
only O
in O
RSG O
, O
while O
chlorogenic B
acid I
was O
found O
only O
in O
RSC O
. O

Gonadal O
hormones O
and O
the O
control O
of O
reactive O
gliosis O
. O

Astrocytes O
and O
microglia O
respond O
to O
central O
nervous O
system O
( O
CNS O
) O
injury O
with O
changes O
in O
morphology O
, O
proliferation O
, O
migration O
and O
expression O
of O
inflammatory O
regulators O
. O

This O
phenomenon O
is O
known O
as O
reactive O
gliosis O
. O

Activation O
of O
astrocytes O
and O
microglia O
after O
acute O
neural O
insults O
, O
such O
as O
stroke O
or O
traumatic O
CNS O
injury O
, O
is O
considered O
to O
be O
an O
adaptive O
response O
that O
contributes O
to O
minimize O
neuronal O
damage O
. O

However O
, O
reactive O
gliosis O
may O
amplify O
CNS O
damage O
under O
chronic O
neurodegenerative O
conditions O
. O

Progesterone B
, O
estradiol B
and O
testosterone B
have O
been O
shown O
to O
control O
reactive O
gliosis O
in O
different O
models O
of O
CNS O
injury O
, O
modifying O
the O
number O
of O
reactive O
astrocytes O
and O
reactive O
microglia O
and O
the O
expression O
of O
anti O
- O
inflammatory O
and O
proinflammatory O
mediators O
. O

The O
actions O
of O
gonadal O
hormones O
on O
reactive O
gliosis O
involve O
different O
mechanisms O
, O
including O
the O
modulation O
of O
the O
activity O
of O
steroid B
receptors O
, O
such O
as O
estrogen B
receptors O
alpha O
and O
beta O
, O
the O
regulation O
of O
nuclear O
factor O
- O
kappa O
B O
mediated O
transcription O
of O
inflammatory O
molecules O
and O
the O
recruitment O
of O
the O
transcriptional O
corepressor O
c B
- O
terminal O
binding O
protein O
to O
proinflammatory O
promoters O
. O

In O
addition O
, O
the O
Parkinson O
' O
s O
disease O
related O
gene O
parkin O
and O
the O
endocannabinoid O
system O
also O
participate O
in O
the O
regulation O
of O
reactive O
gliosis O
by O
estradiol B
. O

The O
control O
exerted O
by O
gonadal O
hormones O
on O
reactive O
gliosis O
may O
affect O
the O
response O
of O
neural O
tissue O
to O
trauma O
and O
neurodegeneration O
and O
may O
contribute O
to O
sex O
differences O
in O
the O
manifestation O
of O
neurodegenerative O
diseases O
. O

However O
, O
the O
precise O
functional O
consequences O
of O
the O
regulation O
of O
reactive O
gliosis O
by O
gonadal O
hormones O
under O
acute O
and O
chronic O
neurodegenerative O
conditions O
are O
still O
not O
fully O
clarified O
. O

A O
90 O
- O
day O
oral O
( O
dietary O
) O
toxicity O
study O
of O
arruva B
, O
an O
R B
, I
R I
- I
monatin I
salt I
isomer O
, O
in O
Crl O
: O
CD O
- O
1 O
( O
ICR O
) O
mice O
. O

R B
, I
R I
- I
Monatin I
[ O
2R O
, O
4R O
- O
isomer O
of O
2 B
- I
hydroxy I
- I
2 I
- I
( I
indol I
- I
3 I
- I
ylmethyl I
) I
- I
4 I
- I
aminoglutaric I
acid I
] O
is O
one O
of O
four O
natural O
constituent O
isomers O
in O
the O
root O
bark O
of O
Sclerochitin O
ilicifolius O
; O
and O
" O
arruva O
" O
is O
the O
common O
/ O
usual O
name O
that O
is O
proposed O
to O
represent O
R B
, I
R I
- I
monatin I
salt O
forms O
, O
which O
have O
potential O
use O
as O
high O
potency O
sweetener O
food O
ingredients O
. O

In O
the O
present O
study O
, O
groups O
of O
male O
and O
female O
Crl O
: O
CD O
- O
1 O
( O
ICR O
) O
mice O
were O
exposed O
to O
0 O
( O
control O
) O
, O
5000 O
, O
10 O
, O
000 O
, O
20 O
, O
000 O
, O
or O
35 O
, O
000ppm O
of O
arruva O
in O
the O
diet O
for O
90days O
. O

There O
were O
no O
toxicologically O
relevant O
clinical O
or O
histopathological O
findings O
in O
any O
of O
the O
test O
article O
- O
treated O
groups O
. O

Significantly O
lower O
mean O
body O
weights O
and O
cumulative O
body O
weight O
gains O
were O
noted O
in O
the O
35 O
, O
000ppm O
group O
when O
compared O
to O
the O
control O
group O
. O

Mean O
body O
weights O
in O
the O
35 O
, O
000ppm O
group O
males O
and O
females O
were O
9 O
% O
and O
7 O
% O
less O
than O
the O
control O
group O
, O
respectively O
, O
at O
week O
13 O
. O

In O
the O
absence O
of O
observations O
associated O
with O
systemic O
toxicity O
and O
in O
consideration O
of O
the O
magnitude O
of O
body O
weight O
difference O
, O
these O
effects O
were O
not O
considered O
toxicologically O
significant O
. O

Based O
on O
the O
results O
of O
this O
study O
, O
the O
dietary O
no O
- O
observed O
- O
adverse O
- O
effect O
level O
( O
NOAEL O
) O
of O
arruva O
for O
90days O
in O
male O
and O
female O
mice O
was O
35 O
, O
000ppm O
( O
equivalent O
to O
an O
exposure O
level O
of O
5764 O
and O
8013mg O
/ O
kg O
bw O
/ O
day O
, O
respectively O
) O
. O

Grewialin B
and O
optivanin B
new O
constituents O
from O
the O
stem O
bark O
of O
Grewia O
optiva O
Drummond O
ex O
Burret O
( O
Tiliaceae O
) O
. O

Studies O
on O
the O
chemical O
constituents O
from O
the O
stem O
bark O
of O
Grewia O
optiva O
have O
led O
to O
the O
isolation O
of O
two O
new O
compounds O
, O
grewialin B
( O
1 O
) O
and O
optivanin B
( O
2 O
) O
, O
along O
with O
three O
known O
constituents O
which O
were O
hitherto O
unreported O
from O
this O
species O
. O

The O
structures O
of O
the O
new O
constituents O
have O
been O
elucidated O
by O
spectral O
studies O
including O
1D O
and O
2D O
NMR O
experiments O
( O
HSQC O
, O
HMBC O
, O
COSY O
, O
NOESY O
and O
J O
- O
resolved O
) O
as O
well O
as O
HR O
EI O
- O
MS O
spectroscopic O
data O
analysis O
, O
as O
2S B
* I
- I
( I
3 I
- I
hydroxy I
- I
4 I
- I
methoxyphenyl I
) I
- I
3R I
* I
- I
methyl I
- I
2H I
- I
[ I
1 I
, I
4 I
] I
- I
dioxin I
[ I
2 I
, I
3 I
] I
- I
chromen I
- I
7 I
( I
3H I
) I
- I
one I
( O
1 O
) O
; O
a O

coumarinolignan B
and O
3 B
- I
hydroxy I
- I
1 I
- I
( I
3 I
- I
hydroxy I
- I
4 I
- I
methoxyphenyl I
) I
propan I
- I
1 I
- I
one I
( O
2 O
) O
. O

The O
known O
compounds O
were O
identified O
as O
beta B
- I
sitosterol I
, O
stigmasterol B
and O
lupeol B
by O
comparing O
their O
spectral O
data O
with O
those O
reported O
in O
the O
literature O
. O

Berberine B
inhibits O
myofibroblast O
differentiation O
in O
nasal O
polyp O
- O
derived O
fibroblasts O
via O
the O
p38 O
pathway O
. O

The O
purposes O
of O
this O
study O
were O
to O
determine O
whether O
berberine B
has O
any O
effect O
on O
phenotype O
changes O
and O
extracellular O
matrix O
( O
ECM O
) O
production O
in O
nasal O
polyp O
- O
derived O
fibroblasts O
( O
NPDFs O
) O
and O
to O
investigate O
the O
underlying O
molecular O
mechanism O
. O

NPDFs O
were O
pre O
- O
treated O
with O
berberine B
prior O
to O
induction O
by O
transforming O
growth O
factor O
( O
TGF O
) O
- O
beta O
1 O
. O

The O
expression O
of O
alpha O
- O
smooth O
muscle O
actin O
( O
SMA O
) O
and O
collagen O
type O
I O
mRNA O
was O
determined O
by O
a O
reverse O
transcription O
- O
polymerase O
chain O
reaction O
, O
and O
the O
expression O
of O
alpha O
- O
SMA O
protein O
and O
collagen O
type O
I O
was O
determined O
by O
western O
blotting O
and O
/ O
or O
immunofluorescent O
staining O
. O

The O
total O
soluble O
collagen O
production O
was O
analysed O
by O
the O
SirCol B
collagen O
assay O
. O

The O
expression O
of O
several O
signaling O
molecules O
of O
the O
TGF O
- O
beta O
1 O
pathway O
was O
evaluated O
by O
western O
blot O
analysis O
. O

In O
TGF O
- O
beta O
1 O
- O
induced O
NPDFs O
, O
berberine B
significantly O
inhibited O
the O
expression O
of O
alpha O
- O
SMA O
and O
collagen O
type O
I O
mRNA O
and O
reduced O
alpha O
- O
SMA O
and O
collagen O
protein O
levels O
. O

Berberine B
only O
suppressed O
the O
expression O
of O
pp38 O
among O
the O
evaluated O
signaling O
molecules O
. O

SB203580 B
( O
a O
specific O
inhibitor O
of O
p38 O
kinase O
) O
markedly O
suppressed O
the O
increased O
expression O
of O
collagen O
type O
I O
and O
alpha O
- O
SMA O
in O
TGF O
- O
beta O
1 O
- O
induced O
NPDFs O
. O

Berberine B
exerts O
suppressive O
effects O
on O
phenotype O
changes O
and O
ECM O
production O
in O
NPDFs O
via O
p38 O
signaling O
pathway O
interference O
. O

The O
findings O
provide O
new O
therapeutic O
options O
for O
ECM O
production O
in O
nasal O
polyps O
. O

The O
nonhematopoietic O
effects O
of O
erythropoietin O
in O
skin O
regeneration O
and O
repair O
: O
from O
basic O
research O
to O
clinical O
use O
. O

Erythropoietin O
( O
EPO O
) O
is O
the O
main O
regulator O
of O
red O
blood O
cell O
production O
but O
there O
exists O
also O
a O
variety O
of O
nonhematopoietic O
properties O
. O

More O
recent O
data O
show O
that O
EPO O
is O
also O
associated O
with O
the O
protection O
of O
tissues O
suffering O
from O
ischemia O
and O
reperfusion O
injury O
as O
well O
as O
with O
improved O
regeneration O
in O
various O
organ O
systems O
, O
in O
particular O
the O
skin O
. O

This O
review O
highlights O
the O
mechanisms O
of O
EPO O
in O
the O
different O
stages O
of O
wound O
healing O
and O
the O
reparative O
processes O
in O
the O
skin O
emphasizing O
pathophysiological O
mechanisms O
and O
potential O
clinical O
applications O
. O

There O
is O
clear O
evidence O
that O
EPO O
effectively O
influences O
all O
wound O
- O
healing O
phases O
in O
a O
dose O
- O
dependent O
manner O
. O

This O
includes O
inflammation O
, O
tissue O
, O
and O
blood O
vessel O
formation O
as O
well O
as O
the O
remodeling O
of O
the O
wound O
. O

The O
molecular O
mechanism O
is O
predominantly O
based O
on O
an O
increased O
expression O
of O
the O
endothelial O
and O
inducible O
nitric B
oxide I
( O
NO B
) O
synthase O
with O
a O
consecutive O
rapid O
supply O
of O
NO B
as O
well O
as O
an O
increased O
content O
of O
vascular O
endothelial O
growth O
factor O
( O
VEGF O
) O
in O
the O
wound O
. O

The O
improved O
understanding O
of O
the O
functions O
and O
regulatory O
mechanisms O
of O
EPO O
in O
the O
context O
of O
wound O
- O
healing O
problems O
and O
ischemia O
/ O
reperfusion O
injury O
, O
especially O
during O
flap O
surgery O
, O
may O
lead O
to O
new O
considerations O
of O
this O
growth O
hormone O
for O
its O
regular O
clinical O
application O
in O
patients O
. O

Essential O
oils O
composition O
of O
Periploca O
laevigata O
Aiton O
subsp O
. O
angustifolia O
( O
Labill O
. O
) O
Markgraf O
( O
Apocynaceae O
- O
Periplocoideae O
) O
. O

The O
essential O
oil O
of O
roots O
, O
branches O
, O
leaves O
, O
flowers O
and O
fruits O
of O
Periploca O
laevigata O
Aiton O
subsp O
. O
angustifolia O
( O
Apocynaceae O
) O
from O
Lampedusa O
Island O
has O
been O
obtained O
by O
hydrodistillation O
and O
its O
composition O
analysed O
. O

The O
analyses O
allowed O
the O
identification O
and O
quantification O
of O
86 O
volatile O
compounds O
. O

Branches O
showed O
the O
higher O
diversity O
with O
57 O
compounds O
followed O
by O
fruits O
with O
33 O
, O
roots O
with O
23 O
, O
flowers O
with O
16 O
and O
leaves O
with O
six O
compounds O
, O
respectively O
. O

In O
the O
matrices O
examined O
three O
constituents O
, O
heneicosane B
, O
docosane B
and O
tricosane B
are O
in O
common O
, O
although O
with O
different O
percentages O
. O

At O
least O
the O
most O
abundant O
compounds O
found O
in O
the O
matrices O
have O
been O
reported O
to O
have O
several O
biological O
activities O
. O

2 B
- I
Hydroxy I
- I
4 I
- I
methoxybenzaldehyde I
identified O
in O
the O
roots O
as O
the O
most O
abundant O
component O
( O
70 O
. O
7 O
% O
) O
and O
present O
with O
8 O
. O
3 O
% O
in O
the O
branches O
is O
a O
potent O
tyrosinase O
inhibitor O
present O
in O
several O
African O
medicinal O
plants O
, O
and O
thus O
being O
used O
as O
an O
ingredient O
in O
cosmetic O
and O
other O
medicinal O
products O
, O
primarily O
in O
relation O
to O
hyperpigmentation O
. O

Among O
the O
compounds O
identified O
, O
several O
play O
a O
role O
as O
semiochemicals O
for O
many O
animals O
, O
and O
28 O
allomones O
, O
43 O
pheromones O
, O
21 O
kairomones O
have O
been O
identified O
. O

P O
. O
laevigata O
subsp O
. O
angustifolia O
in O
Lampedusa O
Island O
is O
host O
to O
a O
community O
of O
visitors O
, O
and O
the O
possible O
ecological O
role O
of O
the O
volatiles O
found O
is O
briefly O
discussed O
. O

P21 O
- O
activated O
kinase O
4 O
( O
PAK4 O
) O
is O
required O
for O
metaphase O
spindle O
positioning O
and O
anchoring O
. O

The O
oncogenic O
kinase O
PAK4 O
was O
recently O
found O
to O
be O
involved O
in O
the O
regulation O
of O
the O
G1 O
phase O
and O
the O
G2 O
/ O
M O
transition O
of O
the O
cell O
cycle O
. O

We O
have O
also O
identified O
that O
PAK4 O
regulates O
Ran O
GTPase O
activity O
during O
mitosis O
. O

Here O
, O
we O
show O
that O
after O
entering O
mitosis O
, O
PAK4 O
- O
depleted O
cells O
maintain O
a O
prolonged O
metaphase O
- O
like O
state O
. O

In O
these O
cells O
, O
chromosome O
congression O
to O
the O
metaphase O
plate O
occurs O
with O
normal O
kinetics O
but O
is O
followed O
by O
an O
extended O
period O
during O
which O
membrane O
blebbing O
and O
spindle O
rotation O
are O
observed O
. O

These O
bipolar O
PAK4 O
- O
depleted O
metaphase O
- O
like O
spindles O
have O
a O
defective O
astral O
microtubule O
( O
MT O
) O
network O
and O
are O
not O
centered O
in O
the O
cell O
but O
are O
in O
close O
contact O
with O
the O
cell O
cortex O
. O

As O
the O
metaphase O
- O
like O
state O
persists O
, O
centrosome O
fragmentation O
occurs O
, O
chromosomes O
scatter O
from O
the O
metaphase O
plate O
and O
move O
toward O
the O
spindle O
poles O
with O
an O
active O
spindle O
assembly O
checkpoint O
, O
a O
phenotype O
that O
is O
reminiscent O
of O
cohesion O
fatigue O
. O

PAK4 O
also O
regulates O
the O
acto O
- O
myosin O
cytoskeleton O
and O
we O
report O
that O
PAK4 O
depletion O
results O
in O
the O
induction O
of O
cortical O
membrane O
blebbing O
during O
prometaphase O
arrest O
. O

However O
, O
we O
show O
that O
membrane O
blebs O
, O
which O
are O
strongly O
enriched O
in O
phospho B
- O
cofilin O
, O
are O
not O
responsible O
for O
the O
poor O
anchoring O
of O
the O
spindle O
. O

As O
PAK4 O
depletion O
interferes O
with O
the O
localization O
of O
components O
of O
the O
dynein O
/ O
dynactin O
complexes O
at O
the O
kinetochores O
and O
on O
the O
astral O
MTs O
, O
we O
propose O
that O
loss O
of O
PAK4 O
could O
induce O
a O
change O
in O
the O
activities O
of O
motor O
proteins O
. O

The O
anxiolytic O
potential O
and O
psychotropic O
side O
effects O
of O
an O
echinacea O
preparation O
in O
laboratory O
animals O
and O
healthy O
volunteers O
. O

We O
investigated O
the O
toxicity O
, O
psychotropic O
side O
effects O
and O
anxiolytic O
potential O
of O
an O
Echinacea O
angustifolia O
extract O
that O
produced O
promising O
effects O
in O
laboratory O
tests O
performed O
earlier O
. O

Rats O
were O
studied O
in O
the O
elevated O
plus O
- O
maze O
, O
conditioned O
fear O
, O
open O
- O
field O
, O
object O
recognition O
and O
conditioned O
place O
preference O
tests O
. O

Toxicity O
was O
studied O
in O
rats O
after O
intragastric O
administration O
. O

The O
preparation O
decreased O
anxiety O
in O
the O
elevated O
plus O
- O
maze O
and O
ameliorated O
contextual O
conditioned O
fear O
. O

No O
lethality O
or O
behavioural O
signs O
of O
discomfort O
were O
noticed O
in O
rats O
treated O
with O
1000 O
and O
3000 O
mg O
/ O
kg O
Echinacea O
angustifolia O
. O

The O
extract O
was O
without O
effect O
in O
tests O
of O
locomotion O
( O
open O
- O
field O
) O
, O
memory O
( O
object O
recognition O
) O
and O
rewarding O
potential O
( O
conditioned O
place O
preference O
) O
within O
a O
wide O
dose O
range O
. O

A O
pharmacological O
formulation O
based O
on O
the O
same O
E O
. O
angustifolia O
extract O
was O
tested O
in O
human O
subjects O
. O

One O
or O
two O
tablets O
per O
day O
were O
administered O
for O
1 O
week O
to O
healthy O
volunteers O
scoring O
high O
on O
the O
State O
- O
Trait O
Anxiety O
Inventory O
( O
STAI O
) O
. O

The O
tablets O
contained O
20 O
mg O
of O
the O
plant O
extract O
. O

Data O
were O
collected O
using O
a O
structured O
self O
- O
assessment O
diary O
technique O
. O

The O
high O
dose O
( O
2 O
tablets O
per O
day O
) O
decreased O
STAI O
scores O
within O
3 O
days O
in O
human O
subjects O
, O
an O
effect O
that O
remained O
stable O
for O
the O
duration O
of O
the O
treatment O
( O
7 O
days O
) O
and O
for O
the O
2 O
weeks O
that O
followed O
treatment O
. O

The O
lower O
dose O
( O
1 O
tablet O
per O
day O
) O
did O
not O
affect O
anxiety O
significantly O
. O

Antitrypanosomal O
properties O
of O
Panax O
ginseng O
C O
. O

A O
. O

Meyer O
: O
new O
possibilities O
for O
a O
remarkable O
traditional O
drug O
. O

African O
trypanosomiasis O
is O
still O
a O
major O
health O
problem O
in O
many O
sub O
- O
Saharan O
countries O
in O
Africa O
. O

We O
investigated O
the O
effects O
of O
three O
preparations O
of O
Panax O
ginseng O
, O
Panax O
notoginseng O
, O
isolated O
ginsenosides B
, O
and O
the O
polyacetylene B
panaxynol B
on O
Trypanosoma O
brucei O
brucei O
and O
the O
human O
cancer O
cell O
line O
HeLa O
. O

Hexane B
extracts O
and O
the O
pure O
panaxynol B
were O
toxic O
and O
at O
the O
same O
time O
highly O
selective O
against O
T O
. O

b O
. O
brucei O
, O
whereas O
methanol B
extracts O
and O
12 O
isolated O
ginsenosides B
were O
significantly O
less O
toxic O
and O
showed O
only O
weak O
selectivity O
. O

Panaxynol B
was O
cytotoxic O
against O
T O
. O

b O
. O
brucei O
at O
the O
concentration O
of O
0 O
. O
01 O
micro O
g O
/ O
mL O
with O
a O
selectivity O
index O
of O
858 O
, O
superior O
even O
to O
established O
antitrypanosomal O
drugs O
. O

We O
suggest O
that O
the O
inhibition O
of O
trypanothione B
reductase O
, O
which O
is O
only O
found O
in O
trypanosomes O
, O
might O
explain O
the O
observed O
selectivity O
. O

The O
high O
selectivity O
together O
with O
a O
cytotoxic O
concentration O
in O
the O
range O
of O
the O
bioavailability O
makes O
panaxynol B
and O
other O
polyacetylenes B
in O
general O
very O
promising O
lead O
compounds O
for O
the O
treatment O
of O
African O
trypanosomiasis O
. O

Androgenic O
and O
spermatogenic O
activity O
of O
alkylamide B
- O
rich O
ethanol B
solution O
extract O
of O
Anacyclus O
pyrethrum O
DC O
. O

Anacyclus O
pyrethrum O
( O
A O
. O
pyrethrum O
) O
has O
been O
used O
as O
Vajikaran O
Rasayana O
( O
aphrodisiac O
) O
in O
traditional O
Indian O
ayurvedic O
medicine O
to O
treat O
male O
sexual O
dysfunction O
, O
including O
infertility O
. O

Aphrodisiac O
activity O
may O
be O
due O
to O
an O
increase O
in O
the O
production O
or O
effect O
of O
androgens B
, O
so O
this O
study O
sought O
to O
evaluate O
the O
androgenic O
and O
spermatogenic O
potential O
of O
the O
alkylamide B
- O
rich O
ethanol B
solution O
extract O
. O

Male O
Wistar O
strain O
rats O
weighing O
between O
150 O
and O
180 O
g O
were O
completely O
randomized O
divided O
into O
five O
groups O
. O

The O
ethanol B
solution O
extract O
of O
A O
. O
pyrethrum O
was O
administered O
to O
groups O
of O
rats O
in O
50 O
, O
100 O
, O
and O
150 O
mg O
/ O
kg O
doses O
for O
a O
period O
of O
28 O
days O
, O
and O
the O
action O
was O
compared O
with O
control O
and O
testosterone B
- O
treated O
rats O
. O

Thirteen O
N B
- I
alkylamides I
were O
detected O
in O
the O
extract O
by O
using O
HPLC O
/ O
UV O
/ O
electrospray O
ionization O
mass O
spectrometry O
method O
. O

Extract O
administration O
at O
all O
the O
doses O
produced O
significant O
increase O
in O
body O
weight O
, O
sperm O
count O
, O
motility O
, O
and O
viability O
along O
with O
serum O
testosterone B
, O
luteinizing O
hormone O
, O
and O
follicle O
- O
stimulating O
hormone O
concentrations O
. O

Histoarchitecture O
of O
testis O
revealed O
increased O
spermatogenic O
activities O
. O

Seminal O
fructose B
content O
was O
also O
significantly O
increased O
after O
28 O
days O
of O
treatment O
. O

Our O
results O
suggest O
that O
the O
ethanol B
solution O
extract O
of O
the O
roots O
of O
A O
. O
pyrethrum O
has O
androgenic O
potential O
and O
may O
improve O
male O
fertility O
by O
enhancing O
spermatogenesis O
. O

eIF4F O
suppression O
in O
breast O
cancer O
affects O
maintenance O
and O
progression O
. O

Levels O
of O
eukaryotic O
initiation O
factor O
4E O
( O
eIF4E O
) O
are O
frequently O
elevated O
in O
human O
cancers O
and O
in O
some O
instances O
have O
been O
associated O
with O
poor O
prognosis O
and O
outcome O
. O

Here O
we O
utilize O
transgenic O
and O
allograft O
breast O
cancer O
models O
to O
demonstrate O
that O
increased O
mammalian O
target O
of O
rapamycin B
( O
mTOR O
) O
signalling O
can O
be O
a O
significant O
contributor O
to O
breast O
cancer O
progression O
in O
vivo O
. O

Suppressing O
mTOR O
activity O
, O
as O
well O
as O
levels O
and O
activity O
of O
the O
downstream O
translation O
regulators O
, O
eIF4E O
and O
eIF4A O
, O
delayed O
breast O
cancer O
progression O
, O
onset O
of O
associated O
pulmonary O
metastasis O
in O
vivo O
and O
breast O
cancer O
cell O
invasion O
and O
migration O
in O
vitro O
. O

Translation O
of O
vascular O
endothelial O
growth O
factor O
( O
VEGF O
) O
, O
matrix O
metallopeptidase O
9 O
( O
MMP9 O
) O
and O
cyclin O
D1 O
mRNAs O
, O
which O
encode O
products O
associated O
with O
the O
metastatic O
phenotype O
, O
is O
inhibited O
upon O
eIF4E O
suppression O
. O

Our O
results O
indicate O
that O
the O
mTOR O
/ O
eIF4F O
axis O
is O
an O
important O
contributor O
to O
tumor O
maintenance O
and O
progression O
programs O
in O
breast O
cancer O
. O

Targeting O
this O
pathway O
may O
be O
of O
therapeutic O
benefit O
. O

Actions O
of O
Xanthurenic B
acid I
, O
a O
putative O
endogenous O
Group O
II O
metabotropic O
glutamate B
receptor O
agonist O
, O
on O
sensory O
transmission O
in O
the O
thalamus O
. O

Xanthurenic B
acid I
( O
XA O
) O
, O
a O
molecule O
arising O
from O
tryptophan B
metabolism O
by O
transamination O
of O
3 B
- I
hydroxykynurenine I
, O
has O
recently O
been O
identified O
as O
an O
endogenous O
Group O
II O
( O
mGlu2 O
and O
mGlu3 O
) O
metabotropic O
glutamate B
( O
mGlu O
) O
receptor O
ligand O
in O
vitro O
. O

Impairments O
in O
Group O
II O
mGlu O
receptor O
expression O
and O
function O
have O
been O
implicated O
in O
the O
pathophysiology O
of O
schizophrenia O
, O
as O
have O
multiple O
steps O
in O
the O
kynurenine B
metabolism O
pathway O
. O

Therefore O
, O
we O
examined O
XA O
in O
vivo O
to O
further O
investigate O
its O
potential O
as O
a O
Group O
II O
mGlu O
receptor O
ligand O
using O
a O
preparation O
that O
has O
been O
previously O
demonstrated O
to O
efficiently O
reveal O
the O
action O
of O
other O
Group O
II O
mGlu O
receptor O
ligands O
in O
vivo O
. O

Extracellular O
single O
- O
neurone O
recordings O
were O
made O
in O
the O
rat O
ventrobasal O
thalamus O
( O
VB O
) O
in O
conjunction O
with O
iontophoresis O
of O
agonists O
, O
an O
antagonist O
and O
a O
positive O
allosteric O
modulator O
and O
/ O
or O
intravenous O
( O
i O
. O
v O
. O
) O
injection O
of O
XA O
. O

We O
found O
the O
XA O
effect O
on O
sensory O
inhibition O
, O
when O
applied O
iontophoretically O
and O
i O
. O
v O
. O
, O
was O
similar O
to O
that O
of O
other O
Group O
II O
mGlu O
receptor O
agonists O
in O
reducing O
inhibition O
evoked O
in O
the O
VB O
from O
the O
thalamic O
reticular O
nucleus O
upon O
physiological O
sensory O
stimulation O
. O

Furthermore O
, O
we O
postulate O
that O
XA O
may O
be O
the O
first O
potential O
endogenous O
allosteric O
agonist O
( O
termed O
' O
endocoid O
' O
) O
for O
the O
mGlu O
receptors O
. O

As O
the O
Group O
II O
receptors O
and O
kynurenine B
metabolism O
pathway O
have O
both O
been O
heavily O
implicated O
in O
the O
pathophysiology O
of O
schizophrenia O
, O
XA O
could O
play O
a O
pivotal O
role O
in O
antipsychotic O
research O
as O
this O
potential O
endocoid O
represents O
both O
a O
convergence O
within O
these O
two O
biological O
parameters O
and O
a O
novel O
class O
of O
Group O
II O
mGlu O
receptor O
ligand O
. O

This O
article O
is O
part O
of O
a O
Special O
Issue O
entitled O
' O
Metabotropic O
Glutamate B
Receptors O
' O
. O

Sol O
- O
flame O
synthesis O
: O
a O
general O
strategy O
to O
decorate O
nanowires O
with O
metal B
oxide I
/ O
noble O
metal O
nanoparticles O
. O

The O
hybrid O
structure O
of O
nanoparticle O
- O
decorated O
nanowires O
( O
NP O
@ O
NW O
) O
combines O
the O
merits O
of O
large O
specific O
surface O
areas O
for O
NPs O
and O
anisotropic O
properties O
for O
NWs O
and O
is O
a O
desirable O
structure O
for O
applications O
including O
batteries O
, O
dye O
- O
sensitized O
solar O
cells O
, O
photoelectrochemical O
water O
splitting O
, O
and O
catalysis O
. O

Here O
, O
we O
report O
a O
novel O
sol O
- O
flame O
method O
to O
synthesize O
the O
NP O
@ O
NW O
hybrid O
structure O
with O
two O
unique O
characteristics O
: O
( O
1 O
) O
large O
loading O
of O
NPs O
per O
NW O
with O
the O
morphology O
of O
NP O
chains O
fanning O
radially O
from O
the O
NW O
core O
and O
( O
2 O
) O
intimate O
contact O
between O
NPs O
and O
NWs O
. O

Both O
features O
are O
advantageous O
for O
the O
above O
applications O
that O
involve O
both O
surface O
reactions O
and O
charge O
transport O
processes O
. O

Moreover O
, O
the O
sol O
- O
flame O
method O
is O
simple O
and O
general O
, O
with O
which O
we O
have O
successfully O
decorated O
various O
NWs O
with O
binary O
/ O
ternary O
metal B
oxide I
and O
even O
noble O
metal O
NPs O
. O

The O
unique O
aspects O
of O
the O
sol O
- O
flame O
method O
arise O
from O
the O
ultrafast O
heating O
rate O
and O
the O
high O
temperature O
of O
flame O
, O
which O
enables O
rapid O
solvent O
evaporation O
and O
combustion O
, O
and O
the O
combustion O
gaseous O
products O
blow O
out O
NPs O
as O
they O
nucleate O
, O
forming O
the O
NP O
chains O
around O
NWs O
. O

Improving O
oral O
absorption O
via O
drug O
- O
loaded O
nanocarriers O
: O
absorption O
mechanisms O
, O
intestinal O
models O
and O
rational O
fabrication O
. O

Although O
it O
is O
acknowledged O
that O
the O
main O
impediment O
of O
orally O
administered O
therapeutic O
agents O
is O
their O
extensive O
and O
changeable O
pre O
- O
systemic O
metabolism O
, O
low O
absorption O
and O
instability O
in O
harsh O
environment O
of O
the O
gastrointestinal O
( O
GI O
) O
tract O
are O
also O
main O
influential O
factors O
, O
resulting O
into O
inadequate O
and O
erratic O
drug O
bioavailability O
. O

To O
overcome O
these O
shortcomings O
, O
nanotechnology O
has O
offered O
new O
promising O
strategies O
to O
prevent O
and O
treat O
a O
wide O
variety O
of O
diseases O
by O
employing O
different O
oral O
drug O
- O
carrier O
structures O
capable O
to O
enhance O
therapeutic O
effects O
and O
minimize O
the O
toxicity O
of O
healthy O
organs O
or O
cells O
. O

This O
review O
, O
in O
general O
, O
elucidates O
some O
considerable O
features O
of O
in O
vitro O
oral O
drug O
delivery O
in O
three O
different O
parts O
. O

The O
first O
one O
summarizes O
the O
main O
challenges O
for O
oral O
drug O
delivery O
and O
available O
absorption O
mechanisms O
. O

The O
second O
part O
embodies O
an O
in O
- O
depth O
discussion O
on O
the O
role O
of O
the O
intestinal O
absorption O
models O
used O
to O
predict O
permeability O
, O
cellular O
uptake O
or O
even O
toxicity O
of O
nanoparticles O
, O
resulting O
into O
the O
design O
of O
nanocarriers O
with O
optimum O
efficacy O
for O
oral O
delivery O
. O

The O
third O
section O
of O
the O
literature O
is O
devoted O
, O
more O
particularly O
, O
to O
nanocarriers O
developed O
for O
oral O
absorption O
in O
the O
past O
few O
years O
, O
including O
the O
behavior O
of O
nanovehicles O
upon O
oral O
administration O
with O
respect O
to O
membrane O
permeability O
, O
retention O
properties O
and O
stability O
, O
as O
well O
as O
methods O
which O
may O
lengthen O
residence O
time O
in O
the O
GI O
environment O
or O
improve O
drug O
absorption O
. O

Precision O
- O
cut O
intestinal O
slices O
as O
in O
vitro O
tool O
for O
studies O
on O
drug O
metabolism O
. O

The O
role O
of O
the O
intestine O
in O
drug O
metabolism O
has O
long O
been O
underestimated O
as O
a O
consequence O
of O
the O
technical O
difficulty O
to O
discern O
the O
role O
of O
the O
intestine O
from O
that O
of O
the O
liver O
in O
in O
vivo O
experiments O
and O
of O
the O
lack O
of O
in O
vitro O
models O
that O
are O
sufficiently O
viable O
and O
fully O
representing O
the O
physiology O
and O
anatomy O
of O
the O
intestine O
. O

Recently O
the O
precision O
- O
cut O
slice O
model O
, O
which O
is O
widely O
used O
for O
liver O
and O
kidney O
, O
was O
also O
adapted O
for O
the O
small O
and O
large O
intestine O
. O

In O
this O
review O
the O
application O
of O
precision O
- O
cut O
intestinal O
slices O
( O
PCIS O
) O
for O
research O
in O
drug O
metabolism O
and O
transport O
is O
discussed O
. O

PCIS O
can O
be O
prepared O
from O
animal O
and O
human O
tissues O
from O
all O
regions O
of O
the O
intestine O
allowing O
investigation O
of O
species O
differences O
and O
regional O
gradients O
of O
activities O
of O
metabolizing O
enzymes O
. O

They O
are O
viable O
for O
8 O
- O
24 O
h O
of O
incubation O
and O
show O
high O
activity O
of O
drug O
metabolizing O
enzymes O
, O
representative O
for O
the O
in O
vivo O
activity O
. O

They O
have O
been O
successfully O
used O
to O
study O
drug O
- O
drug O
interactions O
such O
as O
induction O
, O
inhibition O
and O
regulation O
of O
drug O
metabolizing O
enzymes O
, O
transporters O
and O
nuclear O
factors O
. O

Moreover O
they O
appear O
to O
be O
a O
suitable O
model O
for O
studies O
on O
cold O
preservation O
of O
donor O
organs O
for O
transplantation O
, O
and O
allow O
exploring O
inter O
- O
organ O
interactions O
by O
co O
- O
incubation O
with O
precision O
- O
cut O
slices O
of O
other O
organs O
. O

Their O
application O
as O
model O
for O
drug O
- O
induced O
intestinal O
toxicity O
is O
still O
in O
its O
infancy O
but O
appears O
to O
be O
promising O
. O

PCIS O
, O
prepared O
from O
human O
and O
animal O
tissues O
, O
represent O
a O
powerful O
translational O
model O
for O
drug O
metabolism O
, O
transport O
and O
toxicity O
studies O
and O
as O
such O
contributes O
to O
the O
reduction O
and O
replacement O
of O
animal O
experiments O
. O

Topical O
antiinflammatory O
activity O
of O
essential O
oil O
of O
Lippia O
sidoides O
cham O
: O
possible O
mechanism O
of O
action O
. O

This O
work O
reports O
the O
chemical O
composition O
of O
the O
essential O
oil O
of O
Lippia O
sidoides O
( O
EOLS O
) O
and O
evaluation O
of O
the O
topical O
effect O
of O
EOLS O
and O
thymol B
against O
different O
irritant O
agents O
in O
vivo O
. O

The O
essential O
oil O
was O
obtained O
by O
hydrodistillation O
, O
and O
gas O
chromatography O
/ O
mass O
spectrometry O
analysis O
identified O
the O
main O
constituents O
: O
thymol B
( O
84 O
. O
9 O
% O
) O
and O
p B
- I
cymene I
( O
5 O
. O
33 O
% O
) O
. O

The O
antiinflammatory O
activity O
was O
evaluated O
using O
the O
mouse O
models O
of O
acute O
ear O
inflammation O
induced O
by O
croton O
oil O
, O
arachidonic B
acid I
, O
phenol B
or O
histamine B
, O
and O
chronic O
inflammation O
induced O
by O
croton O
oil O
. O

The O
topical O
application O
of O
EOLS O
or O
thymol B
at O
a O
dose O
of O
2 O
mg O
/ O
ear O
significantly O
reduced O
( O
p O
< O
0 O
. O
001 O
) O
ear O
edema O
induced O
with O
arachidonic B
acid I
by O
45 O
. O
1 O
% O
and O
47 O
. O
4 O
% O
and O
reduced O
ear O
edema O
induced O
with O
phenol B
by O
33 O
. O
2 O
% O
( O
p O
< O
0 O
. O
05 O
) O
and O
54 O
. O
7 O
% O
( O
p O
< O
0 O
. O
01 O
) O
in O
acute O
ear O
edema O
. O

However O
, O
a O
proinflammatory O
effect O
of O
EOLS O
and O
thymol B
was O
evidenced O
when O
it O
was O
applied O
for O
more O
than O
1 O
day O
. O

There O
were O
no O
statistical O
differences O
in O
antiedematogenic O
activity O
between O
EOLS O
and O
thymol B
. O

In O
conclusion O
, O
the O
results O
indicate O
that O
thymol B
is O
the O
constituent O
responsible O
for O
the O
topical O
antiinflammatory O
activity O
of O
EOLS O
. O

Thus O
, O
these O
findings O
could O
justify O
the O
popular O
use O
of O
L O
. O
sidoides O
by O
alternative O
medicine O
, O
but O
chronic O
use O
has O
an O
inflammatory O
effect O
. O

Effects O
of O
synthetic O
peptides O
on O
the O
inflammatory O
response O
and O
their O
therapeutic O
potential O
. O

Recently O
, O
interest O
in O
small O
peptide O
molecules O
as O
potential O
drug O
candidates O
has O
revived O
. O

In O
this O
review O
, O
two O
series O
of O
synthetic O
peptides O
and O
their O
selective O
effects O
on O
the O
inflammatory O
response O
have O
been O
described O
, O
focusing O
on O
the O
intracellular O
pathways O
involved O
and O
on O
their O
therapeutic O
potential O
. O

A O
series O
of O
F O
( O
D O
) O
LF O
( O
D O
) O
LF O
analogs O
has O
been O
synthesized O
, O
including O
either O
N B
- I
t I
- I
Boc I
or O
different O
N B
- I
ureido I
substituents O
. O

The O
free O
acid O
derivatives O
as O
they O
are O
good O
candidates O
as O
antiinflammatory O
drugs O
are O
able O
to O
antagonize O
the O
multiple O
neutrophil O
functions O
evoked O
by O
N B
- I
formyl I
- I
L I
- I
methionyl I
- I
L I
- I
leucyl I
- I
Lphenylalanine I
( O
fMLF B
) O
, O
i O
. O
e O
. O
chemotaxis O
, O
superoxide B
anion O
production O
and O
lysozyme O
release O
. O

Their O
methyl B
- I
ester I
derivatives O
are O
ineffective O
. O

The O
second O
series O
of O
peptides O
derives O
from O
the O
endogenous O
protein O
kinase O
C O
( O
PKC O
) O
inhibitor O
PKI55 B
, O
a O
55 O
- O
amino B
acid I
protein O
, O
whose O
synthesis O
is O
induced O
by O
PKC O
activation O
, O
so O
that O
a O
feedback O
loop O
of O
inhibition O
is O
established O
. O

In O
vitro O
experiments O
showed O
that O
PKI55 O
inhibits O
recombinant O
PKC O
isoforms O
alpha O
, O
beta O
1 O
, O
beta O
2 O
, O
gamma O
, O
delta O
, O
zeta O
, O
; O
to O
identify O
the O
minimal O
amino B
acid I
sequence O
of O
PKI55 O
protein O
maintaining O
the O
inhibitory O
effects O
on O
PKC O
, O
peptides O
derived O
from O
both O
C B
- O
and O
N B
- O
terminal O
sequences O
have O
been O
synthesized O
. O

The O
N B
- O
terminal O
peptides O
5 O
( O
MLYKLHDVCRQLWFSC O
) O
, O
8 O
( O
CRQLWFSC O
) O
and O
9 O
( O
CRQLW O
) O
, O
that O
in O
human O
neutrophils O
retain O
the O
inhibitory O
activity O
on O
PKC O
, O
decrease O
the O
chemotaxis O
, O
and O
, O
in O
mice O
, O
display O
anti O
- O
inflammatory O
and O
analgesic O
action O
, O
after O
both O
central O
and O
peripheral O
administration O
of O
very O
low O
doses O
. O

Furthermore O
, O
the O
peptide O
5 O
shows O
neuroprotective O
activity O
in O
a O
model O
of O
cerebral O
ischemia O
in O
vitro O
, O
favouring O
the O
recovery O
of O
synaptic O
function O
. O

These O
findings O
suggest O
interesting O
possible O
therapeutic O
applications O
for O
these O
peptides O
. O

A O
review O
on O
the O
development O
in O
the O
field O
of O
NIDDM O
based O
thiazolidinedione B
PPAR O
gamma O
agonists O
. O

Peroxisome O
Proliferator O
Activated O
Receptors O
gamma O
( O
PPAR O
gamma O
) O
are O
a O
class O
of O
ligand O
activated O
transcription O
factors O
with O
a O
prominent O
role O
in O
the O
regulation O
of O
metabolic O
processes O
. O

The O
present O
work O
aims O
towards O
examining O
the O
functional O
and O
structural O
features O
that O
facilitate O
the O
binding O
of O
small O
molecules O
based O
on O
Thiazolidinedione B
pharmacophore O
to O
PPARs O
. O

The O
intent O
of O
this O
article O
is O
to O
review O
all O
the O
reported O
thiazolidinediones B
and O
associated O
groups O
of O
PPAR O
gamma O
ligands O
. O

A O
new O
triterpenoid B
from O
the O
rhizomes O
of O
Nelumbo O
nucifera O
. O

A O
new O
triterpenoid B
, O
2 B
alpha I
, I
24 I
- I
diacetoxy I
- I
3 I
beta I
- I
hydroxyolean I
- I
12 I
- I
en I
- I
28 I
- I
oic I
acid I
( O
1 O
) O
, O
was O
characterised O
from O
the O
rhizomes O
of O
Nelumbo O
nucifera O
Gaertn O
by O
spectroscopic O
and O
chemical O
methods O
along O
with O
four O
known O
compounds O
, O
hyptatic B
acid I
- I
A I
( O
2 B
alpha I
, I
3 I
beta I
, I
24 I
- I
trihydroxyolean I
- I
12 I
- I
en I
- I
28 I
- I
oic I
acid I
) O
( O
2 O
) O
, O
maslinic B
acid I
( O
2 B
alpha I
, I
3 I
beta I
- I

dihydroxyoleane I
- I
12 I
- I
ene I
- I
28 I
- I
oic I
acid I
) O
, O
betulin B
and O
lupeol B
. O

Vasodilatory O
effects O
of O
cinnamic B
acid I
via O
the O
nitric B
oxide I
- O
cGMP B
- O
PKG O
pathway O
in O
rat O
thoracic O
aorta O
. O

Cinnamic B
acid I
( O
CA O
) O
and O
its O
derivatives O
have O
a O
broad O
therapeutic O
spectrum O
that O
includes O
antimicrobial O
, O
antifungal O
, O
and O
antitumoral O
activities O
. O

However O
, O
the O
vasodilative O
effect O
of O
CA O
has O
not O
been O
demonstrated O
. O

The O
present O
study O
characterizes O
the O
vasodilative O
activity O
and O
the O
mechanism O
of O
CA O
in O
rat O
thoracic O
aorta O
. O

The O
vasomotion O
of O
aortic O
strips O
following O
CA O
treatment O
was O
measured O
in O
an O
organ O
bath O
system O
. O

In O
addition O
, O
vascular O
strips O
and O
human O
umbilical O
vein O
endothelial O
cells O
( O
HUVECs O
) O
were O
used O
in O
organ O
bath O
, O
Western O
blot O
, O
nitrite B
, O
and O
cyclic B
guanosine I
monophosphate I
( O
cGMP B
) O
measurements O
. O

CA O
relaxed O
phenylephrine B
- O
precontracted O
aortic O
strips O
in O
an O
endothelium O
- O
dependent O
manner O
. O

Pretreatment O
of O
the O
endothelium O
- O
intact O
aortic O
strips O
with O
N B
( I
G I
) I
- I
nitro I
- I
l I
- I
arginine I
methyl I
ester I
( O
10 O
( O
- O
4 O
) O
M O
) O
, O
1 B
H I
- I
[ I
1 I
, I
2 I
, I
4 I
] I
- I
oxadiazolole I
- I
[ I
4 I
, I
3 I
- I
a I
] I
quinoxalin I
- I
10 I
- I
one I
, O
( O
10 O
( O
- O
6 O
) O
M O
) O
and O
methylene B
blue I
( O
10 O
( O
- O
5 O
) O
M O
) O
inhibited O
CA B
- O
induced O
vasorelaxation O
. O

CA O
also O
increased O
the O
phosphorylation O
of O
endothelial O
nitric B
oxide I
synthase O
and O
nitric B
oxide I
generation O
in O
a O
concentration O
- O
dependent O
manner O
in O
HUVECs O
. O

In O
addition O
, O
cGMP B
generation O
and O
cGMP B
- O
dependent O
protein O
kinase O
G O
( O
PKG O
) O
expression O
in O
aortic O
strips O
were O
increased O
by O
CA B
treatment O
. O

Furthermore O
, O
CA B
- O
induced O
vasorelaxation O
was O
inhibited O
by O
the O
PKG O
inhibitor O
KT5823 B
( O
0 O
. O
3 O
mu O
M O
) O
and O
the O
Ca B
( I
2 I
+ I
) I
- O
activated O
K B
( I
+ I
) I
channel O
inhibitor O
tetraethylammonium B
( O
10 O
( O
- O
3 O
) O
M O
) O
. O

These O
findings O
suggest O
that O
CA O
exerts O
an O
endothelium O
- O
dependent O
vasodilation O
effect O
via O
the O
nitric B
oxide I
- O
cGMP B
- O
PKG O
- O
mediated O
pathway O
in O
rat O
thoracic O
aorta O
. O

The O
role O
of O
inflammation O
in O
epileptogenesis O
. O

One O
compelling O
challenge O
in O
the O
therapy O
of O
epilepsy O
is O
to O
develop O
anti O
- O
epileptogenic O
drugs O
with O
an O
impact O
on O
the O
disease O
progression O
. O

The O
search O
for O
novel O
targets O
has O
focused O
recently O
on O
brain O
inflammation O
since O
this O
phenomenon O
appears O
to O
be O
an O
integral O
part O
of O
the O
diseased O
hyperexcitable O
brain O
tissue O
from O
which O
spontaneous O
and O
recurrent O
seizures O
originate O
. O

Although O
the O
contribution O
of O
specific O
proinflammatory O
pathways O
to O
the O
mechanism O
of O
ictogenesis O
in O
epileptic O
tissue O
has O
been O
demonstrated O
in O
experimental O
models O
, O
the O
role O
of O
these O
pathways O
in O
epileptogenesis O
is O
still O
under O
evaluation O
. O

We O
review O
the O
evidence O
conceptually O
supporting O
the O
involvement O
of O
brain O
inflammation O
and O
the O
associated O
blood O
- O
brain O
barrier O
damage O
in O
epileptogenesis O
, O
and O
describe O
the O
available O
pharmacological O
evidence O
where O
post O
- O
injury O
intervention O
with O
anti O
- O
inflammatory O
drugs O
has O
been O
attempted O
. O

Our O
review O
will O
focus O
on O
three O
main O
inflammatory O
pathways O
, O
namely O
the O
IL O
- O
1 O
receptor O
/ O
Toll O
- O
like O
receptor O
signaling O
, O
COX O
- O
2 O
and O
the O
TGF O
- O
beta O
signaling O
. O

The O
mechanisms O
underlying O
neuronal O
- O
glia O
network O
dysfunctions O
induced O
by O
brain O
inflammation O
are O
also O
discussed O
, O
highlighting O
novel O
neuromodulatory O
effects O
of O
classical O
inflammatory O
mediators O
such O
as O
cytokines O
and O
prostaglandins B
. O

The O
increase O
in O
knowledge O
about O
a O
role O
of O
inflammation O
in O
disease O
progression O
, O
may O
prompt O
the O
use O
of O
specific O
anti O
- O
inflammatory O
drugs O
for O
developing O
disease O
- O
modifying O
treatments O
. O

This O
article O
is O
part O
of O
the O
Special O
Issue O
entitled O
' O
New O
Targets O
and O
Approaches O
to O
the O
Treatment O
of O
Epilepsy O
' O
. O

Modulation O
of O
pyramidal O
cell O
output O
in O
the O
medial O
prefrontal O
cortex O
by O
mGluR5 O
interacting O
with O
CB1 O
. O

The O
medial O
prefrontal O
cortex O
( O
mPFC O
) O
serves O
executive O
cognitive O
functions O
such O
as O
decision O
- O
making O
that O
are O
impaired O
in O
neuropsychiatric O
disorders O
and O
pain O
. O

We O
showed O
previously O
that O
amygdala O
- O
driven O
abnormal O
inhibition O
and O
decreased O
output O
of O
mPFC O
pyramidal O
cells O
contribute O
to O
pain O
- O
related O
impaired O
decision O
- O
making O
( O
Ji O
et O
al O
. O
, O
2010 O
) O
. O

Therefore O
, O
modulating O
pyramidal O
output O
is O
desirable O
therapeutic O
goal O
. O

Targeting O
metabotropic O
glutamate B
receptor O
subtype O
mGluR5 O
has O
emerged O
as O
a O
cognitive O
- O
enhancing O
strategy O
in O
neuropsychiatric O
disorders O
, O
but O
synaptic O
and O
cellular O
actions O
of O
mGluR5 O
in O
the O
mPFC O
remain O
to O
be O
determined O
. O

The O
present O
study O
determined O
synaptic O
and O
cellular O
actions O
of O
mGluR5 O
to O
test O
the O
hypothesis O
that O
increasing O
mGluR5 O
function O
can O
enhance O
pyramidal O
cell O
output O
. O

Whole O
- O
cell O
voltage O
- O
and O
current O
- O
clamp O
recordings O
were O
made O
from O
visually O
identified O
pyramidal O
neurons O
in O
layer O
V O
of O
the O
mPFC O
in O
rat O
brain O
slices O
. O

Both O
the O
prototypical O
mGluR5 O
agonist O
CHPG B
and O
a O
positive O
allosteric O
modulator O
( O
PAM O
) O
for O
mGluR5 O
( O
VU0360172 B
) O
increased O
synaptically O
evoked O
spiking O
( O
E O
- O
S O
coupling O
) O
in O
mPFC O
pyramidal O
cells O
. O

The O
facilitatory O
effects O
of O
CHPG B
and O
VU0360172 B
were O
inhibited O
by O
an O
mGluR5 O
antagonist O
( O
MTEP B
) O
. O

CHPG B
, O
but O
not O
VU0360172 B
, O
increased O
neuronal O
excitability O
( O
frequency O
- O
current O
[ O
F O
- O
I O
] O
function O
) O
. O

VU0360172 B
, O
but O
not O
CHPG B
, O
increased O
evoked O
excitatory O
synaptic O
currents O
( O
EPSCs O
) O
and O
amplitude O
, O
but O
not O
frequency O
, O
of O
miniature O
EPSCs O
, O
indicating O
a O
postsynaptic O
action O
. O

VU0360172 B
, O
but O
not O
CHPG B
, O
decreased O
evoked O
inhibitory O
synaptic O
currents O
( O
IPSCs O
) O
through O
an O
action O
that O
involved O
cannabinoid O
receptor O
CB1 O
, O
because O
a O
CB1 O
receptor O
antagonist O
( O
AM281 B
) O
blocked O
the O
inhibitory O
effect O
of O
VU0360172 B
on O
synaptic O
inhibition O
. O

VU0360172 B
also O
increased O
and O
prolonged O
CB1 O
- O
mediated O
depolarization O
- O
induced O
suppression O
of O
synaptic O
inhibition O
( O
DSI O
) O
. O

Activation O
of O
CB1 O
with O
ACEA O
decreased O
inhibitory O
transmission O
through O
a O
presynaptic O
mechanism O
. O

The O
results O
show O
that O
increasing O
mGluR5 O
function O
enhances O
mPFC O
output O
. O

This O
effect O
can O
be O
accomplished O
by O
increasing O
excitability O
with O
an O
orthosteric O
agonist O
( O
CHPG B
) O
or O
by O
increasing O
excitatory O
synaptic O
drive O
and O
CB1 O
- O
mediated O
presynaptic O
suppression O
of O
synaptic O
inhibition O
( O
" O
dis O
- O
inhibition O
" O
) O
with O
a O
PAM O
( O
VU0360172 B
) O
. O

Therefore O
, O
mGluR5 O
may O
be O
a O
useful O
target O
in O
conditions O
of O
impaired O
mPFC O
output O
. O

This O
article O
is O
part O
of O
a O
Special O
Issue O
entitled O
' O
Metabotropic O
Glutamate B
Receptors O
' O
. O

Stratified O
medicine O
in O
psychiatry O
: O
a O
worrying O
example O
or O
new O
opportunity O
in O
the O
treatment O
of O
anxiety O
? O

Stratified O
medicine O
is O
a O
new O
term O
that O
figures O
highly O
in O
current O
MRC O
and O
NHS O
strategy O
. O

It O
has O
developed O
from O
the O
earlier O
terms O
individualised O
or O
personalised O
medicine O
and O
refers O
to O
the O
use O
of O
genetic O
and O
/ O
or O
endophenotypic O
measures O
to O
allow O
better O
targeting O
of O
treatments O
. O

The O
best O
exemplar O
is O
HER2 O
positivity O
in O
breast O
cancer O
to O
determine O
the O
efficacy O
of O
Herceptin O
. O

Clinical O
trials O
of O
this O
anti O
- O
cancer O
drug O
were O
initially O
unpromising O
, O
but O
once O
the O
HER2 O
positive O
subgroup O
was O
identified O
it O
was O
found O
, O
in O
this O
subgroup O
only O
, O
to O
be O
highly O
effective O
. O

It O
is O
presumed O
that O
similar O
subgroups O
will O
be O
found O
for O
many O
common O
disorders O
not O
just O
cancers O
, O
and O
that O
these O
will O
lead O
to O
much O
better O
targeted O
treatments O
. O

Such O
an O
advance O
may O
be O
necessary O
to O
develop O
new O
treatments O
in O
certain O
fields O
where O
the O
development O
of O
broad O
- O
spectrum O
/ O
blockbuster O
treatments O
appears O
to O
have O
reached O
the O
end O
of O
the O
road O
; O
a O
particular O
example O
of O
this O
is O
in O
psychiatry O
. O

In O
this O
paper O
we O
discuss O
this O
issue O
in O
relation O
to O
psychiatry O
using O
a O
new O
and O
interesting O
example O
of O
how O
genotyping O
might O
help O
rescue O
an O
apparently O
failed O
novel O
treatment O
in O
anxiety O
disorders O
. O

Extracts O
of O
Scutellaria O
baicalensis O
reduced O
body O
weight O
and O
blood O
triglyceride B
in O
db O
/ O
db O
Mice O
. O

Scutellaria O
baicalensis O
has O
been O
extensively O
employed O
for O
the O
clinical O
treatment O
of O
hyperlipidemia O
, O
atherosclerosis O
, O
hypertension O
, O
dysentery O
, O
inflammatory O
diseases O
, O
and O
the O
common O
cold O
. O

The O
present O
study O
was O
performed O
to O
investigate O
the O
anti O
- O
obesity O
and O
anti O
- O
dyslipidemia O
effect O
of O
Scutellaria O
baicalensis O
extracts O
( O
SBE O
) O
in O
type O
2 O
diabetic O
db O
/ O
db O
mice O
. O

Male O
db O
/ O
db O
mice O
were O
divided O
into O
three O
groups O
( O
n O
= O
5 O
) O
and O
orally O
administrated O
vehicle O
( O
control O
) O
, O
SBE O
10 O
, O
and O
100 O
mg O
/ O
kg O
body O
weight O
/ O
day O
for O
4 O
weeks O
everyday O
. O

Administration O
of O
SBE O
improves O
weight O
gain O
, O
hypertriglyceridemia O
, O
and O
hyperinsulinemia O
in O
db O
/ O
db O
mice O
. O

In O
obese O
db O
/ O
db O
mice O
, O
SBE O
treatment O
also O
reduced O
plasma O
alanine B
aminotransferase O
levels O
. O

In O
the O
livers O
of O
db O
/ O
db O
mice O
, O
SBE O
promoted O
5 B
' I
AMP I
- O
activated O
protein O
kinase O
activity O
and O
restored O
metabolic O
process O
and O
insulin O
signaling O
pathways O
. O

Our O
data O
demonstrate O
that O
SBE O
exerts O
potent O
anti O
- O
obesity O
and O
anti O
- O
hypertriglyceride O
effects O
suggesting O
its O
useful O
potential O
function O
as O
adjuvant O
therapeutic O
agent O
for O
the O
treatment O
of O
weight O
gain O
and O
hypertriglyceridemia O
. O

A O
new O
lignan B
with O
anti O
- O
tumour O
activity O
from O
Polygonum O
perfoliatum O
L O
. O

The O
methanol B
extract O
of O
the O
tubers O
of O
Polygonum O
perfoliatum O
L O
. O
afforded O
a O
new O
lignan B
: O
8 B
- I
oxo I
- I
pinoresinol I
( O
1 O
) O
, O
and O
five O
known O
compounds O
3 B
' I
, I
5 I
- I
dihydroxy I
- I
3 I
, I
4 I
' I
, I
5 I
' I
, I
7 I
- I
tetramethoxy I
- I
flavone I
( O
2 O
) O
, O
catechin B
( O
3 O
) O
, O
quercetin B
( O
4 O
) O
, O
quercetin B
- I
3 I
- I
O I
- I
beta I
- I
D I
- I
glucuronide I
( O
5 O
) O
and O
rutin B
( O
6 O
) O
. O

Their O
structures O
were O
established O
by O
MS O
, O
one O
- O
and O
two O
- O
dimensional O
NMR O
experiments O
. O

Compound O
1 O
showed O
cytotoxicity O
against O
human O
mammary O
carcinoma O
( O
Bcap O
- O
37 O
) O
, O
human O
colon O
carcinoma O
( O
RKO O
) O
, O
human O
hepatocellular O
carcinoma O
( O
SMMC O
- O
7721 O
) O
, O
human O
prostate O
carcinoma O
( O
PC3 O
) O
and O
human O
erythroleukaemia O
( O
K562 O
) O
cells O
. O

Tonic O
GABA B
( O
A O
) O
receptor O
- O
mediated O
signalling O
in O
temporal O
lobe O
epilepsy O
. O

The O
tonic O
activation O
of O
extrasynaptic O
GABAA O
receptors O
by O
extracellular O
GABA B
provides O
a O
powerful O
means O
of O
regulating O
neuronal O
excitability O
. O

A O
consistent O
finding O
from O
studies O
that O
have O
used O
various O
models O
of O
temporal O
lobe O
epilepsy O
is O
that O
tonic O
GABAA O
receptor O
- O
mediated O
conductances O
are O
largely O
preserved O
in O
epileptic O
brain O
( O
in O
contrast O
to O
synaptic O
inhibition O
which O
is O
often O
reduced O
) O
. O

Tonic O
inhibition O
is O
therefore O
an O
attractive O
target O
for O
antiepileptic O
drugs O
. O

However O
, O
the O
network O
consequences O
of O
a O
commonly O
used O
approach O
to O
augment O
tonic O
GABAA O
receptor O
- O
mediated O
conductances O
by O
global O
manipulation O
of O
extracellular O
GABA B
are O
difficult O
to O
predict O
without O
understanding O
how O
epileptogenesis O
alters O
the O
pharmacology O
and O
GABA B
sensitivity O
of O
tonic O
inhibition O
, O
and O
how O
manipulation O
of O
tonic O
conductances O
modulates O
the O
output O
of O
individual O
neurons O
. O

Here O
we O
review O
the O
current O
literature O
on O
epilepsy O
- O
associated O
changes O
in O
tonic O
GABAA O
receptor O
- O
mediated O
signalling O
, O
and O
speculate O
about O
possible O
effects O
they O
have O
at O
the O
network O
level O
. O

This O
article O
is O
part O
of O
the O
Special O
Issue O
entitled O
' O
New O
Targets O
and O
Approaches O
to O
the O
Treatment O
of O
Epilepsy O
' O
. O

Metabotropic O
glutamate B
7 O
( O
mGlu7 O
) O
receptor O
: O
a O
target O
for O
medication O
development O
for O
the O
treatment O
of O
cocaine B
dependence O
. O

Brain O
glutamate B
has O
been O
shown O
to O
play O
an O
important O
role O
in O
reinstatement O
to O
drug O
seeking O
, O
a O
behavior O
considered O
to O
be O
of O
relevance O
to O
relapse O
to O
drug O
taking O
in O
humans O
. O

Therefore O
, O
glutamate B
receptors O
, O
in O
particular O
metabotropic O
glutamate B
( O
mGlu O
) O
receptors O
, O
have O
become O
important O
targets O
for O
medication O
development O
for O
the O
treatment O
of O
drug O
dependence O
. O

In O
this O
review O
article O
, O
we O
focus O
on O
the O
mGlu7 O
receptor O
subtype O
, O
and O
discuss O
recent O
findings O
with O
AMN082 B
, O
a O
selective O
mGlu7 O
receptor O
allosteric O
agonist O
, O
in O
animal O
models O
with O
relevance O
to O
drug O
dependence O
. O

Systemic O
or O
local O
administration O
of O
AMN082 B
into O
the O
nucleus O
accumbens O
( O
NAc O
) O
, O
a O
critical O
brain O
region O
involved O
in O
reward O
and O
drug O
dependence O
processes O
, O
inhibited O
the O
reinforcing O
and O
motivational O
effects O
of O
cocaine B
, O
heroin B
and O
ethanol B
, O
as O
assessed O
by O
the O
intravenous O
drug O
self O
- O
administration O
procedure O
. O

In O
addition O
, O
AMN082 B
inhibited O
the O
reward O
- O
enhancing O
effects O
induced O
by O
cocaine B
, O
as O
assessed O
in O
the O
intracranial O
self O
- O
stimulation O
procedure O
, O
and O
cocaine B
- O
or O
cue O
- O
induced O
reinstatement O
of O
drug O
- O
seeking O
behavior O
. O

In O
vivo O
microdialysis O
studies O
indicated O
that O
systemic O
or O
intra O
- O
NAc O
administration O
of O
AMN082 B
significantly O
decreased O
extracellular O
gamma B
- I
aminobutyric I
acid I
( O
GABA B
) O
and O
elevated O
extracellular O
glutamate B
, O
but O
had O
no O
effect O
on O
extracellular O
dopamine B
in O
the O
NAc O
, O
suggesting O
that O
a O
non O
- O
dopaminergic O
mechanism O
underlies O
the O
effects O
of O
AMN082 B
on O
the O
actions O
of O
cocaine B
. O

Further O
, O
data O
indicated O
that O
AMN082 B
- O
induced O
changes O
in O
glutamate B
were O
the O
net O
effect O
of O
two O
actions O
: O
one O
is O
the O
direct O
inhibition O
of O
glutamate B
release O
by O
activation O
of O
mGlu7 O
receptors O
on O
glutamatergic O
neurons O
; O
another O
is O
the O
indirect O
increases O
of O
glutamate B
release O
mediated O
by O
decreases O
in O
GABA B
transmission O
. O

These O
increases O
in O
extracellular O
glutamate B
functionally O
antagonized O
cocaine B
- O
induced O
inhibition O
of O
NAc O
- O
ventral O
pallidum O
GABAergic O
neurotransmission O
, O
and O
therefore O
, O
the O
rewarding O
effects O
of O
cocaine B
. O

In O
addition O
, O
elevated O
extracellular O
glutamate B
activated O
presynaptic O
mGlu2 O
/ O
3 O
autoreceptors O
which O
in O
turn O
inhibited O
cocaine B
priming O
- O
or O
cue O
- O
induced O
enhancement O
of O
glutamate B
release O
and O
reinstatement O
of O
drug O
- O
seeking O
behavior O
. O

Taken O
together O
, O
these O
findings O
suggest O
that O
the O
mGlu7 O
receptor O
is O
an O
important O
target O
for O
medication O
development O
for O
the O
treatment O
of O
drug O
dependence O
. O

AMN082 B
or O
other O
mGlu7 O
receptor O
allosteric O
agonists O
may O
have O
potential O
as O
novel O
pharmacotherapies O
for O
cocaine B
addiction O
. O

This O
article O
is O
part O
of O
a O
Special O
Issue O
entitled O
' O
Metabotropic O
Glutamate B
Receptors O
' O
. O

The O
synergistic O
apoptotic O
interaction O
of O
panaxadiol B
and O
epigallocatechin B
gallate I
in O
human O
colorectal O
cancer O
cells O
. O

Panaxadiol B
( O
PD O
) O
is O
a O
purified O
sapogenin O
of O
ginseng O
saponins B
, O
which O
exhibits O
anticancer O
activity O
. O

Epigallocatechin B
gallate I
( O
EGCG B
) O
, O
a O
major O
catechin B
in O
green O
tea O
, O
is O
a O
strong O
botanical O
antioxidant O
. O

In O
this O
study O
, O
we O
investigated O
the O
possible O
synergistic O
anticancer O
effects O
of O
PD O
and O
EGCG B
on O
human O
colorectal O
cancer O
cells O
and O
explored O
the O
potential O
role O
of O
apoptosis O
in O
the O
synergistic O
activities O
. O

Effects O
of O
selected O
compounds O
on O
HCT O
- O
116 O
and O
SW O
- O
480 O
human O
colorectal O
cancer O
cells O
were O
evaluated O
by O
a O
modified O
trichrome O
stain O
cell O
proliferation O
analysis O
. O

Cell O
cycle O
distribution O
and O
apoptotic O
effects O
were O
analyzed O
by O
flow O
cytometry O
after O
staining O
with O
PI O
/ O
RNase O
or O
annexin O
V O
/ O
PI O
. O

Cell O
growth O
was O
suppressed O
after O
treatment O
with O
PD B
( O
10 O
and O
20 O
micro O
m O
) O
for O
48 O
h O
. O

When O
PD O
( O
10 O
and O
20 O
micro O
m O
) O
was O
combined O
with O
EGCG B
( O
10 O
, O
20 O
, O
and O
30 O
micro O
m O
) O
, O
significantly O
enhanced O
antiproliferative O
effects O
were O
observed O
in O
both O
cell O
lines O
. O

Combining O
20 O
micro O
m O
of O
PD O
with O
20 O
and O
30 O
micro O
m O
of O
EGCG B
significantly O
decreased O
S O
- O
phase O
fractions O
of O
cells O
. O

In O
the O
apoptotic O
assay O
, O
the O
combination O
of O
PD O
and O
EGCG B
significantly O
increased O
the O
percentage O
of O
apoptotic O
cells O
compared O
with O
PD O
alone O
( O
p O
< O
0 O
. O
01 O
) O
. O

The O
synergistic O
apoptotic O
effects O
were O
also O
supported O
by O
docking O
analysis O
, O
which O
demonstrated O
that O
PD O
and O
EGCG B
bound O
in O
two O
different O
sites O
of O
the O
annexin O
V O
protein O
. O

Data O
from O
this O
study O
suggested O
that O
apoptosis O
might O
play O
an O
important O
role O
in O
the O
EGCG B
- O
enhanced O
antiproliferative O
effects O
of O
PD O
on O
human O
colorectal O
cancer O
cells O
. O

HPLC O
analysis O
of O
Stephania O
rotunda O
extracts O
and O
correlation O
with O
antiplasmodial O
activity O
. O

Stephania O
rotunda O
( O
Menispermaceae O
) O
, O
a O
creeper O
commonly O
found O
in O
the O
mountainous O
areas O
of O
Cambodia O
, O
has O
been O
mainly O
used O
for O
the O
treatment O
of O
fever O
and O
malaria O
. O

Thus O
, O
the O
aim O
of O
this O
study O
is O
to O
investigate O
the O
chemical O
composition O
and O
antiplasmodial O
activity O
of O
different O
samples O
of O
S O
. O
rotunda O
and O
compare O
their O
antiplasmodial O
activity O
with O
their O
alkaloid O
content O
. O

Sixteen O
samples O
from O
different O
parts O
( O
roots O
, O
stem O
, O
and O
tuber O
) O
of O
S O
. O
rotunda O
were O
collected O
from O
four O
regions O
of O
Cambodia O
( O
Battambang O
, O
Pailin O
, O
Siem O
Reap O
, O
and O
Kampot O
) O
. O

Reversed O
- O
phase O
HPLC O
was O
used O
to O
determine O
the O
content O
of O
three O
bioactive O
alkaloids O
( O
cepharanthine B
, O
tetrahydropalmatine B
, O
and O
xylopinine B
) O
. O

These O
three O
alkaloids O
have O
been O
found O
in O
all O
samples O
from O
Battambang O
and O
Pailin O
( O
samples O
I O
- O
IX O
) O
, O
whereas O
only O
tetrahydropalmatine B
was O
present O
in O
samples O
from O
Siem O
Reap O
and O
Kampot O
( O
samples O
X O
- O
XVI O
) O
. O

The O
analyzed O
extracts O
were O
evaluated O
for O
their O
antiplasmodial O
activity O
on O
W2 O
strain O
of O
Plasmodium O
falciparum O
. O

Among O
them O
, O
13 O
extracts O
were O
significantly O
active O
with O
inhibitory O
concentration O
50 O
( O
IC O
( O
50 O
) O
) O
from O
1 O
. O
2 O
to O
3 O
. O
7 O
micro O
g O
/ O
mL O
and O
2 O
extracts O
were O
moderately O
active O
( O
IC O
( O
50 O
) O
= O
6 O
. O
1 O
and O
10 O
micro O
g O
/ O
mL O
, O
respectively O
) O
, O
whereas O
sample O
XI O
was O
not O
active O
( O
IC O
( O
50 O
) O
= O
19 O
. O
6 O
micro O
g O
/ O
mL O
) O
. O

A O
comparison O
between O
antiplasmodial O
activity O
and O
concentration O
of O
the O
three O
bioactive O
alkaloids O
in O
S O
. O
rotunda O
extracts O
has O
been O
realized O
. O

Preventive O
effects O
of O
North O
American O
ginseng O
( O
Panax O
quinquefolius O
) O
on O
diabetic O
retinopathy O
and O
cardiomyopathy O
. O

Ginseng O
( O
Araliaceae O
) O
has O
multiple O
pharmacological O
actions O
because O
of O
its O
diverse O
phytochemical O
constituents O
. O

The O
aims O
of O
the O
present O
study O
are O
to O
evaluate O
the O
preventive O
effects O
of O
North O
American O
ginseng O
on O
diabetic O
retinopathy O
and O
cardiomyopathy O
and O
to O
delineate O
the O
underlying O
mechanisms O
of O
such O
effects O
. O

Models O
of O
both O
type O
1 O
( O
C57BL O
/ O
6 O
mice O
with O
streptozotocin B
- O
induced O
diabetes O
) O
and O
type O
2 O
diabetes O
( O
db O
/ O
db O
mice O
) O
and O
age O
- O
matched O
and O
sex O
- O
matched O
controls O
were O
examined O
. O

Alcoholic O
ginseng O
root O
( O
200 O
mg O
/ O
kg O
body O
weight O
, O
daily O
oral O
gavage O
) O
extract O
was O
administered O
to O
groups O
of O
both O
type O
1 O
and O
type O
2 O
diabetic O
mice O
for O
2 O
or O
4 O
months O
. O

Dysmetabolic O
state O
in O
the O
diabetic O
mice O
was O
significantly O
improved O
by O
ginseng O
treatment O
. O

In O
both O
the O
heart O
and O
retina O
of O
diabetic O
animals O
, O
ginseng O
treatment O
significantly O
prevented O
oxidative O
stress O
and O
diabetes O
- O
induced O
upregulations O
of O
extracellular O
matrix O
proteins O
and O
vasoactive O
factors O
. O

Ginseng O
treatment O
in O
the O
diabetic O
animals O
resulted O
in O
enhancement O
of O
stroke O
volume O
, O
ejection O
fraction O
, O
cardiac O
output O
, O
and O
left O
ventricle O
pressure O
during O
systole O
and O
diastole O
and O
diminution O
of O
stroke O
work O
. O

In O
addition O
, O
mRNA O
expressions O
of O
atrial O
natriuretic O
factor O
and O
brain O
natriuretic O
factor O
( O
molecular O
markers O
for O
cardiac O
hypertrophy O
) O
were O
significantly O
diminished O
in O
ginseng O
- O
treated O
diabetic O
mice O
. O

These O
data O
indicate O
that O
North O
American O
ginseng O
prevents O
the O
diabetes O
- O
induced O
retinal B
and O
cardiac O
biochemical O
and O
functional O
changes O
probably O
through O
inhibition O
of O
oxidative O
stress O
. O

Evaluation O
of O
food O
- O
drug O
interaction O
of O
guava O
leaf O
tea O
. O

Guava O
leaf O
tea O
( O
GLT O
) O
contains O
guava O
leaf O
polyphenol B
( O
Gvpp O
) O
, O
which O
regulates O
the O
absorption O
of O
dietary O
carbohydrate B
from O
the O
intestines O
. O

Borderline O
diabetics O
, O
who O
are O
at O
high O
risk O
of O
development O
of O
diabetes O
, O
take O
GLT O
to O
suppress O
a O
rapid O
increase O
of O
blood O
sugar B
level O
after O
meals O
. O

However O
, O
patients O
with O
diabetes O
in O
whom O
diabetic O
drugs O
or O
warfarin B
as O
a O
blood O
thinner O
are O
prescribed O
also O
take O
GLT O
with O
the O
expectation O
of O
glycemic O
control O
. O

Therefore O
, O
we O
studied O
whether O
GLT O
had O
potential O
for O
inhibition O
or O
induction O
of O
cytochrome O
P450 O
( O
CYP O
) O
and O
an O
influence O
on O
the O
action O
of O
warfarin B
. O

Extract O
of O
guava O
leaf O
( O
GvEx O
) O
consists O
of O
carbohydrate B
and O
polyphenols B
, O
which O
are O
Gvpp O
, O
quercetin B
, O
and O
ellagic B
acid I
. O

These O
polyphenols B
, O
but O
not O
GvEx O
, O
showed O
a O
certain O
level O
of O
inhibition O
of O
human O
- O
cDNA O
- O
expressed O
CYPs O
. O

In O
a O
comparison O
of O
GLT O
and O
grapefruit O
juice O
, O
GLT O
showed O
weaker O
inhibition O
of O
CYP O
activities O
and O
of O
midazolam B
1 O
' O
- O
hydroxylation O
than O
grapefruit O
juice O
. O

Furthermore O
, O
neither O
liver O
weight O
nor O
CYP3A O
expression O
in O
the O
liver O
was O
changed O
in O
rats O
that O
received O
GvEx O
for O
90 O
days O
compared O
with O
the O
control O
group O
. O

When O
rats O
were O
concomitantly O
treated O
with O
GLT O
and O
warfarin B
, O
the O
prolongation O
of O
clotting O
time O
of O
blood O
by O
warfarin B
was O
not O
influenced O
. O

These O
data O
suggest O
that O
GLT O
is O
unlikely O
to O
interact O
with O
drugs O
. O

A O
new O
phenylethanoid B
glucoside I
from O
Plantago O
depressa O
Willd O
. O

Chemical O
research O
of O
Plantago O
depressa O
Willd O
. O
led O
to O
one O
new O
phenylethanoid B
glucoside I
with O
alpha B
- I
L I
- I
rhamnosyl I
( I
1 I
- I
- I
> I
2 I
) I
- I
beta I
- I
D I
- I
glucose I
structure O
, O
together O
with O
four O
known O
compounds O
. O

These O
five O
compounds O
( O
1 O
- O
5 O
) O
were O
isolated O
from O
the O
family O
Plantaginaceae O
for O
the O
first O
time O
; O
the O
chemotaxonomic O
significance O
of O
cerebrosides O
was O
also O
discussed O
. O

Chemical O
composition O
of O
essential O
oil O
from O
Calligonum O
polygonoides O
Linn O
. O

The O
essential O
oil O
from O
air O
dried O
buds O
and O
roots O
of O
Calligonum O
polygonoides O
Linn O
. O
, O
has O
been O
extracted O
from O
dry O
steam O
distillation O
and O
analysed O
for O
chemical O
composition O
by O
gas O
chromatography O
- O
mass O
spectrometry O
. O

In O
total O
, O
27 O
and O
10 O
compounds O
were O
analysed O
qualitatively O
and O
quantitatively O
, O
accounting O
for O
68 O
. O
42 O
% O
and O
82 O
. O
12 O
% O
total O
contents O
of O
the O
essential O
oils O
of O
buds O
and O
roots O
, O
respectively O
. O

It O
contains O
a O
complex O
mixture O
of O
terpenoids B
, O
hydrocarbons B
, O
phenolic B
compounds O
, O
acid O
derivatives O
and O
ketones B
. O

The O
main O
component O
of O
essential O
oil O
was O
ethyl B
homovanillate I
( O
11 O
. O
79 O
% O
) O
in O
buds O
and O
drimenol B
( O
29 O
. O
42 O
% O
) O
in O
roots O
. O

The O
effects O
of O
temperature O
and O
salinity O
on O
17 B
- I
alpha I
- I
ethynylestradiol I
uptake O
and O
its O
relationship O
to O
oxygen B
consumption O
in O
the O
model O
euryhaline O
teleost O
( O
Fundulus O
heteroclitus O
) O
. O

The O
synthetic O
estrogen B
17 B
- I
alpha I
- I
ethynylestradiol I
( O
EE2 B
) O
, O
a O
component O
of O
birth O
control O
and O
hormone O
replacement O
therapy O
, O
is O
discharged O
into O
the O
environment O
via O
wastewater O
treatment O
plant O
( O
WWTP O
) O
effluents O
. O

The O
present O
study O
employed O
radiolabeled O
EE2 B
to O
examine O
impacts O
of O
temperature O
and O
salinity O
on O
EE2 B
uptake O
in O
male O
killifish O
( O
Fundulus O
heteroclitus O
) O
. O

Fish O
were O
exposed O
to O
a O
nominal O
concentration O
of O
100ng O
/ O
L O
EE2 B
for O
2h O
. O

The O
rate O
of O
EE2 B
uptake O
was O
constant O
over O
the O
2h O
period O
. O

Oxygen B
consumption O
rates O
( O
MO B
( I
2 I
) I
) O
, O
whole O
body O
uptake O
rates O
, O
and O
tissue O
- O
specific O
EE2 B
distribution O
were O
determined O
. O

In O
killifish O
acclimated O
to O
18 O
degrees O
C O
at O
16ppt O
( O
50 O
% O
sea O
water O
) O
, O
MO B
( I
2 I
) I
and O
EE2 B
uptake O
were O
both O
lower O
after O
24h O
exposure O
to O
10 O
degrees O
C O
and O
4 O
degrees O
C O
, O
and O
increased O
after O
24h O
exposure O
to O
26 O
degrees O
C O
. O

Transfer O
to O
fresh O
water O
( O
FW O
) O
for O
24h O
lowered O
EE2 B
uptake O
rate O
, O
and O
long O
- O
term O
acclimation O
to O
fresh O
water O
reduced O
it O
by O
70 O
% O
. O

Both O
long O
- O
term O
acclimation O
to O
100 O
% O
sea O
water O
( O
32ppt O
) O
and O
a O
24h O
transfer O
to O
100 O
% O
sea O
water O
also O
reduced O
EE2 B
uptake O
rate O
by O
50 O
% O
relative O
to O
16ppt O
. O

Tissue O
- O
specific O
accumulation O
of O
EE2 B
was O
highest O
( O
40 O
- O
60 O
% O
of O
the O
total O
) O
in O
the O
liver O
plus O
gall O
bladder O
across O
all O
exposures O
, O
and O
the O
vast O
majority O
of O
this O
was O
in O
the O
bile O
at O
2h O
, O
regardless O
of O
temperature O
or O
salinity O
. O

The O
carcass O
was O
the O
next O
highest O
accumulator O
( O
30 O
- O
40 O
% O
) O
, O
followed O
by O
the O
gut O
( O
10 O
- O
20 O
% O
) O
with O
only O
small O
amounts O
in O
gill O
and O
spleen O
. O

Killifish O
chronically O
exposed O
( O
15 O
days O
) O
to O
100ng O
/ O
L O
EE2 B
displayed O
no O
difference O
in O
EE2 B
uptake O
rate O
or O
tissue O
- O
specific O
distribution O
. O

Drinking O
rate O
, O
measured O
with O
radiolabeled O
polyethylene B
glycol I
- I
4000 I
, O
was O
about O
25 O
times O
greater O
in O
16ppt O
- O
acclimated O
killifish O
relative O
to O
FW O
- O
acclimated O
animals O
. O

However O
, O
drinking O
accounted O
for O
less O
than O
30 O
% O
of O
gut O
accumulation O
, O
and O
therefore O
a O
negligible O
percentage O
of O
whole O
body O
EE2 B
uptake O
rates O
. O

In O
general O
, O
there O
were O
strong O
positive O
relationships O
between O
EE2 B
uptake O
rates O
and O
MO B
( I
2 I
) I
, O
suggesting O
similar O
uptake O
pathways O
of O
these O
lipophilic O
molecules O
across O
the O
gills O
. O

These O
data O
will O
be O
useful O
in O
developing O
a O
predictive O
model O
of O
how O
key O
environmental O
parameter O
variations O
( O
salinity O
, O
temperature O
, O
dissolved O
oxygen B
) O
affect O
EE2 B
uptake O
in O
estuarine O
fish O
, O
to O
determine O
optimal O
timing O
and O
location O
of O
WWTP O
discharges O
. O

One O
new O
antitumour O
cassane B
- O
type O
diterpene B
from O
Caesalpinia O
crista O
. O

1 B
alpha I
- I
acetoxy I
- I
5 I
alpha I
, I
7 I
beta I
- I
dihydroxycassa I
- I
11 I
, I
13 I
( I
15 I
) I
- I
diene I
- I
16 I
, I
12 I
- I
lactone I
, O
a O
new O
cassane B
- O
type O
diterpene B
was O
isolated O
from O
Caesalpinia O
crista O
. O

The O
structure O
of O
this O
compound O
was O
elucidated O
by O
analysis O
of O
NMR O
spectra O
, O
and O
the O
relative O
configuration O
was O
established O
by O
NOE O
experiment O
. O

The O
new O
compound O
was O
evaluated O
for O
antitumour O
activity O
against O
T47D O
, O
DU145 O
and O
showed O
significant O
inhibitory O
activities O
. O

MUC1 O
- O
C O
oncoprotein O
as O
a O
target O
in O
breast O
cancer O
: O
activation O
of O
signaling O
pathways O
and O
therapeutic O
approaches O
. O

Mucin O
1 O
( O
MUC1 O
) O
is O
a O
heterodimeric O
protein O
formed O
by O
two O
subunits O
that O
is O
aberrantly O
overexpressed O
in O
human O
breast O
cancer O
and O
other O
cancers O
. O

Historically O
, O
much O
of O
the O
early O
work O
on O
MUC1 O
focused O
on O
the O
shed O
mucin O
subunit O
. O

However O
, O
more O
recent O
studies O
have O
been O
directed O
at O
the O
transmembrane O
MUC1 O
- O
C B
- O
terminal O
subunit O
( O
MUC1 O
- O
C O
) O
that O
functions O
as O
an O
oncoprotein O
. O

MUC1 O
- O
C O
interacts O
with O
EGFR O
( O
epidermal O
growth O
factor O
receptor O
) O
, O
ErbB2 O
and O
other O
receptor O
tyrosine B
kinases O
at O
the O
cell O
membrane O
and O
contributes O
to O
activation O
of O
the O
PI3K O
< O
E232 O
> O
AKT O
and O
mitogen O
- O
activated O
protein O
kinase O
kinase O
( O
MEK O
) O
< O
E232 O
> O
extracellular O
signal O
- O
regulated O
kinase O
( O
ERK O
) O
pathways O
. O

MUC1 O
- O
C O
also O
localizes O
to O
the O
nucleus O
where O
it O
activates O
the O
Wnt O
/ O
beta O
- O
catenin O
, O
signal O
transducer O
and O
activator O
of O
transcription O
( O
STAT O
) O
and O
NF O
( O
nuclear O
factor O
) O
- O
kappa O
B O
RelA O
pathways O
. O

These O
findings O
and O
the O
demonstration O
that O
MUC1 O
- O
C O
is O
a O
druggable O
target O
have O
provided O
the O
experimental O
basis O
for O
designing O
agents O
that O
block O
MUC1 O
- O
C O
function O
. O

Notably O
, O
inhibitors O
of O
the O
MUC1 O
- O
C O
subunit O
have O
been O
developed O
that O
directly O
block O
its O
oncogenic O
function O
and O
induce O
death O
of O
breast O
cancer O
cells O
in O
vitro O
and O
in O
xenograft O
models O
. O

On O
the O
basis O
of O
these O
findings O
, O
a O
first O
- O
in O
- O
class O
MUC1 O
- O
C O
inhibitor O
has O
entered O
phase O
I O
evaluation O
as O
a O
potential O
agent O
for O
the O
treatment O
of O
patients O
with O
breast O
cancers O
who O
express O
this O
oncoprotein O
. O

beta B
- I
Eudesmol I
induces O
JNK O
- O
dependent O
apoptosis O
through O
the O
mitochondrial O
pathway O
in O
HL60 O
cells O
. O

beta B
- I
eudesmol I
, O
a O
natural O
sesquiterpenol B
present O
in O
a O
variety O
of O
Chinese O
herbs O
, O
is O
known O
to O
inhibit O
the O
proliferation O
of O
human O
tumor O
cells O
. O

However O
, O
the O
molecular O
mechanisms O
of O
the O
effect O
of O
beta B
- I
eudesmol I
on O
human O
tumor O
cells O
are O
unknown O
. O

In O
the O
present O
study O
, O
we O
report O
the O
cytotoxic O
effect O
of O
beta B
- I
eudesmol I
on O
the O
human O
leukemia O
HL60 O
cells O
and O
its O
molecular O
mechanisms O
. O

The O
cytotoxic O
effect O
of O
beta B
- I
eudesmol I
on O
HL60 O
cells O
was O
associated O
with O
apoptosis O
, O
which O
was O
characterized O
by O
the O
presence O
of O
DNA O
fragmentation O
. O

beta B
- I
eudesmol I
- O
induced O
apoptosis O
was O
accompanied O
by O
cleavage O
of O
caspase O
- O
3 O
, O
caspase O
- O
9 O
, O
and O
poly B
( I
ADP I
- I
ribose I
) I
polymerase O
; O
downregulation O
of O
Bcl O
- O
2 O
expression O
; O
release O
of O
cytochrome O
c O
from O
mitochondria O
; O
and O
decrease O
in O
mitochondrial O
membrane O
potential O
( O
MMP O
) O
. O

Activation O
of O
c O
- O
Jun O
N B
- O
terminal O
kinases O
( O
JNK O
) O
mitogen O
- O
activated O
protein O
kinases O
was O
observed O
in O
beta B
- I
eudesmol I
- O
treated O
HL60 O
cells O
, O
and O
the O
inhibitor O
of O
JNK O
blocked O
the O
beta B
- I
eudesmol I
- O
induced O
apoptosis O
, O
downregulation O
of O
Bcl O
- O
2 O
, O
and O
the O
loss O
of O
MMP O
. O

These O
data O
suggest O
that O
beta B
- I
eudesmol I
induces O
apoptosis O
in O
HL60 O
cells O
via O
the O
mitochondrial O
apoptotic O
pathway O
, O
which O
is O
controlled O
through O
JNK O
signaling O
. O

Copyright O
( O
c O
) O
2012 O
John O
Wiley O
& O
Sons O
, O
Ltd O
. O

A O
new O
triterpenoid B
saponin I
from O
Glinus O
oppositifolius O
with O
alpha O
- O
glucosidase O
inhibitory O
activity O
. O

Evaluation O
of O
alpha O
- O
glucosidase O
inhibitory O
activity O
led O
to O
the O
isolation O
of O
six O
triterpene B
saponins I
from O
the O
aerial O
parts O
of O
Glinus O
oppositifolius O
including O
one O
new O
and O
five O
known O
constituents O
. O

The O
structure O
of O
the O
new O
saponin B
, O
glinoside B
C I
( O
1 O
) O
, O
was O
established O
as O
16 B
- I
O I
- I
( I
beta I
- I
D I
- I
glucopyranosyl I
) I
- I
3 I
beta I
, I
12 I
beta I
, I
16 I
beta I
, I
21 I
alpha I
, I
22 I
- I
pentahydroxy I
hopane I
by O
extensive O
use O
of O
1 O
- O
D O
, O
2 O
- O
D O
NMR O
and O
mass O
spectral O
techniques O
. O

The O
other O
constituents O
identified O
were O
3 B
- I
O I
- I
( I
beta I
- I
D I
- I
xylopyranosyl I
) I
- I
spergulagenin I
A I
( O
2 O
) O
, O
spergulacin B
( O
3 O
) O
, O
spergulin B
A I
( O
4 O
) O
, O
spergulacin B
A I
( O
5 O
) O
and O
spergulin B
B I
( O
6 O
) O
. O

Compound O
1 O
exhibited O
the O
greatest O
inhibition O
of O
the O
enzyme O
with O
IC50 O
of O
127 O
+ O
/ O
- O
30 O
micro O
M O
. O

Kinetics O
study O
for O
the O
compound O
1 O
demonstrated O
mixed O
type O
of O
inhibition O
( O
Ki O
= O
157 O
. O
9 O
micro O
M O
) O
. O

Optimization O
of O
PLGA B
nanoparticles O
formulation O
containing O
L B
- I
DOPA I
by O
applying O
the O
central O
composite O
design O
. O

The O
aim O
of O
this O
work O
was O
to O
prepare O
L B
- I
DOPA I
loaded O
poly B
( I
D I
, I
L I
- I
lactide I
- I
co I
- I
glycolide I
) I
( O
PLGA B
) O
nanoparticles O
by O
a O
modified O
water O
- O
in O
- O
oil O
- O
in O
- O
water O
( O
W O
( O
1 O
) O
/ O
O O
/ O
W O
( O
2 O
) O
) O
emulsification O
solvent O
evaporation O
method O
. O

A O
central O
composite O
design O
was O
applied O
for O
optimization O
of O
the O
formulation O
parameters O
and O
for O
studying O
the O
effects O
of O
three O
independent O
variables O
: O
PLGA B
concentration O
, O
polyvinyl B
alcohol I
( O
PVA B
) O
concentration O
and O
organic O
solvent O
removal O
rate O
on O
the O
particle O
size O
and O
the O
entrapment O
efficiency O
( O
response O
variables O
) O
. O

Second O
- O
order O
models O
were O
obtained O
to O
adequately O
describe O
the O
influence O
of O
the O
independent O
variables O
on O
the O
selected O
responses O
. O

The O
analysis O
of O
variance O
showed O
that O
the O
three O
independent O
variables O
had O
significant O
effects O
( O
p O
< O
0 O
. O
05 O
) O
on O
the O
responses O
. O

The O
experimental O
results O
were O
in O
perfect O
accordance O
with O
the O
predictions O
estimated O
by O
the O
models O
. O

Using O
the O
desirability O
approach O
and O
overlay O
contour O
plots O
, O
the O
optimal O
preparation O
area O
can O
be O
highlighted O
. O

It O
was O
found O
that O
the O
optimum O
values O
of O
the O
responses O
could O
be O
obtained O
at O
higher O
concentration O
of O
PLGA B
( O
5 O
% O
, O
w O
/ O
v O
) O
and O
PVA B
( O
6 O
% O
, O
w O
/ O
v O
) O
; O
and O
faster O
organic O
solvent O
removal O
rate O
( O
700 O
rpm O
) O
. O

The O
corresponding O
particle O
size O
was O
256 O
. O
2 O
nm O
and O
the O
entrapment O
efficiency O
was O
62 O
. O
19 O
% O
. O

FTIR O
investigation O
confirmed O
that O
the O
L B
- I
DOPA I
and O
PLGA B
polymer O
maintained O
its O
backbone O
structure O
in O
the O
fabrication O
of O
nanoparticles O
. O

The O
scanning O
electron O
microscopic O
images O
of O
nanoparticles O
showed O
that O
all O
particles O
had O
spherical O
shape O
with O
porous O
outer O
skin O
. O

The O
results O
suggested O
that O
PLGA B
nanoparticles O
might O
represent O
a O
promising O
formulation O
for O
brain O
delivery O
of O
L B
- I
DOPA I
. O

The O
preparation O
of O
L B
- I
DOPA I
loaded O
PLGA B
nanoparticles O
can O
be O
optimized O
by O
the O
central O
composite O
design O
. O

Impact O
of O
early O
- O
life O
stress O
, O
on O
group O
III O
mGlu O
receptor O
levels O
in O
the O
rat O
hippocampus O
: O
effects O
of O
ketamine B
, O
electroconvulsive O
shock O
therapy O
and O
fluoxetine B
treatment O
. O

The O
glutamatergic O
system O
is O
increasingly O
being O
viewed O
as O
a O
promising O
target O
for O
the O
development O
of O
novel O
treatments O
for O
depression O
. O

The O
group O
III O
metabotropic O
glutamate B
( O
mGlu O
) O
receptors O
( O
mGlu O
( O
4 O
, O
7 O
) O
and O
( O
8 O
) O
receptors O
) O
in O
particular O
are O
beginning O
to O
show O
promise O
in O
this O
respect O
. O

It O
remains O
unclear O
how O
antidepressant O
medications O
modulate O
mGlu O
receptors O
. O

In O
this O
study O
we O
investigated O
the O
effects O
of O
three O
antidepressant O
treatments O
( O
fluoxetine B
, O
ketamine B
and O
electroconvulsive O
shock O
therapy O
( O
ECT O
) O
) O
. O

Ketamine B
is O
an O
NMDA B
receptor O
antagonist O
which O
possess O
a O
rapid O
antidepressant O
therapeutic O
profile O
and O
moreover O
is O
effective O
in O
cases O
of O
treatment O
- O
resistant O
depression O
. O

Furthermore O
, O
ECT O
is O
also O
a O
therapeutic O
strategy O
possessing O
increased O
efficacy O
compared O
to O
conventional O
monoamine B
based O
therapies O
. O

The O
effect O
these O
two O
highly O
efficacious O
treatments O
have O
on O
hippocampal O
group O
III O
mGlu O
receptors O
remains O
completely O
unexplored O
. O

To O
redress O
this O
deficit O
we O
investigated O
the O
effects O
these O
treatments O
and O
the O
prototypical O
selective O
serotonin B
reuptake O
inhibitor O
( O
SSRI O
) O
fluoxetine B
would O
have O
on O
hippocampal O
group O
III O
mGlu O
receptor O
mRNA O
levels O
in O
na O
i O
ve O
Sprague O
- O
Dawley O
rats O
and O
rats O
which O
had O
undergone O
early O
- O
life O
stress O
in O
the O
form O
of O
the O
maternal O
separation O
( O
MS O
) O
procedure O
. O

We O
found O
MS O
significantly O
reduced O
mGlu O
( O
4 O
) O
receptor O
expression O
and O
fluoxetine B
reversed O
this O
MS O
induced O
change O
. O

ECT O
and O
ketamine B
treatment O
significantly O
reduced O
mGlu O
( O
4 O
) O
receptor O
expression O
in O
non O
- O
separated O
( O
NS O
) O
animals O
while O
having O
no O
effect O
in O
MS O
animals O
. O

Fluoxetine B
and O
ECT O
significantly O
increased O
mGlu O
( O
7 O
) O
receptor O
expression O
in O
NS O
animals O
. O

This O
work O
demonstrates O
changes O
to O
mGlu O
( O
4 O
) O
receptor O
expression O
may O
be O
a O
lasting O
molecular O
change O
which O
occurs O
due O
to O
early O
- O
life O
stress O
. O

Taken O
together O
our O
data O
shows O
there O
are O
selective O
changes O
to O
group O
III O
mGlu O
receptors O
under O
basal O
and O
early O
- O
life O
stress O
conditions O
. O

This O
article O
is O
part O
of O
a O
Special O
Issue O
entitled O
' O
Metabotropic O
Glutamate B
Receptors O
' O
. O

In O
vitro O
biomonitoring O
of O
the O
genotoxic O
and O
oxidative O
potentials O
of O
two O
commonly O
eaten O
insects O
in O
southwestern O
Nigeria O
. O

In O
this O
study O
, O
the O
cytogenetic O
and O
oxidative O
effects O
of O
water O
soluble O
extracts O
of O
two O
commonly O
eaten O
insects O
, O
Zonocerus O
variegatus O
( O
Orthoptera O
: O
Pyrgomorphidae O
) O
and O
Oryctes O
boas O
( O
Solanales O
: O
Solanaceae O
) O
, O
in O
southwestern O
Nigeria O
were O
evaluated O
on O
cultured O
human O
blood O
cells O
. O

The O
extracts O
were O
added O
to O
the O
cultures O
at O
various O
concentrations O
( O
0 O
- O
2000 O
ppm O
) O
. O

The O
chromosome O
aberration O
and O
micronucleus O
tests O
were O
used O
to O
find O
out O
the O
DNA O
and O
chromosomal O
damage O
potentials O
in O
vitro O
by O
aqueous O
insect O
extracts O
. O

To O
assess O
the O
oxidative O
effects O
of O
these O
insect O
extracts O
, O
total O
antioxidant O
capacity O
( O
TAC O
) O
and O
total O
oxidant O
status O
( O
TOS O
) O
levels O
were O
also O
measured O
. O

Our O
results O
indicated O
that O
these O
extracts O
did O
not O
show O
genotoxic O
effects O
at O
the O
tested O
concentrations O
. O

However O
, O
the O
extracts O
caused O
dose O
- O
dependent O
alterations O
in O
both O
TAC O
and O
TOS O
levels O
. O

Based O
on O
the O
findings O
, O
it O
was O
concluded O
that O
the O
studied O
insects O
can O
be O
consumed O
safely O
, O
but O
it O
is O
necessary O
to O
consider O
the O
cellular O
damages O
that O
are O
likely O
to O
appear O
depending O
on O
the O
oxidative O
stress O
. O

We O
also O
suggest O
that O
this O
in O
vitro O
approach O
for O
oxidative O
and O
genotoxicity O
assessments O
may O
be O
useful O
to O
compare O
the O
potential O
health O
risks O
of O
edible O
insects O
. O

The O
role O
of O
diallyl B
sulfides I
and O
dipropyl B
sulfides I
in O
the O
in O
vitro O
antimicrobial O
activity O
of O
the O
essential O
oil O
of O
garlic O
, O
Allium O
sativum O
L O
. O
, O
and O
Leek O
, O
Allium O
porrum O
L O
. O

The O
in O
vitro O
antibacterial O
activity O
of O
essential O
oils O
( O
EOs O
) O
obtained O
from O
fresh O
bulbs O
of O
garlic O
, O
Allium O
sativum O
L O
. O
, O
and O
leek O
, O
Allium O
porrum O
L O
. O

( O
Alliaceae O
) O
, O
was O
studied O
. O

A O
. O
sativum O
( O
garlic O
) O
EO O
showed O
a O
good O
antimicrobial O
activity O
against O
Staphylococcus O
aureus O
( O
inhibition O
zone O
14 O
. O
8 O
mm O
) O
, O
Pseudomonas O
aeruginosa O
( O
inhibition O
zone O
21 O
. O
1 O
mm O
) O
, O
and O
Escherichia O
coli O
( O
inhibition O
zone O
11 O
. O
0 O
mm O
) O
, O
whereas O
the O
EO O
of O
A O
. O
porrum O
( O
leek O
) O
had O
no O
antimicrobial O
activity O
. O

The O
main O
constituents O
of O
the O
garlic O
EO O
were O
diallyl B
monosulfide I
, O
diallyl B
disulfide I
( O
DADS B
) O
, O
diallyl B
trisulfide I
, O
and O
diallyl B
tetrasulfide I
. O

The O
EO O
of O
A O
. O
porrum O
was O
characterized O
by O
the O
presence O
of O
dipropyl B
disulfide I
( O
DPDS B
) O
, O
dipropyl B
trisulfide I
, O
and O
dipropyl B
tetrasulfide I
. O

The O
antimicrobial O
activities O
of O
the O
DADS O
and O
DPDS O
were O
also O
studied O
. O

The O
results O
obtained O
suggest O
that O
the O
presence O
of O
the O
allyl B
group O
is O
fundamental O
for O
the O
antimicrobial O
activity O
of O
these O
sulfide B
derivatives O
when O
they O
are O
present O
in O
Allium O
or O
in O
other O
species O
( O
DADS O
inhibition O
zone O
on O
S O
. O
aureus O
15 O
. O
9 O
mm O
, O
P O
. O
aeruginosa O
21 O
. O
9 O
mm O
, O
E O
. O
coli O
11 O
. O
4 O
mm O
) O
. O

Copyright O
( O
c O
) O
2012 O
John O
Wiley O
& O
Sons O
, O
Ltd O
. O

MicroRNA O
- O
7 O
functions O
as O
an O
anti O
- O
metastatic O
microRNA O
in O
gastric O
cancer O
by O
targeting O
insulin O
- O
like O
growth O
factor O
- O
1 O
receptor O
. O

Metastasis O
is O
a O
major O
clinical O
obstacle O
in O
the O
treatment O
of O
gastric O
cancer O
( O
GC O
) O
and O
it O
accounts O
for O
the O
majority O
of O
cancer O
- O
related O
mortality O
. O

MicroRNAs O
have O
recently O
emerged O
as O
regulators O
of O
metastasis O
by O
acting O
on O
multiple O
signaling O
pathways O
. O

In O
this O
study O
, O
we O
found O
that O
miR O
- O
7 O
is O
significantly O
downregulated O
in O
highly O
metastatic O
GC O
cell O
lines O
and O
metastatic O
tissues O
. O

Both O
gain O
- O
of O
- O
function O
and O
loss O
- O
of O
- O
function O
experiments O
showed O
that O
increased O
miR O
- O
7 O
expression O
significantly O
reduced O
GC O
cell O
migration O
and O
invasion O
, O
whereas O
decreased O
miR O
- O
7 O
expression O
dramatically O
enhanced O
cell O
migration O
and O
invasion O
. O

In O
vivo O
metastasis O
assays O
also O
demonstrated O
that O
overexpression O
of O
miR O
- O
7 O
markedly O
inhibited O
GC O
metastasis O
. O

Moreover O
, O
the O
insulin O
- O
like O
growth O
factor O
- O
1 O
receptor O
( O
IGF1R O
) O
oncogene O
, O
which O
is O
often O
mutated O
or O
amplified O
in O
human O
cancers O
and O
functions O
as O
an O
important O
regulator O
of O
cell O
growth O
and O
tumor O
invasion O
, O
was O
identified O
as O
a O
direct O
target O
of O
miR O
- O
7 O
. O

Silencing O
of O
IGF1R O
using O
small O
interefering O
RNA O
( O
siRNA O
) O
recapitulated O
the O
anti O
- O
metastatic O
function O
of O
miR O
- O
7 O
, O
whereas O
restoring O
the O
IGF1R O
expression O
attenuated O
the O
function O
of O
miR O
- O
7 O
in O
GC O
cells O
. O

Furthermore O
, O
we O
found O
that O
suppression O
of O
Snail O
by O
miR O
- O
7 O
, O
through O
targeting O
IGF1R O
, O
increased O
E O
- O
cadherin O
expression O
and O
partially O
reversed O
the O
epithelial O
- O
mesenchymal O
transition O
( O
EMT O
) O
. O

Finally O
, O
analyses O
of O
miR O
- O
7 O
and O
IGF1R O
levels O
in O
human O
primary O
GC O
with O
matched O
lymph O
node O
metastasis O
tissue O
arrays O
revealed O
that O
miR O
- O
7 O
is O
inversely O
correlated O
with O
IGF1R O
expression O
. O

The O
present O
study O
provides O
insight O
into O
the O
specific O
biological O
behavior O
of O
miR O
- O
7 O
in O
EMT O
and O
tumor O
metastasis O
. O

Targeting O
this O
novel O
miR O
- O
7 O
/ O
IGF1R O
/ O
Snail O
axis O
would O
be O
helpful O
as O
a O
therapeutic O
approach O
to O
block O
GC O
metastasis O
. O

Flavonoids B
and O
saponins B
from O
Zizyphus O
incurva O
. O

A O
new O
flavonol B
triglycoside I
, O
myricetin B
- I
3 I
- I
O I
- I
[ I
beta I
- I
xylopyranosyl I
- I
( I
1 I
- I
2 I
) I
- I
alpha I
- I
rhamnopyranoside I
] I
- I
4 I
' I
- I
O I
- I
alpha I
- I
rhamnopyranoside I
, O
named O
as O
bayarin B
( O
1 O
) O
, O
was O
isolated O
from O
the O
aerial O
parts O
of O
Zizyphus O
incurva O
Roxb O
. O

( O
Rhamnaceae O
) O
along O
with O
eight O
known O
compounds O
: O
six O
flavonoids B
and O
two O
saponins B
. O

All O
of O
these O
compounds O
were O
isolated O
for O
the O
first O
time O
from O
this O
plant O
. O

Structures O
of O
these O
compounds O
were O
elucidated O
on O
the O
basis O
of O
spectroscopic O
data O
. O

Rapid O
characterisation O
of O
flavonoids B
from O
Sophora O
alopecuroides O
L O
. O
by O
HPLC O
/ O
DAD O
/ O
ESI O
- O
MSn O
. O

An O
HPLC O
/ O
DAD O
/ O
ESI O
- O
MSn O
method O
was O
established O
to O
characterise O
flavonoids B
in O
the O
seeds O
of O
Sophora O
alopecuroides O
L O
. O

All O
the O
flavonoids B
exhibited O
abundant O
[ O
M O
- O
H B
] O
- O
ions O
, O
which O
triggered O
data O
- O
dependent O
multistage O
mass O
spectrometry O
fragmentations O
. O

Characteristic O
UV O
spectra O
were O
used O
to O
confirm O
flavonoid B
subtypes O
. O

In O
total O
, O
22 O
flavonoids B
and O
two O
phenolic B
compounds O
were O
detected O
and O
identified O
. O

Five O
of O
them O
were O
identified O
by O
comparing O
with O
reference O
standards O
, O
and O
the O
others O
were O
characterised O
based O
on O
the O
retention O
behaviour O
, O
multistage O
fragmentation O
feature O
and O
UV O
absorption O
. O

A O
total O
of O
19 O
compounds O
were O
reported O
from O
S O
. O
alopecuroides O
for O
the O
first O
time O
. O

This O
method O
accomplished O
rapid O
profiling O
of O
flavonoid B
constituents O
in O
S O
. O
alopecuroides O
L O
. O

cAMP B
regulation O
of O
airway O
smooth O
muscle O
function O
. O

Agonists O
activating O
beta O
( O
2 O
) O
- O
adrenoceptors O
( O
beta O
( O
2 O
) O
ARs O
) O
on O
airway O
smooth O
muscle O
( O
ASM O
) O
are O
the O
drug O
of O
choice O
for O
rescue O
from O
acute O
bronchoconstriction O
in O
patients O
with O
both O
asthma O
and O
chronic O
obstructive O
pulmonary O
disease O
( O
COPD O
) O
. O

Moreover O
, O
the O
use O
of O
long O
- O
acting O
beta O
- O
agonists O
combined O
with O
inhaled O
corticosteroids O
constitutes O
an O
important O
maintenance O
therapy O
for O
these O
diseases O
. O

beta O
- O
Agonists O
are O
effective O
bronchodilators O
due O
primarily O
to O
their O
ability O
to O
antagonize O
ASM O
contraction O
. O

The O
presumed O
cellular O
mechanism O
of O
action O
involves O
the O
generation O
of O
intracellular O
cAMP B
, O
which O
in O
turn O
can O
activate O
the O
effector O
molecules O
cAMP B
- O
dependent O
protein O
kinase O
( O
PKA O
) O
and O
Epac O
. O

Other O
agents O
such O
as O
prostaglandin B
E I
( I
2 I
) I
and O
phosphodiesterase O
inhibitors O
that O
also O
increase O
intracellular O
cAMP B
levels O
in O
ASM O
, O
can O
also O
antagonize O
ASM O
contraction O
, O
and O
inhibit O
other O
ASM O
functions O
including O
proliferation O
and O
migration O
. O

Therefore O
, O
beta O
( O
2 O
) O
ARs O
and O
cAMP B
are O
key O
players O
in O
combating O
the O
pathophysiology O
of O
airway O
narrowing O
and O
remodeling O
. O

However O
, O
limitations O
of O
beta O
- O
agonist O
therapy O
due O
to O
drug O
tachyphylaxis O
related O
to O
beta O
( O
2 O
) O
AR O
desensitization O
, O
and O
recent O
findings O
regarding O
the O
manner O
in O
which O
beta O
( O
2 O
) O
ARs O
and O
cAMP B
signal O
, O
have O
raised O
new O
and O
interesting O
questions O
about O
these O
well O
- O
studied O
molecules O
. O

In O
this O
review O
we O
discuss O
current O
concepts O
regarding O
beta O
( O
2 O
) O
ARs O
and O
cAMP B
in O
the O
regulation O
of O
ASM O
cell O
functions O
and O
their O
therapeutic O
roles O
in O
asthma O
and O
COPD O
. O

Anxiolytic O
- O
but O
not O
antidepressant O
- O
like O
activity O
of O
Lu B
AF21934 I
, O
a O
novel O
, O
selective O
positive O
allosteric O
modulator O
of O
the O
mGlu O
4 O
receptor O
. O

Previous O
studies O
demonstrated O
that O
the O
Group O
III O
mGlu O
receptor O
- O
selective O
orthosteric O
agonist O
, O
LSP1 B
- I
2111 I
produced O
anxiolytic O
- O
but O
not O
antidepressant O
- O
like O
effects O
upon O
peripheral O
administration O
. O

Herein O
, O
we O
report O
the O
pharmacological O
actions O
of O
Lu B
AF21934 I
, O
a O
novel O
, O
selective O
, O
and O
brain O
- O
penetrant O
positive O
allosteric O
modulator O
( O
PAM O
) O
of O
the O
mGlu O
( O
4 O
) O
receptor O
in O
the O
stress O
- O
induced O
hyperthermia O
( O
SIH O
) O
, O
four O
- O
plate O
, O
marble O
- O
burying O
and O
Vogel O
' O
s O
conflict O
tests O
. O

In O
all O
models O
, O
except O
Vogel O
' O
s O
conflict O
test O
, O
a O
dose O
- O
dependent O
anxiolytic O
- O
like O
effect O
was O
seen O
. O

The O
anti O
- O
hyperthermic O
effect O
of O
Lu B
AF21934 I
( O
5 O
mg O
/ O
kg O
) O
in O
the O
SIH O
test O
was O
inhibited O
by O
the O
benzodiazepine B
receptor O
antagonist O
flumazenil B
( O
10 O
mg O
/ O
kg O
) O
and O
was O
not O
serotonin B
- O
dependent O
, O
as O
it O
persisted O
in O
serotonin B
- O
deficient O
mice O
and O
upon O
blockade O
of O
either O
5 B
- I
HT I
( O
1A O
) O
receptors O
by O
WAY100635 B
, O
or O
5 B
- I
HT I
( O
2A O
/ O
2C O
) O
receptors O
by O
ritanserin B
. O

These O
results O
suggest O
that O
the O
GABAergic B
system O
, O
but O
not O
the O
serotonergic O
system O
, O
is O
involved O
in O
the O
mechanism O
of O
the O
anxiolytic O
- O
like O
phenotype O
of O
Lu B
AF21934 I
in O
rodents O
. O

Lu B
AF21934 I
did O
not O
produce O
antidepressant O
- O
like O
effects O
in O
the O
tail O
suspension O
test O
( O
TST O
) O
in O
mice O
; O
however O
, O
it O
decreased O
the O
basal O
locomotor O
activity O
of O
mice O
that O
were O
not O
habituated O
to O
activity O
cages O
. O

This O
article O
is O
part O
of O
a O
Special O
Issue O
entitled O
' O
Metabotropic O
Glutamate B
Receptors O
' O
. O

Intraspecific O
variability O
of O
the O
essential O
oil O
of O
Calamintha O
nepeta O
subsp O
. O
nepeta O
from O
Southern O
Italy O
( O
Apulia O
) O
. O

The O
essential O
oil O
of O
46 O
spontaneous O
plants O
of O
Calamintha O
nepeta O
( O
L O
. O
) O
Savi O
subsp O
. O
nepeta O
growing O
wild O
in O
Sud O
, O
Italy O
( O
Salento O
, O
Apulia O
) O
, O
were O
investigated O
by O
GC O
/ O
MS O
. O

Fifty O
- O
seven O
components O
were O
identified O
in O
the O
oil O
representing O
over O
the O
98 O
% O
of O
the O
total O
oil O
composition O
. O

Four O
chemotypes O
were O
identified O
: O
piperitone B
oxide I
, O
piperitenone B
oxide I
, O
piperitone B
- I
menthone I
and O
pulegone B
. O

Screening O
of O
venezuelan O
medicinal O
plant O
extracts O
for O
cytostatic O
and O
cytotoxic O
activity O
against O
tumor O
cell O
lines O
. O

There O
are O
estimated O
to O
be O
more O
than O
20 O
, O
000 O
species O
of O
plants O
in O
Venezuela O
, O
of O
which O
more O
than O
1500 O
are O
used O
for O
medicinal O
purposes O
by O
indigenous O
and O
local O
communities O
. O

Only O
a O
relatively O
small O
proportion O
of O
these O
have O
been O
evaluated O
in O
terms O
of O
their O
potential O
as O
antitumor O
agents O
. O

In O
this O
study O
, O
we O
screened O
308 O
extracts O
from O
102 O
species O
for O
cytostatic O
and O
cytotoxic O
activity O
against O
a O
panel O
of O
six O
tumor O
cell O
lines O
using O
a O
24 O
- O
h O
sulphorhodamine B
B I
assay O
. O

Extracts O
from O
Clavija O
lancifolia O
, O
Hamelia O
patens O
, O
Piper O
san O
- O
vicentense O
, O
Physalis O
cordata O
, O
Jacaranda O
copaia O
, O
Heliotropium O
indicum O
, O
and O
Annona O
squamosa O
were O
the O
most O
cytotoxic O
, O
whereas O
other O
extracts O
from O
Calotropis O
gigantea O
, O
Hyptis O
dilatata O
, O
Chromolaena O
odorata O
, O
Siparuna O
guianensis O
, O
Jacaranda O
obtusifolia O
, O
Tapirira O
guianensis O
, O
Xylopia O
aromatica O
, O

Protium O
heptaphyllum O
, O
and O
Piper O
arboreum O
showed O
the O
greatest O
cytostatic O
activity O
. O

These O
results O
confirm O
previous O
reports O
on O
the O
cytotoxic O
activities O
of O
the O
abovementioned O
plants O
as O
well O
as O
prompting O
further O
studies O
on O
others O
such O
as O
C O
. O
lancifolia O
and O
H O
. O
dilatata O
that O
have O
not O
been O
so O
extensively O
studied O
. O

Copyright O
( O
c O
) O
2012 O
John O
Wiley O
& O
Sons O
, O
Ltd O
. O

The O
interaction O
between O
mGluR1 O
and O
the O
calcium B
channel O
Cav O
2 O
. O
1 O
preserves O
coupling O
in O
the O
presence O
of O
long O
Homer O
proteins O
. O

Group O
I O
metabotropic O
glutamate B
receptors O
( O
mGluR1 O
and O
5 O
) O
are O
G O
protein O
coupled O
receptors O
that O
regulate O
neuronal O
activity O
in O
a O
number O
of O
ways O
. O

Some O
of O
the O
most O
well O
studied O
functions O
of O
group O
I O
mGluRs O
, O
such O
as O
initiation O
of O
multiple O
forms O
of O
mGluR O
- O
dependent O
long O
- O
term O
depression O
, O
require O
receptor O
localization O
near O
the O
post O
- O
synaptic O
density O
( O
PSD O
) O
. O

This O
localization O
is O
in O
turn O
dependent O
on O
the O
Homer O
family O
of O
scaffolding O
proteins O
which O
bind O
to O
a O
small O
motif O
on O
the O
distal O
C B
- O
termini O
of O
mGluR1 O
and O
5 O
, O
localize O
the O
receptors O
near O
the O
PSD O
, O
strengthen O
coupling O
to O
post O
- O
synaptic O
effectors O
and O
simultaneously O
uncouple O
the O
mGluRs O
from O
extra O
- O
synaptic O
effectors O
such O
as O
voltage O
dependent O
ion O
channels O
. O

Here O
the O
selectivity O
of O
this O
uncoupling O
process O
was O
examined O
by O
testing O
the O
ability O
of O
Homer O
- O
2b O
to O
uncouple O
mGluR1 O
from O
multiple O
voltage O
dependent O
calcium B
channels O
including O
Ca B
( O
V2 O
. O
2 O
) O
( O
N O
- O
type O
) O
, O
Ca B
( O
V3 O
. O
2 O
) O
( O
T O
- O
type O
) O
, O
and O
Ca B
( O
V2 O
. O
1 O
) O
( O
P O
/ O
Q O
- O
type O
) O
expressed O
in O
rat O
sympathetic O
neurons O
from O
the O
superior O
cervical O
ganglion O
( O
SCG O
) O
. O

Of O
these O
, O
only O
the O
mGluR1 O
- O
Ca B
( O
V2 O
. O
1 O
) O
modulatory O
pathway O
was O
insensitive O
to O
Homer O
- O
2b O
expression O
. O

Uncoupling O
from O
this O
channel O
was O
achieved O
by O
co O
- O
expression O
of O
an O
mGluR1 O
C B
- O
terminal O
protein O
designed O
to O
disrupt O
a O
previously O
described O
direct O
interaction O
between O
these O
two O
proteins O
, O
suggesting O
that O
this O
interaction O
allows O
incorporation O
of O
Ca B
( O
V2 O
. O
1 O
) O
into O
the O
mGluR1 O
/ O
Homer O
signaling O
complex O
, O
thereby O
preserving O
modulation O
in O
the O
presence O
of O
scaffolding O
Homer O
proteins O
. O

This O
article O
is O
part O
of O
a O
Special O
Issue O
entitled O
' O
Metabotropic O
Glutamate B
Receptors O
' O
. O

Pharmacological O
profiling O
of O
native O
group O
II O
metabotropic O
glutamate B
receptors O
in O
primary O
cortical O
neuronal O
cultures O
using O
a O
FLIPR O
. O

The O
group O
II O
metabotropic O
glutamate B
( O
mGlu O
) O
receptors O
comprised O
of O
the O
mGlu2 O
and O
mGlu3 O
receptor O
subtypes O
have O
gained O
recognition O
in O
recent O
years O
as O
potential O
targets O
for O
psychiatric O
disorders O
, O
including O
anxiety O
and O
schizophrenia O
. O

In O
addition O
to O
studies O
already O
indicating O
which O
subtype O
mediates O
the O
anxiolytic O
and O
anti O
- O
psychotic O
effects O
observed O
in O
disease O
models O
, O
studies O
to O
help O
further O
define O
the O
preferred O
properties O
of O
selective O
group O
II O
mGlu O
receptor O
ligands O
will O
be O
essential O
. O

Comparison O
of O
the O
in O
vitro O
properties O
of O
these O
ligands O
to O
their O
in O
vivo O
efficacy O
and O
tolerance O
profiles O
may O
help O
provide O
these O
additional O
insights O
. O

We O
have O
developed O
a O
relatively O
high O
- O
throughput O
native O
group O
II O
mGlu O
receptor O
functional O
assay O
to O
aid O
this O
characterisation O
. O

We O
have O
utilised O
dissociated O
primary O
cortical O
neuronal O
cultures O
, O
which O
after O
7 O
days O
in O
vitro O
have O
formed O
functional O
synaptic O
connections O
and O
display O
periodic O
and O
spontaneous O
synchronised O
calcium B
( O
Ca B
( I
2 I
+ I
) I
) O
oscillations O
in O
response O
to O
intrinsic O
action O
potential O
bursts O
. O

We O
herein O
demonstrate O
that O
in O
addition O
to O
non O
- O
selective O
group O
II O
mGlu O
receptor O
agonists O
, O
( B
2R I
, I
4R I
) I
- I
APDC I
, O
LY379268 B
and O
DCG B
- I
IV I
, O
a O
selective O
mGlu2 O
agonist O
, O
LY541850 B
, O
and O
mGlu2 O
positive O
allosteric O
modulators O
, O
BINA O
and O
CBiPES O
, O
inhibit O
the O
frequency O
of O
synchronised O
Ca B
( I
2 I
+ I
) I
oscillations O
in O
primary O
cultures O
of O
rat O
and O
mouse O
cortical O
neurons O
. O

Use O
of O
cultures O
from O
wild O
- O
type O
, O
mGlu2 O
( O
- O
/ O
- O
) O
, O
mGlu3 O
( O
- O
/ O
- O
) O
and O
mGlu2 O
/ O
3 O
( O
- O
/ O
- O
) O
mice O
allowed O
us O
to O
further O
probe O
the O
contribution O
of O
mGlu2 O
and O
mGlu3 O
, O
and O
revealed O
LY541850 B
to O
be O
a O
partial O
mGlu2 O
agonist O
and O
a O
full O
mGlu3 O
antagonist O
. O

Overnight O
pre O
- O
treatment O
of O
cultures O
with O
these O
ligands O
revealed O
a O
preferred O
desensitisation O
profile O
after O
treatment O
with O
a O
positive O
allosteric O
modulator O
. O

This O
article O
is O
part O
of O
a O
Special O
Issue O
entitled O
' O
Metabotropic O
Glutamate B
Receptors O
' O
. O

Glycine B
release O
is O
regulated O
by O
metabotropic O
glutamate B
receptors O
sensitive O
to O
mGluR2 O
/ O
3 O
ligands O
and O
activated O
by O
N B
- I
acetylaspartylglutam I
( O
NAAG B
) O
. O

The O
presence O
of O
metabotropic O
glutamate B
receptors O
( O
mGluRs O
) O
of O
group O
II O
modulating O
glycine B
exocytosis O
from O
glycinergic O
nerve O
endings O
of O
mouse O
spinal O
cord O
was O
investigated O
. O

Purified O
synaptosomes O
were O
selectively O
prelabeled O
with O
[ B
( I
3 I
) I
H I
] I
glycine I
through O
the O
neuronal O
transporter O
GlyT2 O
and O
subsequently O
depolarized O
by O
superfusion O
with O
12 O
mM O
KCl B
. O

The O
selective O
mGluR2 O
/ O
3 O
agonist O
LY379268 B
inhibited O
the O
K B
( I
+ I
) I
- O
evoked O
overflow O
of O
[ B
( I
3 I
) I
H I
] I
glycine I
in O
a O
concentration O
- O
dependent O
manner O
( O
EC O
( O
50 O
) O
about O
0 O
. O
2 O
nM O
) O
. O

The O
effect O
of O
LY379268 B
was O
prevented O
by O
the O
selective O
mGluR2 O
/ O
3 O
antagonist O
LY341495 B
( O
IC O
( O
50 O
) O
about O
1 O
nM O
) O
. O

N B
- I
acetylaspartylglutam I
( O
NAAG B
) O
inhibited O
[ B
( I
3 I
) I
H I
] I
glycine I
overflow O
with O
extraordinary O
potency O
( O
EC O
( O
50 O
) O
about O
50 O
fmol O
) O
. O

In O
contrast O
, O
glutamate B
was O
ineffective O
up O
to O
0 O
. O
1 O
nM O
, O
excluding O
that O
glutamate B
contamination O
of O
commercial O
NAAG B
samples O
is O
responsible O
for O
the O
reported O
activity O
of O
NAAG B
at O
mGluR3 O
. O

LY341495 B
antagonized O
the O
NAAG B
inhibition O
of O
[ B
( I
3 I
) I
H I
] I
glycine I
release O
. O

The O
effect O
of O
a O
combination O
of O
maximally O
effective O
concentrations O
of O
LY379268 B
and O
NAAG B
exhibited O
no O
additivity O
. O

The O
non O
- O
hydrolysable O
NAAG B
analogue O
N B
- I
acetylaspartyl I
- I
beta I
- I
linked I
glutamate I
( O
beta B
- I
NAAG I
) O
antagonized O
NAAG B
and O
LY379268 B
. O

In O
conclusion O
, O
our O
results O
show O
that O
glycinergic O
nerve O
endings O
in O
spinal O
cord O
are O
endowed O
with O
group O
II O
mGluRs O
mediating O
inhibition O
of O
glycine B
exocytosis O
. O

NAAG B
can O
activate O
these O
presynaptic O
receptors O
with O
extremely O
high O
affinity O
and O
with O
characteristics O
compatible O
with O
the O
reported O
mGluR3 O
pharmacology O
. O

This O
article O
is O
part O
of O
a O
Special O
Issue O
entitled O
' O
Metabotropic O
Glutamate B
Receptors O
' O
. O

Attenuation O
of O
methamphetamine B
seeking O
by O
the O
mGluR2 O
/ O
3 O
agonist O
LY379268 B
in O
rats O
with O
histories O
of O
restricted O
and O
escalated O
self O
- O
administration O
. O

Recent O
findings O
implicate O
group O
II O
metabotropic O
glutamate B
receptors O
( O
mGluR O
( O
2 O
/ O
3 O
) O
) O
in O
the O
reinforcing O
effects O
of O
psychostimulants O
and O
have O
identified O
these O
receptors O
as O
potential O
treatment O
targets O
for O
drug O
addiction O
. O

Here O
, O
we O
investigated O
the O
effects O
of O
mGluR O
( O
2 O
/ O
3 O
) O
stimulation O
on O
cue O
- O
and O
drug O
- O
primed O
reinstatement O
in O
rats O
with O
different O
histories O
of O
methamphetamine B
( O
METH B
) O
self O
- O
administration O
training O
, O
under O
two O
conditions O
: O
16 O
daily O
sessions O
of O
short O
access O
( O
90 O
min O
/ O
day O
, O
ShA O
) O
, O
or O
8 O
daily O
sessions O
of O
short O
access O
followed O
by O
8 O
sessions O
of O
long O
access O
( O
6 O
h O
/ O
day O
, O
LgA O
) O
. O

Following O
self O
- O
administration O
and O
subsequent O
extinction O
training O
, O
rats O
were O
pretreated O
with O
the O
selective O
mGluR O
( O
2 O
/ O
3 O
) O
agonist O
LY379268 B
( O
variable O
dose O
, O
0 O
- O
3 O
mg O
/ O
kg O
) O
, O
exposed O
to O
METH B
- O
paired O
cues O
or O
a O
priming O
injection O
of O
METH B
( O
1 O
mg O
/ O
kg O
) O
, O
and O
tested O
for O
reinstatement O
of O
METH B
- O
seeking O
behavior O
. O

LgA O
rats O
self O
- O
administered O
greater O
amounts O
of O
METH B
during O
the O
second O
half O
of O
training O
, O
but O
when O
pretreated O
with O
vehicle O
, O
ShA O
and O
LgA O
rats O
showed O
cue O
- O
and O
drug O
- O
primed O
reinstatement O
at O
equivalent O
response O
rates O
. O

However O
, O
LgA O
rats O
demonstrated O
greater O
sensitivity O
to O
mGluR O
( O
2 O
/ O
3 O
) O
stimulation O
with O
attenuated O
responding O
during O
cue O
- O
induced O
reinstatement O
after O
0 O
. O
3 O
mg O
/ O
kg O
and O
higher O
doses O
of O
LY379268 B
, O
whereas O
ShA O
rats O
decreased O
cue O
- O
induced O
reinstatement O
behavior O
following O
1 O
. O
0 O
mg O
/ O
kg O
and O
3 O
. O
0 O
mg O
/ O
kg O
LY379268 B
. O

Additionally O
, O
both O
LgA O
and O
ShA O
rats O
exhibited O
decreased O
METH B
- O
primed O
reinstatement O
behavior O
following O
0 O
. O
3 O
mg O
/ O
kg O
and O
higher O
doses O
of O
LY379268 B
. O

A O
separate O
group O
of O
control O
rats O
was O
trained O
to O
self O
- O
administer O
sucrose B
pellets O
, O
and O
demonstrated O
attenuated O
cue O
- O
induced O
sucrose O
- O
seeking O
behavior O
following O
1 O
. O
0 O
and O
3 O
. O
0 O
mg O
/ O
kg O
LY379268 B
. O

Together O
, O
the O
results O
indicate O
that O
LY379268 B
has O
differential O
attenuating O
effects O
on O
cue O
- O
induced O
reinstatement O
behavior O
in O
rats O
with O
different O
histories O
of O
METH B
intake O
. O

This O
article O
is O
part O
of O
a O
Special O
Issue O
entitled O
' O
Metabotropic O
Glutamate B
Receptors O
' O
. O

Stathmin O
1 O
is O
a O
potential O
novel O
oncogene O
in O
melanoma O
. O

In O
previous O
studies O
, O
we O
demonstrated O
that O
miR O
- O
193b O
expression O
is O
reduced O
in O
melanoma O
relative O
to O
benign O
nevi O
, O
and O
also O
that O
miR O
- O
193b O
represses O
cyclin O
D1 O
and O
Mcl O
- O
1 O
expression O
. O

We O
suggested O
that O
stathmin O
1 O
( O
STMN1 O
) O
might O
be O
a O
target O
of O
miR O
- O
193b O
. O

STMN1 O
normally O
regulates O
microtubule O
dynamics O
either O
by O
sequestering O
free O
tubulin O
heterodimers O
or O
by O
promoting O
microtubule O
catastrophe O
. O

Increased O
expression O
of O
STMN1 O
has O
been O
observed O
in O
a O
variety O
of O
human O
malignancies O
, O
but O
its O
association O
with O
melanoma O
is O
unknown O
. O

We O
now O
report O
that O
STMN1 O
is O
upregulated O
during O
the O
progression O
of O
melanoma O
relative O
to O
benign O
nevi O
, O
and O
that O
STMN1 O
is O
directly O
regulated O
by O
miR O
- O
193b O
. O

Using O
an O
experimental O
cell O
culture O
approach O
, O
overexpression O
of O
miR O
- O
193b O
using O
synthetic O
microRNAs O
repressed O
STMN1 O
expression O
, O
whereas O
inhibition O
of O
miR O
- O
193b O
with O
anti O
- O
miR O
oligos O
increased O
STMN1 O
expression O
in O
melanoma O
cells O
. O

The O
use O
of O
a O
luciferase O
reporter O
assay O
confirmed O
that O
miR O
- O
193b O
directly O
regulates O
STMN1 O
by O
targeting O
the O
3 O
' O
- O
untranslated O
region O
of O
STMN1 O
mRNA O
. O

We O
further O
demonstrated O
that O
STMN1 O
is O
overexpressed O
in O
malignant O
melanoma O
compared O
with O
nevi O
in O
two O
independent O
melanoma O
cohorts O
, O
and O
that O
its O
level O
is O
inversely O
correlated O
with O
miR O
- O
193b O
expression O
. O

However O
, O
STMN1 O
expression O
was O
not O
significantly O
associated O
with O
patient O
survival O
, O
Breslow O
depth O
, O
mitotic O
count O
or O
patient O
age O
. O

STMN1 O
knockdown O
by O
small O
- O
interfering O
RNA O
in O
melanoma O
cells O
drastically O
repressed O
cell O
proliferation O
and O
migration O
potential O
, O
whereas O
ectopic O
expression O
of O
STMN1 O
using O
lentivirus O
increased O
cell O
proliferation O
and O
migration O
rates O
. O

Subsequent O
gene O
expression O
analysis O
indicated O
that O
interconnected O
cytoskeletal O
networks O
are O
directly O
affected O
following O
STMN1 O
knockdown O
. O

In O
addition O
, O
we O
identified O
deregulated O
genes O
associated O
with O
proliferation O
and O
migration O
, O
and O
revealed O
that O
p21 O
( O
Cip1 O
/ O
Waf1 O
) O
and O
p27 O
( O
Kip O
) O
could O
be O
downstream O
effectors O
of O
STMN1 O
signaling O
. O

Taken O
together O
, O
our O
study O
suggests O
that O
downregulation O
of O
miR O
- O
193b O
may O
contribute O
to O
increased O
STMN1 O
expression O
in O
melanoma O
, O
which O
consequently O
promotes O
migration O
and O
proliferation O
of O
tumor O
cells O
. O

The O
p44 O
/ O
wdr77 O
- O
dependent O
cellular O
proliferation O
process O
during O
lung O
development O
is O
reactivated O
in O
lung O
cancer O
. O

During O
lung O
development O
, O
cells O
proliferate O
for O
a O
defined O
length O
of O
time O
before O
they O
begin O
to O
differentiate O
. O

Factors O
that O
control O
this O
proliferative O
process O
and O
how O
this O
growth O
process O
is O
related O
to O
lung O
cancer O
are O
currently O
unknown O
. O

Here O
, O
we O
found O
that O
the O
WD40 O
- O
containing O
protein O
( O
p44 O
/ O
wdr77 O
) O
was O
expressed O
in O
growing O
epithelial O
cells O
at O
the O
early O
stages O
of O
lung O
development O
. O

In O
contrast O
, O
p44 O
/ O
wdr77 O
expression O
was O
diminished O
in O
fully O
differentiated O
epithelial O
cells O
in O
the O
adult O
lung O
. O

Loss O
of O
p44 O
/ O
wdr77 O
gene O
expression O
led O
to O
cell O
growth O
arrest O
and O
differentiation O
. O

Re O
- O
expression O
of O
p44 O
/ O
wdr77 O
caused O
terminally O
differentiated O
cells O
to O
re O
- O
enter O
the O
cell O
cycle O
. O

Our O
findings O
suggest O
that O
p44 O
/ O
wdr77 O
is O
essential O
and O
sufficient O
for O
proliferation O
of O
lung O
epithelial O
cells O
. O

P44 O
/ O
Wdr77 O
was O
re O
- O
expressed O
in O
lung O
cancer O
, O
and O
silencing O
p44 O
/ O
wdr77 O
expression O
strongly O
inhibited O
growth O
of O
lung O
adenocarcinoma O
cells O
in O
tissue O
culture O
and O
abolished O
growth O
of O
lung O
adenocarcinoma O
tumor O
xenografts O
in O
mice O
. O

The O
growth O
arrest O
induced O
by O
loss O
of O
p44 O
/ O
wdr77 O
expression O
was O
partially O
through O
the O
p21 O
- O
Rb O
signaling O
. O

Our O
results O
suggest O
that O
p44 O
/ O
wdr77 O
controls O
cellular O
proliferation O
during O
lung O
development O
, O
and O
this O
growth O
process O
is O
reactivated O
during O
lung O
tumorigenesis O
. O

Two O
new O
phenolic B
glycosides I
from O
Inula O
cappa O
DC O
. O

Two O
new O
phenolic B
glycosides I
were O
isolated O
from O
the O
ethanol B
extract O
of O
the O
roots O
of O
Inula O
cappa O
DC O
. O

Their O
structures O
were O
defined O
as O
4 B
- I
[ I
( I
6 I
- I
O I
- I
( I
E I
) I
- I
caffeoyl I
) I
- I
beta I
- I
D I
- I
glucopyranosyl I
] I
vanillic I
acid I
( O
1 O
) O
and O
3 B
- I
O I
- I
[ I
beta I
- I
D I
- I
apiofurarnosyl I
- I
( I
1 I
- I
6 I
) I
- I
beta I
- I
D I
- I
glucopyranoxy I
] I
- I
6 I
- I
hydroxy I
- I
p I
- I
cymene I
( O
2 O
) O
on O
the O
basis O
of O
spectral O
analysis O
. O

In O
vitro O
characterization O
of O
organophosphorus B
compound O
hydrolysis O
by O
native O
and O
recombinant O
human O
prolidase O
. O

Human O
prolidase O
is O
a O
binuclear O
metalloenzyme O
, O
which O
can O
potentially O
function O
as O
a O
catalytic O
bioscavenger O
for O
organophosphorus B
( O
OP O
) O
nerve O
agents O
. O

Although O
the O
biochemical O
properties O
of O
native O
prolidase O
purified O
from O
human O
erythrocytes O
, O
liver O
, O
kidney O
, O
and O
fibroblast O
cells O
are O
well O
known O
, O
it O
is O
very O
poorly O
characterized O
with O
regard O
to O
its O
OP O
hydrolyzing O
activity O
. O

Also O
, O
the O
high O
cost O
of O
purification O
of O
large O
quantities O
of O
native O
enzyme O
limits O
its O
use O
as O
a O
bioscavenger O
. O

Thus O
, O
recombinant O
human O
prolidase O
with O
similar O
biochemical O
properties O
to O
those O
of O
native O
enzyme O
would O
be O
more O
suitable O
as O
a O
catalytic O
bioscavenger O
. O

In O
this O
study O
, O
we O
established O
an O
Escherichia O
coli O
expression O
system O
, O
which O
produced O
a O
large O
amount O
of O
tagged O
human O
liver O
prolidase O
that O
was O
purified O
to O
over O
95 O
% O
purity O
from O
the O
soluble O
fraction O
of O
cell O
lysate O
by O
affinity O
chromatography O
on O
Streptavidin O
- O
agarose O
resin O
. O

The O
catalytic O
properties O
of O
the O
recombinant O
enzyme O
were O
compared O
in O
vitro O
with O
those O
of O
highly O
purified O
prolidase O
I O
isolated O
from O
human O
erythrocytes O
. O

The O
catalytic O
properties O
of O
recombinant O
prolidase O
overlap O
with O
those O
of O
the O
erythrocyte O
- O
derived O
native O
enzyme O
. O

Both O
enzymes O
efficiently O
hydrolyzed O
diisopropylfluoropho B
, O
sarin B
, O
soman B
, O
tabun B
and O
cyclosarin B
, O
but O
were O
much O
less O
efficient O
at O
hydrolyzing O
paraoxon B
and O
methyl B
paraoxon I
. O

These O
results O
suggest O
that O
human O
prolidase O
expressed O
in O
E O
. O
coli O
is O
suitable O
for O
further O
development O
as O
a O
catalytic O
bioscavenger O
for O
OP O
nerve O
agents O
. O

Theoretical O
study O
of O
the O
pH O
- O
dependent O
antioxidant O
properties O
of O
vitamin B
C I
. O

Molecules O
acting O
as O
antioxidants O
capable O
of O
scavenging O
reactive O
oxygen B
species O
( O
ROS O
) O
are O
of O
utmost O
importance O
in O
the O
living O
cell O
. O

Vitamin B
C I
is O
known O
to O
be O
one O
of O
these O
molecules O
. O

In O
this O
study O
we O
have O
analyzed O
the O
reactivity O
of O
vitamin B
C I
toward O
the O
[ O
Formula O
: O
see O
text O
] O
and O
[ O
Formula O
: O
see O
text O
] O
ROS O
species O
, O
in O
all O
acidic O
, O
neutral O
and O
basic O
media O
. O

In O
order O
to O
do O
so O
, O
density O
functional O
theory O
( O
DFT O
) O
have O
been O
used O
. O

More O
concretely O
, O
the O
meta O
- O
GGA O
functional O
MPW1B95 O
have O
been O
used O
. O

Two O
reaction O
types O
have O
been O
studied O
in O
each O
case O
: O
addition O
to O
the O
ring O
atoms O
, O
and O
hydrogen B
/ O
proton O
abstraction O
. O

Our O
results O
show O
that O
[ O
Formula O
: O
see O
text O
] O
is O
the O
most O
reactive O
species O
, O
while O
[ O
Formula O
: O
see O
text O
] O
displays O
low O
reactivity O
. O

In O
all O
three O
media O
, O
vitamin B
C I
reactions O
with O
two O
hydroxyl B
radicals O
show O
a O
wide O
variety O
of O
possible O
products O
. O

Cooperation O
between O
p53 O
and O
the O
telomere O
- O
protecting O
shelterin O
component O
Pot1a O
in O
endometrial O
carcinogenesis O
. O

Type O
II O
endometrial O
cancer O
( O
EMCA O
) O
represents O
only O
10 O
% O
of O
all O
EMCAs O
, O
but O
accounts O
for O
40 O
% O
of O
EMCA O
- O
related O
mortality O
. O

Previous O
studies O
of O
human O
tumors O
have O
shown O
an O
association O
between O
Type O
II O
tumors O
and O
damaged O
telomeres O
. O

We O
hypothesized O
that O
the O
lack O
of O
murine O
Type O
II O
EMCA O
models O
is O
due O
to O
the O
extremely O
long O
telomeres O
in O
laboratory O
mouse O
strains O
. O

We O
previously O
showed O
that O
telomerase O
- O
null O
mice O
with O
critically O
short O
telomeres O
developed O
endometrial O
lesions O
histologically O
resembling O
endometrial O
intraepithelial O
carcinoma O
( O
EIC O
) O
, O
the O
accepted O
precursor O
for O
Type O
II O
EMCA O
. O

However O
, O
these O
mice O
did O
not O
develop O
invasive O
endometrial O
adenocarcinoma O
, O
and O
instead O
succumbed O
prematurely O
to O
multi O
- O
organ O
failure O
. O

Here O
, O
we O
modeled O
critical O
telomere O
attrition O
by O
conditionally O
inactivating O
Pot1a O
, O
a O
component O
of O
the O
shelterin O
complex O
that O
stabilizes O
telomeres O
, O
within O
endometrial O
epithelium O
. O

Inactivation O
of O
Pot1a O
by O
itself O
did O
not O
stimulate O
endometrial O
carcinogenesis O
, O
and O
did O
not O
result O
in O
detectable O
DNA O
damage O
or O
apoptosis O
in O
endometrium O
. O

However O
, O
simultaneous O
inactivation O
of O
Pot1a O
and O
p53 O
resulted O
in O
EIC O
- O
like O
lesions O
by O
9 O
months O
indistinguishable O
from O
those O
seen O
in O
late O
generation O
telomerase O
- O
null O
mice O
. O

These O
lesions O
progressed O
to O
invasive O
endometrial O
adenocarcinomas O
as O
early O
as O
9 O
months O
of O
age O
with O
metastatic O
disease O
in O
100 O
% O
of O
the O
animals O
by O
15 O
months O
. O

These O
tumors O
were O
poorly O
differentiated O
endometrial O
adenocarcinomas O
with O
prominent O
nuclear O
atypia O
, O
resembling O
human O
Type O
II O
cancers O
. O

Furthermore O
, O
these O
tumors O
were O
aneuploid O
with O
double O
- O
stranded O
DNA O
breaks O
and O
end O
- O
to O
- O
end O
telomere O
fusions O
and O
most O
were O
tetraploid O
or O
near O
- O
tetraploid O
. O

These O
studies O
lend O
further O
support O
to O
the O
hypothesis O
that O
telomeric O
instability O
has O
a O
critical O
role O
in O
Type O
II O
endometrial O
carcinogenesis O
and O
provides O
an O
intriguing O
in O
- O
vivo O
correlate O
to O
recent O
studies O
implicating O
telomere O
- O
dependent O
tetraploidization O
as O
an O
important O
mechanism O
in O
carcinogenesis O
. O

Hyperinakin B
, O
a O
new O
anti O
- O
inflammatory O
phloroglucinol B
derivative O
from O
Hypericum O
nakamurai O
. O

Phytochemical O
investigation O
of O
Hypericum O
nakamurai O
( O
Masamune O
) O
Robson O
has O
led O
to O
the O
isolation O
of O
three O
phloroglucinol B
derivatives O
1 O
- O
3 O
. O

The O
structures O
of O
these O
compounds O
were O
determined O
by O
the O
analysis O
of O
their O
spectroscopic O
data O
( O
IR O
, O
mass O
and O
UV O
) O
, O
and O
by O
the O
application O
of O
1 O
- O
D O
and O
2 O
- O
D O
- O
NMR O
techniques O
. O

Hyperinakin O
( O
1 O
) O
is O
a O
new O
compound O
. O

The O
anti O
- O
inflammatory O
activities O
of O
compounds O
1 O
- O
3 O
were O
also O
tested O
and O
evaluated O
. O

A O
biogenetic O
pathway O
for O
compounds O
1 O
- O
3 O
was O
also O
proposed O
. O

Recurrent O
gene O
deletions O
and O
the O
evolution O
of O
adaptive O
cyanogenesis O
polymorphisms O
in O
white O
clover O
( O
Trifolium O
repens O
L O
. O
) O
. O

Understanding O
the O
molecular O
evolution O
of O
genes O
that O
underlie O
intraspecific O
polymorphisms O
can O
provide O
insights O
into O
the O
process O
of O
adaptive O
evolution O
. O

For O
adaptive O
polymorphisms O
characterized O
by O
gene O
presence O
/ O
absence O
( O
P O
/ O
A O
) O
variation O
, O
underlying O
loci O
commonly O
show O
signatures O
of O
long O
- O
term O
balancing O
selection O
, O
with O
gene O
- O
presence O
and O
gene O
- O
absence O
alleles O
maintained O
as O
two O
divergent O
lineages O
. O

We O
examined O
the O
molecular O
evolution O
of O
two O
unlinked O
P O
/ O
A O
polymorphisms O
that O
underlie O
a O
well O
- O
documented O
adaptive O
polymorphism O
for O
cyanogenesis O
( O
hydrogen B
cyanide I
release O
with O
tissue O
damage O
) O
in O
white O
clover O
. O

Both O
cyanogenic O
and O
acyanogenic O
plants O
occur O
in O
this O
species O
, O
and O
the O
ecological O
forces O
that O
maintain O
this O
chemical O
defence O
polymorphism O
have O
been O
studied O
for O
several O
decades O
. O

Using O
a O
sample O
of O
65 O
plants O
, O
we O
investigated O
the O
molecular O
evolution O
of O
sequences O
flanking O
the O
two O
underlying O
cyanogenesis O
genes O
: O
Ac O
/ O
ac O
( O
controlling O
the O
presence O
/ O
absence O
of O
cyanogenic B
glucosides I
) O
and O
Li O
/ O
li O
( O
controlling O
the O
presence O
/ O
absence O
of O
their O
hydrolysing O
enzyme O
, O
linamarase O
) O
. O

A O
combination O
of O
genome O
walking O
, O
PCR O
assays O
, O
DNA O
sequence O
analysis O
and O
Southern O
blotting O
was O
used O
to O
test O
whether O
these O
adaptive O
P O
/ O
A O
polymorphisms O
show O
evidence O
of O
long O
- O
term O
balancing O
selection O
, O
or O
whether O
gene O
- O
absence O
alleles O
have O
evolved O
repeatedly O
through O
independent O
deletion O
events O
. O

For O
both O
loci O
, O
we O
detect O
no O
signatures O
of O
balancing O
selection O
in O
the O
closest O
flanking O
genomic O
sequences O
. O

Instead O
, O
we O
find O
evidence O
for O
variation O
in O
the O
size O
of O
the O
deletions O
characterizing O
gene O
- O
absence O
alleles O
. O

These O
observations O
strongly O
suggest O
that O
both O
of O
these O
polymorphisms O
have O
been O
evolving O
through O
recurrent O
gene O
deletions O
over O
time O
. O

We O
discuss O
the O
genetic O
mechanisms O
that O
could O
account O
for O
this O
surprising O
pattern O
and O
the O
implications O
of O
these O
findings O
for O
mechanisms O
of O
rapid O
adaptive O
evolution O
in O
white O
clover O
. O

Regulation O
of O
gene O
expression O
in O
human O
prostate O
cancer O
cells O
with O
artificially O
constructed O
promoters O
that O
are O
activated O
in O
response O
to O
ultrasound O
stimulation O
. O

We O
chose O
promoters O
responsive O
to O
sonication O
in O
LNCap O
cells O
, O
a O
prostate O
cancer O
cell O
line O
, O
out O
of O
a O
library O
composed O
of O
DNA O
fragments O
constructed O
by O
linking O
the O
TATA O
box O
sequence O
to O
randomly O
combined O
cis O
- O
acting O
elements O
of O
transcription O
factors O
activated O
in O
response O
to O
radiation O
in O
prostate O
cancer O
cells O
. O

When O
a O
plasmid O
containing O
the O
luciferase O
gene O
under O
control O
of O
a O
promoter O
was O
transfected O
into O
LNCap O
cells O
and O
sonicated O
with O
1 O
MHz O
ultrasound O
at O
0 O
. O
5 O
W O
/ O
cm O
( O
2 O
) O
, O
10 O
% O
DF O
for O
60s O
, O
13 O
promoters O
showed O
more O
than O
10 O
- O
fold O
enhancement O
compared O
with O
their O
counterparts O
without O
sonication O
12h O
after O
sonication O
. O

As O
to O
their O
responsiveness O
to O
sonication O
, O
the O
best O
two O
promoters O
were O
then O
compared O
to O
clone O
880 O
- O
8 O
, O
a O
derivative O
from O
clone O
880 O
that O
was O
created O
by O
random O
introduction O
of O
point O
mutations O
and O
was O
shown O
to O
have O
an O
improved O
response O
to O
X O
- O
ray O
irradiation O
. O

We O
then O
took O
clone O
880 O
- O
8 O
for O
further O
analyses O
since O
it O
showed O
the O
highest O
enhancement O
to O
sonication O
, O
though O
not O
statistically O
significant O
from O
the O
others O
. O

Next O
, O
we O
employed O
a O
retrovirus O
vector O
and O
stably O
introduced O
the O
luciferase O
gene O
under O
control O
of O
clone O
880 O
- O
8 O
into O
LNCap O
cells O
to O
establish O
a O
cell O
line O
. O

When O
the O
cell O
line O
was O
sonicated O
with O
1 O
MHz O
ultrasound O
at O
0 O
. O
5 O
W O
/ O
cm O
( O
2 O
) O
, O
10 O
% O
DF O
for O
60s O
, O
luciferase O
expression O
was O
enhanced O
up O
to O
14 O
. O
8 O
- O
fold O
12h O
after O
sonication O
. O

We O
then O
established O
another O
cell O
line O
by O
replacing O
the O
luciferase O
gene O
with O
the O
fcy O
: O
: O
fur O
gene O
, O
a O
suicide O
gene O
, O
and O
when O
the O
cell O
line O
was O
sonicated O
with O
1 O
MHz O
ultrasound O
at O
0 O
. O
5 O
W O
/ O
cm O
( O
2 O
) O
, O
10 O
% O
DF O
for O
60s O
, O
expression O
of O
the O
gene O
was O
enhanced O
, O
showing O
the O
maximum O
expression O
12 O
- O
24h O
after O
sonication O
. O

When O
the O
cells O
were O
incubated O
in O
medium O
containing O
5 B
- I
fluorocytosine I
, O
cell O
survival O
ratio O
decreased O
dose O
dependently O
with O
5 B
- I
fluorocytosine I
only O
after O
sonication O
treatment O
, O
suggesting O
this O
promoter O
could O
be O
utilized O
for O
gene O
expression O
control O
with O
ultrasound O
. O

Genetic O
determinants O
of O
neuronal O
vulnerability O
to O
apoptosis O
. O

Apoptosis O
is O
a O
common O
mode O
of O
cell O
death O
that O
contributes O
to O
neuronal O
loss O
associated O
with O
neurodegeneration O
. O

Single O
- O
nucleotide O
polymorphisms O
( O
SNPs O
) O
in O
chromosomal O
DNA O
are O
contributing O
factors O
dictating O
natural O
susceptibility O
of O
humans O
to O
disease O
. O

Here O
, O
the O
most O
common O
SNPs O
affecting O
neuronal O
vulnerability O
to O
apoptosis O
are O
reviewed O
in O
the O
context O
of O
neurological O
disorders O
. O

Polymorphic O
variants O
in O
genes O
encoding O
apoptotic O
proteins O
, O
either O
from O
the O
extrinsic O
( O
FAS O
, O
TNF O
- O
alpha O
, O
CASP8 O
) O
or O
the O
intrinsic O
( O
BAX O
, O
BCL2 O
, O
CASP3 O
, O
CASP9 O
) O
pathways O
could O
be O
highly O
valuable O
in O
the O
diagnosis O
of O
neurodegenerative O
diseases O
and O
stroke O
. O

Interestingly O
, O
the O
Arg72Pro O
SNP O
in O
TP53 O
, O
the O
gene O
encoding O
tumor O
suppressor O
p53 O
, O
was O
recently O
revealed O
a O
biomarker O
of O
poor O
prognosis O
in O
stroke O
due O
to O
its O
ability O
to O
modulate O
neuronal O
apoptotic O
death O
. O

Search O
for O
new O
SNPs O
responsible O
for O
genetic O
variability O
to O
apoptosis O
will O
ensure O
the O
implementation O
of O
novel O
diagnostic O
and O
prognostic O
tools O
, O
as O
well O
as O
therapeutic O
strategies O
against O
neurological O
diseases O
. O

Dissolved O
gas O
and O
ultrasonic O
cavitation O
- O
- O
a O
review O
. O

The O
physics O
and O
chemistry O
of O
nonlinearly O
oscillating O
acoustic O
cavitation O
bubbles O
are O
strongly O
influenced O
by O
the O
dissolved O
gas O
in O
the O
surrounding O
liquid O
. O

Changing O
the O
gas O
alters O
among O
others O
the O
luminescence O
spectrum O
, O
and O
the O
radical O
production O
of O
the O
collapsing O
bubbles O
. O

An O
overview O
of O
experiments O
with O
various O
gas O
types O
and O
concentration O
described O
in O
literature O
is O
given O
and O
is O
compared O
to O
mechanisms O
that O
lead O
to O
the O
observed O
changes O
in O
luminescence O
spectra O
and O
radical O
production O
. O

The O
dissolved O
gas O
type O
changes O
the O
bubble O
adiabatic O
ratio O
, O
thermal O
conductivity O
, O
and O
the O
liquid O
surface O
tension O
, O
and O
consequently O
the O
hot O
spot O
temperature O
. O

The O
gas O
can O
also O
participate O
in O
chemical O
reactions O
, O
which O
can O
enhance O
radical O
production O
or O
luminescence O
of O
a O
cavitation O
bubble O
. O

With O
this O
knowledge O
, O
the O
gas O
content O
in O
cavitation O
can O
be O
tailored O
to O
obtain O
the O
desired O
output O
. O

Towards O
an O
understanding O
and O
control O
of O
cavitation O
activity O
in O
1 O
MHz O
ultrasound O
fields O
. O

Various O
industrial O
processes O
such O
as O
sonochemical O
processing O
and O
ultrasonic O
cleaning O
strongly O
rely O
on O
the O
phenomenon O
of O
acoustic O
cavitation O
. O

As O
the O
occurrence O
of O
acoustic O
cavitation O
is O
incorporating O
a O
multitude O
of O
interdependent O
effects O
, O
the O
amount O
of O
cavitation O
activity O
in O
a O
vessel O
is O
strongly O
depending O
on O
the O
ultrasonic O
process O
conditions O
. O

It O
is O
therefore O
crucial O
to O
quantify O
cavitation O
activity O
as O
a O
function O
of O
the O
process O
parameters O
. O

At O
1 O
MHz O
, O
the O
active O
cavitation O
bubbles O
are O
so O
small O
that O
it O
is O
becoming O
difficult O
to O
observe O
them O
in O
a O
direct O
way O
. O

Hence O
, O
another O
metrology O
based O
on O
secondary O
effects O
of O
acoustic O
cavitation O
is O
more O
suitable O
to O
study O
cavitation O
activity O
. O

In O
this O
paper O
we O
present O
a O
detailed O
analysis O
of O
acoustic O
cavitation O
phenomena O
at O
1 O
MHz O
ultrasound O
by O
means O
of O
time O
- O
resolved O
measurements O
of O
sonoluminescence O
, O
cavitation O
noise O
, O
and O
synchronized O
high O
- O
speed O
stroboscopic O
Schlieren O
imaging O
. O

It O
is O
shown O
that O
a O
correlation O
exists O
between O
sonoluminescence O
, O
and O
the O
ultraharmonic O
and O
broadband O
signals O
extracted O
from O
the O
cavitation O
noise O
spectra O
. O

The O
signals O
can O
be O
utilized O
to O
characterize O
different O
regimes O
of O
cavitation O
activity O
at O
different O
acoustic O
power O
densities O
. O

When O
cavitation O
activity O
sets O
on O
, O
the O
aforementioned O
signals O
correlate O
to O
fluctuations O
in O
the O
Schlieren O
contrast O
as O
well O
as O
the O
number O
of O
nucleated O
bubbles O
extracted O
from O
the O
Schlieren O
Images O
. O

This O
additionally O
proves O
that O
signals O
extracted O
from O
cavitation O
noise O
spectra O
truly O
represent O
a O
measure O
for O
cavitation O
activity O
. O

The O
cyclic O
behavior O
of O
cavitation O
activity O
is O
investigated O
and O
related O
to O
the O
evolution O
of O
the O
bubble O
populations O
in O
the O
ultrasonic O
tank O
. O

It O
is O
shown O
that O
cavitation O
activity O
is O
strongly O
linked O
to O
the O
occurrence O
of O
fast O
- O
moving O
bubbles O
. O

The O
origin O
of O
this O
" O
bubble O
streamers O
" O
is O
investigated O
and O
their O
role O
in O
the O
initialization O
and O
propagation O
of O
cavitation O
activity O
throughout O
the O
sonicated O
liquid O
is O
discussed O
. O

Finally O
, O
it O
is O
shown O
that O
bubble O
activity O
can O
be O
stabilized O
and O
enhanced O
by O
the O
use O
of O
pulsed O
ultrasound O
by O
conserving O
and O
recycling O
active O
bubbles O
between O
subsequent O
pulsing O
cycles O
. O

The O
potential O
of O
nicotinic O
enhancement O
of O
cognitive O
remediation O
training O
in O
schizophrenia O
. O

Cognitive O
deficits O
in O
schizophrenia O
are O
critically O
important O
predictors O
of O
long O
- O
term O
psychosocial O
outcome O
and O
are O
not O
significantly O
ameliorated O
by O
currently O
available O
medications O
. O

Cognitive O
remediation O
training O
has O
shown O
promise O
for O
alleviating O
cognitive O
symptoms O
of O
schizophrenia O
, O
but O
the O
clinical O
significance O
has O
often O
been O
limited O
by O
small O
effect O
sizes O
. O

Approaches O
that O
achieve O
larger O
improvement O
involve O
time O
requirements O
that O
can O
be O
cost O
- O
prohibitive O
within O
the O
current O
clinical O
care O
system O
. O

This O
mini O
- O
review O
evaluates O
the O
theoretical O
potential O
of O
a O
pharmacological O
enhancement O
strategy O
of O
cognitive O
remediation O
training O
with O
nicotinic O
acetylcholine B
receptor O
( O
nAChR O
) O
agonists O
. O

nAChR O
agonists O
can O
facilitate O
sensory O
processing O
, O
alertness O
, O
attention O
, O
learning O
and O
memory O
. O

While O
these O
effects O
may O
be O
too O
subtle O
and O
short O
- O
lasting O
to O
be O
of O
clinical O
relevance O
as O
a O
primary O
treatment O
of O
cognitive O
deficits O
, O
they O
constitute O
an O
ideal O
effects O
profile O
for O
enhancing O
training O
benefits O
. O

Several O
mechanisms O
are O
described O
through O
which O
repeated O
coupling O
of O
cognitive O
training O
challenges O
with O
nAChR O
stimulation O
may O
enhance O
and O
accelerate O
cognitive O
remediation O
training O
effects O
, O
advancing O
such O
interventions O
into O
more O
effective O
and O
practicable O
treatments O
of O
some O
of O
the O
most O
debilitating O
symptoms O
of O
schizophrenia O
. O

This O
article O
is O
part O
of O
a O
Special O
Issue O
entitled O
' O
Cognitive O
Enhancers O
' O
. O

Enhanced O
mGlu5 O
- O
receptor O
dependent O
long O
- O
term O
depression O
at O
the O
Schaffer O
collateral O
- O
CA1 O
synapse O
of O
congenitally O
learned O
helpless O
rats O
. O

Alterations O
of O
the O
glutamatergic O
system O
have O
been O
implicated O
in O
the O
pathophysiology O
and O
treatment O
of O
major O
depression O
. O

In O
order O
to O
investigate O
the O
expression O
and O
function O
of O
mGlu5 O
receptors O
in O
an O
animal O
model O
for O
treatment O
- O
resistant O
depression O
we O
used O
rats O
bred O
for O
congenital O
learned O
helplessness O
( O
cLH O
) O
and O
the O
control O
strain O
, O
bred O
for O
resistance O
against O
inescapable O
stress O
, O
congenitally O
. O
not O
learned O
helpless O
rats O
( O
cNLH O
) O
. O

Western O
blot O
analysis O
showed O
an O
increased O
expression O
of O
mGlu5 O
( O
but O
not O
mGlu1a O
) O
receptors O
in O
the O
hippocampus O
of O
cLH O
rats O
, O
as O
compared O
with O
control O
cNLH O
rats O
. O

We O
also O
examined O
mGlu1 O
/ O
5 O
receptor O
signaling O
by O
in O
vivo O
measurement O
of O
DHPG B
- O
stimulated O
polyphosphoinositide B
hydrolysis O
. O

Stimulation O
of O
( B
3 I
) I
H I
- I
inositolmonophosphat I
formation O
induced O
by O
i O
. O
c O
. O
v O
. O
injection O
of O
DHPG B
was O
enhanced O
by O
about O
50 O
% O
in O
the O
hippocampus O
of O
cLH O
rats O
. O

Correspondingly O
, O
DHPG B
- O
induced O
long O
- O
term O
depression O
( O
LTD O
) O
at O
Schaffer O
collateral O
/ O
CA1 O
pyramidal O
cell O
synapses O
was O
amplified O
in O
hippocampal O
slices O
of O
cLH O
rats O
, O
whereas O
LTD O
induced O
by O
low O
frequency O
stimulation O
of O
the O
Schaffer O
collaterals O
did O
not O
change O
. O

Moreover O
, O
these O
effects O
were O
associated O
with O
decreased O
basal O
dendritic O
spine O
density O
of O
CA1 O
pyramidal O
cell O
in O
cLH O
rats O
. O

These O
data O
raise O
the O
attractive O
possibility O
that O
changes O
in O
the O
expression O
and O
function O
of O
mGlu5 O
receptors O
in O
the O
hippocampus O
might O
underlie O
the O
changes O
in O
synaptic O
plasticity O
associated O
with O
the O
depressive O
- O
like O
phenotype O
of O
cLH O
rats O
. O

However O
, O
chronic O
treatment O
of O
cLH O
rats O
with O
MPEP B
did O
not O
reverse O
learned O
helplessness O
, O
indicating O
that O
the O
enhanced O
mGlu5 O
receptor O
function O
is O
not O
the O
only O
player O
in O
the O
behavioral O
phenotype O
of O
this O
genetic O
model O
of O
depression O
. O

This O
article O
is O
part O
of O
a O
Special O
Issue O
entitled O
' O
Metabotropic O
Glutamate B
Receptors O
' O
. O

A O
variant O
in O
the O
carboxyl B
- O
terminus O
of O
connexin O
40 O
alters O
GAP O
junctions O
and O
increases O
risk O
for O
tetralogy O
of O
Fallot O
. O

GJA5 O
gene O
( O
MIM O
no O
. O
121013 O
) O
, O
localized O
at O
1q21 O
. O
1 O
, O
encodes O
for O
the O
cardiac O
gap O
junction O
protein O
connexin O
40 O
. O

In O
humans O
, O
copy O
number O
variants O
of O
chromosome O
1q21 O
. O
1 O
have O
been O
associated O
with O
variable O
phenotypes O
comprising O
congenital O
heart O
disease O
( O
CHD O
) O
, O
including O
isolated O
TOF O
. O

In O
mice O
, O
the O
deletion O
of O
Gja5 O
can O
cause O
a O
variety O
of O
complex O
CHDs O
, O
in O
particular O
of O
the O
cardiac O
outflow O
tract O
, O
corresponding O
to O
TOF O
in O
many O
cases O
. O

In O
the O
present O
study O
, O
we O
screened O
for O
mutations O
in O
the O
GJA5 O
gene O
178 O
unrelated O
probands O
with O
isolated O
TOF O
. O

A O
heterozygous O
nucleotide B
change O
( O
c O
. O
793C O
> O
T O
) O
in O
exon O
2 O
of O
the O
gene O
leading O
to O
the O
p O
. O
Pro265Ser O
variant O
at O
the O
carboxyl B
- O
terminus O
of O
the O
protein O
was O
found O
in O
two O
unrelated O
sporadic O
patients O
, O
one O
with O
classic O
anatomy O
and O
one O
with O
pulmonary O
atresia O
. O

This O
GJA5 O
missense O
substitution O
was O
not O
observed O
in O
1568 O
ethnically O
- O
matched O
control O
chromosomes O
. O

Immunofluorescent O
staining O
and O
confocal O
microscopy O
revealed O
that O
cells O
expressing O
the O
mutant O
protein O
form O
sparse O
or O
no O
visible O
gap O
- O
junction O
plaques O
in O
the O
region O
of O
cell O
- O
cell O
contact O
. O

Moreover O
, O
analysis O
of O
the O
transfer O
of O
the O
gap O
junction O
permanent O
tracer O
lucifer B
yellow I
showed O
that O
cells O
expressing O
the O
mutant O
protein O
have O
a O
reduced O
rate O
of O
dye O
transfer O
compared O
with O
wild O
- O
type O
cells O
. O

Finally O
, O
use O
of O
a O
zebrafish O
model O
revealed O
that O
microinjection O
of O
the O
GJA5 O
- O
p O
. O
Pro265Ser O
mutant O
disrupts O
overall O
morphology O
of O
the O
heart O
tube O
in O
the O
37 O
% O
( O
22 O
/ O
60 O
) O
of O
embryos O
, O
compared O
with O
the O
6 O
% O
( O
4 O
/ O
66 O
) O
of O
the O
GJA5 O
wild O
- O
type O
- O
injected O
embryos O
. O

These O
findings O
implicate O
GJA5 O
gene O
as O
a O
novel O
susceptibility O
gene O
for O
TOF O
. O

A O
newly O
identified O
locus O
for O
benign O
adult O
familial O
myoclonic O
epilepsy O
on O
chromosome O
3q26 O
. O
32 O
- O
3q28 O
. O

Benign O
Adult O
Familial O
Myoclonic O
Epilepsy O
( O
BAFME O
) O
is O
an O
autosomal O
dominant O
disorder O
characterized O
by O
adult O
- O
onset O
cortical O
tremor O
or O
action O
myoclonus O
predominantly O
in O
the O
upper O
limbs O
, O
and O
generalized O
seizures O
. O

We O
investigated O
a O
Thai O
BAFME O
family O
. O

Clinical O
and O
electrophysiological O
studies O
revealed O
that O
13 O
were O
affected O
with O
BAFME O
. O

There O
were O
a O
total O
of O
24 O
individuals O
studied O
. O

Genetic O
analysis O
by O
genome O
- O
wide O
linkage O
study O
( O
GWLS O
) O
was O
performed O
using O
400 O
microsatellite O
markers O
and O
excluded O
linkage O
of O
the O
previous O
BAFME O
loci O
, O
8q23 O
. O
3 O
- O
q24 O
. O
1 O
, O
and O
2p11 O
. O
1 O
- O
q12 O
. O
2 O
. O

GWLS O
showed O
that O
the O
disease O
- O
associated O
region O
in O
our O
Thai O
family O
was O
linked O
to O
a O
newly O
identified O
locus O
on O
chromosome O
3q26 O
. O
32 O
- O
3q28 O
. O

This O
locus O
represents O
the O
fourth O
chromosomal O
region O
for O
BAFME O
. O

Sonoluminescence O
quenching O
and O
cavitation O
bubble O
temperature O
measurements O
in O
an O
ionic O
liquid O
. O

A O
comparison O
between O
the O
temperatures O
within O
imploding O
acoustic O
cavitation O
bubbles O
and O
the O
extent O
of O
sonoluminescence O
( O
SL O
) O
quenching O
by O
C B
( I
1 I
) I
- I
C I
( I
5 I
) I
aliphatic I
alcohols I
in O
1 B
- I
ethyl I
- I
3 I
- I
methylimidazolium I
ethylsulfate I
( O
[ B
EMIM I
] I
[ I
EtSO I
( I
4 I
) I
] I
, O
a O
well O
known O
imidazolium B
based O
room O
temperature O
ionic O
liquid O
( O
RTIL O
) O
) O
, O
has O
been O
made O
at O
an O
ultrasound O
frequency O
of O
213 O
kHz O
. O

The O
temperatures O
obtained O
ranged O
from O
3500 O
+ O
/ O
- O
200K O
, O
in O
neat O
[ B
EMIM I
] I
[ I
EtSO I
( I
4 I
) I
] I
, O
to O
about O
3200 O
+ O
/ O
- O
200K O
in O
RTIL O
- O
alcohol B
containing O
solutions O
. O

It O
was O
also O
found O
that O
the O
SL O
intensity O
decreased O
with O
increasing O
concentration O
( O
up O
to O
1M O
) O
of O
the O
alcohols B
to O
a O
greater O
extent O
compared O
with O
the O
relative O
changes O
to O
the O
bubble O
temperatures O
. O

Both O
the O
extent O
of O
the O
reduction O
in O
the O
bubble O
temperatures O
and O
the O
SL O
quenching O
were O
much O
smaller O
than O
those O
obtained O
in O
comparable O
aqueous O
solutions O
containing O
aliphatic B
alcohols I
. O

Possible O
reasons O
for O
the O
differences O
in O
the O
observed O
trends O
between O
water O
/ O
alcohol B
and O
[ B
EMIM I
] I
[ I
EtSO I
( I
4 I
) I
] I
/ O
alcohol B
systems O
under O
sonication O
at O
213 O
kHz O
are O
discussed O
. O

GABAergic O
activity O
in O
autism O
spectrum O
disorders O
: O
an O
investigation O
of O
cortical O
inhibition O
via O
transcranial O
magnetic O
stimulation O
. O

Mounting O
evidence O
suggests O
a O
possible O
role O
for O
gamma B
- I
aminobutyric I
acid I
( O
GABA B
) O
in O
the O
neuropathophysiology O
of O
autism O
spectrum O
disorders O
( O
ASD O
) O
, O
but O
the O
extent O
of O
this O
impairment O
is O
unclear O
. O

A O
non O
- O
invasive O
, O
in O
vivo O
measure O
of O
GABA B
involves O
transcranial O
magnetic O
stimulation O
( O
TMS O
) O
of O
the O
primary O
motor O
cortex O
to O
probe O
cortical O
inhibition O
. O

Individuals O
diagnosed O
with O
ASD O
( O
high O
- O
functioning O
autism O
or O
Asperger O
' O
s O
disorder O
) O
( O
n O
= O
36 O
[ O
28 O
male O
] O
; O
mean O
age O
: O
26 O
. O
00 O
years O
) O
and O
a O
group O
of O
healthy O
individuals O
( O
n O
= O
34 O
[ O
23 O
male O
] O
; O
mean O
age O
: O
26 O
. O
21 O
years O
) O
( O
matched O
for O
age O
, O
gender O
, O
and O
cognitive O
function O
) O
were O
administered O
motor O
cortical O
TMS O
paradigms O
putatively O
measuring O
activity O
at O
GABAA O
and O
GABAB O
receptors O
( O
i O
. O
e O
. O
, O
short O
and O
long O
interval O
paired O
pulse O
TMS O
, O
cortical O
silent O
period O
) O
. O

All O
cortical O
inhibition O
paradigms O
yielded O
no O
difference O
between O
ASD O
and O
control O
groups O
. O

There O
was O
, O
however O
, O
evidence O
for O
short O
interval O
cortical O
inhibition O
( O
SICI O
) O
deficits O
among O
those O
ASD O
participants O
who O
had O
experienced O
early O
language O
delay O
, O
suggesting O
that O
GABA B
may O
be O
implicated O
in O
an O
ASD O
subtype O
. O

The O
current O
findings O
do O
not O
support O
a O
broad O
role O
for O
GABA B
in O
the O
neuropathophysiology O
of O
ASD O
, O
but O
provide O
further O
indication O
that O
GABAA O
could O
be O
involved O
in O
ASD O
where O
there O
is O
a O
delay O
in O
language O
acquisition O
. O

This O
article O
is O
part O
of O
the O
Special O
Issue O
entitled O
' O
Neurodevelopmental O
Disorders O
' O
. O

Pharmacological O
treatment O
of O
tic O
disorders O
and O
Tourette O
Syndrome O
. O

The O
present O
review O
gives O
an O
overview O
of O
current O
pharmacological O
treatment O
options O
of O
tic O
disorders O
and O
Tourette O
Syndrome O
( O
TS O
) O
. O

After O
a O
short O
summary O
on O
phenomenology O
, O
clinical O
course O
and O
comorbid O
conditions O
we O
review O
indications O
for O
pharmacological O
treatment O
in O
detail O
. O

Unfortunately O
, O
standardized O
and O
large O
enough O
drug O
trials O
in O
TS O
patients O
fulfilling O
evidence O
based O
medicine O
standards O
are O
still O
scarce O
. O

Treatment O
decisions O
are O
often O
guided O
by O
individual O
needs O
and O
personal O
experience O
of O
treating O
clinicians O
. O

The O
present O
recommendations O
for O
pharmacological O
tic O
treatment O
are O
therefore O
based O
on O
both O
scientific O
evidence O
and O
expert O
opinion O
. O

As O
first O
- O
line O
treatment O
of O
tics O
risperidone B
( O
best O
evidence O
level O
for O
atypical O
antipsychotics O
) O
or O
tiapride B
( O
largest O
clinical O
experience O
in O
Europe O
and O
low O
rate O
of O
adverse O
reactions O
) O
are O
recommended O
. O

Aripiprazole B
( O
still O
limited O
but O
promising O
data O
with O
low O
risk O
for O
adverse O
reactions O
) O
and O
pimozide B
( O
best O
evidence O
of O
the O
typical O
antipsychotics O
) O
are O
agents O
of O
second O
choice O
. O

In O
TS O
patients O
with O
comorbid O
attention O
deficit O
hyperactivity O
disorder O
( O
ADHD O
) O
atomoxetine B
, O
stimulants O
or O
clonidine B
should O
be O
considered O
, O
or O
, O
if O
tics O
are O
severe O
, O
a O
combination O
of O
stimulants B
and O
risperidone B
. O

When O
mild O
to O
moderate O
tics O
are O
associated O
with O
obsessive O
- O
compulsive O
symptoms O
, O
depression O
or O
anxiety O
sulpiride B
monotherapy O
can O
be O
helpful O
. O

In O
more O
severe O
cases O
the O
combination O
of O
risperidone B
and O
a O
selective O
serotonin B
reuptake O
inhibitor O
should O
be O
given O
. O

In O
summary O
, O
further O
studies O
, O
particularly O
randomized O
, O
double O
- O
blind O
, O
placebo O
- O
controlled O
trials O
including O
larger O
and O
/ O
or O
more O
homogenous O
patient O
groups O
over O
longer O
periods O
are O
urgently O
needed O
to O
enhance O
the O
scientific O
basis O
for O
drug O
treatment O
in O
tic O
disorders O
. O

This O
article O
is O
part O
of O
the O
Special O
Issue O
entitled O
' O
Neurodevelopmental O
Disorders O
' O
. O

Cognitive O
enhancement O
as O
a O
treatment O
for O
drug O
addictions O
. O

Drug O
addiction O
continues O
to O
be O
an O
important O
public O
health O
problem O
, O
with O
an O
estimated O
22 O
. O
6 O
million O
current O
illicit O
drug O
users O
in O
the O
United O
States O
alone O
. O

For O
many O
addictions O
, O
including O
cocaine B
, O
methamphetamine B
, O
and O
marijuana O
addiction O
, O
there O
are O
no O
approved O
pharmacological O
treatments O
. O

Behavioral O
treatments O
are O
effective O
but O
effects O
vary O
widely O
across O
individuals O
. O

Treatments O
that O
are O
effective O
across O
multiple O
addictions O
are O
greatly O
needed O
, O
and O
accumulating O
evidence O
suggests O
that O
one O
such O
approach O
may O
be O
pharmacological O
or O
behavioral O
interventions O
that O
enhance O
executive O
inhibitory O
control O
in O
addicts O
. O

Current O
evidence O
indicates O
that O
most O
forms O
of O
chronic O
drug O
use O
may O
be O
associated O
with O
significant O
cognitive O
impairments O
, O
especially O
in O
attention O
, O
working O
memory O
, O
and O
response O
inhibition O
functions O
. O

In O
some O
studies O
, O
these O
impairments O
predict O
poor O
treatment O
retention O
and O
outcome O
. O

A O
number O
of O
cognitive O
enhancing O
agents O
, O
including O
galantamine B
, O
modafinil B
, O
atomoxetine B
, O
methylphenidate B
, O
and O
guanfacine B
, O
have O
shown O
promising O
findings O
in O
human O
studies O
. O

Specific O
behavioral O
interventions O
, O
including O
cognitive O
remediation O
, O
also O
show O
promise O
. O

However O
, O
whether O
improvement O
of O
selective O
cognitive O
functions O
reduces O
drug O
use O
behavior O
remains O
to O
be O
determined O
. O

Cognitive O
enhancement O
to O
improve O
treatment O
outcomes O
is O
a O
novel O
strategy O
worthy O
of O
future O
research O
, O
as O
are O
related O
questions O
such O
as O
whether O
these O
approaches O
may O
be O
broadly O
beneficial O
to O
most O
addicts O
or O
best O
reserved O
for O
substance O
users O
with O
specific O
demonstrated O
cognitive O
impairments O
. O

This O
article O
is O
part O
of O
a O
Special O
Issue O
entitled O
' O
Cognitive O
Enhancers O
' O
. O

Pinosylvin B
Induces O
Cell O
Survival O
, O
Migration O
and O
Anti O
- O
Adhesiveness O
of O
Endothelial O
Cells O
via O
Nitric B
Oxide I
Production O
. O

Pinosylvin B
is O
a O
phenolic B
compound O
mainly O
found O
in O
the O
Pinus O
species O
. O

To O
determine O
the O
vascular O
functions O
of O
pinosylvin B
, O
we O
first O
examined O
both O
proliferation O
and O
apoptosis O
of O
bovine O
aortic O
endothelial O
cells O
( O
BAECs O
) O
in O
the O
presence O
of O
pinosylvin B
. O

When O
BAECs O
were O
treated O
with O
pinosylvin B
, O
etoposide O
- O
or O
starvation O
- O
induced O
apoptosis O
was O
shown O
to O
be O
significantly O
reduced O
. O

The O
anti O
- O
apoptotic O
effect O
of O
pinosylvin B
was O
mediated O
by O
inhibition O
of O
caspase O
- O
3 O
. O

Moreover O
, O
pinosylvin B
was O
shown O
to O
activate O
endothelial O
nitric B
oxide I
synthetase O
( O
eNOS O
) O
. O

At O
1 O
pM O
, O
pinosylvin B
appeared O
to O
have O
a O
cell O
- O
proliferative O
effect O
in O
the O
endothelial O
cell O
. O

The O
pinosylvin B
- O
induced O
cell O
proliferation O
was O
declined O
by O
treatment O
with O
L B
- I
NAME I
, O
an O
eNOS O
inhibitor O
. O

Then O
, O
we O
found O
that O
pinosylvin B
had O
a O
stimulatory O
effect O
on O
cell O
migration O
and O
tube O
formation O
. O

These O
stimulatory O
effects O
suggest O
that O
pinosylvin B
is O
likely O
to O
act O
as O
a O
pro O
- O
angiogenic O
factor O
. O

Yet O
another O
effect O
of O
pinosylvin B
was O
inhibition O
of O
lipopolysaccharide O
- O
induced O
THP O
- O
1 O
cell O
adhesion O
to O
endothelial O
cells O
. O

Altogether O
, O
we O
propose O
that O
pinosylvin B
may O
be O
utilized O
as O
a O
phytotherapic O
agent O
for O
the O
prevention O
of O
cardiovascular O
inflammatory O
diseases O
. O

Copyright O
( O
c O
) O
2012 O
John O
Wiley O
& O
Sons O
, O
Ltd O
. O

Dihydroxy B
- I
Isosteviol I
Methyl I
Ester I
from O
Pulsatilla O
nigricans O
Induces O
Apoptosis O
in O
HeLa O
Cells O
: O
Its O
Cytoxicity O
and O
Interaction O
with O
Calf O
Thymus O
DNA O
. O

Dihydroxy B
- I
isosteviol I
methyl I
ester I
( O
DIME B
) O
, O
the O
principal O
biological O
compound O
isolated O
from O
the O
medicinal O
plant O
Pulsatilla O
nigricans O
( O
Fam O
: O
Ranunculaceae O
) O
having O
the O
molecular O
formula O
of O
C21 B
H34 I
O3 I
( O
molecular O
weight O
334 O
. O
25 O
) O
, O
was O
administered O
to O
cervical O
cancer O
cells O
( O
HeLa O
) O
in O
vitro O
to O
evaluate O
its O
possible O
apoptotic O
( O
anti O
- O
cancer O
) O
potentials O
. O

We O
analyzed O
the O
expression O
of O
p53 O
, O
Bax O
, O
Bcl2 O
, O
Apaf O
and O
caspase O
3 O
signal O
proteins O
and O
analyzed O
the O
early O
apoptotic O
events O
in O
HeLa O
cells O
induced O
by O
DIME O
using O
protocols O
like O
Annexin O
V O
- O
FITC B
and O
PI O
staining O
. O

DIME B
caused O
a O
significant O
decrease O
in O
cell O
viability O
, O
induced O
nuclear O
condensation O
and O
inter O
- O
nucleosomal O
DNA O
fragmentation O
. O

We O
further O
studied O
the O
interaction O
of O
DIME B
with O
calf O
thymus O
DNA O
as O
target O
through O
circular O
- O
dichroism O
spectra O
. O

Results O
showed O
that O
DIME O
interacted O
with O
DNA O
, O
bringing O
indiscernible O
changes O
in O
structure O
and O
conformation O
. O

Thus O
, O
DIME B
showed O
its O
capability O
to O
induce O
apoptosis O
in O
cancer O
cells O
, O
signifying O
its O
utility O
in O
drug O
design O
as O
a O
possible O
candidate O
for O
chemoprevention O
. O

Copyright O
( O
c O
) O
2012 O
John O
Wiley O
& O
Sons O
, O
Ltd O
. O

Genome O
- O
wide O
patterns O
of O
standing O
genetic O
variation O
in O
a O
marine O
population O
of O
three O
- O
spined O
sticklebacks O
. O

Since O
the O
end O
of O
the O
Pleistocene O
, O
the O
three O
- O
spined O
stickleback O
( O
Gasterosteus O
aculeatus O
) O
has O
repeatedly O
colonized O
and O
adapted O
to O
various O
freshwater O
habitats O
probably O
originating O
from O
ancestral O
marine O
populations O
. O

Standing O
genetic O
variation O
and O
the O
underlying O
genomic O
architecture O
both O
have O
been O
speculated O
to O
contribute O
to O
recent O
adaptive O
radiations O
of O
sticklebacks O
. O

Here O
, O
we O
expand O
on O
the O
current O
genomic O
resources O
of O
this O
fish O
by O
providing O
extensive O
genome O
- O
wide O
variation O
data O
from O
six O
individuals O
from O
a O
marine O
( O
North O
Sea O
) O
stickleback O
population O
. O

Using O
next O
- O
generation O
sequencing O
and O
a O
combination O
of O
paired O
- O
end O
and O
mate O
- O
pair O
libraries O
, O
we O
detected O
a O
wide O
size O
range O
of O
genetic O
variation O
. O

Among O
the O
six O
individuals O
, O
we O
found O
more O
than O
7 O
% O
of O
the O
genome O
is O
polymorphic O
, O
consisting O
of O
2599111 O
SNPs O
, O
233464 O
indels O
and O
structural O
variation O
( O
SV O
) O
( O
> O
50 O
bp O
) O
such O
as O
1054 O
copy O
- O
number O
variable O
regions O
( O
deletions O
and O
duplications O
) O
and O
48 O
inversions O
. O

Many O
of O
these O
polymorphisms O
affect O
gene O
and O
coding O
sequences O
. O

Based O
on O
SNP O
diversity O
, O
we O
determined O
outlier O
regions O
concordant O
with O
signatures O
expected O
under O
adaptive O
evolution O
. O

As O
some O
of O
these O
outliers O
overlap O
with O
pronounced O
regions O
of O
copy O
- O
number O
variation O
, O
we O
propose O
the O
consideration O
of O
such O
SV O
when O
analysing O
SNP O
data O
from O
re O
- O
sequencing O
approaches O
. O

We O
further O
discuss O
the O
value O
of O
this O
resource O
on O
genome O
- O
wide O
variation O
for O
further O
investigation O
upon O
the O
relative O
contribution O
of O
standing O
variation O
on O
the O
parallel O
evolution O
of O
sticklebacks O
and O
the O
importance O
of O
the O
genomic O
architecture O
in O
adaptive O
radiation O
. O

Structure O
- O
based O
optimization O
of O
oxadiazole B
- O
based O
GSK O
- O
3 O
inhibitors O
. O

Inhibition O
of O
glycogen O
synthase O
kinase O
- O
3 O
( O
GSK O
- O
3 O
) O
induces O
neuroprotective O
effects O
, O
e O
. O
g O
. O
decreases O
beta O
- O
amyloid O
production O
and O
reduces O
tau O
hyperphosphorylation O
, O
which O
are O
both O
associated O
with O
Alzheimer O
' O
s O
disease O
( O
AD O
) O
. O

The O
two O
isoforms O
of O
GSK O
- O
3 O
in O
mammalians O
are O
GSK O
- O
3 O
alpha O
and O
beta O
, O
which O
share O
98 O
% O
homology O
in O
their O
catalytic O
domains O
. O

We O
investigated O
GSK O
- O
3 O
inhibitors O
based O
on O
2 O
different O
scaffolds O
in O
order O
to O
elucidate O
the O
demands O
of O
the O
ATP B
- O
binding O
pocket O
[ O
1 O
] O
. O

Particularly O
, O
the O
oxadiazole B
scaffold O
provided O
potent O
and O
selective O
GSK O
- O
3 O
inhibitors O
. O

For O
example O
, O
the O
most O
potent O
inhibitor O
of O
the O
present O
series O
, O
the O
acetamide B
26d O
, O
is O
characterized O
by O
an O
IC50 O
of O
2 O
nM O
for O
GSK O
- O
3 O
alpha O
and O
17 O
nM O
for O
GSK O
- O
3 O
beta O
. O

In O
addition O
, O
the O
benzodioxane B
8g O
showed O
up O
to O
27 O
- O
fold O
selectivity O
for O
GSK O
- O
3 O
alpha O
over O
GSK O
- O
3 O
beta O
, O
with O
an O
IC50 O
of O
35 O
nM O
for O
GSK O
- O
3 O
alpha O
. O

Two O
GSK O
- O
3 O
inhibitors O
were O
further O
profiled O
for O
efficacy O
and O
toxicity O
in O
the O
wild O
- O
type O
( O
wt O
) O
zebrafish O
embryo O
assay O
to O
evaluate O
simultaneously O
permeability O
and O
safety O
. O

Dual O
inhibitor O
of O
PDE7 O
and O
GSK O
- O
3 O
- O
VP1 O
. O
15 O
acts O
as O
antipsychotic O
and O
cognitive O
enhancer O
in O
C57BL O
/ O
6J O
mice O
. O

Cognitive O
deficit O
is O
a O
core O
of O
schizophrenia O
and O
it O
is O
not O
effectively O
treated O
by O
the O
available O
antipsychotic O
drugs O
, O
hence O
new O
and O
more O
effective O
therapy O
is O
needed O
. O

Schizophrenia O
is O
considered O
as O
a O
pathway O
disorder O
where O
Disrupted O
- O
In O
- O
Schizophrenia O
- O
1 O
( O
DISC1 O
) O
is O
important O
molecular O
player O
that O
regulates O
multiple O
cellular O
cascades O
. O

We O
recently O
reported O
synergistic O
action O
between O
phosphodiesterase O
- O
4 O
( O
PDE4 O
) O
and O
glycogen O
synthase O
kinase O
- O
3 O
( O
GSK O
- O
3 O
) O
as O
DISC1 O
interacting O
proteins O
. O

In O
the O
current O
study O
we O
characterized O
behavioural O
effects O
of O
a O
newly O
developed O
compound O
, O
VP1 O
. O
15 O
that O
inhibits O
both O
PDE7 O
and O
GSK O
- O
3 O
with O
main O
focus O
on O
its O
antipsychotic O
and O
cognitive O
capacities O
. O

VP1 O
. O
15 O
reduced O
ambulation O
in O
C57BL O
/ O
6J O
mice O
in O
a O
dose O
- O
dependent O
manner O
( O
7 O
. O
5 O
mg O
/ O
kg O
and O
3 O
mg O
/ O
kg O
, O
respectively O
) O
and O
, O
hence O
, O
lower O
dose O
was O
chosen O
for O
the O
further O
analysis O
. O

VP1 O
. O
1 O
. O
5 O
facilitated O
pre O
- O
pulse O
inhibition O
( O
PPI O
) O
, O
reversed O
amphetamine B
- O
but O
not O
MK B
- I
801 I
- O
induced O
PPI O
deficit O
. O

The O
drug O
was O
able O
to O
ameliorate O
the O
disrupted O
latent O
inhibition O
( O
LI O
) O
induced O
by O
the O
increased O
number O
of O
conditioning O
trials O
and O
reversed O
amphetamine B
- O
induced O
LI O
deficit O
, O
supporting O
further O
its O
antipsychotic O
effects O
. O

The O
drug O
also O
significantly O
improved O
episodic O
memory O
in O
the O
spatial O
object O
recognition O
test O
, O
facilitated O
working O
memory O
in O
Y O
- O
maze O
and O
enhanced O
cued O
fear O
memory O
, O
but O
had O
no O
effect O
on O
executive O
function O
in O
the O
Puzzle O
box O
and O
contextual O
fear O
conditioning O
. O

Taken O
together O
, O
VP1 O
. O
15 O
elicited O
antipsychotic O
effects O
and O
also O
facilitated O
cognitive O
domains O
in O
mice O
, O
suggesting O
that O
multitarget O
drugs O
, O
affecting O
molecular O
substrates O
from O
the O
same O
pathway O
, O
perhaps O
could O
be O
antipsychotics O
of O
new O
- O
generation O
that O
open O
a O
new O
possibilities O
in O
drug O
discoveries O
. O

This O
article O
is O
part O
of O
a O
Special O
Issue O
entitled O
' O
Cognitive O
Enhancers O
' O
. O

The O
novel O
phosphodiesterase O
10A O
inhibitor O
THPP B
- I
1 I
has O
antipsychotic O
- O
like O
effects O
in O
rat O
and O
improves O
cognition O
in O
rat O
and O
rhesus O
monkey O
. O

Phosphodiesterase O
10A O
( O
PDE10A O
) O
is O
a O
novel O
target O
for O
the O
treatment O
of O
schizophrenia O
that O
may O
address O
multiple O
symptomatic O
domains O
associated O
with O
this O
disorder O
. O

PDE10A O
is O
highly O
expressed O
in O
the O
brain O
and O
functions O
to O
metabolically O
inactivate O
the O
important O
second O
messengers O
cAMP B
and O
cGMP B
. O

Here O
we O
describe O
effects O
of O
a O
potent O
and O
orally O
bioavailable O
PDE10A O
inhibitor O
[ O
2 I
- I
( I
6 I
- I
chloropyridin I
- I
3 I
- I
yl I
) I
- I
4 I
- I
( I
2 I
- I
methoxyethoxy I
) I
- I
7 I
, I
8 I
- I
dihydropyrido I
[ I
4 I
, I
3 I
- I
d I
] I
pyrimidin I
- I
6 I
( I
5H I
) I
- I
yl I
] I
( I
imidazo I
[ I
1 I
, I
5 I
- I
a I
] I
pyridin I
- I
1 I
- I
yl I
) I
methanone I
] I
( O
THPP B
- I
1 I
) O
on O
striatal O
signaling O
pathways O
, O
in O
behavioral O
tests O
that O

predict O
antipsychotic O
potential O
, O
and O
assays O
that O
measure O
episodic O
- O
like O
memory O
in O
rat O
and O
executive O
function O
in O
rhesus O
monkey O
. O

THPP O
- O
1 O
exhibits O
nanomolar O
potency O
on O
the O
PDE10A O
enzyme O
, O
demonstrates O
excellent O
pharmacokinetic O
properties O
in O
multiple O
preclinical O
animal O
species O
, O
and O
is O
selective O
for O
PDE10A O
over O
other O
PDE O
families O
of O
enzymes O
. O

THPP O
- O
1 O
significantly O
increased O
phosphorylation O
of O
proteins O
in O
the O
striatum O
involved O
in O
synaptic O
plasticity O
, O
including O
the O
a B
- I
amino I
- I
3 I
- I
hydroxy I
- I
5 I
- I
methylisoxazole I
- I
4 I
- I
proprionic I
acid I
receptor O
( O
AMPA O
) O
GluR1 O
subunit O
, O
extracellular O
receptor O
kinase O
( O
ERK O
) O
, O
and O
cAMP B
- O
response O
element O
binding O
protein O
( O
CREB O
) O
. O

THPP B
- I
1 I
produced O
dose O
- O
dependent O
effects O
in O
preclinical O
assays O
predictive O
of O
antipsychotic O
activity O
including O
attenuation O
of O
MK B
- I
801 I
- O
induced O
psychomotor O
activation O
and O
condition O
avoidance O
responding O
in O
rats O
. O

At O
similar O
plasma O
exposures O
, O
THPP B
- I
1 I
significantly O
increased O
object O
recognition O
memory O
in O
rat O
and O
attenuated O
a O
ketamine B
- O
induced O
deficit O
in O
the O
object O
retrieval O
detour O
task O
in O
rhesus O
monkey O
. O

These O
findings O
suggest O
that O
PDE10A O
inhibitors O
have O
the O
potential O
to O
impact O
multiple O
symptomatic O
domains O
of O
schizophrenia O
including O
positive O
symptoms O
and O
cognitive O
impairment O
. O

This O
article O
is O
part O
of O
a O
Special O
Issue O
entitled O
' O
Cognitive O
Enhancers O
' O
. O

Quetiapine B
ameliorates O
stress O
- O
induced O
cognitive O
inflexibility O
in O
rats O
. O

The O
antidepressant O
action O
of O
quetiapine B
has O
been O
demonstrated O
in O
clinical O
and O
preclinical O
studies O
. O

Nevertheless O
, O
little O
is O
known O
about O
its O
effectiveness O
in O
the O
treatment O
of O
frontal O
- O
like O
cognitive O
disturbances O
that O
may O
be O
associated O
with O
stress O
- O
related O
disorder O
. O

Therefore O
, O
the O
aim O
of O
the O
present O
study O
was O
to O
investigate O
whether O
quetiapine B
would O
prevent O
and O
/ O
or O
reverse O
stress O
- O
induced O
cognitive O
impairments O
in O
a O
rat O
model O
of O
prefrontal O
cortex O
( O
PFC O
) O
- O
dependent O
attentional O
set O
- O
shifting O
task O
( O
ASST O
) O
. O

Because O
quetiapine B
augmentation O
to O
selective O
serotonin B
reuptake O
inhibitors O
( O
SSRIs O
) O
has O
recently O
been O
proven O
to O
be O
beneficial O
in O
neuropsychiatric O
disorders O
, O
a O
separate O
experiment O
was O
designed O
to O
assess O
the O
impact O
of O
combined O
administration O
of O
inactive O
doses O
of O
quetiapine B
and O
escitalopram B
on O
ASST O
performance O
in O
rats O
. O

According O
to O
our O
previous O
studies O
, O
1 O
h O
daily O
exposure O
to O
restraint O
stress O
for O
7 O
days O
significantly O
and O
specifically O
impaired O
extra O
- O
dimensional O
( O
ED O
) O
set O
- O
shifting O
ability O
of O
rats O
. O

Quetiapine B
( O
2 O
. O
5 O
mg O
/ O
kg O
, O
PO O
) O
given O
to O
rats O
prior O
to O
the O
restraint O
sessions O
completely O
prevented O
this O
stress O
- O
induced O
cognitive O
inflexibility O
. O

Similar O
effect O
was O
demonstrated O
after O
pretreatment O
with O
the O
alpha O
1 O
- O
adrenoceptor O
antagonist O
, O
prazosin B
( O
1 O
mg O
/ O
kg O
, O
IP O
) O
. O

Moreover O
, O
acute O
administration O
of O
quetiapine B
before O
the O
test O
reversed O
set O
- O
shifting O
deficits O
in O
stressed O
rats O
( O
0 O
. O
63 O
, O
1 O
. O
25 O
and O
2 O
. O
5 O
mg O
/ O
kg O
, O
PO O
) O
and O
improved O
ED O
performance O
of O
cognitively O
unimpaired O
control O
animals O
( O
1 O
. O
25 O
and O
2 O
. O
5 O
mg O
/ O
kg O
, O
PO O
) O
. O

Finally O
, O
the O
combined O
administration O
of O
inactive O
doses O
of O
quetiapine B
( O
0 O
. O
63 O
and O
0 O
. O
3 O
mg O
/ O
kg O
in O
control O
and O
stressed O
rats O
, O
respectively O
) O
and O
escitalopram B
( O
0 O
. O
3 O
mg O
/ O
kg O
, O
IP O
) O
facilitated O
set O
- O
shifting O
performance O
in O
either O
control O
or O
stressed O
rats O
. O

In O
conclusion O
, O
quetiapine B
administration O
either O
prevented O
or O
reversed O
stress O
- O
induced O
cognitive O
inflexibility O
in O
rats O
. O

In O
addition O
to O
promoting O
of O
set O
- O
shifting O
by O
itself O
, O
quetiapine B
also O
enhanced O
the O
procognitive O
efficacy O
of O
escitalopram B
. O

The O
potential O
contribution O
of O
the O
antagonism O
at O
alpha O
1 O
- O
adrenoceptors O
to O
the O
mechanisms O
underlying O
the O
protective O
action O
of O
quetiapine B
requires O
further O
evaluation O
. O

These O
findings O
may O
have O
therapeutic O
implications O
for O
the O
treatment O
of O
frontal O
- O
like O
disturbances O
, O
particularly O
cognitive O
inflexibility O
, O
in O
stress O
- O
related O
psychiatric O
disorders O
. O

This O
article O
is O
part O
of O
a O
Special O
Issue O
entitled O
' O
Cognitive O
Enhancers O
' O
. O

Modified O
- O
release O
prednisone B
decreases O
complaints O
and O
fatigue O
compared O
to O
standard O
prednisolone B
in O
patients O
with O
adrenal O
insufficiency O
. O

Patients O
with O
adrenal O
insufficiency O
( O
AI O
) O
receive O
first O
glucocorticoid O
replacement O
dose O
after O
waking O
, O
resulting O
in O
a O
3 O
- O
5 O
h O
delay O
compared O
to O
physiological O
secretion O
. O

Impaired O
quality O
of O
life O
( O
QoL O
) O
and O
fatigue O
might O
be O
due O
to O
this O
delayed O
dose O
scheme O
. O

Modified O
- O
release O
glucocorticoid O
preparations O
might O
have O
therapeutic O
advantages O
. O

Exploratory O
pilot O
study O
including O
14 O
patients O
with O
AI O
was O
conducted O
in O
a O
single O
university O
center O
. O

Patients O
on O
morning O
dose O
prednisolone B
( O
5 O
mg O
) O
were O
included O
, O
switched O
to O
modified O
- O
release O
prednisone B
( O
5 O
mg O
) O
at O
10 O
PM O
for O
3 O
months O
, O
and O
then O
switched O
back O
on O
standard O
prednisolone B
. O

3 O
standardized O
questionnaires O
( O
GBB O
- O
24 O
, O
MFI O
, O
and O
AddiQoL O
) O
investigating O
complaints O
and O
fatigue O
were O
completed O
at O
baseline O
, O
after O
3 O
, O
and O
6 O
months O
. O

Data O
regarding O
clinical O
and O
hormonal O
parameters O
were O
assessed O
. O

Modified O
- O
release O
prednisone B
showed O
significant O
improvement O
in O
one O
of O
4 O
scales O
of O
GBB O
- O
24 O
and O
positive O
trends O
to O
better O
scores O
in O
3 O
of O
4 O
scales O
. O

The O
global O
score O
of O
discomfort O
improved O
significantly O
. O

The O
MFI O
showed O
also O
significant O
improvement O
in O
3 O
of O
5 O
scales O
and O
positive O
trend O
to O
better O
scores O
in O
2 O
scales O
. O

Significant O
changes O
to O
better O
scores O
were O
seen O
in O
4 O
out O
of O
30 O
items O
of O
the O
AddiQoL O
. O

Modified O
- O
release O
prednisone B
showed O
decreased O
complaints O
and O
fatigue O
compared O
to O
standard O
prednisolone B
indicating O
importance O
of O
glucocorticoid O
increase O
in O
early O
morning O
hours O
before O
waking O
. O

Bioactivity O
of O
Diosmetin B
Glycosides I
Isolated O
from O
the O
Epicarp O
of O
Date O
Fruits O
, O
Phoenix O
dactylifera O
, O
on O
the O
Biochemical O
Profile O
of O
Alloxan B
Diabetic O
Male O
Rats O
. O

The O
new O
natural O
flavonoid B
compounds O
- O
diosmetin B
7 I
- I
O I
- I
beta I
- I
L I
- I
arabinofuranosyl I
( I
1 I
- I
- I
> I
2 I
) I
beta I
- I
D I
- I
apiofuranoside I
( O
1 O
) O
and O
diosmetin B
7 I
- I
O I
- I
beta I
- I
D I
- I
apiofuranoside I
( O
2 O
) O
- O
were O
isolated O
from O
the O
acetone B
extract O
of O
date O
fruits O
epicarp O
belonging O
to O
family O
Arecaceae O
( O
Palmae O
) O
. O

Elucidation O
of O
their O
chemical O
structures O
was O
determined O
by O
different O
spectroscopic O
methods O
in O
addition O
to O
the O
chemical O
and O
physical O
methods O
of O
analysis O
. O

These O
compounds O
were O
assessed O
for O
their O
biological O
activity O
on O
alloxan B
diabetic O
rats O
. O

A O
dose O
of O
1 O
. O
5 O
ml O
of O
( O
1 O
) O
and O
( O
2 O
) O
suspensions O
/ O
100 O
gm O
b O
. O

wt O
were O
orally O
administrated O
to O
alloxan B
diabetic O
rats O
for O
30 O
days O
. O

The O
treatment O
of O
diabetic O
rats O
with O
these O
compounds O
resulted O
in O
marked O
improvement O
of O
the O
different O
biochemical O
results O
, O
i O
. O
e O
. O
the O
serum O
glucose B
level O
( O
highly O
significant O
, O
from O
330 O
+ O
5 O
. O
5 O
mg O
/ O
dL O
to O
140 O
+ O
1 O
. O
2 O
mg O
/ O
dL O
) O
treated O
with O
( O
1 O
) O
; O
liver O
functions O
markedly O
developed O
both O
by O
AST O
and O
ALT O
levels O
, O
( O
reduced O
significantly O
from O
68 O
. O
3 O
+ O
4 O
. O
8 O
mu O
/ O
L O
to O
54 O
+ O
5 O
. O
5 O
mu O
/ O
L O
and O
from O
61 O
. O
0 O
+ O
3 O
. O
6 O
mu O
/ O
L O
to O
40 O
. O
1 O
+ O
3 O
. O
6 O
mu O
/ O
L O
, O
respectively O

) O
treated O
with O
( O
2 O
) O
, O
accompanying O
with O
mild O
decrease O
in O
both O
cholesterol B
and O
triglycerides B
levels O
with O
( O
1 O
) O
or O
( O
2 O
) O
. O

Decrease O
of O
TBARS O
level O
was O
observed O
in O
whole O
blood O
when O
treated O
with O
( O
1 O
) O
or O
( O
2 O
) O
, O
while O
levels O
of O
glutathione B
peroxidase O
and O
superoxide B
dismutase O
were O
increased O
in O
liver O
. O

Serum O
testosterone B
level O
was O
highly O
significantly O
increased O
( O
from O
705 O
. O
1 O
+ O
3 O
. O
6 O
mg O
/ O
100 O
ml O
to O
720 O
+ O
4 O
. O
7 O
mg O
/ O
100 O
ml O
) O
, O
total O
acid O
phosphatase O
and O
prostate O
acid O
phosphatase O
activities O
were O
highly O
significantly O
decreased O
( O
from O
16 O
. O
9 O
+ O
0 O
. O
28 O
mu O
/ O
L O
to O
10 O
. O
7 O
+ O
1 O
. O
2 O
mu O
/ O
L O
and O
from O
9 O
. O
7 O
+ O
0 O
. O
7 O
mu O
/ O
L O
to O
6 O
. O
5 O
+ O
1 O
mu O
/ O
L O
, O
respectively O
) O
for O
compound O
( O
1 O
) O
. O

Copyright O
( O
c O
) O
2012 O
John O
Wiley O
& O
Sons O
, O
Ltd O
. O

Haplotype O
analysis O
of O
the O
185delAG O
BRCA1 O
mutation O
in O
ethnically O
diverse O
populations O
. O

The O
185delAG O
* O
BRCA1 O
mutation O
is O
encountered O
primarily O
in O
Jewish O
Ashkenazi O
and O
Iraqi O
individuals O
, O
and O
sporadically O
in O
non O
- O
Jews O
. O

Previous O
studies O
estimated O
that O
this O
is O
a O
founder O
mutation O
in O
Jewish O
mutation O
carriers O
that O
arose O
before O
the O
dispersion O
of O
Jews O
in O
the O
Diaspora O
~ O
2500 O
years O
ago O
. O

The O
aim O
of O
this O
study O
was O
to O
assess O
the O
haplotype O
in O
ethnically O
diverse O
185delAG O
* O
BRCA1 O
mutation O
carriers O
, O
and O
to O
estimate O
the O
age O
at O
which O
the O
mutation O
arose O
. O

Ethnically O
diverse O
Jewish O
and O
non O
- O
Jewish O
185delAG O
* O
BRCA1 O
mutation O
carriers O
and O
their O
relatives O
were O
genotyped O
using O
15 O
microsatellite O
markers O
and O
three O
SNPs O
spanning O
12 O
. O
5 O
MB O
, O
encompassing O
the O
BRCA1 O
gene O
locus O
. O

Estimation O
of O
mutation O
age O
was O
based O
on O
a O
subset O
of O
11 O
markers O
spanning O
a O
region O
of O
~ O
5 O
MB O
, O
using O
a O
previously O
developed O
algorithm O
applying O
the O
maximum O
likelihood O
method O
. O

Overall O
, O
188 O
participants O
( O
154 O
carriers O
and O
34 O
noncarriers O
) O
from O
115 O
families O
were O
included O
: O
Ashkenazi O
, O
Iraq O
, O
Kuchin O
- O
Indians O
, O
Syria O
, O
Turkey O
, O
Iran O
, O
Tunisia O
, O
Bulgaria O
, O
non O
- O
Jewish O
English O
, O
non O
- O
Jewish O
Malaysian O
, O
and O
Hispanics O
. O

Haplotype O
analysis O
indicated O
that O
the O
185delAG O
mutation O
arose O
750 O
- O
1500 O
years O
ago O
. O

In O
Ashkenazim O
, O
it O
is O
a O
founder O
mutation O
that O
arose O
61 O
generations O
ago O
, O
and O
with O
a O
small O
group O
of O
founder O
mutations O
was O
introduced O
into O
the O
Hispanic O
population O
( O
conversos O
) O
~ O
650 O
years O
ago O
, O
and O
into O
the O
Iraqi O
- O
Jewish O
community O
~ O
450 O
years O
ago O
. O

The O
185delAG O
mutation O
in O
the O
non O
- O
Jewish O
populations O
in O
Malaysia O
and O
the O
UK O
arose O
at O
least O
twice O
independently O
. O

We O
conclude O
that O
the O
185delAG O
* O
BRCA1 O
mutation O
resides O
on O
a O
common O
haplotype O
among O
Ashkenazi O
Jews O
, O
and O
arose O
about O
61 O
generations O
ago O
and O
arose O
independently O
at O
least O
twice O
in O
non O
- O
Jews O
. O

Role O
of O
AMPK O
in O
pancreatic O
beta O
cell O
function O
. O

Pharmacological O
activation O
of O
AMP B
activated O
kinase O
( O
AMPK O
) O
by O
metformin B
has O
proven O
to O
be O
a O
beneficial O
therapeutic O
approach O
for O
the O
treatment O
of O
type O
II O
diabetes O
. O

Despite O
improved O
glucose B
regulation O
achieved O
by O
administration O
of O
small O
molecule O
activators O
of O
AMPK O
, O
the O
potential O
negative O
impact O
of O
enhanced O
AMPK O
activity O
on O
insulin O
secretion O
by O
the O
pancreatic O
beta O
cell O
is O
an O
important O
consideration O
. O

In O
this O
review O
, O
we O
discuss O
our O
current O
understanding O
of O
the O
role O
of O
AMPK O
in O
central O
functions O
of O
the O
pancreatic O
beta O
cell O
, O
including O
glucose B
- O
stimulated O
insulin O
secretion O
( O
GSIS O
) O
, O
proliferation O
, O
and O
survival O
. O

In O
addition O
we O
discuss O
the O
controversy O
surrounding O
the O
role O
of O
AMPK O
in O
insulin O
secretion O
, O
underscoring O
the O
merits O
and O
caveats O
of O
methods O
used O
to O
date O
. O

Enhancement O
of O
cognitive O
function O
in O
models O
of O
brain O
disease O
through O
environmental O
enrichment O
and O
physical O
activity O
. O

This O
review O
will O
provide O
an O
overview O
of O
the O
non O
- O
drug O
based O
approaches O
that O
have O
been O
demonstrated O
to O
enhance O
cognitive O
function O
of O
the O
compromised O
brain O
, O
primarily O
focussed O
on O
the O
two O
most O
widely O
adopted O
paradigms O
of O
environmental O
enrichment O
and O
enhanced O
physical O
exercise O
. O

Environmental O
enrichment O
involves O
the O
generation O
of O
novelty O
and O
complexity O
in O
animal O
housing O
conditions O
which O
facilitates O
enhanced O
sensory O
and O
cognitive O
stimulation O
as O
well O
as O
physical O
activity O
. O

In O
a O
wide O
variety O
of O
animal O
models O
of O
brain O
disorders O
, O
environmental O
enrichment O
and O
exercise O
have O
been O
found O
to O
have O
beneficial O
effects O
, O
including O
cognitive O
enhancement O
, O
delayed O
disease O
onset O
, O
enhanced O
cellular O
plasticity O
and O
associated O
molecular O
processes O
. O

Potential O
cellular O
and O
molecular O
mechanisms O
will O
also O
be O
discussed O
, O
which O
have O
relevance O
for O
the O
future O
development O
of O
' O
enviromimetics O
' O
, O
drugs O
which O
could O
mimic O
or O
enhance O
the O
beneficial O
effects O
of O
environmental O
stimulation O
. O

This O
article O
is O
part O
of O
a O
Special O
Issue O
entitled O
' O
Cognitive O
Enhancers O
' O
. O

Human O
neuronal O
coenzyme B
Q10 I
deficiency O
results O
in O
global O
loss O
of O
mitochondrial O
respiratory O
chain O
activity O
, O
increased O
mitochondrial O
oxidative O
stress O
and O
reversal O
of O
ATP B
synthase O
activity O
: O
implications O
for O
pathogenesis O
and O
treatment O
. O

Disorders O
of O
coenzyme B
Q I
( I
10 I
) I
( O
CoQ B
( I
10 I
) I
) O
biosynthesis O
represent O
the O
most O
treatable O
subgroup O
of O
mitochondrial O
diseases O
. O

Neurological O
involvement O
is O
frequently O
observed O
in O
CoQ B
( I
10 I
) I
deficiency O
, O
typically O
presenting O
as O
cerebellar O
ataxia O
and O
/ O
or O
seizures O
. O

The O
aetiology O
of O
the O
neurological O
presentation O
of O
CoQ B
( I
10 I
) I
deficiency O
has O
yet O
to O
be O
fully O
elucidated O
and O
therefore O
in O
order O
to O
investigate O
these O
phenomena O
we O
have O
established O
a O
neuronal O
cell O
model O
of O
CoQ B
( I
10 I
) I
deficiency O
by O
treatment O
of O
neuronal O
SH O
- O
SY5Y O
cell O
line O
with O
para B
- I
aminobenzoic I
acid I
( O
PABA B
) O
. O

PABA B
is O
a O
competitive O
inhibitor O
of O
the O
CoQ B
( I
10 I
) I
biosynthetic O
pathway O
enzyme O
, O
COQ2 O
. O

PABA B
treatment O
( O
1 O
mM O
) O
resulted O
in O
a O
54 O
% O
decrease O
( O
46 O
% O
residual O
CoQ B
( I
10 I
) I
) O
decrease O
in O
neuronal O
CoQ B
( I
10 I
) I
status O
( O
p O
< O
0 O
. O
01 O
) O
. O

Reduction O
of O
neuronal O
CoQ B
( I
10 I
) I
status O
was O
accompanied O
by O
a O
progressive O
decrease O
in O
mitochondrial O
respiratory O
chain O
enzyme O
activities O
, O
with O
a O
67 O
. O
5 O
% O
decrease O
in O
cellular O
ATP B
production O
at O
46 O
% O
residual O
CoQ B
( I
10 I
) I
. O

Mitochondrial O
oxidative O
stress O
increased O
four O
- O
fold O
at O
77 O
% O
and O
46 O
% O
residual O
CoQ B
( I
10 I
) I
. O

A O
40 O
% O
increase O
in O
mitochondrial O
membrane O
potential O
was O
detected O
at O
46 O
% O
residual O
CoQ B
( I
10 I
) I
with O
depolarisation O
following O
oligomycin O
treatment O
suggesting O
a O
reversal O
of O
complex O
V O
activity O
. O

This O
neuronal O
cell O
model O
provides O
insights O
into O
the O
effects O
of O
CoQ B
( I
10 I
) I
deficiency O
on O
neuronal O
mitochondrial O
function O
and O
oxidative O
stress O
, O
and O
will O
be O
an O
important O
tool O
to O
evaluate O
candidate O
therapies O
for O
neurological O
conditions O
associated O
with O
CoQ B
( I
10 I
) I
deficiency O
. O

Evaluation O
of O
potential O
Myt1 O
kinase O
inhibitors O
by O
TR O
- O
FRET O
based O
binding O
assay O
. O

In O
the O
human O
cell O
cycle O
, O
the O
Myt1 O
kinase O
is O
a O
crucial O
regulator O
of O
the O
G2 O
/ O
M O
transition O
. O

Because O
this O
membrane O
- O
associated O
kinase O
is O
hard O
to O
obtain O
and O
assay O
, O
there O
is O
a O
distinct O
lack O
of O
data O
so O
far O
. O

Here O
we O
report O
the O
derivatization O
of O
a O
glycoglycerolipid B
which O
was O
shown O
previously O
to O
be O
active O
in O
a O
Myt1 O
activity O
assay O
. O

These O
compounds O
were O
tested O
in O
a O
binding O
assay O
together O
with O
a O
set O
of O
common O
kinase O
inhibitors O
against O
a O
full O
- O
length O
Myt1 O
expressed O
in O
a O
human O
cell O
line O
. O

Dasatinib B
exhibited O
nanomolar O
affinity O
whereas O
broad O
coverage O
inhibitors O
such O
as O
sunitinib B
and O
staurosporine B
derivatives O
did O
not O
show O
any O
effect O
. O

We O
also O
carried O
out O
docking O
studies O
for O
the O
most O
potent O
compounds O
allowing O
further O
insights O
into O
the O
inhibitor O
interaction O
of O
this O
kinase O
. O

The O
glycoglycerolipids B
showed O
no O
significant O
effects O
in O
the O
binding O
assay O
, O
endorsing O
the O
idea O
of O
a O
mechanism O
of O
action O
distant O
from O
the O
active O
site O
. O

Nicotine B
improves O
performance O
in O
an O
attentional O
set O
shifting O
task O
in O
rats O
. O

A O
large O
number O
of O
studies O
in O
both O
humans O
and O
experimental O
animals O
have O
demonstrated O
nicotine B
- O
induced O
improvements O
in O
various O
aspects O
of O
cognitive O
function O
, O
including O
attention O
and O
memory O
. O

The O
prefrontal O
cortex O
( O
PFC O
) O
is O
thought O
to O
be O
critically O
involved O
in O
the O
modulation O
of O
executive O
function O
and O
these O
attentional O
processes O
are O
enhanced O
by O
nicotine B
acting O
at O
nicotinic O
acetylcholine B
receptors O
. O

The O
involvement O
of O
nicotinic O
processes O
on O
cognitive O
flexibility O
in O
particular O
has O
not O
been O
specifically O
investigated O
. O

The O
effects O
of O
nicotine B
on O
attentional O
flexibility O
were O
therefore O
evaluated O
using O
the O
rodent O
attentional O
set O
shifting O
task O
in O
rats O
. O

Nicotine B
injected O
both O
acutely O
and O
following O
repeated O
pre O
- O
exposure O
significantly O
improved O
both O
intradimensional O
and O
extradimensional O
set O
shifting O
performance O
in O
the O
task O
. O

Further O
investigation O
of O
the O
acute O
effects O
of O
nicotine B
demonstrated O
this O
improvement O
in O
attentional O
flexibility O
to O
be O
dose O
- O
dependent O
. O

These O
results O
implicate O
the O
nicotinic O
receptor O
system O
in O
the O
mediation O
of O
processes O
underlying O
cognitive O
flexibility O
and O
suggest O
that O
nicotine B
improves O
attentional O
flexibility O
in O
rats O
, O
both O
within O
and O
between O
perceptual O
dimensions O
of O
a O
compound O
stimulus O
. O

Nicotine B
- O
induced O
alterations O
in O
prefrontal O
circuitry O
may O
underlie O
these O
effects O
on O
cognitive O
flexibility O
. O

This O
article O
is O
part O
of O
a O
Special O
Issue O
entitled O
' O
Cognitive O
Enhancers O
' O
. O

Co O
- O
learning O
facilitates O
memory O
in O
mice O
: O
a O
new O
avenue O
in O
social O
neuroscience O
. O

Social O
context O
affects O
brain O
function O
but O
our O
understanding O
of O
its O
neurobiology O
is O
at O
an O
early O
stage O
. O

The O
mere O
presence O
of O
one O
individual O
can O
alter O
the O
cognitive O
capacities O
of O
another O
and O
social O
learning O
has O
been O
demonstrated O
in O
many O
species O
, O
including O
the O
mouse O
. O

We O
asked O
several O
questions O
: O
1 O
. O

How O
can O
active O
engagement O
of O
two O
familiar O
mice O
in O
the O
same O
learning O
activity O
( O
co O
- O
learning O
) O
alter O
their O
memory O
? O

2 O
. O

Under O
which O
environmental O
conditions O
( O
aversive O
vs O
non O
- O
aversive O
) O
can O
we O
expect O
the O
memory O
to O
be O
enhanced O
, O
impaired O
, O
or O
not O
affected O
? O

3 O
. O

Can O
a O
genetic O
factor O
modify O
the O
co O
- O
learning O
effect O
on O
memory O
? O

More O
specifically O
, O
can O
co O
- O
learning O
correct O
memory O
deficits O
in O
autistic O
- O
like O
BTBR O
inbred O
mice O
with O
deficient O
sociability O
? O

We O
demonstrated O
that O
pairs O
of O
familiar O
inbred O
mice O
of O
the O
same O
or O
different O
genotypes O
( O
C57BL O
/ O
6J O
and O
BTBR O
) O
that O
were O
habituated O
to O
new O
objects O
and O
their O
spatial O
location O
, O
had O
enhanced O
episodic O
memory O
in O
the O
spatial O
object O
recognition O
test O
, O
whereas O
individually O
- O
trained O
animals O
failed O
to O
solve O
this O
task O
. O

Notably O
, O
the O
co O
- O
learning O
effect O
was O
genotype O
- O
dependent O
. O

BTBR O
mice O
paired O
with O
BTBR O
cage O
- O
mates O
in O
the O
habituation O
session O
modestly O
ameliorated O
their O
performance O
in O
the O
object O
recognition O
test O
but O
co O
- O
learning O
with O
a O
familiar O
C57BL O
/ O
6J O
mouse O
completely O
normalized O
episodic O
memory O
deficit O
. O

Next O
, O
we O
explored O
the O
co O
- O
learning O
effect O
on O
fear O
memory O
in O
these O
inbred O
strains O
. O

Interestingly O
, O
mice O
of O
both O
genotypes O
displayed O
significantly O
enhanced O
contextual O
fear O
memory O
once O
they O
had O
been O
conditioned O
together O
with O
BTBR O
animals O
. O

The O
same O
influence O
of O
BTBR O
presence O
was O
observed O
on O
cued O
fear O
memory O
in O
C57BL O
/ O
6J O
mice O
, O
whereas O
a O
modest O
co O
- O
learning O
effect O
was O
found O
on O
cued O
fear O
conditioning O
in O
the O
BTBR O
strain O
. O

Taken O
together O
, O
we O
demonstrated O
for O
the O
first O
time O
the O
co O
- O
learning O
effect O
on O
cognitive O
capacities O
in O
mice O
, O
which O
can O
be O
modified O
by O
genetic O
background O
and O
environmental O
conditions O
. O

The O
possible O
implications O
of O
this O
methodological O
approach O
in O
social O
neuroscience O
are O
discussed O
. O

This O
article O
is O
part O
of O
a O
Special O
Issue O
entitled O
' O
Cognitive O
Enhancers O
' O
. O

Passive O
stiffness O
of O
airway O
smooth O
muscle O
: O
the O
next O
target O
for O
improving O
airway O
distensibility O
and O
treatment O
for O
asthma O
? O

Reduced O
airway O
distensibility O
due O
to O
increased O
airway O
stiffness O
is O
a O
characteristic O
of O
asthma O
. O

Airway O
stiffness O
is O
determined O
by O
the O
property O
and O
structural O
organization O
of O
the O
various O
elements O
of O
the O
airway O
wall O
, O
and O
is O
often O
divided O
into O
active O
and O
passive O
components O
. O

Active O
stiffness O
is O
thought O
to O
be O
associated O
with O
activation O
of O
muscle O
cells O
in O
the O
airway O
wall O
. O

This O
component O
of O
stiffness O
can O
be O
inhibited O
when O
active O
force O
produced O
by O
the O
muscle O
is O
abolished O
. O

Passive O
stiffness O
, O
on O
the O
other O
hand O
, O
is O
thought O
to O
stem O
from O
non O
- O
muscle O
component O
of O
the O
airway O
wall O
, O
especially O
the O
collagen O
/ O
elastin O
fibrous O
network O
of O
the O
extracellular O
matrix O
within O
which O
the O
muscle O
cells O
are O
embedded O
. O

In O
this O
brief O
review O
, O
the O
notion O
that O
passive O
stiffness O
is O
exclusively O
extracellular O
in O
origin O
is O
challenged O
. O

Recent O
evidence O
suggests O
that O
a O
substantial O
portion O
of O
the O
passive O
stiffness O
of O
an O
in O
vitro O
preparation O
of O
tracheal O
smooth O
muscle O
is O
calcium B
sensitive O
and O
is O
regulated O
by O
Rho O
- O
kinase O
, O
although O
the O
underlying O
mechanism O
and O
the O
details O
of O
regulation O
for O
the O
development O
of O
this O
intracellular O
passive O
stiffness O
are O
still O
largely O
unknown O
. O

To O
reduce O
airway O
stiffness O
different O
lines O
of O
attack O
must O
be O
tailored O
to O
different O
components O
of O
the O
stiffness O
. O

The O
regulatable O
passive O
stiffness O
is O
distinct O
from O
the O
relatively O
permanent O
stiffness O
of O
the O
extracellular O
matrix O
and O
the O
stiffness O
associated O
with O
active O
muscle O
contraction O
. O

To O
improve O
airway O
distensibility O
during O
asthma O
exacerbation O
, O
a O
comprehensive O
approach O
to O
reduce O
overall O
airway O
stiffness O
should O
therefore O
include O
a O
strategy O
for O
targeting O
the O
regulatable O
passive O
stiffness O
. O

Harmonization O
of O
description O
and O
classification O
of O
fetal O
observations O
: O
achievements O
and O
problems O
still O
unresolved O
: O
report O
of O
the O
7th O
Workshop O
on O
the O
Terminology O
in O
Developmental O
Toxicology O
Berlin O
, O
4 O
- O
6 O
May O
2011 O
. O

This O
article O
summarizes O
the O
7th O
Workshop O
on O
the O
Terminology O
in O
Developmental O
Toxicology O
held O
in O
Berlin O
, O
May O
4 O
- O
6 O
, O
2011 O
. O

The O
series O
of O
Berlin O
Workshops O
has O
been O
mainly O
concerned O
with O
the O
harmonization O
of O
terminology O
and O
classification O
of O
fetal O
anomalies O
in O
developmental O
toxicity O
studies O
. O

The O
main O
topics O
of O
the O
7th O
Workshop O
were O
knowledge O
on O
the O
fate O
of O
anomalies O
after O
birth O
, O
use O
of O
Version O
2 O
terminology O
for O
maternal O
- O
fetal O
observations O
and O
non O
- O
routinely O
used O
species O
, O
reclassification O
of O
" O
grey O
zone O
" O
anomalies O
and O
categorization O
of O
fetal O
observations O
for O
human O
health O
risk O
assessment O
. O

The O
paucity O
of O
data O
on O
health O
consequences O
of O
the O
postnatal O
permanence O
of O
fetal O
anomalies O
is O
relevant O
and O
further O
studies O
are O
needed O
. O

The O
Version O
2 O
terminology O
is O
an O
important O
step O
forward O
and O
the O
terms O
listed O
in O
this O
glossary O
are O
considered O
also O
to O
be O
appropriate O
for O
most O
observations O
in O
non O
- O
routinely O
used O
species O
. O

Continuation O
of O
the O
Berlin O
Workshops O
was O
recommended O
. O

Topics O
suggested O
for O
the O
next O
Workshop O
were O
grouping O
of O
fetal O
observations O
for O
reporting O
and O
statistical O
analysis O
. O

Natural O
anthocyanins B
from O
phytoresources O
and O
their O
chemical O
researches O
. O

Anthocyanins B
are O
a O
class O
of O
naturally O
occurring O
polyphenols B
which O
have O
been O
most O
widely O
studied O
in O
recent O
decades O
for O
the O
rapid O
development O
of O
relative O
techniques O
. O

This O
article O
first O
reviews O
the O
various O
anthocyanin B
resources O
including O
fruits O
, O
flowers O
, O
vegetables O
and O
beverages O
. O

Besides O
the O
direct O
extraction O
from O
natural O
resources O
, O
anthocyanins B
can O
also O
be O
obtained O
by O
semi O
- O
or O
total O
synthesis O
. O

After O
the O
introduction O
of O
new O
representative O
anthocyanins B
found O
in O
the O
past O
few O
years O
and O
the O
major O
relationships O
between O
structures O
and O
stability O
, O
modern O
separation O
and O
analysis O
technologies O
in O
related O
studies O
were O
summarised O
, O
which O
play O
an O
important O
role O
in O
chemical O
researches O
of O
anthocyanins B
. O

Classification O
of O
Aurora O
kinase O
inhibitors O
by O
self O
- O
organizing O
map O
( O
SOM O
) O
and O
support O
vector O
machine O
( O
SVM O
) O
. O

The O
Aurora O
kinase O
family O
( O
consisting O
of O
Aurora O
- O
A O
, O
- O
B O
and O
- O
C O
) O
is O
an O
important O
group O
of O
enzymes O
that O
controls O
several O
aspects O
of O
cell O
division O
in O
mammalian O
cells O
. O

In O
this O
study O
, O
512 O
compounds O
of O
Aurora O
- O
A O
and O
- O
B O
inhibitors O
were O
collected O
. O

They O
were O
classified O
into O
three O
classes O
: O
dual O
Aurora O
- O
A O
and O
Aurora O
- O
B O
inhibitors O
, O
selective O
inhibitors O
of O
Aurora O
- O
A O
and O
selective O
inhibitors O
of O
Aurora O
- O
B O
by O
Self O
- O
Organizing O
Map O
( O
SOM O
) O
and O
Support O
Vector O
Machine O
( O
SVM O
) O
. O

The O
prediction O
accuracies O
of O
the O
models O
( O
based O
on O
the O
training O
/ O
test O
set O
splitting O
using O
SOM O
method O
) O
for O
the O
test O
set O
were O
92 O
. O
2 O
% O
for O
SOM1 O
and O
93 O
. O
8 O
% O
for O
SVM1 O
, O
respectively O
. O

In O
addition O
, O
the O
extended O
connectivity O
fingerprints O
( O
ECFP O
_ O
4 O
) O
for O
all O
the O
molecules O
were O
calculated O
and O
structure O
- O
activity O
relationship O
of O
Aurora O
kinase O
inhibitors O
was O
summarized O
, O
which O
may O
be O
helpful O
to O
find O
the O
important O
structural O
features O
of O
inhibitors O
relating O
to O
the O
selectivity O
to O
Aurora O
kinases O
. O

Role O
of O
metabotropic O
glutamate B
receptor O
1 O
in O
the O
basolateral O
amygdala O
- O
driven O
prefrontal O
cortical O
deactivation O
in O
inflammatory O
pain O
in O
the O
rat O
. O

Plastic O
changes O
in O
the O
amygdala O
and O
limbic O
cortex O
networks O
have O
been O
widely O
shown O
in O
chronic O
pain O
. O

We O
have O
here O
investigated O
the O
role O
of O
group O
I O
metabotropic O
glutamate B
receptors O
( O
mGluRs O
) O
in O
the O
basolateral O
amygdala O
( O
BLA O
) O
pre O
- O
infra O
- O
limbic O
( O
PL O
- O
IL O
) O
divisions O
of O
the O
medial O
prefrontal O
cortex O
( O
mPFC O
) O
neuron O
connections O
after O
carrageenan O
- O
induced O
inflammatory O
pain O
in O
the O
rat O
. O

Intra O
- O
plantar O
injection O
of O
carrageenan O
decreased O
either O
spontaneous O
or O
mechanically O
/ O
electrically O
evoked O
activity O
of O
PL O
cortex O
pyramidal O
neurons O
which O
responded O
with O
excitation O
in O
a O
way O
prevented O
by O
CPCOOEt B
, O
a O
selective O
mGluR1 O
antagonist O
, O
though O
not O
by O
MPEP B
, O
a O
selective O
mGluR5 O
antagonist O
. O

Accordingly O
, O
intra O
- O
BLA O
microinjection O
of O
DHPG B
, O
a O
group O
I O
mGluR O
agonist O
, O
caused O
PL O
cortex O
neuron O
activity O
depression O
, O
antagonized O
by O
CPCCOEt B
. O

CPCOOEt B
, O
but O
not O
MPEP B
, O
reduced O
also O
carrageenan O
- O
induced O
mechanical O
allodynia O
. O

The O
PL O
cortex O
cell O
deactivation O
in O
inflammatory O
pain O
condition O
was O
associated O
with O
increased O
GABA B
( O
conversely O
glutamate B
was O
decreased O
) O
in O
the O
PL O
/ O
IL O
cortex O
. O

The O
local O
application O
of O
bicuculline B
, O
a O
GABA B
( O
A O
) O
receptor O
selective O
antagonist O
, O
reduced O
mechanical O
allodynia O
. O

An O
over O
- O
expression O
of O
mGluR1 O
, O
but O
not O
mGluR5 O
, O
have O
been O
observed O
in O
the O
PL O
- O
IL O
cortex O
after O
inflammatory O
pain O
suggesting O
an O
increased O
mGluR1 O
- O
dependent O
cross O
- O
talk O
among O
BLA O
and O
IL O
- O
PL O
cortex O
neurons O
in O
inflammatory O
pain O
conditions O
. O

This O
article O
is O
part O
of O
a O
Special O
Issue O
entitled O
' O
Metabotropic O
Glutamate B
Receptors O
' O
. O

Emerging O
role O
of O
AMP B
- O
activated O
protein O
kinase O
in O
endocrine O
control O
of O
metabolism O
in O
the O
liver O
. O

This O
review O
summarizes O
the O
emerging O
role O
of O
AMP B
- O
activated O
protein O
kinase O
( O
AMPK O
) O
in O
mediating O
endocrine O
regulation O
of O
metabolic O
fluxes O
in O
the O
liver O
. O

There O
are O
a O
number O
of O
hormones O
which O
, O
when O
acting O
on O
the O
liver O
, O
alter O
AMPK O
activation O
. O

Here O
we O
describe O
those O
hormones O
associated O
with O
activation O
and O
de O
- O
activation O
of O
AMPK O
and O
the O
potential O
mechanisms O
for O
changes O
in O
AMPK O
activation O
state O
. O

The O
actions O
of O
these O
hormones O
, O
in O
many O
cases O
, O
are O
consistent O
with O
downstream O
effects O
of O
AMPK O
signaling O
thus O
strengthening O
the O
circumstantial O
case O
for O
AMPK O
- O
mediated O
hormone O
action O
. O

In O
recent O
years O
, O
genetic O
mouse O
models O
have O
also O
been O
used O
in O
an O
attempt O
to O
establish O
the O
role O
of O
AMPK O
in O
hormone O
- O
stimulated O
metabolism O
in O
the O
liver O
. O

Few O
experiments O
have O
, O
however O
, O
firmly O
established O
a O
causal O
relationship O
between O
hormone O
action O
at O
the O
liver O
and O
AMPK O
signaling O
. O

Rectifying O
behavior O
of O
charge O
transfer O
complexes O
of O
tetrakis B
( I
dimethylamino I
) I
ethene I
with O
acceptor O
molecules O
: O
a O
theoretical O
study O
. O

The O
effect O
of O
electric O
field O
induced O
electron O
transfer O
on O
the O
rectification O
properties O
of O
molecular O
rectifiers O
based O
on O
charge O
transfer O
complexes O
of O
tetrakis B
( I
dimethylamino I
) I
ethane I
( O
TDAE B
) O
with O
acceptor O
molecules O
was O
explored O
. O

The O
current O
- O
voltage O
curves O
and O
the O
rectification O
ratios O
( O
RR O
) O
for O
two O
different O
molecular O
rectifiers O
were O
obtained O
using O
a O
direct O
ab O
initio O
method O
at O
M06 O
/ O
LACVP O
( O
d O
) O
level O
of O
theory O
in O
the O
range O
from O
- O
2 O
to O
+ O
2 O
V O
. O

The O
highest O
RR O
of O
25 O
. O
7 O
was O
determined O
for O
the O
complex O
of O
TDAE O
with O
2 B
- I
nitropyrene I
- I
4 I
, I
5 I
, I
9 I
, I
10 I
- I
tetraone I
at O
0 O
. O
5 O
V O
( O
D1 O
) O
, O
while O
another O
rectifier O
[ O
complex O
of O
TDAE O
with O
2 B
, I
7 I
- I
dimethyl I
nitropyrene I
- I
4 I
, I
5 I
, I
9 I
, I
10 I
- I
tetraone I
( O
D2 O
) O
] O
showed O
a O
maximum O
RR O
of O
only O
2 O
. O
9 O
at O
0 O
. O
3 O
V O
. O

The O
electric O
field O
induced O
electron O
transfer O
occurring O
in O
D1 O
creates O
a O
one O
- O
way O
conducting O
channel O
consisting O
of O
two O
SOMOs O
involving O
the O
entire O
D1 O
complex O
. O

In O
the O
case O
of O
D2 O
, O
no O
electron O
transfer O
occurs O
at O
the O
applied O
bias O
voltages O
due O
to O
the O
relatively O
high O
energy O
difference O
between O
HOMO O
and O
LUMO O
. O

Increased O
expression O
of O
P450scc O
and O
CYP17 O
in O
development O
of O
endogenous O
hyperandrogenism O
in O
a O
rat O
model O
of O
PCOS O
. O

The O
objective O
of O
the O
present O
study O
was O
to O
characterize O
the O
effect O
of O
insulin O
plus O
hCG O
on O
the O
expression O
of O
steroidogenic O
enzymes O
( O
P450scc O
and O
CYP17 O
) O
in O
polycystic O
ovaries O
of O
rats O
. O

Changes O
in O
estrous O
cycle O
, O
ovarian O
morphology O
, O
hormonal O
levels O
, O
and O
protein O
levels O
by O
immunohistochemistry O
and O
western O
- O
blot O
were O
determined O
. O

Rats O
treated O
with O
insulin O
plus O
hCG O
displayed O
abnormal O
estrous O
cycles O
with O
increasing O
androgen B
biosynthesis O
. O

Meanwhile O
, O
insulin O
plus O
hCG O
resulted O
in O
multiple O
large O
cysts O
with O
diminished O
granulosa O
layers O
and O
increased O
thecal O
layers O
and O
stromal O
- O
interstitial O
tissue O
. O

Moreover O
, O
there O
was O
an O
increase O
in O
the O
expression O
of O
P450scc O
and O
CYP17 O
in O
thecal O
and O
stromal O
cells O
in O
our O
PCOS O
rat O
model O
compared O
with O
control O
rats O
. O

These O
results O
indicate O
that O
administration O
of O
insulin O
with O
hCG O
can O
synergistically O
result O
in O
endogenous O
hyperandrogenism O
which O
may O
partially O
upregulate O
the O
expression O
of O
steroidogenic O
enzymes O
in O
ovarian O
tissue O
. O

beta B
- I
Orcinol I
- O
type O
depsides O
from O
the O
lichen O
Thamnolia O
vermicularis O
. O

A O
phytochemical O
investigation O
of O
a O
herb O
tea O
made O
from O
Thamnolia O
vermicularis O
led O
to O
the O
isolation O
of O
three O
new O
beta B
- I
orcinol I
- O
type O
depsides O
( O
1 O
, O
2 O
and O
3 O
) O
, O
along O
with O
seven O
known O
compounds O
hypothamnolic B
acid I
( O
4 O
) O
, O
3 B
' I
- I
methylevenic I
acid I
( O
5 O
) O
, O
baeomycesic B
acid I
( O
6 O
) O
, O
squamatic B
acid I
( O
7 O
) O
, O
methyl B
3 I
' I
- I
methyllecanorate I
( O
8 O
) O
, O
barbatinic B
acid I
( O
9 O
) O
and O
atranorin B
( O
10 O
) O
. O

The O
structures O
of O
the O
new O
compounds O
were O
determined O
on O
the O
basis O
of O
spectroscopic O
evidence O
, O
including O
1 O
- O
D O
and O
2 O
- O
D O
NMR O
and O
ESI O
- O
MS O
techniques O
. O

AMPAKINE B
enhancement O
of O
social O
interaction O
in O
the O
BTBR O
mouse O
model O
of O
autism O
. O

Autism O
is O
a O
neurodevelopmental O
disorder O
in O
which O
the O
first O
diagnostic O
symptom O
is O
unusual O
reciprocal O
social O
interactions O
. O

Approximately O
half O
of O
the O
children O
diagnosed O
with O
an O
autism O
spectrum O
disorder O
also O
have O
intellectual O
impairments O
. O

General O
cognitive O
abilities O
may O
be O
fundamental O
to O
many O
aspects O
of O
social O
cognition O
. O

Cognitive O
enhancers O
could O
conceivably O
be O
of O
significant O
benefit O
to O
children O
and O
adults O
with O
autism O
. O

AMPAKINE B
compounds O
are O
a O
novel O
class O
of O
pharmacological O
agents O
that O
act O
as O
positive O
modulators O
of O
AMPA B
receptors O
to O
enhance O
excitatory O
glutamatergic O
neurotransmission O
. O

This O
class O
of O
compounds O
was O
reported O
to O
improve O
learning O
and O
memory O
in O
several O
rodent O
and O
non O
- O
human O
primate O
tasks O
, O
and O
to O
normalize O
respiratory O
abnormalities O
in O
a O
mouse O
model O
of O
Rett O
syndrome O
. O

Here O
we O
evaluate O
the O
actions O
of O
AMPA B
compounds O
in O
adult O
male O
and O
female O
BTBR O
mice O
, O
a O
well O
characterized O
mouse O
model O
of O
autism O
. O

Acute O
treatment O
with O
CX1837 B
and O
CX1739 B
reversed O
the O
deficit O
in O
sociability O
in O
BTBR O
mice O
on O
the O
most O
sensitive O
parameter O
, O
time O
spent O
sniffing O
a O
novel O
mouse O
as O
compared O
to O
time O
spent O
sniffing O
a O
novel O
object O
. O

The O
less O
sensitive O
parameter O
, O
time O
in O
the O
chamber O
containing O
the O
novel O
mouse O
versus O
time O
in O
the O
chamber O
containing O
the O
novel O
object O
, O
was O
not O
rescued O
by O
CX1837 B
or O
CX1739 B
treatment O
. O

Preliminary O
data O
with O
CX546 B
, O
in O
which O
beta B
- I
cyclodextrin I
was O
the O
vehicle O
, O
revealed O
behavioral O
effects O
of O
the O
acute O
intraperitoneal O
and O
oral O
administration O
of O
vehicle O
alone O
. O

To O
circumvent O
the O
artifacts O
introduced O
by O
the O
vehicle O
administration O
, O
we O
employed O
a O
novel O
treatment O
regimen O
using O
pellets O
of O
peanut O
butter O
for O
drug O
delivery O
. O

Absence O
of O
vehicle O
treatment O
effects O
when O
CX1837 B
and O
CX1739 B
were O
given O
in O
the O
peanut O
butter O
pellets O
, O
to O
multiple O
cohorts O
of O
BTBR O
and O
B6 O
control O
mice O
, O
confirmed O
that O
the O
pharmacologically O
- O
induced O
improvements O
in O
sociability O
in O
BTBR O
were O
not O
confounded O
by O
the O
administration O
procedures O
. O

The O
highest O
dose O
of O
CX1837 B
improved O
the O
cognitive O
deficit O
in O
novel O
object O
recognition O
in O
BTBR O
. O

No O
drug O
effects O
were O
detected O
on O
the O
high O
levels O
of O
repetitive O
self O
- O
grooming O
in O
BTBR O
. O

In O
open O
field O
tests O
, O
CX1837 B
and O
CX1739 B
did O
not O
induce O
hyperactivity O
or O
sedation O
in O
either O
strain O
. O

It O
is O
interesting O
to O
speculate O
that O
the O
ability O
of O
CX1837 B
and O
CX1739 B
to O
restore O
aspects O
of O
sociability O
in O
BTBR O
mice O
could O
utilize O
synaptic O
mechanisms O
regulating O
social O
cognition O
, O
suggesting O
a O
potential O
pharmacological O
target O
for O
interventions O
to O
treat O
symptoms O
of O
autism O
. O

This O
article O
is O
part O
of O
a O
Special O
Issue O
entitled O
' O
Cognitive O
Enhancers O
' O
. O

Androgen B
insensitivity O
syndrome O
. O

Androgen B
insensitivity O
syndrome O
( O
AIS O
) O
is O
a O
disorder O
caused O
by O
a O
mutation O
of O
the O
gene O
encoding O
the O
androgen B
receptor O
( O
AR O
; O
Xq11 O
- O
q12 O
) O
. O

The O
prevalence O
of O
AIS O
has O
been O
estimated O
to O
be O
one O
case O
in O
every O
20 O
, O
000 O
to O
64 O
, O
000 O
newborn O
males O
for O
the O
complete O
syndrome O
( O
CAIS O
) O
, O
and O
the O
prevalence O
is O
unknown O
for O
the O
partial O
syndrome O
( O
PAIS O
) O
. O

The O
symptoms O
range O
from O
phenotypically O
normal O
males O
with O
impaired O
spermatogenesis O
to O
phenotypically O
normal O
women O
with O
primary O
amenorrhea O
. O

Various O
forms O
of O
ambiguous O
genitalia O
have O
been O
observed O
at O
birth O
. O

The O
diagnosis O
is O
confirmed O
by O
determining O
the O
exact O
mutation O
in O
the O
AR O
gene O
. O

PAIS O
individuals O
require O
precise O
diagnosis O
as O
early O
as O
possible O
so O
that O
the O
sex O
can O
be O
assigned O
, O
treatment O
can O
be O
recommended O
, O
and O
they O
can O
receive O
proper O
genetic O
counseling O
. O

After O
birth O
, O
differential O
diagnosis O
should O
be O
performed O
using O
other O
forms O
of O
abnormal O
sexual O
differentiation O
of O
primary O
amenorrhea O
. O

The O
treatment O
of O
AIS O
is O
based O
on O
reinforcement O
sexual O
identity O
, O
gonadectomy O
planning O
, O
and O
hormone O
replacement O
therapy O
. O

The O
prognosis O
for O
CAIS O
is O
good O
if O
the O
testicular O
tissue O
is O
removed O
at O
the O
appropriate O
time O
. O

For O
PAIS O
, O
the O
prognosis O
depends O
on O
the O
ambiguity O
of O
the O
genitalia O
and O
physical O
and O
psychosocial O
adjustment O
to O
the O
assigned O
sex O
. O

Deep O
understanding O
of O
the O
interaction O
between O
thienorphine B
and O
UDP B
- O
glucuronosyltransfer O
( O
UGT O
) O
isoforms O
. O

Thienorphine B
has O
been O
demonstrated O
to O
be O
a O
potent O
, O
long O
- O
acting O
partial O
opioid O
agonist O
. O

It O
is O
being O
developed O
as O
a O
good O
candidate O
to O
treat O
opioid O
dependence O
. O

The O
thienorphine B
' I
s I
glucuronide I
was O
detected O
after O
thienorphine B
was O
incubated O
with O
human O
liver O
microsomes O
( O
HLMs O
) O
. O

Recombinant O
UGT O
isoforms O
screening O
experiment O
and O
enzyme O
kinetic O
study O
showed O
that O
UGT1A1 O
completely O
contributed O
to O
the O
glucuronidation O
of O
thienorphine B
. O

Among O
the O
tested O
UGT O
isoforms O
, O
UGT1A3 O
and O
UGT2B7 O
were O
inhibited O
by O
thienorphine B
, O
with O
other O
UGT O
isoforms O
negligibly O
influenced O
. O

The O
inhibition O
type O
is O
competitive O
, O
and O
inhibition O
kinetic O
parameters O
( O
K O
( O
i O
) O
) O
were O
1 O
. O
65 O
and O
5 O
. O
27 O
mu O
M O
for O
UGT1A3 O
and O
UGT2B7 O
, O
respectively O
. O

However O
, O
due O
to O
low O
plasma O
concentration O
of O
thienorphine B
, O
in O
vivo O
drug O
- O
drug O
interaction O
might O
not O
occur O
. O

Adnexal O
torsion O
in O
children O
and O
adolescents O
: O
new O
trends O
to O
conservative O
surgical O
approach O
- O
- O
our O
experience O
and O
review O
of O
literature O
. O

The O
purpose O
of O
this O
study O
is O
to O
discuss O
the O
surgical O
treatment O
for O
ovarian O
torsion O
in O
children O
and O
adolescents O
with O
a O
focus O
on O
the O
procedures O
of O
adnexal O
conservation O
surgery O
and O
its O
frequency O
in O
the O
literature O
of O
the O
last O
10 O
years O
. O

We O
retrospectively O
reviewed O
the O
medical O
charts O
of O
127 O
operative O
ovarian O
lesions O
including O
30 O
ovarian O
torsions O
( O
23 O
. O
6 O
% O
) O
treated O
in O
two O
pediatric O
centers O
over O
a O
10 O
- O
year O
period O
. O

Age O
at O
presentation O
, O
presenting O
symptoms O
, O
diagnostic O
studies O
, O
surgical O
procedure O
and O
pathological O
findings O
were O
analyzed O
. O

Mean O
age O
was O
13 O
. O
7 O
years O
. O

Conservative O
surgery O
has O
been O
performed O
in O
46 O
. O
7 O
% O
of O
the O
cases O
and O
laparoscopic O
approach O
in O
40 O
% O
. O

Ovarian O
torsion O
occurred O
in O
56 O
. O
7 O
% O
on O
ovaries O
with O
functional O
lesion O
, O
in O
23 O
. O
3 O
% O
on O
normal O
adnexa O
and O
in O
20 O
% O
on O
ovaries O
with O
benign O
neoplasm O
. O

The O
article O
includes O
a O
literature O
review O
( O
2000 O
- O
2010 O
) O
and O
a O
statistical O
analysis O
which O
shows O
a O
slow O
increase O
in O
conservative O
surgery O
from O
28 O
to O
45 O
% O
. O

Laparoscopic O
surgery O
accounts O
for O
23 O
. O
5 O
% O
. O

Literature O
review O
shows O
40 O
. O
5 O
% O
normal O
adnexa O
, O
33 O
. O
2 O
% O
non O
- O
neoplastic O
lesions O
, O
25 O
. O
3 O
% O
benign O
neoplasms O
and O
1 O
% O
malignant O
neoplasms O
. O

The O
surgical O
treatment O
of O
children O
and O
adolescents O
presenting O
adnexal O
torsion O
should O
be O
practiced O
as O
an O
emergency O
and O
it O
should O
be O
more O
conservative O
as O
possible O
in O
order O
to O
maximize O
the O
future O
reproductive O
potential O
. O

Silibinin B
protects O
H9c2 O
cardiac O
cells O
from O
oxidative O
stress O
and O
inhibits O
phenylephrine B
- O
induced O
hypertrophy O
: O
potential O
mechanisms O
. O

Cardiac O
hypertrophy O
is O
the O
main O
response O
of O
the O
heart O
to O
various O
extrinsic O
and O
intrinsic O
stimuli O
, O
and O
it O
is O
characterized O
by O
specific O
molecular O
and O
phenotypic O
changes O
. O

Recent O
in O
vitro O
and O
in O
vivo O
studies O
indicate O
the O
involvement O
of O
reactive O
oxygen B
species O
in O
the O
hypertrophic O
response O
. O

In O
this O
study O
, O
silibinin B
, O
a O
plant O
flavonolignan B
extracted O
from O
milk O
thistle O
with O
potent O
antioxidant O
activity O
, O
was O
evaluated O
for O
its O
effects O
in O
( O
a O
) O
preventing O
hydrogen B
peroxide I
( O
H2O2 B
) O
- O
induced O
cellular O
damage O
and O
( O
b O
) O
blocking O
the O
phenylephrine B
- O
induced O
hypertrophic O
response O
. O

Using O
the O
in O
vitro O
model O
of O
embryonic O
rat O
heart O
- O
derived O
H9c2 O
cells O
, O
we O
showed O
that O
silibinin B
has O
a O
rather O
safe O
profile O
as O
concentrations O
up O
to O
200 O
mu O
M O
did O
not O
affect O
cell O
viability O
. O

Pretreatment O
of O
H9c2 O
cells O
with O
silibinin B
resulted O
in O
better O
protection O
of O
H9c2 O
cells O
under O
conditions O
of O
H2O2 B
- O
induced O
cellular O
stress O
compared O
to O
untreated O
cells O
as O
indicated O
by O
cell O
viability O
and O
DNA O
fragmentation O
assays O
. O

Furthermore O
, O
silibinin B
attenuated O
the O
phenylephrine B
- O
induced O
hypertrophic O
response O
as O
evidenced O
by O
the O
measurement O
of O
cell O
surface O
, O
up O
- O
regulation O
of O
atrial O
natriuretic O
peptide O
and O
increase O
of O
cellular O
protein O
levels O
. O

Moreover O
, O
silibinin B
repressed O
the O
phenylephrine B
- O
induced O
phosphorylation O
of O
ERK1 O
/ O
2 O
kinases O
, O
while O
it O
appeared O
to O
inhibit O
the O
weakly O
activated O
by O
phenylephrine B
phosphorylation O
of O
Akt O
. O

Based O
on O
our O
results O
, O
silibinin B
may O
attenuate O
the O
phenylephrine B
- O
induced O
hypertrophic O
response O
of O
H9c2 O
cells O
via O
antioxidant O
mechanisms O
involving O
mainly O
the O
inhibition O
of O
the O
intracellular O
signaling O
pathways O
mediated O
by O
ERK1 O
/ O
2 O
MAPKs O
and O
Akt O
. O

Modafinil B
effects O
on O
cognition O
and O
emotion O
in O
schizophrenia O
and O
its O
neurochemical O
modulation O
in O
the O
brain O
. O

Modafinil B
is O
a O
central O
nervous O
system O
wake O
promoting O
agent O
used O
for O
the O
treatment O
of O
excessive O
daytime O
sleeping O
. O

Its O
vigilance O
promoting O
properties O
and O
low O
abuse O
potential O
has O
intrigued O
the O
scientific O
community O
and O
has O
led O
to O
use O
it O
as O
a O
cognitive O
enhancer O
, O
before O
its O
neural O
functions O
were O
understood O
. O

Here O
, O
we O
review O
the O
effects O
of O
modafinil B
in O
human O
cognition O
and O
emotion O
and O
its O
specific O
actions O
on O
symptoms O
in O
patients O
with O
schizophrenia O
and O
whether O
these O
are O
consistently O
effective O
throughout O
the O
literature O
. O

We O
also O
performed O
a O
systematic O
review O
on O
the O
effects O
of O
modafinil B
on O
neurotransmitter O
signalling O
in O
different O
areas O
of O
the O
brain O
in O
order O
to O
better O
understand O
the O
neuromechanisms O
of O
its O
cognitive O
and O
emotional O
enhancing O
properties O
. O

A O
review O
of O
its O
effects O
in O
schizophrenia O
suggests O
that O
modafinil B
facilitates O
cognitive O
functions O
, O
with O
pro O
- O
mnemonic O
effects O
and O
problem O
solving O
improvements O
. O

Emotional O
processing O
also O
appears O
to O
be O
enhanced O
by O
the O
drug O
, O
although O
to O
date O
there O
are O
only O
a O
limited O
number O
of O
studies O
. O

The O
systematic O
review O
on O
the O
neurochemical O
modulation O
of O
the O
modafinil B
suggests O
that O
its O
mnemonic O
enhancing O
properties O
might O
be O
the O
result O
of O
glutamatergic O
and O
dopaminergic O
increased O
neuronal O
activation O
in O
the O
hippocampus O
and O
in O
the O
prefrontal O
cortex O
respectively O
. O

Other O
neurotransmitters O
were O
also O
activated O
by O
modafinil B
in O
various O
limbic O
brain O
areas O
, O
suggesting O
that O
the O
drug O
acts O
on O
these O
brain O
regions O
to O
influence O
emotional O
responses O
. O

These O
reviews O
seek O
to O
delineate O
the O
neuronal O
mechanisms O
by O
which O
modafinil B
affects O
cognitive O
and O
emotional O
function O
. O

This O
article O
is O
part O
of O
a O
Special O
Issue O
entitled O
' O
Cognitive O
Enhancers O
' O
. O

Current O
understanding O
of O
TRPM7 O
pharmacology O
and O
drug O
development O
for O
stroke O
. O

The O
initial O
excitement O
and O
countless O
efforts O
to O
find O
a O
pharmacological O
agent O
that O
disrupts O
the O
excitotoxic O
pathway O
of O
ischemic O
neuronal O
death O
have O
only O
led O
to O
disappointing O
clinical O
trials O
. O

Currently O
, O
a O
thrombolytic O
agent O
called O
recombinant O
tissue O
plasminogen O
activator O
( O
rt O
- O
PA O
) O
is O
the O
only O
pharmacological O
treatment O
available O
for O
patients O
with O
acute O
ischemic O
stroke O
in O
most O
countries O
. O

Even O
though O
its O
efficacy O
has O
been O
confirmed O
repeatedly O
, O
rt O
- O
PA O
is O
considerably O
underused O
due O
to O
reasons O
including O
a O
short O
therapeutic O
window O
and O
repeated O
complications O
associated O
with O
its O
use O
. O

A O
search O
for O
alternative O
mechanisms O
that O
may O
operate O
dependently O
or O
independently O
with O
the O
well O
- O
established O
excitotoxic O
mechanism O
has O
led O
researchers O
to O
the O
discovery O
of O
newly O
described O
non O
- O
glutamate B
mechanisms O
. O

Among O
the O
latter O
, O
transient O
receptor O
potential O
melastatin O
7 O
( O
TRPM7 O
) O
is O
one O
of O
the O
important O
nonglutamate O
mechanisms O
in O
stroke O
, O
which O
has O
been O
evaluated O
in O
both O
in O
- O
vitro O
and O
in O
- O
vivo O
. O

In O
this O
review O
, O
we O
will O
discuss O
the O
current O
state O
of O
pharmacological O
treatments O
of O
ischemic O
stroke O
and O
provide O
evidence O
that O
TRPM7 O
is O
a O
promising O
therapeutic O
target O
of O
stroke O
. O

Altered O
gene O
expression O
involved O
in O
insulin O
signaling O
pathway O
in O
type O
II O
diabetic O
osteoporosis O
rats O
model O
. O

It O
is O
well O
established O
that O
both O
estrogen B
loss O
and O
type O
II O
diabetes O
mellitus O
( O
DMII O
) O
can O
impair O
bone O
metabolism O
, O
but O
whether O
estrogen B
loss O
exacerbates O
the O
effects O
of O
DMII O
is O
unclear O
. O

Therefore O
, O
we O
determined O
if O
ovariectomy O
( O
OVX O
) O
of O
rats O
on O
a O
long O
- O
term O
high O
- O
fat O
/ O
sugar B
diet O
and O
injection O
of O
a O
low O
dose O
of O
streptozotocin B
( O
DMII O
) O
decreased O
bone O
mineral O
density O
( O
BMD O
) O
more O
than O
OVX O
or O
DMII O
alone O
. O

Bone O
insulin O
signaling O
is O
known O
to O
support O
bone O
metabolism O
; O
therefore O
, O
we O
also O
tested O
the O
hypothesis O
that O
OVX O
DMII O
rats O
( O
DOVX O
) O
would O
exhibit O
greater O
reductions O
in O
the O
expression O
of O
proteins O
important O
in O
insulin O
signaling O
, O
including O
IRS O
- O
1 O
, O
IRS O
- O
2 O
, O
and O
IGF O
- O
1 O
. O

As O
hypothesized O
, O
BMD O
and O
plasma O
estrogen B
levels O
were O
decreased O
more O
in O
DOVX O
rats O
than O
in O
rats O
following O
OVX O
( O
NOVX O
) O
or O
DMII O
( O
DS O
) O
alone O
. O

IGF O
- O
1 O
expression O
was O
decreased O
in O
the O
liver O
, O
kidney O
, O
skeletal O
muscle O
, O
and O
bone O
of O
DOVX O
, O
DS O
, O
and O
NOVX O
rats O
; O
however O
, O
the O
decrease O
was O
larger O
and O
occurred O
sooner O
in O
DOVX O
rats O
. O

While O
IRS O
- O
1 O
and O
IRS O
- O
2 O
decreased O
in O
most O
groups O
in O
all O
tissues O
examined O
, O
the O
expression O
patterns O
differed O
in O
both O
a O
group O
- O
and O
tissue O
- O
dependent O
fashion O
. O

In O
conclusion O
, O
these O
data O
demonstrate O
that O
estrogen B
loss O
and O
DMII O
induced O
by O
a O
high O
- O
fat O
/ O
sugar B
diet O
interact O
to O
produce O
osteoporosis O
and O
support O
the O
hypothesis O
that O
the O
bone O
loss O
may O
be O
mediated O
at O
least O
in O
part O
by O
concurrent O
decreases O
in O
the O
insulin O
signaling O
proteins O
in O
bone O
. O

Egis B
- I
11150 I
: O
a O
candidate O
antipsychotic O
compound O
with O
procognitive O
efficacy O
in O
rodents O
. O

Classical O
antipsychotics O
, O
e O
. O
g O
. O
haloperidol B
, O
chlorpromazine B
, O
are O
potent O
at O
controlling O
the O
positive O
symptoms O
of O
schizophrenia O
but O
frequently O
elicit O
extrapyramidal O
motor O
side O
- O
effects O
. O

The O
introduction O
of O
atypical O
antipsychotics O
such O
as O
risperidone B
, O
olanzapine B
and O
clozapine B
has O
obviated O
this O
problem O
, O
but O
none O
of O
the O
current O
drugs O
seem O
to O
improve O
the O
cognitive O
deficits O
accompanying O
schizophrenia O
. O

Thus O
there O
is O
an O
unmet O
need O
for O
agents O
that O
not O
only O
suppress O
the O
psychotic O
symptoms O
but O
also O
ameliorate O
the O
impairment O
of O
cognition O
. O

Here O
, O
we O
report O
the O
preclinical O
properties O
of O
a O
candidate O
antipsychotic O
, O
Egis B
- I
11150 I
, O
that O
shows O
marked O
pro O
- O
cognitive O
efficacy O
. O

Egis B
- I
11150 I
displayed O
high O
affinity O
for O
adrenergic O
alpha O
( O
1 O
) O
, O
alpha O
( O
2c O
) O
, O
5 B
- I
HT I
( O
2A O
) O
5 B
- I
HT I
7 O
, O
moderate O
affinity O
for O
adrenergic O
alpha O
( O
2a O
) O
and O
D O
2 O
receptors O
. O

It O
was O
a O
functional O
antagonist O
on O
all O
of O
the O
above O
receptors O
, O
with O
the O
exception O
of O
5 B
- I
HT I
7 O
receptors O
, O
where O
it O
was O
an O
inverse O
agonist O
. O

Phencyclidine B
- O
induced O
hypermotility O
in O
mice O
and O
inhibition O
of O
conditioned O
avoidance O
response O
in O
rats O
were O
assessed O
to O
estimate O
efficacy O
against O
the O
positive O
and O
social O
withdrawal O
test O
in O
rats O
was O
used O
to O
predict O
efficacy O
against O
the O
negative O
symptoms O
of O
schizophrenia O
. O

Passive O
- O
avoidance O
learning O
, O
novel O
object O
recognition O
and O
radial O
maze O
tests O
in O
rats O
were O
used O
to O
assess O
pro O
- O
cognitive O
activity O
, O
while O
phencyclidine B
- O
induced O
disruption O
of O
prepulse O
inhibition O
in O
mice O
was O
examined O
to O
test O
for O
effects O
on O
attention O
. O

Egis B
- I
11150 I
( O
0 O
. O
01 O
- O
0 O
. O
3 O
mg O
/ O
kg O
, O
ip O
. O
) O
was O
effective O
in O
all O
of O
the O
preclinical O
models O
of O
schizophrenia O
examined O
. O

Moreover O
, O
a O
robust O
pro O
- O
cognitive O
profile O
was O
apparent O
. O

In O
summary O
, O
work O
in O
preclinical O
models O
indicates O
that O
Egis B
- I
11150 I
is O
a O
potential O
treatment O
for O
controlling O
the O
psychosis O
as O
well O
as O
the O
cognitive O
dysfunction O
in O
schizophrenia O
. O

This O
article O
is O
part O
of O
a O
Special O
Issue O
entitled O
' O
Cognitive O
Enhancers O
' O
. O

Propranolol B
restores O
cognitive O
deficits O
and O
improves O
amyloid O
and O
Tau O
pathologies O
in O
a O
senescence O
- O
accelerated O
mouse O
model O
. O

Ageing O
is O
associated O
with O
a O
deterioration O
of O
cognitive O
performance O
and O
with O
increased O
risk O
of O
neurodegenerative O
disorders O
. O

Hypertension O
is O
the O
most O
- O
prevalent O
modifiable O
risk O
factor O
for O
cardiovascular O
morbidity O
and O
mortality O
worldwide O
, O
and O
clinical O
data O
suggest O
that O
hypertension O
is O
a O
risk O
factor O
for O
Alzheimer O
' O
s O
disease O
( O
AD O
) O
. O

In O
the O
present O
study O
we O
tested O
whether O
propranolol B
, O
a O
beta O
- O
receptor O
antagonist O
commonly O
used O
as O
antihypertensive O
drug O
, O
could O
ameliorate O
the O
cognitive O
impairments O
and O
increases O
in O
AD O
- O
related O
markers O
shown O
by O
the O
senescence O
- O
accelerated O
mouse O
prone O
- O
8 O
( O
SAMP8 O
) O
. O

Propranolol B
administration O
( O
5 O
mg O
/ O
kg O
for O
3 O
weeks O
) O
to O
6 O
- O
month O
- O
old O
SAMP8 O
mice O
attenuated O
cognitive O
memory O
impairments O
shown O
by O
these O
mice O
in O
the O
novel O
object O
recognition O
test O
. O

In O
the O
hippocampus O
of O
SAMP8 O
mice O
it O
has O
been O
found O
increases O
in O
A O
beta O
( O
42 O
) O
levels O
, O
the O
principal O
constituent O
of O
amyloid O
plaques O
observed O
in O
AD O
, O
accompanied O
by O
both O
an O
increased O
expression O
of O
the O
cleaving O
enzyme O
BACE1 O
and O
a O
decreased O
expression O
of O
the O
degrading O
enzyme O
IDE O
. O

All O
these O
effects O
were O
reversed O
by O
propranolol B
treatment O
. O

Tau O
hyperphosphorylation O
( O
PHF O
- O
1 O
epitope O
) O
shown O
by O
SAMP8 O
mice O
at O
this O
age O
was O
also O
decreased O
in O
the O
hippocampus O
of O
propranolol B
- O
treated O
mice O
, O
an O
effect O
probably O
related O
to O
a O
decrease O
in O
JNK1 O
expression O
. O

Interestingly O
, O
propranolol B
also O
phosphorylated O
Akt O
in O
SAMP8 O
mice O
, O
which O
was O
associated O
with O
an O
increase O
of O
glycogen O
synthase O
kinase O
- O
3 O
beta O
phosphorylation O
, O
contributing O
therefore O
to O
the O
reductions O
in O
Tau O
hyperphosphorylation O
. O

Synaptic O
pathology O
in O
SAMP8 O
mice O
, O
as O
shown O
by O
decreases O
in O
synaptophysin O
and O
BDNF O
, O
was O
also O
counteracted O
by O
propranolol B
treatment O
. O

Overall O
, O
propranolol B
might O
be O
beneficial O
in O
age O
- O
related O
brain O
dysfunction O
and O
could O
be O
an O
emerging O
candidate O
for O
the O
treatment O
of O
other O
neurodegenerative O
diseases O
. O

This O
article O
is O
part O
of O
a O
Special O
Issue O
entitled O
' O
Cognitive O
Enhancers O
' O
. O

Metabolism O
and O
disposition O
of O
[ B
14C I
] I
n I
- I
butyl I
- I
p I
- I
hydroxybenzoate I
in O
male O
and O
female O
Harlan O
Sprague O
Dawley O
rats O
following O
oral O
administration O
and O
dermal O
application O
. O

n B
- I
Butyl I
- I
p I
- I
hydroxybenzoate I
( O
n B
- I
butylparaben I
, O
BPB B
) O
is O
an O
antioxidant O
used O
in O
foods O
, O
pharmaceuticals O
and O
cosmetics O
. O

This O
study O
investigated O
the O
disposition O
of O
ring O
- O
labelled O
[ B
( I
14 I
) I
C I
] I
BPB I
in O
Harlan O
Sprague O
Dawley O
rats O
, O
and O
in O
rat O
and O
human O
hepatocytes O
. O

BPB B
was O
rapidly O
cleared O
in O
hepatocytes O
from O
rat O
( O
t O
( O
1 O
/ O
2 O
) O
= O
3 O
- O
4 O
min O
) O
and O
human O
( O
t O
( O
1 O
/ O
2 O
) O
= O
20 O
- O
30 O
min O
) O
. O

The O
major O
metabolites O
detected O
in O
rat O
hepatocytes O
were O
hydroxybenzoic B
acid I
and O
in O
human O
hepatocytes O
were O
hydroxybenzoic B
acid I
and O
hydroxyhippuric B
acid I
. O

[ B
( I
14 I
) I
C I
] I
BPB I
was O
administered O
to O
male O
rats O
orally O
at O
10 O
, O
100 O
or O
1000 O
mg O
/ O
kg O
, O
intravenously O
at O
10 O
mg O
/ O
kg O
and O
dermally O
at O
10 O
and O
100 O
mg O
/ O
kg O
; O
female O
rats O
were O
administered O
oral O
doses O
at O
10 O
mg O
/ O
kg O
. O

Oral O
doses O
of O
BPB B
were O
well O
- O
absorbed O
( O
> O
83 O
% O
) O
and O
eliminated O
chiefly O
in O
urine O
( O
83 O
- O
84 O
% O
) O
; O
< O
= O
1 O
% O
of O
the O
radioactivity O
remained O
in O
tissues O
at O
24 O
h O
or O
72 O
h O
after O
dosing O
. O

About O
4 O
% O
and O
8 O
% O
, O
respectively O
, O
of O
100 O
mg O
/ O
kg O
dermal O
doses O
were O
absorbed O
in O
24 O
h O
and O
72 O
h O
, O
and O
about O
50 O
% O
of O
a O
10 O
mg O
/ O
kg O
dose O
was O
absorbed O
in O
72 O
h O
. O

Metabolites O
detected O
in O
urine O
included O
those O
previously O
reported O
, O
BPB B
- I
glucuronide I
, O
BPB B
- I
sulfate I
, O
hydroxybenzoic B
acid I
and O
hydroxyhippuric B
acid I
, O
but O
also O
novel O
metabolites O
arising O
from O
ring O
hydroxylation O
followed O
by O
glucuronidation O
and O
sulfation O
. O

Fertility O
and O
endocrine O
outcome O
after O
robot O
- O
assisted O
laparoscopic O
myomectomy O
( O
RALM O
) O
. O

Introduction O
: O
Laparoscopic O
myomectomy O
has O
recently O
gained O
wide O
acceptance O
but O
this O
procedure O
remains O
technically O
highly O
demanding O
and O
concerns O
have O
been O
raised O
about O
the O
increased O
blood O
loss O
and O
an O
higher O
risk O
of O
postoperative O
uterine O
rupture O
of O
the O
pregnant O
uterus O
. O

Objective O
: O
The O
aim O
of O
the O
present O
study O
is O
to O
evaluate O
the O
fertility O
and O
endocrine O
outcome O
in O
women O
underwent O
robot O
- O
assisted O
laparoscopic O
myomectomy O
( O
RALM O
) O
. O

Methods O
: O
Data O
from O
48 O
RALM O
performed O
in O
our O
department O
between O
the O
years O
2007 O
and O
2011 O
have O
been O
collected O
. O

Conception O
rate O
, O
abortion O
rate O
, O
incidence O
of O
feto O
- O
maternal O
morbidity O
or O
severe O
pregnancy O
and O
labor O
- O
related O
complications O
were O
reported O
; O
FSH O
and O
AMH O
levels O
and O
ultrasound O
valuation O
of O
AFC O
has O
been O
made O
before O
and O
6 O
months O
after O
operation O
. O

Number O
of O
cesarean O
sections O
and O
vaginal O
deliveries O
were O
described O
. O

Results O
: O
The O
average O
age O
of O
the O
patients O
was O
35 O
years O
and O
median O
Body O
Mass O
Index O
was O
23 O
kg O
/ O
m O
( O
2 O
) O
( O
range O
18 O
- O
35 O
kg O
/ O
m O
( O
2 O
) O
) O
. O

Seven O
women O
( O
13 O
% O
) O
became O
pregnant O
after O
RALM B
with O
eight O
pregnancies O
. O

One O
pregnancy O
is O
actually O
on O
going O
; O
there O
were O
six O
deliveries O
with O
caesarian O
section O
and O
one O
spontaneous O
delivery O
. O

No O
spontaneous O
abortions O
. O

No O
uterine O
ruptures O
occurred O
. O

No O
significant O
modification O
of O
ovarian O
function O
was O
found O
after O
myomectomy O
. O

Conclusion O
: O
RALM B
seems O
to O
have O
a O
favorable O
impact O
on O
the O
reproductive O
outcome O
of O
young O
patients O
with O
no O
impact O
on O
the O
ovarian O
function O
. O

Sour O
Cherry O
Seed O
Kernel O
Extract O
Increases O
Heme B
Oxygenase O
- O
1 O
Expression O
and O
Decreases O
Representation O
of O
CD3 O
+ O
TNF O
- O
alpha O
+ O
and O
CD3 O
+ O
IL O
- O
8 O
+ O
Subpopulations O
in O
Peripheral O
Blood O
Leukocyte O
Cultures O
from O
Type O
2 O
Diabetes O
Patients O
. O

The O
present O
study O
evaluates O
a O
hypothesis O
that O
sour O
cherry O
( O
Prunus O
cerasus O
) O
seed O
extracts O
( O
SCE O
) O
modulate O
CD3 O
+ O
T O
lymphocyte O
activity O
in O
ways O
predictive O
of O
potential O
for O
uses O
of O
SCE O
in O
management O
of O
inflammatory O
diseases O
. O

Peripheral O
blood O
mononuclear O
cells O
( O
PBMC O
) O
from O
12 O
type O
2 O
diabetes O
( O
T2DM O
) O
patients O
and O
eight O
healthy O
control O
subjects O
were O
cultured O
24 O
h O
with O
100 O
ng O
/ O
ml O
lipopolysaccharide O
( O
LPS O
) O
to O
increase O
inflammatory O
signaling O
and O
co O
- O
incubated O
with O
0 O
. O
5 O
- O
100 O
micro O
g O
/ O
ml O
SCE O
. O

Cultures O
were O
evaluated O
by O
two O
- O
color O
flow O
cytometry O
for O
percent O
representation O
of O
CD3 O
+ O
IL8 O
+ O
and O
CD3 O
+ O
TNF O
- O
alpha O
+ O
cells O
which O
express O
interleukin O
- O
8 O
( O
IL O
- O
8 O
) O
, O
and O
tumor O
necrosis O
factor O
- O
alpha O
, O
( O
TNF O
- O
alpha O
+ O
) O
respectively O
, O
and O
by O
enzyme O
- O
linked O
immunoassay O
for O
lymphocyte O
- O
associated O
heme O
oxygenase O
- O
1 O
( O
HO O
- O
1 O
, O
known O
to O
be O
induced O
by O
SCE O
) O
. O

SCE O
dosage O
ranges O
of O
0 O
. O
5 O
- O
100 O
micro O
g O
/ O
ml O
in O
cell O
cultures O
significantly O
suppressed O
LPS O
- O
increased O
CD3 O
+ O
TNF O
- O
alpha O
+ O
and O
CD3 O
+ O
IL8 O
+ O
representation O
from O
all O
participants O
( O
p O
< O
0 O
. O
05 O
) O
, O
with O
greater O
pharmacological O
effect O
noted O
in O
suppression O
of O
CD3 O
+ O
TNF O
- O
alpha O
+ O
noted O
in O
cells O
from O
T2DM O
patients O
versus O
healthy O
control O
subjects O
. O

These O
effects O
correlated O
with O
increased O
HO O
- O
1 O
expression O
in O
SCE O
- O
treated O
PBMC O
from O
all O
subjects O
( O
p O
< O
0 O
. O
05 O
) O
. O

Since O
TNF O
- O
alpha O
and O
IL O
- O
8 O
are O
diagnostic O
/ O
prognostic O
biomarkers O
for O
many O
inflammatory O
syndromes O
, O
the O
capacity O
of O
SCE O
to O
down O
- O
regulate O
representation O
of O
cells O
that O
express O
them O
suggests O
potential O
for O
therapeutic O
use O
of O
SCE O
in O
T2DM O
and O
other O
diseases O
. O

Copyright O
( O
c O
) O
2012 O
John O
Wiley O
& O
Sons O
, O
Ltd O
. O

Combined O
effects O
of O
treatment O
with O
vitamin B
C I
, O
vitamin B
E I
and O
selenium B
on O
the O
skin O
of O
diabetic O
rats O
. O

The O
aim O
of O
this O
study O
was O
to O
investigate O
the O
effects O
of O
vitamin B
C I
, O
vitamin B
E I
and O
selenium B
( O
Se B
) O
on O
the O
skin O
tissue O
of O
streptozotocin B
- O
induced O
diabetic O
rats O
. O

Swiss O
albino O
rats O
were O
divided O
into O
four O
groups O
: O
control O
, O
control O
+ O
antioxidants O
, O
diabetic O
, O
diabetic O
+ O
antioxidants O
groups O
. O

Diabetes O
was O
induced O
by O
intraperitoneal O
injection O
of O
65 O
mg O
/ O
kg O
streptozotocin B
. O

Vitamin B
C I
( O
250 O
mg O
/ O
kg O
) O
, O
vitamin B
E I
( O
250 O
mg O
/ O
kg O
) O
and O
Se B
( O
0 O
. O
2 O
mg O
/ O
kg O
) O
were O
given O
by O
gavage O
technique O
to O
rats O
of O
one O
diabetic O
and O
one O
control O
group O
for O
30 O
days O
. O

In O
the O
diabetic O
group O
, O
the O
levels O
of O
serum O
urea B
and O
creatinine B
, O
skin O
lipid O
peroxidation O
and O
nonenzymatic O
glycosylation O
levels O
increased O
, O
but O
skin O
glutathione B
levels O
decreased O
. O

Treatment O
with O
vitamin B
C I
, O
vitamin B
E I
and O
Se B
reversed O
these O
effects O
. O

The O
present O
study O
showed O
that O
vitamin B
C I
, O
vitamin B
E I
and O
Se B
exerted O
antioxidant O
effects O
and O
consequently O
may O
prevent O
skin O
damage O
caused O
by O
streptozotocin B
- O
induced O
diabetes O
. O

Dopamine B
D O
2 O
- O
agonist O
rotigotine B
effects O
on O
cortical O
excitability O
and O
central O
cholinergic O
transmission O
in O
Alzheimer O
' O
s O
disease O
patients O
. O

Dopamine B
is O
a O
neurotransmitter O
involved O
in O
several O
brain O
functions O
ranging O
from O
emotions O
control O
, O
movement O
organization O
to O
memory O
formation O
. O

It O
is O
also O
involved O
in O
the O
regulation O
of O
mechanisms O
of O
synaptic O
plasticity O
. O

However O
, O
its O
role O
in O
Alzheimer O
' O
s O
disease O
( O
AD O
) O
pathogenesis O
is O
still O
puzzling O
. O

Several O
recent O
line O
of O
research O
instead O
indicates O
a O
clear O
role O
for O
dopamine B
in O
both O
amyloid O
beta O
formation O
as O
well O
as O
in O
cognitive O
decline O
progression O
. O

In O
particular O
it O
has O
been O
shown O
that O
dopamine B
D O
2 O
- O
like O
receptors O
( O
namely O
D O
3 O
and O
D O
2 O
) O
could O
be O
mostly O
responsible O
for O
dopamine B
dysfunction O
in O
AD O
. O

Here O
we O
aimed O
to O
study O
the O
effects O
of O
the O
dopamine B
agonist O
Rotigotine B
on O
cortical O
excitability O
and O
on O
central O
cholinergic O
transmission O
in O
cases O
of O
AD O
. O

Rotigotine B
is O
a O
dopamine B
agonist O
with O
a O
pharmacological O
profile O
with O
high O
affinity O
for O
D O
3 O
and O
D O
2 O
receptors O
. O

We O
used O
paired O
pulse O
protocols O
assessing O
short O
intracortical O
inhibition O
( O
SICI O
) O
and O
intracortical O
facilitation O
( O
ICF O
) O
to O
asses O
cortical O
excitability O
over O
the O
primary O
motor O
cortex O
and O
Short O
Latency O
Afferent O
Inhibition O
( O
SLAI O
) O
protocols O
, O
to O
verify O
the O
effects O
of O
the O
drug O
on O
central O
cholinergic O
transmission O
in O
a O
group O
of O
AD O
patients O
compared O
to O
age O
- O
matched O
controls O
. O

We O
observed O
that O
rotigotine B
induces O
unexpected O
changes O
in O
both O
cortical O
excitability O
( O
increased O
) O
and O
central O
cholinergic O
transmission O
( O
restored O
) O
of O
AD O
patients O
. O

These O
unexpected O
effects O
might O
depend O
on O
the O
dopamine B
D O
2 O
- O
like O
receptors O
dysfunction O
previously O
described O
in O
AD O
brains O
. O

The O
current O
findings O
could O
indicate O
that O
future O
strategies O
aimed O
to O
ameliorate O
symptoms O
of O
the O
related O
AD O
cognitive O
decline O
could O
also O
involve O
some O
dopaminergic O
drugs O
. O

This O
article O
is O
part O
of O
a O
Special O
Issue O
entitled O
' O
Cognitive O
Enhancers O
' O
. O

Absorption O
of O
TAK O
- O
491 O
, O
a O
new O
angiotensin O
II O
receptor O
antagonist O
, O
in O
animals O
. O

The O
absorption O
process O
in O
animals O
of O
TAK B
- I
491 I
, O
designed O
as O
ester B
- O
based O
prodrug O
with O
medoxomil B
moiety O
, O
was O
evaluated O
. O

In O
the O
plasma O
of O
rats O
and O
dogs O
, O
TAK B
- I
536 I
, O
the O
pharmacologically O
active O
metabolite O
, O
was O
present O
as O
the O
main O
component O
with O
hardly O
detectable O
concentrations O
of O
TAK B
- I
491 I
after O
oral O
administration O
of O
TAK B
- I
491 I
. O

In O
the O
rat O
portal O
plasma O
, O
TAK O
- O
536 O
was O
also O
present O
as O
the O
main O
component O
with O
hardly O
detectable O
concentrations O
of O
TAK O
- O
491 O
after O
jejunal O
loop O
injection O
of O
TAK O
- O
491 O
, O
suggesting O
TAK O
- O
491 O
was O
absorbed O
from O
small O
intestine O
and O
hydrolyzed O
almost O
completely O
during O
absorption O
. O

Caco O
- O
2 O
study O
indicated O
the O
permeability O
of O
TAK B
- I
491 I
was O
improved O
by O
prodrug O
modification O
and O
the O
compound O
could O
be O
mainly O
transferred O
as O
TAK B
- I
491 I
. O

This O
is O
well O
consistent O
with O
the O
facts O
that O
the O
AUC O
and O
T O
( O
max O
) O
of O
TAK B
- I
536 I
after O
oral O
administration O
of O
TAK B
- I
491 I
were O
higher O
and O
shorter O
than O
those O
after O
oral O
administration O
of O
TAK B
- I
536 I
in O
dogs O
Hydrolysis O
of O
TAK B
- I
491 I
is O
observed O
not O
only O
by O
the O
intestinal O
and O
hepatic O
S9 O
fraction O
, O
but O
also O
by O
plasma O
and O
human O
serum O
albumin O
. O

However O
, O
medoxomil B
alcohol I
wasn O
' O
t O
detected O
during O
the O
hydrolysis O
of O
TAK B
- I
491 I
. O

These O
metabolic O
features O
of O
TAK O
- O
491 O
were O
similar O
to O
olmesartan B
medoxomil I
, O
suggesting O
the O
hydrolytic O
pathway O
and O
enzymes O
for O
TAK O
- O
491 O
when O
catalyzing O
to O
TAK O
- O
536 O
would O
be O
the O
same O
as O
olmesartan B
medoxomil I
. O

Synthesis O
, O
characterization O
, O
screening O
and O
docking O
analysis O
of O
4 B
- I
anilinoquinazoline I
derivatives O
as O
tyrosine B
kinase O
inhibitors O
. O

We O
report O
here O
the O
design O
and O
synthesis O
of O
a O
series O
of O
4 B
- I
anilinoquinazoline I
derivatives O
, O
of O
which O
7 O
compounds O
were O
crystallographically O
characterized O
, O
as O
epidermal O
growth O
factor O
receptor O
( O
EGFR O
) O
inhibitors O
by O
modifications O
on O
the O
aniline B
ring O
or O
at O
the O
6 B
- I
alkoxy I
site O
of O
the O
6 B
, I
7 I
- I
dimethoxy I
- I
4 I
- I
anilinoquinazoline I
pharmacophore O
. O

The O
relative O
inhibition O
efficiency O
on O
EGFR O
of O
all O
as O
- O
prepared O
compounds O
were O
measured O
and O
ordered O
, O
and O
the O
IC50 O
values O
of O
nine O
highly O
active O
compounds O
were O
determined O
by O
ELISA O
. O

Docking O
studies O
indicated O
that O
all O
4 B
- I
anilinoquinazoline I
derivatives O
could O
be O
inserted O
into O
the O
ATP B
- O
binding O
pocket O
of O
the O
EGFR O
via O
indirect O
docking O
, O
and O
that O
the O
modifications O
at O
the O
3 O
' O
- O
position O
of O
the O
anilino B
group O
and O
6 B
- I
alkoxy I
site O
of O
the O
quinazoline B
ring O
have O
little O
interference O
with O
the O
formation O
of O
the O
two O
essential O
H B
- O
bonds O
between O
the O
N3 O
of O
the O
quinazoline B
ring O
and O
Thr766 B
through O
a O
water O
molecule O
, O
and O
the O
N1 O
of O
the O
quinazoline B
ring O
and O
N B
- I
H I
of O
Met769 B
. O

The O
displacing O
of O
the O
phenyl B
at O
4 O
- O
position O
with O
pyridinyl B
dramatically O
reduces O
the O
activity O
of O
the O
quinazoline B
pharmacophore O
, O
the O
resulting O
derivative O
( O
10 O
) O
being O
the O
least O
active O
compound O
. O

The O
docking O
results O
also O
showed O
that O
the O
formation O
of O
new O
H B
- O
bonds O
between O
the O
N B
- I
H I
of O
the O
ethylenediamine B
group O
linked O
to O
the O
6 O
- O
alkoxy B
site O
and O
Asp776 B
/ O
Cys773 B
in O
the O
binding O
pocket O
of O
EGFR O
makes O
compounds O
19 O
( O
IC50 O
= O
12 O
. O
1 O
+ O
/ O
- O
1 O
. O
6 O
nM O
) O
and O
20 O
( O
IC50 O
= O
13 O
. O
6 O
+ O
/ O
- O
0 O
. O
8 O
nM O
) O
the O
most O
potent O
EGFR O
inhibitors O
in O
this O
class O
and O
worthy O
of O
further O
modification O
to O
obtain O
more O
potent O
anticancer O
compounds O
. O

Small O
molecule O
modulation O
of O
nuclear O
receptor O
conformational O
dynamics O
: O
implications O
for O
function O
and O
drug O
discovery O
. O

Nuclear O
receptors O
are O
targets O
for O
a O
wide O
range O
of O
ligands O
, O
both O
natural O
and O
synthetic O
, O
that O
regulate O
their O
activity O
and O
provide O
a O
means O
to O
pharmacologically O
modulate O
the O
receptor O
. O

Recent O
emphasis O
in O
the O
nuclear O
receptor O
field O
has O
focused O
on O
selective O
nuclear O
receptor O
modulators O
, O
which O
can O
display O
graded O
transcriptional O
responses O
and O
tissue O
selective O
pharmacological O
responses O
that O
deviate O
from O
the O
prototypical O
agonist O
or O
antagonist O
. O

Understanding O
the O
molecular O
mechanism O
of O
action O
of O
these O
selective O
modulators O
will O
provide O
significant O
insight O
toward O
the O
development O
of O
the O
next O
generation O
of O
modulators O
. O

Although O
most O
nuclear O
receptor O
structural O
studies O
have O
primarily O
focused O
on O
obtaining O
ligand O
- O
receptor O
cocrystal O
structures O
, O
recent O
studies O
implicate O
an O
important O
role O
for O
protein O
dynamics O
in O
the O
mechanism O
of O
action O
of O
nuclear O
receptor O
ligands O
. O

Here O
we O
review O
nuclear O
receptor O
studies O
reporting O
how O
ligands O
modulate O
the O
conformational O
dynamics O
of O
the O
nuclear O
receptor O
ligand O
- O
binding O
domain O
( O
LBD O
) O
. O

A O
particular O
emphasis O
is O
placed O
on O
protein O
NMR O
and O
hydrogen B
/ O
deuterium B
exchange O
( O
HDX O
) O
techniques O
and O
how O
they O
provide O
complementary O
information O
that O
, O
when O
combined O
with O
crystallography O
, O
provide O
detailed O
insight O
into O
the O
function O
of O
nuclear O
receptors O
. O

Gelucire B
44 O
/ O
14 O
based O
immediate O
release O
formulations O
for O
poorly O
water O
- O
soluble O
drugs O
. O

Here O
, O
we O
aim O
to O
evaluate O
Gelucire B
44 O
/ O
14 O
as O
non O
- O
ionic O
surface O
- O
active O
excipient O
to O
produce O
immediate O
- O
release O
solid O
dosage O
forms O
for O
poorly O
water O
- O
soluble O
drugs O
. O

Gelucires O
are O
polyethylene B
glycol I
( O
PEG B
) O
glycerides O
composed O
of O
mono B
- I
, I
di I
- I
and I
triglycerides I
and O
mono I
- I
and I
diesters I
of I
PEG B
. O

They O
are O
inert O
semi O
- O
solid O
waxy O
amphiphilic O
excipients O
with O
surface O
- O
active O
properties O
that O
spontaneously O
form O
a O
fine O
dispersion O
or O
emulsion O
upon O
contact O
with O
water O
. O

Monolithic O
Gelucire B
44 O
/ O
14 O
structures O
are O
prone O
to O
prolonged O
erosion O
times O
, O
thereby O
slowing O
down O
drug O
dissolution O
. O

To O
overcome O
this O
issue O
, O
we O
combine O
either O
granulation O
or O
spray O
- O
drying O
, O
followed O
by O
compression O
into O
tablets O
, O
with O
an O
optimized O
composition O
of O
disintegration O
promoting O
agents O
. O

This O
formulation O
strategy O
allows O
obtaining O
nearly O
100 O
% O
drug O
release O
within O
10 O
min O
dissolution O
time O
. O

Modeling O
the O
structure O
and O
proton O
transfer O
pathways O
of O
the O
mutant O
His B
- O
107 O
- O
Tyr B
of O
human O
carbonic O
anhydrase O
II O
. O

We O
present O
molecular O
modeling O
of O
the O
structure O
and O
possible O
proton O
transfer O
pathways O
from O
the O
surface O
of O
the O
protein O
to O
the O
zinc B
- O
bound O
water O
molecule O
in O
the O
active O
site O
of O
the O
mutant O
His B
- O
107 O
- O
Tyr B
of O
human O
carbonic O
anhydrase O
II O
( O
HCAII O
) O
. O

No O
high O
- O
resolution O
structure O
or O
crystal O
structure O
is O
available O
till O
now O
for O
this O
particular O
mutant O
due O
to O
its O
lack O
of O
stability O
at O
physiological O
temperature O
. O

Our O
analysis O
utilizes O
as O
starting O
point O
a O
series O
of O
structures O
derived O
from O
high O
- O
resolution O
crystal O
structure O
of O
the O
wild O
type O
protein O
. O

While O
many O
of O
the O
structures O
investigated O
do O
not O
reveal O
a O
complete O
path O
between O
the O
zinc B
bound O
water O
and O
His B
- O
64 O
, O
several O
others O
do O
indicate O
the O
presence O
of O
a O
transient O
connection O
even O
when O
His B
- O
64 O
is O
present O
in O
its O
outward O
conformation O
. O

Mutation O
at O
the O
residue O
107 O
also O
reveals O
the O
formation O
of O
a O
new O
path O
into O
the O
active O
site O
. O

Competing O
contributions O
from O
His B
- O
64 O
sidechain O
rotation O
from O
its O
outward O
conformation O
are O
also O
evaluated O
in O
terms O
of O
optimal O
path O
analysis O
. O

No O
indication O
of O
a O
lower O
catalytic O
efficiency O
of O
the O
mutant O
is O
evident O
from O
our O
results O
under O
the O
condition O
of O
thermal O
stability O
of O
the O
mutant O
. O

Oxysterol B
generation O
and O
liver O
X O
receptor O
- O
dependent O
reverse O
cholesterol B
transport O
: O
not O
all O
roads O
lead O
to O
Rome O
. O

Cell O
cholesterol B
metabolism O
is O
a O
tightly O
regulated O
process O
, O
dependent O
in O
part O
on O
activation O
of O
nuclear O
liver O
X O
receptors O
( O
LXRs O
) O
to O
increase O
expression O
of O
genes O
mediating O
removal O
of O
excess O
cholesterol B
from O
cells O
in O
the O
reverse O
cholesterol B
transport O
pathway O
. O

LXRs O
are O
thought O
to O
be O
activated O
predominantly O
by O
oxysterols B
generated O
enzymatically O
from O
cholesterol B
in O
different O
cell O
organelles O
. O

Defects O
resulting O
in O
slowed O
release O
of O
cholesterol B
from O
late O
endosomes O
and O
lysosomes O
or O
reduction O
in O
sterol B
- O
27 O
- O
hydroxylase O
activity O
lead O
to O
specific O
blocks O
in O
oxysterol B
production O
and O
impaired O
LXR O
- O
dependent O
gene O
activation O
. O

This O
block O
does O
not O
appear O
to O
be O
compensated O
by O
oxysterol B
production O
in O
other O
cell O
compartments O
. O

The O
purpose O
of O
this O
review O
is O
to O
summarize O
current O
knowledge O
about O
oxysterol B
- O
dependent O
activation O
by O
LXR O
of O
genes O
involved O
in O
reverse O
cholesterol B
transport O
, O
and O
what O
these O
defects O
of O
cell O
cholesterol B
homeostasis O
can O
teach O
us O
about O
the O
critical O
pathways O
of O
oxysterol B
generation O
for O
expression O
of O
LXR O
- O
dependent O
genes O
. O

The O
mGlu O
5 O
positive O
allosteric O
modulator O
LSN2463359 B
differentially O
modulates O
motor O
, O
instrumental O
and O
cognitive O
effects O
of O
NMDA B
receptor O
antagonists O
in O
the O
rat O
. O

Metabotropic O
glutamate B
5 O
( O
mGlu O
5 O
) O
receptors O
are O
known O
to O
functionally O
interact O
with O
N B
- I
methyl I
- I
d I
- I
aspartate I
( O
NMDA B
) O
receptors O
at O
both O
neuronal O
and O
behavioural O
levels O
, O
in O
a O
manner O
that O
may O
be O
of O
relevance O
to O
the O
treatment O
of O
schizophrenia O
. O

We O
have O
previously O
described O
a O
novel O
mGlu O
5 O
positive O
allosteric O
modulator O
( O
PAM O
) O
, O
LSN2463359 B
and O
provided O
evidence O
of O
its O
ability O
to O
attenuate O
aspects O
of O
the O
behavioural O
response O
to O
administration O
of O
the O
competitive O
NMDA B
receptor O
antagonist O
, O
SDZ B
220 I
, I
581 I
. O

In O
addition O
, O
LSN2463359 B
was O
found O
to O
selectively O
attenuate O
reversal O
learning O
deficits O
observed O
in O
the O
neurodevelopmental O
MAM O
E17 O
model O
but O
not O
in O
the O
acute O
phencyclidine B
( O
PCP B
) O
model O
. O

In O
the O
present O
study O
, O
the O
interactions O
between O
this O
mGlu O
5 O
PAM O
and O
the O
NMDA B
receptor O
were O
explored O
further O
by O
assessing O
the O
effects O
of O
LSN2463359 B
against O
some O
of O
the O
motor O
, O
instrumental O
and O
cognitive O
effects O
induced O
by O
the O
non O
- O
competitive O
NMDA B
receptor O
antagonists O
PCP B
and O
MK B
- I
801 I
, O
the O
competitive O
NMDA B
receptor O
antagonist O
SDZ B
220 I
, I
581 I
and O
the O
GluN2B O
selective O
NMDA B
receptor O
antagonist O
, O
Ro B
63 I
- I
1908 I
. O

LSN2463359 B
had O
either O
no O
or O
minor O
impact O
on O
locomotor O
hyperactivity O
induced O
by O
either O
PCP B
or O
SDZ B
220 I
, I
581 I
. O

However O
, O
in O
rats O
lever O
pressing O
for O
food O
rewards O
under O
a O
variable O
interval O
30s O
schedule O
of O
instrumental O
responding O
, O
the O
drug O
clearly O
attenuated O
not O
only O
the O
suppression O
of O
response O
rate O
induced O
by O
SDZ B
220 I
, I
581 I
but O
also O
the O
stimulation O
of O
response O
rate O
induced O
by O
Ro B
63 I
- I
1908 I
. O

In O
contrast O
, O
LSN2463359 B
failed O
to O
alter O
both O
of O
the O
instrumental O
effects O
induced O
by O
the O
open O
channel O
blockers O
PCP B
and O
MK B
- I
801 I
. O

In O
addition O
, O
although O
PCP B
and O
SDZ B
220 I
, I
581 I
induced O
similar O
deficits O
in O
a O
discrimination O
and O
reversal O
learning O
task O
, O
LSN2463359 B
was O
again O
only O
able O
to O
reverse O
the O
deficit O
induced O
by O
SDZ B
220 I
, I
581 I
. O

The O
results O
indicate O
that O
the O
interactions O
between O
mGlu O
5 O
and O
NMDA B
receptors O
are O
dependent O
on O
both O
the O
mechanism O
of O
the O
blockade O
of O
the O
receptor O
and O
the O
behavioural O
domain O
under O
investigation O
. O

Our O
work O
has O
implications O
for O
the O
preclinical O
use O
of O
NMDA B
receptor O
antagonists O
in O
the O
prediction O
of O
potential O
therapeutic O
efficacy O
in O
the O
search O
for O
novel O
treatments O
for O
schizophrenia O
. O

Positive O
allosteric O
modulators O
of O
the O
mGlu O
5 O
receptor O
certainly O
question O
the O
predictive O
validity O
of O
such O
approaches O
. O

This O
article O
is O
part O
of O
a O
Special O
Issue O
entitled O
' O
Cognitive O
Enhancers O
' O
. O

In O
vitro O
characterisation O
of O
the O
novel O
positive O
allosteric O
modulators O
of O
the O
mGlu O
5 O
receptor O
, O
LSN2463359 B
and O
LSN2814617 B
, O
and O
their O
effects O
on O
sleep O
architecture O
and O
operant O
responding O
in O
the O
rat O
. O

The O
demonstrated O
functional O
interaction O
of O
metabotropic O
glutamate B
5 O
( O
mGlu O
5 O
) O
receptors O
with O
N B
- I
methyl I
- I
d I
- I
aspartate I
( O
NMDA B
) O
receptors O
has O
prompted O
speculation O
that O
their O
activation O
may O
offer O
a O
potential O
treatment O
for O
aspects O
of O
schizophrenia O
. O

Development O
of O
selective O
mGlu O
5 O
agonists O
has O
been O
difficult O
, O
but O
several O
different O
positive O
allosteric O
modulator O
( O
PAM O
) O
molecules O
have O
now O
been O
identified O
. O

This O
study O
describes O
two O
novel O
mGlu O
5 O
PAMs O
, O
LSN2463359 B
( O
N B
- I
( I
1 I
- I
methylethyl I
) I
- I
5 I
- I
( I
pyridin I
- I
4 I
- I
ylethynyl I
) I
pyridine I
- I
2 I
- I
carboxamide I
) O
and O
LSN2814617 B
[ O
( B
7S I
) I
- I
3 I
- I
tert I
- I
butyl I
- I
7 I
- I
[ I
3 I
- I
( I
4 I
- I
fluorophenyl I
) I
- I
1 I
, I
2 I
, I
4 I
- I
oxadiazol I
- I
5 I
- I
yl I
] I
- I
5 I
, I
6 I
, I
7 I
, I
8 I
- I
tetrahydro I

[ B
1 I
, I
2 I
, I
4 I
] I
triazolo I
[ I
4 I
, I
3 I
- I
A I
] I
pyridine I
] I
, O
which O
are O
useful O
tools O
for O
this O
field O
of O
research O
. O

Both O
compounds O
are O
potent O
and O
selective O
potentiators O
of O
human O
and O
rat O
mGlu O
5 O
receptors O
in O
vitro O
, O
displaying O
curve O
shift O
ratios O
of O
two O
to O
three O
fold O
in O
the O
concentration O
- O
response O
relationship O
to O
glutamate B
or O
the O
glutamate B
receptor O
agonist O
, O
DHPG B
, O
with O
no O
detectable O
intrinsic O
agonist O
properties O
. O

Both O
compounds O
displaced O
the O
mGlu O
5 O
receptor O
antagonist O
radioligand O
, O
[ B
( I
3 I
) I
H I
] I
MPEP I
in O
vitro O
and O
, O
following O
oral O
administration O
reached O
brain O
concentrations O
sufficient O
to O
occupy O
hippocampal O
mGlu O
5 O
receptors O
as O
measured O
in O
vivo O
by O
dose O
- O
dependent O
displacement O
from O
the O
hippocampus O
of O
intravenously O
administered O
MPEPy B
. O

In O
vivo O
EEG O
studies O
demonstrated O
that O
these O
mGlu O
5 O
PAMs O
have O
marked O
wake O
- O
promoting O
properties O
but O
little O
in O
the O
way O
of O
rebound O
hypersomnolence O
. O

In O
contrast O
, O
the O
previously O
described O
mGlu O
5 O
PAMs O
CDPPB B
and O
ADX47273 B
showed O
relatively O
poor O
evidence O
of O
in O
vivo O
target O
engagement O
in O
either O
receptor O
occupancy O
assays O
or O
EEG O
disturbance O
. O

Wake O
- O
promoting O
doses O
of O
LSN2463359 B
and O
LSN2814617 B
attenuated O
deficits O
in O
performance O
induced O
by O
the O
competitive O
NMDA B
receptor O
antagonist O
SDZ B
220 I
, I
581 I
in O
two O
tests O
of O
operant O
behaviour O
: O
the O
variable O
interval O
30 O
s O
task O
and O
the O
DMTP O
task O
. O

These O
effects O
were O
lost O
if O
the O
dose O
of O
either O
compound O
extended O
into O
the O
range O
which O
disrupted O
performance O
in O
the O
baseline O
DMTP O
task O
. O

However O
, O
the O
improvements O
in O
response O
accuracy O
induced O
by O
the O
mGlu O
5 O
potentiators O
in O
SDZ B
220 I
, I
581 I
- O
treated O
rats O
were O
not O
delay O
- O
dependent O
and O
, O
therefore O
, O
perhaps O
more O
likely O
reflected O
optimization O
of O
general O
arousal O
than O
specific O
beneficial O
effects O
on O
discrete O
cognitive O
processes O
. O

The O
systematic O
profiling O
of O
LSN2463359 B
and O
LSN2814617 B
alongside O
other O
previously O
described O
molecules O
will O
help O
determine O
more O
precisely O
how O
mGlu O
5 O
potentiator O
pharmacology O
might O
provide O
therapeutic O
benefit O
. O

This O
article O
is O
part O
of O
a O
Special O
Issue O
entitled O
' O
Cognitive O
Enhancers O
' O
. O

The O
development O
and O
application O
of O
small O
molecule O
modulators O
of O
SF3b O
as O
therapeutic O
agents O
for O
cancer O
. O

The O
identification O
of O
potent O
spliceosome O
modulators O
that O
demonstrate O
antitumor O
activity O
indicates O
that O
this O
complex O
may O
be O
a O
target O
for O
drug O
development O
. O

Several O
natural O
products O
have O
been O
demonstrated O
to O
bind O
to O
the O
SF3b1 O
subunit O
of O
this O
macromolecule O
and O
these O
agents O
modulate O
alternative O
RNA O
splicing O
. O

In O
this O
article O
we O
describe O
their O
biological O
properties O
, O
discuss O
the O
validity O
of O
the O
spliceosome O
as O
a O
therapeutic O
target O
, O
and O
propose O
that O
alteration O
of O
alternative O
splicing O
represents O
a O
viable O
approach O
for O
inducing O
tumor O
- O
selective O
cytotoxicity O
. O

Size O
of O
TiO B
( I
2 I
) I
nanoparticles O
influences O
their O
phototoxicity O
: O
an O
in O
vitro O
investigation O
. O

To O
uncover O
the O
size O
influence O
of O
TiO B
( I
2 I
) I
nanoparticles O
on O
their O
potential O
toxicity O
, O
the O
cytotoxicity O
of O
different O
- O
sized O
TiO B
( I
2 I
) I
nanoparticles O
with O
and O
without O
photoactivation O
was O
tested O
. O

It O
was O
demonstrated O
that O
without O
photoactivation O
, O
TiO B
( I
2 I
) I
nanoparticles O
were O
inert O
up O
to O
100 O
mu O
g O
/ O
ml O
. O

On O
the O
contrary O
, O
with O
photoactivation O
, O
the O
toxicity O
of O
TiO B
( I
2 I
) I
nanoparticles O
significantly O
increased O
, O
which O
correlated O
well O
with O
the O
specific O
surface O
area O
of O
the O
particles O
. O

Our O
results O
also O
suggest O
that O
the O
generation O
of O
hydroxyl B
radicals O
and O
reactive O
oxygen B
species O
( O
ROS O
) O
- O
mediated O
damage O
to O
the O
surface O
- O
adsorbed O
biomolecules O
could O
be O
the O
two O
major O
reasons O
for O
the O
cytotoxicity O
of O
TiO B
( I
2 I
) I
nanoparticles O
after O
photoactivation O
. O

Higher O
ROS O
generation O
from O
smaller O
particles O
was O
detected O
under O
both O
biotic O
and O
abiotic O
conditions O
. O

Smaller O
particles O
could O
adsorb O
more O
proteins O
, O
which O
was O
confirmed O
by O
thermogravimetric O
analysis O
. O

To O
further O
investigate O
the O
influence O
of O
the O
generation O
of O
hydroxyl B
radicals O
and O
adsorption O
of O
protein O
, O
poly B
( I
ethylene I
- I
alt I
- I
maleic I
anhydride I
) I
( O
PEMA B
) O
and O
chitosan O
were O
used O
to O
coat O
TiO B
( I
2 I
) I
nanoparticles O
. O

The O
results O
confirmed O
that O
surface O
coating O
of O
TiO B
( I
2 I
) I
nanoparticles O
could O
reduce O
such O
toxicity O
after O
photoactivation O
, O
by O
hindering O
adsorption O
of O
biomolecules O
and O
generation O
of O
hydroxyl B
radical O
( O
. B
OH I
) O
during O
photoactivation O
. O

Fibroblast O
growth O
factor O
23 O
inhibits O
extrarenal O
synthesis O
of O
1 B
, I
25 I
- I
dihydroxyvitamin I
D I
in O
human O
monocytes O
. O

Vitamin B
D I
is O
a O
potent O
stimulator O
of O
monocyte O
innate O
immunity O
, O
and O
this O
effect O
is O
mediated O
via O
intracrine O
conversion O
of O
25 B
- I
hydroxyvitamin I
D I
( O
25OHD B
) O
to O
1 B
, I
25 I
- I
dihydroxyvitamin I
D I
( O
1 B
, I
25 I
( I
OH I
) I
( I
2 I
) I
D I
) O
. O

In O
the O
kidney O
, O
synthesis O
of O
1 B
, I
25 I
( I
OH I
) I
( I
2 I
) I
D I
is O
suppressed O
by O
fibroblast O
growth O
factor O
23 O
( O
FGF23 O
) O
, O
via O
transcriptional O
suppression O
of O
the O
vitamin B
D I
- O
activating O
enzyme O
1 O
alpha O
- O
hydroxylase O
( O
CYP27B1 O
) O
. O

We O
hypothesized O
that O
FGF23 O
also O
suppresses O
CYP27B1 O
in O
monocytes O
, O
with O
concomitant O
effects O
on O
intracrine O
responses O
to O
1 B
, I
25 I
( I
OH I
) I
( I
2 I
) I
D I
. O

Healthy O
donor O
peripheral O
blood O
mononuclear O
cell O
monocytes O
( O
PBMCm O
) O
and O
peritoneal O
dialysate O
monocyte O
( O
PDm O
) O
effluent O
from O
kidney O
disease O
patients O
were O
assessed O
at O
baseline O
to O
confirm O
the O
presence O
of O
mRNA O
for O
FGF23 O
receptors O
( O
FGFRs O
) O
, O
with O
Klotho O
and O
FGFR1 O
being O
more O
strongly O
expressed O
than O
FGFR2 O
/ O
3 O
/ O
4 O
in O
both O
cell O
types O
. O

Immunohistochemistry O
showed O
coexpression O
of O
Klotho O
and O
FGFR1 O
in O
PBMCm O
and O
PDm O
, O
with O
this O
effect O
being O
enhanced O
following O
treatment O
with O
FGF23 O
in O
PBMCm O
but O
not O
PDm O
. O

Treatment O
with O
FGF23 O
activated O
mitogen O
- O
activated O
protein O
kinase O
( O
MAPK O
) O
and O
protein O
kinase O
B O
( O
Akt O
) O
pathways O
in O
PBMCm O
, O
demonstrating O
functional O
FGFR O
signaling O
in O
these O
cells O
. O

FGF23 O
treatment O
of O
PBMCm O
and O
PDm O
decreased O
expression O
of O
mRNA O
for O
CYP27B1 O
. O

In O
PBMCm O
this O
was O
associated O
with O
downregulation O
of O
25OHD B
to O
1 B
, I
25 I
( I
OH I
) I
( I
2 I
) I
D I
metabolism O
, O
and O
concomitant O
suppression O
of O
intracrine O
induced O
24 O
- O
hydroxylase O
( O
CYP24A1 O
) O
and O
antibacterial O
cathelicidin O
( O
LL37 O
) O
. O

FGF23 O
suppression O
of O
CYP27B1 O
was O
particularly O
pronounced O
in O
PBMCm O
treated O
with O
interleukin O
- O
15 O
to O
stimulate O
synthesis O
of O
1 B
, I
25 I
( I
OH I
) I
( I
2 I
) I
D I
. O

These O
data O
indicate O
that O
FGF23 O
can O
inhibit O
extra O
- O
renal O
expression O
of O
CYP27B1 O
and O
subsequent O
intracrine O
responses O
to O
1 B
, I
25 I
( I
OH I
) I
( I
2 I
) I
D I
in O
two O
different O
human O
monocyte O
models O
. O

Elevated O
expression O
of O
FGF23 O
may O
therefore O
play O
a O
crucial O
role O
in O
defining O
immune O
responses O
to O
vitamin B
D I
and O
this O
, O
in O
turn O
, O
may O
be O
a O
key O
determinant O
of O
infection O
in O
patients O
with O
chronic O
kidney O
disease O
( O
CKD O
) O
. O

A O
crown O
- O
ether O
loop O
- O
derivatized O
oligothiophene B
doubly O
attached O
on O
gold O
surface O
as O
cation O
- O
binding O
switchable O
molecular O
junction O
. O

A O
crown B
- I
ether I
dithiol I
quaterthiophene I
is O
synthesized O
and O
immobilized O
on O
gold O
surface O
by O
double O
covalent O
fixation O
. O

UV O
- O
vis O
spectroscopy O
and O
cyclic O
voltammetry O
show O
that O
the O
corresponding O
dithioester B
precursor O
can O
complex O
Pb B
( I
2 I
+ I
) I
in O
solution O
and O
that O
this O
property O
is O
maintained O
for O
monolayers O
of O
the O
dithiol B
on O
gold O
. O

Current O
- O
voltage O
measurements O
by O
eutectic O
GaIn O
drop O
contact O
on O
the O
monolayer O
show O
a O
significant O
increase O
( O
up O
to O
1 O
. O
6 O
x O
10 O
( O
3 O
) O
times O
) O
of O
the O
current O
at O
low O
bias O
after O
Pb B
( I
2 I
+ I
) I
complexation O
. O

Microindentation O
for O
in O
vivo O
measurement O
of O
bone O
tissue O
material O
properties O
in O
atypical O
femoral O
fracture O
patients O
and O
controls O
. O

Atypical O
femoral O
fractures O
( O
AFF O
) O
associated O
with O
long O
- O
term O
bisphosphonates B
( O
LTB O
) O
are O
a O
growing O
concern O
. O

Their O
etiology O
is O
unknown O
, O
but O
bone O
material O
properties O
might O
be O
deteriorated O
. O

In O
an O
AFF O
series O
, O
we O
analyzed O
the O
bone O
material O
properties O
by O
microindentation O
. O

Four O
groups O
of O
patients O
were O
included O
: O
6 O
AFF O
, O
38 O
typical O
osteoporotic O
fractures O
, O
6 O
LTB O
, O
and O
20 O
controls O
without O
fracture O
. O

Neither O
typical O
osteoporotic O
fractures O
nor O
controls O
have O
received O
any O
antiosteoporotic O
medication O
. O

A O
general O
laboratory O
workup O
, O
bone O
densitometry O
by O
dual O
- O
energy O
X O
- O
ray O
absorptiometry O
( O
DXA O
) O
, O
and O
microindentation O
testing O
at O
the O
tibia O
were O
done O
in O
all O
patients O
. O

Total O
indentation O
distance O
( O
Total O
ID O
) O
, O
indentation O
distance O
increase O
( O
IDI O
) O
, O
and O
creep O
indentation O
distance O
( O
Creep O
ID O
) O
were O
measured O
( O
microns O
) O
. O

Age O
- O
adjusted O
analysis O
of O
covariance O
( O
ANCOVA O
) O
was O
used O
for O
comparisons O
. O

Controls O
were O
significantly O
younger O
than O
fracture O
groups O
. O

Bisphosphonate B
exposure O
was O
on O
average O
5 O
. O
5 O
years O
( O
range O
5 O
to O
12 O
years O
) O
for O
the O
AFF O
and O
5 O
. O
4 O
years O
( O
range O
5 O
to O
8 O
years O
) O
for O
the O
LTB O
groups O
. O

Total O
ID O
( O
microns O
) O
showed O
better O
material O
properties O
( O
lower O
Total O
ID O
) O
for O
controls O
36 O
( O
+ O
/ O
- O
6 O
; O
mean O
+ O
/ O
- O
SD O
) O
than O
for O
AFF O
46 O
( O
+ O
/ O
- O
4 O
) O
and O
for O
typical O
femoral O
fractures O
47 O
( O
+ O
/ O
- O
13 O
) O
, O
respectively O
. O

Patients O
on O
LTB B
showed O
values O
between O
controls O
and O
fractures O
, O
38 O
( O
+ O
/ O
- O
4 O
) O
, O
although O
not O
significantly O
different O
from O
any O
of O
the O
other O
three O
groups O
. O

IDI O
values O
showed O
a O
similar O
pattern O
13 O
( O
+ O
/ O
- O
2 O
) O
, O
16 O
( O
+ O
/ O
- O
6 O
) O
, O
19 O
( O
+ O
/ O
- O
3 O
) O
, O
and O
18 O
( O
+ O
/ O
- O
5 O
) O
. O

After O
adjusting O
by O
age O
, O
significant O
differences O
were O
seen O
between O
controls O
and O
typical O
( O
p O
< O
0 O
. O
001 O
) O
and O
atypical O
fractures O
( O
p O
= O
0 O
. O
03 O
) O
for O
Total O
ID O
and O
for O
IDI O
( O
p O
< O
0 O
. O
001 O
and O
p O
< O
0 O
. O
05 O
, O
respectively O
) O
. O

There O
were O
no O
differences O
in O
Creep O
ID O
between O
groups O
. O

Our O
data O
suggest O
that O
patients O
with O
AFF O
have O
a O
deep O
deterioration O
in O
bone O
material O
properties O
at O
a O
tissue O
level O
similar O
to O
that O
for O
the O
osteoporotic O
fracture O
group O
. O

The O
LTB B
group O
shows O
levels O
that O
are O
in O
between O
controls O
and O
both O
type O
of O
fractures O
, O
although O
not O
statistically O
different O
. O

These O
results O
suggest O
that O
bisphosphonate B
therapy O
probably O
does O
not O
put O
the O
majority O
of O
patients O
at O
risk O
for O
AFF O
. O

Biotransformation O
of O
serotonin B
derivatives O
by O
the O
larvae O
of O
common O
cutworm O
( O
Spodoptera O
litura O
) O
. O

Seven O
serotonin B
derivatives O
( O
1 O
- O
7 O
) O
were O
biotransformed O
using O
larvae O
of O
Spodoptera O
litura O
. O

N B
- I
p I
- I
methoxy I
cinnamoyl I
serotonin I
( O
3 O
) O
was O
converted O
into O
its O
O B
- O
demethylated O
compound O
, O
N B
- I
p I
- I
coumaroyl I
serotonin I
( O
2 O
) O
. O

Furthermore O
, O
N B
- I
feruloyl I
serotonin I
( O
5 O
) O
and O
N B
- I
isoferuloyl I
serotonin I
( O
6 O
) O
were O
converted O
into O
, O
two O
new O
compounds O
, O
N B
- I
feruloyl I
serotonin I
- I
4 I
' I
- I
O I
- I
beta I
- I
D I
- I
glucopyranoside I
( O
8 O
) O
and O
N B
- I
isoferuloyl I
serotonin I
- I
3 I
' I
- I
O I
- I
beta I
- I
D I
- I
glucopyranoside I
( O
9 O
) O
, O
respectively O
. O

These O
structures O
were O
established O
by O
IR O
, O
1D O
- O
NMR O
and O
2D O
- O
NMR O
spectral O
studies O
. O

New O
precursor O
of O
tetraterpenoids B
from O
the O
soft O
coral O
Sarcophyton O
glaucum O
. O

One O
new O
precursor O
of O
tetraterpenoids B
, O
Sarglaucol B
( O
1 O
) O
, O
along O
with O
eight O
known O
compounds O
have O
been O
isolated O
from O
the O
soft O
coral O
Sarcophyton O
glaucum O
collected O
from O
the O
Sanya O
Bay O
, O
Hainan O
Island O
, O
China O
. O

Their O
structures O
were O
elucidated O
through O
spectroscopic O
techniques O
including O
1D O
- O
and O
2D O
- O
NMR O
, O
and O
their O
relative O
configurations O
were O
also O
assigned O
by O
NMR O
and O
NOESY O
analysis O
. O

Compounds O
1 O
showed O
weak O
antitumour O
activities O
. O

Theoretical O
study O
of O
the O
decomposition O
of O
ethyl B
and I
ethyl I
3 I
- I
phenyl I
glycidate I
. O

The O
mechanism O
of O
the O
decomposition O
of O
ethyl B
and I
ethyl I
3 I
- I
phenyl I
glycidate I
in O
gas O
phase O
was O
studied O
by O
density O
functional O
theory O
( O
DFT O
) O
and O
MP2 O
methods O
. O

A O
proposed O
mechanism O
for O
the O
reaction O
indicates O
that O
the O
ethyl B
side O
of O
the O
ester B
is O
eliminated O
as O
ethylene B
through O
a O
concerted O
six O
- O
membered O
cyclic O
transition O
state O
, O
and O
the O
unstable O
intermediate O
glycidic B
acid I
decarboxylates O
rapidly O
to O
give O
the O
corresponding O
aldehyde B
. O

Two O
possible O
pathways O
for O
glycidic B
acid I
decarboxylation O
were O
studied O
: O
one O
via O
a O
five O
- O
membered O
cyclic O
transition O
state O
, O
and O
the O
other O
via O
a O
four O
- O
membered O
cyclic O
transition O
state O
. O

The O
results O
of O
the O
calculations O
indicate O
that O
the O
decarboxylation O
reaction O
occurs O
via O
a O
mechanism O
with O
five O
- O
membered O
cyclic O
transition O
state O
. O

Coordination O
and O
bond O
activation O
in O
complexes O
of O
regioisomeric O
phenylpyridines B
with O
the O
nickel B
( I
II I
) I
chloride I
cation O
in O
the O
gas O
phase O
. O

Electrospray O
ionization O
of O
dilute O
solutions O
of O
phenylpyridines B
( O
phpy B
) O
in O
the O
presence O
of O
nickel B
( I
II I
) I
chloride I
leads O
to O
gaseous O
ions O
of O
the O
type O
[ B
Ni I
( I
phpy I
) I
( I
m I
) I
] I
( I
2 I
+ I
) I
with O
m O
= O
3 O
- O
5 O
and O
[ B
NiCl I
( I
phpy I
) I
( I
n I
) I
] I
( I
+ I
) I
with O
n O
= O
1 O
- O
3 O
, O
which O
are O
characterized O
by O
various O
gas O
- O
phase O
experiments O
in O
combination O
with O
calculations O
using O
density O
functional O
theory O
. O

Of O
the O
regioisomeric O
phpy B
' O
s O
, O
2 B
- I
phpy I
behaves O
drastically O
different O
compared O
to O
3 B
- I
and I
4 I
- I
phpy I
. O

Ion O
mobility O
mass O
spectrometry O
allows O
a O
differentiation O
of O
the O
gaseous O
ions O
and O
an O
elucidation O
of O
characteristic O
properties O
of O
the O
metal O
complexes O
. O

For O
2 B
- I
phpy I
, O
C B
- I
H I
bond O
activation O
in O
the O
[ B
NiCl I
( I
phpy I
) I
( I
2 I
) I
] I
( I
+ I
) I
complex O
is O
significant O
, O
whereas O
this O
route O
is O
almost O
suppressed O
for O
the O
corresponding O
complexes O
of O
3 B
- I
and I
4 I
- I
phpy I
and O
only O
occurs O
at O
elevated O
energies O
. O

Show O
me O
your O
license O
, O
please O
: O
deregulation O
of O
centriole O
duplication O
mechanisms O
that O
promote O
amplification O
. O

Centrosomes O
are O
organelles O
involved O
in O
generating O
and O
organizing O
the O
interphase O
microtubule O
cytoskeleton O
, O
mitotic O
spindles O
and O
cilia O
. O

At O
the O
centrosome O
core O
are O
a O
pair O
of O
centrioles O
, O
structures O
that O
act O
as O
the O
duplicating O
elements O
of O
this O
organelle O
. O

Centrioles O
function O
to O
recruit O
and O
organize O
pericentriolar O
material O
which O
nucleates O
microtubules O
. O

While O
centrioles O
are O
relatively O
simple O
in O
construction O
, O
the O
mechanics O
of O
centriole O
biogenesis O
remain O
an O
important O
yet O
poorly O
understood O
process O
. O

More O
mysterious O
still O
are O
the O
regulatory O
mechanisms O
that O
oversee O
centriole O
assembly O
. O

The O
fidelity O
of O
centriole O
duplication O
is O
critical O
as O
defects O
in O
either O
the O
assembly O
or O
number O
of O
centrioles O
promote O
aneuploidy O
, O
primary O
microcephaly O
, O
birth O
defects O
, O
ciliopathies O
and O
tumorigenesis O
. O

In O
addition O
, O
some O
pathogens O
employ O
mechanisms O
to O
promote O
centriole O
overduplication O
to O
the O
detriment O
of O
the O
host O
cell O
. O

This O
review O
summarizes O
our O
current O
understanding O
of O
this O
important O
topic O
, O
highlighting O
the O
need O
for O
further O
study O
if O
new O
therapeutics O
are O
to O
be O
developed O
to O
treat O
diseases O
arising O
from O
defects O
of O
centrosome O
duplication O
. O

A O
significant O
dose O
- O
dependent O
relationship O
between O
mercury B
exposure O
from O
dental O
amalgams B
and O
kidney O
integrity O
biomarkers O
: O
A O
further O
assessment O
of O
the O
Casa O
Pia O
children O
' O
s O
dental O
amalgam B
trial O
. O

Dental O
amalgams B
are O
a O
commonly O
used O
dental O
restorative O
material O
. O

Amalgams B
are O
about O
50 O
% O
mercury B
( O
Hg B
) O
, O
and O
Hg B
is O
known O
to O
significantly O
accumulate O
in O
the O
kidney O
. O

It O
was O
hypothesized O
that O
because O
Hg B
accumulates O
in O
the O
proximal O
tubules O
( O
PTs O
) O
, O
glutathione B
- O
S B
- O
transferases O
( O
GST O
) O
- O
alpha O
( O
suggestive O
of O
kidney O
damage O
at O
the O
level O
of O
PT O
) O
would O
be O
expected O
to O
be O
more O
related O
to O
Hg B
exposure O
than O
GST O
- O
pi O
( O
suggestive O
of O
kidney O
damage O
at O
the O
level O
of O
the O
distal O
tubules O
) O
. O

Urinary O
biomarkers O
of O
kidney O
integrity O
were O
examined O
in O
children O
of O
8 O
- O
18 O
years O
old O
, O
with O
and O
without O
dental O
amalgam B
fillings O
, O
from O
a O
completed O
clinical O
trial O
( O
parent O
study O
) O
. O

Our O
study O
determined O
whether O
there O
was O
a O
significant O
dose O
- O
dependent O
correlation O
between O
increasing O
Hg B
exposure O
from O
dental O
amalgams B
and O
GST O
- O
alpha O
and O
GST O
- O
pi O
as O
biomarkers O
of O
kidney O
integrity O
. O

Overall O
, O
the O
present O
study O
, O
using O
a O
different O
and O
more O
sensitive O
statistical O
model O
than O
the O
parent O
study O
, O
revealed O
a O
statistically O
significant O
dose O
- O
dependent O
correlation O
between O
cumulative O
exposure O
to O
Hg B
from O
dental O
amalgams B
and O
urinary O
levels O
of O
GST O
- O
alpha O
, O
after O
covariate O
adjustment O
; O
where O
as O
, O
a O
nonsignificant O
relationship O
was O
observed O
with O
urinary O
levels O
of O
GST O
- O
pi O
. O

Furthermore O
, O
it O
was O
observed O
that O
urinary O
GST O
- O
alpha O
levels O
increased O
by O
about O
10 O
% O
over O
the O
8 O
- O
year O
course O
of O
the O
study O
among O
individuals O
with O
an O
average O
exposure O
to O
amalgams B
among O
the O
study O
subjects O
from O
the O
amalgam B
group O
, O
in O
comparison O
with O
study O
subjects O
with O
no O
exposure O
to O
dental O
amalgams B
. O

The O
results O
of O
our O
study O
suggest O
that O
dental O
amalgams B
contribute O
to O
ongoing O
kidney O
damage O
at O
the O
level O
of O
the O
PTs O
in O
a O
dose O
- O
dependent O
fashion O
. O

Emergency O
Do O
Not O
Consume O
/ O
do O
Not O
Use O
concentrations O
for O
potassium B
permanganate I
in O
drinking O
water O
. O

Over O
the O
past O
decade O
, O
regulatory O
authorities O
and O
water O
purveyors O
have O
become O
increasingly O
concerned O
with O
accidental O
or O
intentional O
adulteration O
of O
municipal O
drinking O
water O
. O

Emergency O
response O
guidelines O
, O
such O
as O
the O
' O
Do O
Not O
Consume O
' O
or O
use O
concentration O
limits O
derived O
herein O
, O
can O
be O
used O
to O
notify O
the O
public O
in O
such O
cases O
. O

Potassium B
permanganate I
( O
KMnO B
( I
4 I
) I
) O
is O
used O
to O
control O
iron B
concentrations O
and O
to O
reduce O
the O
levels O
of O
nuisance O
materials O
that O
affect O
odor O
or O
taste O
of O
finished O
drinking O
water O
. O

Manganese B
( O
Mn B
) O
is O
recognized O
an O
essential O
nutrient O
, O
permanganate B
( O
MnO4 B
( I
- I
) I
) O
and O
manganous B
( O
Mn B
( I
+ I
2 I
) I
) O
ions O
are O
caustic O
, O
and O
the O
acute O
toxicity O
of O
KMnO B
( I
4 I
) I
is O
defined O
by O
its O
oxidant O
/ O
irritant O
properties O
and O
by O
the O
toxicity O
of O
Mn B
. O

Ingestion O
of O
small O
amounts O
( O
4 O
- O
20 O
mg O
/ O
kg O
) O
of O
aqueous O
KMnO B
( I
4 I
) I
solutions O
that O
are O
above O
200 O
mg O
/ O
L O
causes O
gastrointestinal O
distress O
, O
while O
bolus O
ingestion O
has O
caused O
respiratory O
arrest O
following O
coagulative O
necrosis O
and O
hemorrhage O
in O
the O
esophagus O
, O
stomach O
, O
or O
liver O
. O

Dilute O
KMnO B
( I
4 I
) I
solutions O
( O
1 O
- O
100 O
mg O
/ O
L O
) O
are O
used O
as O
a O
topical O
antiseptics O
and O
astringents O
, O
but O
> O
1 O
: O
5000 O
( O
200 O
mg O
/ O
L O
) O
dilutions O
can O
irritate O
or O
discolor O
sensitive O
mucous O
membranes O
and O
direct O
skin O
or O
ocular O
contact O
with O
concentrated O
KMnO B
( I
4 I
) I
can O
perforate O
tissues O
. O

Based O
on O
clinical O
experience O
with O
200 O
mg O
/ O
L O
KMnO B
( I
4 I
) I
, O
a O
Do O
Not O
Consume O
concentration O
of O
7 O
mg O
/ O
L O
KMnO B
( I
4 I
) I
( O
equivalent O
to O
2 O
mg O
Mn O
/ O
L O
) O
is O
recommended O
. O

Recognizing O
limited O
empirical O
data O
from O
which O
to O
calculate O
an O
ocular O
reference O
value O
, O
a O
skin O
contact O
' O
Do O
Not O
Use O
' O
concentration O
of O
30 O
mg O
Mn O
/ O
L O
is O
recommended O
based O
on O
the O
skin O
irritation O
in O
some O
patients O
after O
a O
10 O
- O
min O
contact O
with O
100 O
mg O
KMnO4 B
/ O
L O
. O

Cresyl B
saligenin I
phosphate I
makes O
multiple O
adducts O
on O
free O
histidine B
, O
but O
does O
not O
form O
an O
adduct O
on O
histidine B
438 O
of O
human O
butyrylcholinesteras O
. O

Cresyl B
saligenin I
phosphate I
( O
CBDP B
) O
is O
a O
suspected O
causative O
agent O
of O
" O
aerotoxic O
syndrome O
" O
, O
affecting O
pilots O
, O
crew O
members O
and O
passengers O
. O

CBDP B
is O
produced O
in O
vivo O
from O
ortho O
- O
containing O
isomers O
of O
tricresyl B
phosphate I
( O
TCP B
) O
, O
a O
component O
of O
jet O
engine O
lubricants O
and O
hydraulic O
fluids O
. O

CBDP B
irreversibly O
inhibits O
butyrylcholinesteras O
( O
BChE O
) O
in O
human O
plasma O
by O
forming O
adducts O
on O
the O
active O
site O
serine B
( O
Ser B
- O
198 O
) O
. O

Inhibited O
BChE O
undergoes O
aging O
to O
release O
saligenin B
and O
o B
- I
cresol I
. O

The O
active O
site O
histidine B
( O
His B
- O
438 O
) O
was O
hypothesized O
to O
abstract O
o B
- I
hydroxybenzyl I
moiety O
from O
the O
initial O
adduct O
on O
Ser B
- O
198 O
. O

Our O
goal O
was O
to O
test O
this O
hypothesis O
. O

Mass O
spectral O
analysis O
of O
CBDP B
- O
inhibited O
BChE O
digested O
with O
Glu O
- O
C O
showed O
an O
o B
- I
hydroxybenzyl I
adduct O
( O
+ O
106amu O
) O
on O
lysine B
499 O
, O
a O
residue O
far O
from O
the O
active O
site O
, O
but O
not O
on O
His B
- O
438 O
. O

Nevertheless O
, O
the O
nitrogen B
of O
the O
imidazole B
ring O
of O
free O
l B
- I
histidine I
formed O
a O
variety O
of O
adducts O
upon O
reaction O
with O
CBDP B
, O
including O
the O
o B
- I
hydroxybenzyl I
adduct O
, O
suggesting O
that O
histidine B
- O
CBDP B
adducts O
may O
form O
on O
other O
proteins O
. O

Training O
your O
brain O
: O
Do O
mental O
and O
physical O
( O
MAP O
) O
training O
enhance O
cognition O
through O
the O
process O
of O
neurogenesis O
in O
the O
hippocampus O
? O

New O
neurons O
are O
produced O
each O
day O
in O
the O
hippocampus O
through O
the O
process O
of O
neurogenesis O
. O

Both O
mental O
and O
physical O
training O
can O
modify O
this O
process O
by O
increasing O
the O
number O
of O
new O
cells O
that O
mature O
into O
functional O
neurons O
in O
the O
adult O
brain O
. O

However O
, O
the O
mechanisms O
whereby O
these O
increases O
occur O
are O
not O
necessarily O
the O
same O
. O

Physical O
activity O
, O
especially O
aerobic O
exercise O
greatly O
increases O
the O
number O
of O
new O
neurons O
that O
are O
produced O
in O
the O
hippocampal O
formation O
. O

In O
contrast O
, O
mental O
training O
via O
skill O
learning O
increases O
the O
numbers O
that O
survive O
, O
particularly O
when O
the O
training O
goals O
are O
challenging O
. O

Both O
manipulations O
can O
increase O
cognitive O
performance O
in O
the O
future O
, O
some O
of O
which O
are O
reportedly O
mediated O
by O
the O
presence O
of O
new O
neurons O
in O
the O
adult O
hippocampus O
. O

Based O
on O
these O
data O
, O
we O
suggest O
that O
a O
combination O
of O
mental O
and O
physical O
training O
, O
referred O
to O
here O
as O
MAP O
training O
, O
is O
more O
beneficial O
for O
neuronal O
recruitment O
and O
overall O
mental O
health O
than O
either O
activity O
alone O
. O

This O
article O
is O
part O
of O
a O
Special O
Issue O
entitled O
' O
Cognitive O
Enhancers O
' O
. O

Organochlorine B
pesticide O
levels O
and O
risk O
of O
Alzheimer O
' O
s O
disease O
in O
north O
Indian O
population O
. O

Alzheimer O
' O
s O
disease O
( O
AD O
) O
could O
result O
from O
a O
multifactorial O
process O
involving O
both O
genetic O
predisposition O
and O
exposure O
to O
environmental O
factors O
like O
pesticides O
. O

A O
case O
control O
study O
of O
70 O
patients O
of O
AD O
and O
75 O
controls O
was O
done O
to O
examine O
the O
association O
between O
organochlorine B
pesticides O
( O
OCPs O
) O
and O
risk O
of O
AD O
. O

OCPs B
( O
hexachlorocyclohexan B
( O
HCH B
) O
, O
aldrin B
, O
dieldrin B
, O
endosulfan B
, O
pp B
' I
- I
dichlorodiphenyldich I
( O
pp B
' I
- I
DDE I
) O
, O
op B
' I
- I
DDE I
, O
pp B
' I
- I
dichlorodiphenyltric I
( O
pp B
' I
- I
DDT I
) O
, O
op B
' I
- I
DDT I
, O
pp B
' I
- I
dichlorodiphenyldich I
( O
pp B
' I
- I
DDD I
) O
and O
op B
' I
- I
DDD I
) O
were O
extracted O
from O
blood O
and O
quantitatively O
estimated O
using O
gas O
chromatography O
. O

A O
Mann O
- O
Whitney O
U O
test O
revealed O
significant O
difference O
in O
beta B
- I
HCH I
levels O
( O
U O
= O
1237 O
. O
00 O
, O
W O
= O
4087 O
. O
00 O
, O
z O
= O
- O
6 O
. O
296 O
, O
p O
= O
0 O
. O
000 O
, O
r O
= O
- O
0 O
. O
71 O
) O
, O
dieldrin B
levels O
( O
U O
= O
1449 O
. O
00 O
, O
W O
= O
4299 O
. O
00 O
, O
z O
= O
- O
5 O
. O
809 O
, O
p O
= O
0 O
. O
000 O
, O
r O
= O
- O
0 O
. O
68 O
) O
and O
pp B
' I
- I
DDE I
levels O
( O
U O
= O
2062 O
. O
00 O
, O
W O
= O
4912 O
. O
00 O
, O
z O
= O
- O
2 O
. O
698 O
, O
p O
= O

0 O
. O
007 O
, O
r O
= O
- O
0 O
. O
59 O
) O
between O
AD O
patients O
and O
controls O
. O

In O
conclusion O
, O
this O
study O
supports O
epidemiological O
studies O
that O
associate O
exposure O
to O
pesticides O
with O
increased O
risk O
of O
AD O
, O
and O
we O
identified O
the O
specific O
pesticides O
beta B
- I
HCH I
, O
dieldrin B
and O
pp B
' I
- I
DDE I
that O
are O
associated O
with O
the O
risk O
of O
AD O
in O
the O
north O
Indian O
population O
. O

However O
, O
further O
research O
is O
needed O
to O
establish O
the O
potential O
role O
of O
these O
OCPs O
as O
an O
etiologic O
agent O
for O
AD O
case O
. O

Therapeutic O
efficacy O
of O
silymarin O
from O
milk O
thistle O
in O
reducing O
manganese B
- O
induced O
hepatic O
damage O
and O
apoptosis O
in O
rats O
. O

Oxidative O
stress O
has O
been O
proposed O
as O
a O
possible O
mechanism O
involved O
in O
manganese B
( O
Mn B
) O
toxicity O
. O

Using O
natural O
antioxidants O
against O
metal O
- O
induced O
hepatotoxicity O
is O
a O
modern O
approach O
. O

The O
present O
study O
investigated O
the O
beneficial O
role O
of O
silymarin O
, O
a O
natural O
flavonoid B
, O
in O
Mn B
- O
induced O
hepatotoxicity O
focusing O
on O
histopathology O
and O
biochemical O
approaches O
. O

Male O
Wistar O
rats O
were O
exposed O
orally O
to O
manganese B
chloride I
( O
20 O
mg O
/ O
mL O
) O
for O
30 O
days O
followed O
by O
intraperitoneal O
cotreatment O
with O
silymarin B
( O
100 O
mg O
/ O
kg O
) O
. O

Exposure O
to O
Mn B
resulted O
in O
a O
significant O
elevation O
of O
the O
plasma O
marker O
enzyme O
activities O
and O
bilirubin B
level O
related O
to O
liver O
dysfunction O
of O
reactive O
oxygen B
species O
( O
ROS O
) O
production O
and O
hepatic O
oxidative O
stress O
indices O
. O

This O
metal O
reduced O
the O
activities O
of O
superoxide B
dismutase O
, O
catalase O
and O
glutathione B
peroxidase O
and O
nonenzymatic O
antioxidant O
levels O
such O
as O
reduced B
glutathione I
, O
total O
sulfhydryl B
groups O
and O
vitamin B
C I
. O

In O
addition O
, O
it O
caused O
hepatic O
hemorrhage O
, O
cellular O
degeneration O
and O
necrosis O
of O
hepatocytes O
as O
indicated O
by O
liver O
histopathology O
and O
DNA O
fragmentation O
studies O
. O

Coadministration O
of O
silymarin O
alleviated O
Mn B
oxidative O
damage O
effects O
by O
inhibiting O
ROS O
generation O
. O

Histological O
studies O
also O
supported O
the O
beneficial O
role O
of O
silymarin O
against O
Mn B
- O
induced O
hepatic O
damages O
. O

Combining O
all O
, O
results O
suggested O
that O
silymarin O
could O
protect O
hepatic O
tissues O
against O
Mn B
- O
induced O
oxidative O
stress O
probably O
through O
its O
antioxidant O
activity O
. O

Therefore O
, O
its O
supplementation O
could O
provide O
a O
new O
approach O
for O
the O
reduction O
in O
hepatic O
complication O
due O
to O
Mn B
poisoning O
. O

Effect O
of O
copper B
overload O
on O
the O
survival O
of O
HepG2 O
and O
A O
- O
549 O
human O
- O
derived O
cells O
. O

We O
investigated O
the O
effect O
of O
copper B
( O
Cu B
) O
overload O
( O
20 O
- O
160 O
micro O
M O
/ O
24 O
h O
) O
in O
two O
cell O
lines O
of O
human O
hepatic O
( O
HepG2 O
) O
and O
pulmonary O
( O
A O
- O
549 O
) O
origin O
by O
determining O
lipid O
and O
protein O
damage O
and O
the O
response O
of O
the O
antioxidant O
defence O
system O
. O

A O
- O
549 O
cells O
were O
more O
sensitive O
to O
Cu B
overload O
than O
HepG2 O
cells O
. O

A O
marked O
increase O
was O
observed O
in O
both O
the O
cell O
lines O
in O
the O
nitrate B
plus O
nitrite B
concentration O
, O
protein O
carbonyls B
and O
thiobarbituric B
acid I
reactive O
substances O
( O
TBARS O
) O
. O

The O
TBARS O
increase O
was O
consistent O
with O
an O
increment O
in O
saturated B
fatty I
acids I
at O
the O
expense O
of O
polyunsaturated B
acids I
in O
a O
Cu B
concentration O
- O
dependent O
fashion O
. O

Antioxidant O
enzymes O
were O
stimulated O
by O
Cu B
overload O
. O

Superoxide B
dismutase O
activity O
increased O
significantly O
in O
both O
the O
cell O
lines O
, O
with O
greater O
increases O
in O
HepG2 O
than O
in O
A O
- O
549 O
cells O
. O

A O
marked O
increase O
in O
ceruloplasmin O
and O
metallothionein O
content O
in O
both O
the O
cell O
types O
was O
also O
observed O
. O

Dose O
- O
dependent O
decreases O
in O
alpha B
- I
tocopherol I
and O
ferric B
reducing O
ability O
were O
observed O
. O

Total O
glutathione B
content O
was O
lower O
in O
A O
- O
549 O
cells O
and O
higher O
in O
HepG2 O
. O

Calpain O
and O
caspase O
- O
3 O
were O
differentially O
activated O
in O
a O
dose O
- O
dependent O
manner O
under O
copper B
- O
induced O
reactive O
oxygen B
species O
production O
. O

We O
conclude O
that O
Cu B
exposure O
of O
human O
lung O
- O
and O
liver O
- O
derived O
cells O
should O
be O
considered O
a O
reliable O
experimental O
system O
for O
detailed O
study O
of O
mechanism O
/ O
mechanisms O
by O
which O
Cu B
overload O
exerts O
its O
deleterious O
effects O
. O

A O
human O
hemi O
- O
cornea O
model O
for O
eye O
irritation O
testing O
: O
quality O
control O
of O
production O
, O
reliability O
and O
predictive O
capacity O
. O

We O
have O
developed O
a O
3 O
- O
dimensional O
human O
hemi O
- O
cornea O
which O
comprises O
an O
immortalized O
epithelial O
cell O
line O
and O
keratocytes O
embedded O
in O
a O
collagen O
stroma O
. O

In O
the O
present O
study O
, O
we O
have O
used O
MTT B
reduction O
of O
the O
whole O
tissue O
to O
clarify O
whether O
the O
production O
of O
this O
complex O
3 O
- O
D O
- O
model O
is O
transferable O
into O
other O
laboratories O
and O
whether O
these O
tissues O
can O
be O
constructed O
reproducibly O
. O

Our O
results O
demonstrate O
the O
reproducible O
production O
of O
the O
hemi O
- O
cornea O
model O
according O
to O
standard O
operation O
procedures O
using O
15 O
independent O
batches O
of O
reconstructed O
hemi O
- O
cornea O
models O
in O
two O
independent O
laboratories O
each O
. O

Furthermore O
, O
the O
hemi O
- O
cornea O
tissues O
have O
been O
treated O
with O
20 O
chemicals O
of O
different O
eye O
- O
irritating O
potential O
under O
blind O
conditions O
to O
assess O
the O
performance O
and O
limitations O
of O
our O
test O
system O
comparing O
three O
different O
prediction O
models O
. O

The O
most O
suitable O
prediction O
model O
revealed O
an O
overall O
in O
vitro O
- O
in O
vivo O
concordance O
of O
80 O
% O
and O
70 O
% O
in O
the O
participating O
laboratories O
, O
respectively O
, O
and O
an O
inter O
- O
laboratory O
concordance O
of O
80 O
% O
. O

Sensitivity O
of O
the O
test O
was O
77 O
% O
and O
specificity O
was O
between O
57 O
% O
and O
86 O
% O
to O
discriminate O
classified O
from O
non O
- O
classified O
chemicals O
. O

We O
conclude O
that O
additional O
physiologically O
relevant O
endpoints O
in O
both O
epithelium O
and O
stroma O
have O
to O
be O
developed O
for O
the O
reliable O
prediction O
of O
all O
GHS O
classes O
of O
eye O
irritation O
in O
one O
stand O
alone O
test O
system O
. O

High O
levels O
of O
arachidonic B
acid I
and O
peroxisome O
proliferator O
- O
activated O
receptor O
- O
alpha O
in O
breast O
cancer O
tissues O
are O
associated O
with O
promoting O
cancer O
cell O
proliferation O
. O

Fatty B
acids I
are O
endogenous O
ligands O
of O
peroxisome O
proliferator O
- O
activated O
receptor O
- O
alpha O
( O
PPAR O
alpha O
) O
, O
which O
is O
linked O
to O
the O
regulation O
of O
fatty B
acid I
uptake O
, O
lipid O
metabolism O
and O
breast O
cancer O
cell O
growth O
. O

This O
study O
was O
designed O
to O
screen O
candidate O
fatty B
acids I
from O
breast O
cancer O
tissue O
and O
to O
investigate O
the O
effects O
of O
these O
candidate O
fatty B
acids I
on O
PPAR O
alpha O
expression O
, O
cell O
growth O
and O
cell O
cycle O
progression O
in O
breast O
cancer O
cell O
lines O
. O

One O
breast O
cancer O
tissue O
and O
one O
reference O
tissue O
were O
each O
taken O
from O
30 O
individual O
breasts O
to O
examine O
for O
fatty B
acid I
composition O
and O
PPAR O
alpha O
expression O
. O

The O
cancer O
cell O
lines O
MDA O
- O
MB O
- O
231 O
( O
ER O
- O
) O
, O
MCF O
- O
7 O
( O
ER O
+ O
+ O
+ O
+ O
) O
and O
BT O
- O
474 O
( O
ER O
+ O
+ O
) O
were O
used O
to O
explore O
the O
mechanisms O
regulating O
cell O
proliferation O
. O

We O
found O
that O
arachidonic B
acid I
( O
AA O
) O
and O
PPAR O
alpha O
were O
highly O
expressed O
in O
the O
breast O
cancer O
tissues O
. O

AA O
stimulated O
the O
growth O
of O
all O
three O
breast O
cancer O
cells O
in O
a O
time O
- O
and O
dose O
- O
dependent O
manner O
. O

The O
growth O
stimulatory O
effect O
of O
AA O
was O
associated O
with O
PPAR O
alpha O
activation O
, O
and O
the O
most O
potent O
effect O
was O
found O
in O
MCF O
- O
7 O
cells O
. O

The O
stimulation O
of O
cell O
proliferation O
by O
AA O
was O
accompanied O
by O
the O
increased O
expression O
of O
cyclin O
E O
, O
a O
reduced O
population O
of O
G1 O
phase O
cells O
, O
and O
a O
faster O
G1 O
/ O
S O
phase O
transition O
. O

In O
contrast O
, O
AA O
had O
no O
effects O
on O
the O
levels O
of O
CDK2 O
, O
CDK4 O
, O
cyclin O
D1 O
, O
p27 O
, O
Bcl O
- O
2 O
and O
Bax O
. O

Our O
results O
demonstrate O
that O
high O
levels O
of O
AA O
and O
PPAR O
alpha O
expression O
in O
human O
breast O
cancer O
tissues O
are O
associated O
with O
ER O
- O
overexpressed O
breast O
cancer O
cell O
proliferation O
, O
which O
is O
involved O
in O
activating O
PPAR O
alpha O
, O
stimulating O
cyclin O
E O
expression O
, O
and O
promoting O
faster O
G1 O
/ O
S O
transition O
. O

Vitamin B
E I
deficiency O
impairs O
the O
somatostatinergic O
receptor O
- O
effector O
system O
and O
leads O
to O
phosphotyrosine B
phosphatase O
overactivation O
and O
cell O
death O
in O
the O
rat O
hippocampus O
. O

Vitamin B
E I
plays O
an O
essential O
role O
in O
maintaining O
the O
structure O
and O
function O
of O
the O
nervous O
system O
, O
and O
its O
deficiency O
, O
commonly O
associated O
with O
fat O
malabsorption O
diseases O
, O
may O
reduce O
neuronal O
survival O
. O

We O
previously O
demonstrated O
that O
the O
somatostatinergic O
system O
, O
implicated O
in O
neuronal O
survival O
control O
, O
can O
be O
modulated O
by O
alpha B
- I
tocopherol I
in O
the O
rat O
dentate O
gyrus O
, O
increasing O
cyclic B
adenosine I
monophosphate I
response O
element O
binding O
protein O
phosphorylation O
. O

To O
gain O
a O
better O
understanding O
of O
the O
molecular O
actions O
of O
tocopherols B
and O
examine O
the O
link O
among O
vitamin B
E I
, O
somatostatin B
and O
neuronal O
survival O
, O
we O
have O
investigated O
the O
effects O
of O
a O
deficiency O
and O
subsequent O
administration O
of O
tocopherol B
on O
the O
somatostatin B
signaling O
pathway O
and O
neuronal O
survival O
in O
the O
rat O
hippocampus O
. O

No O
changes O
in O
somatostatin O
expression O
were O
detected O
in O
vitamin B
- I
E I
- O
deficient O
rats O
. O

These O
rats O
, O
however O
, O
showed O
a O
significant O
increase O
in O
the O
somatostatin B
receptor O
density O
and O
dissociation O
constant O
, O
which O
correlated O
with O
a O
significant O
increase O
in O
the O
protein O
levels O
of O
somatostatin B
receptors O
. O

Nevertheless O
, O
vitamin B
E I
deficiency O
impaired O
the O
ability O
of O
the O
somatostatin O
receptors O
to O
couple O
to O
the O
effectors O
adenylyl O
cyclase O
and O
phosphotyrosine B
phosphatase O
by O
diminishing O
Gi O
protein O
functionality O
. O

Furthermore O
, O
vitamin B
E I
deficiency O
significantly O
increased O
phosphotyrosine B
phosphatase O
activity O
and O
PTP O
eta O
expression O
, O
as O
well O
as O
PKC O
delta O
activation O
, O
and O
decreased O
extracellular O
- O
signal O
- O
regulated O
kinase O
phosphorylation O
. O

All O
these O
changes O
were O
accompanied O
by O
an O
increase O
in O
neuronal O
cell O
death O
. O

Subsequent O
alpha B
- I
tocopherol I
administration O
partially O
or O
completely O
reversed O
all O
these O
values O
to O
control O
levels O
. O

Altogether O
, O
our O
results O
prove O
the O
importance O
of O
vitamin B
E I
homeostasis O
in O
the O
somatostatin B
receptor O
- O
effector O
system O
and O
suggest O
a O
possible O
mechanism O
by O
which O
this O
vitamin B
may O
regulate O
the O
neuronal O
cell O
survival O
in O
the O
adult O
hippocampus O
. O

Emergence O
of O
zebrafish O
models O
in O
oncology O
for O
validating O
novel O
anticancer O
drug O
targets O
and O
nanomaterials O
. O

The O
in O
vivo O
zebrafish O
models O
have O
recently O
attracted O
great O
attention O
in O
molecular O
oncology O
to O
investigate O
multiple O
genetic O
alterations O
associated O
with O
the O
development O
of O
human O
cancers O
and O
validate O
novel O
anticancer O
drug O
targets O
. O

Particularly O
, O
the O
transparent O
zebrafish O
models O
can O
be O
used O
as O
a O
xenotransplantation O
system O
to O
rapidly O
assess O
the O
tumorigenicity O
and O
metastatic O
behavior O
of O
cancer O
stem O
and O
/ O
or O
progenitor O
cells O
and O
their O
progenies O
. O

Moreover O
, O
the O
zebrafish O
models O
have O
emerged O
as O
powerful O
tools O
for O
an O
in O
vivo O
testing O
of O
novel O
anticancer O
agents O
and O
nanomaterials O
for O
counteracting O
tumor O
formation O
and O
metastases O
and O
improving O
the O
efficacy O
of O
current O
radiation O
and O
chemotherapeutic O
treatments O
against O
aggressive O
, O
metastatic O
and O
lethal O
cancers O
. O

Skin O
phototoxicity O
of O
cosmetic O
formulations O
containing O
photounstable O
and O
photostable O
UV O
- O
filters O
and O
vitamin B
A I
palmitate I
. O

The O
aim O
of O
this O
study O
was O
to O
evaluate O
the O
in O
vitro O
skin O
phototoxicity O
of O
cosmetic O
formulations O
containing O
photounstable O
and O
photostable O
UV O
- O
filters O
and O
vitamin B
A I
palmitate I
, O
assessed O
by O
two O
in O
vitro O
techniques O
: O
3T3 O
Neutral B
Red I
Uptake O
Phototoxicity O
Test O
and O
Human O
3 O
- O
D O
Skin O
Model O
In O
Vitro O
Phototoxicity O
Test O
. O

For O
this O
, O
four O
different O
formulations O
containing O
vitamin B
A I
palmitate I
and O
different O
UV O
- O
filters O
combinations O
, O
two O
of O
them O
considered O
photostable O
and O
two O
of O
them O
considered O
photounstable O
, O
were O
prepared O
. O

Solutions O
of O
each O
UV O
- O
filter O
and O
vitamin O
under O
study O
and O
solutions O
of O
four O
different O
combinations O
under O
study O
were O
also O
prepared O
. O

The O
phototoxicity O
was O
assessed O
in O
vitro O
by O
the O
3T3 O
NRU O
phototoxicity O
test O
( O
3T3 O
- O
NRU O
- O
PT O
) O
and O
subsequently O
in O
a O
phototoxicity O
test O
on O
reconstructed O
human O
skin O
model O
( O
H3D O
- O
PT O
) O
. O

Avobenzone B
presented O
a O
pronounced O
phototoxicity O
and O
vitamin B
A I
presented O
a O
tendency O
to O
a O
weak O
phototoxic O
potential O
. O

A O
synergistic O
effect O
of O
vitamin B
A I
palmitate I
on O
the O
phototoxicity O
of O
combinations O
containing O
avobenzone B
was O
observed O
. O

H3D O
- O
PT O
results O
did O
not O
confirm O
the O
positive O
3T3 O
- O
NRU O
- O
PT O
results O
. O

However O
, O
despite O
the O
four O
formulations O
studied O
did O
not O
present O
any O
acute O
phototoxicity O
potential O
, O
the O
combination O
2 O
containing O
octyl B
methoxycinnamate I
( O
OMC B
) O
, O
avobenzone B
( O
AVB B
) O
and O
4 B
- I
methylbenzilidene I
camphor I
( O
MBC B
) O
presented O
an O
indication O
of O
phototoxicity O
that O
should O
be O
better O
investigated O
in O
terms O
of O
the O
frequency O
of O
photoallergic O
or O
chronic O
phototoxicity O
in O
humans O
, O
once O
these O
tests O
are O
scientifically O
validated O
only O
to O
detect O
phototoxic O
potential O
with O
the O
aim O
of O
preventing O
phototoxic O
reactions O
in O
the O
general O
population O
, O
and O
positive O
results O

cannot O
predict O
the O
exact O
incidence O
of O
phototoxic O
reactions O
in O
humans O
. O

Improved O
procedures O
for O
in O
vitro O
skin O
irritation O
testing O
of O
sticky O
and O
greasy O
natural O
botanicals O
. O

Skin O
irritation O
evaluation O
is O
an O
important O
endpoint O
for O
the O
safety O
assessment O
of O
cosmetic O
ingredients O
required O
by O
various O
regulatory O
authorities O
for O
notification O
and O
/ O
or O
import O
of O
test O
substances O
. O

The O
present O
study O
was O
undertaken O
to O
investigate O
possible O
protocol O
adaptations O
of O
the O
currently O
validated O
in O
vitro O
skin O
irritation O
test O
methods O
based O
on O
reconstructed O
human O
epidermis O
( O
RhE O
) O
for O
the O
testing O
of O
plant O
extracts O
and O
natural O
botanicals O
. O

Due O
to O
their O
specific O
physico O
- O
chemical O
properties O
, O
such O
as O
lipophilicity O
, O
sticky O
/ O
buttery O
- O
like O
texture O
, O
waxy O
/ O
creamy O
foam O
characteristics O
, O
normal O
washing O
procedures O
can O
lead O
to O
an O
incomplete O
removal O
of O
these O
materials O
and O
/ O
or O
to O
mechanical O
damage O
to O
the O
tissues O
, O
resulting O
in O
an O
impaired O
prediction O
of O
the O
true O
skin O
irritation O
potential O
of O
the O
materials O
. O

For O
this O
reason O
different O
refined O
washing O
procedures O
were O
evaluated O
for O
their O
ability O
to O
ensure O
appropriate O
removal O
of O
greasy O
and O
sticky O
substances O
while O
not O
altering O
the O
normal O
responses O
of O
the O
validated O
RhE O
test O
method O
. O

Amongst O
the O
different O
procedures O
evaluated O
, O
the O
use O
of O
a O
SDS B
0 O
. O
1 O
% O
PBS O
solution O
to O
remove O
the O
sticky O
and O
greasy O
test O
material O
prior O
to O
the O
normal O
washing O
procedures O
was O
found O
to O
be O
the O
most O
suitable O
adaptation O
to O
ensure O
efficient O
removal O
of O
greasy O
and O
sticky O
in O
- O
house O
controls O
without O
affecting O
the O
results O
of O
the O
negative O
control O
. O

The O
predictive O
capacity O
of O
the O
refined O
SDS B
0 O
. O
1 O
% O
washing O
procedure O
, O
was O
investigated O
by O
using O
twelve O
oily O
and O
viscous O
compounds O
having O
known O
skin O
irritation O
effects O
supported O
by O
raw O
and O
/ O
or O
peer O
reviewed O
in O
vivo O
data O
. O

The O
normal O
washing O
procedure O
resulted O
in O
8 O
out O
of O
10 O
correctly O
predicted O
compounds O
as O
compared O
to O
9 O
out O
of O
10 O
with O
the O
refined O
washing O
procedures O
, O
showing O
an O
increase O
in O
the O
predictive O
ability O
of O
the O
assay O
. O

The O
refined O
washing O
procedure O
allowed O
to O
correctly O
identify O
all O
in O
vivo O
skin O
irritant O
materials O
showing O
the O
same O
sensitivity O
as O
the O
normal O
washing O
procedures O
, O
and O
further O
increased O
the O
specificity O
of O
the O
assay O
from O
5 O
to O
6 O
correct O
predictions O
out O
of O
7 O
non O
irritants O
as O
compared O
to O
the O
normal O
washing O
procedures O
. O

In O
addition O
, O
when O
exposed O
to O
non O
- O
irritant O
oily O
and O
viscous O
materials O
, O
tissues O
rinsed O
with O
0 O
. O
1 O
% O
SDS B
generally O
showed O
increased O
viabilities O
accompanied O
by O
decreased O
variabilities O
as O
compared O
to O
the O
normal O
washing O
procedures O
. O

Similar O
results O
were O
obtained O
when O
testing O
typical O
in O
- O
house O
natural O
botanical O
ingredients O
. O

In O
conclusion O
, O
the O
use O
of O
a O
refined O
washing O
procedure O
making O
use O
of O
SDS B
0 O
. O
1 O
% O
in O
PBS O
was O
found O
a O
suitable O
procedure O
to O
ensure O
efficient O
removal O
of O
greasy O
and O
sticky O
materials O
, O
leading O
to O
an O
increased O
predictive O
capacity O
and O
decreased O
variability O
of O
the O
tissue O
responses O
while O
maintaining O
its O
sensitivity O
and O
not O
affecting O
untreated O
tissues O
morphology O
and O
viability O
. O

Photochromic O
materials O
: O
more O
than O
meets O
the O
eye O
. O

Photochromic O
materials O
are O
a O
family O
of O
compounds O
which O
can O
undergo O
reversible O
photo O
- O
switches O
between O
two O
different O
states O
or O
isomers O
with O
remarkably O
different O
properties O
. O

Inspired O
by O
their O
smart O
photo O
- O
switchable O
characteristics O
, O
a O
variety O
of O
light O
- O
driven O
functional O
materials O
have O
been O
exploited O
, O
such O
as O
ultrahigh O
- O
density O
optical O
data O
storage O
, O
molecular O
switches O
, O
logic O
gates O
, O
molecular O
wires O
, O
optic O
/ O
electronic O
devices O
, O
sensors O
, O
bio O
- O
imaging O
and O
so O
on O
. O

This O
review O
commences O
with O
a O
brief O
description O
of O
exciting O
progress O
in O
this O
field O
, O
from O
systems O
in O
solution O
to O
modified O
functional O
surfaces O
. O

Further O
development O
of O
these O
photo O
- O
switchable O
systems O
into O
practical O
applications O
as O
well O
as O
existing O
challenges O
are O
also O
discussed O
and O
put O
in O
prospect O
. O

Group O
II O
metabotropic O
glutamate B
receptor O
type O
2 O
allosteric O
potentiators O
prevent O
sodium B
lactate I
- O
induced O
panic O
- O
like O
response O
in O
panic O
- O
vulnerable O
rats O
. O

Rats O
with O
chronic O
inhibition O
of O
GABA B
synthesis O
by O
infusion O
of O
l B
- I
allyglycine I
, O
a O
glutamic B
acid I
decarboxylase O
inhibitor O
, O
into O
their O
dorsomedial O
/ O
perifornical O
hypothalamus O
are O
anxious O
and O
exhibit O
panic O
- O
like O
cardio O
- O
respiratory O
responses O
to O
treatment O
with O
intravenous O
( O
i O
. O
v O
. O
) O
sodium B
lactate I
( O
NaLac B
) O
infusions O
, O
in O
a O
manner O
similar O
to O
what O
occurs O
in O
patients O
with O
panic O
disorder O
. O

We O
previously O
showed O
that O
either O
NMDA B
receptor O
antagonists O
or O
metabotropic O
glutamate B
receptor O
type O
2 O
/ O
3 O
receptor O
agonists O
can O
block O
such O
a O
NaLac O
response O
, O
suggesting O
that O
a O
glutamate B
mechanism O
is O
contributing O
to O
this O
panic O
- O
like O
state O
. O

Using O
this O
animal O
model O
of O
panic O
, O
we O
tested O
the O
efficacy O
of O
CBiPES O
and O
THIIC B
, O
which O
are O
selective O
group O
II O
metabotropic O
glutamate B
type O
2 O
receptor O
allosteric O
potentiators O
( O
at O
10 O
- O
30 O
mg O
/ O
kg O
i O
. O
p O
. O
) O
, O
in O
preventing O
NaLac O
- O
induced O
panic O
- O
like O
behavioral O
and O
cardiovascular O
responses O
. O

The O
positive O
control O
was O
alprazolam B
( O
3mg O
/ O
kg O
i O
. O
p O
. O
) O
, O
a O
clinically O
effective O
anti O
- O
panic O
benzodiazepine B
. O

As O
predicted O
, O
panic O
- O
prone O
rats O
given O
a O
NaLac O
challenge O
displayed O
NaLac O
- O
induced O
panic O
- O
like O
cardiovascular O
( O
i O
. O
e O
. O
tachycardia O
and O
hypertensive O
) O
responses O
and O
" O
anxiety O
" O
( O
i O
. O
e O
. O
decreased O
social O
interaction O
time O
) O
and O
" O
flight O
" O
( O
i O
. O
e O
. O
increased O
locomotion O
) O
- O
associated O
behaviors O
; O
however O
, O
systemic O
injection O
of O
the O
panic O
- O
prone O
rats O
with O
CBiPES O
, O
THIIC B
or O
alprazolam B
prior O
to O
the O
NaLac O
dose O
blocked O
all O
NaLac O
- O
induced O
panic O
- O
like O
behaviors O
and O
cardiovascular O
responses O
. O

These O
data O
suggested O
that O
in O
a O
rat O
animal O
model O
, O
selective O
group O
II O
metabotropic O
glutamate B
type O
2 O
receptor O
allosteric O
potentiators O
show O
an O
anti O
- O
panic O
efficacy O
similar O
to O
alprazolam B
. O

High O
multivitamin O
intakes O
during O
pregnancy O
and O
postweaning O
obesogenic O
diets O
interact O
to O
affect O
the O
relationship O
between O
expression O
of O
PPAR O
genes O
and O
glucose B
regulation O
in O
the O
offspring O
. O

High O
multivitamin O
intake O
( O
HV O
) O
during O
pregnancy O
increases O
body O
fat O
and O
weight O
and O
alters O
glucose B
and O
fatty B
acid I
metabolism O
in O
Wistar O
rat O
offspring O
. O

This O
study O
investigated O
the O
expression O
of O
peroxisome O
- O
proliferator O
activated O
receptors O
( O
PPARs O
) O
genes O
involved O
in O
regulation O
of O
glucose B
and O
fatty B
acid I
metabolism O
in O
their O
tissues O
. O

Dams O
received O
the O
AIN O
- O
93G O
diet O
with O
either O
the O
regular O
( O
RV O
) O
or O
10 O
- O
fold O
multivitamins O
( O
HV O
) O
during O
pregnancy O
. O

Male O
offspring O
were O
weaned O
to O
either O
the O
RV O
diet O
( O
RV O
- O
RV O
and O
HV O
- O
RV O
) O
or O
an O
obesogenic O
diet O
( O
RV O
- O
Ob O
and O
HV O
- O
Ob O
) O
. O

Gene O
expression O
of O
PPARs O
in O
tissues O
was O
analyzed O
by O
real O
- O
time O
reverse O
transcriptase O
polymerase O
chain O
reaction O
. O

Gestational O
diet O
( O
GD O
) O
did O
not O
affect O
PPARs O
gene O
expression O
in O
offspring O
at O
either O
birth O
or O
weaning O
. O

In O
liver O
, O
at O
14 O
weeks O
postweaning O
, O
PPAR O
- O
gamma O
was O
30 O
% O
lower O
in O
the O
HV O
- O
RV O
and O
30 O
% O
higher O
in O
HV O
- O
Ob O
than O
in O
the O
RV O
- O
RV O
group O
[ O
GD O
P O
= O
. O
76 O
, O
postweaning O
diet O
( O
PD O
) O
P O
= O
. O
19 O
, O
interaction O
P O
= O
. O
02 O
, O
by O
two O
- O
way O
analysis O
of O
variance O
] O
. O

In O
muscle O
, O
PPAR O
- O
alpha O
expression O
was O
affected O
by O
GD O
and O
PD O
( O
GD O
P O
= O
. O
05 O
, O
PD O
P O
< O
. O
01 O
, O
interaction O
P O
= O
. O
07 O
) O
. O

In O
adipose O
tissue O
, O
PPAR O
- O
alpha O
expression O
was O
higher O
in O
all O
groups O
compared O
to O
RV O
- O
RV O
( O
GD O
P O
= O
. O
25 O
, O
PD O
P O
= O
. O
85 O
, O
interaction O
P O
= O
. O
03 O
) O
. O

PPAR O
- O
gamma O
mRNA O
levels O
correlated O
with O
abdominal O
fat O
( O
r O
= O
0 O
. O
45 O
, O
P O
< O
. O
05 O
) O
and O
insulin O
resistance O
index O
( O
r O
= O
0 O
. O
39 O
, O
P O
< O
. O
05 O
) O
. O

In O
liver O
, O
PPAR O
- O
gamma O
expression O
correlated O
with O
insulin O
resistance O
index O
in O
offspring O
from O
RV O
( O
r O
= O
- O
0 O
. O
62 O
, O
P O
< O
. O
05 O
) O
, O
but O
not O
in O
those O
from O
HV O
dams O
( O
r O
= O
0 O
. O
13 O
, O
P O
> O
. O
05 O
) O
. O

In O
conclusion O
, O
the O
HV O
diet O
during O
pregnancy O
interacts O
with O
postweaning O
diets O
in O
determining O
the O
expression O
of O
PPARs O
genes O
in O
a O
tissue O
- O
and O
age O
- O
dependent O
manner O
and O
uncouples O
the O
relationship O
between O
these O
genes O
and O
glucose B
regulation O
and O
fat O
mass O
in O
the O
rat O
offspring O
. O

CCAAT O
/ O
Enhancer O
- O
binding O
protein O
- O
homologous O
protein O
sensitizes O
to O
SU5416 B
by O
modulating O
p21 O
and O
PI3K O
/ O
Akt O
signal O
pathway O
in O
FRO O
anaplastic O
thyroid O
carcinoma O
cells O
. O

SU5416 B
, O
vascular O
endothelial O
cell O
growth O
factor O
receptor O
inhibitor O
, O
suppresses O
hypoxia O
- O
induced O
angiogenesis O
, O
growth O
, O
proliferation O
, O
and O
metastasis O
in O
cancer O
cells O
. O

CCAAT O
/ O
enhancer O
- O
binding O
protein O
- O
homologous O
protein O
( O
CHOP O
) O
has O
pivotal O
roles O
in O
regulation O
of O
growth O
and O
survival O
. O

In O
the O
present O
study O
, O
we O
evaluated O
the O
effects O
of O
SU5416 B
on O
cell O
survival O
, O
p21 O
, O
and O
PI3K O
/ O
Akt O
signal O
pathway O
in O
FRO O
anaplastic O
thyroid O
carcinoma O
( O
ATC O
) O
cells O
. O

Moreover O
, O
we O
investigated O
the O
roles O
of O
CHOP O
in O
cell O
survival O
under O
condition O
of O
SU5416 B
treatment O
in O
FRO O
ATC O
cells O
. O

After O
SU5416 B
treatment O
, O
cell O
viability O
, O
PARP O
- O
1 O
, O
and O
caspase O
- O
3 O
protein O
levels O
were O
not O
changed O
. O

p53 O
and O
p27 O
protein O
levels O
decreased O
while O
p21 O
protein O
levels O
increased O
. O

Phospho O
- O
Akt O
protein O
levels O
were O
not O
altered O
. O

In O
SU5416 B
- O
treated O
situation O
, O
cell O
viability O
was O
not O
different O
before O
and O
after O
administration O
of O
either O
p21 O
siRNA O
or O
LY294002 B
whereas O
it O
was O
lessened O
after O
co O
- O
administration O
of O
p21 O
siRNA O
and O
LY294002 B
. O

Compared O
to O
SU5416 B
treatment O
alone O
, O
cell O
viability O
was O
reduced O
with O
CHOP O
plasmid O
but O
it O
was O
unchanged O
with O
CHOP O
siRNA O
. O

PARP O
- O
1 O
and O
caspase O
- O
3 O
protein O
levels O
with O
CHOP O
plasmid O
were O
elevated O
whereas O
the O
protein O
levels O
with O
CHOP O
siRNA O
were O
similar O
. O

While O
CHOP O
plasmid O
transfection O
diminished O
p21 O
and O
phospho O
- O
Akt O
protein O
levels O
, O
CHOP O
siRNA O
transfection O
did O
not O
alter O
the O
protein O
levels O
. O

In O
conclusion O
, O
these O
results O
suggest O
that O
CHOP O
may O
sensitize O
FRO O
ATC O
cells O
to O
SU5416 B
thereby O
inhibiting O
cell O
survival O
by O
modulating O
p21 O
and O
PI3K O
/ O
Akt O
signal O
pathway O
. O

Furthermore O
, O
these O
findings O
imply O
that O
CHOP O
may O
be O
a O
possible O
candidate O
as O
the O
chemosensitizing O
factor O
for O
induction O
of O
cytotoxicity O
in O
ATC O
cells O
exposed O
to O
SU5416 B
. O

Functional O
phenotype O
of O
airway O
myocytes O
from O
asthmatic O
airways O
. O

In O
asthma O
, O
the O
airway O
smooth O
muscle O
( O
ASM O
) O
cell O
plays O
a O
central O
role O
in O
disease O
pathogenesis O
through O
cellular O
changes O
which O
may O
impact O
on O
its O
microenvironment O
and O
alter O
ASM O
response O
and O
function O
. O

The O
answer O
to O
the O
long O
debated O
question O
of O
what O
makes O
a O
' O
healthy O
' O
ASM O
cell O
become O
' O
asthmatic O
' O
still O
remains O
speculative O
. O

What O
is O
known O
of O
an O
' O
asthmatic O
' O
ASM O
cell O
, O
is O
its O
ability O
to O
contribute O
to O
the O
hallmarks O
of O
asthma O
such O
as O
bronchoconstriction O
( O
contractile O
phenotype O
) O
, O
inflammation O
( O
synthetic O
phenotype O
) O
and O
ASM O
hyperplasia O
( O
proliferative O
phenotype O
) O
. O

The O
phenotype O
of O
healthy O
or O
diseased O
ASM O
cells O
or O
tissue O
for O
the O
most O
part O
is O
determined O
by O
expression O
of O
key O
phenotypic O
markers O
. O

ASM O
is O
commonly O
accepted O
to O
have O
different O
phenotypes O
: O
the O
contractile O
( O
differentiated O
) O
state O
versus O
the O
synthetic O
( O
dedifferentiated O
) O
state O
( O
with O
the O
capacity O
to O
synthesize O
mediators O
, O
proliferate O
and O
migrate O
) O
. O

There O
is O
now O
accumulating O
evidence O
that O
the O
synthetic O
functions O
of O
ASM O
in O
culture O
derived O
from O
asthmatic O
and O
non O
- O
asthmatic O
donors O
differ O
. O

Some O
of O
these O
differences O
include O
an O
altered O
profile O
and O
increased O
production O
of O
extracellular O
matrix O
proteins O
, O
pro O
- O
inflammatory O
mediators O
and O
adhesion O
receptors O
, O
collectively O
suggesting O
that O
ASM O
cells O
from O
asthmatic O
subjects O
have O
the O
capacity O
to O
alter O
their O
environment O
, O
actively O
participate O
in O
repair O
processes O
and O
functionally O
respond O
to O
changes O
in O
their O
microenvironment O
. O

Lead O
- O
induced O
ER O
calcium B
release O
and O
inhibitory O
effects O
of O
methionine B
choline I
in O
cultured O
rat O
hippocampal O
neurons O
. O

Lead O
, O
a O
ubiquitous O
neurotoxicant O
, O
can O
result O
in O
learning O
and O
memory O
dysfunction O
. O

Long O
term O
potentiation O
in O
the O
hippocampus O
, O
a O
potential O
neural O
substrate O
for O
learning O
and O
memory O
, O
is O
thought O
to O
be O
linked O
to O
calcium B
- O
triggered O
intracellular O
events O
. O

In O
this O
study O
, O
laser O
scanning O
confocal O
microscopy O
was O
used O
to O
examine O
the O
effects O
of O
Pb B
( I
2 I
+ I
) I
on O
intracellular O
and O
endoplasmic O
reticulum O
free O
calcium B
concentration O
( O
[ O
Ca B
( I
2 I
+ I
) I
] O
( O
i O
) O
and O
[ O
Ca B
( I
2 I
+ I
) I
] O
( O
ER O
) O
) O
in O
cultured O
neonatal O
rat O
hippocampal O
neurons O
and O
their O
possible O
antagonism O
by O
methionine B
choline I
; O
understanding O
these O
effects O
would O
help O
explain O
the O
lead O
- O
induced O
cognitive O
and O
learning O
dysfunction O
and O
explore O
efficient O
safety O
and O
relief O
strategies O
. O

The O
results O
showed O
that O
Pb B
( I
2 I
+ I
) I
increased O
[ O
Ca B
( I
2 I
+ I
) I
] O
( O
i O
) O
and O
decreased O
[ O
Ca B
( I
2 I
+ I
) I
] O
( O
ER O
) O
linearly O
in O
a O
time O
- O
and O
concentration O
- O
dependant O
manner O
, O
and O
Pb B
( I
2 I
+ I
) I
addition O
after O
the O
applying O
of O
a O
ryanodine B
receptor O
( O
RyR O
) O
antagonist O
and O
an O
inositol B
- I
1 I
, I
4 I
, I
5 I
- I
triphosphate I
receptor O
( O
IP O
( O
3 O
) O
R O
) O
antagonist O
did O
not O
increase O
[ O
Ca B
( I
2 I
+ I
) I
] O
( O
i O
) O
. O

The O
addition O
of O
10 O
, O
20 O
, O
or O
40 O
mmol O
/ O
L O
methionine B
choline I
simultaneously O
with O
addition O
of O
10 O
mu O
mol O
/ O
L O
Pb B
( I
2 I
+ I
) I
decreased O
[ O
Ca B
( I
2 I
+ I
) I
] O
( O
i O
) O
in O
Ca B
( I
2 I
+ I
) I
- O
free O
culture O
medium O
by O
39 O
. O
0 O
% O
, O
66 O
. O
0 O
% O
, O
and O
61 O
. O
6 O
% O
, O
respectively O
, O
in O
a O
concentration O
- O
dependant O
manner O
in O
a O
certain O
dose O
range O
. O

Our O
results O
suggest O
that O
Pb B
( I
2 I
+ I
) I
induces O
ER O
calcium B
release O
to O
increase O
the O
resting O
[ O
Ca B
( I
2 I
+ I
) I
] O
( O
i O
) O
; O
and O
methionine B
choline I
inhibit O
this O
increase O
in O
[ O
Ca B
( I
2 I
+ I
) I
] O
( O
i O
) O
. O

Interactions O
between O
bufadienolides B
derived O
from O
toad O
venom O
and O
verapamil B
in O
langendorff O
- O
perfused O
guinea O
- O
pig O
hearts O
. O

Drug O
toxicity O
may O
occur O
due O
to O
dangerous O
drug O
combination O
. O

We O
aimed O
to O
investigate O
the O
influence O
of O
verapamil B
( O
a O
P O
- O
gp O
inhibitor O
) O
- B
- I
bufadienolides I
interaction O
on O
cardiotoxicity O
and O
bufadienolide B
uptake O
by O
the O
isolated O
heart O
. O

The O
study O
was O
performed O
in O
Langendorff O
isolated O
perfused O
guinea O
- O
pig O
hearts O
by O
bufadienolides B
infusion O
in O
the O
absence O
and O
presence O
of O
verapamil B
( O
250 O
, O
500ng O
/ O
ml O
) O
. O

Arrhythmia O
parameters O
were O
evaluated O
by O
ECG O
and O
the O
content O
of O
bufadienolides B
in O
heart O
were O
measured O
by O
ultra O
- O
performance O
liquid O
chromatography O
tandem O
mass O
spectrometry O
( O
UPLC O
- O
MS O
) O
. O

In O
the O
present O
of O
verapamil B
, O
the O
wide O
QRS O
duration O
and O
lightly O
rapid O
heart O
rate O
( O
HR O
) O
were O
markedly O
reduced O
in O
the O
early O
stage O
of O
bufadienolide B
intoxication O
. O

However O
, O
the O
ECG O
changes O
characterized O
by O
prolonged O
P O
- O
R O
interval O
, O
and O
slow O
heart O
rate O
and O
low O
QRS O
amplitude O
in O
the O
late O
stage O
of O
bufadienolide B
intoxication O
were O
significantly O
enhanced O
. O

Furthermore O
, O
the O
contents O
of O
a O
variety O
of O
bufadienolide B
compounds O
in O
the O
verapamil B
+ O
bufadienolide B
group O
were O
significantly O
higher O
when O
cardiac O
arrest O
occurred O
. O

Although O
verapamil B
reduced O
the O
bufadienolide B
- O
induced O
ventricular O
arrhythmias O
, O
verapamil B
worsened O
heart O
block O
and O
lethal O
bradycardia O
of O
bufadienolides B
partly O
via O
increasing O
the O
uptake O
of O
bufadienolides B
in O
heart O
tissue O
, O
which O
could O
compromise O
the O
protective O
effects O
of O
verapamil B
against O
bufadienolide B
intoxication O
. O

These O
results O
suggested O
that O
the O
verapamil B
may O
produce O
dangerous O
interactions O
with O
drugs O
containing O
bufadienolides B
. O

Synthesis O
of O
NaP B
zeolite B
at O
room O
temperature O
and O
short O
crystallization O
time O
by O
sonochemical O
method O
. O

NaP B
zeolite B
nano O
crystals O
were O
synthesized O
by O
sonochemical O
method O
at O
room O
temperature O
with O
crystallization O
time O
of O
3h O
. O

For O
comparison O
, O
to O
insure O
the O
effect O
of O
sonochemical O
method O
, O
the O
hydrothermal O
method O
at O
conventional O
synthesis O
condition O
, O
with O
same O
initial O
sol O
composition O
was O
studied O
. O

NaP B
zeolites B
are O
directly O
formed O
by O
ultrasonic O
treatment O
without O
the O
application O
of O
autogenous O
pressure O
and O
also O
hydrothermal O
treatment O
. O

The O
effect O
of O
ultrasonic O
energy O
and O
irradiation O
time O
showed O
that O
with O
increasing O
sonication O
energy O
, O
the O
crystallinity O
of O
the O
powders O
decreased O
but O
phase O
purity O
remain O
unchanged O
. O

The O
synthesized O
powders O
were O
characterized O
by O
XRD O
, O
IR O
, O
DTA O
TGA O
, O
FESEM O
, O
and O
TEM O
analysis O
. O

FESEM O
images O
revealed O
that O
50 O
nm O
zeolite B
crystals O
were O
formed O
at O
room O
temperature O
by O
using O
sonochemical O
method O
. O

However O
, O
agglomerated O
particles O
having O
cactus O
/ O
cabbage O
like O
structure O
was O
obtained O
by O
sonochemical O
method O
followed O
by O
hydrothermal O
treatment O
. O

In O
sonochemical O
process O
, O
formation O
of O
cavitation O
and O
the O
collapsing O
of O
bubbles O
produced O
huge O
energy O
which O
is O
sufficient O
for O
crystallization O
of O
zeolite B
compared O
to O
that O
supplied O
by O
hydrothermal O
process O
for O
conventional O
synthesis O
. O

With O
increasing O
irradiation O
energy O
and O
time O
, O
the O
crystallinity O
of O
the O
synthesized O
zeolite B
samples O
increased O
slightly O
. O

The O
value O
of O
selected O
in O
vitro O
and O
in O
silico O
methods O
to O
predict O
acute O
oral O
toxicity O
in O
a O
regulatory O
context O
: O
Results O
from O
the O
European O
Project O
ACuteTox O
. O

ACuteTox O
is O
a O
project O
within O
the O
6th O
European O
Framework O
Programme O
which O
had O
as O
one O
of O
its O
goals O
to O
develop O
, O
optimise O
and O
prevalidate O
a O
non O
- O
animal O
testing O
strategy O
for O
predicting O
human O
acute O
oral O
toxicity O
. O

In O
its O
last O
6months O
, O
a O
challenging O
exercise O
was O
conducted O
to O
assess O
the O
predictive O
capacity O
of O
the O
developed O
testing O
strategies O
and O
final O
identification O
of O
the O
most O
promising O
ones O
. O

Thirty O
- O
two O
chemicals O
were O
tested O
blind O
in O
the O
battery O
of O
in O
vitro O
and O
in O
silico O
methods O
selected O
during O
the O
first O
phase O
of O
the O
project O
. O

This O
paper O
describes O
the O
classification O
approaches O
studied O
: O
single O
step O
procedures O
and O
two O
step O
tiered O
testing O
strategies O
. O

In O
summary O
, O
four O
in O
vitro O
testing O
strategies O
were O
proposed O
as O
best O
performing O
in O
terms O
of O
predictive O
capacity O
with O
respect O
to O
the O
European O
acute O
oral O
toxicity O
classification O
. O

In O
addition O
, O
a O
heuristic O
testing O
strategy O
is O
suggested O
that O
combines O
the O
prediction O
results O
gained O
from O
the O
neutral B
red I
uptake O
assay O
performed O
in O
3T3 O
cells O
, O
with O
information O
on O
neurotoxicity O
alerts O
identified O
by O
the O
primary O
rat O
brain O
aggregates O
test O
method O
. O

Octanol B
- O
water O
partition O
coefficients O
and O
in O
silico O
prediction O
of O
intestinal O
absorption O
and O
blood O
- O
brain O
barrier O
passage O
are O
also O
considered O
. O

This O
approach O
allows O
to O
reduce O
the O
number O
of O
chemicals O
wrongly O
predicted O
as O
not O
classified O
( O
LD50 O
> O
2000mg O
/ O
kg O
b O
. O
w O
. O
) O
. O

Amino B
acid I
sequence O
of O
the O
ligand O
- O
binding O
domain O
of O
the O
aryl B
hydrocarbon I
receptor O
1 O
predicts O
sensitivity O
of O
wild O
birds O
to O
effects O
of O
dioxin B
- O
like O
compounds O
. O

The O
sensitivity O
of O
avian O
species O
to O
the O
toxic O
effects O
of O
dioxin B
- O
like O
compounds O
( O
DLCs O
) O
varies O
up O
to O
1000 O
- O
fold O
among O
species O
, O
and O
this O
variability O
has O
been O
associated O
with O
interspecies O
differences O
in O
aryl B
hydrocarbon I
receptor O
1 O
ligand O
- O
binding O
domain O
( O
AHR1 O
LBD O
) O
sequence O
. O

We O
previously O
showed O
that O
LD O
( O
50 O
) O
values O
, O
based O
on O
in O
ovo O
exposures O
to O
DLCs O
, O
were O
significantly O
correlated O
with O
in O
vitro O
EC O
( O
50 O
) O
values O
obtained O
with O
a O
luciferase O
reporter O
gene O
( O
LRG O
) O
assay O
that O
measures O
AHR1 O
- O
mediated O
induction O
of O
cytochrome O
P4501A O
in O
COS O
- O
7 O
cells O
transfected O
with O
avian O
AHR1 O
constructs O
. O

Those O
findings O
suggest O
that O
the O
AHR1 O
LBD O
sequence O
and O
the O
LRG O
assay O
can O
be O
used O
to O
predict O
avian O
species O
sensitivity O
to O
DLCs O
. O

In O
the O
present O
study O
, O
the O
AHR1 O
LBD O
sequences O
of O
86 O
avian O
species O
were O
studied O
, O
and O
differences O
at O
amino B
acid I
sites O
256 O
, O
257 O
, O
297 O
, O
324 O
, O
337 O
, O
and O
380 O
were O
identified O
. O

Site O
- O
directed O
mutagenesis O
, O
the O
LRG O
assay O
, O
and O
homology O
modeling O
highlighted O
the O
importance O
of O
each O
amino B
acid I
site O
in O
AHR1 O
sensitivity O
to O
2 B
, I
3 I
, I
7 I
, I
8 I
- I
tetrachlorodibenzo I
- I
p I
- I
dioxin I
and O
other O
DLCs O
. O

The O
results O
of O
the O
study O
revealed O
that O
( O
1 O
) O
only O
amino B
acids I
at O
sites O
324 O
and O
380 O
affect O
the O
sensitivity O
of O
AHR1 O
expression O
constructs O
of O
the O
86 O
avian O
species O
to O
DLCs O
and O
( O
2 O
) O
in O
vitro O
luciferase O
activity O
of O
AHR1 O
constructs O
containing O
only O
the O
LBD O
of O
the O
species O
of O
interest O
is O
significantly O
correlated O
( O
r O
( O
2 O
) O
= O
0 O
. O
93 O
, O
p O
< O
0 O
. O
0001 O
) O
with O
in O
ovo O
toxicity O
data O
for O
those O
species O
. O

These O
results O
indicate O
promise O
for O
the O
use O
of O
AHR1 O
LBD O
amino B
acid I
sequences O
independently O
, O
or O
combined O
with O
the O
LRG O
assay O
, O
to O
predict O
avian O
species O
sensitivity O
to O
DLCs O
. O

Acid O
- O
induced O
gelation O
behavior O
of O
soybean O
protein O
isolate O
with O
high O
intensity O
ultrasonic O
pre O
- O
treatments O
. O

High O
intensity O
ultrasonic O
( O
HUS O
, O
20 O
kHz O
, O
400 O
W O
) O
pre O
- O
treatments O
of O
soybean O
protein O
isolate O
( O
SPI O
) O
improved O
the O
water O
holding O
capacity O
( O
WHC O
) O
, O
gel O
strength O
and O
gel O
firmness O
( O
final O
elastic O
moduli O
) O
of O
glucono B
- I
delta I
- I
lactone I
induced O
SPI O
gels O
( O
GISG O
) O
. O

Sonication O
time O
( O
0 O
, O
5 O
, O
20 O
, O
and O
40 O
min O
) O
had O
a O
significant O
effect O
on O
the O
above O
three O
properties O
. O

20 O
min O
HUS O
- O
GISG O
had O
the O
highest O
WHC O
( O
95 O
. O
53 O
+ O
/ O
- O
0 O
. O
25 O
% O
) O
, O
gel O
strength O
( O
60 O
. O
90 O
+ O
/ O
- O
2 O
. O
87 O
g O
) O
and O
gel O
firmness O
( O
96340Pa O
) O
, O
compared O
with O
other O
samples O
. O

Moreover O
, O
SH B
groups O
and O
non O
- O
covalent O
interactions O
of O
GISG O
also O
changed O
after O
HUS O
pre O
- O
treatments O
. O

The O
HUS O
GISG O
had O
denser O
and O
more O
uniform O
microstructures O
than O
the O
untreated O
GISG O
. O

Rheological O
investments O
showed O
that O
the O
cooling O
step O
( O
reduce O
the O
temperature O
from O
95 O
to O
25 O
degrees O
C O
at O
a O
speed O
of O
2 O
degrees O
C O
/ O
min O
) O
was O
more O
important O
for O
the O
HUS O
GISG O
network O
formation O
while O
the O
heat O
preservation O
step O
( O
keep O
temperature O
at O
95 O
for O
20 O
min O
) O
was O
more O
important O
for O
the O
untreated O
GISG O
. O

HUS O
reduced O
the O
particle O
size O
of O
SPI O
and O
Pearson O
correlation O
test O
showed O
that O
the O
particle O
size O
of O
SPI O
dispersions O
was O
negatively O
correlated O
with O
WHC O
, O
gel O
strength O
and O
gel O
firmness O
. O

Proteomic O
allergen O
- O
peptide O
/ O
protein O
interaction O
assay O
for O
the O
identification O
of O
human O
skin O
sensitizers O
. O

Modification O
of O
proteins O
by O
skin O
sensitizers O
is O
a O
pivotal O
step O
in O
T O
cell O
mediated O
allergic O
contact O
dermatitis O
( O
ACD O
) O
. O

In O
this O
process O
small O
reactive O
chemicals O
interact O
covalently O
or O
non O
- O
covalently O
with O
cellular O
or O
extracellular O
skin O
self O
- O
proteins O
or O
self O
- O
peptides O
to O
become O
recognized O
by O
the O
human O
immune O
system O
. O

Aiming O
to O
develop O
a O
novel O
non O
- O
animal O
in O
vitro O
test O
system O
for O
predicting O
sensitization O
potential O
of O
small O
reactive O
chemicals O
in O
human O
skin O
the O
allergen O
- O
peptide O
/ O
protein O
interaction O
assay O
( O
APIA O
) O
has O
been O
developed O
. O

By O
applying O
modern O
proteomic O
technologies O
together O
with O
a O
target O
peptide O
containing O
all O
amino B
acids I
, O
the O
assay O
permits O
the O
profiling O
of O
all O
amino B
acid I
specific O
allergen O
- O
peptide O
interactions O
. O

Moreover O
, O
potentially O
crucial O
allergen O
- O
specific O
Cys B
- O
modifications O
are O
qualitatively O
monitored O
by O
mass O
spectrometry O
and O
confirmed O
by O
a O
dual O
peptide O
approach O
. O

Assay O
conditions O
chosen O
mimic O
the O
distinct O
human O
epidermal O
reactivity O
compartments O
of O
the O
skin O
surface O
( O
pH O
5 O
. O
5 O
) O
, O
stratum O
basale O
( O
pH O
6 O
. O
8 O
) O
, O
and O
typical O
physiological O
conditions O
( O
pH O
7 O
. O
4 O
) O
. O

An O
extreme O
as O
well O
as O
a O
moderate O
human O
contact O
sensitizer O
produced O
Cys O
- O
specific O
mass O
shifts O
, O
whereas O
a O
skin O
irritant O
did O
not O
. O

Our O
data O
indicate O
that O
MALDI O
- O
MS O
based O
and O
skin O
- O
related O
in O
vitro O
technology O
platforms O
- O
like O
the O
APIA O
- O
are O
promising O
tools O
in O
developing O
alternative O
non O
- O
animal O
allergen O
assays O
. O

This O
will O
assist O
in O
chemical O
classification O
and O
next O
generation O
risk O
assessment O
strategies O
, O
including O
REACH O
and O
experimental O
immunotoxicology O
. O

An O
overview O
of O
transcriptional O
regulation O
in O
response O
to O
toxicological O
insult O
. O

The O
completion O
of O
the O
human O
genome O
project O
and O
the O
subsequent O
advent O
of O
DNA O
microarray O
and O
high O
- O
throughput O
sequencing O
technologies O
have O
led O
to O
a O
renaissance O
in O
molecular O
toxicology O
. O

Toxicogenomic O
data O
sets O
, O
from O
both O
in O
vivo O
and O
in O
vitro O
studies O
, O
are O
growing O
exponentially O
, O
providing O
a O
wealth O
of O
information O
on O
regulation O
of O
stress O
pathways O
at O
the O
transcriptome O
level O
. O

Through O
such O
studies O
, O
we O
are O
now O
beginning O
to O
appreciate O
the O
diversity O
and O
complexity O
of O
biological O
responses O
to O
xenobiotics O
. O

In O
this O
review O
, O
we O
aim O
to O
consolidate O
and O
summarise O
the O
major O
toxicologically O
relevant O
transcription O
factor O
- O
governed O
molecular O
pathways O
. O

It O
is O
becoming O
clear O
that O
different O
chemical O
entities O
can O
cause O
oxidative O
, O
genotoxic O
and O
proteotoxic O
stress O
, O
which O
induce O
cellular O
responses O
in O
an O
effort O
to O
restore O
homoeostasis O
. O

Primary O
among O
the O
response O
pathways O
involved O
are O
NFE2L2 O
( O
Nrf2 O
) O
, O
NFE2L1 O
( O
Nrf1 O
) O
, O
p53 O
, O
heat O
shock O
factor O
and O
the O
unfolded O
protein O
response O
. O

Additionally O
, O
more O
specific O
mechanisms O
exist O
where O
xenobiotics O
act O
as O
ligands O
, O
including O
the O
aryl B
hydrocarbon I
receptor O
, O
metal O
- O
responsive O
transcription O
factor O
- O
1 O
and O
the O
nuclear O
receptor O
family O
of O
transcription O
factors O
. O

Other O
pathways O
including O
the O
immunomodulatory O
transcription O
factors O
NF O
- O
kappa O
B O
and O
STAT O
together O
with O
the O
hypoxia O
- O
inducible O
transcription O
factor O
HIF O
are O
also O
implicated O
in O
cellular O
responses O
to O
xenobiotic O
exposure O
. O

A O
less O
specific O
but O
equally O
important O
aspect O
to O
cellular O
injury O
controlled O
by O
transcriptional O
activity O
is O
loss O
of O
tissue O
- O
specific O
gene O
expression O
, O
resulting O
in O
dedifferentiation O
of O
target O
cells O
and O
compromise O
of O
tissue O
function O
. O

Here O
, O
we O
review O
these O
pathways O
and O
the O
genes O
they O
regulate O
in O
order O
to O
provide O
an O
overview O
of O
this O
growing O
field O
of O
molecular O
toxicology O
. O

Creaming O
enhancement O
in O
a O
liter O
scale O
ultrasonic O
reactor O
at O
selected O
transducer O
configurations O
and O
frequencies O
. O

Recent O
research O
has O
shown O
that O
high O
frequency O
ultrasound O
( O
0 O
. O
4 O
- O
3 O
MHz O
) O
, O
can O
enhance O
milkfat O
separation O
in O
small O
scale O
systems O
able O
to O
treat O
only O
a O
few O
milliliters O
of O
sample O
. O

In O
this O
work O
, O
the O
effect O
of O
ultrasonic O
standing O
waves O
on O
milkfat O
creaming O
was O
studied O
in O
a O
6L O
reactor O
and O
the O
influence O
of O
different O
frequencies O
and O
transducer O
configurations O
in O
direct O
contact O
with O
the O
fluid O
was O
investigated O
. O

A O
recombined O
coarse O
milk O
emulsion O
with O
fat O
globules O
stained O
with O
oil B
- I
red I
- I
O I
dye O
was O
selected O
for O
the O
separation O
trials O
. O

Runs O
were O
performed O
with O
one O
or O
two O
transducers O
placed O
in O
vertical O
( O
parallel O
or O
perpendicular O
) O
and O
horizontal O
positions O
( O
at O
the O
reactor O
base O
) O
at O
0 O
. O
4 O
, O
1 O
and O
/ O
or O
2 O
MHz O
( O
specific O
energy O
8 O
. O
5 O
+ O
/ O
- O
0 O
. O
6 O
kJ O
/ O
kg O
per O
transducer O
) O
. O

Creaming O
behavior O
was O
assessed O
by O
measuring O
the O
thickness O
of O
the O
separated O
cream O
layer O
. O

Other O
methods O
supporting O
this O
assessment O
included O
the O
measurement O
of O
fat O
content O
, O
backscattering O
, O
particle O
size O
distribution O
, O
and O
microscopy O
of O
samples O
taken O
at O
the O
bottom O
and O
top O
of O
the O
reactor O
. O

Most O
efficient O
creaming O
was O
found O
after O
treatment O
at O
0 O
. O
4 O
MHz O
in O
single O
and O
double O
vertical O
transducer O
configurations O
. O

Among O
these O
configurations O
, O
a O
higher O
separation O
rate O
was O
obtained O
when O
sonicating O
at O
0 O
. O
4 O
MHz O
in O
a O
vertical O
perpendicular O
double O
transducer O
setup O
. O

The O
horizontal O
transducer O
configuration O
promoted O
creaming O
at O
2 O
MHz O
only O
. O

Fat O
globule O
size O
increase O
was O
observed O
when O
creaming O
occurred O
. O

This O
research O
highlights O
the O
potential O
for O
enhanced O
separation O
of O
milkfat O
in O
larger O
scale O
systems O
from O
selected O
transducer O
configurations O
in O
contact O
with O
a O
dairy O
emulsion O
, O
or O
emulsion O
splitting O
in O
general O
. O

Variations O
in O
the O
nature O
of O
behavioral O
experience O
can O
differentially O
alter O
the O
consequences O
of O
developmental O
exposures O
to O
lead O
, O
prenatal O
stress O
, O
and O
the O
combination O
. O

Behavioral O
experience O
( O
BE O
) O
can O
critically O
influence O
later O
behavior O
and O
brain O
function O
, O
but O
the O
central O
nervous O
system O
( O
CNS O
) O
consequences O
of O
most O
developmental O
neurotoxicants O
are O
examined O
in O
the O
absence O
of O
any O
such O
context O
. O

We O
previously O
demonstrated O
marked O
differences O
in O
neurotransmitter O
changes O
produced O
by O
developmental O
lead O
( O
Pb B
) O
exposure O
+ O
/ O
- O
prenatal O
stress O
( O
PS O
) O
depending O
upon O
whether O
or O
not O
rats O
had O
been O
given O
BE O
( O
Cory O
- O
Slechta O
, O
D O
. O

A O
. O
, O
Virgolini O
, O
M O
. O

B O
. O
, O
Rossi O
- O
George O
, O
A O
. O
, O
Weston O
, O
D O
. O
, O
and O
Thiruchelvam O
, O
M O
. O

( O
2009 O
) O
. O

The O
current O
study O
examined O
the O
hypothesis O
that O
the O
nature O
of O
the O
BE O
itself O
would O
be O
a O
critical O
determinant O
of O
outcome O
in O
mice O
that O
had O
been O
continually O
exposed O
to O
0 O
or O
100 O
ppm O
Pb B
acetate I
in O
drinking O
water O
alone O
or O
in O
combination O
with O
prenatal O
restraint O
stress O
. O

Half O
of O
the O
offspring O
in O
each O
of O
the O
four O
resulting O
groups O
/ O
gender O
were O
exposed O
to O
positively O
reinforced O
( O
food O
- O
rewarded O
Fixed O
Interval O
schedule O
- O
controlled O
behavior O
) O
or O
negatively O
reinforced O
( O
inescapable O
forced O
swim O
) O
BE O
. O

Brain O
monoamines B
and O
amino B
acids I
differed O
significantly O
in O
relation O
to O
BE O
, O
even O
in O
control O
animals O
, O
as O
did O
the O
trajectory O
of O
effects O
of O
Pb B
+ O
/ O
- O
PS O
, O
particularly O
in O
frontal O
cortex O
, O
hippocampus O
( O
both O
genders O
) O
, O
and O
midbrain O
( O
males O
) O
. O

In O
males O
, O
Pb B
+ O
/ O
- O
PS O
- O
related O
changes O
in O
neurotransmitters O
correlated O
with O
behavioral O
performance O
. O

These O
findings O
suggest O
that O
CNS O
consequences O
of O
developmental O
toxicants O
studied O
in O
the O
absence O
of O
a O
broader O
spectrum O
of O
BEs O
may O
not O
necessarily O
be O
predictive O
of O
human O
outcomes O
. O

Evaluating O
the O
role O
of O
specific O
BEs O
as O
a O
modulator O
of O
neurodevelopmental O
insults O
offers O
the O
opportunity O
to O
determine O
what O
specific O
BEs O
may O
ameliorate O
the O
associated O
impacts O
and O
can O
assist O
in O
establishing O
underlying O
neurobiological O
mechanisms O
. O

alpha B
- I
Amino I
- I
alpha I
' I
- I
Halomethylketones I
: O
Synthetic O
Methodologies O
and O
Pharmaceutical O
Applications O
as O
Serine B
and O
Cysteine B
Protease O
Inhibitors O
. O

alpha B
- I
Amino I
- I
alpha I
' I
- I
halomethylketones I
are O
interesting O
scaffolds O
bearing O
( O
at O
least O
) O
two O
sequential O
electrophilic O
carbons B
that O
by O
interacting O
with O
the O
nucleophilic O
moieties O
of O
several O
enzymes O
, O
represent O
the O
ideal O
candidates O
for O
in O
vivo O
and O
in O
vitro O
inhibition O
studies O
. O

In O
this O
work O
a O
summary O
of O
their O
use O
as O
optimal O
inhibitors O
of O
physiologically O
relevant O
serine B
and O
cysteine B
proteases O
is O
given O
with O
a O
particular O
emphasis O
on O
recently O
established O
SAR O
studies O
. O

A O
brief O
survey O
of O
the O
most O
relevant O
synthetic O
processes O
for O
their O
obtainment O
and O
the O
importance O
they O
possess O
in O
synthetic O
medicinal O
chemistry O
is O
reported O
. O

Cholinergic O
modulation O
by O
opioid O
receptor O
ligands O
: O
potential O
application O
to O
Alzheimer O
' O
s O
disease O
. O

Morphinans B
have O
a O
storied O
history O
in O
medicinal O
chemistry O
as O
pain O
management O
drugs O
but O
have O
received O
attention O
as O
modulators O
of O
cholinergic O
signaling O
for O
the O
treatment O
of O
Alzheimer O
' O
s O
Disease O
( O
AD O
) O
. O

Galantamine B
is O
a O
reversible O
, O
competitive O
acetylcholinesterase O
( O
AChE O
) O
inhibitor O
and O
allosteric O
potentiating O
ligand O
of O
nicotinic O
acetylcholine B
receptors O
( O
nAChR O
- O
APL O
) O
that O
shares O
many O
common O
structural O
elements O
with O
morphinan B
- O
based O
opioids O
. O

The O
structurally O
diverse O
opioids O
codeine B
and O
eseroline B
, O
like O
galantamine B
, O
are O
also O
nAChR O
- O
APL O
that O
have O
greatly O
diminished O
affinity O
for O
AChE O
, O
representing O
potential O
lead O
compounds O
for O
selective O
nAChR O
- O
APL O
development O
. O

In O
accordance O
with O
the O
emerging O
repurposing O
trend O
of O
evaluating O
known O
compounds O
for O
novel O
pharmacological O
activity O
, O
ongoing O
research O
on O
augmentation O
of O
cholinergic O
signaling O
that O
has O
been O
aided O
by O
the O
use O
of O
opioids O
will O
be O
reviewed O
. O

Adhesion O
of O
osteoblasts O
to O
a O
vertically O
aligned O
TiO2 B
nanotube O
surface O
. O

The O
adhesion O
of O
cells O
to O
vertically O
aligned O
TiO2 B
nanotubes O
is O
reviewed O
. O

The O
attraction O
between O
a O
negatively O
charged O
nanotube O
surface O
and O
a O
negatively O
charged O
osteoblast O
is O
facilitated O
by O
charged O
protein O
- O
mediators O
like O
proteins O
with O
a O
quadrupolar O
internal O
charge O
distribution O
, O
fibronectin O
and O
vitronectin O
. O

It O
is O
shown O
that O
adhesion O
and O
spreading O
of O
osteoblasts O
on O
vertically O
aligned O
TiO2 B
nanotube O
surfaces O
depend O
on O
the O
diameter O
of O
the O
nanotubes O
. O

Apparently O
, O
a O
small O
diameter O
nanotube O
surface O
has O
on O
average O
more O
sharp O
convex O
edges O
per O
unit O
area O
than O
a O
large O
one O
, O
leading O
to O
stronger O
binding O
affinity O
on O
its O
surface O
. O

Manganese B
- O
enhanced O
magnetic O
resonance O
imaging O
detects O
declining O
pancreatic O
beta O
- O
cell O
mass O
in O
a O
cyclophosphamide B
- O
accelerated O
mouse O
model O
of O
type O
1 O
diabetes O
. O

Currently O
, O
there O
is O
no O
ideal O
noninvasive O
method O
to O
quantify O
the O
progressive O
loss O
of O
pancreatic O
beta O
- O
cell O
mass O
( O
BCM O
) O
that O
occurs O
in O
type O
1 O
diabetes O
. O

Magnetic O
resonance O
imaging O
has O
detected O
gross O
differences O
in O
BCM O
between O
healthy O
and O
diabetic O
mice O
using O
the O
contrast O
agent O
manganese B
, O
which O
labels O
functional O
beta O
- O
cells O
and O
increases O
the O
water O
proton O
relaxation O
rate O
( O
R1 O
) O
, O
but O
its O
ability O
to O
measure O
gradations O
in O
BCM O
during O
disease O
progression O
is O
unknown O
. O

Our O
objective O
was O
to O
test O
the O
hypothesis O
that O
measurements O
of O
the O
manganese B
- O
enhanced O
pancreatic O
R1 O
could O
detect O
decreasing O
BCM O
in O
a O
mouse O
model O
of O
type O
1 O
diabetes O
. O

We O
used O
cyclophosphamide B
- O
accelerated O
BDC2 O
. O
5 O
T O
- O
cell O
receptor O
transgenic O
nonobese O
diabetic O
mice O
, O
which O
experience O
development O
of O
type O
1 O
diabetes O
during O
a O
7 O
- O
day O
time O
period O
after O
cyclophosphamide B
injection O
, O
whereas O
transgene O
- O
negative O
mice O
do O
not O
. O

We O
measured O
the O
manganese B
- O
enhanced O
pancreatic O
R1 O
before O
cyclophosphamide B
injection O
( O
day O
0 O
) O
and O
on O
days O
3 O
, O
4 O
, O
5 O
, O
and O
7 O
afterward O
. O

Pancreatic O
R1 O
remained O
constant O
in O
transgene O
- O
negative O
mice O
and O
decreased O
stepwise O
day O
- O
to O
- O
day O
in O
transgene O
- O
positive O
mice O
, O
mirroring O
their O
loss O
of O
BCM O
, O
confirmed O
by O
pancreatic O
insulin O
measurements O
and O
histology O
. O

Changes O
in O
R1 O
in O
transgene O
- O
positive O
mice O
occurred O
before O
elevations O
in O
blood O
glucose B
, O
a O
clinical O
indicator O
of O
diabetes O
, O
suggesting O
potential O
for O
early O
noninvasive O
detection O
of O
changes O
in O
functional O
BCM O
. O

Bcl O
- O
2 O
and O
Bcl O
- O
xL O
suppress O
glucose B
signaling O
in O
pancreatic O
beta O
- O
cells O
. O

B O
- O
cell O
lymphoma O
2 O
( O
Bcl O
- O
2 O
) O
family O
proteins O
are O
established O
regulators O
of O
cell O
survival O
, O
but O
their O
involvement O
in O
the O
normal O
function O
of O
primary O
cells O
has O
only O
recently O
begun O
to O
receive O
attention O
. O

In O
this O
study O
, O
we O
demonstrate O
that O
chemical O
and O
genetic O
loss O
- O
of O
- O
function O
of O
antiapoptotic O
Bcl O
- O
2 O
and O
Bcl O
- O
x O
( O
L O
) O
significantly O
augments O
glucose B
- O
dependent O
metabolic O
and O
Ca B
( I
2 I
+ I
) I
signals O
in O
primary O
pancreatic O
beta O
- O
cells O
. O

Antagonism O
of O
Bcl O
- O
2 O
/ O
Bcl O
- O
x O
( O
L O
) O
by O
two O
distinct O
small O
- O
molecule O
compounds O
rapidly O
hyperpolarized O
beta O
- O
cell O
mitochondria O
, O
increased O
cytosolic O
Ca B
( I
2 I
+ I
) I
, O
and O
stimulated O
insulin O
release O
via O
the O
ATP B
- O
dependent O
pathway O
in O
beta O
- O
cell O
under O
substimulatory O
glucose B
conditions O
. O

Experiments O
with O
single O
and O
double O
Bax O
- O
Bak O
knockout O
beta O
- O
cells O
established O
that O
this O
occurred O
independently O
of O
these O
proapoptotic O
binding O
partners O
. O

Pancreatic O
beta O
- O
cells O
from O
Bcl O
- O
2 O
( O
- O
/ O
- O
) O
mice O
responded O
to O
glucose B
with O
significantly O
increased O
NAD B
( I
P I
) I
H I
levels O
and O
cytosolic O
Ca B
( I
2 I
+ I
) I
signals O
, O
as O
well O
as O
significantly O
augmented O
insulin O
secretion O
. O

Inducible O
deletion O
of O
Bcl O
- O
x O
( O
L O
) O
in O
adult O
mouse O
beta O
- O
cells O
also O
increased O
glucose B
- O
stimulated O
NAD B
( I
P I
) I
H I
and O
Ca B
( I
2 I
+ I
) I
responses O
and O
resulted O
in O
an O
improvement O
of O
in O
vivo O
glucose B
tolerance O
in O
the O
conditional O
Bcl O
- O
x O
( O
L O
) O
knockout O
animals O
. O

Our O
work O
suggests O
that O
prosurvival O
Bcl O
proteins O
normally O
dampen O
the O
beta O
- O
cell O
response O
to O
glucose B
and O
thus O
reveals O
these O
core O
apoptosis O
proteins O
as O
integrators O
of O
cell O
death O
and O
physiology O
in O
pancreatic O
beta O
- O
cells O
. O

Dual O
- O
responsive O
nanoparticles O
and O
their O
self O
- O
assembly O
. O

Dual O
- O
responsive O
nanoparticles O
are O
designed O
by O
functionalizing O
magnetic O
cores O
with O
light O
- O
responsive O
ligands O
. O

These O
materials O
respond O
to O
both O
light O
and O
magnetic O
fields O
and O
can O
be O
assembled O
into O
various O
higher O
- O
order O
structures O
, O
depending O
on O
the O
relative O
contributions O
of O
these O
two O
stimuli O
. O

Pharmacokinetics O
, O
pharmacodynamics O
and O
clinical O
use O
of O
valganciclovir B
in O
newborns O
with O
symptomatic O
congenital O
cytomegalovirus O
infection O
. O

Congenital O
cytomegalovirus O
infection O
is O
the O
most O
common O
cause O
of O
nonhereditary O
sensorineural O
hearing O
loss O
and O
an O
important O
cause O
of O
psychomotor O
retardation O
. O

Newborns O
suffering O
from O
symptomatic O
congenital O
cytomegalovirus O
infection O
have O
been O
typically O
treated O
with O
i O
. O
v O
. O
ganciclovir B
( O
GCV B
) O
. O

Nowadays O
valganciclovir B
( O
V B
- I
GCV I
) O
, O
a O
mono B
- I
valyl I
ester I
pro O
- O
drug O
of O
GCV B
, O
is O
available O
as O
an O
oral O
syrup O
. O

The O
existing O
literature O
demonstrated O
that O
V O
- O
GCV B
is O
well O
absorbed O
from O
the O
gastrointestinal O
tract O
and O
is O
rapidly O
converted O
into O
GCV B
in O
the O
intestinal O
wall O
and O
liver O
. O

The O
mechanism O
of O
antiviral O
action O
is O
the O
same O
that O
has O
been O
described O
for O
GCV B
. O

All O
these O
characteristics O
make O
this O
formulation O
particularly O
suitable O
for O
the O
symptomatic O
congenitally O
infected O
newborns O
. O

In O
neonates O
, O
V O
- O
GCV B
oral O
formulation O
proved O
stable O
and O
constant O
GVC O
plasma O
concentrations O
, O
in O
the O
suggested O
therapeutic O
range O
. O

The O
syrup O
demonstrated O
to O
be O
clinically O
effective O
and O
well O
tolerated O
and O
to O
be O
appropriate O
for O
a O
prolonged O
post O
- O
discharge O
therapy O
avoiding O
the O
discomfort O
of O
hospitalization O
, O
reducing O
the O
risk O
for O
nosocomial O
infections O
and O
decreasing O
the O
cost O
for O
the O
National O
Health O
Service O
. O

This O
article O
reviews O
all O
the O
available O
literature O
about O
V O
- O
GCV B
syrup O
in O
the O
treatment O
of O
newborns O
and O
infants O
with O
congenital O
CMV O
infection O
with O
the O
regard O
to O
pharmacokinetics O
, O
pharmacodynamic O
properties O
and O
clinical O
use O
, O
focussing O
on O
new O
data O
and O
on O
our O
experience O
. O

Noncanonical O
control O
of O
C O
. O
elegans O
germline O
apoptosis O
by O
the O
insulin O
/ O
IGF O
- O
1 O
and O
Ras O
/ O
MAPK O
signaling O
pathways O
. O

The O
insulin O
/ O
IGF O
- O
1 O
pathway O
controls O
a O
number O
of O
physiological O
processes O
in O
the O
nematode O
worm O
Caenorhabditis O
elegans O
, O
including O
development O
, O
aging O
and O
stress O
response O
. O

We O
previously O
found O
that O
the O
Akt O
/ O
PKB O
ortholog O
AKT O
- O
1 O
dampens O
the O
apoptotic O
response O
to O
genotoxic O
stress O
in O
the O
germline O
by O
negatively O
regulating O
the O
p53 O
- O
like O
transcription O
factor O
CEP O
- O
1 O
. O

Here O
, O
we O
report O
unexpected O
rearrangements O
to O
the O
insulin O
/ O
IGF O
- O
1 O
pathway O
, O
whereby O
the O
insulin O
- O
like O
receptor O
DAF O
- O
2 O
and O
3 O
- O
phosphoinositide O
- O
dependent O
protein O
kinase O
PDK O
- O
1 O
oppose O
AKT O
- O
1 O
to O
promote O
DNA O
damage O
- O
induced O
apoptosis O
. O

While O
DNA O
damage O
does O
not O
affect O
phosphorylation O
at O
the O
PDK O
- O
1 O
site O
Thr350 B
/ O
Thr308 B
of O
AKT O
- O
1 O
, O
it O
increased O
phosphorylation O
at O
Ser517 B
/ O
Ser473 B
. O

Although O
ablation O
of O
daf O
- O
2 O
or O
pdk O
- O
1 O
completely O
suppressed O
akt O
- O
1 O
- O
dependent O
apoptosis O
, O
the O
transcriptional O
activation O
of O
CEP O
- O
1 O
was O
unaffected O
, O
suggesting O
that O
daf O
- O
2 O
and O
pdk O
- O
1 O
act O
independently O
or O
downstream O
of O
cep O
- O
1 O
and O
akt O
- O
1 O
. O

Ablation O
of O
the O
akt O
- O
1 O
paralog O
akt O
- O
2 O
or O
the O
downstream O
target O
of O
the O
insulin O
/ O
IGF O
- O
1 O
pathway O
daf O
- O
16 O
( O
a O
FOXO O
transcription O
factor O
) O
restored O
sensitivity O
to O
damage O
- O
induced O
apoptosis O
in O
daf O
- O
2 O
and O
pdk O
- O
1 O
mutants O
. O

In O
addition O
, O
daf O
- O
2 O
and O
pdk O
- O
1 O
mutants O
have O
reduced O
levels O
of O
phospho B
- O
MPK O
- O
1 O
/ O
ERK O
in O
their O
germ O
cells O
, O
indicating O
that O
the O
insulin O
/ O
IGF O
- O
1 O
pathway O
promotes O
Ras O
signaling O
in O
the O
germline O
. O

Ablation O
of O
the O
Ras O
effector O
gla O
- O
3 O
, O
a O
negative O
regulator O
of O
mpk O
- O
1 O
, O
restored O
sensitivity O
to O
apoptosis O
in O
daf O
- O
2 O
mutants O
, O
suggesting O
that O
gla O
- O
3 O
acts O
downstream O
of O
daf O
- O
2 O
. O

In O
addition O
, O
the O
hypersensitivity O
of O
let O
- O
60 O
/ O
Ras O
gain O
- O
of O
- O
function O
mutants O
to O
damage O
- O
induced O
apoptosis O
was O
suppressed O
to O
wild O
- O
type O
levels O
by O
ablation O
of O
daf O
- O
2 O
. O

Thus O
, O
insulin O
/ O
IGF O
- O
1 O
signaling O
selectively O
engages O
AKT O
- O
2 O
/ O
DAF O
- O
16 O
to O
promote O
DNA O
damage O
- O
induced O
germ O
cell O
apoptosis O
downstream O
of O
CEP O
- O
1 O
through O
the O
Ras O
pathway O
. O

Inactivation O
of O
anoctamin O
- O
6 O
/ O
Tmem16f O
, O
a O
regulator O
of O
phosphatidylserine B
scrambling O
in O
osteoblasts O
, O
leads O
to O
decreased O
mineral O
deposition O
in O
skeletal O
tissues O
. O

During O
vertebrate O
skeletal O
development O
, O
osteoblasts O
produce O
a O
mineralized O
bone O
matrix O
by O
deposition O
of O
hydroxyapatite B
crystals O
in O
the O
extracellular O
matrix O
. O

Anoctamin6 O
/ O
Tmem16F O
( O
Ano6 O
) O
belongs O
to O
a O
conserved O
family O
of O
transmembrane O
proteins O
with O
chloride B
channel O
properties O
. O

In O
addition O
, O
Ano6 B
has O
been O
linked O
to O
phosphatidylserine B
( O
PS O
) O
scrambling O
in O
the O
plasma O
membrane O
. O

During O
skeletogenesis O
, O
Ano6 O
mRNA O
is O
expressed O
in O
differentiating O
and O
mature O
osteoblasts O
. O

Deletion O
of O
Ano6 O
in O
mice O
results O
in O
reduced O
skeleton O
size O
and O
skeletal O
deformities O
. O

Molecular O
analysis O
revealed O
that O
chondrocyte O
and O
osteoblast O
differentiation O
are O
not O
disturbed O
. O

However O
, O
mutant O
mice O
display O
increased O
regions O
of O
nonmineralized O
, O
Ibsp O
- O
expressing O
osteoblasts O
in O
the O
periosteum O
during O
embryonic O
development O
and O
increased O
areas O
of O
uncalcified O
osteoid O
postnatally O
. O

In O
primary O
Ano6 O
( O
- O
/ O
- O
) O
osteoblasts O
, O
mineralization O
is O
delayed O
, O
indicating O
a O
cell O
autonomous O
function O
of O
Ano6 O
. O

Furthermore O
, O
we O
demonstrate O
that O
calcium B
- O
dependent O
PS O
scrambling O
is O
impaired O
in O
osteoblasts O
. O

Our O
study O
is O
the O
first O
to O
our O
knowledge O
to O
reveal O
the O
requirement O
of O
Ano6 O
in O
PS O
scrambling O
in O
osteoblasts O
, O
supporting O
a O
function O
of O
PS O
exposure O
in O
the O
deposition O
of O
hydroxyapatite B
. O

Fragrance O
chemicals O
lyral O
and O
lilial O
decrease O
viability O
of O
HaCat O
cells O
' O
by O
increasing O
free O
radical O
production O
and O
lowering O
intracellular O
ATP B
level O
: O
protection O
by O
antioxidants O
. O

We O
investigate O
in O
this O
study O
the O
biochemical O
effects O
on O
cells O
in O
culture O
of O
two O
commonly O
used O
fragrance O
chemicals O
: O
lyral O
and O
lilial O
. O

Whereas O
both O
chemicals O
exerted O
a O
significant O
effect O
on O
primary O
keratinocyte O
( O
s O
) O
, O
HaCat O
cells O
, O
no O
effect O
was O
obtained O
with O
any O
of O
HepG2 O
, O
Hek293 O
, O
Caco2 O
, O
NIH3T3 O
, O
and O
MCF7 O
cells O
. O

Lyral O
and O
lilial O
: O
( O
a O
) O
decreased O
the O
viability O
of O
HaCat O
cells O
with O
a O
50 O
% O
cell O
death O
at O
100 O
and O
60 O
nM O
respectively O
; O
( O
b O
) O
decreased O
significantly O
in O
a O
dose O
dependant O
manner O
the O
intracellular O
ATP B
level O
following O
12 O
- O
h O
of O
treatment O
; O
( O
c O
) O
inhibited O
complexes O
I O
and O
II O
of O
electron O
transport O
chain O
in O
liver O
sub O
- O
mitochondrial O
particles O
; O
and O
( O
d O
) O
increased O
reactive O
oxygen B
species O
generation O
that O
was O
reversed O
by O
N B
- I
acetyl I
cysteine I
and O
trolox B
and O
the O
natural O
antioxidant O
lipoic B
acid I
, O
without O
influencing O
the O
level O
of O
free O

and O
/ O
or O
oxidized B
glutathione I
. O

Lipoic B
acid I
protected O
HaCat O
cells O
against O
the O
decrease O
in O
viability O
induced O
by O
either O
compound O
. O

Dehydrogenation O
of O
lyral O
and O
lilial O
produce O
alpha B
, I
beta I
- I
unsaturated I
aldehydes I
, O
that O
reacts O
with O
lipoic B
acid I
requiring O
proteins O
resulting O
in O
their O
inhibition O
. O

We O
propose O
lyral O
and O
lilial O
as O
toxic O
to O
mitochondria O
that O
have O
a O
direct O
effect O
on O
electron O
transport O
chain O
, O
increase O
ROS O
production O
, O
derange O
mitochondrial O
membrane O
potential O
, O
and O
decrease O
cellular O
ATP B
level O
, O
leading O
thus O
to O
cell O
death O
. O

Silver B
nanoparticles O
induce O
toxicity O
in O
A549 O
cells O
via O
ROS O
- O
dependent O
and O
ROS O
- O
independent O
pathways O
. O

Silver B
nanoparticles O
( O
AgNPs O
) O
are O
incorporated O
into O
a O
large O
number O
of O
consumer O
and O
medical O
products O
. O

Several O
experiments O
have O
demonstrated O
that O
AgNPs O
can O
be O
toxic O
to O
the O
vital O
organs O
of O
humans O
and O
especially O
to O
the O
lung O
. O

The O
present O
study O
evaluated O
the O
in O
vitro O
mechanisms O
of O
AgNP O
( O
< O
100 O
nm O
) O
toxicity O
in O
relationship O
to O
the O
generation O
of O
reactive O
oxygen B
species O
( O
ROS O
) O
in O
A549 O
cells O
. O

AgNPs O
caused O
ROS O
formation O
in O
the O
cells O
, O
a O
reduction O
in O
their O
cell O
viability O
and O
mitochondrial O
membrane O
potential O
( O
MMP O
) O
, O
an O
increase O
in O
the O
proportion O
of O
cells O
in O
the O
sub O
- O
G1 O
( O
apoptosis O
) O
population O
, O
S O
phase O
arrest O
and O
down O
- O
regulation O
of O
the O
cell O
cycle O
associated O
proliferating O
cell O
nuclear O
antigen O
( O
PCNA O
) O
protein O
, O
in O
a O
concentration O
- O
and O
time O
- O
dependent O
manner O
. O

Pretreatment O
of O
the O
A549 O
cells O
with O
N B
- I
acetyl I
- I
cysteine I
( O
NAC B
) O
, O
an O
antioxidant O
, O
decreased O
the O
effects O
of O
AgNPs O
on O
the O
reduced O
cell O
viability O
, O
change O
in O
the O
MMP O
and O
proportion O
of O
cells O
in O
the O
sub O
- O
G1population O
, O
but O
had O
no O
effect O
on O
the O
AgNP O
- O
mediated O
S O
phase O
arrest O
or O
down O
- O
regulation O
of O
PCNA O
. O

These O
observations O
allow O
us O
to O
propose O
that O
the O
in O
vitro O
toxic O
effects O
of O
AgNPs O
on O
A549 O
cells O
are O
mediated O
via O
both O
ROS O
- O
dependent O
( O
cytotoxicity O
) O
and O
ROS O
- O
independent O
( O
cell O
cycle O
arrest O
) O
pathways O
. O

In O
silico O
structural O
and O
functional O
analysis O
of O
the O
human O
TOPK O
protein O
by O
structure O
modeling O
and O
molecular O
dynamics O
studies O
. O

Over O
expression O
of O
T O
- O
lymphokine O
- O
activated O
killer O
cell O
- O
originated O
protein O
kinase O
( O
TOPK O
) O
has O
been O
associated O
with O
leukemia O
, O
myeloma O
tumors O
and O
various O
other O
cancers O
. O

The O
function O
and O
regulatory O
mechanism O
of O
TOPK O
in O
tumor O
cells O
remains O
unclear O
. O

Structural O
studies O
that O
could O
reveal O
the O
regulatory O
mechanism O
have O
been O
a O
challenge O
because O
of O
the O
unavailabity O
of O
TOPK O
' O
s O
crystal O
structure O
. O

Hence O
, O
in O
this O
study O
, O
the O
3D O
structure O
of O
TOPK O
protein O
has O
been O
constructed O
by O
using O
multiple O
templates O
. O

The O
quality O
and O
reliability O
of O
the O
generated O
model O
was O
checked O
and O
the O
molecular O
dynamics O
method O
was O
utilized O
to O
refine O
the O
model O
. O

APBS O
method O
was O
employed O
to O
know O
the O
electrostatic O
potential O
surface O
of O
the O
modeled O
protein O
and O
it O
was O
found O
that O
the O
optimum O
pH O
for O
protein O
stability O
is O
3 O
. O
4 O
which O
will O
further O
help O
in O
mechanistic O
hypothesis O
of O
TOPK O
protein O
. O

Active O
site O
of O
TOPK O
was O
identified O
from O
available O
literature O
and O
HTVS O
was O
employed O
to O
identify O
the O
lead O
molecules O
. O

The O
expected O
binding O
modes O
of O
protein O
- O
ligand O
complexes O
were O
reproduced O
in O
the O
MD O
simulation O
which O
indicates O
that O
the O
complex O
is O
relatively O
stable O
. O

The O
pharmacokinetic O
properties O
of O
the O
lead O
molecules O
are O
also O
under O
acceptable O
range O
. O

TOPK O
act O
as O
a O
substrate O
for O
CDK1 O
and O
the O
protein O
- O
protein O
docking O
and O
dynamics O
studies O
were O
carried O
out O
to O
analyze O
the O
effect O
of O
Thr9Ala O
mutation O
of O
TOPK O
in O
the O
two O
protein O
complex O
formation O
. O

It O
shows O
that O
the O
wild O
type O
complex O
is O
more O
stable O
when O
compared O
with O
the O
mutant O
type O
. O

Such O
structural O
information O
at O
atomic O
level O
not O
only O
exhibits O
the O
action O
modes O
of O
TOPK O
inhibitors O
but O
also O
furnishes O
a O
novel O
starting O
point O
for O
structure O
based O
drug O
design O
of O
TOPK O
inhibitors O
. O

Low O
calorie O
and O
carbohydrate B
diet O
: O
to O
improve O
the O
cardiovascular O
risk O
indicators O
in O
overweight O
or O
obese O
adults O
with O
prediabetes O
. O

Our O
objective O
was O
to O
evaluate O
the O
effects O
of O
a O
moderate O
calorie O
and O
carbohydrate B
- O
restricted O
diet O
on O
cardiovascular O
risk O
indicators O
in O
overweight O
or O
obese O
patients O
with O
prediabetes O
. O

A O
clinical O
trial O
was O
conducted O
in O
which O
86 O
subjects O
presenting O
with O
overweight O
or O
obesity O
and O
prediabetes O
received O
a O
personalized O
diet O
of O
1 O
, O
200 O
to O
1 O
, O
700 O
calories O
with O
a O
distribution O
of O
50 O
% O
carbohydrates B
, O
20 O
% O
proteins O
, O
and O
30 O
% O
fat O
. O

Body O
weight O
, O
fat O
mass O
, O
and O
lean O
mass O
were O
measured O
through O
bioimpedance O
. O

Glucose B
, O
total O
cholesterol B
, O
high O
density O
lipoprotein O
cholesterol B
and O
low O
density O
cholesterol B
, O
and O
triglycerides B
were O
measured O
. O

The O
measurements O
were O
taken O
at O
the O
beginning O
of O
, O
and O
at O
, O
6 O
and O
12 O
months O
during O
the O
intervention O
, O
and O
the O
differences O
were O
compared O
by O
paired O
Student O
' O
s O
t O
and O
chi O
( O
2 O
) O
tests O
. O

At O
12 O
months O
, O
a O
significant O
reduction O
was O
noticed O
in O
body O
weight O
in O
patients O
with O
overweight O
and O
obesity O
( O
72 O
. O
4 O
+ O
/ O
- O
7 O
. O
8 O
- O
69 O
. O
6 O
+ O
/ O
- O
7 O
. O
5 O
kg O
) O
( O
85 O
. O
7 O
+ O
/ O
- O
14 O
. O
8 O
- O
80 O
. O
2 O
+ O
/ O
- O
12 O
. O
7 O
kg O
) O
with O
body O
mass O
index O
( O
28 O
. O
2 O
+ O
/ O
- O
0 O
. O
8 O
- O
27 O
. O
2 O
+ O
/ O
- O
2 O
. O
1 O
kg O
/ O
m O
( O
2 O
) O
) O
( O
34 O
. O
3 O
+ O
/ O
- O
3 O
. O
5 O
- O
32 O
. O
1 O
+ O
/ O
- O
3 O
. O
2 O
kg O
/ O
m O
( O
2 O
) O
) O
, O

systolic O
( O
120 O
. O
9 O
+ O
/ O
- O
14 O
. O
2 O
- O
112 O
. O
4 O
+ O
/ O
- O
11 O
. O
5 O
mmHg O
) O
( O
124 O
. O
1 O
+ O
/ O
- O
11 O
. O
9 O
- O
115 O
. O
7 O
+ O
/ O
- O
14 O
. O
0 O
mmHg O
) O
, O
diastolic O
blood O
pressures O
( O
79 O
. O
0 O
+ O
/ O
- O
9 O
. O
3 O
- O
71 O
. O
8 O
+ O
/ O
- O
8 O
. O
3 O
mmHg O
) O
( O
80 O
. O
4 O
+ O
/ O
- O
9 O
. O
0 O
- O
73 O
. O
7 O
+ O
/ O
- O
13 O
. O
1 O
mmHg O
) O
, O
glucose B
( O
106 O
. O
0 O
+ O
/ O
- O
8 O
. O
9 O
- O
95 O
. O
9 O
+ O
/ O
- O
7 O

. O
5 O
mg O
/ O
dL O
) O
( O
107 O
. O
3 O
+ O
/ O
- O
7 O
. O
0 O
- O
97 O
. O
0 O
+ O
/ O
- O
8 O
. O
2 O
mg O
/ O
dL O
) O
, O
and O
significant O
improvement O
on O
lipid O
profile O
( O
p O
< O
0 O
. O
05 O
) O
. O

The O
restrictions O
in O
the O
calorie O
and O
carbohydrate B
diet O
decrease O
the O
cardiovascular O
risk O
indicators O
in O
overweight O
or O
obese O
adults O
with O
prediabetes O
. O

Quantitation O
of O
UGT1A1 O
in O
human O
liver O
microsomes O
using O
stable O
isotope O
- O
labelled O
peptides O
and O
mass O
spectrometry O
based O
proteomic O
approaches O
. O

1 O
. O
UDP B
- O
glucuronosyltransfer O
( O
UGTs O
) O
are O
a O
group O
of O
drug O
- O
metabolizing O
enzymes O
that O
catalyse O
the O
conjugation O
of O
endogeonous O
compounds O
and O
xenobiotics O
to O
yield O
hydrophilic O
glucuronides O
which O
subsequently O
undergo O
excretion O
. O

This O
report O
describes O
an O
approach O
for O
the O
identification O
and O
accurate O
quantitation O
of O
human O
UGT1A1 O
in O
complex O
biological O
matrices O
using O
liquid O
chromatography O
/ O
mass O
spectrometry O
/ O
mass O
spectrometry O
( O
LC O
- O
MS O
/ O
MS O
) O
analysis O
of O
protein O
digests O
. O

2 O
. O
A O
stable O
isotope O
- O
labelled O
( O
SIL O
) O
peptide O
of O
a O
unique O
peptide O
spanning O
residues O
54 O
- O
69 O
in O
exon O
1 O
of O
the O
human O
UGT1A1 O
protein O
with O
the O
sequence O
RIYLSADPALVVIEHG O
was O
synthesized O
. O

The O
peptide O
sequence O
synthesized O
was O
in O
the O
reverse O
order O
of O
the O
human O
peptide O
with O
the O
stable O
isotope O
- O
labels O
in O
the O
amino B
acid I
arginine I
( O
( B
13 I
) I
C6 I
( I
15 I
) I
N4 I
) O
resulting O
in O
an O
increase O
in O
the O
mass O
of O
the O
SIL O
peptide O
of O
10 O
amu O
, O
from O
1753 O
to O
1763 O
. O

The O
SIL O
peptide O
was O
quantitated O
by O
injecting O
increasing O
concentrations O
of O
the O
peptide O
into O
the O
LC O
- O
MS O
to O
obtain O
a O
standard O
curve O
. O

3 O
. O
The O
labelled O
peptide O
along O
with O
precursor O
ion O
monitoring O
was O
used O
to O
quantify O
the O
levels O
of O
UGT1A1 O
in O
commercial O
recombinant O
preparations O
( O
supersomes O
) O
and O
individual O
human O
liver O
microsomal O
samples O
and O
pooled O
human O
liver O
micrsomes O
obtained O
from O
BD O
Biosciences O
. O

4 O
. O
Glucuronidation O
activity O
studies O
were O
performed O
, O
which O
demonstrated O
a O
positive O
correlation O
between O
enzyme O
activity O
levels O
and O
the O
UGT1A1 O
content O
in O
the O
liver O
microsomes O
obtained O
from O
individual O
human O
donors O
. O

A O
dose O
response O
study O
to O
assess O
effects O
after O
dietary O
administration O
of O
diisononyl B
phthalate I
( O
DINP B
) O
in O
gestation O
and O
lactation O
on O
male O
rat O
sexual O
development O
. O

Male O
rat O
sexual O
development O
was O
evaluated O
after O
dietary O
administration O
of O
0 O
, O
760 O
, O
3800 O
, O
11 O
, O
400 O
ppm O
diisononyl B
phthalate I
( O
DiNP B
) O
and O
7600 O
ppm O
dibutyl B
phthalate I
( O
DBP B
) O
from O
gestation O
day O
( O
GD O
) O
12 O
to O
postnatal O
day O
( O
PND O
) O
14 O
. O

Maternal O
weight O
was O
reduced O
on O
GD O
20 O
, O
PND O
2 O
and O
14 O
at O
11 O
, O
400 O
ppm O
DiNP B
. O

Pup O
weight O
was O
reduced O
on O
PND O
2 O
and O
14 O
at O
11 O
, O
400 O
and O
3800 O
ppm O
DiNP B
. O

DBP B
induced O
multinucleated O
germ O
cells O
( O
MNGs O
) O
and O
Leydig O
cell O
aggregates O
( O
LCAs O
) O
in O
PND O
2 O
testes O
. O

7600 O
ppm O
DBP B
reduced O
anogenital O
distance O
( O
AGD O
) O
on O
PND O
2 O
and O
14 O
, O
and O
increased O
nipple O
retention O
and O
reproductive O
tract O
malformations O
on O
PND O
49 O
. O

DiNP B
induced O
MNGs O
( O
3800 O
ppm O
) O
and O
LCAs B
( O
11 O
, O
400 O
ppm O
) O
on O
PND O
2 O
, O
and O
reduced O
AGD O
( O
11 O
, O
400 O
ppm O
) O
on O
PND O
14 O
. O

DiNP B
did O
not O
alter O
AGD O
, O
nipple O
retention O
or O
reproductive O
tract O
malformations O
on O
PND O
49 O
. O

Global O
endpoint O
analysis O
showed O
no O
evidence O
of O
a O
rat O
" O
phthalate B
syndrome O
" O
on O
PND O
49 O
with O
DiNP B
administration O
. O

Suppression O
of O
collagen O
Q O
expression O
in O
the O
extrajunctional O
regions O
of O
rat O
fast O
muscles O
is O
encoded O
in O
their O
stem O
cells O
( O
satellite O
cells O
) O
. O

In O
rat O
fast O
muscles O
, O
collagen O
Q O
( O
ColQ O
) O
expression O
is O
restricted O
to O
the O
neuromuscular O
junctions O
. O

In O
contrast O
, O
it O
is O
high O
also O
extrajunctionally O
in O
the O
slow O
soleus O
muscles O
. O

Fast O
muscles O
activated O
by O
chronic O
low O
- O
frequency O
electrical O
stimulation O
, O
similar O
to O
neural O
activation O
of O
the O
soleus O
muscles O
, O
did O
not O
increase O
their O
extrajunctional O
expression O
of O
ColQ O
. O

We O
assumed O
that O
the O
myogenic O
stem O
cells O
( O
satellite O
cells O
) O
in O
fast O
and O
slow O
muscles O
were O
intrinsically O
different O
in O
regard O
to O
the O
capacity O
that O
they O
convey O
to O
their O
respective O
muscle O
fibers O
to O
increase O
the O
extrajunctional O
ColQ O
expression O
upon O
innervation O
. O

ColQ O
mRNA O
levels O
were O
determined O
by O
quantitative O
real O
- O
time O
PCR O
. O

Extensive O
neural O
suppression O
of O
the O
extrajunctional O
ColQ O
expression O
in O
regenerating O
fast O
muscles O
during O
maturation O
is O
a O
very O
slow O
process O
requiring O
30 O
- O
60days O
. O

If O
the O
immature O
regenerating O
fast O
EDL O
muscles O
were O
indirectly O
or O
directly O
electrically O
stimulated O
immediately O
after O
innervation O
by O
chronic O
low O
- O
frequency O
impulse O
pattern O
for O
8days O
, O
no O
significant O
increase O
of O
the O
extrajunctional O
ColQ O
mRNA O
levels O
was O
observed O
in O
stimulated O
regenerates O
in O
comparison O
to O
non O
- O
stimulated O
ones O
. O

In O
contrast O
, O
the O
extrajunctional O
ColQ O
mRNA O
levels O
in O
the O
regenerates O
of O
the O
soleus O
muscles O
, O
trans O
- O
innervated O
by O
the O
EDL O
nerve O
at O
the O
time O
of O
muscle O
injury O
, O
increased O
4 O
- O
to O
5 O
- O
fold O
after O
8days O
of O
the O
same O
chronic O
low O
- O
frequency O
electrical O
stimulation O
in O
comparison O
to O
those O
in O
the O
stimulated O
EDL O
regenerates O
. O

Since O
both O
fast O
and O
slow O
muscles O
completely O
regenerated O
only O
from O
their O
own O
myogenic O
stem O
cells O
and O
were O
innervated O
by O
the O
same O
nerve O
and O
later O
activated O
by O
the O
same O
tonic O
pattern O
of O
impulses O
, O
these O
results O
demonstrated O
that O
the O
mechanism O
causing O
incapacity O
of O
regenerating O
fast O
muscles O
to O
increase O
their O
extrajunctional O
ColQ O
expression O
upon O
tonic O
activation O
is O
encoded O
in O
their O
satellite O
cells O
, O
which O
in O
this O
respect O
differ O
from O
those O
in O
the O
slow O
muscles O
. O

Lithium B
treatment O
induces O
proteasomal O
degradation O
of O
over O
- O
expressed O
acetylcholinesterase O
( O
AChE O
- O
S O
) O
and O
inhibit O
GSK3 O
beta O
. O

Lithium B
is O
one O
of O
the O
most O
widely O
used O
mood O
- O
stabilizing O
agents O
for O
the O
treatment O
of O
bipolar O
disorder O
. O

Lithium B
is O
also O
a O
potent O
inhibitor O
of O
glycogen O
synthase O
kinase O
- O
3 O
beta O
( O
GSK3 O
beta O
) O
activity O
, O
which O
is O
linked O
to O
Alzheimer O
' O
s O
disease O
( O
AD O
) O
. O

In O
experiments O
with O
cultured O
HEK293T O
cells O
, O
we O
show O
here O
that O
GSK3 O
beta O
stabilizes O
synaptic O
acetylcholinesterase O
( O
AChE O
- O
S O
) O
, O
a O
critical O
component O
of O
AD O
development O
. O

Cells O
treated O
with O
lithium B
exhibited O
rapid O
proteasomal O
degradation O
of O
AChE O
- O
S O
. O

Furthermore O
treatment O
of O
the O
cells O
with O
MG132 O
, O
an O
inhibitor O
of O
the O
26S O
proteasome O
, O
prevented O
the O
destabilizing O
effect O
of O
lithium B
on O
AChE O
- O
S O
. O

Taken O
together O
, O
these O
findings O
suggest O
that O
regulation O
of O
AChE O
- O
S O
protein O
stability O
may O
be O
an O
important O
biological O
target O
of O
lithium B
therapy O
. O

Toxicity O
of O
terpenes B
on O
fibroblast O
cells O
compared O
to O
their O
hemolytic O
potential O
and O
increase O
in O
erythrocyte O
membrane O
fluidity O
. O

Terpenes B
are O
considered O
potent O
skin O
permeation O
enhancers O
with O
low O
toxicity O
. O

Electron O
paramagnetic O
resonance O
( O
EPR O
) O
spectroscopy O
of O
the O
spin O
label O
5 B
- I
doxyl I
stearic I
acid I
( O
5 B
- I
DSA I
) O
was O
used O
to O
monitor O
the O
effect O
of O
sesquiterpene O
nerolidol B
and O
various O
monoterpenes B
on O
membrane O
fluidity O
in O
erythrocyte O
and O
fibroblast O
cells O
. O

In O
addition O
, O
the O
hemolytic O
levels O
and O
cytotoxic O
effects O
on O
cultured O
fibroblast O
cells O
were O
also O
measured O
to O
investigate O
possible O
relationships O
between O
the O
cellular O
irritation O
potentials O
of O
terpenes B
and O
the O
ability O
to O
modify O
membrane O
fluidity O
. O

All O
terpenes B
increased O
cell O
membrane O
fluidity O
with O
no O
significant O
differences O
between O
the O
monoterpenes B
, O
but O
the O
effect O
of O
sesquiterpene B
was O
significantly O
greater O
than O
that O
of O
the O
monoterpenes B
. O

The O
IC O
( O
50 O
) O
values O
for O
the O
terpenes B
in O
the O
cytotoxicity O
assay O
indicated O
that O
1 B
, I
8 I
- I
cineole I
showed O
lower O
cytotoxicity O
and O
alpha B
- I
terpineol I
and O
nerolidol B
showed O
higher O
cytotoxicity O
. O

The O
correlation O
between O
the O
hemolytic O
effect O
and O
the O
IC O
( O
50 O
) O
values O
for O
fibroblast O
viability O
was O
low O
( O
R O
= O
0 O
. O
61 O
) O
; O
however O
, O
in O
both O
tests O
, O
nerolidol B
was O
among O
the O
most O
aggressive O
of O
terpenes B
and O
1 B
, I
8 I
- I
cineole I
was O
among O
the O
least O
aggressive O
. O

Obtaining O
information O
concerning O
the O
toxicity O
and O
potency O
of O
terpenes B
could O
aid O
in O
the O
design O
of O
topical O
formulations O
optimized O
to O
facilitate O
drug O
absorption O
for O
the O
treatment O
of O
many O
skin O
diseases O
. O

A O
probable O
clinically O
significant O
interaction O
between O
warfarin B
and O
cloxacillin B
: O
three O
case O
reports O
. O

CASES O
: O
Three O
patients O
were O
admitted O
to O
the O
Imam O
Hospital O
, O
Tehran O
, O
Iran O
with O
a O
diagnosis O
of O
bacterial O
endocarditis O
. O

The O
patients O
had O
indications O
for O
valve O
replacement O
surgery O
and O
anticoagulant O
therapy O
. O

The O
administration O
of O
cloxacillin B
reduced O
the O
effect O
of O
warfarin B
, O
and O
subsequent O
increases O
in O
warfarin B
doses O
were O
unable O
to O
overcome O
this O
effect O
. O

CONCLUSION O
: O
A O
decrease O
in O
warfarin B
anticoagulation O
effects O
was O
detected O
in O
our O
three O
patients O
following O
cloxacillin B
therapy O
for O
infective O
endocarditis O
. O

Penicillinase O
- O
resistant O
penicillins B
remain O
essential O
antibiotics O
in O
the O
treatment O
of O
severe O
infections O
caused O
by O
Staphylococcus O
aureus O
due O
to O
their O
bactericidal O
activity O
, O
safety O
, O
and O
cost O
. O

Thus O
, O
in O
situations O
where O
anticoagulants O
are O
indicated O
in O
patients O
with O
infective O
endocarditis O
, O
it O
would O
be O
better O
to O
replace O
warfarin B
with O
low O
- O
molecular O
- O
weight O
or O
unfractionated O
heparin O
. O

Abnormal O
uterine O
bleeding O
and O
dysfunctional O
uterine O
bleeding O
in O
pediatric O
and O
adolescent O
gynecology O
. O

Abnormal O
uterine O
bleeding O
( O
AUB O
) O
, O
which O
is O
defined O
as O
excessively O
heavy O
, O
prolonged O
and O
/ O
or O
frequent O
bleeding O
of O
uterine O
origin O
, O
is O
a O
frequent O
cause O
of O
visits O
to O
the O
Emergency O
Department O
and O
/ O
or O
health O
care O
provider O
. O

While O
there O
are O
many O
etiologies O
of O
AUB O
, O
the O
one O
most O
likely O
among O
otherwise O
healthy O
adolescents O
is O
dysfunctional O
uterine O
bleeding O
( O
DUB O
) O
, O
which O
is O
characterizing O
any O
AUB O
when O
all O
possible O
underlying O
pathologic O
causes O
have O
been O
previously O
excluded O
. O

The O
most O
common O
cause O
of O
DUB O
in O
adolescence O
is O
anovulation O
, O
which O
is O
very O
frequent O
in O
the O
first O
2 O
- O
3 O
post O
- O
menarchal O
years O
and O
is O
associated O
with O
immaturity O
of O
the O
hypothalamic O
- O
pituitary O
- O
ovarian O
axis O
. O

Management O
of O
AUB O
is O
based O
on O
the O
underlying O
etiology O
and O
the O
severity O
of O
the O
bleeding O
and O
primary O
goals O
are O
prevention O
of O
complications O
, O
such O
as O
anemia O
and O
reestablishment O
of O
regular O
cyclical O
bleeding O
, O
while O
the O
management O
of O
DUB O
can O
in O
part O
be O
directed O
by O
the O
amount O
of O
flow O
, O
the O
degree O
of O
associated O
anemia O
, O
as O
well O
as O
patient O
and O
family O
comfort O
with O
different O
treatment O
modalities O
. O

Treatment O
options O
for O
DUB O
are O
: O
combined O
oral O
contraceptives O
( O
COCs O
) O
, O
progestogens B
, O
non O
steroidal O
anti O
inflammatory O
drugs O
( O
NSAIDs O
) O
, O
tranexamic B
acid I
( O
anti O
- O
fibrinolytic O
) O
, O
GnRH B
analogues O
, O
Danazol B
and O
Levonorgestrel B
releasing O
intra O
uterine O
system O
( O
LNG B
IUS O
) O
. O

An O
assessment O
of O
pure O
, O
hybrid O
, O
meta O
, O
and O
hybrid O
- O
meta O
GGA O
density O
functional O
theory O
methods O
for O
open O
- O
shell O
systems O
: O
the O
case O
of O
the O
nonheme O
iron B
enzyme O
8R O
- O
LOX O
. O

The O
performance O
of O
a O
range O
density O
functional O
theory O
functionals O
combined O
in O
a O
quantum O
mechanical O
( O
QM O
) O
/ O
molecular O
mechanical O
( O
MM O
) O
approach O
was O
investigated O
in O
their O
ability O
to O
reliably O
provide O
geometries O
, O
electronic O
distributions O
, O
and O
relative O
energies O
of O
a O
multicentered O
open O
- O
shell O
mechanistic O
intermediate O
in O
the O
mechanism O
8R O
- O
Lipoxygenase O
. O

With O
the O
use O
of O
large O
QM O
/ O
MM O
active O
site O
chemical O
models O
, O
the O
smallest O
average O
differences O
in O
geometries O
between O
the O
catalytically O
relevant O
quartet O
and O
sextet O
complexes O
were O
obtained O
with O
the O
B3LYP O
( O
* O
) O
functional O
. O

Moreover O
, O
in O
the O
case O
of O
the O
relative O
energies O
between O
( O
4 O
) O
II O
and O
( O
6 O
) O
II O
, O
the O
use O
of O
the O
B3LYP O
( O
* O
) O
functional O
provided O
a O
difference O
of O
0 O
. O
0 O
kcal O
mol O
( O
- O
1 O
) O
. O

However O
, O
B3LYP O
( O
+ O
/ O
- O
) O
and O
B3LYP O
also O
predicted O
differences O
in O
energies O
of O
less O
than O
1 O
kcal O
mol O
( O
- O
1 O
) O
. O

In O
the O
case O
of O
describing O
the O
electronic O
distribution O
( O
i O
. O
e O
. O
, O
spin O
density O
) O
, O
the O
B3LYP O
( O
* O
) O
, O
B3LYP O
, O
or O
M06 O
- O
L O
functionals O
appeared O
to O
be O
the O
most O
suitable O
. O

Overall O
, O
the O
results O
obtained O
suggest O
that O
for O
systems O
with O
multiple O
centers O
having O
unpaired O
electrons O
, O
the O
B3LYP O
( O
* O
) O
appears O
most O
well O
rounded O
to O
provide O
reliable O
geometries O
, O
electronic O
structures O
, O
and O
relative O
energies O
. O

Design O
of O
a O
testing O
strategy O
using O
non O
- O
animal O
based O
test O
methods O
: O
Lessons O
learnt O
from O
the O
ACuteTox O
project O
. O

In O
the O
framework O
of O
toxicology O
, O
a O
testing O
strategy O
can O
be O
viewed O
as O
a O
series O
of O
steps O
which O
are O
taken O
to O
come O
to O
a O
final O
prediction O
about O
a O
characteristic O
of O
a O
compound O
under O
study O
. O

The O
testing O
strategy O
is O
performed O
as O
a O
single O
- O
step O
procedure O
, O
usually O
called O
a O
test O
battery O
, O
using O
simultaneously O
all O
information O
collected O
on O
different O
endpoints O
, O
or O
as O
tiered O
approach O
in O
which O
a O
decision O
tree O
is O
followed O
. O

Design O
of O
a O
testing O
strategy O
involves O
statistical O
considerations O
, O
such O
as O
the O
development O
of O
a O
statistical O
prediction O
model O
. O

During O
the O
EU O
FP6 O
ACuteTox O
project O
, O
several O
prediction O
models O
were O
proposed O
on O
the O
basis O
of O
statistical O
classification O
algorithms O
which O
we O
illustrate O
here O
. O

The O
final O
choice O
of O
testing O
strategies O
was O
not O
based O
on O
statistical O
considerations O
alone O
. O

However O
, O
without O
thorough O
statistical O
evaluations O
a O
testing O
strategy O
cannot O
be O
identified O
. O

We O
present O
here O
a O
number O
of O
observations O
made O
from O
the O
statistical O
viewpoint O
which O
relate O
to O
the O
development O
of O
testing O
strategies O
. O

The O
points O
we O
make O
were O
derived O
from O
problems O
we O
had O
to O
deal O
with O
during O
the O
evaluation O
of O
this O
large O
research O
project O
. O

A O
central O
issue O
during O
the O
development O
of O
a O
prediction O
model O
is O
the O
danger O
of O
overfitting O
. O

Procedures O
are O
presented O
to O
deal O
with O
this O
challenge O
. O

Role O
of O
TNF O
- O
alpha O
in O
renal O
damage O
in O
mice O
showing O
hepatic O
steatosis O
induced O
by O
high O
fat O
diet O
. O

The O
present O
study O
was O
designed O
to O
investigate O
the O
role O
of O
TNF O
- O
alpha O
in O
renal O
damage O
observed O
in O
mice O
with O
hepatic O
steatosis O
. O

We O
induced O
hepatic O
steatosis O
in O
mice O
using O
high O
fat O
diet O
and O
treated O
mice O
with O
ectanercept O
at O
the O
dose O
sufficient O
to O
block O
TNF O
- O
alpha O
receptors O
or O
vehicle O
for O
1 O
month O
. O

Plasma O
TNF O
- O
alpha O
, O
total O
cholesterol B
( O
TC O
) O
, O
triglyceride B
( O
TG O
) O
, O
LDL O
- O
cholesterol B
( O
LDL O
- O
C O
) O
, O
and O
HDL O
- O
cholesterol B
( O
HDL O
- O
C O
) O
were O
determined O
at O
the O
end O
of O
this O
treatment O
. O

Renal O
damage O
was O
identified O
by O
histologic O
observation O
and O
the O
higher O
of O
serum O
blood O
urea B
nitrogen B
( O
BUN O
) O
and O
creatinine B
. O

Also O
, O
changes O
of O
PPAR O
- O
delta O
in O
kidney O
and O
renal O
mesangial O
cell O
( O
RMC O
) O
were O
analyzed O
using O
Western O
blot O
. O

Plasma O
TNF O
- O
alpha O
was O
markedly O
raised O
in O
mice O
showing O
hepatic O
steatosis O
. O

However O
, O
the O
levels O
of O
blood O
lipids O
( O
TC O
, O
TG O
, O
HDL O
- O
C O
, O
and O
LDL O
- O
C O
) O
and O
TNF O
- O
alpha O
were O
not O
modified O
by O
the O
treatment O
of O
etanercept O
although O
the O
hepatic O
steatosis O
has O
been O
improved O
. O

Etanercept O
shows O
renal O
protection O
from O
histological O
identification O
and O
recovery O
of O
serum O
BUN O
and O
creatinine B
levels O
. O

Moreover O
, O
restoration O
of O
PPAR O
- O
delta O
expression O
by O
etanercept O
was O
observed O
in O
mice O
kidney O
. O

Direct O
effect O
of O
TNF O
- O
alpha O
on O
PPAR O
- O
delta O
expression O
was O
also O
characterized O
in O
RMC O
cell O
. O

We O
suggest O
that O
renal O
damage O
in O
mice O
with O
hepatic O
steatosis O
is O
mainly O
induced O
by O
increase O
of O
TNF O
- O
alpha O
through O
the O
decrease O
of O
renal O
PPAR O
- O
delta O
. O

Etanercept O
could O
block O
TNF O
- O
alpha O
receptors O
to O
restore O
PPAR O
- O
delta O
and O
improve O
renal O
function O
in O
mice O
with O
hepatic O
steatosis O
. O

Loss O
of O
A O
( O
1 O
) O
adenosine B
receptor O
attenuates O
alpha B
- I
naphthylisothiocyana I
- O
induced O
cholestatic O
liver O
injury O
in O
mice O
. O

Cholestasis O
has O
limited O
therapeutic O
options O
and O
is O
associated O
with O
high O
morbidity O
and O
mortality O
. O

The O
A O
( O
1 O
) O
adenosine B
receptor O
( O
A O
( O
1 O
) O
AR O
) O
was O
postulated O
to O
participate O
in O
the O
pathogenesis O
of O
hepatic O
fibrosis O
induced O
by O
experimental O
extrahepatic O
cholestasis O
; O
however O
, O
the O
contribution O
of O
A O
( O
1 O
) O
AR O
to O
intrahepatic O
cholestatic O
liver O
injury O
remains O
unknown O
. O

Here O
, O
we O
found O
that O
mice O
lacking O
A O
( O
1 O
) O
AR O
were O
resistant O
to O
alpha B
- I
naphthyl I
isothiocyanate I
( O
ANIT B
) O
- O
induced O
liver O
injury O
, O
as O
evidenced O
by O
lower O
serum O
liver O
enzyme O
levels O
and O
reduced O
extent O
of O
histological O
necrosis O
. O

Bile B
acid I
accumulation O
in O
liver O
and O
serum O
was O
markedly O
diminished O
in O
A O
( O
1 O
) O
AR O
( O
- O
/ O
- O
) O
mice O
compared O
with O
wild O
- O
type O
( O
WT O
) O
mice O
. O

However O
, O
biliary O
and O
urinary O
outputs O
of O
bile B
acids I
were O
significantly O
enhanced O
in O
A O
( O
1 O
) O
AR O
( O
- O
/ O
- O
) O
mice O
. O

In O
the O
liver O
, O
mRNA O
expression O
of O
genes O
related O
to O
bile B
acid I
transport O
( O
Bsep O
and O
Mdr2 O
) O
and O
hydroxylation O
( O
Cyp3a11 O
) O
was O
increased O
in O
A O
( O
1 O
) O
AR O
( O
- O
/ O
- O
) O
mice O
. O

In O
the O
kidney O
, O
A O
( O
1 O
) O
AR O
deficiency O
prevented O
the O
decrease O
of O
glomerular O
filtration O
rate O
caused O
by O
ANIT O
. O

Treatment O
of O
WT O
mice O
with O
A O
( O
1 O
) O
AR O
antagonist O
DPCPX B
also O
protected O
against O
ANIT O
hepatotoxicity O
. O

Our O
results O
indicated O
that O
lack O
of O
A O
( O
1 O
) O
AR O
gene O
protects O
mice O
from O
ANIT O
- O
induced O
cholestasis O
by O
enhancing O
toxic O
biliary O
constituents O
efflux O
through O
biliary O
excretory O
route O
and O
renal O
elimination O
system O
and O
suggested O
a O
potential O
role O
of O
A O
( O
1 O
) O
AR O
as O
therapeutic O
target O
for O
the O
treatment O
of O
intrahepatic O
cholestasis O
. O

Methamphetamine B
- O
induced O
nitric B
oxide I
promotes O
vesicular O
transport O
in O
blood O
- O
brain O
barrier O
endothelial O
cells O
. O

Methamphetamine B
' O
s O
( O
METH B
) O
neurotoxicity O
is O
thought O
to O
be O
in O
part O
due O
to O
its O
ability O
to O
induce O
blood O
- O
brain O
barrier O
( O
BBB O
) O
dysfunction O
. O

Here O
, O
we O
investigated O
the O
effect O
of O
METH B
on O
barrier O
properties O
of O
cultured O
rat O
primary O
brain O
microvascular O
endothelial O
cells O
( O
BMVECs O
) O
. O

Transendothelial O
flux O
doubled O
in O
response O
to O
METH B
, O
irrespective O
of O
the O
size O
of O
tracer O
used O
. O

At O
the O
same O
time O
, O
transendothelial O
electrical O
resistance O
was O
unchanged O
as O
was O
the O
ultrastructural O
appearance O
of O
inter O
- O
endothelial O
junctions O
and O
the O
distribution O
of O
key O
junction O
proteins O
, O
suggesting O
that O
METH B
promoted O
vesicular O
but O
not O
junctional O
transport O
. O

Indeed O
, O
METH B
significantly O
increased O
uptake O
of O
horseradish O
peroxidase O
into O
vesicular O
structures O
. O

METH B
also O
enhanced O
transendothelial O
migration O
of O
lymphocytes O
indicating O
that O
the O
endothelial O
barrier O
against O
both O
molecules O
and O
cells O
was O
compromised O
. O

Barrier O
breakdown O
was O
only O
observed O
in O
response O
to O
METH B
at O
low O
micromolar O
concentrations O
, O
with O
enhanced O
vesicular O
uptake O
peaking O
at O
1 O
mu O
M O
METH B
. O

The O
BMVEC O
response O
to O
METH B
also O
involved O
rapid O
activation O
of O
endothelial O
nitric B
oxide I
synthase O
and O
its O
inhibition O
abrogated O
METH B
- O
induced O
permeability O
and O
lymphocyte O
migration O
, O
indicating O
that O
nitric B
oxide I
was O
a O
key O
mediator O
of O
BBB O
disruption O
in O
response O
to O
METH B
. O

This O
study O
underlines O
the O
key O
role O
of O
nitric B
oxide I
in O
BBB O
function O
and O
describes O
a O
novel O
mechanism O
of O
drug O
- O
induced O
fluid O
- O
phase O
transcytosis O
at O
the O
BBB O
. O

Centrally O
acting O
oximes B
in O
reactivation O
of O
tabun B
- O
phosphoramidated O
AChE O
. O

Organophosphates B
( O
OP O
) O
inhibit O
acetylcholinesterase O
( O
AChE O
, O
EC O
3 O
. O
1 O
. O
1 O
. O
7 O
) O
, O
both O
in O
peripheral O
tissues O
and O
central O
nervous O
system O
( O
CNS O
) O
, O
causing O
adverse O
and O
sometimes O
fatal O
effects O
due O
to O
the O
accumulation O
of O
neurotransmitter O
acetylcholine B
( O
ACh O
) O
. O

The O
currently O
used O
therapy O
, O
focusing O
on O
the O
reactivation O
of O
inhibited O
AChE O
, O
is O
limited O
to O
peripheral O
tissues O
because O
commonly O
used O
quaternary B
pyridinium I
oxime I
reactivators O
do O
not O
cross O
the O
blood O
brain O
barrier O
( O
BBB O
) O
at O
therapeutically O
relevant O
levels O
. O

A O
directed O
library O
of O
thirty O
uncharged O
oximes B
that O
contain O
tertiary B
amine I
or O
imidazole B
protonable O
functional O
groups O
that O
should O
cross O
the O
BBB O
as O
unionized O
species O
was O
tested O
as O
tabun B
- O
hAChE O
conjugate O
reactivators O
along O
with O
three O
reference O
oximes B
: O
DAM B
( O
diacetylmonoxime B
) O
, O
MINA B
( O
monoisonitrosoaceton B
) O
, O
and O
2 B
- I
PAM I
. O

The O
oxime B
RS150D B
[ O
N B
- I
( I
( I
1 I
- I
( I
3 I
- I
( I
2 I
- I
( I
( I
hydroxyimino I
) I
methyl I
) I
- I
1H I
- I
imidazol I
- I
1 I
- I
yl I
) I
propyl I
) I
- I
1H I
- I
1 I
, I
2 I
, I
3 I
- I
triazol I
- I
4 I
- I
yl I
) I
methyl I
) I
benzamide I
] O
was O
highlighted O
as O
the O
most O
promising O
reactivator O
of O
the O
tabun O
- O
hAChE O
conjugate O
. O

We O
also O
observed O
that O
oximes B
RS194B B
[ O
N B
- I
( I
2 I
- I
( I
azepan I
- I
1 I
- I
yl I
) I
ethyl I
) I
- I
2 I
- I
( I
hydroxyimino I
) I
acetamide I
] O
and O
RS41A B
[ O
2 B
- I
( I
hydroxyimino I
) I
- I
N I
- I
( I
2 I
- I
( I
pyrrolidin I
- I
1 I
- I
yl I
) I
ethyl I
) I
acetamide I
] O
, O
which O
emerged O
as O
lead O
uncharged O
reactivators O
of O
phosphylated O
hAChE O
with O
other O
OPs O
( O
sarin B
, O
cyclosarin B
and O
VX O
) O
, O
exhibited O
only O
moderate O
reactivation O

potency O
for O
tabun O
inhibited O
hAChE O
. O

This O
implies O
that O
geometry O
of O
oxime B
access O
to O
the O
phosphorus B
atom O
conjugated O
to O
the O
active O
serine B
is O
an O
important O
criterion O
for O
efficient O
reactivation O
, O
along O
with O
the O
chemical O
nature O
of O
the O
conjugated O
moiety O
: O
phosphorate B
, O
phosphonate B
, O
or O
phosphoramidate B
. O

Moreover O
, O
modification O
of O
the O
active O
center O
through O
mutagenesis O
enhances O
the O
rates O
of O
reactivation O
. O

The O
phosphoramidated B
- O
hAChE O
choline B
- O
binding O
site O
mutant O
Y337A O
showed O
three O
- O
times O
enhanced O
reactivation O
capacity O
with O
non O
- O
triazole B
imidazole I
containing O
aldoximes B
( O
RS113B O
, O
RS113A O
and O
RS115A O
) O
and O
acetamide B
derivative O
( O
RS194B B
) O
than O
with O
2PAM B
. O

Increased O
nuclear O
thioredoxin O
- O
1 O
potentiates O
cadmium B
- O
induced O
cytotoxicity O
. O

Cadmium B
( O
Cd B
) O
is O
a O
widely O
dispersed O
environmental O
agent O
that O
causes O
oxidative O
toxicity O
through O
mechanisms O
that O
are O
sensitive O
to O
thioredoxin O
- O
1 O
( O
Trx1 O
) O
. O

Trx1 O
is O
a O
cytoplasmic O
protein O
that O
translocates O
to O
nuclei O
during O
oxidative O
stress O
. O

Recent O
research O
shows O
that O
interaction O
of O
Trx1 O
with O
actin O
plays O
a O
critical O
role O
in O
cell O
survival O
and O
that O
increased O
nuclear O
Trx O
- O
1 O
potentiates O
proinflammatory O
signaling O
and O
death O
in O
cell O
and O
mouse O
models O
. O

These O
observations O
indicate O
that O
oxidative O
toxicity O
caused O
by O
low O
- O
dose O
Cd B
could O
involve O
disruption O
of O
actin O
- O
Trx1 O
interaction O
, O
nuclear O
Trx1 O
translocation O
, O
and O
potentiation O
of O
proinflammatory O
cell O
death O
mechanisms O
. O

In O
this O
study O
, O
we O
investigated O
the O
role O
of O
nuclei O
- O
localized O
Trx1 O
in O
Cd B
- O
induced O
inflammation O
and O
cytotoxicity O
using O
in O
vitro O
and O
in O
vivo O
models O
. O

The O
results O
show O
that O
Cd B
stimulated O
nuclear O
translocation O
of O
Trx1 O
and O
p65 O
of O
NF O
- O
kappa O
B O
. O

Elevation O
of O
Trx1 O
in O
nuclei O
in O
in O
vitro O
cells O
and O
kidney O
of O
transgenic O
mice O
potentiated O
Cd B
- O
stimulated O
NF O
- O
kappa O
B O
activation O
and O
cell O
death O
. O

Cd B
- O
stimulated O
Trx1 O
nuclear O
translocation O
and O
NF O
- O
kappa O
B O
activation O
were O
inhibited O
by O
cytochalasin B
D I
, O
an O
inhibitor O
of O
actin O
polymerization O
, O
suggesting O
that O
actin O
regulates O
Trx1 O
nuclear O
translocation O
and O
NF O
- O
kappa O
B O
activation O
by O
Cd B
. O

A O
nuclear O
- O
targeted O
dominant O
negative O
form O
of O
Trx1 O
blocked O
Cd B
- O
stimulated O
NF O
- O
kappa O
B O
activation O
and O
decreased O
cell O
death O
. O

Addition O
of O
zinc B
, O
known O
to O
antagonize O
Cd B
toxicity O
by O
increasing O
metallothionein O
, O
had O
no O
effect O
on O
Cd B
- O
stimulated O
nuclear O
translocation O
of O
Trx1 O
and O
NF O
- O
kappa O
B O
activation O
. O

Taken O
together O
, O
the O
results O
show O
that O
nuclear O
translocation O
and O
accumulation O
of O
redox O
- O
active O
Trx1 O
in O
nuclei O
play O
an O
important O
role O
in O
Cd B
- O
induced O
inflammation O
and O
cell O
death O
. O

The O
influence O
of O
pH O
on O
phosphatidylethanola B
monolayer O
at O
the O
air O
/ O
aqueous O
solution O
interface O
. O

The O
dependence O
of O
the O
interfacial O
tension O
of O
a O
phosphatidylethanola B
( O
PE O
) O
monolayer O
on O
the O
pH O
of O
the O
aqueous O
solution O
has O
been O
studied O
. O

A O
theoretical O
equation O
is O
derived O
to O
describe O
this O
dependence O
. O

A O
simple O
model O
of O
the O
influence O
of O
pH O
on O
the O
phosphatidylethanola B
monolayer O
at O
the O
air O
/ O
hydrophobic O
chains O
of O
PE O
is O
presented O
. O

The O
contributions O
of O
additive O
phosphatidylethanola B
forms O
( O
both O
interfacial O
tension O
values O
and O
molecular O
area O
values O
) O
depend O
on O
pH O
. O

The O
interfacial O
tension O
values O
and O
the O
molecular O
area O
values O
for O
PEH B
( I
+ I
) I
and O
PEOH B
( I
- I
) I
forms O
of O
phosphatidylethanola B
were O
calculated O
. O

The O
assumed O
model O
was O
verified O
experimentally O
. O

The O
experimental O
results O
agreed O
with O
those O
derived O
from O
the O
theoretical O
equation O
in O
a O
whole O
range O
of O
pH O
values O
. O

A O
new O
flavonoid B
and O
other O
polar O
compounds O
from O
Galeopsis O
angustifolia O
Ehrh O
. O

ex O
Hoffm O
. O

The O
analysis O
of O
the O
polar O
fraction O
of O
Galeopsis O
angustifolia O
Ehrh O
. O

ex O
Hoffm O
. O
indicates O
that O
the O
main O
components O
are O
iridoids B
and O
flavonoids B
. O

Six O
compounds O
were O
identified O
: O
a O
new O
flavonoid B
, O
3 B
' I
- I
hydroxy I
- I
isoscutellarein I
7 I
- I
O I
- I
[ I
6 I
' I
' I
' I
acetyl I
- I
beta I
- I
D I
- I
glucopyranosyl I
- I
( I
1 I
- I
- I
> I
2 I
) I
- I
beta I
- I
D I
- I
glucopyranoside I
] I
; O
three O
iridoid B
glucosides I
: O
harpagide B
, O
acetyl B
harpagide I
and O
for O
the O
first O
time O
in O
this O
species O
, O
8 B
- I
epi I
- I
loganin I
; O
two O
known O
acetylated B
flavonoid I
glycosides I
: O
3 B
' I
- I
hydroxy I
- I
4 I

' I
- I
O I
- I
methylisoscutellarei I
7 I
- I
O I
- I
[ I
6 I
' I
' I
' I
acetyl I
- I
beta I
- I
D I
- I
allopyranosyl I
- I
( I
1 I
- I
- I
> I
2 I
) I
- I
6 I
' I
' I
- I
acetyl I
- I
beta I
- I
D I
- I
glucopyranoside I
] O
, O
3 B
' I
- I
hydroxy I
- I
4 I
' I
- I
O I
- I
methylisoscutellarei I
7 I
- I
O I
- I
[ I
6 I
' I
' I
' I
acetyl I
- I
beta I
- I
D I
- I
allopyranosyl I
- I
( I
1 I
- I
- I
> I
2 I
) I
- I
beta I
- I
D I
- I
glucopyranoside I
] O
. O

Both O
flavonoids B
and O
iridoids B
are O
present O
in O
high O
amount O
; O
respectively O
, O
16 O
. O
7 O
% O
and O
4 O
. O
5 O
% O
of O
the O
crude O
extract O
. O

Pharmacological O
and O
dietary O
antioxidant O
therapies O
for O
chronic O
obstructive O
pulmonary O
disease O
. O

The O
progression O
and O
exacerbations O
of O
chronic O
obstructive O
pulmonary O
disease O
( O
COPD O
) O
are O
intimately O
associated O
with O
tobacco O
smoke O
/ O
biomass O
fuel O
- O
induced O
oxidative O
and O
aldehyde B
/ O
carbonyl B
stress O
. O

Alterations O
in O
redox O
signaling O
proinflammatory O
kinases O
and O
transcription O
factors O
, O
steroid O
resistance O
, O
unfolded O
protein O
response O
, O
mucus O
hypersecretion O
, O
extracellular O
matrix O
remodeling O
, O
autophagy O
/ O
apoptosis O
, O
epigenetic O
changes O
, O
cellular O
senescence O
/ O
aging O
, O
endothelial O
dysfunction O
, O
autoimmunity O
, O
and O
skeletal O
muscle O
dysfunction O
are O
some O
of O
the O
pathological O
hallmarks O
of O
COPD O
. O

In O
light O
of O
the O
above O
it O
would O
be O
prudent O
to O
target O
systemic O
and O
local O
oxidative O
stress O
with O
agents O
that O
can O
modulate O
the O
antioxidants O
/ O
redox O
system O
or O
by O
boosting O
the O
endogenous O
levels O
of O
antioxidants O
for O
the O
treatment O
and O
management O
of O
COPD O
. O

Identification O
of O
various O
antioxidant O
agents O
, O
such O
as O
thiol B
molecules O
( O
glutathione B
and O
mucolytic O
drugs O
, O
such O
as O
N B
- I
acetyl I
- I
Lcysteine I
, O
N B
- I
acystelyn I
, O
erdosteine B
, O
fudosteine B
, O
ergothioneine B
, O
and O
carbocysteine B
lysine I
salt I
) O
, O
dietary O
natural O
productderived O
polyphenols B
and O
other O
compounds O
( O
curcumin B
, O
resveratrol B
, O
green O
tea O
catechins B
, O
quercetin B
sulforaphane I
, O
lycopene B
, O

acai B
, O
alpha B
- I
lipoic I
acid I
, O
tocotrienols B
, O
and O
apocynin B
) O
have O
made O
it O
possible O
to O
modulate O
various O
biochemical O
aspects O
of O
COPD O
. O

Various O
researches O
and O
clinical O
trials O
have O
revealed O
that O
these O
antioxidants O
can O
detoxify O
free O
radicals O
and O
oxidants O
, O
control O
expression O
of O
redox O
and O
glutathione B
biosynthesis O
genes O
, O
chromatin O
remodeling O
, O
and O
ultimately O
inflammatory O
gene O
expression O
. O

In O
addition O
, O
modulation O
of O
cigarette O
smoke O
- O
induced O
oxidative O
stress O
and O
related O
cellular O
changes O
have O
also O
been O
reported O
to O
be O
effected O
by O
synthetic O
molecules O
. O

This O
includes O
specific O
spin O
traps O
like O
alpha B
- I
phenyl I
- I
N I
- I
tert I
- I
butyl I
nitrone I
, O
a O
catalytic O
antioxidant O
( O
ECSOD O
mimetic O
) O
, O
porphyrins B
( O
AEOL B
10150 I
and O
AEOL B
10113 I
) O
, O
and O
a O
superoxide B
dismutase O
mimetic O
M40419 B
, O
lipid O
peroxidation O
and O
protein O
carbonylation O
blockers O
/ O
inhibitors O
, O
such O
as O
edaravone B
and O
lazaroids B
/ O
tirilazad B
, O
myeloperoxidase O
inhibitors O
, O
as O
well O
as O
specialized O
pro O
- O
resolving O

mediators O
/ O
inflammatory O
resolving O
lipid O
mediators O
, O
omega B
- I
3 I
fatty I
acids I
, O
vitamin B
D I
, O
and O
hydrogen B
sulfide I
. O

According O
to O
various O
studies O
it O
appears O
that O
the O
administration O
of O
multiple O
antioxidants O
could O
be O
a O
more O
effective O
mode O
used O
in O
the O
treatment O
of O
COPD O
. O

In O
this O
review O
, O
various O
pharmacological O
and O
dietary O
approaches O
to O
enhance O
lung O
antioxidant O
levels O
and O
beneficial O
effects O
of O
antioxidant O
therapeutics O
in O
treating O
or O
intervening O
the O
progression O
of O
COPD O
have O
been O
discussed O
. O

A O
photochemical O
mechanism O
for O
homochirogenesis O
. O

Part O
2 O
. O

A O
theoretical O
investigation O
of O
the O
photochemistry O
of O
racemic O
compounds O
with O
circularly O
polarized O
light O
was O
undertaken O
. O

The O
exact O
solutions O
of O
the O
differential O
equations O
by O
numerical O
integration O
to O
the O
approximate O
solutions O
used O
in O
an O
earlier O
article O
were O
compared O
. O

The O
exact O
solutions O
showed O
that O
sequential O
reactions O
yield O
enhanced O
optical O
activities O
in O
the O
products O
. O

For O
irreversible O
reactions O
, O
all O
enantiomeric O
excesses O
are O
lost O
if O
the O
reactions O
are O
carried O
to O
completion O
, O
but O
appreciable O
resolution O
occurs O
in O
many O
cases O
for O
partial O
conversion O
. O

For O
reversible O
reactions O
, O
significant O
enantiomeric O
excesses O
are O
found O
at O
the O
photostationary O
state O
. O

Clear O
evidence O
of O
carcinogenic O
activity O
by O
a O
whole O
- O
leaf O
extract O
of O
Aloe O
barbadensis O
miller O
( O
aloe O
vera O
) O
in O
F344 O
/ O
N O
rats O
. O

Aloe O
barbadensis O
Miller O
( O
Aloe O
vera O
) O
is O
an O
herbal O
remedy O
promoted O
to O
treat O
a O
variety O
of O
illnesses O
; O
however O
, O
only O
limited O
data O
are O
available O
on O
the O
safety O
of O
this O
dietary O
supplement O
. O

Drinking O
water O
exposure O
of O
F344 O
/ O
N O
rats O
and O
B6C3F1 O
mice O
to O
an O
Aloe O
vera O
whole O
- O
leaf O
extract O
( O
1 O
, O
2 O
, O
and O
3 O
% O
) O
for O
13 O
weeks O
resulted O
in O
goblet O
cell O
hyperplasia O
of O
the O
large O
intestine O
in O
both O
species O
. O

Based O
upon O
this O
observation O
, O
2 O
- O
year O
drinking O
water O
studies O
were O
conducted O
to O
assess O
the O
carcinogenic O
potential O
of O
an O
Aloe O
vera O
whole O
- O
leaf O
extract O
when O
administered O
to O
F344 O
/ O
N O
rats O
( O
48 O
per O
sex O
per O
group O
) O
at O
0 O
. O
5 O
, O
1 O
, O
and O
1 O
. O
5 O
% O
, O
and O
B6C3F1 O
mice O
( O
48 O
per O
sex O
per O
group O
) O
at O
1 O
, O
2 O
, O
and O
3 O
% O
. O

Compared O
with O
controls O
, O
survival O
was O
decreased O
in O
the O
1 O
. O
5 O
% O
dose O
group O
of O
female O
rats O
. O

Treatment O
- O
related O
neoplasms O
and O
nonneoplastic O
lesions O
in O
both O
species O
were O
confined O
primarily O
to O
the O
large O
intestine O
. O

Incidences O
of O
adenomas O
and O
/ O
or O
carcinomas O
of O
the O
ileo O
- O
cecal O
and O
cecal O
- O
colic O
junction O
, O
cecum O
, O
and O
ascending O
and O
transverse O
colon O
were O
significantly O
higher O
than O
controls O
in O
male O
and O
female O
rats O
in O
the O
1 O
and O
1 O
. O
5 O
% O
dose O
groups O
. O

There O
were O
no O
neoplasms O
of O
the O
large O
intestine O
in O
mice O
or O
in O
the O
0 O
or O
0 O
. O
5 O
% O
dose O
groups O
of O
rats O
. O

Increased O
incidences O
of O
mucosa O
hyperplasia O
of O
the O
large O
intestine O
were O
observed O
in O
F344 O
/ O
N O
rats O
, O
and O
increased O
incidences O
of O
goblet O
cell O
hyperplasia O
of O
the O
large O
intestine O
occurred O
in O
B6C3F1 O
mice O
. O

These O
results O
indicate O
that O
Aloe O
vera O
whole O
- O
leaf O
extract O
is O
an O
intestinal O
irritant O
in O
F344 O
/ O
N O
rats O
and O
B6C3F1 O
mice O
and O
a O
carcinogen O
of O
the O
large O
intestine O
in O
F344 O
/ O
N O
rats O
. O

Advances O
in O
supramolecular O
electronics O
- O
from O
randomly O
self O
- O
assembled O
nanostructures O
to O
addressable O
self O
- O
organized O
interconnects O
. O

Supramolecular O
organic O
electronics O
rests O
on O
the O
use O
of O
bottom O
- O
up O
chemical O
self O
- O
assembly O
processes O
in O
order O
to O
design O
conducting O
components O
on O
the O
5 O
- O
100 O
nm O
scale O
. O

The O
challenges O
in O
this O
field O
are O
both O
the O
construction O
of O
1D O
- O
nanostructures O
displaying O
optimized O
transport O
properties O
and O
their O
precise O
connections O
to O
electrodes O
. O

The O
present O
Research O
News O
highlights O
important O
advances O
in O
such O
materials O
regarding O
their O
electrical O
performances O
, O
from O
semiconductors O
to O
organic O
metals O
, O
but O
also O
regarding O
their O
processability O
. O

In O
particular O
, O
by O
externally O
controlling O
light O
- O
responsive O
supramolecular O
polymerization O
processes O
, O
and O
by O
using O
appropriate O
methods O
of O
casting O
with O
an O
applied O
electric O
field O
, O
it O
becomes O
possible O
to O
pre O
- O
determine O
the O
accurate O
positioning O
of O
organic O
interconnects O
within O
patterned O
nano O
- O
circuitry O
. O

These O
strategies O
using O
external O
stimuli O
to O
obtain O
addressability O
, O
thus O
hold O
promising O
alternatives O
to O
other O
conducting O
materials O
such O
as O
carbon B
nanotubes O
for O
further O
technological O
applications O
in O
nanosciences O
. O

Recent O
developments O
in O
antimalarial O
natural O
products O
isolated O
from O
medicinal O
plants O
. O

Malaria O
is O
an O
infectious O
disease O
causing O
almost O
one O
million O
deaths O
each O
year O
. O

There O
is O
an O
urgent O
need O
for O
discovery O
of O
new O
antimalarial O
compounds O
. O

Natural O
products O
have O
been O
the O
single O
most O
productive O
source O
of O
leads O
for O
the O
development O
of O
drugs O
, O
because O
of O
their O
great O
variety O
of O
chemical O
structures O
. O

This O
review O
covers O
studies O
on O
antimalarial O
natural O
products O
isolated O
from O
plants O
, O
published O
from O
January O
2010 O
until O
April O
2012 O
. O

A O
total O
of O
171 O
structures O
comprising O
alkaloids O
, O
terpenoids B
, O
phenolics B
and O
other O
metabolites O
are O
listed O
in O
this O
review O
, O
including O
information O
on O
their O
antiplasmodial O
and O
cytotoxic O
activity O
. O

Four O
new O
coumarinolignoids B
from O
seeds O
of O
Solanum O
indicum O
. O

Activity O
- O
guided O
fractionation O
of O
seeds O
of O
Solanum O
indicum O
for O
anti O
- O
HBV O
activity O
led O
to O
the O
isolation O
of O
two O
novel O
coumarinolignoid B
alkaloids I
( O
indicumines B
A I
- I
B I
, O
1 O
- O
2 O
) O
and O
two O
new O
coumarinolignoids B
( O
indicumines B
C I
- I
D I
, O
3 O
- O
4 O
) O
, O
together O
with O
four O
known O
coumarins B
( O
5 O
- O
8 O
) O
. O

Their O
structures O
were O
established O
on O
the O
basis O
of O
spectroscopic O
data O
. O

The O
two O
novel O
coumarinolignoid B
alkaloids I
shows O
anti O
- O
HBV O
activities O
through O
specifically O
inhibiting O
the O
secretion O
of O
HBsAg O
in O
HepG2 O
. O
2 O
. O
15 O
. O

Relevance O
of O
non O
- O
guideline O
studies O
for O
risk O
assessment O
: O
the O
coverage O
model O
based O
on O
most O
frequent O
targets O
in O
repeated O
dose O
toxicity O
studies O
. O

A O
common O
challenge O
for O
human O
risk O
assessment O
is O
the O
quality O
of O
the O
available O
animal O
studies O
. O

Non O
- O
guideline O
studies O
are O
often O
limited O
for O
different O
aspects O
of O
study O
design O
and O
documentation O
. O

Within O
this O
publication O
the O
relevance O
of O
a O
limited O
scope O
of O
examination O
is O
discussed O
. O

Preliminary O
analyses O
of O
the O
RepDose O
database O
have O
shown O
that O
liver O
, O
body O
weight O
, O
kidney O
and O
clinical O
symptoms O
are O
frequently O
affected O
in O
oral O
repeated O
dose O
toxicity O
in O
rats O
and O
mice O
( O
Bitsch O
et O
al O
. O
, O
2006 O
) O
, O
while O
many O
other O
targets O
are O
seldom O
affected O
. O

As O
most O
of O
these O
targets O
are O
investigated O
frequently O
also O
in O
non O
- O
guideline O
studies O
, O
it O
is O
likely O
that O
they O
provide O
a O
reliable O
NOEL O
, O
although O
the O
full O
spectrum O
of O
endpoints O
has O
not O
been O
covered O
. O

Based O
on O
RepDose O
data O
we O
investigate O
the O
relevance O
of O
individual O
targets O
for O
determining O
the O
LOEL O
and O
the O
consequences O
for O
risk O
assessment O
. O

The O
resulting O
coverage O
model O
for O
subchronic O
oral O
rat O
studies O
includes O
up O
to O
six O
targets O
and O
an O
additional O
assessment O
factor O
for O
LOEL O
extrapolation O
. O

It O
can O
be O
applied O
to O
assess O
the O
reliability O
of O
non O
- O
guideline O
studies O
with O
respect O
to O
the O
scope O
of O
examination O
. O

Furthermore O
the O
application O
of O
the O
coverage O
model O
to O
other O
databases O
will O
increase O
and O
/ O
or O
specify O
the O
chemical O
domain O
and O
reveal O
respective O
targets O
as O
well O
as O
effects O
. O

Molecular O
characterization O
of O
355 O
mucopolysaccharidosi O
patients O
reveals O
104 O
novel O
mutations O
. O

Mucopolysaccharidosi O
( O
MPS O
) O
disorders O
are O
heterogeneous O
and O
caused O
by O
deficient O
lysosomal O
degradation O
of O
glycosaminoglycans O
, O
resulting O
in O
distinct O
but O
sometimes O
overlapping O
phenotypes O
. O

Molecular O
analysis O
was O
performed O
for O
a O
total O
of O
355 O
MPS O
patients O
with O
MPSI O
( O
n O
= O
15 O
) O
, O
MPSII O
( O
n O
= O
218 O
) O
, O
MPSIIIA O
( O
n O
= O
86 O
) O
, O
MPSIIIB O
( O
n O
= O
20 O
) O
, O
MPSIVA O
( O
n O
= O
6 O
) O
or O
MPSVI O
( O
n O
= O
10 O
) O
. O

This O
analysis O
revealed O
104 O
previously O
unreported O
mutations O
: O
seven O
in O
IDUA O
( O
MPSI O
) O
, O
61 O
in O
IDS O
( O
MPSII O
) O
, O
19 O
in O
SGSH O
( O
MPSIIIA O
) O
, O
11 O
in O
NAGLU O
( O
MPSIIIB O
) O
, O
two O
in O
GALNS O
( O
MPSIVA O
) O
and O
four O
in O
ARSB O
( O
MPSVI O
) O
. O

The O
intergenic O
comparison O
of O
the O
mutation O
data O
for O
these O
disorders O
has O
revealed O
interesting O
differences O
. O

Whereas O
IDUA O
, O
IDS O
, O
NAGLU O
and O
ARSB O
demonstrate O
similar O
levels O
of O
mutation O
heterogeneity O
( O
0 O
. O
6 O
- O
0 O
. O
675 O
different O
mutations O
per O
total O
alleles O
) O
, O
SGSH O
and O
GALNS O
have O
lower O
levels O
of O
mutation O
heterogeneity O
( O
0 O
. O
282 O
and O
0 O
. O
455 O
, O
respectively O
) O
, O
due O
to O
more O
recurrent O
mutations O
. O

The O
type O
of O
mutation O
also O
varies O
significantly O
by O
gene O
. O

SGSH O
, O
GALNS O
and O
ARSB O
mutations O
are O
usually O
missense O
( O
76 O
. O
5 O
% O
, O
81 O
. O
8 O
% O
and O
85 O
% O
) O
, O
while O
IDUA O
has O
many O
more O
nonsense O
mutations O
( O
56 O
% O
) O
than O
the O
other O
genes O
( O
< O
= O
20 O
% O
) O
. O

The O
mutation O
spectrum O
is O
most O
diverse O
for O
IDS O
, O
including O
intergenic O
inversions O
and O
multi O
- O
exon O
deletions O
. O

By O
testing O
102 O
mothers O
of O
MPSII O
patients O
, O
we O
determined O
that O
22 O
. O
5 O
% O
of O
IDS O
mutations O
are O
de O
novo O
. O

We O
report O
the O
allele O
frequency O
of O
common O
mutations O
for O
each O
gene O
in O
our O
patient O
cohort O
and O
the O
exonic O
distribution O
of O
coding O
sequence O
alterations O
in O
the O
IDS O
, O
SGSH O
and O
NAGLU O
genes O
, O
which O
reveals O
several O
potential O
" O
hot O
- O
spots O
" O
. O

This O
further O
molecular O
characterization O
of O
these O
MPS O
disorders O
is O
expected O
to O
assist O
in O
the O
diagnosis O
and O
counseling O
of O
future O
patients O
. O

The O
role O
of O
residues O
T248 O
, O
Y249 O
and O
T422 O
in O
the O
function O
of O
human O
pregnane B
X O
receptor O
. O

The O
pregnane O
X O
receptor O
( O
PXR O
) O
is O
a O
key O
xenobiotic O
receptor O
that O
regulates O
the O
expression O
of O
numerous O
drug O
- O
metabolizing O
enzymes O
. O

Some O
posttranslational O
mechanisms O
modulate O
its O
transcriptional O
activity O
. O

Although O
several O
kinases O
have O
been O
shown O
to O
directly O
phosphorylate O
this O
receptor O
, O
little O
is O
known O
about O
phosphorylation O
sites O
of O
PXR O
. O

In O
the O
present O
work O
, O
we O
examined O
T248 O
, O
Y249 O
and O
T422 O
putative O
phosphorylation O
sites O
determined O
based O
on O
in O
silico O
consensus O
kinase O
site O
prediction O
analysis O
. O

T248 O
and O
T422 O
residues O
are O
critical O
for O
the O
interaction O
of O
the O
PXR O
ligand O
- O
binding O
domain O
and O
the O
activation O
function O
- O
2 O
( O
AF2 O
) O
domain O
. O

Site O
- O
directed O
mutagenesis O
analysis O
was O
performed O
to O
generate O
phospho B
- O
deficient O
and O
phospho B
- O
mimetic O
mutants O
. O

We O
examined O
transactivation O
activity O
of O
the O
PXR O
mutants O
in O
gene O
reporter O
assays O
, O
formation O
of O
PXRmutant O
/ O
RXR O
alpha O
heterodimer O
, O
binding O
of O
PXR O
mutants O
to O
the O
CYP3A4 O
gene O
response O
element O
DR3 O
and O
CYP3A4 O
expression O
in O
HepG2 O
cells O
after O
expression O
of O
the O
mutants O
. O

We O
found O
that O
T248D O
mutant O
activated O
CYP3A4 O
transactivation O
constitutively O
regardless O
of O
the O
presence O
or O
absence O
of O
a O
ligand O
. O

Contrary O
, O
T248V O
mutant O
exhibited O
low O
basal O
and O
ligand O
- O
inducible O
transactivation O
capacity O
as O
compared O
to O
wild O
- O
type O
PXR O
. O

Dose O
- O
response O
analysis O
revealed O
reduced O
ligand O
- O
dependent O
transactivation O
potency O
of O
PXR O
Y249D O
mutant O
. O

Transactivation O
of O
the O
CYP3A4 O
promoter O
was O
abolished O
with O
T422A O
/ O
D O
mutants O
. O

All O
PXR O
mutants O
formed O
heterodimer O
with O
RXR O
alpha O
at O
a O
similar O
level O
to O
that O
observed O
with O
wild O
- O
type O
PXR O
. O

The O
ability O
to O
bind O
to O
DNA O
in O
vitro O
was O
substantially O
decreased O
in O
case O
of O
T248D O
, O
T422D O
and O
T248V O
mutants O
. O

Our O
data O
thus O
indicate O
that O
phosphorylation O
of O
T248 O
, O
Y249 O
and O
T422 O
residues O
may O
be O
critical O
for O
the O
both O
basal O
and O
ligand O
- O
activated O
function O
of O
PXR O
. O

Circadian O
rhythm O
of O
salivary O
cortisol B
in O
infants O
with O
congenital O
heart O
disease O
. O

Children O
with O
congenital O
heart O
disease O
( O
CHD O
) O
have O
associated O
extracardiac O
co O
- O
morbidities O
at O
the O
time O
of O
surgery O
and O
during O
ongoing O
growth O
and O
development O
. O

Perioperative O
events O
include O
disrupted O
glucose B
homeostasis O
, O
capillary O
leak O
, O
and O
fluid O
retention O
. O

The O
hypothalamic O
- O
pituitary O
- O
adrenal O
( O
HPA O
) O
axis O
has O
an O
important O
role O
in O
homeostasis O
in O
that O
the O
secretion O
of O
cortisol B
contributes O
to O
the O
response O
to O
stress O
, O
glucose B
regulation O
, O
blood O
volume O
control O
, O
and O
immune O
regulation O
. O

We O
investigated O
the O
diurnal O
rhythm O
of O
the O
HPA O
axis O
in O
infants O
with O
CHD O
by O
measuring O
salivary O
cortisol B
in O
the O
morning O
( O
0600 O
- O
0900 O
h O
- O
circadian O
peak O
) O
and O
evening O
( O
2100 O
- O
2400 O
h O
- O
circadian O
nadir O
) O
. O

Twenty O
- O
nine O
infants O
aged O
12 O
weeks O
to O
1 O
year O
were O
included O
: O
16 O
with O
acyanotic O
disease O
( O
SpO O
( O
2 O
) O
> O
= O
90 O
% O
) O
and O
13 O
with O
cyanotic O
disease O
( O
SpO2 O
< O
90 O
% O
) O
. O

Morning O
salivary O
cortisol B
was O
similar O
between O
the O
two O
groups O
[ O
acyanotic O
7 O
. O
0 O
nmol O
/ O
L O
( O
1 O
. O
8 O
- O
23 O
. O
1 O
) O
; O
cyanotic O
9 O
. O
7 O
nmol O
/ O
L O
( O
0 O
. O
9 O
- O
15 O
. O
6 O
) O
; O
p O
= O
0 O
. O
68 O
] O
. O

Evening O
salivary O
cortisol B
was O
similar O
between O
the O
two O
groups O
[ O
acyanotic O
0 O
. O
9 O
nmol O
/ O
L O
( O
0 O
. O
2 O
- O
8 O
. O
5 O
) O
; O
cyanotic O
1 O
. O
4 O
nmol O
/ O
L O
( O
0 O
. O
5 O
- O
14 O
. O
9 O
) O
; O
p O
= O
0 O
. O
32 O
] O
. O

Both O
cyanotic O
and O
acyanotic O
groups O
demonstrated O
an O
intact O
diurnal O
rhythm O
. O

In O
conclusion O
, O
chronic O
hypoxia O
secondary O
to O
cyanotic O
CHD O
does O
not O
affect O
the O
circadian O
rhythm O
of O
the O
HPA O
axis O
. O

By O
12 O
weeks O
of O
age O
, O
infants O
with O
hypoxia O
secondary O
to O
cyanotic O
CHD O
have O
a O
normal O
cortisol B
diurnal O
rhythm O
. O

Brain O
involvement O
in O
glaucoma O
: O
advanced O
neuroimaging O
for O
understanding O
and O
monitoring O
a O
new O
target O
for O
therapy O
. O

On O
the O
basis O
of O
a O
large O
body O
of O
experimental O
data O
the O
notion O
that O
glaucoma O
damages O
retinal B
ganglion O
cells O
and O
central O
areas O
of O
the O
visual O
system O
has O
been O
put O
forward O
. O

The O
mechanisms O
underlying O
glaucomatous O
involvement O
of O
the O
central O
areas O
are O
not O
known O
: O
the O
most O
likely O
hypothesis O
is O
that O
this O
event O
is O
the O
result O
of O
an O
anterograde O
transynaptic O
neurodegeneration O
triggered O
by O
ganglion O
cells O
' O
death O
. O

However O
, O
it O
is O
possible O
that O
in O
some O
cases O
it O
may O
be O
the O
consequence O
of O
a O
neurodegenerative O
disease O
of O
the O
central O
nervous O
system O
. O

In O
any O
event O
, O
novel O
mechanisms O
leading O
to O
cell O
demise O
might O
be O
implicated O
. O

The O
development O
of O
powerful O
neuroimaging O
techniques O
in O
conjunction O
with O
sophisticated O
analysis O
has O
recently O
provided O
compelling O
support O
to O
the O
involvement O
of O
central O
stations O
of O
the O
visual O
pathway O
in O
patients O
suffering O
of O
glaucoma O
. O

Diffusion O
Tensor O
- O
MRI O
allows O
the O
central O
damage O
associated O
with O
glaucoma O
to O
be O
assessed O
and O
therapeutic O
efficacy O
of O
novel O
neuroprotective O
interventions O
to O
be O
quantified O
. O

Peptide O
reactivity O
assay O
using O
spectrophotometric O
method O
for O
high O
- O
throughput O
screening O
of O
skin O
sensitization O
potential O
of O
chemical O
haptens O
. O

Haptens O
must O
react O
with O
cellular O
proteins O
to O
be O
recognized O
by O
antigen O
presenting O
cells O
. O

Therefore O
, O
monitoring O
reactivity O
of O
chemicals O
with O
peptide O
/ O
protein O
has O
been O
considered O
an O
in O
vitro O
skin O
sensitization O
testing O
method O
. O

The O
reactivity O
of O
peptides O
with O
chemicals O
( O
peptide O
reactivity O
) O
has O
usually O
been O
monitored O
by O
chromatographic O
methods O
like O
HPLC O
or O
LC O
/ O
MS O
, O
which O
are O
robust O
tools O
for O
monitoring O
common O
chemical O
reactions O
but O
are O
rather O
expensive O
and O
time O
consuming O
. O

Here O
, O
we O
examined O
the O
possibility O
of O
using O
spectrophotometric O
methods O
to O
monitor O
peptide O
reactivity O
. O

Two O
synthetic O
peptides O
, O
Ac O
- O
RWAACAA O
and O
Ac O
- O
RWAAKAA O
, O
were O
reacted O
with O
48 O
chemicals O
( O
34 O
sensitizers O
and O
14 O
non O
- O
sensitizers O
) O
. O

Peptide O
reactivity O
was O
measured O
by O
monitoring O
unreacted O
peptides O
with O
UV O
- O
Vis O
spectrophotometer O
using O
5 B
, I
5 I
' I
- I
dithiobis I
- I
2 I
- I
nitrobenzoic I
acid I
as O
a O
detection O
reagent O
for O
the O
free O
thiol B
group O
of O
cysteine B
- O
containing O
peptide O
or O
fluorometer O
using O
fluorescamine B
( O
TM O
) O
as O
a O
detection O
reagent O
for O
the O
free O
amine B
group O
of O
lysine B
- O
containing O
peptide O
. O

Chemicals O
were O
categorized O
as O
sensitizers O
when O
they O
induced O
more O
than O
10 O
% O
depletion O
of O
cysteine B
- O
containing O
peptide O
or O
20 O
% O
depletion O
of O
lysine B
- O
containing O
peptide O
. O

The O
sensitivity O
, O
specificity O
, O
and O
accuracy O
of O
this O
method O
were O
82 O
. O
4 O
% O
, O
85 O
. O
7 O
% O
, O
and O
83 O
. O
3 O
% O
, O
respectively O
. O

These O
results O
demonstrate O
that O
spectrophotometric O
methods O
can O
be O
easy O
, O
fast O
, O
and O
high O
- O
throughput O
screening O
tools O
for O
the O
prediction O
of O
the O
skin O
sensitization O
potential O
of O
chemical O
haptens O
. O

Biomarkers O
of O
Parkinson O
' O
s O
disease O
: O
current O
status O
and O
future O
perspectives O
. O

This O
review O
summarizes O
major O
advances O
in O
biomarker O
discovery O
for O
diagnosis O
, O
differential O
diagnosis O
and O
progression O
of O
Parkinson O
' O
s O
disease O
( O
PD O
) O
, O
with O
emphasis O
on O
neuroimaging O
and O
biochemical O
markers O
. O

Potential O
strategies O
to O
develop O
biomarkers O
capable O
of O
predicting O
PD O
in O
the O
prodromal O
stage O
before O
the O
appearance O
of O
motor O
symptoms O
or O
correlating O
with O
nonmotor O
symptoms O
, O
an O
active O
area O
of O
research O
, O
are O
also O
discussed O
. O

Leukotriene B
D4 I
induces O
cognitive O
impairment O
through O
enhancement O
of O
CysLT O
1 O
R O
- O
mediated O
amyloid O
- O
beta O
generation O
in O
mice O
. O

Amyloid O
plaques O
in O
the O
extracellular O
parenchyma O
mainly O
consist O
of O
amyloid O
- O
beta O
peptides O
( O
A O
beta O
) O
, O
one O
of O
the O
pathological O
hallmarks O
in O
Alzheimer O
' O
s O
disease O
( O
AD O
) O
. O

In O
the O
present O
study O
, O
we O
examined O
neuroinflammation O
, O
amyloidogenesis O
, O
and O
memory O
performance O
following O
intracerebral O
infusions O
of O
leukotriene B
D4 I
( O
LTD4 B
) O
in O
mice O
. O

The O
results O
demonstrated O
that O
intracerebral O
infusions O
of O
LTD4 B
( O
1 O
ng O
/ O
mouse O
) O
produced O
memory O
impairment O
as O
determined O
by O
Morris O
water O
maze O
test O
and O
Y O
- O
maze O
test O
in O
mice O
, O
and O
caused O
the O
accumulation O
of O
A O
beta O
1 O
- O
40 O
and O
A O
beta O
1 O
- O
42 O
in O
the O
hippocampus O
and O
cortex O
through O
increased O
activity O
of O
beta O
- O
and O
gamma O
- O
secretases O
accompanied O
with O
increased O
expression O
of O
amyloid O
precursor O
protein O
( O
APP O
) O
. O

LTD4 B
also O
induced O
expression O
of O
cysteinyl B
leukotriene B
receptor O
1 O
( O
CysLT O
( O
1 O
) O
R O
) O
and O
NF O
- O
kappa O
B O
p65 O
in O
the O
hippocampus O
and O
cortex O
. O

Pretreatment O
with O
pranlukast B
( O
1 O
. O
5 O
ng O
/ O
mouse O
, O
intracerebroventricu O
) O
, O
a O
CysLT O
( O
1 O
) O
R O
antagonist O
, O
blocked O
LTD4 O
- O
induced O
amyloidogenesis O
, O
memory O
deficits O
. O

Pranlukast B
( O
0 O
. O
6 O
mu O
M O
) O
also O
prevented O
LTD4 O
( O
20 O
nM O
) O
- O
induced O
amyloidogenesis O
in O
the O
cultured O
neurons O
in O
vitro O
. O

Moreover O
, O
LTD4 B
- O
induced O
increases O
in O
CysLT O
( O
1 O
) O
R O
and O
NF O
- O
kappa O
B O
p65 O
in O
the O
brain O
were O
also O
attenuated O
by O
pranlukast B
. O

These O
results O
suggest O
that O
LTD4 B
increases O
A O
beta O
peptide O
burden O
via O
activation O
of O
CysLT O
( O
1 O
) O
R O
, O
which O
further O
affects O
APP O
levels O
and O
activity O
of O
beta O
- O
and O
gamma O
- O
secretases O
via O
the O
NF O
- O
kappa O
B O
pathway O
. O

Our O
findings O
identify O
CysLT O
( O
1 O
) O
R O
signaling O
as O
a O
novel O
proinflammatory O
and O
proamyloidogenic O
pathway O
, O
and O
suggest O
a O
rationale O
for O
development O
of O
therapeutics O
targeting O
the O
CysLT O
( O
1 O
) O
R O
in O
neuroinflammatory O
diseases O
such O
as O
AD O
. O

Comparative O
gene O
expression O
profiling O
in O
human O
- O
induced O
pluripotent O
stem O
cell O
- O
- O
derived O
cardiocytes O
and O
human O
and O
cynomolgus O
heart O
tissue O
. O

Cardiotoxicity O
is O
one O
of O
the O
leading O
causes O
of O
drug O
attrition O
. O

Current O
in O
vitro O
models O
insufficiently O
predict O
cardiotoxicity O
, O
and O
there O
is O
a O
need O
for O
alternative O
physiologically O
relevant O
models O
. O

Here O
we O
describe O
the O
gene O
expression O
profile O
of O
human O
- O
induced O
pluripotent O
stem O
cell O
- O
derived O
cardiocytes O
( O
iCC O
) O
postthaw O
over O
a O
period O
of O
42 O
days O
in O
culture O
and O
compare O
this O
profile O
to O
human O
fetal O
and O
adult O
as O
well O
as O
adult O
cynomolgus O
nonhuman O
primate O
( O
NHP O
, O
Macaca O
fascicularis O
) O
heart O
tissue O
. O

Our O
results O
indicate O
that O
iCC O
express O
relevant O
cardiac O
markers O
such O
as O
ion O
channels O
( O
SCN5A O
, O
KCNJ2 O
, O
CACNA1C O
, O
KCNQ1 O
, O
and O
KCNH2 O
) O
, O
tissue O
- O
specific O
structural O
markers O
( O
MYH6 O
, O
MYLPF O
, O
MYBPC3 O
, O
DES O
, O
TNNT2 O
, O
and O
TNNI3 O
) O
, O
and O
transcription O
factors O
( O
NKX2 O
. O
5 O
, O
GATA4 O
, O
and O
GATA6 O
) O
and O
lack O
the O
expression O
of O
stem O
cell O
markers O
( O
FOXD3 O
, O
GBX2 O
, O
NANOG O
, O

POU5F1 O
, O
SOX2 O
, O
and O
ZFP42 O
) O
. O

Furthermore O
, O
we O
performed O
a O
functional O
evaluation O
of O
contractility O
of O
the O
iCC O
and O
showed O
functional O
and O
pharmacological O
correlations O
with O
myocytes O
isolated O
from O
adult O
NHP O
hearts O
. O

These O
results O
suggest O
that O
stem O
cell O
- O
derived O
cardiocytes O
may O
represent O
a O
novel O
in O
vitro O
model O
to O
study O
human O
cardiac O
toxicity O
with O
potential O
ex O
vivo O
and O
in O
vivo O
translation O
. O

A O
modern O
in O
vivo O
pharmacokinetic O
paradigm O
: O
combining O
snapshot O
, O
rapid O
and O
full O
PK O
approaches O
to O
optimize O
and O
expedite O
early O
drug O
discovery O
. O

Successful O
drug O
discovery O
relies O
on O
the O
selection O
of O
drug O
candidates O
with O
good O
in O
vivo O
pharmacokinetic O
( O
PK O
) O
properties O
as O
well O
as O
appropriate O
preclinical O
efficacy O
and O
safety O
profiles O
. O

In O
vivo O
PK O
profiling O
is O
often O
a O
bottleneck O
in O
the O
discovery O
process O
. O

In O
this O
review O
, O
we O
focus O
on O
the O
tiered O
in O
vivo O
PK O
approaches O
implemented O
at O
the O
Genomics O
Institute O
of O
the O
Novartis O
Research O
Foundation O
( O
GNF O
) O
, O
which O
includes O
snapshot O
PK O
, O
rapid O
PK O
and O
full O
PK O
studies O
. O

These O
in O
vivo O
PK O
approaches O
are O
well O
integrated O
within O
discovery O
research O
, O
allow O
tremendous O
flexibility O
and O
are O
highly O
efficient O
in O
supporting O
the O
diverse O
needs O
and O
increasing O
demand O
for O
in O
vivo O
profiling O
. O

The O
tiered O
in O
vivo O
PK O
studies O
expedite O
compound O
profiling O
and O
help O
guide O
the O
selection O
of O
more O
desirable O
compounds O
into O
efficacy O
models O
and O
for O
progression O
into O
development O
. O

Enhancement O
of O
social O
novelty O
discrimination O
by O
positive O
allosteric O
modulators O
at O
metabotropic O
glutamate B
5 O
receptors O
: O
adolescent O
administration O
prevents O
adult O
- O
onset O
deficits O
induced O
by O
neonatal O
treatment O
with O
phencyclidine B
. O

Metabotropic O
glutamate B
- O
5 O
receptors O
( O
mGluR5 O
) O
, O
which O
physically O
and O
functionally O
interact O
with O
N B
- I
methyl I
- I
D I
- I
Aspartate I
( O
NMDA B
) O
receptors O
, O
likewise O
control O
cognitive O
processes O
and O
have O
been O
proposed O
as O
targets O
for O
novel O
classes O
of O
antipsychotic O
agent O
. O

Since O
social O
cognition O
is O
impaired O
in O
schizophrenia O
and O
disrupted O
by O
NMDA B
receptor O
antagonists O
like O
dizocilpine B
, O
we O
evaluated O
its O
potential O
modulation O
by O
mGluR5 O
. O

Acute O
administration O
( O
0 O
. O
63 O
- O
40 O
mg O
/ O
kg O
) O
of O
the O
mGluR5 O
positive O
allosteric O
modulators O
( O
PAMs O
) O
, O
3 B
- I
cyano I
- I
N I
- I
( I
1 I
, I
3 I
- I
diphenyl I
- I
1H I
- I
pyrazol I
- I
5 I
- I
yl I
) I
benzamide I
( O
CDPPB B
) O
and O
ADX47273 B
, O
reversed O
a O
delay O
- O
induced O
impairment O
in O
social O
novelty O
discrimination O
( O
SND O
) O
in O
adult O
rats O
. O

The O
action O
of O
CDPPB B
was O
blocked O
by O
the O
mGluR5 O
antagonist O
, O
2 B
- I
methyl I
- I
6 I
- I
( I
phenylethynyl I
) I
- I
pyridine I
( O
2 O
. O
5 O
- O
10 O
mg O
/ O
kg O
) O
, O
and O
was O
also O
expressed O
upon O
microinjection O
into O
frontal O
cortex O
( O
0 O
. O
63 O
- O
10 O
mu O
g O
/ O
side O
) O
, O
but O
not O
striatum O
. O

Supporting O
an O
interrelationship O
between O
mGluR5 O
and O
NMDA B
receptors O
, O
enhancement O
of O
SND O
by O
CDPPB B
was O
blocked O
by O
dizocilpine B
( O
0 O
. O
08 O
mg O
/ O
kg O
) O
while O
, O
reciprocally O
, O
dizocilpine B
- O
induced O
impairment O
in O
SND O
was O
attenuated O
by O
CDPPB B
( O
10 O
mg O
/ O
kg O
) O
. O

The O
SND O
deficit O
elicited O
by O
post O
- O
natal O
administration O
of O
phencyclidine B
( O
10 O
mg O
/ O
kg O
, O
days O
7 O
- O
11 O
) O
was O
reversed O
by O
CDPPB B
or O
ADX47273 B
in O
adults O
at O
week O
8 O
. O

This O
phencyclidine B
- O
induced O
impairment O
in O
cognition O
emerged O
in O
adult O
rats O
from O
week O
7 O
on O
, O
and O
chronic O
, O
pre O
- O
symptomatic O
treatment O
of O
adolescent O
rats O
with O
CDPPB B
over O
weeks O
5 O
- O
6 O
( O
10 O
mg O
/ O
kg O
per O
day O
) O
prevented O
the O
appearance O
of O
SND O
deficits O
in O
adults O
until O
at O
least O
week O
13 O
. O

In O
conclusion O
, O
as O
evaluated O
by O
a O
SND O
procedure O
, O
mGluR5 O
PAMs O
promote O
social O
cognition O
via O
actions O
expressed O
in O
interaction O
with O
NMDA B
receptors O
and O
exerted O
in O
frontal O
cortex O
. O

MGluR5 O
PAMs O
not O
only O
reverse O
but O
also O
( O
when O
given O
during O
adolescence O
) O
prevent O
the O
emergence O
of O
cognitive O
impairment O
associated O
with O
a O
developmental O
model O
of O
schizophrenia O
. O

Swim O
training O
of O
monosodium B
L I
- I
glutamate I
- O
obese O
mice O
improves O
the O
impaired O
insulin O
receptor O
tyrosine B
phosphorylation O
in O
pancreatic O
islets O
. O

The O
goal O
of O
the O
present O
study O
was O
to O
investigate O
changes O
on O
glucose B
homoeostasis O
and O
of O
the O
insulin O
receptor O
( O
IR O
) O
and O
insulin O
receptor O
substrate O
- O
1 O
( O
IRS O
- O
1 O
) O
signalling O
in O
pancreatic O
islets O
from O
MSG O
- O
obese O
mice O
submitted O
to O
or O
not O
submitted O
to O
swim O
training O
. O

Swim O
training O
of O
90 O
- O
day O
- O
old O
MSG O
mice O
was O
used O
to O
evaluate O
whether O
signalling O
pathways O
of O
the O
IR O
and O
IRS O
- O
1 O
in O
islets O
are O
involved O
with O
the O
insulin O
resistance O
and O
glucose B
intolerance O
observed O
in O
this O
obese O
animal O
model O
. O

The O
results O
showed O
that O
IR O
tyrosine B
phosphorylation O
( O
pIR O
) O
was O
reduced O
by O
42 O
% O
in O
MSG O
- O
obese O
mice O
( O
MSG O
, O
6 O
. O
7 O
+ O
/ O
- O
0 O
. O
2 O
arbitrary O
units O
( O
a O
. O
u O
. O
) O
; O
control O
, O
11 O
. O
5 O
+ O
/ O
- O
0 O
. O
4 O
a O
. O
u O
. O
) O
; O
on O
the O
other O
hand O
, O
exercise O
training O
increased O
pIR O
by O
76 O
% O
in O
MSG O
mice O
without O
affecting O
control O
mice O
( O
MSG O
, O
11 O
. O
8 O
+ O
/ O
- O
0 O
. O
3 O
; O
control O
, O
12 O
. O
8 O
+ O
/ O
- O
0 O
. O
2 O
a O
. O
u O
. O
) O
. O

Although O
the O
treatment O
with O
MSG B
increased O
IRS O
- O
1 O
tyrosine B
phosphorylation O
( O
pIRS O
- O
1 O
) O
by O
96 O
% O
( O
MSG B
, O
17 O
. O
02 O
+ O
/ O
- O
0 O
. O
6 O
; O
control O
, O
8 O
. O
7 O
+ O
/ O
- O
0 O
. O
2 O
a O
. O
u O
. O
) O
, O
exercise O
training O
also O
increased O
it O
in O
both O
groups O
( O
control O
, O
13 O
. O
6 O
+ O
/ O
- O
0 O
. O
1 O
; O
MSG B
, O
22 O
. O
2 O
+ O
/ O
- O
1 O
. O
1 O
a O
. O
u O
. O
) O
. O

Current O
research O
shows O
that O
the O
practice O
of O
swim O
training O
increases O
the O
tyrosine B
phosphorylation O
of O
IRS O
- O
1 O
which O
can O
modulate O
the O
effect O
caused O
by O
obesity O
in O
insulin O
receptors O
. O

Juvenile O
hormone O
levels O
reflect O
social O
opportunities O
in O
the O
facultatively O
eusocial O
sweat O
bee O
Megalopta O
genalis O
( O
Hymenoptera O
: O
Halictidae O
) O
. O

The O
evolution O
of O
eusociality O
is O
hypothesized O
to O
have O
involved O
de O
- O
coupling O
parental O
care O
from O
reproduction O
mediated O
by O
changes O
in O
endocrine O
regulation O
. O

While O
data O
for O
obligately O
eusocial O
insects O
are O
consistent O
with O
this O
hypothesis O
, O
we O
lack O
information O
from O
species O
representative O
of O
the O
transition O
from O
solitary O
reproduction O
to O
eusociality O
. O

Here O
we O
report O
the O
first O
evidence O
for O
a O
link O
between O
endocrine O
processes O
and O
social O
behavior O
in O
a O
facultatively O
eusocial O
bee O
, O
Megalopta O
genalis O
( O
Halictidae O
) O
. O

Using O
females O
that O
varied O
in O
social O
, O
reproductive O
, O
and O
ecological O
context O
, O
we O
measured O
juvenile O
hormone O
( O
JH O
) O
, O
a O
major O
regulator O
of O
colony O
caste O
dynamics O
in O
other O
eusocial O
species O
. O

JH O
was O
low O
at O
adult O
emergence O
, O
but O
elevated O
after O
10 O
days O
in O
all O
nesting O
females O
. O

Females O
reared O
in O
cages O
with O
ad O
lib O
nutrition O
, O
however O
, O
did O
not O
elevate O
JH O
levels O
after O
10 O
days O
. O

All O
reproductive O
females O
had O
significantly O
more O
JH O
than O
all O
age O
- O
matched O
non O
- O
reproductive O
females O
, O
suggesting O
a O
gonadotropic O
function O
. O

Among O
females O
in O
established O
nests O
, O
JH O
was O
higher O
in O
queens O
than O
workers O
and O
solitary O
reproductives O
, O
suggesting O
a O
role O
for O
JH O
in O
social O
dominance O
. O

A O
lack O
of O
significant O
differences O
in O
JH O
between O
solitary O
reproductives O
and O
non O
- O
reproductive O
workers O
suggests O
that O
JH O
content O
reflects O
more O
than O
reproductive O
status O
. O

Our O
data O
support O
the O
hypothesis O
that O
endocrine O
modifications O
are O
involved O
in O
the O
evolutionary O
decoupling O
of O
reproductive O
and O
somatic O
effort O
in O
social O
insects O
. O

These O
are O
the O
first O
measurements O
of O
JH O
in O
a O
solitary O
- O
nesting O
hymenopteran O
, O
and O
the O
first O
to O
compare O
eusocial O
and O
solitary O
nesting O
individuals O
of O
the O
same O
species O
. O

Friedelin B
and O
lanosterol B
from O
Garcinia O
prainiana O
stimulated O
glucose B
uptake O
and O
adipocytes O
differentiation O
in O
3T3 O
- O
L1 O
adipocytes O
. O

Friedelin B
and O
lanosterol B
have O
been O
isolated O
from O
twigs O
of O
Garcinia O
prainiana O
. O

Their O
structures O
were O
elucidated O
by O
spectroscopic O
methods O
. O

The O
compounds O
were O
examined O
for O
their O
effects O
on O
3T3 O
- O
L1 O
adipocytes O
. O

In O
the O
MTT B
assay O
, O
it O
was O
found O
that O
the O
compounds O
had O
no O
cytotoxic O
effects O
up O
to O
25 O
micro O
M O
. O

Adipocyte O
differentiation O
analysis O
was O
carried O
out O
by O
Oil O
Red O
O O
staining O
method O
. O

In O
the O
presence O
of O
adipogenic O
cocktail O
( O
MDI O
) O
, O
it O
was O
found O
that O
friedelin B
and O
lanosterol B
enhanced O
intracellular O
fat O
accumulation O
by O
2 O
. O
02 O
and O
2 O
. O
18 O
- O
fold O
, O
respectively O
, O
compared O
with O
the O
vehicle O
- O
treated O
cells O
. O

Deoxyglucose B
uptake O
assay O
was O
used O
to O
examine O
the O
insulin O
sensitivity O
of O
adipocytes O
in O
the O
presence O
of O
the O
compounds O
. O

It O
was O
found O
that O
friedelin B
was O
able O
to O
stimulate O
glucose B
uptake O
up O
to O
1 O
. O
8 O
- O
fold O
compared O
with O
insulin O
- O
treated O
cells O
. O

It O
was O
suggested O
that O
friedelin B
and O
lanosterol B
may O
be O
beneficial O
to O
mimic O
insulin O
action O
that O
would O
be O
useful O
in O
the O
treatment O
of O
diabetes O
type O
2 O
patients O
. O

Airway O
contractility O
and O
remodeling O
: O
links O
to O
asthma O
symptoms O
. O

Respiratory O
symptoms O
are O
largely O
caused O
by O
obstruction O
of O
the O
airways O
. O

In O
asthma O
, O
airway O
narrowing O
mediated O
by O
airway O
smooth O
muscle O
( O
ASM O
) O
contraction O
contributes O
significantly O
to O
obstruction O
. O

The O
spasmogens O
produced O
following O
exposure O
to O
environmental O
triggers O
, O
such O
as O
viruses O
or O
allergens O
, O
are O
initially O
responsible O
for O
ASM O
activation O
. O

However O
, O
the O
extent O
of O
narrowing O
of O
the O
airway O
lumen O
due O
to O
ASM O
shortening O
can O
be O
influenced O
by O
many O
factors O
and O
it O
remains O
a O
real O
challenge O
to O
decipher O
the O
exact O
role O
of O
ASM O
in O
causing O
asthmatic O
symptoms O
. O

Innovative O
tools O
, O
such O
as O
the O
forced O
oscillation O
technique O
, O
continue O
to O
develop O
and O
have O
been O
proven O
useful O
to O
assess O
some O
features O
of O
ASM O
function O
in O
vivo O
. O

Despite O
these O
technologic O
advances O
, O
it O
is O
still O
not O
clear O
whether O
excessive O
narrowing O
in O
asthma O
is O
driven O
by O
ASM O
abnormalities O
, O
by O
other O
alterations O
in O
non O
- O
muscle O
factors O
or O
simply O
because O
of O
the O
overexpression O
of O
spasmogens O
. O

This O
is O
because O
a O
multitude O
of O
forces O
are O
acting O
on O
the O
airway O
wall O
, O
and O
because O
not O
only O
are O
these O
forces O
constantly O
changing O
but O
they O
are O
also O
intricately O
interconnected O
. O

To O
counteract O
these O
limitations O
, O
investigators O
have O
utilized O
in O
vitro O
and O
ex O
vivo O
systems O
to O
assess O
and O
compare O
asthmatic O
and O
non O
- O
asthmatic O
ASM O
contractility O
. O

This O
review O
describes O
: O
1 O
- O
some O
muscle O
and O
non O
- O
muscle O
factors O
that O
are O
altered O
in O
asthma O
that O
may O
lead O
to O
airway O
narrowing O
and O
asthma O
symptoms O
; O
2 O
- O
some O
technologies O
such O
as O
the O
forced O
oscillation O
technique O
that O
have O
the O
potential O
to O
unveil O
the O
role O
of O
ASM O
in O
airway O
narrowing O
in O
vivo O
; O
and O
3 O
- O
some O
data O
from O
ex O
vivo O
and O
in O
vitro O
methods O
that O
probe O
the O
possibility O
that O
airway O
hyperresponsiveness O
is O
due O
to O
the O
altered O
environment O
surrounding O
the O
ASM O
or O
, O
alternatively O
, O
to O
a O
hypercontractile O
ASM O
phenotype O
that O
can O
be O
either O

innate O
or O
acquired O
. O

Cost O
- O
effectiveness O
of O
alendronate B
for O
the O
treatment O
of O
osteopenic O
postmenopausal O
women O
in O
Japan O
. O

Many O
postmenopausal O
women O
have O
osteopenia O
, O
a O
condition O
characterized O
by O
loss O
of O
bone O
mineral O
density O
( O
BMD O
) O
that O
is O
not O
as O
severe O
as O
in O
osteoporosis O
. O

The O
objective O
of O
this O
study O
was O
to O
estimate O
the O
cost O
- O
effectiveness O
of O
alendronate B
to O
prevent O
fractures O
in O
osteopenic O
postmenopausal O
women O
without O
a O
history O
of O
fracture O
in O
Japan O
. O

An O
individual O
simulation O
model O
was O
developed O
to O
predict O
lifetime O
costs O
and O
quality O
- O
adjusted O
life O
years O
( O
QALYs O
) O
of O
5 O
years O
of O
preventive O
alendronate B
therapy O
versus O
no O
preventive O
therapy O
. O

The O
risk O
of O
hip O
and O
vertebral O
fracture O
associated O
with O
age O
and O
BMD O
was O
derived O
from O
epidemiologic O
studies O
in O
Japan O
. O

We O
ran O
the O
model O
with O
different O
combinations O
of O
age O
( O
65 O
, O
70 O
, O
and O
75 O
years O
) O
, O
BMD O
( O
70 O
% O
, O
75 O
% O
, O
and O
80 O
% O
of O
young O
adult O
mean O
[ O
YAM O
] O
) O
, O
and O
additional O
clinical O
risk O
factors O
. O

For O
70 O
- O
year O
- O
old O
women O
with O
a O
BMD O
of O
70 O
% O
of O
the O
YAM O
having O
one O
of O
the O
following O
risk O
factors O
: O
a O
family O
history O
of O
hip O
fracture O
, O
high O
alcohol B
intake O
, O
or O
current O
smoking O
, O
the O
incremental O
cost O
- O
effectiveness O
ratio O
( O
ICER O
) O
of O
alendronate B
was O
$ O
92 O
, O
937 O
, O
$ O
126 O
, O
251 O
, O
and O
$ O
129 O
, O
067 O
per O
QALY O
, O
respectively O
. O

These O
results O
were O
sensitive O
to O
age O
, O
BMD O
, O
and O
number O
of O
clinical O
risk O
factors O
. O

Probabilistic O
sensitivity O
analysis O
for O
the O
base O
case O
showed O
that O
in O
the O
presence O
of O
one O
, O
two O
, O
and O
three O
risk O
factors O
, O
alendronate B
was O
cost O
- O
effective O
in O
0 O
. O
2 O
% O
to O
2 O
. O
6 O
% O
, O
13 O
. O
1 O
% O
to O
56 O
. O
1 O
% O
, O
and O
99 O
. O
1 O
% O
of O
the O
simulations O
, O
respectively O
, O
if O
society O
is O
willing O
to O
pay O
$ O
50 O
, O
000 O
per O
QALY O
. O

Additional O
analysis O
indicated O
that O
alendronate B
can O
be O
a O
good O
value O
in O
osteopenic O
women O
if O
the O
10 O
- O
year O
probability O
for O
a O
osteoporotic O
hip O
or O
vertebral O
fracture O
is O
more O
than O
26 O
. O
2 O
% O
. O

Our O
results O
indicate O
that O
whether O
to O
treat O
osteopenia O
with O
alendronate B
should O
be O
determined O
on O
the O
basis O
of O
age O
, O
BMD O
, O
and O
number O
of O
clinical O
risk O
factors O
in O
terms O
of O
cost O
- O
effectiveness O
. O

Targeted O
disruption O
of O
inducible O
nitric B
oxide I
synthase O
protects O
against O
aging O
, O
S B
- O
nitrosation O
, O
and O
insulin O
resistance O
in O
muscle O
of O
male O
mice O
. O

Accumulating O
evidence O
has O
demonstrated O
that O
S B
- O
nitrosation O
of O
proteins O
plays O
a O
critical O
role O
in O
several O
human O
diseases O
. O

Here O
, O
we O
explored O
the O
role O
of O
inducible O
nitric B
oxide I
synthase O
( O
iNOS O
) O
in O
the O
S B
- O
nitrosation O
of O
proteins O
involved O
in O
the O
early O
steps O
of O
the O
insulin O
- O
signaling O
pathway O
and O
insulin O
resistance O
in O
the O
skeletal O
muscle O
of O
aged O
mice O
. O

Aging O
increased O
iNOS O
expression O
and O
S B
- O
nitrosation O
of O
major O
proteins O
involved O
in O
insulin O
signaling O
, O
thereby O
reducing O
insulin O
sensitivity O
in O
skeletal O
muscle O
. O

Conversely O
, O
aged O
iNOS O
- O
null O
mice O
were O
protected O
from O
S B
- O
nitrosation O
- O
induced O
insulin O
resistance O
. O

Moreover O
, O
pharmacological O
treatment O
with O
an O
iNOS O
inhibitor O
and O
acute O
exercise O
reduced O
iNOS O
- O
induced O
S B
- O
nitrosation O
and O
increased O
insulin O
sensitivity O
in O
the O
muscle O
of O
aged O
animals O
. O

These O
findings O
indicate O
that O
the O
insulin O
resistance O
observed O
in O
aged O
mice O
is O
mainly O
mediated O
through O
the O
S B
- O
nitrosation O
of O
the O
insulin O
- O
signaling O
pathway O
. O

Variation O
in O
osteocyte O
lacunar O
morphology O
and O
density O
in O
the O
human O
femur O
- O
- O
a O
synchrotron O
radiation O
micro O
- O
CT O
study O
. O

In O
recent O
years O
there O
has O
been O
growing O
interest O
in O
the O
spatial O
properties O
of O
osteocytes O
( O
including O
density O
and O
morphology O
) O
and O
how O
these O
potentially O
relate O
to O
adaptation O
, O
disease O
and O
aging O
. O

This O
interest O
has O
, O
in O
part O
, O
arisen O
from O
the O
availability O
of O
increasingly O
high O
- O
resolution O
3D O
imaging O
modalities O
such O
as O
synchrotron O
radiation O
( O
SR O
) O
micro O
- O
CT O
. O

As O
resolution O
increases O
, O
field O
of O
view O
generally O
decreases O
. O

Thus O
, O
while O
increasingly O
detailed O
spatial O
information O
is O
obtained O
, O
it O
is O
unclear O
how O
representative O
this O
information O
is O
of O
the O
skeleton O
or O
even O
the O
isolated O
bone O
. O

The O
purpose O
of O
this O
research O
was O
to O
describe O
the O
variation O
in O
osteocyte O
lacunar O
density O
, O
morphology O
and O
orientation O
within O
the O
femur O
from O
a O
healthy O
young O
male O
human O
. O

Multiple O
anterior O
, O
posterior O
, O
medial O
and O
lateral O
blocks O
( O
2 O
mm O
x O
2 O
mm O
) O
were O
prepared O
from O
the O
proximal O
femoral O
shaft O
and O
SR O
micro O
- O
CT O
imaged O
at O
the O
Advanced O
Photon O
Source O
. O

Average O
lacunar O
densities O
( O
+ O
/ O
- O
standard O
deviation O
) O
from O
the O
anterior O
, O
posterior O
, O
medial O
and O
lateral O
regions O
were O
27 O
, O
169 O
+ O
/ O
- O
1935 O
, O
26 O
, O
3643 O
+ O
/ O
- O
1262 O
, O
37 O
, O
521 O
+ O
/ O
- O
6416 O
and O
33 O
, O
972 O
+ O
/ O
- O
2513 O
lacunae O
per O
mm O
( O
3 O
) O
of O
bone O
tissue O
, O
respectively O
. O

These O
values O
were O
significantly O
different O
between O
the O
medial O
and O
both O
the O
anterior O
and O
posterior O
regions O
( O
p O
< O
0 O
. O
05 O
) O
. O

The O
density O
of O
the O
combined O
anterior O
and O
posterior O
regions O
was O
also O
significantly O
lower O
( O
p O
= O
0 O
. O
001 O
) O
than O
the O
density O
of O
the O
combined O
medial O
and O
lateral O
regions O
. O

Although O
no O
difference O
was O
found O
in O
predominant O
orientation O
, O
shape O
differences O
were O
found O
; O
with O
the O
combined O
anterior O
and O
posterior O
regions O
having O
more O
elongated O
( O
p O
= O
0 O
. O
004 O
) O
and O
flattened O
( O
p O
= O
0 O
. O
045 O
) O
lacunae O
, O
than O
those O
of O
the O
medial O
and O
lateral O
regions O
. O

This O
study O
reveals O
variation O
in O
osteocyte O
lacunar O
density O
and O
morphology O
within O
the O
cross O
- O
section O
of O
a O
single O
bone O
and O
that O
this O
variation O
can O
be O
considerable O
( O
up O
to O
30 O
% O
difference O
in O
density O
between O
regions O
) O
. O

The O
underlying O
functional O
significance O
of O
the O
observed O
variation O
in O
lacunar O
density O
likely O
relates O
to O
localized O
variations O
in O
loading O
conditions O
as O
the O
pattern O
corresponds O
well O
with O
mechanical O
axes O
. O

Lower O
density O
and O
more O
elongate O
shapes O
being O
associated O
with O
the O
antero O
- O
posterior O
oriented O
neutral O
axis O
. O

Our O
findings O
demonstrate O
that O
the O
functional O
and O
pathological O
interpretations O
that O
are O
increasingly O
being O
drawn O
from O
high O
resolution O
imaging O
of O
osteocyte O
lacunae O
need O
to O
be O
better O
situated O
within O
the O
broader O
context O
of O
normal O
variation O
, O
including O
that O
which O
occurs O
even O
within O
a O
single O
skeletal O
element O
. O

In O
vivo O
imaging O
of O
retinal O
ganglion O
cell O
apoptosis O
. O

Apoptosis O
, O
or O
programmed O
cell O
death O
, O
plays O
a O
vital O
role O
in O
normal O
development O
and O
ageing O
. O

However O
, O
dysregulation O
of O
this O
process O
is O
responsible O
for O
many O
disease O
states O
including O
; O
cancer O
, O
autoimmune O
and O
neurodegeneration O
. O

For O
this O
reason O
, O
in O
vivo O
visualisation O
of O
apoptosis O
may O
prove O
a O
useful O
tool O
for O
both O
laboratory O
research O
and O
clinical O
diagnostics O
. O

Glaucoma O
comprises O
a O
distinctive O
group O
of O
chronic O
optic O
neuropathies O
, O
characterised O
by O
the O
progressive O
loss O
of O
retinal B
ganglion O
cells O
( O
RGCs O
) O
. O

Early O
diagnosis O
of O
glaucoma O
remains O
a O
clear O
and O
unmet O
need O
. O

Recently O
, O
there O
have O
been O
significant O
advances O
in O
the O
detection O
of O
apoptosis O
in O
vivo O
using O
fluorescent O
probes O
to O
visualise O
single O
RGCs O
undergoing O
apoptosis O
, O
specifically O
DARC O
( O
Detection O
of O
Apoptotic O
Retinal O
Cells O
) O
[ O
1 O
] O
and O
capQ O
technology O
[ O
2 O
( O
* O
* O
) O
] O
. O

Microtubule O
network O
is O
required O
for O
insulin O
- O
induced O
signal O
transduction O
and O
actin O
remodeling O
. O

Both O
microtubule O
and O
actin O
are O
required O
for O
insulin O
- O
induced O
glucose B
uptake O
. O

However O
, O
the O
roles O
of O
these O
two O
cytoskeletons O
and O
their O
relationship O
in O
insulin O
action O
still O
remain O
unclear O
. O

In O
this O
work O
, O
we O
examined O
the O
morphological O
change O
of O
microtubule O
/ O
actin O
and O
their O
involvement O
in O
insulin O
signal O
transduction O
using O
rat O
skeletal O
muscle O
cells O
. O

Insulin O
rapidly O
led O
to O
microtubule O
clustering O
from O
ventral O
to O
dorsal O
surface O
of O
the O
cell O
. O

Microtubule O
filaments O
were O
rearranged O
to O
create O
space O
where O
new O
actin O
structures O
formed O
. O

Disruption O
of O
microtubule O
prevented O
insulin O
- O
induced O
actin O
remodeling O
and O
distal O
insulin O
signal O
transduction O
, O
with O
reduction O
in O
surface O
glucose B
transporter O
isoform O
4 O
( O
GLUT4 O
) O
and O
glucose B
uptake O
. O

Though O
microtubule O
mediated O
actin O
remodeling O
through O
PKC O
zeta O
, O
reorganization O
of O
microtubule O
depended O
on O
tyrosine B
phosphorylation O
of O
insulin O
receptor O
, O
the O
mechanism O
is O
different O
from O
insulin O
- O
induced O
actin O
remodeling O
, O
which O
relied O
on O
the O
activity O
of O
PI3 O
- O
kinase O
and O
PKC O
zeta O
. O

We O
propose O
that O
microtubule O
network O
is O
required O
for O
insulin O
- O
induced O
signal O
transduction O
and O
actin O
remodeling O
in O
skeletal O
muscle O
cells O
. O

Selective O
regulation O
of O
nicotine B
and O
polyamines B
biosynthesis O
in O
tobacco O
cells O
by O
enantiomers O
of O
ornithine B
. O

L B
- I
and I
D I
- I
amino I
acids I
have O
diverse O
functions O
and O
effects O
on O
the O
metabolism O
, O
growth O
, O
and O
development O
of O
plants O
. O

Ornithine B
( O
Orn B
) O
plays O
a O
main O
role O
in O
the O
biosynthesis O
of O
many O
amino B
acids I
, O
nicotinic B
alkaloids I
, O
and O
polyamines B
in O
tobacco O
. O

This O
investigation O
describes O
the O
impact O
of O
Orn B
enantiomers O
on O
the O
production O
and O
distribution O
of O
free O
, O
conjugated O
, O
and O
bound O
polyamines B
, O
as O
well O
as O
nicotine B
in O
tobacco O
cells O
. O

It O
was O
recognized O
that O
the O
biosynthesis O
of O
metabolites O
was O
differently O
upregulated O
by O
each O
enantiomer O
. O

Putrescine B
was O
abundantly O
produced O
by O
exogenous O
L B
- I
ornithine I
( O
L B
- I
Orn I
) O
, O
and O
both O
spermidine B
and O
spermine B
were O
significantly O
accumulated O
in O
D B
- I
ornithine I
( O
D B
- I
Orn I
) O
- O
supplied O
tobacco O
cells O
. O

Furthermore O
, O
nicotine B
production O
was O
highly O
upregulated O
by O
L B
- I
Orn I
, O
while O
the O
addition O
of O
D B
- I
Orn I
had O
no O
effect O
on O
the O
nicotine B
content O
of O
tobacco O
cells O
. O

It O
was O
observed O
that O
transcript O
expression O
of O
S B
- I
adenosylmethionine I
decarboxylase O
, O
as O
the O
key O
enzyme O
of O
spermidine B
/ O
spermine B
biosynthesis O
, O
is O
coincident O
with O
their O
metabolic O
levels O
and O
is O
highly O
upregulated O
by O
D B
- I
Orn I
, O
as O
opposed O
to O
L B
- I
Orn I
. O

These O
results O
indicate O
that O
both O
enantiomers O
of O
Orn B
can O
trigger O
selected O
biosynthetic O
pathways O
in O
the O
cells O
, O
at O
the O
transcript O
level O
. O

Regarding O
these O
observations O
, O
it O
is O
proposed O
that O
L B
- I
and I
D I
- I
Orn I
function O
differently O
in O
the O
same O
biological O
pathways O
in O
which O
the O
latter O
, O
D B
- I
Orn I
specifically O
regulates O
important O
polyamines B
in O
the O
plant O
cells O
. O

Human O
gastric O
TFF2 O
peptide O
contains O
an O
N B
- O
linked O
fucosylated O
N B
, I
N I
' I
- I
diacetyllactosediami I
( O
LacdiNAc B
) O
oligosaccharide O
. O

In O
the O
human O
stomach O
, O
the O
peptide O
trefoil O
factor O
family O
2 O
( O
TFF2 O
) O
is O
secreted O
together O
with O
the O
mucin O
MUC6 O
by O
mucous O
neck O
cells O
( O
MNCs O
) O
and O
antral O
gland O
cells O
. O

TFF2 O
is O
strongly O
associated O
with O
the O
gastric O
mucus O
and O
promotes O
gastric O
restitution O
. O

Here O
, O
TFF2 O
was O
purified O
from O
the O
human O
corpus O
and O
antrum O
, O
respectively O
, O
by O
size O
- O
exclusion O
chromatography O
, O
and O
the O
N B
- O
linked O
glycan O
structure O
at O
N O
- O
15 O
of O
the O
mature O
peptide O
was O
determined O
. O

As O
a O
hallmark O
, O
the O
unusual O
monofucosylated B
N I
, I
N I
' I
- I
diacetylhexosediamin I
( O
tentatively O
assigned O
as O
GalNAc B
beta I
1 I
- I
- I
> I
4GlcNAc I
, O
LacdiNAc B
) O
modification O
was O
detected O
as O
the O
terminal O
structure O
of O
a O
bi O
- O
antennary O
complex O
type O
N B
- O
glycan O
exhibiting O
also O
core O
fucosylation O
. O

Replicate O
analyses O
did O
not O
show O
microheterogeneities O
in O
the O
fraction O
of O
peptide O
- O
N B
- O
glycosidase O
F O
cleaved O
and O
permethylated O
N B
- O
glycans O
when O
analyzed O
by O
matrix O
- O
assisted O
laser O
desorption O
ionization O
( O
MALDI O
) O
mass O
spectrometry O
( O
MS O
) O
. O

On O
the O
glycopeptide O
level O
, O
a O
minor O
glycan O
microheterogeneity O
was O
evident O
in O
liquid O
chromatography O
- O
electrospray O
ionization O
( O
ESI O
) O
- O
MS O
, O
demonstrating O
the O
presence O
of O
underfucosylated O
species O
. O

The O
tryptic O
TFF2 O
N B
- O
glycopeptide O
p34 O
- O
39 O
( O
LSPHNR O
N B
- O
glycosylated O
with O
Fuc3Hex3HexNAc6 B
) O
was O
identified O
by O
both O
ESI O
- O
tandem O
mass O
spectrometry O
and O
MALDI O
- O
post O
- O
source O
decay O
analysis O
. O

Lectin O
analyses O
with O
the O
Wisteria O
floribunda O
agglutinin O
indicated O
the O
potential O
presence O
of O
LacdiNAc O
terminating O
glycans O
and O
revealed O
minor O
differences O
between O
TFF2 O
from O
fundic O
units O
, O
i O
. O
e O
. O
MNCs O
, O
and O
antral O
units O
, O
i O
. O
e O
. O
antral O
gland O
cells O
. O

Strikingly O
, O
on O
the O
level O
of O
the O
primary O
structure O
, O
there O
was O
no O
indication O
that O
the O
formation O
of O
the O
proposed O
LacdiNAc O
structure O
is O
cis O
- O
controlled O
by O
a O
peptidic O
determinant O
related O
to O
the O
published O
sequences O
. O

Altering O
the O
way O
the O
optic O
nerve O
head O
responds O
to O
intraocular O
pressure O
- O
a O
potential O
approach O
to O
glaucoma O
therapy O
. O

Over O
the O
past O
decade O
, O
engineering O
principles O
have O
been O
used O
to O
explain O
why O
a O
mechanical O
load O
, O
intraocular O
pressure O
, O
can O
lead O
to O
the O
development O
of O
glaucomatous O
optic O
neuropathy O
. O

This O
has O
led O
to O
the O
' O
biomechanical O
theory O
' O
of O
glaucoma O
, O
which O
posits O
that O
the O
behavior O
of O
optic O
nerve O
head O
connective O
tissues O
( O
specifically O
within O
the O
peripapillary O
sclera O
and O
lamina O
cribrosa O
) O
in O
response O
to O
intraocular O
pressure O
( O
regardless O
of O
its O
magnitude O
) O
can O
directly O
and O
indirectly O
influence O
the O
physiology O
and O
pathophysiology O
of O
the O
optic O
nerve O
head O
. O

Given O
that O
the O
biomechanics O
of O
the O
sclera O
and O
lamina O
cribrosa O
probably O
influence O
retinal O
ganglion O
cell O
loss O
in O
glaucoma O
, O
the O
idea O
that O
altering O
biomechanical O
behavior O
might O
be O
protective O
against O
glaucoma O
is O
an O
appealing O
notion O
. O

There O
is O
some O
evidence O
to O
suggest O
that O
stiffening O
the O
peripapillary O
sclera O
may O
be O
protective O
against O
the O
development O
of O
glaucoma O
in O
an O
animal O
model O
. O

It O
is O
technically O
possible O
to O
stiffen O
the O
sclera O
in O
vivo O
using O
collagen O
cross O
- O
linking O
techniques O
already O
applied O
in O
vivo O
to O
the O
cornea O
in O
the O
treatment O
of O
keratoconus O
. O

It O
has O
yet O
to O
be O
established O
whether O
scleral O
cross O
- O
linking O
is O
safe O
in O
humans O
and O
that O
it O
confers O
anything O
more O
than O
a O
theoretical O
advantage O
in O
terms O
of O
reducing O
the O
risk O
of O
glaucomatous O
damage O
. O

Maintenance O
of O
retinal B
ganglion O
cell O
mitochondrial O
functions O
as O
a O
neuroprotective O
strategy O
in O
glaucoma O
. O

Loss O
of O
vision O
in O
glaucoma O
occurs O
because O
retinal O
ganglion O
cells O
( O
RGCs O
) O
die O
. O

RGCs O
have O
probably O
more O
mitochondria O
than O
any O
other O
neurone O
in O
the O
CNS O
. O

It O
is O
proposed O
that O
stress O
to O
mitochondria O
of O
individual O
RGCs O
is O
a O
major O
trigger O
of O
the O
disease O
and O
also O
provides O
an O
explanation O
why O
different O
RGCs O
die O
at O
different O
times O
. O

Pharmacological O
agents O
that O
can O
maintain O
mitochondrial O
functions O
, O
in O
particular O
to O
attenuate O
oxidative O
stress O
and O
to O
sustain O
energy O
production O
, O
might O
therefore O
provide O
a O
novel O
way O
of O
slowing O
down O
RGC O
death O
and O
help O
in O
the O
treatment O
of O
glaucoma O
. O

Cannabinoid O
CB O
1 O
receptor O
in O
the O
modulation O
of O
stress O
coping O
behavior O
in O
mice O
: O
the O
role O
of O
serotonin B
and O
different O
forebrain O
neuronal O
subpopulations O
. O

The O
endocannabinoid O
system O
( O
ECS O
) O
may O
either O
enhance O
or O
inhibit O
responses O
to O
aversive O
stimuli O
, O
possibly O
caused O
by O
its O
modulatory O
activity O
on O
diverse O
neurotransmitters O
. O

The O
aim O
of O
this O
work O
was O
to O
investigate O
the O
involvement O
of O
serotonin B
( O
5 B
- I
HT I
) O
and O
catecholamines B
, O
as O
well O
as O
the O
role O
of O
glutamatergic O
and O
GABAergic O
cannabinoid O
type O
1 O
( O
CB O
( O
1 O
) O
) O
receptor O
, O
in O
responses O
to O
the O
antidepressant O
- O
like O
doses O
of O
the O
CB O
( O
1 O
) O
receptor O
agonist O
Delta B
( I
9 I
) I
- I
tetrahydrocannabinol I
( O
THC B
) O
and O
the O
antagonist O
rimonabant B
in O
the O
forced O
swim O
test O
( O
FST O
) O
. O

Mice O
received O
acute O
injections O
of O
low O
doses O
of O
THC B
( O
0 O
. O
1 O
or O
0 O
. O
5 O
mg O
/ O
kg O
) O
or O
high O
dose O
of O
rimonabant B
( O
3 O
or O
10 O
mg O
/ O
kg O
) O
after O
treatment O
with O
the O
5 B
- I
HT I
synthesis O
inhibitor O
pCPA B
( O
100 O
mg O
/ O
kg O
, O
4 O
days O
) O
, O
the O
5 O
- O
HT O
( O
1A O
) O
receptor O
antagonist O
WAY100635 B
( O
1 O
mg O
/ O
kg O
, O
acute O
) O
or O
the O
non O
- O
selective O
blocker O
of O
catecholamine B
synthesis O
, O
AMPT B
( O
20 O
mg O
/ O
kg O
, O
acute O
) O
. O

THC B
and O
rimonabant B
were O
also O
tested O
in O
mutant O
mice O
lacking O
CB O
( O
1 O
) O
receptor O
in O
specific O
forebrain O
neuronal O
subpopulations O
. O

Both O
THC B
and O
rimonabant B
induced O
antidepressant O
- O
like O
effects O
, O
quantified O
as O
immobility O
in O
the O
FST O
. O

However O
, O
only O
THC B
effects O
were O
reversed O
by O
pCPA B
or O
WAY100635 B
. O

In O
contrast O
, O
only O
AMPT B
could O
attenuate O
the O
rimonabant B
effect O
. O

We O
also O
found O
decreased O
immobility O
in O
mice O
lacking O
the O
CB O
( O
1 O
) O
receptor O
in O
glutamatergic O
cortical O
neurons O
, O
but O
not O
in O
forebrain O
GABAergic O
neurons O
, O
as O
compared O
with O
wild O
- O
type O
controls O
. O

The O
effect O
of O
THC B
persisted O
in O
mutant O
mice O
with O
CB O
( O
1 O
) O
receptor O
inactivation O
in O
GABAergic O
neurons O
, O
whereas O
rimonabant B
effects O
were O
alleviated O
in O
these O
mutants O
. O

Thus O
, O
employing O
both O
pharmacological O
and O
genetic O
tools O
, O
we O
could O
show O
that O
the O
ECS O
regulates O
stress O
responses O
by O
influencing O
GABAergic O
, O
glutamatergic O
and O
monoaminergic O
transmission O
. O

The O
antidepressant O
- O
like O
action O
of O
THC B
depends O
on O
serotonergic O
neurotransmission O
, O
whereas O
rimonabant B
effects O
are O
mediated O
by O
CB O
( O
1 O
) O
receptor O
on O
GABAergic O
neurons O
and O
by O
catecholamine B
signaling O
. O

Pharmacological O
targeting O
of O
endoplasmic O
reticulum O
stress O
signaling O
in O
cancer O
. O

The O
endoplasmic O
reticulum O
( O
ER O
) O
stress O
response O
constitutes O
a O
cellular O
process O
that O
can O
be O
triggered O
by O
a O
great O
variety O
of O
conditions O
that O
cause O
imbalances O
in O
intracellular O
homeostasis O
and O
threaten O
proper O
cell O
functioning O
. O

In O
response O
, O
the O
ER O
stress O
response O
activates O
an O
adaptive O
effort O
aimed O
at O
neutralizing O
these O
threats O
and O
reestablishing O
homeostasis O
. O

However O
, O
if O
these O
countermeasures O
are O
unsuccessful O
and O
severe O
imbalances O
persist O
, O
the O
ER O
stress O
response O
may O
abandon O
its O
pro O
- O
survival O
efforts O
and O
instead O
may O
initiate O
a O
pro O
- O
apoptotic O
program O
to O
eliminate O
the O
faulty O
cell O
for O
the O
benefit O
of O
the O
organism O
as O
a O
whole O
. O

Because O
vigorous O
growth O
of O
malignant O
tumors O
may O
create O
stressful O
conditions O
, O
such O
as O
hypoglycemia O
, O
hypoxia O
, O
or O
accumulation O
of O
misfolded O
proteins O
during O
revved O
up O
protein O
synthesis O
, O
the O
adaptive O
, O
pro O
- O
survival O
components O
of O
the O
ER O
stress O
response O
system O
( O
e O
. O
g O
. O
, O
GRP78 O
/ O
BiP O
) O
are O
frequently O
found O
chronically O
activated O
in O
tumor O
cells O
. O

This O
differential O
to O
non O
- O
stressed O
normal O
cells O
has O
been O
proposed O
to O
represent O
an O
Achilles O
' O
heel O
of O
tumor O
cells O
that O
may O
be O
exploitable O
by O
therapeutic O
intervention O
. O

In O
this O
model O
, O
the O
goal O
would O
be O
to O
further O
aggravate O
the O
pre O
- O
existing O
stress O
conditions O
in O
tumor O
cells O
with O
appropriate O
pharmacological O
agents O
, O
so O
that O
the O
already O
engaged O
pro O
- O
survival O
mechanism O
would O
be O
overwhelmed O
and O
the O
ER O
stress O
response O
forced O
to O
switch O
to O
its O
pro O
- O
apoptotic O
mode O
( O
e O
. O
g O
. O
, O
CHOP O
/ O
GADD153 O
) O
. O

This O
review O
will O
discuss O
the O
principle O
of O
pharmacological O
ER O
stress O
aggravation O
, O
and O
will O
present O
preclinical O
models O
with O
promise O
for O
cancer O
therapeutic O
applications O
. O

The O
risky O
cocktail O
: O
what O
combination O
effects O
can O
we O
expect O
between O
ecstasy B
and O
other O
amphetamines B
? O

The O
recreational O
and O
illicit O
use O
of O
amphetaminic O
designer O
compounds O
, O
specially O
3 B
, I
4 I
- I
methylenedioxymetham I
( O
MDMA B
; O
Ecstasy B
) O
, O
is O
of O
concern O
worldwide O
. O

Such O
psychostimulating O
drugs O
are O
frequently O
present O
as O
complex O
mixtures O
in O
' O
rave O
' O
pills O
, O
making O
concomitant O
polysubstance O
use O
a O
common O
trend O
. O

However O
, O
the O
understanding O
of O
possible O
combination O
effects O
with O
these O
substances O
is O
still O
scarce O
. O

The O
present O
study O
was O
aimed O
at O
predicting O
the O
cytotoxic O
effects O
of O
mixtures O
of O
four O
amphetaminic B
derivatives O
: O
MDMA B
, O
methamphetamine B
, O
4 B
- I
methylthioamphetamin I
and O
d B
- I
amphetamine I
in O
a O
human O
hepatoma O
cell O
line O
. O

Concentration O
- O
response O
curves O
for O
all O
single O
- O
mixture O
components O
were O
recorded O
by O
the O
MTT B
assay O
. O

Data O
obtained O
for O
individual O
agents O
were O
then O
used O
to O
compute O
the O
additivity O
expectations O
for O
mixtures O
of O
definite O
composition O
, O
using O
the O
pharmacological O
models O
of O
concentration O
addition O
( O
CA O
) O
and O
independent O
action O
. O

By O
comparing O
the O
predicted O
calculations O
with O
the O
experimentally O
observed O
effects O
, O
we O
concluded O
that O
CA O
accurately O
predicts O
the O
combination O
of O
amphetamines B
, O
which O
act O
together O
to O
generate O
additive O
effects O
over O
a O
large O
range O
of O
concentrations O
. O

Notably O
, O
we O
observed O
substantial O
mixture O
effects O
even O
when O
each O
drug O
was O
present O
at O
low O
concentrations O
, O
which O
individually O
produced O
unnoticeable O
effects O
. O

Nonetheless O
, O
for O
all O
tested O
mixtures O
, O
a O
small O
deviation O
from O
additivity O
was O
observed O
towards O
higher O
concentrations O
, O
particularly O
at O
high O
effect O
levels O
. O

A O
possible O
metabolic O
interaction O
, O
which O
could O
explain O
such O
deviation O
, O
was O
investigated O
, O
and O
it O
was O
observed O
that O
at O
higher O
mixture O
concentrations O
increased O
MDMA B
metabolism O
could O
be O
contributing O
to O
divergences O
from O
additivity O
. O

In O
conclusion O
, O
the O
present O
work O
clearly O
demonstrates O
that O
potentially O
harmful O
interactions O
among O
amphetaminic O
drugs O
are O
expected O
when O
these O
drugs O
are O
taken O
concomitantly O
. O

Resistin O
knockout O
mice O
exhibit O
impaired O
adipocyte O
glucose B
- O
dependent O
insulinotropic O
polypeptide O
receptor O
( O
GIPR O
) O
expression O
. O

Glucose B
- O
dependent O
insulinotropic O
polypeptide O
( O
GIP O
) O
is O
an O
incretin O
hormone O
that O
also O
plays O
a O
regulatory O
role O
in O
fat O
metabolism O
. O

In O
3T3 O
- O
L1 O
cells O
, O
resistin O
was O
demonstrated O
to O
be O
a O
key O
mediator O
of O
GIP O
stimulation O
of O
lipoprotein O
lipase O
( O
LPL O
) O
activity O
, O
involving O
activation O
of O
protein O
kinase O
B O
( O
PKB O
) O
and O
reduced O
phosphorylation O
of O
liver O
kinase O
B1 O
( O
LKB1 O
) O
and O
AMP B
- O
activated O
protein O
kinase O
( O
AMPK O
) O
. O

The O
current O
study O
was O
initiated O
to O
determine O
whether O
resistin O
has O
additional O
roles O
in O
GIP O
- O
regulated O
adipocyte O
functions O
. O

Analysis O
of O
primary O
adipocytes O
isolated O
from O
Retn O
( O
- O
/ O
- O
) O
, O
Retn O
( O
+ O
/ O
- O
) O
, O
and O
Retn O
( O
+ O
/ O
+ O
) O
mice O
found O
that O
GIP O
stimulated O
the O
PKB O
/ O
LKB1 O
/ O
AMPK O
/ O
LPL O
pathway O
and O
fatty B
acid I
uptake O
only O
in O
Retn O
( O
+ O
/ O
+ O
) O
adipocytes O
, O
suggesting O
that O
GIP O
signaling O
and O
/ O
or O
GIP O
responsiveness O
were O
compromised O
in O
Retn O
( O
+ O
/ O
- O
) O
and O
Retn O
( O
- O
/ O
- O
) O
adipocytes O
. O

GIP O
receptor O
( O
GIPR O
) O
protein O
and O
mRNA O
were O
decreased O
in O
Retn O
( O
+ O
/ O
- O
) O
and O
Retn O
( O
- O
/ O
- O
) O
adipocytes O
, O
but O
resistin O
treatment O
rescued O
LPL O
responsiveness O
to O
GIP O
. O

In O
addition O
, O
genes O
encoding O
tumor O
necrosis O
factor O
( O
TNF O
) O
, O
TNF O
receptor O
2 O
( O
TNFR2 O
) O
, O
and O
the O
signaling O
proteins O
stress O
- O
activated O
protein O
kinase O
( O
SAPK O
) O
/ O
Jun O
NH B
( I
2 I
) I
- O
terminal O
kinase O
( O
JNK O
) O
, O
were O
downregulated O
, O
and O
phosphorylated O
levels O
of O
SAPK O
/ O
JNK O
/ O
c O
- O
Jun O
were O
decreased O
in O
Retn O
( O
- O
/ O
- O
) O
mice O
. O

Chromatin O
immunoprecipitation O
assays O
were O
used O
to O
identify O
a O
12 B
- I
O I
- I
tetradecanoylphorbol I
- I
13 I
- I
acetate I
( O
TPA B
) O
- O
response O
element O
( O
TRE O
- O
III O
) O
responsible O
for O
c O
- O
Jun O
- O
mediated O
transcriptional O
activation O
of O
Gipr O
. O

Blunted O
GIP O
responsiveness O
in O
Retn O
( O
+ O
/ O
- O
) O
and O
Retn O
( O
- O
/ O
- O
) O
adipocytes O
was O
therefore O
largely O
due O
to O
the O
greatly O
reduced O
GIPR O
expression O
associated O
with O
decreased O
c O
- O
Jun O
- O
mediated O
transcriptional O
activation O
of O
Gipr O
. O

When O
did O
decapods O
invade O
hydrothermal O
vents O
? O

Clues O
from O
the O
Western O
Pacific O
and O
Indian O
Oceans O
. O

Hydrothermal O
vents O
are O
typically O
located O
in O
midocean O
ridges O
and O
back O
- O
arc O
basins O
and O
are O
usually O
generated O
by O
the O
movement O
of O
tectonic O
plates O
. O

Life O
thrives O
in O
these O
environments O
despite O
the O
extreme O
conditions O
. O

In O
addition O
to O
chemoautotrophic O
bacteria O
, O
decapod O
crustaceans O
are O
dominant O
in O
many O
of O
the O
hydrothermal O
vents O
discovered O
to O
date O
. O

Contrary O
to O
the O
hypothesis O
that O
these O
species O
are O
remnants O
of O
relic O
fauna O
, O
increasing O
evidence O
supports O
the O
notion O
that O
hydrothermal O
vent O
decapods O
have O
diversified O
in O
more O
recent O
times O
with O
previous O
research O
attributing O
the O
origin O
of O
alvinocarid O
shrimps O
to O
the O
Miocene O
. O

This O
study O
investigated O
seven O
representative O
decapod O
species O
from O
four O
hydrothermal O
vents O
throughout O
the O
Western O
Pacific O
and O
Indian O
Oceans O
. O

A O
partitioned O
mix O
- O
model O
phylogenomic O
analysis O
of O
mitochondrial O
DNA O
produced O
a O
consistent O
phylogenetic O
topology O
of O
these O
vent O
- O
endemic O
species O
. O

Additionally O
, O
molecular O
dating O
analysis O
calibrated O
using O
multiple O
fossils O
suggested O
that O
both O
bythograeid O
crabs O
and O
alvinocarid O
shrimps O
originated O
in O
the O
late O
Mesozoic O
and O
early O
Cenozoic O
. O

Although O
of O
limited O
sampling O
, O
our O
estimates O
support O
the O
extinction O
/ O
repopulation O
hypothesis O
, O
which O
postulates O
recent O
diversification O
times O
for O
most O
hydrothermal O
vent O
species O
due O
to O
their O
mass O
extinction O
by O
global O
deep O
- O
water O
anoxic O
/ O
dysoxic O
events O
during O
the O
Late O
Cretaceous O
and O
Early O
Tertiary O
. O

The O
continental O
- O
derived O
property O
of O
the O
West O
Pacific O
province O
is O
compatible O
with O
the O
possibility O
that O
vent O
decapods O
diversified O
from O
ancestors O
from O
shallow O
- O
water O
regions O
such O
as O
cold O
seeps O
. O

Our O
results O
move O
us O
a O
step O
closer O
toward O
understanding O
the O
evolutionary O
origin O
of O
hydrothermal O
vent O
species O
and O
their O
distribution O
in O
the O
Western O
Pacific O
- O
Indian O
Ocean O
Region O
. O

Cellular O
and O
molecular O
mechanisms O
of O
hepatocellular O
carcinoma O
: O
an O
update O
. O

Hepatocellular O
carcinoma O
( O
HCC O
) O
is O
the O
most O
common O
primary O
malignant O
tumor O
that O
accounts O
for O
~ O
80 O
% O
of O
all O
liver O
cancer O
cases O
worldwide O
. O

It O
is O
a O
multifactorial O
disease O
caused O
by O
a O
variety O
of O
risk O
factors O
and O
often O
develops O
in O
the O
background O
of O
underlying O
cirrhosis O
. O

A O
number O
of O
cellular O
phenomena O
, O
such O
as O
tumor O
microenvironment O
, O
inflammation O
, O
oxidative O
stress O
, O
and O
hypoxia O
act O
in O
concert O
with O
various O
molecular O
events O
to O
facilitate O
tumor O
initiation O
, O
progression O
, O
and O
metastasis O
. O

The O
emergence O
of O
microRNAs O
and O
molecular O
- O
targeted O
therapies O
adds O
a O
new O
dimension O
in O
our O
efforts O
to O
combat O
this O
deadly O
disease O
. O

Intense O
research O
in O
this O
multitude O
of O
areas O
has O
led O
to O
significant O
progress O
in O
our O
understanding O
of O
cellular O
processes O
and O
molecular O
mechanisms O
that O
occur O
during O
multistage O
events O
that O
lead O
to O
hepatocarcinogenesis O
. O

In O
this O
review O
, O
we O
discuss O
the O
current O
knowledge O
of O
HCC O
, O
focusing O
mainly O
on O
advances O
that O
have O
occurred O
during O
the O
past O
5 O
years O
and O
on O
the O
development O
of O
novel O
therapeutics O
for O
liver O
cancer O
. O

The O
influence O
of O
chronic O
fluorosis O
on O
mitochondrial O
dynamics O
morphology O
and O
distribution O
in O
cortical O
neurons O
of O
the O
rat O
brain O
. O

The O
present O
study O
was O
designed O
to O
evaluate O
the O
effects O
of O
chronic O
fluorosis O
on O
the O
dynamics O
( O
including O
fusion O
and O
fission O
proteins O
) O
, O
fragmentation O
, O
and O
distribution O
of O
mitochondria O
in O
the O
cortical O
neurons O
of O
the O
rat O
brain O
in O
an O
attempt O
to O
elucidate O
molecular O
mechanisms O
underlying O
the O
brain O
damage O
associated O
with O
excess O
accumulation O
of O
fluoride B
. O

Sixty O
Sprague O
- O
Dawley O
rats O
were O
divided O
randomly O
into O
three O
groups O
of O
20 O
each O
, O
that O
is O
, O
the O
untreated O
control O
group O
( O
drinking O
water O
naturally O
containing O
< O
0 O
. O
5 O
mg O
fluoride B
/ O
l O
, O
NaF B
) O
, O
the O
low O
- O
fluoride B
group O
( O
whose O
drinking O
water O
was O
supplemented O
with O
10 O
mg O
fluoride B
/ O
l O
) O
and O
the O
high O
- O
fluoride B
group O
( O
50 O
mg O
fluoride B
/ O
l O
) O
. O

After O
6 O
months O
of O
exposure O
, O
the O
expression O
of O
mitofusin O
- O
1 O
( O
Mfn1 O
) O
, O
fission O
- O
1 O
( O
Fis1 O
) O
, O
and O
dynamin O
- O
related O
protein O
- O
1 O
( O
Drp1 O
) O
at O
both O
the O
protein O
and O
mRNA O
levels O
were O
detected O
by O
Western O
blotting O
, O
immunohistochemistry O
, O
and O
real O
- O
time O
PCR O
, O
respectively O
. O

Moreover O
, O
mitochondrial O
morphology O
and O
distribution O
in O
neurons O
were O
observed O
by O
transmission O
electron O
or O
fluorescence O
microscopy O
. O

In O
the O
cortices O
of O
the O
brains O
of O
rats O
with O
chronic O
fluorosis O
, O
the O
level O
of O
Mfn1 O
protein O
was O
clearly O
reduced O
, O
whereas O
the O
levels O
of O
Fis1 O
and O
Drp1 O
were O
elevated O
. O

The O
alternations O
of O
expression O
of O
the O
mRNAs O
encoding O
all O
three O
of O
these O
proteins O
were O
almost O
the O
same O
as O
the O
corresponding O
changes O
at O
the O
protein O
levels O
. O

The O
mitochondria O
were O
fragmented O
and O
the O
redistributed O
away O
from O
the O
axons O
of O
the O
cortical O
neurons O
. O

These O
findings O
indicate O
that O
chronic O
fluorosis O
induces O
abnormal O
mitochondrial O
dynamics O
, O
which O
might O
in O
turn O
result O
in O
a O
high O
level O
of O
oxidative O
stress O
. O

Cyclooxygenase O
( O
COX O
) O
- O
1 O
and O
COX O
- O
2 O
both O
play O
an O
important O
role O
in O
the O
protection O
of O
the O
duodenal O
mucosa O
in O
cats O
. O

Although O
nonsteroidal O
anti O
- O
inflammatory O
drugs O
often O
cause O
ulcers O
in O
the O
duodenum O
in O
humans O
, O
the O
role O
of O
cyclooxygenase O
( O
COX O
) O
isoforms O
in O
the O
pathogenesis O
of O
duodenal O
ulcers O
has O
not O
been O
fully O
elucidated O
. O

We O
examined O
in O
cats O
the O
1 O
) O
ulcerogenic O
effects O
of O
selective O
COX O
- O
1 O
( O
SC B
- I
560 I
, O
ketorolac B
) O
and O
COX O
- O
2 O
( O
celecoxib B
, O
meloxicam B
) O
inhibitors O
on O
the O
gastrointestinal O
mucosa O
, O
2 O
) O
effect O
of O
feeding O
and O
cimetidine B
on O
the O
expression O
of O
COX O
isoforms O
and O
prostaglandin B
E I
( I
2 I
) I
( O
PGE B
( I
2 I
) I
) O
level O
in O
the O
duodenum O
, O
and O
3 O
) O
localization O
of O
COX O
isoforms O
in O
the O
duodenum O
. O

COX O
inhibitors O
were O
administered O
after O
the O
morning O
meal O
in O
cats O
once O
daily O
for O
3 O
days O
. O

Gastrointestinal O
lesions O
were O
examined O
on O
day O
4 O
. O

Localization O
and O
expression O
of O
COX O
isoforms O
( O
by O
immunohistochemistry O
, O
Western O
blot O
) O
and O
PGE B
( I
2 I
) I
level O
( O
by O
enzyme O
immunoassay O
) O
were O
examined O
. O

Results O
were O
as O
follows O
. O

First O
, O
selective O
COX O
- O
1 O
or O
COX O
- O
2 O
inhibitors O
alone O
produced O
marked O
ulcers O
in O
the O
duodenum O
but O
did O
not O
cause O
obvious O
lesions O
in O
the O
small O
intestine O
. O

Coadministration O
of O
SC B
- I
560 I
and O
celecoxib B
produced O
marked O
lesions O
in O
the O
small O
intestine O
. O

Second O
, O
feeding O
increased O
both O
the O
expression O
of O
COX O
isoforms O
and O
PGE B
( I
2 I
) I
level O
in O
the O
duodenum O
, O
and O
the O
effects O
were O
markedly O
inhibited O
by O
pretreatment O
with O
cimetidine B
. O

Third O
, O
COX O
- O
1 O
was O
localized O
in O
goblet O
and O
Brunner O
' O
s O
gland O
cells O
, O
Meissner O
' O
s O
and O
Auerbach O
' O
s O
plexus O
, O
smooth O
muscle O
cells O
, O
and O
arterioles O
; O
and O
COX O
- O
2 O
was O
observed O
in O
capillaries O
, O
venules O
, O
and O
basal O
granulated O
cells O
. O

The O
expression O
of O
COX O
isoforms O
in O
the O
duodenum O
is O
up O
- O
regulated O
by O
feeding O
, O
and O
inhibition O
of O
either O
COX O
- O
1 O
or O
COX O
- O
2 O
causes O
ulcers O
in O
the O
duodenum O
, O
suggesting O
that O
both O
isoforms O
play O
an O
important O
role O
in O
the O
protection O
of O
the O
duodenal O
mucosa O
. O

Development O
of O
a O
live O
tissue O
microtome O
: O
reflections O
of O
an O
amateur O
machinist O
. O

Live O
circular O
tissue O
slices O
of O
nearly O
identical O
diameter O
and O
thickness O
can O
be O
generated O
from O
most O
tissues O
by O
the O
use O
of O
two O
instruments O
; O
a O
coring O
tool O
to O
cut O
cylindrical O
tissue O
cores O
which O
are O
subsequently O
sliced O
by O
a O
microtome O
into O
thin O
circular O
sections O
5 O
- O
8 O
mm O
in O
diameter O
and O
50 O
- O
300 O
microns O
thick O
. O

The O
sections O
are O
of O
very O
similar O
geometry O
permitting O
direct O
comparisons O
without O
normalization O
. O

Both O
instruments O
operate O
submerged O
in O
a O
cold O
isotonic O
medium O
that O
caries O
the O
cut O
slices O
outside O
the O
microtome O
. O

The O
slices O
are O
cut O
by O
a O
rapidly O
oscillating O
disposable O
Gillette O
blade O
mounted O
at O
an O
angle O
of O
20 O
degrees O
to O
the O
vertical O
main O
axis O
of O
the O
tissue O
core O
. O

The O
latter O
is O
advanced O
against O
the O
oscillating O
blade O
by O
a O
weighted O
plunger O
pushing O
it O
against O
a O
screw O
adjustable O
limit O
plate O
that O
defines O
the O
desired O
slice O
thickness O
. O

Both O
instruments O
can O
be O
sterilized O
and O
slices O
can O
be O
obtained O
at O
a O
rate O
of O
approximately O
one O
every O
ten O
seconds O
. O

pH O
- O
and O
thermo O
- O
sensitive O
pluronic B
/ O
poly B
( I
acrylic I
acid I
) I
in O
situ O
hydrogels O
for O
sustained O
release O
of O
an O
anticancer O
drug O
. O

In O
this O
study O
, O
we O
developed O
oral O
in O
situ O
gelling O
formulations O
composed O
of O
pluronic B
( O
Plu B
) O
and O
polyacrylic B
acid I
( O
PAA B
) O
for O
the O
delivery O
of O
an O
anticancer O
drug O
, O
epirubicin B
( O
Epi B
) O
. O

We O
investigated O
various O
Plu B
/ O
PAA B
/ O
Epi B
formulations O
for O
their O
physicochemical O
properties O
and O
in O
vitro O
permeation O
and O
accumulation O
, O
as O
well O
as O
for O
in O
vivo O
pharmacokinetic O
and O
antitumor O
efficacy O
. O

A O
scanning O
electron O
microscopic O
( O
SEM O
) O
image O
of O
Plu B
14 O
% O
/ O
PAA B
0 O
. O
75 O
% O
/ O
Epi B
hydrogel O
showed O
a O
sponge O
- O
like O
structure O
. O

This O
formulation O
has O
suitable O
gelation O
time O
, O
water O
content O
, O
bioadhesive O
force O
, O
structural O
stability O
, O
and O
a O
high O
permeation O
percentage O
of O
Epi B
, O
with O
sustained O
drug O
release O
characteristics O
for O
96 O
h O
. O

This O
hydrogel O
was O
retained O
at O
the O
end O
of O
the O
ileum O
near O
the O
colon O
of O
Sprague O
- O
Dawley O
( O
SD O
) O
rats O
for O
at O
least O
12 O
h O
. O

An O
in O
vivo O
pharmacokinetic O
study O
using O
SD O
rats O
showed O
that O
after O
oral O
administration O
in O
this O
formulation O
, O
Epi B
had O
prolonged O
half O
- O
life O
, O
greater O
area O
under O
the O
curve O
, O
and O
higher O
relative O
bioavailability O
than O
in O
an O
oral O
Epi B
solution O
. O

In O
vivo O
tumor O
growth O
inhibition O
of O
Epi B
in O
this O
formulation O
was O
more O
pronounced O
compared O
with O
oral O
Epi B
and O
intravenous O
Epi B
solutions O
in O
CT O
- O
26 O
mouse O
colon O
adenocarcinoma O
bearing O
Balb O
/ O
c O
mice O
. O

This O
study O
highlights O
the O
advantages O
of O
using O
oral O
in O
situ O
temperature O
- O
and O
pH O
- O
sensitive O
hydrogels O
for O
future O
cancer O
therapy O
. O

For O
whom O
the O
bell O
tolls O
: O
Distress O
signals O
from O
long O
- O
lived O
osteocytes O
and O
the O
pathogenesis O
of O
metabolic O
bone O
diseases O
. O

Osteocytes O
are O
long O
- O
lived O
and O
far O
more O
numerous O
than O
the O
short O
- O
lived O
osteoblasts O
and O
osteoclasts O
. O

Immured O
within O
the O
lacunar O
- O
canalicular O
system O
and O
mineralized O
matrix O
, O
osteocytes O
are O
ideally O
located O
throughout O
the O
bone O
to O
detect O
the O
need O
for O
, O
and O
accordingly O
choreograph O
, O
the O
bone O
regeneration O
process O
by O
independently O
controlling O
rate O
limiting O
steps O
of O
bone O
resorption O
and O
formation O
. O

Consistent O
with O
this O
role O
, O
emerging O
evidence O
indicates O
that O
signals O
arising O
from O
apoptotic O
and O
old O
/ O
or O
dysfunctional O
osteocytes O
are O
seminal O
culprits O
in O
the O
pathogenesis O
of O
involutional O
, O
post O
- O
menopausal O
, O
steroid B
- O
, O
and O
immobilization O
- O
induced O
osteoporosis O
. O

Osteocyte O
- O
originated O
signals O
may O
also O
contribute O
to O
the O
increased O
bone O
fragility O
associated O
with O
bone O
matrix O
disorders O
like O
osteogenesis O
imperfecta O
, O
and O
perhaps O
the O
rapid O
reversal O
of O
bone O
turnover O
above O
baseline O
following O
discontinuation O
of O
anti O
- O
resorptive O
treatments O
, O
like O
denosumab O
. O

This O
article O
is O
part O
of O
a O
Special O
Issue O
entitled O
" O
The O
Osteocyte O
" O
. O

The O
continuing O
saga O
of O
snake O
venom O
disintegrins O
. O

Disintegrins O
, O
a O
family O
of O
polypeptides O
released O
in O
the O
venoms O
of O
viperid O
snakes O
( O
vipers O
and O
rattlesnakes O
) O
by O
the O
proteolytic O
processing O
of O
multidomain O
metalloproteinases O
, O
selectively O
block O
the O
function O
of O
beta O
( O
1 O
) O
and O
beta O
( O
3 O
) O
integrin O
receptors O
. O

Few O
of O
the O
proteins O
isolated O
and O
characterized O
from O
snake O
venoms O
have O
proven O
to O
be O
more O
structural O
and O
functional O
versatile O
than O
the O
disintegrins O
. O

Not O
surprisingly O
, O
25 O
years O
after O
their O
discovery O
, O
our O
knowledge O
on O
the O
evolutionary O
history O
and O
the O
molecular O
determinants O
modulating O
the O
integrin O
inhibitory O
activity O
of O
disintegrins O
still O
remain O
fragmentary O
. O

This O
paper O
highlights O
some O
seminal O
contributions O
, O
including O
personal O
accounts O
of O
pioneer O
authors O
, O
related O
to O
basic O
and O
applied O
research O
on O
disintegrins O
. O

Investigators O
have O
evaluated O
disintegrin O
applications O
in O
therapies O
for O
a O
number O
of O
pathologies O
in O
which O
integrin O
receptors O
play O
relevant O
roles O
, O
particularly O
myocardial O
infarction O
and O
inappropriate O
tumor O
angiogenesis O
. O

Completing O
the O
continuing O
story O
of O
the O
disintegrin O
family O
by O
applying O
novel O
research O
approaches O
may O
hold O
the O
key O
to O
learn O
how O
to O
use O
deadly O
toxins O
as O
therapeutic O
agents O
. O

Development O
of O
histopathological O
indices O
in O
a O
commercial O
marine O
bivalve O
( O
Ruditapes O
decussatus O
) O
to O
determine O
environmental O
quality O
. O

Bivalve O
histopathology O
is O
an O
acknowledged O
tool O
in O
environmental O
toxicology O
studies O
, O
however O
geographically O
restricted O
, O
limited O
to O
a O
few O
species O
and O
still O
lacking O
the O
degree O
of O
detail O
needed O
to O
develop O
effective O
( O
semi O
) O
quantitative O
approaches O
. O

A O
first O
- O
time O
detailed O
histopathological O
screening O
was O
performed O
on O
grooved O
carpet O
shell O
clams O
collected O
from O
commercial O
shellfish O
beds O
in O
distinct O
coastal O
ecosystems O
of O
the O
Southern O
Portuguese O
coast O
: O
two O
parted O
sites O
within O
an O
impacted O
estuary O
( O
S O
( O
1 O
) O
and O
S O
( O
2 O
) O
) O
, O
an O
inlet O
channel O
of O
a O
fish O
farm O
at O
a O
considered O
pristine O
estuary O
( O
site O
M O
) O
and O
a O
site O
allocated O
in O
a O
clean O
coastal O
lagoon O
( O
A O
) O
. O

A O
total O
of O
thirty O
histopathological O
lesions O
and O
alterations O
were O
analysed O
in O
the O
gills O
and O
digestive O
glands O
following O
a O
weighted O
condition O
indices O
approach O
, O
including O
inflammation O
- O
related O
responses O
, O
necrosis O
, O
neoplastic O
diseases O
and O
parasites O
. O

Digestive O
glands O
were O
consistently O
more O
damaged O
than O
gills O
, O
except O
for O
animals O
collected O
from O
site O
M O
, O
where O
the O
most O
severe O
lesions O
were O
found O
in O
both O
organs O
, O
immediately O
followed O
by O
S O
( O
2 O
) O
. O

Clams O
from O
sites O
S O
( O
1 O
) O
and O
A O
were O
overall O
the O
least O
damaged O
. O

Neoplastic O
diseases O
were O
infrequent O
in O
all O
cases O
. O

Inflammation O
- O
related O
traits O
were O
some O
of O
the O
most O
common O
alterations O
progressing O
in O
animals O
enduring O
severe O
lesions O
such O
as O
digestive O
tubule O
( O
diverticula O
) O
and O
intertubular O
tissue O
necrosis O
. O

Some O
alterations O
, O
such O
as O
lipofuscin O
aggregates O
within O
digestive O
tubule O
cells O
, O
did O
not O
relate O
to O
histological O
lesions O
. O

Granulocytomas O
only O
occurred O
in O
heavily O
infected O
tissues O
. O

Animals O
from O
M O
and O
A O
presented O
the O
highest O
infections O
in O
the O
digestive O
gland O
, O
especially O
by O
protozoa O
. O

Gill O
infections O
were O
more O
similar O
between O
sites O
. O

Still O
, O
the O
level O
of O
infection O
does O
not O
account O
for O
all O
histopathological O
lesions O
in O
either O
organ O
. O

Overall O
, O
the O
results O
are O
in O
accordance O
with O
environmental O
parameters O
, O
such O
as O
distance O
to O
pollution O
sources O
, O
sediment O
type O
and O
hydrodynamics O
, O
and O
show O
that O
the O
combination O
of O
multiple O
histopathological O
features O
in O
these O
clams O
provides O
good O
sensitivity O
for O
inter O
- O
site O
distinction O
even O
when O
low O
or O
moderate O
anthropogenic O
impacts O
are O
at O
stake O
. O

Changes O
in O
trace O
elements O
during O
lactation O
in O
a O
marine O
top O
predator O
, O
the O
grey O
seal O
. O

Lactation O
in O
pinnipeds O
represents O
the O
most O
significant O
cost O
to O
mothers O
during O
the O
reproductive O
cycle O
. O

Dynamics O
of O
trace O
elements O
and O
their O
mobilization O
associated O
with O
energy O
reserves O
during O
such O
an O
intense O
physiological O
process O
remains O
poorly O
understood O
in O
marine O
mammals O
. O

The O
changes O
in O
tissue O
concentrations O
of O
11 O
elements O
( O
Ca B
, O
Cd B
, O
Cr B
, O
Cu B
, O
Fe B
, O
Hg B
, O
Ni B
, O
Pb B
, O
Se B
, O
V B
, O
and O
Zn B
) O
were O
investigated O
in O
a O
longitudinal O
study O
during O
the O
lactation O
period O
and O
during O
the O
post O
- O
weaning O
fast O
period O
. O

Blood O
, O
milk O
, O
blubber O
, O
and O
hair O
samples O
were O
collected O
sequentially O
from O
21 O
mother O
- O
pup O
pairs O
of O
grey O
seals O
( O
Halichoerus O
grypus O
) O
from O
the O
Isle O
of O
May O
in O
Scotland O
. O

Maternal O
transfer O
through O
the O
milk O
was O
observed O
for O
all O
trace O
elements O
, O
except O
for O
Cd B
. O

As O
an O
indicator O
of O
the O
placental O
transfer O
, O
levels O
in O
pup O
lanugo O
( O
natal O
coat O
) O
revealed O
also O
the O
existence O
of O
maternal O
transfer O
and O
accumulation O
of O
all O
assayed O
trace O
elements O
during O
the O
foetal O
development O
. O

The O
placental O
and O
mammary O
barriers O
against O
non O
- O
essential O
metal O
transfer O
to O
offspring O
appear O
to O
be O
absent O
or O
weak O
in O
grey O
seals O
. O

Examining O
the O
contamination O
levels O
showed O
that O
this O
grey O
seal O
population O
seems O
more O
highly O
exposed O
to O
Pb B
than O
other O
phocid O
populations O
( O
2 O
. O
2 O
mg O
/ O
kg O
dw O
of O
grey O
seal O
hair O
) O
. O

In O
contrast O
, O
blood O
and O
hair O
levels O
reflected O
a O
lower O
Hg B
exposure O
in O
grey O
seals O
from O
the O
Isle O
of O
May O
than O
in O
harbour O
seals O
from O
the O
southeastern O
North O
Sea O
. O

This O
study O
also O
showed O
that O
trace O
element O
concentrations O
in O
blood O
and O
blubber O
could O
change O
rapidly O
over O
the O
lactation O
period O
. O

Such O
physiological O
processes O
must O
be O
considered O
carefully O
during O
biomonitoring O
of O
trace O
elements O
, O
and O
potential O
impacts O
that O
rapid O
fluctuations O
in O
concentrations O
can O
exert O
on O
seal O
health O
should O
be O
further O
investigated O
. O

Iodinated O
nano O
- O
emulsions O
as O
contrast O
agents O
for O
preclinical O
X O
- O
ray O
imaging O
: O
Impact O
of O
the O
free O
surfactants O
on O
the O
pharmacokinetics O
. O

This O
study O
presents O
new O
important O
aspects O
in O
the O
design O
of O
contrast O
agents O
for O
X O
- O
ray O
preclinical O
imaging O
. O

The O
first O
one O
is O
a O
new O
simple O
formulation O
of O
long O
circulating O
contrast O
agents O
, O
formulated O
from O
a O
commercial O
iodinated O
oil O
, O
and O
resulting O
in O
CT O
contrast O
agents O
containing O
more O
than O
twice O
the O
iodine B
concentration O
commercial O
contrast O
agents O
. O

The O
second O
point O
is O
a O
methodological O
aspect O
, O
utilizing O
tangential O
filtration O
for O
reducing O
the O
residual O
surfactants O
in O
the O
bulk O
phase O
and O
serving O
as O
well O
for O
concentrating O
droplets O
( O
and O
iodine B
) O
in O
the O
suspension O
. O

The O
last O
point O
is O
a O
more O
general O
aspect O
regarding O
the O
influence O
of O
the O
free O
surfactant O
on O
the O
pharmacokinetics O
and O
biodistribution O
of O
the O
nano O
- O
emulsion O
droplets O
on O
mice O
. O

We O
showed O
that O
cross O
- O
flow O
filtration O
is O
efficient O
for O
concentrating O
the O
droplets O
and O
reducing O
the O
concentration O
of O
free O
surfactant O
from O
10wt O
. O
% O
to O
1wt O
. O
% O
, O
without O
any O
changes O
in O
the O
nano O
- O
emulsion O
droplet O
morphologies O
or O
surface O
properties O
. O

We O
also O
showed O
that O
the O
presence O
of O
free O
surfactant O
has O
a O
significant O
impact O
on O
the O
elimination O
way O
of O
the O
nano O
- O
emulsion O
droplets O
, O
shared O
between O
liver O
and O
kidneys O
. O

The O
purified O
nano O
- O
emulsions O
are O
preferentially O
eliminated O
by O
the O
kidneys O
in O
contrast O
to O
raw O
nano O
- O
emulsions O
, O
predominantly O
eliminated O
by O
the O
liver O
. O

In O
practice O
, O
for O
two O
similar O
suspensions O
, O
half O
- O
life O
decreases O
from O
4 O
. O
1 O
+ O
/ O
- O
1 O
. O
10h O
to O
2 O
. O
5 O
+ O
/ O
- O
0 O
. O
77h O
before O
and O
after O
purification O
. O

Since O
the O
design O
and O
development O
of O
long O
circulating O
systems O
are O
critical O
in O
numerous O
domains O
, O
and O
not O
for O
preclinical O
CT O
imaging O
, O
this O
study O
presents O
important O
results O
in O
that O
field O
, O
taken O
under O
a O
formulation O
and O
technical O
point O
of O
view O
. O

Medium O
and O
high O
oxidation O
state O
metal O
/ O
non O
- O
metal B
fluoride I
and I
oxide I
- O
fluoride B
complexes O
with O
neutral O
donor O
ligands O
. O

While O
most O
high O
and O
medium O
oxidation O
state O
( O
O O
. O
S O
. O
> O
= O
3 O
) O
metal O
and O
non O
- O
metal B
fluorides I
and I
oxide I
fluorides I
are O
strong O
Lewis B
acids I
, O
exploration O
of O
their O
coordination O
chemistry O
with O
neutral O
ligands O
has O
been O
limited O
and O
mostly O
non O
- O
systematic O
. O

This O
is O
despite O
the O
very O
different O
properties O
conferred O
on O
the O
acceptor O
centre O
by O
the O
small O
electronegative O
fluoride B
ligands O
compared O
to O
the O
heavier O
halides B
. O

This O
article O
sets O
out O
these O
key O
differences O
, O
discusses O
possible O
synthetic O
routes O
, O
the O
key O
characterisation O
techniques O
, O
and O
appropriate O
bonding O
models O
. O

Current O
knowledge O
of O
the O
coordination O
chemistry O
of O
d B
, O
f B
and O
p B
- I
block I
fluorides B
and I
oxide I
fluorides I
with O
neutral O
ligands O
( O
with O
donor O
atoms O
drawn O
from O
Groups O
15 O
and O
16 O
and O
including O
N B
- I
heterocyclic I
carbenes I
) O
is O
then O
presented O
and O
discussed O
, O
and O
the O
differences O
in O
properties O
compared O
to O
complexes O
containing O
the O
heavier O
halides B
are O
illustrated O
. O

The O
emphasis O
is O
on O
work O
published O
post O
1990 O
, O
but O
earlier O
work O
is O
also O
included O
as O
essential O
background O
and O
where O
no O
more O
recent O
information O
exists O
. O

Attention O
is O
drawn O
to O
unexplored O
areas O
meriting O
investigation O
and O
to O
possible O
applications O
of O
these O
complexes O
. O

Caffeine B
, O
extraversion O
and O
working O
memory O
. O

Research O
has O
shown O
that O
extraverts O
performing O
a O
working O
memory O
task O
benefit O
more O
from O
caffeine B
than O
do O
introverts O
. O

The O
present O
study O
aimed O
to O
replicate O
this O
and O
extend O
our O
knowledge O
by O
using O
a O
lower O
dose O
of O
caffeine B
( O
65 O
mg O
) O
and O
a O
range O
of O
tasks O
related O
to O
different O
components O
of O
working O
memory O
. O

In O
addition O
, O
tasks O
assessing O
psychomotor O
speed O
and O
the O
encoding O
of O
new O
information O
were O
included O
to O
determine O
whether O
caffeine B
- O
extraversion O
interactions O
were O
restricted O
to O
working O
memory O
tasks O
. O

A O
double O
- O
blind O
design O
was O
used O
, O
with O
128 O
participants O
being O
randomly O
assigned O
to O
caffeinated O
or O
de O
- O
caffeinated O
coffee O
conditions O
. O

The O
results O
showed O
that O
caffeine B
interacted O
with O
extraversion O
in O
the O
predicted O
direction O
for O
serial O
recall O
and O
running O
memory O
tasks O
. O

Caffeine B
improved O
simple O
reaction O
time O
and O
the O
speed O
of O
encoding O
of O
new O
information O
, O
effects O
which O
were O
not O
modified O
by O
extraversion O
. O

These O
results O
suggest O
possible O
biological O
mechanisms O
underlying O
effects O
of O
caffeine B
on O
cognitive O
performance O
. O

Quantitative O
analysis O
of O
the O
interaction O
of O
constitutive O
androstane B
receptor O
with O
chemicals O
and O
steroid B
receptor O
coactivator O
1 O
using O
surface O
plasmon O
resonance O
biosensor O
systems O
: O
a O
case O
study O
of O
the O
Baikal O
seal O
( O
Pusa O
sibirica O
) O
and O
the O
mouse O
. O

The O
constitutive O
androstane B
receptor O
( O
CAR O
) O
not O
only O
displays O
a O
high O
basal O
transcriptional O
activity O
but O
also O
acts O
as O
a O
ligand O
- O
dependent O
transcriptional O
factor O
. O

It O
is O
known O
that O
CAR O
exhibits O
different O
ligand O
profiles O
across O
species O
. O

However O
, O
the O
mechanisms O
underlying O
CAR O
activation O
by O
chemicals O
and O
the O
species O
- O
specific O
responses O
are O
not O
fully O
understood O
. O

The O
objectives O
of O
this O
study O
are O
to O
establish O
a O
high O
- O
throughput O
tool O
to O
screen O
CAR O
ligands O
and O
to O
clarify O
how O
CAR O
proteins O
from O
the O
Baikal O
seal O
( O
bsCAR O
) O
and O
the O
mouse O
( O
mCAR O
) O
interact O
with O
chemicals O
and O
steroid B
receptor O
coactivator O
1 O
( O
SRC1 O
) O
. O

We O
developed O
the O
surface O
plasmon O
resonance O
( O
SPR O
) O
system O
to O
assess O
quantitatively O
the O
interaction O
of O
CAR O
with O
potential O
ligands O
and O
SRC1 O
. O

The O
ligand O
- O
binding O
domain O
( O
LBD O
) O
of O
bsCAR O
and O
mCAR O
was O
synthesized O
in O
a O
wheat O
germ O
cell O
- O
free O
system O
. O

The O
purified O
CAR O
LBD O
was O
then O
immobilized O
on O
the O
sensor O
chip O
for O
the O
SPR O
assay O
, O
and O
the O
kinetics O
of O
direct O
interaction O
of O
CARs O
with O
ligand O
candidates O
was O
measured O
. O

Androstanol B
and O
androstenol B
, O
estrone B
, O
17 B
beta I
- I
estradiol I
, O
TCPOBOP B
, O
and O
CITCO B
showed O
compound O
- O
specific O
but O
similar O
affinities O
for O
both O
CARs O
. O

The O
CAR O
- O
SRC1 O
interaction O
was O
ligand O
dependent O
but O
exhibited O
a O
different O
ligand O
profile O
between O
the O
seal O
and O
the O
mouse O
. O

The O
results O
of O
SRC1 O
interaction O
assay O
accounted O
for O
those O
of O
our O
previous O
in O
vitro O
CAR O
- O
mediated O
transactivation O
assay O
. O

In O
silico O
analyses O
also O
supported O
the O
results O
of O
CAR O
- O
SRC1 O
interaction O
; O
there O
is O
little O
structural O
difference O
in O
the O
ligand O
- O
binding O
pocket O
of O
bsCAR O
and O
mCAR O
, O
but O
there O
is O
a O
distinct O
discrimination O
in O
the O
helix O
11 O
and O
12 O
of O
these O
receptors O
, O
suggesting O
that O
the O
interaction O
of O
ligand O
- O
bound O
CAR O
and O
SRC1 O
is O
critical O
for O
determining O
species O
- O
specific O
and O
ligand O
- O
dependent O
transactivation O
over O
the O
basal O
activity O
. O

The O
SPR O
assays O
demonstrated O
a O
potential O
as O
a O
high O
- O
throughput O
screening O
tool O
of O
CAR O
ligands O
. O

Obesity O
and O
addiction O
: O
neurobiological O
overlaps O
. O

Drug O
addiction O
and O
obesity O
appear O
to O
share O
several O
properties O
. O

Both O
can O
be O
defined O
as O
disorders O
in O
which O
the O
saliency O
of O
a O
specific O
type O
of O
reward O
( O
food O
or O
drug O
) O
becomes O
exaggerated O
relative O
to O
, O
and O
at O
the O
expense O
of O
others O
rewards O
. O

Both O
drugs O
and O
food O
have O
powerful O
reinforcing O
effects O
, O
which O
are O
in O
part O
mediated O
by O
abrupt O
dopamine B
increases O
in O
the O
brain O
reward O
centres O
. O

The O
abrupt O
dopamine B
increases O
, O
in O
vulnerable O
individuals O
, O
can O
override O
the O
brain O
' O
s O
homeostatic O
control O
mechanisms O
. O

These O
parallels O
have O
generated O
interest O
in O
understanding O
the O
shared O
vulnerabilities O
between O
addiction O
and O
obesity O
. O

Predictably O
, O
they O
also O
engendered O
a O
heated O
debate O
. O

Specifically O
, O
brain O
imaging O
studies O
are O
beginning O
to O
uncover O
common O
features O
between O
these O
two O
conditions O
and O
delineate O
some O
of O
the O
overlapping O
brain O
circuits O
whose O
dysfunctions O
may O
underlie O
the O
observed O
deficits O
. O

The O
combined O
results O
suggest O
that O
both O
obese O
and O
drug O
- O
addicted O
individuals O
suffer O
from O
impairments O
in O
dopaminergic O
pathways O
that O
regulate O
neuronal O
systems O
associated O
not O
only O
with O
reward O
sensitivity O
and O
incentive O
motivation O
, O
but O
also O
with O
conditioning O
, O
self O
- O
control O
, O
stress O
reactivity O
and O
interoceptive O
awareness O
. O

In O
parallel O
, O
studies O
are O
also O
delineating O
differences O
between O
them O
that O
centre O
on O
the O
key O
role O
that O
peripheral O
signals O
involved O
with O
homeostatic O
control O
exert O
on O
food O
intake O
. O

Here O
, O
we O
focus O
on O
the O
shared O
neurobiological O
substrates O
of O
obesity O
and O
addiction O
. O

Cellular O
assessment O
of O
the O
extract O
of O
bambangan O
( O
Mangifera O
pajang O
) O
as O
a O
potential O
cytoprotective O
agent O
for O
the O
human O
hepatocellular O
HepG2 O
cell O
line O
. O

This O
study O
was O
conducted O
to O
investigate O
the O
potential O
of O
bambangan O
( O
Mangifera O
pajang O
) O
fruit O
extracts O
in O
the O
protection O
against O
oxidative O
damage O
caused O
by O
tert B
- I
butyl I
hydroperoxide I
in O
the O
human O
hepatocellular O
HepG2 O
cell O
line O
. O

Proteins O
which O
might O
be O
involved O
in O
the O
cytoprotective O
mechanism O
were O
investigated O
using O
western O
blotting O
technique O
. O

Quercetin B
was O
used O
as O
a O
positive O
control O
. O

The O
results O
showed O
that O
only O
the O
kernel O
extract O
of O
M O
. O
pajang O
and O
quercetin B
displayed O
cytoprotective O
activity O
in O
HepG2 O
cells O
, O
with O
EC O
( O
50 O
) O
values O
of O
1 O
. O
2 O
and O
5 O
. O
3 O
mu O
g O
/ O
ml O
, O
respectively O
. O

Expression O
of O
quinone B
reductase O
, O
glutathione B
reductase O
and O
methionine B
sulfoxide I
reductase O
A O
proteins O
were O
significantly O
up O
- O
regulated O
by O
quercetin B
, O
suggesting O
their O
involvement O
in O
the O
cytoprotective O
activity O
of O
quercetin B
. O

However O
, O
expressions O
of O
only O
glutathione B
reductase O
and O
methionine B
sulfoxide I
reductase O
A O
proteins O
were O
significantly O
up O
- O
regulated O
by O
the O
kernel O
extract O
, O
again O
suggesting O
their O
involvement O
in O
the O
cytoprotective O
activity O
of O
bambangan O
kernel O
extract O
. O

Future O
study O
is O
needed O
to O
investigate O
the O
involvement O
of O
other O
cytoprotective O
proteins O
in O
the O
cytoprotection O
mechanism O
. O

Stability O
of O
bioactive O
polyphenols B
from O
honey O
during O
different O
extraction O
methods O
. O

The O
LC O
- O
MS O
/ O
MS O
technique O
was O
applied O
to O
the O
stability O
study O
of O
several O
flavonoids B
and O
phenolic B
acids I
in O
honey O
samples O
during O
the O
ultrasonic O
extraction O
( O
USE O
) O
and O
microwave O
- O
assisted O
extraction O
( O
MAE O
) O
. O

Phenolic O
compounds O
from O
the O
standard O
mixture O
were O
stable O
under O
ultrasounds O
action O
with O
the O
mean O
recovery O
of O
( O
90 O
. O
4 O
% O
+ O
/ O
- O
7 O
. O
1 O
% O
) O
, O
but O
during O
microwave O
- O
assisted O
extraction O
the O
benzoic B
acid I
derivatives O
and O
aglycones O
of O
flavonoids B
showed O
lower O
recovery O
( O
70 O
- O
80 O
% O
) O
. O

In O
honey O
matrix O
, O
the O
phenolic B
acids I
and O
the O
glycosides O
exhibited O
the O
high O
stability O
for O
MAE O
and O
USE O
treatments O
. O

However O
, O
the O
recoveries O
of O
tested O
aglycones O
were O
below O
10 O
% O
. O

In O
the O
presence O
of O
an O
artificial O
sugar B
matrix O
, O
flavonols B
were O
almost O
completely O
degraded O
after O
successive O
treatment O
under O
MAE O
and O
USE O
conditions O
. O

The O
obtained O
results O
indicated O
that O
standard O
addition O
method O
for O
flavonoids B
quantification O
in O
honey O
samples O
should O
not O
be O
recommended O
. O

Application O
of O
the O
USE O
conditions O
provided O
higher O
and O
/ O
or O
similar O
extraction O
yields O
for O
phenolic B
acids I
than O
usually O
applied O
shaking O
with O
solvent O
. O

It O
also O
allowed O
shortening O
the O
time O
required O
for O
the O
whole O
sample O
preparation O
procedure O
. O

Phenolic B
acids I
and I
glycosides I
such O
as O
quercetrin B
, O
rutin B
and O
hesperidin B
appeared O
to O
be O
stable O
under O
such O
conditions O
. O

A O
novel O
one O
- O
step O
microbial O
transformation O
of O
betulin B
to O
betulinic B
acid I
catalysed O
by O
Cunninghamella O
blakesleeana O
. O

Betulinic B
acid I
and O
its O
derivatives O
are O
potential O
bioactive O
compounds O
present O
in O
nature O
. O

This O
study O
investigated O
the O
biotransformation O
of O
betulin B
to O
betulinic B
acid I
by O
Cunninghamella O
blakesleeana O
cells O
. O

LC O
- O
MS O
analysis O
demonstrated O
that O
betulin B
could O
be O
transformed O
into O
at O
least O
five O
products O
from O
cultured O
C O
. O
blakesleeana O
cells O
, O
among O
which O
betulinic B
acid I
was O
the O
most O
important O
. O

The O
presented O
method O
provides O
an O
attractive O
alternative O
approach O
to O
chemical O
synthesis O
, O
because O
is O
less O
time O
- O
consuming O
and O
more O
environmentally O
friendly O
. O

C O
. O
blakesleeana O
can O
transform O
betulin B
into O
potent O
derivatives O
with O
high O
pharmacological O
activities O
. O

Bioefficacy O
of O
EPA B
- O
DHA B
from O
lipids O
recovered O
from O
fish O
processing O
wastes O
through O
biotechnological O
approaches O
. O

The O
effect O
of O
fish O
oil O
recovered O
from O
fish O
visceral O
waste O
( O
FVW O
- O
FO O
) O
on O
serum O
and O
liver O
lipids O
, O
activity O
of O
HMG B
- I
CoA I
reductase O
in O
liver O
microsomes O
and O
EPA B
+ O
DHA B
incorporation O
in O
liver O
, O
heart O
and O
brain O
were O
evaluated O
. O

Rats O
were O
fed O
different O
concentrations O
of O
FVW O
- O
FO O
providing O
1 O
. O
25 O
% O
, O
2 O
. O
50 O
% O
, O
5 O
. O
0 O
% O
EPA B
+ O
DHA B
recovered O
by O
either O
fermentation O
or O
enzymatic O
hydrolysis O
for O
8weeks O
. O

Feeding O
FVW O
- O
FO O
reduce O
triacylglycerols B
( O
5 O
. O
96 O
- O
20 O
. O
3 O
% O
) O
, O
total O
cholesterol B
( O
7 O
. O
9 O
- O
21 O
. O
5 O
% O
) O
and O
LDL O
( O
7 O
. O
39 O
- O
21 O
. O
7 O
% O
) O
cholesterol B
levels O
in O
serum O
compared O
to O
group O
fed O
on O
a O
control O
diet O
( O
groundnut O
oil O
) O
. O

The O
activity O
of O
HMG B
- I
CoA I
reductase O
was O
reduced O
( O
p O
< O
0 O
. O
05 O
) O
in O
the O
FVW O
- O
FO O
fed O
groups O
compared O
to O
the O
control O
. O

EPA B
+ O
DHA B
level O
in O
serum O
, O
liver O
, O
brain O
and O
heart O
increased O
with O
increments O
in O
dietary O
EPA B
+ O
DHA B
. O

Results O
show O
the O
hypolipidemic O
property O
of O
FVW O
- O
FO O
and O
reduced O
HMG B
- I
CoA I
reductase O
activity O
which O
is O
proportional O
to O
the O
incorporation O
of O
EPA B
+ O
DHA B
. O

Recovery O
of O
FVW O
- O
FO O
will O
address O
the O
increasing O
demand O
for O
fish O
oil O
and O
reduce O
pollution O
problems O
. O

C B
- I
dideoxyhexosyl I
flavones I
from O
the O
stems O
and O
leaves O
of O
Passiflora O
edulis O
Sims O
. O

The O
stems O
and O
leaves O
of O
Passiflora O
edulis O
Sims O
, O
are O
used O
as O
a O
folk O
medicine O
for O
treating O
both O
anxiety O
and O
nervousness O
in O
American O
countries O
. O

Phytochemical O
investigation O
of O
the O
n B
- I
butanol I
( O
n B
- I
BuOH I
) O
fraction O
of O
this O
plant O
led O
to O
the O
isolation O
of O
four O
new O
2 B
, I
6 I
- I
dideoxyhexose I
- I
C I
- I
glycosyl I
flavones I
, O
including O
luteolin B
- I
8 I
- I
C I
- I
beta I
- I
digitoxopyranosyl I
- I
4 I
' I
- I
O I
- I
beta I
- I
d I
- I
glucopyranoside I
( O
1 O
) O
, O
apigenin B
- I
8 I
- I
C I
- I
beta I
- I
digitoxopyranoside I
( O
2 O
) O
, O
apigenin B
- I
8 I
- I
C I
- I
beta I
- I
boivinopyranoside I
( O

3 O
) O
and O
luteolin B
- I
8 I
- I
C I
- I
beta I
- I
boivinopyranoside I
( O
4 O
) O
, O
together O
with O
five O
known O
compounds O
( O
5 O
- O
9 O
) O
. O

The O
structures O
of O
these O
compounds O
were O
elucidated O
by O
extensive O
spectroscopic O
methods O
. O

All O
compounds O
were O
evaluated O
for O
their O
neurite O
outgrowth O
enhancing O
activities O
and O
the O
results O
indicated O
that O
luteolin B
( O
7 O
) O
enhanced O
NGF O
- O
induced O
neurite O
outgrowth O
in O
PC12 O
cells O
at O
50 O
. O
0 O
mu O
M O
. O

Phytochemical O
profile O
of O
Rosmarinus O
officinalis O
and O
Salvia O
officinalis O
extracts O
and O
correlation O
to O
their O
antioxidant O
and O
anti O
- O
proliferative O
activity O
. O

The O
goal O
of O
this O
study O
was O
to O
monitor O
the O
anti O
- O
proliferative O
activity O
of O
Rosmarinus O
officinalis O
and O
Salvia O
officinalis O
extracts O
against O
cancer O
cells O
and O
to O
correlate O
this O
activity O
with O
their O
phytochemical O
profiles O
using O
liquid O
chromatography O
/ O
diode O
array O
detection O
/ O
electrospray O
ion O
trap O
tandem O
mass O
spectrometry O
( O
LC O
/ O
DAD O
/ O
ESI O
- O
MS O
( O
n O
) O
) O
. O

For O
the O
quantitative O
estimation O
of O
triterpenic B
acids I
in O
the O
crude O
extracts O
an O
NMR O
based O
methodology O
was O
used O
and O
compared O
with O
the O
HPLC O
measurements O
, O
both O
applied O
for O
the O
first O
time O
, O
for O
the O
case O
of O
betulinic B
acid I
. O

Both O
extracts O
exerted O
cytotoxic O
activity O
through O
dose O
- O
dependent O
impairment O
of O
viability O
and O
mitochondrial O
activity O
of O
rat O
insulinoma O
m5F O
( O
RINm5F O
) O
cells O
. O

Decrease O
of O
RINm5F O
viability O
was O
mediated O
by O
nitric B
oxide I
( O
NO B
) O
- O
induced O
apoptosis O
. O

Importantly O
, O
these O
extracts O
potentiated O
NO B
and O
TNF O
- O
alpha O
release O
from O
macrophages O
therefore O
enhancing O
their O
cytocidal O
action O
. O

The O
rosemary O
extract O
developed O
more O
pronounced O
antioxidant O
, O
cytotoxic O
and O
immunomodifying O
activities O
, O
probably O
due O
to O
the O
presence O
of O
betulinic B
acid I
and O
a O
higher O
concentration O
of O
carnosic B
acid I
in O
its O
phytochemical O
profile O
. O

Phenylalanine B
ammonia B
lyase O
( O
PAL O
) O
enzyme O
activity O
and O
antioxidant O
properties O
of O
some O
cyanobacteria O
isolates O
. O

In O
the O
present O
study O
, O
six O
cyanobacteria O
isolates O
were O
evaluated O
for O
the O
PAL O
enzyme O
activity O
, O
and O
their O
methanol B
extracts O
were O
assessed O
for O
the O
total O
phenolic O
amount O
and O
other O
antioxidant O
parameters O
. O

Synechocystis O
sp O
. O

BASO444 O
and O
Synechocystis O
sp O
. O

BASO673 O
isolates O
with O
high O
levels O
of O
total O
phenols B
( O
66 O
. O
0 O
+ O
/ O
- O
1 O
. O
2 O
mu O
g O
/ O
mg O
, O
78 O
. O
1 O
+ O
/ O
- O
1 O
. O
8 O
mu O
g O
/ O
mg O
, O
respectively O
) O
also O
showed O
high O
levels O
of O
PAL O
activities O
( O
20 O
. O
5 O
+ O
/ O
- O
3 O
. O
1U O
/ O
mg O
protein O
, O
17 O
. O
2 O
+ O
/ O
- O
2 O
. O
3U O
/ O
mg O
protein O
, O
respectively O
) O
and O
strong O
antioxidant O
activities O
. O

To O
understand O
the O
effect O
of O
l B
- I
phenylalanine I
( O
l B
- I
phe I
) O
on O
the O
PAL O
activity O
, O
total O
phenolic O
amount O
, O
and O
phenolic B
constituents O
, O
isolates O
were O
evaluated O
with O
100mg O
/ O
l O
l B
- I
phe I
. O

While O
PAL O
activities O
exhibited O
no O
significant O
change O
with O
l B
- I
phe I
addition O
, O
total O
phenolic O
amount O
of O
the O
isolates O
significantly O
increased O
. O

HPLC O
analysis O
revealed O
gallic B
acid I
, O
trans B
- I
cinnamic I
acid I
, O
p B
- I
coumaric I
acid I
, O
and O
ferulic B
acid I
as O
the O
main O
compounds O
. O

Results O
suggested O
that O
the O
two O
isolate O
mights O
be O
an O
important O
source O
for O
the O
l B
- I
phe I
inducible O
phenolic O
compounds O
. O

Ginger O
extract O
and O
zingerone B
ameliorated O
trinitrobenzene B
sulphonic I
acid I
- O
induced O
colitis O
in O
mice O
via O
modulation O
of O
nuclear O
factor O
- O
kappa O
B O
activity O
and O
interleukin O
- O
1 O
beta O
signalling O
pathway O
. O

Ginger O
is O
a O
commonly O
used O
spice O
with O
anti O
- O
inflammatory O
potential O
. O

Colitis O
is O
the O
common O
pathological O
lesion O
of O
inflammatory O
bowel O
diseases O
. O

In O
this O
study O
, O
we O
investigated O
the O
therapeutic O
effects O
of O
ginger O
and O
its O
component O
zingerone B
in O
mice O
with O
2 B
, I
4 I
, I
6 I
- I
trinitrobenzene I
sulphonic I
acid I
( O
TNBS B
) O
- O
induced O
colitis O
. O

Ginger O
and O
zingerone B
ameliorated O
TNBS O
- O
induced O
colonic O
injury O
in O
a O
dose O
- O
dependent O
manner O
. O

Pathway O
analysis O
of O
ginger O
- O
and O
zingerone B
- O
regulated O
gene O
expression O
profiles O
showed O
that O
ginger O
and O
zingerone B
significantly O
regulated O
cytokine O
- O
related O
pathways O
. O

Network O
analysis O
showed O
that O
nuclear O
factor O
- O
kappa O
B O
( O
NF O
- O
kappa O
B O
) O
and O
interleukin O
- O
1 O
beta O
( O
IL O
- O
1 O
beta O
) O
were O
key O
molecules O
involved O
in O
the O
expression O
of O
ginger O
- O
and O
zingerone B
- O
affected O
genes O
. O

Ex O
vivo O
imaging O
and O
immunohistochemical O
staining O
further O
verified O
that O
ginger O
and O
zingerone B
suppressed O
TNBS O
- O
induced O
NF O
- O
kappa O
B O
activation O
and O
IL O
- O
1 O
beta O
protein O
level O
in O
the O
colon O
. O

In O
conclusion O
, O
ginger O
improved O
TNBS O
- O
induced O
colitis O
via O
modulation O
of O
NF O
- O
kappa O
B O
activity O
and O
IL O
- O
1 O
beta O
signalling O
pathway O
. O

Moreover O
, O
zingerone B
might O
be O
the O
active O
component O
of O
ginger O
responsible O
for O
the O
amelioration O
of O
colitis O
induced O
by O
TNBS O
. O

Metabolite O
profiling O
of O
phenolic B
and O
carotenoid O
contents O
in O
tomatoes O
after O
moderate O
- O
intensity O
pulsed O
electric O
field O
treatments O
. O

A O
metabolite O
profiling O
approach O
was O
used O
to O
study O
the O
effect O
of O
moderate O
- O
intensity O
pulsed O
electric O
field O
( O
MIPEF O
) O
treatments O
on O
the O
individual O
polyphenol B
and O
carotenoid O
contents O
of O
tomato O
fruit O
after O
refrigeration O
at O
4 O
degrees O
C O
for O
24h O
. O

The O
MIPEF O
processing O
variables O
studied O
were O
electric O
field O
strength O
( O
from O
0 O
. O
4 O
to O
2 O
. O
0kV O
/ O
cm O
) O
and O
number O
of O
pulses O
( O
from O
5 O
to O
30 O
) O
. O

Twenty O
four O
hours O
after O
MIPEF O
treatments O
, O
an O
increase O
was O
observed O
in O
hydroxycinnamic B
acids I
and O
flavanones B
, O
whereas O
flavonols B
, O
coumaric B
and I
ferulic I
acid I
- I
O I
- I
glucoside I
were O
not O
affected O
. O

Major O
changes O
were O
also O
observed O
for O
carotenoids O
, O
except O
for O
the O
5 B
- I
cis I
- I
lycopene I
isomer O
, O
which O
remain O
unchanged O
after O
24h O
of O
MIPEF O
treatments O
. O

MIPEF O
treatments O
, O
conducted O
at O
1 O
. O
2kV O
/ O
cm O
and O
30 O
pulses O
, O
led O
to O
the O
greatest O
increases O
in O
chlorogenic B
( O
152 O
% O
) O
, O
caffeic B
acid I
- I
O I
- I
glucoside I
( O
170 O
% O
) O
and O
caffeic B
( O
140 O
% O
) O
acids O
. O

On O
the O
other O
hand O
, O
treatments O
at O
1 O
. O
2kV O
/ O
cm O
and O
5 O
pulses O
led O
to O
maximum O
increases O
of O
alpha B
- I
carotene I
, O
9 B
- I
and I
13 I
- I
cis I
- I
lycopene I
, O
which O
increased O
by O
93 O
% O
, O
94 O
% O
and O
140 O
% O
, O
respectively O
. O

Therefore O
, O
MIPEF O
could O
stimulate O
synthesis O
of O
secondary O
metabolites O
and O
contribute O
to O
production O
of O
tomatoes O
with O
high O
individual O
polyphenol B
and O
carotenoid O
contents O
. O

Amino B
acid I
composition O
, O
antinutrients O
and O
allergens O
in O
the O
peanut O
protein O
fraction O
obtained O
by O
an O
aqueous O
enzymatic O
process O
. O

Enzyme O
- O
assisted O
aqueous O
extraction O
( O
EAE O
) O
of O
peanut O
kernel O
was O
used O
to O
extract O
oil O
and O
protein O
. O

The O
aqueous O
fraction O
( O
AF O
) O
obtained O
by O
EAE O
had O
a O
better O
essential O
amino B
acid I
profile O
than O
the O
residues O
obtained O
by O
solvent O
extraction O
( O
Rs O
) O
and O
cold O
pressing O
( O
Rc O
) O
. O

No O
major O
difference O
in O
the O
trypsin O
inhibitor O
activity O
among O
AF O
, O
Rs O
and O
Rc O
was O
observed O
; O
however O
, O
the O
trypsin O
inhibitor O
activity O
was O
drastically O
reduced O
in O
the O
residue O
obtained O
after O
EAE O
. O

AF O
was O
subjected O
to O
MALDI O
- O
TOF O
/ O
MS O
, O
revealing O
it O
to O
be O
rich O
in O
peptides O
( O
107 O
) O
with O
molecular O
masses O
from O
m O
/ O
z O
700 O
to O
2369Da O
. O

AF O
had O
an O
extremely O
low O
phytate B
content O
and O
was O
rich O
in O
peptides O
, O
which O
could O
be O
used O
as O
a O
food O
supplement O
. O

ESI O
- O
MS O
/ O
MS O
data O
were O
used O
for O
the O
identification O
of O
major O
peanut O
allergens O
, O
viz O
. O
, O
Ara O
h1 O
, O
h3 O
, O
h6 O
- O
8 O
. O

Their O
allergenic O
potential O
needs O
to O
be O
established O
. O

Determination O
of O
volatile O
compounds O
in O
New O
Zealand O
Greenshell O
( O
TM O
) O
mussels O
( O
Perna O
canaliculus O
) O
during O
chilled O
storage O
using O
solid O
phase O
microextraction O
gas O
chromatography O
- O
mass O
spectrometry O
. O

Greenshell O
( O
TM O
) O
mussels O
( O
Perna O
canaliculus O
) O
were O
dry O
- O
stored O
at O
6 O
. O
44 O
+ O
/ O
- O
0 O
. O
54 O
degrees O
C O
for O
8 O
days O
during O
which O
time O
volatile O
organic O
compounds O
( O
VOCs O
) O
were O
monitored O
using O
SPME O
GC O
- O
MS O
. O

Thirty O
- O
four O
VOCs O
were O
identified O
in O
homogenised O
mussel O
meat O
and O
29 O
in O
the O
mussel O
liquor O
( O
i O
. O
e O
. O
the O
seawater O
enclosed O
in O
the O
mantle O
cavity O
) O
. O

Of O
the O
34 O
VOCs O
identified O
20 O
were O
reliably O
identified O
throughout O
the O
storage O
treatment O
and O
9 O
were O
found O
to O
change O
in O
relative O
concentration O
in O
homogenised O
mussel O
meat O
. O

Dimethyl B
sulphide I
, O
1 B
- I
penten I
- I
3 I
- I
ol I
, O
1 B
- I
hexen I
- I
3 I
- I
ol I
and O
1 B
- I
octen I
- I
3 I
- I
ol I
increased O
during O
storage O
, O
whereas O
pentanal B
, O
hexanal B
, O
heptanal B
, O
octanal B
and O
3 B
- I
undecen I
- I
2 I
- I
one I
decreased O
. O

In O
the O
mussel O
liquor O
, O
dimethyl B
sulphide I
was O
undetectable O
pre O
- O
storage O
, O
becoming O
detectable O
after O
2 O
days O
, O
and O
a O
large O
increase O
was O
noted O
after O
6 O
days O
. O

SPME O
GC O
- O
MS O
was O
a O
useful O
tool O
for O
monitoring O
VOC O
profiles O
of O
Greenshell O
( O
TM O
) O
mussels O
and O
could O
aid O
in O
the O
development O
of O
technologies O
that O
monitor O
and O
improve O
product O
quality O
and O
consistency O
. O

Phytochemical O
composition O
and O
in O
vitro O
antimicrobial O
and O
antioxidant O
activities O
of O
some O
medicinal O
plants O
. O

Different O
parts O
of O
three O
plants O
( O
Primula O
auriculata O
, O
Fumaria O
vaillantii O
and O
Falcaria O
vulgaris O
) O
were O
extracted O
with O
three O
different O
solvents O
to O
yield O
72 O
crude O
extracts O
. O

The O
phytochemical O
analysis O
( O
chemical O
screening O
, O
GC O
- O
MS O
) O
of O
three O
plants O
was O
investigated O
for O
their O
antioxidant O
and O
antibacterial O
activity O
using O
nine O
Gram O
- O
positive O
and O
Gram O
- O
negative O
bacteria O
. O

The O
principal O
antioxidant O
and O
antimicrobial O
components O
were O
determined O
using O
HPLC O
with O
UV O
detection O
. O

All O
extracts O
possessed O
antibacterial O
activity O
especially O
methanolic O
extracts O
from O
flowers O
of O
P O
. O
auriculata O
. O

The O
DPPH B
- O
radical O
scavenging O
assay O
exhibited O
high O
antioxidant O
activities O
in O
three O
plants O
( O
more O
than O
80 O
% O
at O
50 O
mu O
g O
) O
. O

The O
F O
. O
vulgaris O
showed O
high O
content O
of O
carvacrol B
( O
29 O
. O
8 O
% O
) O
as O
main O
component O
. O

The O
contents O
of O
carvacrol B
and O
fumaric B
acid I
in O
the O
methanolic O
- O
water O
extracts O
were O
1119 O
and O
1966mg O
/ O
l O
respectively O
. O

Our O
results O
indicate O
that O
these O
plants O
would O
be O
able O
to O
promise O
sources O
of O
natural O
products O
with O
potential O
antibacterial O
and O
antioxidant O
activity O
. O

Hypocholesterolemic O
effects O
of O
low O
calorie O
structured O
lipids O
on O
rats O
and O
rabbits O
fed O
on O
normal O
and O
atherogenic O
diet O
. O

The O
hypocholesterolemic O
effects O
of O
two O
low O
calorie O
structured O
lipids O
( O
SL1 O
and O
SL2 O
) O
containing O
essential O
fatty B
acids I
, O
prepared O
by O
lipase O
catalysed O
interesterification O
of O
ethyl B
behenate I
respectively O
with O
sunflower O
and O
soybean O
oils O
were O
studied O
in O
rats O
and O
rabbits O
. O

The O
feeding O
experiment O
conducted O
on O
rats O
as O
well O
as O
rabbits O
, O
fed O
on O
normal O
and O
atherogenic O
diet O
containing O
10 O
% O
of O
SL1 O
and O
SL2 O
( O
experimental O
) O
and O
sunflower O
oil O
( O
control O
) O
indicated O
no O
adverse O
effects O
on O
growth O
and O
food O
intake O
. O

However O
, O
the O
structured O
lipids O
beneficially O
lowered O
serum O
and O
liver O
lipids O
, O
particularly O
cholesterol B
, O
LDL O
cholesterol B
, O
triglycerides B
and O
also O
maintains O
the O
essential O
fatty B
acid I
status O
in O
serum O
and O
liver O
. O

The O
lipid O
deposition O
observed O
in O
the O
arteries O
of O
rabbits O
fed O
on O
atherogenic O
diets O
was O
significantly O
reduced O
when O
structured O
lipids O
were O
included O
in O
the O
diet O
. O

These O
observations O
coincided O
with O
reduced O
levels O
of O
serum O
cholesterol B
particularly O
LDL O
cholesterol B
observed O
in O
experimental O
groups O
. O

Therefore O
the O
structured O
lipids O
, O
designed O
to O
have O
low O
calorific O
value O
also O
beneficially O
lower O
serum O
lipids O
and O
lipid O
deposition O
in O
animals O
fed O
on O
atherogenic O
diets O
. O

Effects O
of O
solvent O
and O
alkaline O
earth O
metals O
on O
the O
heat O
- O
induced O
precipitation O
process O
of O
sodium B
caseinate O
. O

The O
precipitation O
temperatures O
of O
sodium B
caseinate O
in O
H B
( I
2 I
) I
O I
and O
D B
( I
2 I
) I
O I
in O
the O
presence O
of O
Mg B
( I
2 I
+ I
) I
, O
Ca B
( I
2 I
+ I
) I
, O
Sr B
( I
2 I
+ I
) I
and O
Ba B
( I
2 I
+ I
) I
were O
investigated O
through O
fluorescence O
, O
turbidity O
and O
conductivity O
experiments O
. O

As O
for O
the O
ability O
of O
the O
divalent O
cations O
( O
1 O
- O
17 O
. O
5mM O
) O
to O
induce O
the O
precipitation O
process O
in O
H B
( I
2 I
) I
O I
, O
the O
sequence O
Ba B
( I
2 I
+ I
) I
> O
= O
Ca B
( I
2 I
+ I
) I
> O
Mg B
( I
2 I
+ I
) I
> O
Sr B
( I
2 I
+ I
) I
was O
found O
. O

Remarkably O
, O
while O
at O
low O
salt O
concentrations O
( O
< O
10mM O
) O
precipitation O
temperatures O
( O
T O
( O
Ps O
) O
) O
were O
found O
to O
change O
significantly O
depending O
on O
the O
specific O
cation O
, O
at O
higher O
concentrations O
( O
> O
10mM O
) O
the O
differences O
among O
the O
different O
cations O
were O
greatly O
reduced O
. O

By O
fitting O
these O
results O
with O
a O
modified O
Jones O
- O
Dole O
equation O
, O
we O
confirmed O
that O
the O
less O
hydrated O
ions O
possess O
a O
greater O
capacity O
to O
induce O
precipitation O
. O

In O
D B
( I
2 I
) I
O I
, O
the O
order O
of O
ion O
ability O
to O
induce O
caseinate O
precipitation O
was O
Ba B
( I
2 I
+ I
) I
> O
Ca B
( I
2 I
+ I
) I
> O
Sr B
( I
2 I
+ I
) I
> O
Mg B
( I
2 I
+ I
) I
. O

The O
different O
hydrophobicity O
between O
D B
( I
2 I
) I
O I
and O
H B
( I
2 I
) I
O I
was O
shown O
to O
affect O
significantly O
the O
T O
( O
Ps O
) O
of O
caseinate O
in O
the O
presence O
of O
calcium B
, O
strontium B
and O
barium B
. O

Purification O
and O
characterisation O
of O
antibacterial O
peptide O
- O
containing O
compound O
derived O
from O
palm O
kernel O
cake O
. O

Palm O
kernel O
cake O
( O
PKC O
) O
, O
the O
most O
useful O
by O
- O
product O
resulted O
from O
palm O
kernel O
oil O
production O
. O

In O
this O
study O
, O
PKC O
- O
derived O
protein O
product O
was O
found O
suitable O
for O
use O
as O
an O
antimicrobial O
agent O
with O
potent O
antibacterial O
activity O
, O
particularly O
against O
Bacillus O
species O
, O
after O
enzymatic O
hydrolysis O
with O
alcalase O
. O

The O
hydrolysate O
was O
further O
purified O
by O
gel O
filtration O
chromatography O
. O

The O
purified O
fraction O
was O
found O
to O
have O
14 O
. O
63 O
+ O
/ O
- O
0 O
. O
70 O
% O
( O
w O
/ O
w O
) O
protein O
, O
a O
molecular O
mass O
of O
2 O
. O
4kDa O
and O
low O
hemolytic O
activity O
( O
< O
50 O
% O
hemolysis O
of O
human O
erythrocytes O
at O
concentration O
of O
1000 O
mu O
g O
/ O
ml O
) O
. O

The O
presence O
of O
lysine B
and O
the O
major O
component O
lauric B
acid I
derivative O
, O
as O
indicated O
by O
electrospray O
ionisation O
- O
mass O
spectrometry O
( O
ESI O
- O
MS O
) O
direct O
infusion O
and O
nuclear O
magnetic O
resonance O
( O
NMR O
) O
spectroscopy O
, O
may O
have O
contributed O
to O
the O
antibacterial O
effect O
of O
purified O
PKC O
fraction O
. O

This O
study O
suggests O
that O
the O
antibacterial O
PKC O
compound O
may O
be O
not O
a O
pure O
peptide O
but O
instead O
a O
peptide O
- O
containing O
compound O
high O
in O
lauric B
acid I
derivative O
. O

Therapeutic O
modulation O
of O
intestinal O
dysbiosis O
. O

The O
human O
gastrointestinal O
tract O
is O
home O
to O
an O
extremely O
numerous O
and O
diverse O
collection O
of O
microbes O
, O
collectively O
termed O
the O
" O
intestinal O
microbiota O
" O
. O

This O
microbiota O
is O
considered O
to O
play O
a O
number O
of O
key O
roles O
in O
the O
maintenance O
of O
host O
health O
, O
including O
aiding O
digestion O
of O
otherwise O
indigestible O
dietary O
compounds O
, O
synthesis O
of O
vitamins O
and O
other O
beneficial O
metabolites O
, O
immune O
system O
regulation O
and O
enhanced O
resistance O
against O
colonisation O
by O
pathogenic O
microorganisms O
. O

Conversely O
, O
the O
intestinal O
microbiota O
is O
also O
a O
potent O
source O
of O
antigens O
and O
potentially O
harmful O
compounds O
. O

In O
health O
, O
humans O
can O
therefore O
be O
considered O
to O
exist O
in O
a O
state O
of O
natural O
balance O
with O
their O
microbial O
inhabitants O
. O

A O
shift O
in O
the O
balance O
of O
microbiota O
composition O
such O
that O
it O
may O
become O
deleterious O
to O
host O
health O
is O
termed O
" O
dysbiosis O
" O
. O

Dysbiosis O
of O
the O
gut O
microbiota O
has O
been O
implicated O
in O
numerous O
disorders O
, O
ranging O
from O
intestinal O
maladies O
such O
as O
inflammatory O
bowel O
diseases O
and O
colorectal O
cancer O
to O
disorders O
with O
more O
systemic O
effects O
such O
as O
diabetes O
, O
metabolic O
syndrome O
and O
atopy O
. O

Given O
the O
far O
reaching O
influence O
of O
the O
intestinal O
microbiota O
on O
human O
health O
a O
clear O
future O
goal O
must O
be O
to O
develop O
reliable O
means O
to O
alter O
the O
composition O
of O
the O
microbiota O
and O
restore O
a O
healthy O
balance O
of O
microbial O
species O
. O

While O
it O
is O
clear O
that O
much O
fundamental O
research O
remains O
to O
be O
done O
, O
potentially O
important O
therapeutic O
options O
include O
narrow O
spectrum O
antibiotics O
, O
novel O
probiotics O
, O
dietary O
interventions O
and O
more O
radical O
techniques O
such O
as O
faecal O
transplantation O
, O
all O
of O
which O
aim O
to O
suppress O
clinical O
dysbiosis O
, O
restore O
intestinal O
microbiota O
diversity O
and O
improve O
host O
health O
. O

A O
review O
on O
antioxidants O
, O
prooxidants O
and O
related O
controversy O
: O
natural O
and O
synthetic O
compounds O
, O
screening O
and O
analysis O
methodologies O
and O
future O
perspectives O
. O

Many O
studies O
have O
been O
conducted O
with O
regard O
to O
free O
radicals O
, O
oxidative O
stress O
and O
antioxidant O
activity O
of O
food O
, O
giving O
antioxidants O
a O
prominent O
beneficial O
role O
, O
but O
, O
recently O
many O
authors O
have O
questioned O
their O
importance O
, O
whilst O
trying O
to O
understand O
the O
mechanisms O
behind O
oxidative O
stress O
. O

Many O
scientists O
defend O
that O
regardless O
of O
the O
quantity O
of O
ingested O
antioxidants O
, O
the O
absorption O
is O
very O
limited O
, O
and O
that O
in O
some O
cases O
prooxidants O
are O
beneficial O
to O
human O
health O
. O

The O
detection O
of O
antioxidant O
activity O
as O
well O
as O
specific O
antioxidant O
compounds O
can O
be O
carried O
out O
with O
a O
large O
number O
of O
different O
assays O
, O
all O
of O
them O
with O
advantages O
and O
disadvantages O
. O

The O
controversy O
around O
antioxidant O
in O
vivo O
benefits O
has O
become O
intense O
in O
the O
past O
few O
decades O
and O
the O
present O
review O
tries O
to O
shed O
some O
light O
on O
research O
on O
antioxidants O
( O
natural O
and O
synthetic O
) O
and O
prooxidants O
, O
showing O
the O
potential O
benefits O
and O
adverse O
effects O
of O
these O
opposing O
events O
, O
as O
well O
as O
their O
mechanisms O
of O
action O
and O
detection O
methodologies O
. O

It O
also O
identifies O
the O
limitations O
of O
antioxidants O
and O
provides O
a O
perspective O
on O
the O
likely O
future O
trends O
in O
this O
field O
. O

Effects O
of O
vitamin B
D I
on O
antigen O
- O
specific O
and O
non O
- O
antigen O
- O
specific O
immune O
modulation O
: O
relevance O
for O
type O
1 O
diabetes O
. O

Vitamin B
D I
is O
a O
fat O
- O
soluble O
precursor O
of O
the O
circulating O
25 B
- I
hydroxyvitamin I
D I
3 I
( O
25 B
( I
OH I
) I
D I
3 I
) O
which O
can O
be O
converted O
by O
the O
1 O
alpha O
- O
hydroxylase O
( O
1 B
alpha I
( I
OH I
) I
ase I
) O
enzyme O
into O
the O
bioactive O
hormonal O
metabolite O
1 B
, I
25 I
- I
dihydroxyvitamin I
D I
3 I
( O
1 B
, I
25 I
( I
OH I
) I
2 I
D I
3 I
) O
, O
generally O
known O
to O
promote O
bone O
mineralization O
through O
its O
ability O
to O
enhance O
calcium B
absorption O
from O
the O
gut O
. O

Importantly O
, O
in O
humans O
, O
vitamin B
D I
is O
mainly O
derived O
from O
endogenous O
production O
of O
vitamin B
D I
3 I
from O
ultraviolet O
( O
UV O
) O
radiation O
exposure O
to O
the O
skin O
while O
a O
small O
part O
( O
< O
10 O
% O
) O
is O
obtained O
via O
dietary O
intake O
of O
dairy O
products O
and O
fatty O
fish O
( O
1 O
) O
. O

Taking O
these O
factors O
into O
account O
, O
geographic O
distribution O
and O
seasonality O
, O
skin O
pigmentation O
, O
age O
, O
and O
lifestyle O
may O
predispose O
certain O
populations O
to O
be O
at O
a O
higher O
risk O
of O
developing O
vitamin B
D I
insufficiency O
or O
deficiency O
( O
2 O
) O
. O

The O
first O
valid O
reports O
correlating O
the O
importance O
of O
an O
adequate O
vitamin B
D I
status O
to O
optimal O
human O
health O
originate O
from O
the O
early O
part O
of O
the O
20th O
century O
, O
when O
vitamin B
D I
was O
described O
to O
prevent O
and O
treat O
the O
bone O
disease O
rickets O
. O

Since O
then O
, O
the O
findings O
that O
vitamin B
D I
receptors O
( O
VDR O
) O
are O
present O
in O
many O
body O
tissues O
and O
that O
vitamin B
D I
metabolizing O
enzymes O
can O
be O
found O
in O
various O
cells O
outside O
the O
kidney O
, O
including O
the O
intestine O
, O
prostate O
, O
immune O
cells O
, O
and O
within O
the O
skin O
itself O
( O
reviewed O
in O
reference O
3 O
) O
, O
have O
revolutionized O
the O
vitamin B
D I
business O
. O

In O
this O
review O
, O
we O
will O
mainly O
focus O
on O
vitamin B
D I
as O
a O
component O
of O
immune O
regulation O
and O
on O
the O
role O
of O
vitamin B
D I
in O
antigen O
- O
specific O
and O
non O
- O
specific O
therapies O
with O
potential O
relevance O
for O
type O
1 O
diabetes O
( O
T1D O
) O
. O

Developmental O
effects O
of O
prenatal O
di B
- I
n I
- I
hexyl I
phthalate I
and O
dicyclohexyl B
phthalate I
exposure O
on O
reproductive O
tract O
of O
male O
rats O
: O
Postnatal O
outcomes O
. O

The O
present O
study O
is O
to O
investigate O
the O
effects O
of O
in O
utero O
di B
- I
n I
- I
hexyl I
phthalate I
( O
DHP B
) O
and O
dicyclohexyl B
phthalate I
exposure O
( O
DCHP B
) O
on O
the O
development O
of O
male O
reproductive O
tract O
at O
prepubertal O
, O
pubertal O
and O
adult O
stages O
. O

Pregnant O
rats O
were O
exposed O
to O
DHP B
and O
DCHP B
at O
doses O
of O
0 O
, O
20 O
, O
100 O
and O
500mg O
/ O
kg O
/ O
day O
, O
by O
gavage O
, O
on O
gestational O
days O
( O
GD O
) O
6 O
- O
19 O
. O

Testosterone B
( O
T O
) O
levels O
of O
prepubertal O
rats O
diminished O
at O
high O
dose O
DHP B
and O
middle O
dose O
DCHP B
groups O
. O

MIS B
/ O
AMH O
levels O
elevated O
in O
DHP B
and O
DCHP B
groups O
. O

T O
levels O
of O
pubertal O
rats O
decreased O
in O
low O
and O
high O
dose O
DHP B
and O
DCHP B
groups O
. O

Inhibin O
B O
levels O
of O
adult O
rats O
diminished O
in O
DCHP B
groups O
. O

Atrophic O
and O
amorphous O
tubules O
, O
spermatogenic O
cell O
debris O
, O
apoptotic O
cells O
, O
adherent O
tubules O
, O
Sertoli O
cell O
vacuolisation O
, O
prostatic O
atrophic O
tubules O
and O
prostatic O
intraepithelial O
neoplasia O
( O
PIN O
) O
were O
observed O
in O
the O
reproductive O
organs O
of O
treated O
animals O
at O
all O
developmental O
stages O
. O

There O
was O
an O
increase O
in O
immunoexpression O
of O
MIS O
/ O
AMH O
in O
testes O
of O
treated O
rats O
. O

There O
were O
no O
changes O
in O
sperm O
head O
count O
but O
percentages O
of O
abnormal O
sperms O
increased O
. O

The O
diameters O
of O
seminiferous O
and O
epididymal O
tubules O
in O
treatment O
groups O
were O
significantly O
lower O
. O

This O
study O
shows O
that O
DHP B
and O
DCHP B
may O
have O
antiandrogenic O
effects O
on O
male O
reproductive O
development O
before O
and O
after O
birth O
. O

Modeling O
the O
binding O
mechanism O
of O
Alzheimer O
' O
s O
A O
beta O
1 O
- O
4 O
2 O
to O
nicotinic O
acetylcholine B
receptors O
based O
on O
similarity O
with O
snake O
alpha O
- O
neurotoxins O
. O

For O
over O
a O
decade O
, O
it O
has O
been O
known O
that O
amyloid O
beta O
( O
A O
beta O
) O
peptides O
of O
Alzheimer O
' O
s O
disease O
bind O
to O
the O
nicotinic O
alpha O
7 O
acetylcholine B
receptor O
( O
AChR O
) O
with O
picomolar O
affinity O
, O
and O
that O
snake O
alpha O
- O
neurotoxins O
competitively O
inhibit O
this O
binding O
. O

Here O
we O
propose O
a O
model O
of O
the O
binding O
mechanism O
of O
A O
beta O
peptides O
to O
alpha O
7 O
- O
AChR O
at O
atomic O
level O
. O

The O
binding O
mechanism O
is O
based O
on O
sequence O
and O
structure O
similarities O
of O
A O
beta O
residues O
with O
functional O
residues O
of O
snake O
alpha O
- O
neurotoxins O
( O
ATX O
) O
in O
complex O
with O
AChR O
. O

The O
binding O
mechanism O
involves O
residue O
( O
A O
beta O
) O
K28 O
( O
similar O
to O
( O
ATX O
) O
R32 O
) O
which O
forms O
cation O
/ O
pi O
interactions O
in O
the O
acetylcholine B
binding O
site O
, O
and O
residues O
( O
A O
beta O
) O
G29 O
- O
( O
A O
beta O
) O
I32 O
[ O
GAII O
] O
( O
similar O
to O
( O
ATX O
) O
G33 O
- O
( O
ATX O
) O
I36 O
[ O
GTII O
] O
) O
which O
form O
an O
intermolecular O
beta O
- O
sheet O
with O
residues O
( O
alpha O
7 O
) O
F189 O
- O
( O
alpha O
7 O
) O
E191 O
of O
AChR O
. O

Through O
these O
interactions O
, O
we O
propose O
that O
the O
AChR O
serves O
as O
a O
chaperone O
for O
A O
beta O
conformational O
changes O
from O
alpha O
- O
to O
beta O
- O
hairpin O
. O

The O
interactions O
which O
block O
channel O
opening O
provide O
fundamental O
insight O
into O
A O
beta O
neurotoxicity O
and O
cognition O
impairment O
, O
that O
could O
contribute O
to O
pathogenic O
processes O
in O
Alzheimer O
' O
s O
disease O
, O
thus O
paving O
the O
way O
for O
structure O
based O
therapies O
. O

Electrical O
detection O
of O
spin O
precession O
in O
freely O
suspended O
graphene B
spin O
valves O
on O
cross O
- O
linked O
poly B
( I
methyl I
methacrylate I
) I
. O

Spin O
injection O
and O
detection O
is O
achieved O
in O
freely O
suspended O
graphene B
using O
cobalt B
electrodes O
and O
a O
nonlocal O
spin O
- O
valve O
geometry O
. O

The O
devices O
are O
fabricated O
with O
a O
single O
electron O
- O
beam O
- O
resist O
poly B
( I
methyl I
methacrylate I
) I
process O
that O
minimizes O
both O
the O
fabrication O
steps O
and O
the O
number O
of O
( O
aggressive O
) O
chemicals O
used O
, O
greatly O
reducing O
contamination O
and O
increasing O
the O
yield O
of O
high O
- O
quality O
, O
mechanically O
stable O
devices O
. O

As O
- O
grown O
devices O
can O
present O
mobilities O
exceeding O
10 O
( O
4 O
) O
cm O
( O
2 O
) O
V O
( O
- O
1 O
) O
s O
( O
- O
1 O
) O
at O
room O
temperature O
and O
, O
because O
the O
contacts O
deposited O
on O
graphene B
are O
only O
exposed O
to O
acetone B
and O
isopropanol B
, O
the O
method O
is O
compatible O
with O
almost O
any O
contacting O
material O
. O

Spin O
accumulation O
and O
spin O
precession O
are O
studied O
in O
these O
nonlocal O
spin O
valves O
. O

Fitting O
of O
Hanle O
spin O
precession O
data O
in O
bilayer O
and O
multilayer O
graphene B
yields O
a O
spin O
relaxation O
time O
of O
~ O
125 O
- O
250 O
ps O
and O
a O
spin O
diffusion O
length O
of O
1 O
. O
7 O
- O
1 O
. O
9 O
mu O
m O
at O
room O
temperature O
. O

The O
organometallic O
chemistry O
of O
cycloheptatrienyl B
zirconium I
complexes O
. O

This O
tutorial O
review O
summarizes O
the O
organometallic O
chemistry O
derived O
from O
the O
half O
- O
sandwich O
complex O
[ B
( I
eta I
( I
7 I
) I
- I
C I
( I
7 I
) I
H I
( I
7 I
) I
) I
ZrCl I
( I
tmeda I
) I
] I
, O
which O
was O
used O
as O
an O
efficient O
and O
versatile O
starting O
material O
for O
the O
incorporation O
of O
monoanionic O
ligands O
into O
the O
cycloheptatrienyl B
zirconium I
coordination O
sphere O
by O
conventional O
salt O
metathesis O
reactions O
. O

A O
broad O
variety O
of O
ligands O
was O
employed O
, O
affording O
novel O
and O
previously O
inaccessible O
cycloheptatrienyl B
( O
sandwich O
) O
complexes O
of O
the O
type O
[ B
( I
eta I
( I
7 I
) I
- I
C I
( I
7 I
) I
H I
( I
7 I
) I
) I
Zr I
( I
Y I
) I
] I
; O
Y O
comprises O
pentadienyl B
, O
cyclopentadienyl B
, O
allyl B
, O
phospholyl B
, O
boratabenzene B
, O
imidazolin B
- I
2 I
- I
iminato I
and O
amido B
systems O
. O

The O
cycloheptatrienyl B
ring O
in O
these O
systems O
usually O
acts O
as O
an O
" O
innocent O
spectator O
ligand O
" O
, O
but O
reactivity O
can O
arise O
from O
the O
second O
ligand O
Y O
or O
the O
Lewis O
acidity O
of O
the O
, O
formally O
, O
Zr B
( I
+ I
iv I
) I
center O
, O
which O
was O
probed O
in O
selected O
examples O
and O
put O
in O
perspective O
to O
related O
studies O
. O

The O
corresponding O
results O
emphasize O
why O
the O
use O
of O
[ B
( I
eta I
( I
7 I
) I
- I
C I
( I
7 I
) I
H I
( I
7 I
) I
) I
ZrCl I
( I
tmeda I
) I
] I
is O
clearly O
an O
advancement O
in O
the O
chemistry O
of O
the O
still O
fairly O
unexplored O
area O
of O
cycloheptatrienyl B
transition I
metal I
complexes O
. O

Portal O
vein O
glucose B
entry O
triggers O
a O
coordinated O
cellular O
response O
that O
potentiates O
hepatic O
glucose B
uptake O
and O
storage O
in O
normal O
but O
not O
high O
- O
fat O
/ O
high O
- O
fructose B
- O
fed O
dogs O
. O

The O
cellular O
events O
mediating O
the O
pleiotropic O
actions O
of O
portal O
vein O
glucose B
( O
PoG O
) O
delivery O
on O
hepatic O
glucose B
disposition O
have O
not O
been O
clearly O
defined O
. O

Likewise O
, O
the O
molecular O
defects O
associated O
with O
postprandial O
hyperglycemia O
and O
impaired O
hepatic O
glucose B
uptake O
( O
HGU O
) O
following O
consumption O
of O
a O
high O
- O
fat O
, O
high O
- O
fructose B
diet O
( O
HFFD O
) O
are O
unknown O
. O

Our O
goal O
was O
to O
identify O
hepatocellular O
changes O
elicited O
by O
hyperinsulinemia O
, O
hyperglycemia O
, O
and O
PoG O
signaling O
in O
normal O
chow O
- O
fed O
( O
CTR O
) O
and O
HFFD O
- O
fed O
dogs O
. O

In O
CTR O
dogs O
, O
we O
demonstrated O
that O
PoG O
infusion O
in O
the O
presence O
of O
hyperinsulinemia O
and O
hyperglycemia O
triggered O
an O
increase O
in O
the O
activity O
of O
hepatic O
glucokinase O
( O
GK O
) O
and O
glycogen O
synthase O
( O
GS O
) O
, O
which O
occurred O
in O
association O
with O
further O
augmentation O
in O
HGU O
and O
glycogen O
synthesis O
( O
GSYN O
) O
in O
vivo O
. O

In O
contrast O
, O
4 O
weeks O
of O
HFFD O
feeding O
markedly O
reduced O
GK O
protein O
content O
and O
impaired O
the O
activation O
of O
GS O
in O
association O
with O
diminished O
HGU O
and O
GSYN O
in O
vivo O
. O

Furthermore O
, O
the O
enzymatic O
changes O
associated O
with O
PoG O
sensing O
in O
chow O
- O
fed O
animals O
were O
abolished O
in O
HFFD O
- O
fed O
animals O
, O
consistent O
with O
loss O
of O
the O
stimulatory O
effects O
of O
PoG O
delivery O
. O

These O
data O
reveal O
new O
insight O
into O
the O
molecular O
physiology O
of O
the O
portal O
glucose B
signaling O
mechanism O
under O
normal O
conditions O
and O
to O
the O
pathophysiology O
of O
aberrant O
postprandial O
hepatic O
glucose B
disposition O
evident O
under O
a O
diet O
- O
induced O
glucose B
- O
intolerant O
condition O
. O

Identification O
of O
the O
metabolites O
of O
lesogaberan B
using O
linear O
trap O
quadrupole O
orbitrap O
mass O
spectrometry O
and O
hydrophilic O
interaction O
liquid O
chromatography O
. O

1 O
. O
In O
this O
study O
, O
hydrophilic O
interaction O
liquid O
chromatography O
( O
HILIC O
) O
, O
radiochemical O
activity O
monitoring O
and O
linear O
trap O
quadrupole O
orbitrap O
mass O
spectrometry O
( O
MS O
) O
and O
tandem O
mass O
spectrometry O
( O
MS O
/ O
MS O
) O
were O
used O
to O
identify O
the O
metabolites O
of O
a O
highly O
polar O
novel O
gamma B
- I
aminobutyric I
acid I
type O
- O
B O
receptor O
agonist O
, O
lesogaberan B
, O
in O
rats O
. O

2 O
. O
Urine O
was O
collected O
from O
three O
male O
Wistar O
rats O
for O
24 O
h O
after O
dosing O
with O
( B
14 I
) I
C I
- O
labelled O
lesogaberan B
( O
170 O
mg O
/ O
kg O
, O
10 O
MBq O
/ O
kg O
) O
; O
plasma O
samples O
were O
taken O
2 O
and O
24 O
h O
after O
dosing O
. O

Pooled O
samples O
were O
separated O
by O
HILIC O
and O
eluents O
were O
analysed O
by O
radiochemical O
activity O
monitoring O
, O
MS O
and O
MS O
/ O
MS O
. O

3 O
. O
Only O
the O
parent O
compound O
was O
detected O
in O
plasma O
, O
but O
six O
metabolites O
( O
M1 O
- O
M6 O
) O
were O
detected O
in O
urine O
. O

Analysis O
of O
MS O
and O
MS O
/ O
MS O
data O
and O
comparison O
with O
synthetic O
reference O
standards O
enabled O
the O
identification O
of O
the O
structure O
of O
each O
metabolite O
. O

M1 O
was O
identified O
as O
the O
N B
- O
acetylated O
species O
[ B
( I
2R I
) I
- I
3 I
- I
acetamido I
- I
2 I
- I
fluoropropyl I
] I
- I
phosphinic I
acid I
, O
and O
M6 O
as O
[ B
( I
2R I
) I
- I
3 I
- I
amino I
- I
2 I
- I
fluoropropyl I
] I
- I
phosphonic I
acid I
. O

Metabolites O
M2 O
and O
M5 O
were O
the O
alcohol B
and O
carboxylic B
acid I
species O
3 B
- I
hydroxypropyl I
- I
phosphinic I
acid I
and O
3 B
- I
hydroxyphosphonoyl I
- I
propanoic I
acid I
, O
respectively O
, O
both O
of O
which O
had O
lost O
the O
fluorine B
atom O
present O
in O
the O
parent O
compound O
. O

M3 O
was O
the O
corresponding O
carboxylic B
acid I
species O
retaining O
the O
fluorine B
atom O
, O
( B
2R I
) I
- I
2 I
- I
fluoro I
- I
3 I
- I
hydroxyphosphonoyl I
- I
propanoic I
acid I
. O

Finally O
M4 O
was O
identified O
as O
[ B
( I
2R I
) I
- I
2 I
- I
fluoro I
- I
3 I
- I
guanidino I
- I
propyl I
] I
- I
phosphinic I
acid I
. O

Preparation O
and O
culture O
of O
precision O
- O
cut O
organ O
slices O
from O
human O
and O
animal O
. O

1 O
. O
Human O
and O
animal O
precision O
- O
cut O
organ O
slices O
are O
being O
widely O
used O
to O
obtain O
drug O
metabolism O
and O
toxicity O
profiles O
in O
vitro O
. O

These O
data O
are O
then O
used O
to O
predict O
what O
might O
be O
seen O
in O
human O
patients O
. O

The O
accuracy O
of O
this O
prediction O
and O
extrapolation O
of O
the O
findings O
based O
on O
human O
or O
animal O
in O
vitro O
systems O
to O
the O
findings O
that O
occur O
in O
vivo O
is O
dependent O
on O
both O
the O
quality O
of O
the O
tissue O
itself O
and O
the O
quality O
of O
the O
in O
vitro O
system O
. O

2 O
. O
The O
quality O
of O
human O
organs O
used O
in O
research O
is O
dependent O
on O
procurement O
methods O
, O
warm O
ischaemia O
time O
, O
preservation O
solutions O
, O
cold O
ischaemia O
time O
, O
and O
donor O
- O
specific O
factors O
. O

It O
is O
important O
to O
confirm O
that O
the O
organs O
being O
used O
are O
highly O
viable O
and O
fully O
functional O
before O
using O
them O
in O
scientific O
studies O
. O

3 O
. O
The O
optimal O
preparation O
and O
incubation O
of O
organ O
slices O
is O
also O
essential O
in O
maintaining O
slice O
viability O
and O
function O
. O

It O
is O
important O
to O
prepare O
the O
slices O
in O
a O
cold O
preservation O
solution O
, O
to O
prepare O
the O
slices O
at O
a O
correct O
thickness O
, O
and O
to O
incubate O
the O
slices O
in O
a O
system O
where O
the O
slice O
rotates O
in O
out O
of O
the O
oxygen B
atmosphere O
and O
medium O
. O

4 O
. O
Meeting O
the O
criteria O
outlined O
here O
will O
lead O
to O
successful O
organ O
slice O
cultures O
for O
investigating O
drug O
- O
induced O
mechanisms O
and O
organ O
- O
specific O
toxicity O
. O

Wnt O
/ O
beta O
- O
catenin O
signaling O
activates O
bone O
morphogenetic O
protein O
2 O
expression O
in O
osteoblasts O
. O

The O
BMP O
and O
Wnt O
/ O
beta O
- O
catenin O
signaling O
pathways O
cooperatively O
regulate O
osteoblast O
differentiation O
and O
bone O
formation O
. O

Although O
BMP O
signaling O
regulates O
gene O
expression O
of O
the O
Wnt O
pathway O
, O
much O
less O
is O
known O
about O
whether O
Wnt O
signaling O
modulates O
BMP O
expression O
in O
osteoblasts O
. O

Given O
the O
presence O
of O
putative O
Tcf O
/ O
Lef O
response O
elements O
that O
bind O
beta O
- O
catenin O
/ O
TCF O
transcription O
complex O
in O
the O
BMP2 O
promoter O
, O
we O
hypothesized O
that O
the O
Wnt O
/ O
beta O
- O
catenin O
pathway O
stimulates O
BMP2 O
expression O
in O
osteogenic O
cells O
. O

In O
this O
study O
, O
we O
showed O
that O
Wnt O
/ O
beta O
- O
catenin O
signaling O
is O
active O
in O
various O
osteoblast O
or O
osteoblast O
precursor O
cell O
lines O
, O
including O
MC3T3 O
- O
E1 O
, O
2T3 O
, O
C2C12 O
, O
and O
C3H10T1 O
/ O
2 O
cells O
. O

Furthermore O
, O
crosstalk O
between O
the O
BMP O
and O
Wnt O
pathways O
affected O
BMP O
signaling O
activity O
, O
osteoblast O
differentiation O
, O
and O
bone O
formation O
, O
suggesting O
Wnt O
signaling O
is O
an O
upstream O
regulator O
of O
BMP O
signaling O
. O

Activation O
of O
Wnt O
signaling O
by O
Wnt3a O
or O
overexpression O
of O
beta O
- O
catenin O
/ O
TCF4 O
both O
stimulated O
BMP2 O
transcription O
at O
promoter O
and O
mRNA O
levels O
. O

In O
contrast O
, O
transcription O
of O
BMP2 O
in O
osteogenic O
cells O
was O
decreased O
by O
either O
blocking O
the O
Wnt O
pathway O
with O
DKK1 O
and O
sFRP4 O
, O
or O
inhibiting O
beta O
- O
catenin O
/ O
TCF4 O
activity O
with O
FWD1 O
/ O
beta O
- O
TrCP O
, O
ICAT O
, O
or O
Delta O
TCF4 O
. O

Using O
a O
site O
- O
directed O
mutagenesis O
approach O
, O
we O
confirmed O
that O
Wnt O
/ O
beta O
- O
catenin O
transactivation O
of O
BMP2 O
transcription O
is O
directly O
mediated O
through O
the O
Tcf O
/ O
Lef O
response O
elements O
in O
the O
BMP2 O
promoter O
. O

These O
results O
, O
which O
demonstrate O
that O
the O
Wnt O
/ O
beta O
- O
catenin O
signaling O
pathway O
is O
an O
upstream O
activator O
of O
BMP2 O
expression O
in O
osteoblasts O
, O
provide O
novel O
insights O
into O
the O
nature O
of O
functional O
cross O
talk O
integrating O
the O
BMP O
and O
Wnt O
/ O
beta O
- O
catenin O
pathways O
in O
osteoblastic O
differentiation O
and O
maintenance O
of O
skeletal O
homeostasis O
. O

Imaging O
in O
the O
cardiovascular O
and O
metabolic O
disease O
area O
. O

There O
is O
a O
widely O
held O
belief O
that O
the O
use O
of O
non O
- O
invasive O
imaging O
can O
reduce O
the O
gap O
between O
basic O
science O
and O
clinical O
proof O
- O
of O
- O
concept O
, O
ultimately O
improving O
decision O
- O
making O
and O
therefore O
the O
efficiency O
of O
the O
drug O
development O
process O
. O

Imaging O
techniques O
such O
as O
positron O
emission O
tomography O
( O
PET O
) O
and O
magnetic O
resonance O
imaging O
( O
MRI O
) O
are O
routinely O
used O
in O
oncology O
and O
neuroscience O
drug O
development O
. O

However O
, O
less O
attention O
has O
been O
paid O
to O
the O
systematic O
use O
of O
imaging O
in O
the O
cardiovascular O
and O
metabolic O
disease O
area O
. O

Here O
, O
with O
an O
emphasis O
on O
' O
early O
clinical O
' O
development O
, O
we O
discuss O
the O
application O
of O
imaging O
in O
those O
areas O
, O
highlighting O
opportunities O
and O
challenges O
. O

Prenatal O
exposure O
to O
polychlorinated B
biphenyls I
and O
dioxins B
from O
the O
maternal O
diet O
may O
be O
associated O
with O
immunosuppressive O
effects O
that O
persist O
into O
early O
childhood O
. O

We O
investigated O
whether O
prenatal O
exposure O
from O
the O
maternal O
diet O
to O
the O
toxicants O
polychlorinated B
biphenyls I
( O
PCBs B
) O
and O
dioxins B
is O
associated O
with O
the O
development O
of O
immune O
- O
related O
diseases O
in O
childhood O
. O

Children O
participating O
in O
BraMat O
, O
a O
sub O
- O
cohort O
of O
the O
Norwegian O
Mother O
and O
Child O
Cohort O
Study O
( O
MoBa O
) O
, O
were O
followed O
in O
the O
three O
first O
years O
of O
life O
using O
annual O
questionnaires O
( O
0 O
- O
3years O
; O
n O
= O
162 O
, O
2 O
- O
3years O
; O
n O
= O
180 O
) O
, O
and O
blood O
parameters O
were O
examined O
at O
three O
years O
of O
age O
( O
n O
= O
114 O
) O
. O

The O
maternal O
intake O
of O
the O
toxicants O
was O
calculated O
using O
a O
validated O
food O
frequency O
questionnaire O
from O
MoBa O
. O

Maternal O
exposure O
to O
PCBs B
and O
dioxins B
was O
found O
to O
be O
associated O
with O
an O
increased O
risk O
of O
wheeze O
and O
more O
frequent O
upper O
respiratory O
tract O
infections O
. O

Furthermore O
, O
maternal O
exposure O
to O
PCBs B
and O
dioxins B
was O
found O
to O
be O
associated O
with O
reduced O
antibody O
response O
to O
a O
measles O
vaccine O
. O

No O
associations O
were O
found O
between O
prenatal O
exposure O
and O
immunophenotype O
data O
, O
allergic O
sensitization O
and O
vaccine O
- O
induced O
antibody O
responses O
other O
than O
measles O
. O

Our O
results O
suggest O
that O
prenatal O
dietary O
exposure O
to O
PCBs B
and O
dioxins B
may O
increase O
the O
risk O
of O
wheeze O
and O
the O
susceptibility O
to O
infectious O
diseases O
in O
early O
childhood O
. O

A O
subchronic O
dietary O
toxicity O
study O
of O
rice O
hull O
fiber O
in O
rats O
. O

We O
conducted O
a O
90 O
- O
day O
feeding O
study O
to O
investigate O
subchronic O
toxicity O
of O
rice O
hull O
fiber O
. O

Sprague O
Dawley O
rats O
were O
randomly O
divided O
into O
four O
groups O
; O
each O
received O
a O
diet O
containing O
0 O
% O
, O
2 O
. O
5 O
% O
, O
3 O
. O
75 O
% O
and O
5 O
. O
0 O
% O
( O
w O
/ O
w O
) O
rice O
hull O
fiber O
for O
90days O
. O

Clinical O
observations O
were O
carried O
out O
daily O
, O
with O
weekly O
measurements O
of O
body O
weight O
and O
food O
consumption O
. O

We O
performed O
ophthalmic O
and O
histological O
examinations O
at O
termination O
. O

Blood O
and O
urine O
samples O
were O
collected O
to O
measure O
hematology O
and O
clinical O
chemistry O
parameters O
. O

No O
mortality O
, O
ophthalmic O
abnormalities O
, O
or O
adverse O
treatment O
- O
related O
effects O
were O
seen O
during O
clinical O
observations O
, O
hematological O
tests O
, O
or O
analyses O
of O
urine O
. O

Macroscopic O
or O
microscopic O
examinations O
of O
organs O
revealed O
no O
treatment O
related O
abnormalities O
. O

The O
only O
treatment O
related O
significant O
changes O
were O
reduced O
concentrations O
of O
fasting O
blood O
glucose B
( O
up O
to O
17 O
. O
6 O
% O
) O
and O
cholesterol B
( O
up O
to O
22 O
. O
0 O
% O
) O
, O
typical O
benefits O
of O
dietary O
fiber O
, O
in O
males O
treated O
with O
3 O
. O
75 O
and O
5 O
% O
rice O
hull O
fiber O
. O

The O
no O
- O
observed O
- O
adverse O
- O
effect O
- O
level O
( O
NOAEL O
) O
for O
rice O
hull O
fiber O
was O
5 O
. O
0 O
% O
for O
both O
genders O
( O
females O
, O
3 O
. O
80g O
/ O
kg O
body O
weight O
/ O
day O
; O
males O
, O
4 O
. O
11g O
/ O
kg O
body O
weight O
/ O
day O
) O
. O

PUB O
- O
NChIP O
- O
- O
" O
in O
vivo O
biotinylation O
" O
approach O
to O
study O
chromatin O
in O
proximity O
to O
a O
protein O
of O
interest O
. O

We O
have O
developed O
an O
approach O
termed O
PUB O
- O
NChIP O
( O
proximity O
utilizing O
biotinylation O
with O
native O
ChIP O
) O
to O
purify O
and O
study O
the O
protein O
composition O
of O
chromatin O
in O
proximity O
to O
a O
nuclear O
protein O
of O
interest O
. O

It O
is O
based O
on O
coexpression O
of O
( O
1 O
) O
a O
protein O
of O
interest O
, O
fused O
with O
the O
bacterial O
biotin B
ligase O
BirA O
, O
together O
with O
( O
2 O
) O
a O
histone O
fused O
to O
a O
biotin B
acceptor O
peptide O
( O
BAP O
) O
, O
which O
is O
specifically O
biotinylated O
by O
BirA O
- O
fusion O
in O
the O
proximity O
of O
the O
protein O
of O
interest O
. O

Using O
the O
RAD18 O
protein O
as O
a O
model O
, O
we O
demonstrate O
that O
the O
RAD18 O
- O
proximal O
chromatin O
is O
enriched O
in O
some O
H4 O
acetylated O
species O
. O

Moreover O
, O
the O
RAD18 O
- O
proximal O
chromatin O
containing O
a O
replacement O
histone O
H2AZ O
has O
a O
different O
pattern O
of O
H4 O
acetylation O
. O

Finally O
, O
biotin B
pulse O
- O
chase O
experiments O
show O
that O
the O
H4 O
acetylation O
pattern O
starts O
to O
resemble O
the O
acetylation O
pattern O
of O
total O
H4 O
after O
the O
proximity O
of O
chromatin O
to O
RAD18 O
has O
been O
lost O
. O

Anatomical O
and O
functional O
damage O
in O
experimental O
glaucoma O
. O

Glaucoma O
is O
a O
progressive O
neurodegenerative O
disease O
caused O
by O
retinal B
ganglion O
cell O
( O
RGC O
) O
loss O
. O

One O
important O
risk O
factor O
for O
glaucoma O
is O
elevated O
intraocular O
pressure O
and O
thus O
many O
animal O
models O
are O
based O
on O
spontaneous O
or O
induced O
ocular O
hypertension O
( O
OHT O
) O
. O

Using O
these O
models O
it O
has O
been O
shown O
that O
RGCs O
initially O
suffer O
an O
impairment O
of O
the O
active O
axonal O
transport O
that O
progresses O
to O
a O
lack O
of O
passive O
diffusion O
along O
the O
axon O
. O

This O
axonal O
damage O
eventually O
causes O
the O
death O
of O
the O
parent O
RGCs O
in O
pie O
- O
shaped O
sectors O
of O
the O
retina O
, O
but O
there O
is O
also O
diffuse O
RGC O
loss O
, O
without O
involving O
displaced O
amacrine O
cells O
. O

Recent O
data O
show O
that O
OHT B
results O
in O
a O
protracted O
insult O
to O
the O
inner O
and O
outer O
retina O
that O
causes O
functional O
alterations O
and O
ultimately O
, O
degeneration O
and O
death O
of O
cones O
. O

Phlorotannin B
- O
rich O
Ecklonia O
cava O
reduces O
the O
production O
of O
beta O
- O
amyloid O
by O
modulating O
alpha O
- O
and O
gamma O
- O
secretase O
expression O
and O
activity O
. O

Beta O
- O
amyloid O
( O
A O
beta O
) O
is O
a O
major O
pathogenic O
peptide O
in O
Alzheimer O
' O
s O
disease O
( O
AD O
) O
and O
is O
generated O
by O
the O
processing O
of O
amyloid O
precursor O
protein O
( O
APP O
) O
. O

We O
have O
previously O
reported O
that O
the O
brown O
algae O
Ecklonia O
cava O
, O
which O
has O
anti O
- O
oxidant O
and O
anti O
- O
inflammatory O
functions O
, O
decreased O
A O
beta O
production O
and O
further O
aggregation O
in O
HEK293 O
cells O
expressing O
the O
APP O
Swedish O
mutation O
. O

Here O
, O
we O
show O
the O
reduction O
mechanism O
of O
A O
beta O
production O
using O
the O
butanol B
extract O
of O
Ecklonia O
cava O
through O
the O
examination O
of O
expression O
and O
activity O
of O
alpha O
- O
, O
beta O
- O
, O
and O
gamma O
- O
secretase O
. O

Treatment O
with O
the O
extract O
resulted O
in O
the O
activation O
of O
alpha O
- O
secretase O
with O
a O
contrasting O
decrease O
in O
its O
mRNA O
and O
protein O
expression O
. O

This O
activation O
was O
consistent O
with O
the O
translocation O
of O
the O
extract O
into O
the O
plasma O
membrane O
of O
the O
secretase O
. O

Gamma O
- O
secretase O
activity O
was O
lowered O
by O
E O
. O
cava O
, O
and O
this O
effect O
may O
be O
due O
to O
the O
decreased O
expression O
of O
PSEN1 O
mRNA O
and O
protein O
. O

In O
addition O
, O
the O
basal O
nuclear O
location O
of O
PSEN1 O
, O
which O
may O
affect O
chromosome O
missegregation O
in O
neurodegenerative O
disease O
, O
was O
reduced O
by O
the O
extract O
, O
despite O
the O
significance O
of O
this O
finding O
remains O
unclear O
. O

Taken O
together O
, O
these O
results O
led O
us O
to O
conclude O
that O
E O
. O
cava O
regulated O
the O
expression O
and O
activity O
of O
gamma O
- O
secretase O
and O
alpha O
- O
secretase O
, O
leading O
to O
a O
reduction O
in O
A O
beta O
production O
by O
the O
stable O
cells O
. O

Our O
data O
indicate O
that O
E O
. O
cava O
is O
a O
novel O
natural O
- O
product O
candidate O
for O
AD O
treatment O
, O
although O
further O
in O
vivo O
studies O
are O
needed O
. O

Apoptosis O
induced O
neurotoxicity O
of O
Di B
- I
n I
- I
butyl I
- I
di I
- I
( I
4 I
- I
chlorobenzohydroxama I
) I
Tin I
( I
IV I
) I
via O
mitochondria O
- O
mediated O
pathway O
in O
PC12 O
cells O
. O

The O
severe O
toxicity O
of O
antitumor O
organotin B
( I
IV I
) I
compounds O
limits O
their O
application O
in O
clinic O
, O
however O
, O
the O
toxic O
mechanism O
is O
still O
unclear O
. O

Di B
- I
n I
- I
butyl I
- I
di I
- I
( I
4 I
- I
chlorobenzohydroxama I
) I
Tin I
( I
IV I
) I
( O
DBDCT B
) O
, O
an O
antitumor O
agent O
with O
high O
activity O
and O
obvious O
neurotoxicity O
was O
chosen O
as O
a O
typical O
diorganotin B
( I
IV I
) I
compound O
to O
investigate O
its O
neurotoxic O
mechanism O
using O
PC12 O
cells O
and O
comprehensive O
methods O
. O

Treatment O
with O
DBDCT B
resulted O
in O
a O
dose O
- O
and O
time O
- O
dependent O
growth O
inhibition O
of O
PC12 O
cells O
. O

The O
changes O
in O
cell O
morphology O
were O
observed O
using O
light O
microscopy O
, O
fluorescence O
microscopy O
and O
transmission O
electron O
microscopy O
. O

PC12 O
cell O
apoptosis O
induced O
by O
DBDCT B
was O
confirmed O
by O
annexin O
V O
/ O
propidium B
iodide I
staining O
, O
and O
characterized O
by O
cleavage O
of O
caspase O
- O
9 O
and O
caspase O
- O
3 O
proteins O
. O

DBDCT B
induced O
the O
release O
of O
cytochrome O
c O
from O
the O
mitochondria O
to O
the O
cytosol O
and O
the O
generation O
of O
reactive O
oxygen B
species O
. O

DBDCT B
up O
- O
regulated O
the O
expression O
of O
Bax O
, O
down O
- O
regulated O
the O
expression O
of O
Bcl O
- O
2 O
, O
and O
significantly O
increased O
the O
ratio O
of O
Bax O
/ O
Bcl O
- O
2 O
. O

DBDCT B
also O
caused O
the O
phosphorylation O
of O
JNK O
and O
p38 O
( O
MAPK O
) O
. O

In O
rats O
exposed O
to O
DBDCT B
, O
apoptosis O
was O
also O
observed O
in O
brain O
, O
as O
shown O
by O
the O
detection O
of O
cleaved O
caspase O
- O
9 O
and O
caspase O
- O
3 O
proteins O
and O
increased O
TUNEL O
positive O
staining O
. O

In O
conclusion O
, O
the O
results O
demonstrated O
that O
DBDCT B
caused O
the O
neurotoxicity O
by O
inducing O
apoptosis O
via O
mitochondria O
- O
mediated O
pathway O
. O

Inclusion O
compound O
based O
approach O
to O
forming O
arrays O
of O
artificial O
dipolar O
molecular O
rotors O
: O
a O
search O
for O
optimal O
rotor O
structures O
. O

Hexagonal O
tris B
( I
o I
- I
phenylenedioxy I
) I
cyclotriphosphazene I
( O
TPP B
) O
is O
used O
as O
ahost O
for O
organizing O
dipolar O
molecular O
rotor O
guests O
into O
regular O
trigonal O
arrays O
. O

Inclusion O
of O
molecular O
rotors O
with O
transversely O
dipolar O
rotators O
into O
TPP B
channels O
is O
followed O
by O
solid O
- O
state O
nuclear O
magnetic O
resonance O
, O
diifferential O
scanning O
calorimetry O
, O
X O
- O
ray O
diffraction O
, O
and O
dielectric O
spectroscopy O
. O

The O
more O
polar O
of O
the O
two O
rotors O
does O
not O
form O
an O
inclusion O
. O

The O
second O
rotor O
forms O
two O
different O
inclusions O
differing O
in O
crystallite O
size O
and O
the O
rotational O
barriers O
. O

Glycopolymers O
and O
glyco O
- O
nanoparticles O
in O
biomolecular O
recognition O
processes O
and O
vaccine O
development O
. O

With O
advances O
in O
polymerization O
techniques O
as O
well O
as O
selective O
chemical O
modification O
of O
carbohydrates B
, O
glycopolymers O
and O
glyco O
- O
nanoparticles O
are O
emerging O
as O
an O
important O
class O
of O
materials O
with O
tailored O
properties O
or O
novel O
nanotechnology O
- O
based O
platforms O
for O
a O
number O
of O
applications O
. O

The O
field O
of O
the O
so O
- O
called O
glyco O
- O
nanotechnology O
is O
starting O
to O
show O
some O
promises O
for O
future O
clinical O
applications O
. O

Glyco O
- O
nanoparticles O
, O
due O
to O
their O
versatile O
nature O
, O
could O
offer O
a O
platform O
for O
the O
design O
of O
carbohydrate B
- O
based O
vaccines O
and O
possibly O
allow O
the O
development O
of O
new O
single O
- O
dose O
vaccines O
in O
disease O
areas O
of O
unmet O
need O
. O

This O
paper O
surveys O
the O
emerging O
roles O
of O
carbohydrate B
- O
based O
polymeric O
and O
nanomaterials O
for O
biomolecular O
recognition O
processes O
and O
vaccine O
development O
. O

Interactions O
between O
CYP2E1 O
and O
CYP2B4 O
: O
effects O
on O
affinity O
for O
NADPH B
- O
cytochrome O
P450 O
reductase O
and O
substrate O
metabolism O
. O

Studies O
in O
microsomal O
and O
reconstituted O
systems O
have O
shown O
that O
the O
presence O
of O
one O
cytochrome O
P450 O
isoform O
can O
significantly O
influence O
the O
catalytic O
activity O
of O
another O
isoform O
. O

In O
this O
study O
, O
we O
assessed O
whether O
CYP2E1 O
could O
influence O
the O
catalytic O
activity O
of O
CYP2B4 O
under O
steady O
- O
state O
turnover O
conditions O
. O

The O
results O
show O
that O
CYP2E1 O
inhibits O
CYP2B4 O
- O
mediated O
metabolism O
of O
benzphetamine B
( O
BNZ B
) O
with O
a O
K O
( O
i O
) O
of O
0 O
. O
04 O
micro O
M O
. O

However O
, O
CYP2B4 O
is O
not O
an O
inhibitor O
of O
CYP2E1 O
- O
mediated O
p B
- I
nitrophenol I
hydroxylation O
. O

When O
these O
inhibition O
studies O
were O
performed O
with O
the O
artificial O
oxidant O
tert B
- I
butyl I
hydroperoxide I
, O
CYP2E1 O
did O
not O
significantly O
inhibit O
CYP2B4 O
activity O
. O

Determinations O
of O
the O
apparent O
K O
( O
M O
) O
and O
k O
( O
cat O
) O
of O
CYP2B4 O
for O
CPR O
in O
the O
presence O
of O
increasing O
concentrations O
of O
CYP2E1 O
revealed O
a O
mixed O
inhibition O
of O
CYP2B4 O
by O
CYP2E1 O
. O

At O
low O
concentrations O
of O
CYP2E1 O
, O
the O
apparent O
K O
( O
M O
) O
of O
CYP2B4 O
for O
CPR O
increased O
up O
to O
23 O
- O
fold O
with O
virtually O
no O
change O
in O
the O
k O
( O
cat O
) O
for O
the O
reaction O
, O
however O
, O
at O
higher O
concentrations O
of O
CYP2E1 O
, O
the O
apparent O
K O
( O
M O
) O
of O
CYP2B4 O
for O
CPR B
decreased O
to O
levels O
similar O
to O
those O
observed O
in O
the O
absence O
of O
CYP2E1 O
and O
the O
k O
( O
cat O
) O
also O
decreased O
by O
11 O
- O
fold O
. O

Additionally O
, O
CYP2E1 O
increased O
the O
apparent O
K O
( O
M O
) O
of O
CYP2B4 O
for O
BNZ B
by O
8 O
- O
fold O
and O
the O
apparent O
K O
( O
M O
) O
did O
not O
decrease O
to O
its O
original O
value O
when O
saturating O
concentrations O
of O
CPR O
were O
used O
. O

While O
the O
individual O
apparent O
K O
( O
M O
) O
values O
of O
CYP2B4 O
and O
CYP2E1 O
for O
CPR O
are O
similar O
, O
the O
apparent O
K O
( O
M O
) O
of O
CYP2E1 O
for O
CPR O
in O
the O
presence O
of O
CYP2B4 O
decreased O
significantly O
, O
thus O
suggesting O
that O
CYP2B4 O
enhances O
the O
affinity O
of O
CYP2E1 O
for O
CPR O
and O
this O
may O
allow O
CYP2E1 O
to O
out O
- O
compete O
CYP2B4 O
for O
CPR O
. O

Songaricalarins B
A I
- I
E I
, O
cytotoxic O
oplopane B
sesquiterpenes B
from O
Ligularia O
songarica O
. O

Five O
new O
highly O
oxygenated O
oplopane B
sesquiterpenes B
, O
songaricalarins B
A I
- I
E I
( O
1 O
- O
5 O
) O
, O
and O
two O
known O
analogues O
( O
6 O
and O
7 O
) O
were O
isolated O
from O
the O
roots O
and O
rhizomes O
of O
Ligularia O
songarica O
. O

Their O
structures O
and O
configurations O
were O
elucidated O
by O
spectroscopic O
methods O
, O
including O
2D O
- O
NMR O
techniques O
, O
and O
the O
structure O
of O
1 O
was O
confirmed O
by O
single O
- O
crystal O
X O
- O
ray O
diffraction O
. O

All O
compounds O
were O
evaluated O
for O
in O
vitro O
cytotoxic O
activity O
against O
cultured O
A O
- O
549 O
, O
MCF O
- O
7 O
, O
KB O
, O
and O
KBVIN O
cells O
, O
and O
4 O
exhibited O
cytotoxicity O
with O
EC50 O
values O
of O
4 O
. O
9 O
, O
0 O
. O
8 O
, O
3 O
. O
4 O
, O
and O
3 O
. O
2 O
mu O
g O
/ O
mL O
, O
respectively O
. O

Angiogenesis O
is O
required O
for O
stress O
fracture O
healing O
in O
rats O
. O

Although O
angiogenesis O
and O
osteogenesis O
are O
critically O
linked O
, O
the O
importance O
of O
angiogenesis O
for O
stress O
fracture O
healing O
is O
unknown O
. O

In O
this O
study O
, O
mechanical O
loading O
was O
used O
to O
create O
a O
non O
- O
displaced O
stress O
fracture O
in O
the O
adult O
rat O
forelimb O
. O

Fumagillin B
, O
an O
anti O
- O
angiogenic O
agent O
, O
was O
used O
as O
the O
water O
soluble O
analogue O
TNP B
- I
470 I
( O
25mg O
/ O
kg O
) O
as O
well O
as O
incorporated O
into O
lipid O
- O
encapsulated O
alpha O
( O
v O
) O
beta O
( O
3 O
) O
integrin O
targeted O
nanoparticles O
( O
0 O
. O
25mg O
/ O
kg O
) O
. O

In O
the O
first O
experiment O
, O
TNP B
- I
470 I
was O
administered O
daily O
for O
5 O
days O
following O
mechanical O
loading O
, O
and O
changes O
in O
gene O
expression O
, O
vascularity O
, O
and O
woven O
bone O
formation O
were O
quantified O
. O

Although O
no O
changes O
in O
vascularity O
were O
detected O
3 O
days O
after O
loading O
, O
treatment O
- O
related O
downregulation O
of O
angiogenic O
( O
Pecam1 O
) O
and O
osteogenic O
( O
Bsp O
, O
Osx O
) O
genes O
was O
observed O
at O
this O
early O
time O
point O
. O

On O
day O
7 O
, O
microCT O
imaging O
of O
loaded O
limbs O
revealed O
diminished O
woven O
bone O
formation O
in O
treated O
limbs O
compared O
to O
vehicle O
treated O
limbs O
. O

In O
the O
second O
experiment O
, O
alpha O
( O
v O
) O
beta O
( O
3 O
) O
integrin O
targeted O
fumagillin O
nanoparticles O
were O
administered O
as O
before O
, O
albeit O
with O
a O
100 O
- O
fold O
lower O
dose O
, O
and O
changes O
in O
vascularity O
and O
woven O
bone O
formation O
were O
determined O
. O

There O
were O
no O
treatment O
- O
related O
changes O
in O
vessel O
count O
or O
volume O
3 O
days O
after O
loading O
, O
although O
fewer O
angiogenic O
( O
CD105 O
positive O
) O
blood O
vessels O
were O
present O
in O
treated O
limbs O
compared O
to O
vehicle O
treated O
limbs O
. O

This O
result O
manifested O
on O
day O
7 O
as O
a O
reduction O
in O
total O
vascularity O
, O
as O
measured O
by O
histology O
( O
vessel O
count O
) O
and O
microCT O
( O
vessel O
volume O
) O
. O

Similar O
to O
the O
first O
experiment O
, O
treated O
limbs O
had O
diminished O
woven O
bone O
formation O
on O
day O
7 O
compared O
to O
vehicle O
treated O
limbs O
. O

These O
results O
indicate O
that O
angiogenesis O
is O
required O
for O
stress O
fracture O
healing O
, O
and O
may O
have O
implications O
for O
inducing O
rapid O
repair O
of O
stress O
fractures O
. O

Amino B
acid I
residues O
at O
the O
N B
- O
and O
C B
- O
termini O
are O
essential O
for O
the O
folding O
of O
active O
human O
butyrylcholinesteras O
polypeptide O
. O

Human O
serum O
butyrylcholinesteras O
( O
HuBChE O
) O
is O
currently O
the O
most O
suitable O
bioscavenger O
for O
the O
prophylaxis O
of O
highly O
toxic O
organophosphate B
( O
OP O
) O
nerve O
agents O
. O

A O
dose O
of O
200mg O
of O
HuBChE O
is O
envisioned O
as O
a O
prophylactic O
treatment O
that O
can O
protect O
humans O
from O
an O
exposure O
of O
up O
to O
2 O
x O
LD50 O
of O
soman B
. O

The O
limited O
availability O
and O
administration O
of O
multiple O
doses O
of O
this O
stoichiometric O
bioscavenger O
make O
this O
pretreatment O
difficult O
. O

Thus O
, O
the O
goal O
of O
this O
study O
was O
to O
produce O
a O
smaller O
enzymatically O
active O
HuBChE O
polypeptide O
( O
HBP O
) O
that O
could O
bind O
to O
nerve O
agents O
with O
high O
affinity O
thereby O
reducing O
the O
dose O
of O
enzyme O
. O

Studies O
have O
indicated O
that O
the O
three O
- O
dimensional O
structure O
and O
the O
domains O
of O
HuBChE O
( O
acyl B
pocket O
, O
lip O
of O
the O
active O
center O
gorge O
, O
and O
the O
anionic O
substrate O
- O
binding O
domain O
) O
that O
are O
critical O
for O
the O
binding O
of O
substrate O
are O
also O
essential O
for O
the O
selectivity O
and O
binding O
of O
inhibitors O
including O
OPs O
. O

Therefore O
, O
we O
designed O
three O
HBPs O
by O
deleting O
some O
N B
- O
and O
C B
- O
terminal O
residues O
of O
HuBChE O
by O
maintaining O
the O
folds O
of O
the O
active O
site O
core O
that O
includes O
the O
three O
active O
site O
residues O
( O
S198 O
, O
E325 O
, O
and O
H438 O
) O
. O

HBP O
- O
4 O
that O
lacks O
45 O
residues O
from O
C B
- O
terminus O
but O
known O
to O
have O
BChE O
activity O
was O
used O
as O
a O
control O
. O

The O
cDNAs O
for O
the O
HBPs O
containing O
signal O
sequences O
were O
synthesized O
, O
cloned O
into O
different O
mammalian O
expression O
vectors O
, O
and O
recombinant O
polypeptides O
were O
transiently O
expressed O
in O
different O
cell O
lines O
. O

No O
BChE O
activity O
was O
detected O
in O
the O
culture O
media O
of O
cells O
transfected O
with O
any O
of O
the O
newly O
designed O
HBPs O
, O
and O
the O
inactive O
polypeptides O
remained O
inside O
the O
cells O
. O

Only O
enzymatically O
active O
HBP O
- O
4 O
was O
secreted O
into O
the O
culture O
medium O
. O

These O
results O
suggest O
that O
residues O
at O
the O
N B
- O
and O
C B
- O
termini O
are O
required O
for O
the O
folding O
and O
/ O
or O
maintenance O
of O
HBP O
into O
an O
active O
stable O
, O
conformation O
. O

Overexpression O
of O
H1 O
calponin O
in O
osteoblast O
lineage O
cells O
leads O
to O
a O
decrease O
in O
bone O
mass O
by O
disrupting O
osteoblast O
function O
and O
promoting O
osteoclast O
formation O
. O

H1 O
calponin O
( O
CNN1 O
) O
is O
known O
as O
a O
smooth O
muscle O
- O
specific O
, O
actin O
- O
binding O
protein O
which O
regulates O
smooth O
muscle O
contractive O
activity O
. O

Although O
previous O
studies O
have O
shown O
that O
CNN1 O
has O
effect O
on O
bone O
, O
the O
mechanism O
is O
not O
well O
defined O
. O

To O
investigate O
the O
role O
of O
CNN1 O
in O
maintaining O
bone O
homeostasis O
, O
we O
generated O
transgenic O
mice O
overexpressing O
Cnn1 O
under O
the O
control O
of O
the O
osteoblast O
- O
specific O
3 O
. O
6 O
- O
kb O
Col1a1 O
promoter O
. O

Col1a1 O
- O
Cnn1 O
transgenic O
mice O
showed O
delayed O
bone O
formation O
at O
embryonic O
stage O
and O
decreased O
bone O
mass O
at O
adult O
stage O
. O

Morphology O
analyses O
showed O
reduced O
trabecular O
number O
, O
thickness O
and O
defects O
in O
bone O
formation O
. O

The O
proliferation O
and O
migration O
of O
osteoblasts O
were O
decreased O
in O
Col1a1 O
- O
Cnn1 O
mice O
due O
to O
alterations O
in O
cytoskeleton O
. O

The O
early O
osteoblast O
differentiation O
of O
Col1a1 O
- O
Cnn1 O
mice O
was O
increased O
, O
but O
the O
late O
stage O
differentiation O
and O
mineralization O
of O
osteoblasts O
derived O
from O
Col1a1 O
- O
Cnn1 O
mice O
were O
significantly O
decreased O
. O

In O
addition O
to O
impaired O
bone O
formation O
, O
the O
decreased O
bone O
mass O
was O
also O
associated O
with O
enhanced O
osteoclastogenesis O
. O

Tartrate B
- O
resistant O
acid O
phosphatase O
( O
TRAP O
) O
staining O
revealed O
increased O
osteoclast O
numbers O
in O
tibias O
of O
2 O
- O
month O
- O
old O
Col1a1 O
- O
Cnn1 O
mice O
, O
and O
increased O
numbers O
of O
osteoclasts O
co O
- O
cultured O
with O
Col1a1 O
- O
Cnn1 O
osteoblasts O
. O

The O
ratio O
of O
RANKL O
to O
OPG O
was O
significantly O
increased O
in O
Col1a1 O
- O
Cnn1 O
osteoblasts O
. O

These O
findings O
reveal O
a O
novel O
function O
of O
CNN1 O
in O
maintaining O
bone O
homeostasis O
by O
coupling O
bone O
formation O
to O
bone O
resorption O
. O

Optical O
imaging O
techniques O
for O
point O
- O
of O
- O
care O
diagnostics O
. O

Improving O
access O
to O
effective O
and O
affordable O
healthcare O
has O
long O
been O
a O
global O
endeavor O
. O

In O
this O
quest O
, O
the O
development O
of O
cost O
- O
effective O
and O
easy O
- O
to O
- O
use O
medical O
testing O
equipment O
that O
enables O
rapid O
and O
accurate O
diagnosis O
is O
essential O
to O
reduce O
the O
time O
and O
costs O
associated O
with O
healthcare O
services O
. O

To O
this O
end O
, O
point O
- O
of O
- O
care O
( O
POC O
) O
diagnostics O
plays O
a O
crucial O
role O
in O
healthcare O
delivery O
in O
both O
developed O
and O
developing O
countries O
by O
bringing O
medical O
testing O
to O
patients O
, O
or O
to O
sites O
near O
patients O
. O

As O
the O
diagnosis O
of O
a O
wide O
range O
of O
diseases O
, O
including O
various O
types O
of O
cancers O
and O
many O
endemics O
, O
relies O
on O
optical O
techniques O
, O
numerous O
compact O
and O
cost O
- O
effective O
optical O
imaging O
platforms O
have O
been O
developed O
in O
recent O
years O
for O
use O
at O
the O
POC O
. O

Here O
, O
we O
review O
the O
state O
- O
of O
- O
the O
- O
art O
optical O
imaging O
techniques O
that O
can O
have O
a O
significant O
impact O
on O
global O
health O
by O
facilitating O
effective O
and O
affordable O
POC O
diagnostics O
. O

Glucocorticoid O
effects O
on O
changes O
in O
bone O
mineral O
density O
and O
cortical O
structure O
in O
childhood O
nephrotic O
syndrome O
. O

The O
impact O
of O
glucocorticoids O
( O
GC O
) O
on O
skeletal O
development O
has O
not O
been O
established O
. O

The O
objective O
of O
this O
study O
was O
to O
examine O
changes O
in O
volumetric O
bone O
mineral O
density O
( O
vBMD O
) O
and O
cortical O
structure O
over O
1 O
year O
in O
childhood O
nephrotic O
syndrome O
( O
NS O
) O
and O
to O
identify O
associations O
with O
concurrent O
GC O
exposure O
and O
growth O
. O

Fifty O
- O
six O
NS O
participants O
, O
aged O
5 O
to O
21 O
years O
, O
were O
enrolled O
a O
median O
of O
4 O
. O
3 O
( O
0 O
. O
5 O
to O
8 O
. O
1 O
) O
years O
after O
diagnosis O
. O

Tibia O
peripheral O
quantitative O
computed O
tomography O
( O
pQCT O
) O
scans O
were O
obtained O
at O
enrollment O
and O
6 O
and O
12 O
months O
later O
. O

Sex O
, O
race O
, O
and O
age O
- O
specific O
Z O
- O
scores O
were O
generated O
for O
trabecular O
vBMD O
( O
TrabBMD O
- O
Z O
) O
, O
cortical O
vBMD O
( O
CortBMD O
- O
Z O
) O
, O
and O
cortical O
area O
( O
CortArea O
- O
Z O
) O
based O
on O
> O
650 O
reference O
participants O
. O

CortArea B
- O
Z O
was O
further O
adjusted O
for O
tibia O
length O
- O
for O
- O
age O
Z O
- O
score O
. O

Quasi O
- O
least O
squares O
regression O
was O
used O
to O
identify O
determinants O
of O
changes O
in O
pQCT O
Z O
- O
scores O
. O

At O
enrollment O
, O
mean O
TrabBMD O
- O
Z O
( O
- O
0 O
. O
54 O
+ O
/ O
- O
1 O
. O
32 O
) O
was O
significantly O
lower O
( O
p O
= O
0 O
. O
0001 O
) O
and O
CortBMD O
- O
Z O
( O
0 O
. O
73 O
+ O
/ O
- O
1 O
. O
16 O
, O
p O
< O
0 O
. O
0001 O
) O
and O
CortArea B
- O
Z O
( O
0 O
. O
27 O
+ O
/ O
- O
0 O
. O
91 O
, O
p O
= O
0 O
. O
03 O
) O
significantly O
greater O
in O
NS O
versus O
reference O
participants O
, O
as O
previously O
described O
. O

Forty O
- O
eight O
( O
86 O
% O
) O
participants O
were O
treated O
with O
GC O
over O
the O
study O
interval O
( O
median O
dose O
0 O
. O
29 O
mg O
/ O
kg O
/ O
day O
) O
. O

On O
average O
, O
TrabBMD O
- O
Z O
and O
CortBMD O
- O
Z O
did O
not O
change O
significantly O
over O
the O
study O
interval O
; O
however O
, O
CortArea B
- O
Z O
decreased O
( O
p O
= O
0 O
. O
003 O
) O
. O

Greater O
GC O
dose O
( O
p O
< O
0 O
. O
001 O
) O
, O
lesser O
increases O
in O
tibia O
length O
( O
p O
< O
0 O
. O
001 O
) O
, O
and O
lesser O
increases O
in O
CortArea O
- O
Z O
( O
p O
= O
0 O
. O
003 O
) O
were O
independently O
associated O
with O
greater O
increases O
in O
CortBMD O
- O
Z O
. O

Greater O
increases O
in O
tibia O
length O
were O
associated O
with O
greater O
declines O
in O
CortArea O
- O
Z O
( O
p O
< O
0 O
. O
01 O
) O
; O
this O
association O
was O
absent O
in O
reference O
participants O
( O
interaction O
p O
< O
0 O
. O
02 O
) O
. O

In O
conclusion O
, O
GC O
therapy O
was O
associated O
with O
increases O
in O
CortBMD O
- O
Z O
, O
potentially O
related O
to O
suppressed O
bone O
formation O
and O
greater O
secondary O
mineralization O
. O

Conversely O
, O
greater O
growth O
and O
expansion O
of O
CortArea O
- O
Z O
( O
ie O
, O
new O
bone O
formation O
) O
were O
associated O
with O
declines O
in O
CortBMD O
- O
Z O
. O

Greater O
linear O
growth O
was O
associated O
with O
impaired O
expansion O
of O
cortical O
area O
in O
NS O
. O

Studies O
are O
needed O
to O
determine O
the O
fracture O
implications O
of O
these O
findings O
. O

Neuropeptide O
Y O
is O
a O
critical O
modulator O
of O
leptin O
' O
s O
regulation O
of O
cortical O
bone O
. O

Leptin O
signaling O
is O
required O
for O
normal O
bone O
homeostasis O
; O
however O
, O
loss O
of O
leptin O
results O
in O
differing O
effects O
on O
cortical O
and O
cancellous O
bone O
, O
as O
well O
as O
altered O
responses O
between O
the O
axial O
and O
appendicular O
regions O
. O

Local O
beta O
- O
adrenergic O
actions O
are O
responsible O
for O
the O
greater O
cancellous O
bone O
volume O
in O
leptin O
- O
deficient O
( O
ob O
/ O
ob O
) O
mice O
; O
however O
, O
the O
mechanism O
responsible O
for O
the O
opposing O
reduction O
in O
cortical O
bone O
in O
ob O
/ O
ob O
mice O
is O
not O
known O
. O

Here O
we O
show O
that O
blocking O
the O
leptin O
- O
deficient O
increase O
in O
neuropeptide O
Y O
( O
NPY O
) O
expression O
reverses O
the O
cortical O
bone O
loss O
in O
ob O
/ O
ob O
mice O
. O

Mice O
null O
for O
both O
NPY O
and O
leptin O
( O
NPY O
( O
- O
/ O
- O
) O
ob O
/ O
ob O
) O
, O
display O
greater O
cortical O
bone O
mass O
in O
both O
long O
- O
bones O
and O
vertebra O
, O
with O
NPY O
( O
- O
/ O
- O
) O
ob O
/ O
ob O
mice O
exhibiting O
thicker O
and O
denser O
cortical O
bone O
, O
associated O
with O
greater O
endocortical O
and O
periosteal O
mineral O
apposition O
rate O
( O
MAR O
) O
, O
compared O
to O
ob O
/ O
ob O
animals O
. O

Importantly O
, O
these O
cortical O
changes O
occurred O
without O
significant O
increases O
in O
body O
weight O
, O
with O
NPY O
( O
- O
/ O
- O
) O
ob O
/ O
ob O
mice O
showing O
significantly O
reduced O
adiposity O
compared O
to O
ob O
/ O
ob O
controls O
, O
most O
likely O
due O
to O
the O
reduced O
respiratory O
exchange O
ratio O
seen O
in O
these O
animals O
. O

Interestingly O
, O
cancellous O
bone O
volume O
was O
not O
different O
between O
NPY O
( O
- O
/ O
- O
) O
ob O
/ O
ob O
and O
ob O
/ O
ob O
, O
suggesting O
that O
NPY O
is O
not O
influencing O
the O
adrenergic O
axis O
. O

Taken O
together O
, O
this O
work O
demonstrates O
the O
critical O
role O
of O
NPY O
signaling O
in O
the O
regulation O
of O
bone O
and O
energy O
homeostasis O
, O
and O
more O
importantly O
, O
suggests O
that O
reduced O
leptin O
levels O
or O
leptin O
resistance O
, O
which O
occurs O
in O
obesity O
, O
could O
potentially O
inhibit O
cortical O
bone O
formation O
via O
increased O
central O
NPY O
signaling O
. O

Characterisation O
of O
acetylcholinesterase O
release O
from O
neuronal O
cells O
. O

Although O
acetylcholinesterase O
( O
AChE O
) O
is O
primarily O
a O
hydrolytic O
enzyme O
, O
metabolising O
the O
neurotransmitter O
acetylcholine B
in O
cholinergic O
synapses O
, O
it O
also O
has O
some O
non O
- O
catalytic O
functions O
in O
the O
brain O
which O
are O
far O
less O
well O
characterised O
. O

AChE O
was O
shown O
to O
be O
secreted O
or O
shed O
from O
the O
neuronal O
cell O
surface O
like O
several O
other O
membrane O
proteins O
, O
such O
as O
the O
amyloid O
precursor O
protein O
( O
APP O
) O
. O

Since O
AChE O
does O
not O
possess O
a O
transmembrane O
domain O
, O
its O
anchorage O
in O
the O
membrane O
is O
established O
via O
the O
Proline B
Rich O
Membrane O
Anchor O
( O
PRiMA O
) O
, O
a O
transmembrane O
protein O
. O

Both O
the O
subunit O
oligomerisation O
and O
membrane O
anchor O
of O
AChE O
are O
shared O
by O
a O
related O
enzyme O
, O
butyrylcholinesteras O
( O
BChE O
) O
, O
the O
physiological O
function O
of O
which O
in O
the O
brain O
is O
unclear O
. O

In O
this O
work O
, O
we O
have O
assayed O
the O
relative O
activities O
of O
AChE O
and O
BChE O
in O
membrane O
fractions O
and O
culture O
medium O
of O
three O
different O
neuronal O
cell O
lines O
, O
namely O
the O
neuroblastoma O
cell O
lines O
SH O
- O
SY5Y O
and O
NB7 O
and O
the O
mouse O
basal O
forebrain O
cell O
line O
SN56 O
. O

In O
an O
effort O
to O
understand O
the O
shedding O
process O
of O
AChE O
, O
we O
have O
used O
several O
pharmacological O
treatments O
, O
which O
showed O
that O
it O
is O
likely O
to O
be O
mediated O
in O
part O
by O
an O
EDTA B
- O
and O
batimastat B
- O
sensitive O
, O
but O
GM6001 B
- O
insensitive O
metalloprotease O
, O
with O
the O
possible O
additional O
involvement O
of O
a O
thiol B
isomerase O
. O

Cellular O
release O
of O
AChE O
by O
SH O
- O
SY5Y O
is O
significantly O
enhanced O
by O
the O
muscarinic O
acetylcholine B
receptor O
( O
mAChR O
) O
agonists O
carbachol B
or O
muscarine B
, O
with O
the O
effect O
of O
carbachol B
blocked O
by O
the O
mAChR O
antagonist O
atropine B
. O

AChE O
has O
been O
implicated O
in O
the O
pathogenesis O
of O
Alzheimer O
' O
s O
disease O
and O
it O
has O
been O
shown O
that O
it O
accelerates O
formation O
and O
increases O
toxicity O
of O
amyloid O
fibrils O
, O
which O
have O
been O
closely O
linked O
to O
the O
pathology O
of O
AD O
. O

In O
light O
of O
this O
, O
greater O
understanding O
of O
AChE O
and O
BChE O
physiology O
may O
also O
benefit O
AD O
research O
. O

Cholinesterases O
in O
development O
: O
AChE O
as O
a O
firewall O
to O
inhibit O
cell O
proliferation O
and O
support O
differentiation O
. O

Acetylcholinesterase O
( O
AChE O
) O
is O
a O
most O
remarkable O
protein O
, O
not O
only O
because O
it O
is O
one O
of O
the O
fastest O
enzymes O
in O
nature O
, O
but O
also O
since O
it O
appears O
in O
many O
molecular O
forms O
and O
is O
regulated O
by O
elaborate O
genetic O
networks O
. O

AChE O
is O
expressed O
in O
many O
tissues O
during O
development O
and O
in O
mature O
organisms O
, O
as O
well O
as O
in O
healthy O
and O
diseased O
states O
. O

In O
search O
for O
alternative O
, O
" O
non O
- O
classical O
" O
functions O
of O
cholinesterases O
( O
ChEs O
) O
, O
AChE O
could O
either O
work O
within O
the O
frame O
of O
classic O
cholinergic O
systems O
, O
but O
in O
non O
- O
neural O
tissues O
( O
" O
non O
- O
synaptic O
function O
" O
) O
, O
or O
act O
non O
- O
enzymatically O
. O

Here O
, O
we O
review O
briefly O
some O
of O
the O
major O
ideas O
and O
advances O
of O
this O
field O
, O
and O
report O
on O
some O
recent O
progress O
from O
our O
own O
experimental O
work O
, O
e O
. O
g O
. O
that O
( O
i O
) O
non O
- O
neural O
ChEs O
have O
pronounced O
, O
predominantly O
enzymatic O
effects O
on O
early O
embryonic O
( O
limb O
) O
development O
in O
chick O
and O
mouse O
, O
that O
( O
ii O
) O
retinal O
R28 O
cells O
of O
the O
rat O
overexpressing O
synaptic O
AChE O
present O
a O
significantly O
decreased O
cell O
proliferation O
, O
and O
that O
( O
iii O
) O
in O
developing O
chick O
retina O
ACh B
- O
synthesizing O
and O
ACh B
- O
degrading O
cells O
originate O
from O
the O
same O
postmitotic O
precursor O

cells O
, O
which O
later O
form O
two O
locally O
opposing O
cell O
populations O
. O

We O
suggest O
that O
such O
distinct O
distributions O
of O
ChAT O
( O
+ O
) O
vs O
. O
AChE O
( O
+ O
) O
cells O
in O
the O
inner O
half O
retina O
provide O
graded O
distributions O
of O
ACh O
, O
which O
can O
direct O
cell O
differentiation O
and O
network O
formation O
. O

Thus O
, O
as O
corroborated O
by O
works O
from O
many O
labs O
, O
AChE O
can O
be O
considered O
a O
highly O
co O
- O
opting O
protein O
, O
which O
can O
combine O
enzymatic O
and O
non O
- O
enzymatic O
functions O
within O
one O
molecule O
. O

Nanoengineered O
colloidal O
probes O
for O
Raman O
- O
based O
detection O
of O
biomolecules O
inside O
living O
cells O
. O

Gold O
nanoparticle O
aggregate O
carbon B
nanotube O
functionalized O
colloidal O
particles O
serve O
as O
an O
efficient O
platform O
for O
probing O
the O
intracellular O
environment O
. O

The O
probes O
provide O
the O
means O
of O
effective O
localization O
of O
signal O
and O
detection O
of O
molecular O
fingerprints O
of O
biomolecules O
in O
living O
cells O
. O

The O
approach O
demonstrated O
in O
this O
work O
opens O
significant O
opportunities O
in O
molecular O
imaging O
as O
well O
as O
intracellular O
sensing O
and O
trafficking O
. O

Sex O
and O
dose O
- O
dependent O
effects O
of O
developmental O
exposure O
to O
bisphenol B
A I
on O
anxiety O
and O
spatial O
learning O
in O
deer O
mice O
( O
Peromyscus O
maniculatus O
bairdii O
) O
offspring O
. O

Bisphenol B
A I
( O
BPA B
) O
is O
a O
widely O
produced O
, O
endocrine O
disrupting O
compound O
that O
is O
pervasive O
in O
the O
environment O
. O

Data O
suggest O
that O
developmental O
exposure O
to O
BPA B
during O
sexual O
differentiation O
of O
the O
brain O
leads O
to O
later O
behavioral O
consequences O
in O
offspring O
. O

Outbred O
deer O
mice O
( O
Peromyscus O
maniculatus O
bairdii O
) O
are O
an O
excellent O
animal O
model O
for O
such O
studies O
as O
they O
exhibit O
well O
- O
defined O
sex O
- O
and O
steroid B
- O
dependent O
behaviors O
. O

Here O
, O
dams O
during O
gestation O
and O
lactation O
were O
fed O
with O
a O
phytoestrogen O
- O
free O
control O
diet O
, O
the O
same O
diet O
supplemented O
with O
either O
ethinyl B
estradiol I
( O
0 O
. O
1 O
ppb O
) O
, O
or O
one O
of O
the O
three O
doses O
of O
BPA B
( O
50 O
mg O
, O
5 O
mg O
, O
50 O
mu O
g O
/ O
kg O
feed O
weight O
) O
. O

After O
weaning O
, O
the O
pups O
were O
maintained O
on O
control O
diet O
until O
they O
reached O
sexual O
maturity O
and O
then O
assessed O
for O
both O
spatial O
learning O
capabilities O
and O
anxiety O
- O
like O
and O
exploratory O
behaviors O
. O

Relative O
to O
controls O
, O
males O
exposed O
to O
the O
two O
upper O
but O
not O
the O
lowest O
dose O
of O
BPA B
demonstrated O
similar O
impairments O
in O
spatial O
learning O
, O
increased O
anxiety O
and O
reduced O
exploratory O
behaviors O
as O
ethinyl B
estradiol I
- O
exposed O
males O
, O
while O
females O
exposed O
to O
ethinyl B
estradiol I
, O
but O
not O
to O
BPA B
, O
consistently O
exhibited O
masculinized O
spatial O
abilities O
. O

We O
also O
determined O
whether O
dams O
maintained O
chronically O
on O
the O
upper O
dose O
of O
BPA B
contained O
environmentally O
relevant O
concentrations O
of O
BPA B
in O
their O
blood O
. O

While O
serum O
concentrations O
of O
unconjugated O
BPA B
in O
controls O
were O
below O
the O
minimum O
level O
of O
detection O
, O
those O
from O
dams O
on O
the O
BPA B
diet O
were O
comparable O
( O
5 O
. O
48 O
+ O
/ O
- O
2 O
. O
07 O
ng O
/ O
ml O
) O
to O
concentrations O
that O
have O
been O
observed O
in O
humans O
. O

Together O
, O
these O
studies O
demonstrate O
that O
developmental O
exposure O
to O
environmentally O
relevant O
concentrations O
of O
BPA B
can O
disrupt O
adult O
behaviors O
in O
a O
dose O
- O
and O
sex O
- O
dependent O
manner O
. O

Self O
- O
propelled O
nanojets O
via O
template O
electrodeposition O
. O

In O
this O
paper O
, O
we O
present O
a O
rapid O
, O
high O
- O
yield O
, O
low O
- O
end O
and O
low O
- O
cost O
fabrication O
of O
nanojet O
motors O
using O
a O
template O
directed O
electrochemical O
deposition O
method O
. O

Using O
an O
electrochemical O
deposition O
method O
, O
the O
bubble O
- O
ejecting O
nanojets O
were O
grown O
within O
the O
alumina B
template O
, O
which O
is O
commercially O
available O
. O

These O
fabricated O
nanosized O
devices O
have O
typical O
dimensions O
of O
300 O
nm O
( O
diameter O
) O
by O
4 O
. O
5 O
mu O
m O
( O
length O
) O
, O
and O
they O
are O
able O
to O
move O
in O
a O
hydrogen B
peroxide I
fuel O
solution O
with O
velocities O
up O
to O
approximately O
40 O
body O
lengths O
per O
second O
. O

They O
are O
also O
capable O
of O
exhibiting O
various O
modes O
of O
movement O
such O
as O
straight O
, O
screw O
- O
like O
and O
circular O
motions O
, O
in O
a O
similar O
manner O
comparable O
to O
larger O
micro O
- O
sized O
jets O
. O

In O
addition O
, O
due O
to O
their O
small O
dimensions O
, O
the O
movements O
of O
these O
nanojets O
can O
be O
strongly O
influenced O
by O
colliding O
them O
with O
microbubbles O
. O

This O
highly O
parallel O
method O
which O
is O
of O
low O
- O
cost O
and O
requires O
the O
usage O
of O
low O
- O
end O
equipment O
that O
can O
be O
easily O
located O
in O
any O
laboratory O
opens O
up O
the O
doors O
for O
world O
- O
wide O
nanojet O
fabrication O
in O
the O
near O
future O
. O

Endocrine O
disruptors O
fludioxonil B
and O
fenhexamid B
stimulate O
miR O
- O
21 O
expression O
in O
breast O
cancer O
cells O
. O

Fenhexamid B
and O
fludioxonil B
are O
antifungal O
agents O
used O
in O
agricultural O
applications O
, O
which O
are O
present O
at O
measurable O
amounts O
in O
fruits O
and O
vegetables O
. O

Fenhexamid B
and O
fludioxonil B
showed O
endocrine O
disruptor O
activity O
as O
antiandrogens O
in O
an O
androgen B
receptor O
reporter O
assay O
in O
engineered O
human O
breast O
cancer O
cells O
. O

Little O
is O
known O
about O
how O
environmental O
chemicals O
regulate O
microRNA O
( O
miRNA O
) O
expression O
. O

This O
study O
examined O
the O
effect O
of O
fenhexamid B
and O
fludioxonil B
on O
the O
expression O
of O
the O
oncomiR O
miR O
- O
21 O
in O
MCF O
- O
7 O
, O
T47D O
, O
and O
MDA O
- O
MB O
- O
231 O
human O
breast O
cancer O
cells O
and O
downstream O
targets O
of O
miR O
- O
21 O
in O
MCF O
- O
7 O
cells O
. O

Fenhexamid B
and O
fludioxonil B
stimulated O
miR O
- O
21 O
expression O
in O
a O
concentration O
- O
dependent O
manner O
and O
reduced O
the O
expression O
of O
miR O
- O
21 O
target O
Pdcd4 O
protein O
. O

Antisense O
to O
miR O
- O
21 O
blocked O
the O
increase O
in O
Pdcd4 O
protein O
by O
fenhexamid B
and O
fludioxonil B
. O

Fenhexamid B
and O
fludioxonil B
reduced O
miR O
- O
125b O
and O
miR O
- O
181a O
, O
demonstrating O
specificity O
of O
miRNA O
regulation O
. O

Induction O
of O
miR O
- O
21 O
was O
inhibited O
by O
the O
estrogen B
receptor O
antagonist O
fulvestrant B
, O
by O
androgen B
receptor O
antagonist O
bicalutamide B
, O
by O
actinomycin B
D I
and O
cycloheximide B
, O
and O
by O
inhibitors O
of O
the O
mitogen O
- O
activated O
protein O
kinases O
and O
phosphoinositide O
3 O
- O
kinase O
pathways O
. O

Fenhexamid B
activation O
was O
inhibited O
by O
the O
arylhydrocarbon B
receptor O
antagonist O
alpha B
- I
napthoflavone I
. O

Fenhexamid B
and O
fludioxonil B
did O
not O
affect O
dihydrotestosterone B
- O
induced O
miR O
- O
21 O
expression O
. O

Fludioxonil B
, O
but O
not O
fenhexamid B
, O
inhibited O
MCF O
- O
7 O
cell O
viability O
, O
and O
both O
inhibited O
estradiol B
- O
induced O
cell O
proliferation O
and O
reduced O
cell O
motility O
. O

Together O
these O
data O
indicate O
that O
fenhexamid B
and O
fludioxonil B
use O
similar O
and O
distinct O
mechanisms O
to O
increase O
miR O
- O
21 O
expression O
with O
downstream O
antiestrogenic O
activity O
. O

Benzo B
[ I
a I
] I
pyrene I
- O
induced O
transcriptomic O
responses O
in O
primary O
hepatocytes O
and O
in O
vivo O
liver O
: O
toxicokinetics O
is O
essential O
for O
in O
vivo O
- O
in O
vitro O
comparisons O
. O

The O
traditional O
2 O
- O
year O
cancer O
bioassay O
needs O
replacement O
by O
more O
cost O
- O
effective O
and O
predictive O
tests O
. O

The O
use O
of O
toxicogenomics O
in O
an O
in O
vitro O
system O
may O
provide O
a O
more O
high O
- O
throughput O
method O
to O
investigate O
early O
alterations O
induced O
by O
carcinogens O
. O

Recently O
, O
the O
differential O
gene O
expression O
response O
in O
wild O
- O
type O
and O
cancer O
- O
prone O
Xpa O
( O
- O
/ O
- O
) O
p53 O
( O
+ O
/ O
- O
) O
primary O
mouse O
hepatocytes O
after O
exposure O
to O
benzo B
[ I
a I
] I
pyrene I
( O
B B
[ I
a I
] I
P I
) O
revealed O
downregulation O
of O
cancer O
- O
related O
pathways O
in O
Xpa O
( O
- O
/ O
- O
) O
p53 O
( O
+ O
/ O
- O
) O
hepatocytes O
only O
. O

Here O
, O
we O
investigated O
pathway O
regulation O
upon O
in O
vivo O
B B
[ I
a I
] I
P I
exposure O
of O
wild O
- O
type O
and O
Xpa O
( O
- O
/ O
- O
) O
p53 O
( O
+ O
/ O
- O
) O
mice O
. O

In O
vivo O
transcriptomics O
analysis O
revealed O
a O
limited O
gene O
expression O
response O
in O
mouse O
livers O
, O
but O
with O
a O
significant O
induction O
of O
DNA O
replication O
and O
apoptotic O
/ O
anti O
- O
apoptotic O
cellular O
responses O
in O
Xpa O
( O
- O
/ O
- O
) O
p53 O
( O
+ O
/ O
- O
) O
livers O
only O
. O

In O
order O
to O
be O
able O
to O
make O
a O
meaningful O
in O
vivo O
- O
in O
vitro O
comparison O
we O
estimated O
internal O
in O
vivo O
B B
[ I
a I
] I
P I
concentrations O
using O
DNA O
adduct O
levels O
and O
physiologically O
based O
kinetic O
modeling O
. O

Based O
on O
these O
results O
, O
the O
in O
vitro O
concentration O
that O
corresponded O
best O
with O
the O
internal O
in O
vivo O
dose O
was O
chosen O
. O

Comparison O
of O
in O
vivo O
and O
in O
vitro O
data O
demonstrated O
similarities O
in O
transcriptomics O
response O
: O
xenobiotic O
metabolism O
, O
lipid O
metabolism O
and O
oxidative O
stress O
. O

However O
, O
we O
were O
unable O
to O
detect O
cancer O
- O
related O
pathways O
in O
either O
wild O
- O
type O
or O
Xpa O
( O
- O
/ O
- O
) O
p53 O
( O
+ O
/ O
- O
) O
exposed O
livers O
, O
which O
were O
previously O
found O
to O
be O
induced O
by O
B B
[ I
a I
] I
P I
in O
Xpa O
( O
- O
/ O
- O
) O
p53 O
( O
+ O
/ O
- O
) O
primary O
hepatocytes O
. O

In O
conclusion O
, O
we O
showed O
parallels O
in O
gene O
expression O
responses O
between O
livers O
and O
primary O
hepatocytes O
upon O
exposure O
to O
equivalent O
concentrations O
of O
B B
[ I
a I
] I
P I
. O

Furthermore O
, O
we O
recommend O
considering O
toxicokinetics O
when O
modeling O
a O
complex O
in O
vivo O
endpoint O
with O
in O
vitro O
models O
. O

Environmentally O
relevant O
concentrations O
of O
a O
common O
insecticide O
increase O
predation O
risk O
in O
a O
freshwater O
gastropod O
. O

Ecological O
receptors O
are O
faced O
with O
a O
multitude O
of O
stressors O
that O
include O
abiotic O
and O
biotic O
factors O
creating O
a O
challenge O
for O
assessing O
risk O
of O
chemical O
exposure O
. O

Of O
particular O
interest O
and O
importance O
are O
the O
effects O
of O
contaminants O
on O
inter O
- O
species O
interactions O
such O
as O
competition O
and O
predator O
- O
prey O
relationships O
. O

The O
objective O
of O
this O
study O
was O
to O
determine O
whether O
environmentally O
relevant O
concentrations O
of O
the O
commonly O
used O
insecticide O
, O
malathion B
, O
would O
alter O
predator O
avoidance O
behavior O
in O
a O
freshwater O
gastropod O
that O
could O
translate O
to O
increased O
predation O
risk O
. O

We O
exposed O
adult O
Physa O
pomilia O
snails O
to O
0 O
, O
0 O
. O
25 O
, O
or O
1 O
. O
0 O
mg O
/ O
L O
malathion B
for O
2 O
, O
24 O
, O
or O
48 O
h O
and O
evaluated O
predator O
avoidance O
using O
a O
behavioral O
assay O
in O
which O
snails O
were O
exposed O
to O
cues O
from O
predatory O
crayfish O
. O

We O
found O
a O
significant O
reduction O
in O
predator O
avoidance O
in O
snails O
exposed O
to O
both O
concentrations O
of O
malathion B
after O
48 O
h O
of O
exposure O
. O

To O
evaluate O
whether O
observed O
effects O
of O
malathion B
on O
predator O
avoidance O
actually O
increased O
susceptibility O
of O
snails O
to O
predators O
, O
we O
conducted O
a O
predator O
challenge O
experiment O
. O

Snails O
exposed O
to O
0 O
. O
25 O
mg O
/ O
L O
malathion B
for O
48 O
h O
were O
significantly O
more O
susceptible O
to O
predation O
. O

That O
increased O
predation O
risk O
was O
evident O
48 O
h O
after O
initial O
malathion B
exposures O
is O
a O
unique O
result O
because O
most O
studies O
have O
evaluated O
behavioral O
responses O
soon O
after O
( O
< O
12 O
h O
) O
initiation O
of O
pesticide O
exposure O
. O

The O
extent O
to O
which O
the O
observed O
interactions O
affect O
natural O
populations O
, O
and O
the O
mechanisms O
through O
which O
they O
are O
mediated O
are O
largely O
unexplored O
. O

However O
, O
our O
study O
is O
the O
first O
to O
show O
that O
a O
commonly O
used O
insecticide O
decreases O
predator O
avoidance O
and O
may O
actually O
increase O
predation O
susceptibility O
in O
gastropods O
at O
concentrations O
several O
orders O
of O
magnitude O
below O
acute O
toxicity O
levels O
. O

Contamination O
by O
metals O
and O
pharmaceuticals O
in O
northern O
Taihu O
Lake O
( O
China O
) O
and O
its O
relation O
to O
integrated O
biomarker O
response O
in O
fish O
. O

Taihu O
Lake O
is O
the O
largest O
shallow O
freshwater O
lake O
in O
eastern O
China O
and O
is O
suffering O
not O
only O
from O
an O
increasingly O
serious O
threat O
of O
eutrophication O
but O
also O
potential O
ecological O
risk O
due O
to O
the O
input O
of O
emerging O
contaminants O
. O

Active O
biomonitoring O
was O
conducted O
in O
Taihu O
Lake O
using O
transplanted O
goldfish O
( O
Carassius O
auratus O
) O
to O
determine O
the O
contamination O
by O
pharmaceuticals O
and O
metals O
and O
to O
assess O
the O
potential O
ecological O
risk O
. O

A O
suite O
of O
biomarkers O
including O
acetylcholinesterase O
, O
ethoxyresorufin B
O B
- O
deethylase O
, O
glutathione B
S B
- O
transferase O
, O
glutathione B
peroxidase O
and O
superoxide B
dismutase O
activities O
in O
fish O
after O
7 O
, O
14 O
, O
21 O
and O
28 O
days O
of O
exposure O
in O
situ O
, O
as O
well O
as O
pharmaceuticals O
and O
metals O
in O
water O
, O
were O
determined O
during O
the O
field O
exposure O
period O
. O

The O
results O
indicate O
that O
pharmaceuticals O
exist O
mainly O
in O
Zhushan O
Bay O
and O
Meiliang O
Bay O
, O
while O
metals O
are O
present O
mainly O
in O
Gong O
Bay O
. O

An O
integrated O
biomarker O
response O
( O
IBR O
) O
was O
calculated O
and O
used O
to O
evaluate O
the O
ecological O
risk O
of O
the O
polluted O
area O
of O
Taihu O
Lake O
. O

It O
was O
found O
that O
Zhushan O
Bay O
might O
present O
higher O
risk O
to O
fish O
, O
followed O
by O
Meiliang O
Bay O
. O

IBR O
values O
were O
in O
good O
agreement O
with O
copper B
and O
caffeine B
concentrations O
. O

New O
markers O
of O
apoptosis O
in O
children O
on O
chronic O
dialysis O
. O

Enhanced O
apoptosis O
is O
characteristic O
for O
chronic O
kidney O
disease O
( O
CKD O
) O
. O

A O
specific O
type O
of O
apoptosis O
, O
anoikis O
, O
is O
connected O
with O
the O
extracellular O
matrix O
turnover O
and O
cell O
detachment O
. O

Although O
E O
- O
cadherin O
, O
extracellular O
matrix O
metalloproteinase O
inducer O
( O
EMMPRIN O
) O
and O
matrix O
metalloproteinase O
( O
MMP O
) O
- O
8 O
may O
play O
an O
important O
role O
in O
this O
process O
, O
they O
have O
not O
been O
analyzed O
in O
any O
nephrological O
aspect O
, O
either O
in O
CKD O
. O

The O
aim O
of O
study O
was O
to O
evaluate O
the O
serum O
concentrations O
of O
E O
- O
cadherin O
, O
EMMPRIN O
and O
their O
potential O
regulators O
( O
MMP O
- O
8 O
, O
MMP O
- O
7 O
, O
TIMP O
- O
1 O
, O
TIMP O
- O
2 O
) O
, O
with O
relevance O
to O
apoptosis O
/ O
cell O
damage O
markers O
( O
sFas O
, O
sFasL O
, O
Hsp27 O
) O
, O
in O
children O
with O
CKD O
. O

39 O
CKD O
children O
stages O
3 O
- O
4 O
, O
26 O
CKD O
children O
stage O
5 O
still O
on O
conservative O
treatment O
, O
19 O
patients O
on O
hemodialysis O
( O
HD O
) O
, O
22 O
children O
on O
automated O
peritoneal O
dialysis O
( O
APD O
) O
and O
30 O
controls O
were O
examined O
. O

Serum O
concentrations O
of O
those O
parameters O
were O
assessed O
by O
ELISA O
. O

Median O
E O
- O
cadherin O
, O
EMMPRIN O
and O
MMP O
- O
8 O
values O
were O
significantly O
increased O
in O
patients O
on O
dialysis O
versus O
those O
in O
pre O
- O
dialysis O
period O
and O
versus O
controls O
. O

The O
highest O
values O
were O
noticed O
in O
the O
HD O
subjects O
. O

Regression O
analysis O
revealed O
that O
EMMPRIN O
and O
MMP O
- O
8 O
predicted O
various O
apoptosis O
markers O
, O
whereas O
E O
- O
cadherin O
turned O
out O
the O
best O
predictor O
of O
both O
apoptosis O
( O
Hsp27 O
, O
sFas O
, O
sFasL O
) O
and O
matrix O
turnover O
( O
MMP O
- O
7 O
, O
TIMP O
- O
1 O
, O
TIMP O
- O
2 O
) O
indexes O
in O
dialyzed O
patients O
. O

Children O
with O
CKD O
are O
prone O
to O
E O
- O
cadherin O
, O
EMMPRIN O
and O
MMP O
- O
8 O
elevation O
, O
aggravated O
by O
the O
dialysis O
commencement O
and O
most O
evident O
on O
hemodialysis O
. O

Correlations O
between O
parameters O
suggest O
their O
role O
as O
indexes O
of O
apoptosis O
in O
children O
on O
dialysis O
. O

E O
- O
cadherin O
seems O
the O
most O
accurate O
marker O
of O
anoikis O
in O
this O
population O
. O

Regulation O
of O
hepatic O
phase O
II O
metabolism O
in O
pregnant O
mice O
. O

Phase O
II O
enzymes O
, O
including O
Ugts O
, O
Sults O
, O
and O
Gsts O
, O
are O
critical O
for O
the O
disposition O
and O
detoxification O
of O
endo O
- O
and O
xenobiotics O
. O

In O
this O
study O
, O
the O
mRNA O
and O
protein O
expression O
of O
major O
phase O
II O
enzymes O
, O
as O
well O
as O
key O
regulatory O
transcription O
factors O
, O
were O
quantified O
in O
livers O
of O
time O
- O
matched O
pregnant O
and O
virgin O
control O
C57BL O
/ O
6 O
mice O
on O
gestation O
days O
( O
GD O
) O
7 O
, O
11 O
, O
14 O
, O
17 O
, O
and O
postnatal O
days O
( O
PND O
) O
1 O
, O
15 O
, O
and O
30 O
. O

Compared O
with O
virgin O
controls O
, O
the O
mRNA O
expression O
of O
Ugt1a1 O
, O
1a6 O
, O
1a9 O
, O
2a3 O
, O
2b1 O
, O
2b34 O
, O
and O
2b35 O
decreased O
40 O
to O
80 O
% O
in O
pregnant O
dams O
. O

Protein O
expression O
of O
Ugt1a6 O
also O
decreased O
and O
corresponded O
with O
reduced O
in O
vitro O
glucuronidation O
of O
bisphenol B
A I
in O
S9 O
fractions O
from O
livers O
of O
pregnant O
mice O
. O

Similar O
to O
Ugts O
levels O
, O
Gsta1 O
and O
a4 O
mRNAs O
were O
reduced O
in O
pregnant O
dams O
in O
mid O
to O
late O
gestation O
; O
however O
no O
change O
in O
protein O
expression O
was O
observed O
. O

Conversely O
, O
Sult1a1 O
, O
2a1 O
/ O
2 O
, O
and O
3a1 O
mRNAs O
increased O
100 O
to O
500 O
% O
at O
various O
time O
points O
in O
pregnant O
and O
lactating O
mice O
and O
corresponded O
with O
enhanced O
in O
vitro O
sulfation O
of O
acetaminophen B
in O
liver O
S9 O
fractions O
. O

Coinciding O
with O
maximal O
decreases O
in O
Ugts O
as O
well O
as O
increases O
in O
Sults O
, O
the O
expression O
of O
transcription O
factors O
CAR O
, O
PPAR O
alpha O
, O
and O
PXR O
and O
their O
target O
genes O
were O
downregulated O
, O
whereas O
ER O
alpha O
mRNA O
was O
upregulated O
. O

Collectively O
, O
these O
data O
demonstrate O
altered O
regulation O
of O
hepatic O
phase O
II O
metabolism O
in O
mice O
during O
pregnancy O
and O
suggest O
that O
CAR O
, O
PPAR O
alpha O
, O
PXR O
, O
and O
ER O
alpha O
signaling O
pathways O
may O
be O
candidate O
signaling O
pathways O
responsible O
for O
these O
changes O
. O

Dendritic O
arbor O
of O
neurons O
in O
the O
hypothalamic O
ventromedial O
nucleus O
in O
female O
prairie O
voles O
( O
Microtus O
ochrogaster O
) O
. O

Female O
mating O
behavior O
in O
rats O
is O
associated O
with O
hormone O
- O
induced O
changes O
in O
the O
dendritic O
arbor O
of O
neurons O
in O
the O
ventromedial O
nucleus O
of O
the O
hypothalamus O
( O
VMH O
) O
, O
particularly O
the O
ventrolateral O
portion O
. O

Regulation O
of O
mating O
behavior O
in O
female O
prairie O
voles O
differs O
substantially O
from O
that O
in O
rats O
; O
therefore O
, O
we O
examined O
the O
dendritic O
morphology O
of O
VMH O
neurons O
in O
this O
species O
. O

Sexually O
na O
i O
ve O
adult O
female O
prairie O
voles O
were O
housed O
with O
a O
male O
to O
activate O
the O
females O
' O
reproductive O
endocrine O
system O
. O

Following O
48 O
h O
of O
cohabitation O
, O
females O
were O
tested O
for O
evidence O
of O
reproductive O
activation O
by O
assessing O
the O
level O
of O
male O
sexual O
interest O
, O
after O
which O
their O
brains O
were O
processed O
using O
Golgi O
impregnation O
, O
which O
allowed O
ventrolateral O
VMH O
neurons O
to O
be O
visualized O
and O
analyzed O
. O

Dendritic O
arborization O
in O
the O
female O
prairie O
vole O
VMH O
neurons O
was O
strikingly O
similar O
to O
that O
of O
female O
rats O
. O

The O
key O
difference O
was O
that O
in O
the O
prairie O
voles O
the O
long O
primary O
dendrites O
extended O
considerably O
further O
than O
those O
observed O
in O
rats O
. O

Although O
most O
female O
voles O
paired O
with O
males O
exhibited O
sexual O
activation O
, O
some O
females O
did O
not O
. O

These O
two O
groups O
displayed O
specific O
differences O
in O
their O
VMH O
dendrites O
. O

In O
particular O
, O
the O
long O
primary O
dendrites O
were O
longer O
in O
the O
reproductively O
active O
females O
compared O
with O
those O
in O
the O
non O
- O
activated O
females O
. O

Overall O
, O
dendrite O
lengths O
were O
positively O
correlated O
with O
plasma O
estradiol B
levels O
in O
females O
exposed O
to O
males O
, O
but O
not O
in O
unpaired O
females O
. O

Although O
causal O
relationships O
between O
the O
neuroendocrine O
events O
, O
dendrite O
length O
, O
and O
the O
outward O
, O
behavioral O
manifestation O
of O
reproductive O
activation O
cannot O
be O
determined O
from O
this O
study O
, O
these O
results O
suggest O
an O
association O
between O
ventrolateral O
VMH O
dendrite O
morphology O
and O
female O
mating O
behavior O
in O
prairie O
voles O
, O
akin O
to O
what O
has O
been O
observed O
in O
female O
rats O
. O

Hormesis O
: O
its O
impact O
on O
medicine O
and O
health O
. O

This O
article O
offers O
a O
broad O
assessment O
of O
the O
hormetic O
dose O
response O
and O
its O
relevance O
to O
biomedical O
researchers O
, O
physicians O
, O
the O
pharmaceutical O
industry O
, O
and O
public O
health O
scientists O
. O

This O
article O
contains O
a O
series O
of O
61 O
questions O
followed O
by O
relatively O
brief O
but O
referenced O
responses O
that O
provides O
support O
for O
the O
conclusion O
that O
hormesis O
is O
a O
reproducible O
phenomenon O
, O
commonly O
observed O
, O
with O
a O
frequency O
far O
greater O
than O
other O
dose O
- O
response O
models O
such O
as O
the O
threshold O
and O
linear O
nonthreshold O
dose O
- O
response O
models O
. O

The O
article O
provides O
a O
detailed O
background O
information O
on O
the O
historical O
foundations O
of O
hormesis O
, O
its O
quantitative O
features O
, O
mechanistic O
foundations O
, O
as O
well O
as O
how O
hormesis O
is O
currently O
being O
used O
within O
medicine O
and O
identifying O
how O
this O
concept O
could O
be O
further O
applied O
in O
the O
development O
of O
new O
therapeutic O
advances O
and O
in O
improved O
public O
health O
practices O
. O

APP O
independent O
and O
dependent O
effects O
on O
neurite O
outgrowth O
are O
modulated O
by O
the O
receptor O
associated O
protein O
( O
RAP O
) O
. O

Amyloid O
precursor O
protein O
( O
APP O
) O
and O
its O
secreted O
form O
, O
sAPP O
, O
contribute O
to O
the O
development O
of O
neurons O
in O
hippocampus O
, O
a O
brain O
region O
critical O
for O
learning O
and O
memory O
. O

Full O
- O
length O
APP O
binds O
the O
low O
- O
density O
lipoprotein O
receptor O
- O
related O
protein O
( O
LRP O
) O
, O
which O
stimulates O
APP O
endocytosis O
. O

LRP O
also O
contributes O
to O
neurite O
growth O
. O

Furthermore O
, O
the O
receptor O
associated O
protein O
( O
RAP O
) O
binds O
LRP O
in O
a O
manner O
that O
blocks O
APP O
- O
LRP O
interactions O
. O

To O
elucidate O
APP O
contributions O
to O
neurite O
growth O
for O
full O
- O
length O
APP O
and O
sAPP O
, O
we O
cultured O
wild O
type O
( O
WT O
) O
and O
APP O
knockout O
( O
KO O
) O
neurons O
in O
sAPP O
alpha O
and O
/ O
or O
RAP O
and O
measured O
neurite O
outgrowth O
at O
1 O
day O
in O
vitro O
. O

Our O
data O
reveal O
that O
WT O
neurons O
had O
less O
axonal O
outgrowth O
including O
less O
axon O
branching O
. O

RAP B
treatment O
potentiated O
the O
inhibitory O
effects O
of O
APP O
. O

KO O
neurons O
had O
significantly O
more O
outgrowth O
and O
branching O
, O
especially O
in O
response O
to O
RAP B
, O
effects O
which O
were O
also O
associated O
with O
ERK2 O
activation O
. O

Our O
results O
affirm O
a O
major O
inhibitory O
role O
by O
full O
- O
length O
APP O
on O
all O
aspects O
of O
axonal O
and O
dendritic O
outgrowth O
, O
and O
show O
that O
RAP B
- O
LRP O
binding O
stimulated O
axon O
growth O
independently O
of O
APP O
. O

These O
findings O
support O
a O
major O
role O
for O
APP O
as O
an O
inhibitor O
of O
neurite O
growth O
and O
reveal O
novel O
signaling O
functions O
for O
LRP O
that O
may O
be O
disrupted O
by O
Alzheimer O
' O
s O
pathology O
or O
therapies O
aimed O
at O
APP O
processing O
. O

Human O
ether O
- O
a O
- O
go O
- O
go O
- O
related O
gene O
channel O
blockers O
and O
its O
structural O
analysis O
for O
drug O
design O
. O

The O
human O
ether O
- O
a O
- O
go O
- O
go O
- O
related O
gene O
( O
hERG O
) O
is O
a O
K B
+ I
channel O
protein O
mainly O
expressed O
in O
the O
heart O
and O
the O
nervous O
systems O
and O
its O
blockade O
by O
non O
- O
cardiovascular O
acting O
drugs O
resulted O
in O
tachycardia O
and O
sudden O
death O
. O

In O
this O
present O
review O
, O
we O
have O
focused O
the O
physicochemical O
properties O
responsible O
for O
the O
hERG O
blocking O
activity O
of O
structurally O
different O
compounds O
. O

The O
reported O
research O
works O
showed O
that O
the O
hydrophobicity O
on O
the O
van O
der O
Waals O
( O
vdW O
) O
surface O
of O
the O
molecules O
( O
aroused O
from O
the O
aromatic O
ring O
) O
necessary O
for O
the O
hERG O
blocking O
activity O
along O
with O
topological O
and O
electronic O
properties O
. O

The O
quinolizidine B
alkaloids I
( O
natural O
products O
) O
such O
as O
oxymatrine B
, O
sophoridine B
, O
sophocarpine B
and O
matrine B
carry O
the O
common O
molecular O
structure O
of O
O B
= I
C I
= I
N I
- I
C I
- I
C I
- I
C I
- I
N I
that O
possessed O
positive O
ionotropic O
effect O
and O
hERG O
blocking O
activity O
. O

Acehytisine B
hydrochloride I
( O
previously O
named O
Guangfu B
base I
A I
) O
was O
isolated O
from O
the O
root O
of O
Aconitum O
coreanum O
( O
Levl O
. O
) O
, O
is O
an O
anti O
- O
arrhythmic O
drug O
in O
phase O
IV O
clinical O
trial O
. O

The O
isoquinoline B
alkaloid I
, O
neferine B
( O
Nef B
) O
induces O
a O
concentration O
- O
dependent O
decrease O
in O
current O
amplitude O
( O
IC50 O
of O
7 O
. O
419 O
MM O
) O
. O

Most O
of O
these O
natural O
product O
compounds O
contain O
non O
- O
flexible O
aromatic O
structures O
but O
have O
significant O
activity O
due O
to O
the O
presence O
of O
optimum O
hydrophobicity O
. O

Recent O
research O
works O
revealed O
that O
Eag O
and O
hERG O
channels O
are O
expressed O
by O
a O
variety O
of O
cancer O
cell O
lines O
and O
tissues O
. O

The O
Eag O
channel O
showed O
an O
oncogenic O
potential O
while O
hERG O
channels O
are O
associated O
with O
more O
aggressive O
tumors O
and O
have O
a O
role O
in O
mediating O
invasion O
. O

This O
review O
concluded O
that O
the O
consideration O
of O
physicochemical O
properties O
necessary O
for O
the O
hERG O
blocking O
activity O
will O
guide O
to O
develop O
novel O
drugs O
with O
less O
cardiotoxicity O
. O

In O
vitro O
synergistic O
interaction O
between O
amide B
piplartine B
and O
antimicrobial O
peptide O
dermaseptin O
against O
Schistosoma O
mansoni O
schistosomula O
and O
adult O
worms O
. O

Schistosomiasis O
is O
one O
of O
the O
world O
' O
s O
major O
public O
health O
problems O
, O
and O
praziquantel B
is O
the O
only O
available O
drug O
to O
treat O
this O
notable O
neglected O
disease O
. O

Drug O
combinations O
have O
been O
considered O
an O
important O
strategy O
for O
treatment O
of O
infectious O
diseases O
, O
which O
might O
enhance O
therapeutic O
efficacy O
and O
delaying O
resistance O
. O

In O
this O
study O
, O
we O
have O
examined O
the O
in O
vitro O
activities O
of O
the O
amide O
piplartine B
and O
the O
antimicrobial O
peptide O
dermaseptin O
01 O
administered O
singly O
or O
in O
combination O
against O
Schistosoma O
mansoni O
of O
different O
ages O
including O
3 O
- O
hour O
- O
old O
and O
7 O
- O
day O
- O
old O
schistosomula O
and O
49 O
- O
day O
- O
old O
adult O
schistosomes O
as O
well O
as O
on O
egg O
output O
by O
adult O
worms O
. O

We O
calculated O
the O
median O
lethal O
concentrations O
( O
LC O
( O
50 O
) O
) O
of O
7 O
. O
87 O
and O
17 O
. O
99 O
mu O
M O
on O
49 O
- O
day O
- O
old O
adults O
, O
11 O
. O
02 O
and O
71 O
. O
58 O
mu O
M O
on O
7 O
- O
day O
- O
old O
schistosomula O
, O
and O
70 O
. O
87 O
and O
98 O
. O
42 O
mu O
M O
on O
3 O
- O
hour O
- O
old O
schistosomula O
for O
piplartine B
and O
dermaseptin B
, O
respectively O
. O

Most O
Piplartine B
/ O
dermaseptin B
combinations O
showed O
synergistic O
effect O
, O
with O
combination O
index O
( O
CI O
) O
values O
less O
than O
0 O
. O
9 O
when O
S O
. O
mansoni O
adults O
or O
schistosomula O
were O
simultaneously O
incubated O
with O
both O
drugs O
in O
vitro O
; O
synergy O
between O
these O
two O
compounds O
was O
also O
indicated O
using O
isobolograms O
. O

Additionally O
, O
we O
observed O
alterations O
on O
the O
tegumental O
surface O
of O
schistosomula O
and O
adult O
schistosomes O
by O
means O
of O
laser O
scanning O
confocal O
microscopy O
. O

Furthermore O
, O
egg O
laying O
of O
surviving O
worms O
was O
considerably O
more O
reduced O
when O
exposed O
to O
the O
piplartine B
/ O
dermaseptin B
combinations O
than O
each O
drug O
alone O
, O
and O
this O
inhibition O
was O
irreversible O
. O

This O
is O
the O
first O
report O
on O
the O
synergistic O
effect O
between O
piplartine B
and O
dermaseptin O
against O
S O
. O
mansoni O
and O
opens O
the O
route O
to O
further O
studies O
( O
e O
. O
g O
. O
in O
vivo O
) O
to O
characterize O
this O
combination O
in O
greater O
detail O
. O

Physiological O
effects O
of O
waterborne O
lead O
exposure O
in O
spiny O
dogfish O
( O
Squalus O
acanthias O
) O
. O

To O
broaden O
our O
knowledge O
about O
the O
toxicity O
of O
metals O
in O
marine O
elasmobranchs O
, O
cannulated O
spiny O
dogfish O
( O
Squalus O
acanthias O
) O
were O
exposed O
to O
20 O
mu O
M O
and O
100 O
mu O
M O
lead O
( O
Pb B
) O
. O

Since O
we O
wanted O
to O
focus O
on O
sub O
lethal O
ion O
- O
osmoregulatory O
and O
respiratory O
disturbances O
, O
arterial O
blood O
samples O
were O
analysed O
for O
pH O
( O
a O
) O
, O
PaO B
( I
2 I
) I
, O
haematocrit O
and O
total O
CO B
( I
2 I
) I
values O
at O
several O
time O
points O
. O

Plasma O
was O
used O
to O
determine O
urea B
, O
TMAO B
, O
lactate B
and O
ion O
concentrations O
. O

After O
96 O
h O
, O
Pb B
concentrations O
were O
determined O
in O
a O
number O
of O
tissues O
, O
such O
as O
gill O
, O
rectal O
gland O
, O
skin O
and O
liver O
. O

To O
further O
investigate O
ion O
and O
osmoregulation O
, O
Na B
( I
+ I
) I
/ O
K B
( I
+ I
) I
- O
ATPase O
activities O
in O
gill O
and O
rectal O
gland O
were O
analysed O
as O
well O
as O
rates O
of O
ammonia B
and O
urea B
excretion O
. O

Additionally O
, O
we O
studied O
the O
energy O
reserves O
in O
muscle O
and O
liver O
. O

Pb B
strongly O
accumulated O
in O
gills O
and O
especially O
in O
skin O
. O

Lower O
accumulation O
rates O
occurred O
in O
gut O
, O
kidney O
and O
rectal O
gland O
. O

A O
clear O
disturbance O
in O
acid O
- O
base O
status O
was O
observed O
after O
one O
day O
of O
exposure O
indicating O
a O
transient O
period O
of O
hyperventilation O
. O

The O
increase O
in O
pH O
( O
a O
) O
was O
temporary O
at O
20 O
mu O
M O
, O
but O
persisted O
at O
100 O
mu O
M O
. O

After O
2 O
days O
, O
plasma O
Na B
and O
Cl B
concentrations O
were O
reduced O
compared O
to O
controls O
at O
100 O
mu O
M O
Pb B
and O
urea B
excretion O
rates O
were O
elevated O
. O

Pb B
caused O
impaired O
Na B
( I
+ I
) I
/ O
K B
( I
+ I
) I
- O
ATPase O
activity O
in O
gills O
, O
but O
not O
in O
rectal O
gland O
. O

We O
conclude O
that O
spiny O
dogfish O
experienced O
relatively O
low O
ion O
- O
osmoregulatory O
and O
respiratory O
distress O
when O
exposed O
to O
lead O
, O
particularly O
when O
compared O
to O
effects O
of O
other O
metals O
such O
as O
silver B
. O

These O
elasmobranchs O
appear O
to O
be O
able O
to O
minimize O
the O
disturbance O
and O
maintain O
physiological O
homeostasis O
during O
an O
acute O
Pb B
exposure O
. O

An O
omics O
based O
assessment O
of O
cadmium B
toxicity O
in O
the O
green O
alga O
Chlamydomonas O
reinhardtii O
. O

The O
effects O
of O
cadmium B
were O
assessed O
in O
the O
freshwater O
alga O
Chlamydomonas O
reinhardtii O
. O

Algae O
were O
exposed O
to O
concentrations O
of O
0 O
, O
8 O
. O
1 O
or O
114 O
. O
8 O
mu O
M O
of O
cadmium B
and O
growth O
rates O
, O
gene O
transcription O
and O
metabolite O
profiles O
were O
examined O
after O
48 O
and O
72 O
h O
of O
exposure O
. O

In O
algae O
exposed O
to O
8 O
. O
1 O
mu O
M O
Cd B
, O
several O
genes O
were O
differentially O
transcribed O
after O
48 O
h O
but O
no O
adverse O
growth O
related O
effects O
were O
detected O
. O

A O
transient O
effect O
on O
both O
gene O
transcription O
patterns O
and O
metabolite O
profiles O
could O
be O
discerned O
after O
48 O
h O
of O
exposure O
but O
the O
majority O
of O
these O
changes O
disappeared O
after O
72 O
h O
. O

In O
contrast O
, O
all O
effects O
were O
more O
pronounced O
at O
the O
114 O
. O
8 O
mu O
M O
cadmium B
exposure O
. O

Here O
growth O
was O
clearly O
reduced O
and O
transcription O
of O
a O
large O
number O
of O
genes O
involved O
in O
oxidative O
stress O
defense O
mechanisms O
was O
differentially O
increased O
. O

Metabolites O
involved O
in O
the O
glutathione B
synthesis O
pathway O
( O
an O
important O
antioxidant O
defense O
) O
were O
also O
affected O
but O
the O
effects O
of O
cadmium B
were O
found O
to O
be O
more O
pronounced O
at O
the O
transcript O
level O
than O
in O
the O
metabolome O
, O
suggesting O
that O
the O
former O
exhibits O
greater O
sensitivity O
toward O
cadmium B
exposure O
. O

Establishment O
of O
a O
robust O
hepatitis O
C O
virus O
replicon O
cell O
line O
over O
- O
expressing O
P O
- O
glycoprotein O
that O
facilitates O
analysis O
of O
P O
- O
gp O
drug O
transporter O
effects O
on O
inhibitor O
antiviral O
activity O
. O

P O
- O
glycoprotein O
( O
P O
- O
gp O
) O
is O
an O
active O
efflux O
pump O
affecting O
the O
pharmacokinetic O
( O
PK O
) O
profiles O
of O
drugs O
that O
are O
P O
- O
gp O
substrates O
. O

The O
Caco O
- O
2 O
bi O
- O
directional O
assay O
is O
widely O
used O
to O
identify O
drug O
- O
P O
- O
gp O
interactions O
in O
vitro O
. O

For O
molecules O
exhibiting O
non O
- O
classical O
drug O
properties O
however O
, O
ambiguous O
results O
limit O
its O
use O
in O
lead O
optimization O
. O

The O
goal O
of O
this O
study O
was O
to O
develop O
a O
robust O
cell O
- O
based O
assay O
system O
to O
directly O
measure O
the O
role O
of O
P O
- O
gp O
- O
driven O
efflux O
in O
reducing O
the O
potency O
of O
hepatitis O
C O
virus O
( O
HCV O
) O
replication O
inhibitors O
. O

Vinblastine B
( O
Vin B
) O
was O
employed O
to O
select O
for O
a O
Vin B
- O
resistant O
HCV O
replicon O
( O
313 O
- O
11 O
) O
from O
the O
parental O
cell O
line O
( O
377 O
- O
2 O
) O
. O

The O
313 O
- O
11 O
cell O
line O
was O
> O
50 O
- O
fold O
resistant O
to O
Vin B
and O
over O
- O
expressed O
P O
- O
gp O
, O
as O
determined O
by O
Western O
immunoblots O
. O

Increased O
expression O
of O
P O
- O
gp O
was O
mediated O
by O
up O
- O
regulation O
of O
the O
MDR1 O
transcript O
. O

The O
reduced O
potency O
of O
different O
classes O
of O
HCV O
replication O
inhibitors O
in O
the O
313 O
- O
11 O
P O
- O
gp O
cell O
line O
was O
restored O
in O
the O
presence O
of O
known O
P O
- O
gp O
inhibitors O
. O

Addition O
of O
the O
P O
- O
gp O
inhibitor O
, O
tariquidar B
, O
increased O
the O
uptake O
of O
a O
radiolabeled O
HCV O
replication O
inhibitor O
by O
14 O
- O
fold O
in O
the O
313 O
- O
11 O
replicon O
cell O
line O
. O

Finally O
, O
a O
positive O
correlation O
was O
demonstrated O
between O
potency O
in O
the O
313 O
- O
11 O
replicon O
and O
the O
bi O
- O
directional O
Caco O
- O
2 O
efflux O
ratio O
for O
a O
panel O
of O
HCV O
protease O
inhibitors O
. O

In O
conclusion O
, O
a O
robust O
P O
- O
gp O
HCV O
replicon O
cell O
- O
based O
assay O
has O
been O
developed O
to O
measure O
the O
effect O
of O
the O
P O
- O
gp O
efflux O
pump O
on O
the O
potency O
of O
different O
classes O
of O
HCV O
replication O
inhibitors O
. O

This O
system O
establishes O
a O
direct O
correlation O
between O
antiviral O
activity O
and O
the O
effect O
of O
P O
- O
gp O
efflux O
in O
a O
single O
cell O
line O
. O

Multifunctional O
targets O
of O
dietary O
polyphenols B
in O
disease O
: O
a O
case O
for O
the O
chemokine O
network O
and O
energy O
metabolism O
. O

Chronic O
, O
non O
- O
acute O
inflammation O
is O
behind O
conditions O
that O
represent O
most O
of O
the O
disease O
burden O
in O
humans O
and O
is O
clearly O
linked O
to O
immune O
and O
metabolic O
mechanisms O
. O

The O
convergence O
of O
pathways O
involving O
the O
immune O
response O
, O
oxidative O
stress O
, O
increased O
circulating O
lipids O
and O
aberrant O
insulin O
signaling O
results O
in O
CCL2 O
- O
associated O
macrophage O
recruitment O
and O
altered O
energy O
metabolism O
. O

The O
CCL2 O
/ O
CCR2 O
pathway O
and O
the O
energy O
sensor O
AMP B
- O
activated O
protein O
kinase O
( O
AMPK O
) O
are O
attractive O
therapeutic O
targets O
as O
a O
part O
of O
preventive O
management O
of O
disease O
. O

Several O
effects O
of O
polyphenols B
are O
useful O
in O
this O
scenario O
, O
including O
a O
reduction O
in O
the O
activities O
of O
cytokines O
and O
modulation O
of O
cellular O
metabolism O
through O
histone O
deacetylase O
inhibitors O
, O
AMPK O
activators O
, O
calorie O
- O
restriction O
mimetics O
or O
epigenetic O
regulators O
. O

Research O
is O
currently O
underway O
to O
develop O
orally O
active O
drugs O
with O
these O
effects O
, O
but O
it O
is O
convenient O
to O
examine O
more O
closely O
what O
we O
are O
eating O
. O

If O
a O
lack O
of O
relevance O
in O
terms O
of O
toxicity O
and O
substantial O
effectiveness O
are O
confirmed O
, O
plant O
- O
derived O
components O
may O
provide O
useful O
druggable O
components O
and O
dietary O
supplements O
. O

We O
consider O
therapeutic O
actions O
as O
a O
combination O
of O
synergistic O
and O
/ O
or O
antagonistic O
interactions O
in O
a O
multi O
- O
target O
strategy O
. O

Hence O
, O
improvement O
in O
food O
through O
enrichment O
with O
polyphenols B
with O
demonstrated O
activity O
may O
represent O
a O
major O
advance O
in O
the O
design O
of O
diets O
with O
both O
industrial O
and O
sanitary O
value O
. O

Emerging O
Fusarium O
mycotoxins O
in O
organic O
and O
conventional O
pasta O
collected O
in O
Spain O
. O

One O
of O
the O
main O
sources O
of O
emerging O
Fusarium O
mycotoxins O
in O
human O
nutrition O
is O
the O
cereals O
and O
cereal O
products O
. O

In O
this O
study O
, O
an O
analytical O
method O
to O
determine O
enniatins B
A I
, I
A1 I
, I
B I
and I
B1 I
( O
ENs B
) O
, O
beauvericin B
( O
BEA B
) O
and O
fusaproliferin B
( O
FUS B
) O
based O
on O
Ultra O
- O
Turrax O
extraction O
followed O
by O
liquid O
chromatography O
coupled O
to O
triple O
quadrupole O
mass O
spectrometer O
detector O
( O
MS O
/ O
MS O
QqQ O
) O
, O
was O
applied O
for O
the O
analysis O
of O
pasta O
. O

For O
this O
purpose O
, O
114 O
commercial O
samples O
of O
pasta O
were O
acquired O
from O
supermarkets O
located O
in O
Valencia O
. O

The O
results O
showed O
higher O
frequencies O
of O
contamination O
in O
organic O
pasta O
than O
in O
conventional O
pasta O
, O
while O
the O
concentration O
levels O
were O
variable O
for O
both O
types O
of O
pasta O
. O

In O
positive O
samples O
, O
BEA B
levels O
varied O
from O
0 O
. O
10 O
to O
20 O
. O
96 O
mu O
g O
/ O
kg O
and O
FUS O
levels O
varied O
from O
0 O
. O
05 O
to O
8 O
. O
02 O
mu O
g O
/ O
kg O
. O

ENs B
levels O
ranged O
from O
0 O
. O
25 O
to O
979 O
. O
56 O
mu O
g O
/ O
kg O
, O
though O
the O
majority O
of O
the O
values O
were O
below O
25 O
mu O
g O
/ O
kg O
. O

Besides O
, O
it O
was O
observed O
the O
simultaneous O
presence O
of O
two O
or O
more O
mycotoxins O
in O
a O
high O
percentage O
of O
the O
samples O
. O

Finally O
, O
an O
evaluation O
of O
the O
dietary O
exposure O
of O
the O
emerging O
Fusarium O
mycotoxins O
was O
performed O
in O
the O
Spanish O
population O
. O

The O
prevalence O
of O
ENs O
, O
BEA O
and O
FUS O
in O
cereal O
products O
suggests O
that O
the O
toxins O
may O
pose O
a O
health O
risk O
to O
Spanish O
population O
. O

Structure O
- O
based O
design O
and O
synthesis O
of O
novel O
pseudosaccharine B
derivatives O
as O
antiproliferative O
agents O
and O
kinase O
inhibitors O
. O

This O
study O
is O
concerned O
with O
the O
implementation O
of O
structure O
- O
based O
techniques O
for O
the O
design O
of O
new O
heterocyclic O
compounds O
based O
on O
pseudosaccharine O
scaffold O
with O
protein O
kinase O
inhibition O
activity O
. O

This O
nucleus O
was O
exploited O
based O
on O
the O
well O
- O
known O
quinazoline B
core O
and O
its O
interactions O
with O
several O
protein O
kinases O
. O

Two O
series O
of O
compounds O
employing O
this O
new O
scaffold O
were O
synthesized O
and O
evaluated O
at O
enzymatic O
and O
cellular O
levels O
. O

Compound O
9b O
displayed O
broad O
spectrum O
antiproliferative O
activity O
on O
NCI O
60 O
- O
cell O
lines O
panel O
with O
mean O
GI50 O
of O
5 O
. O
4 O
mu O
M O
. O

Investigation O
of O
the O
molecular O
mechanism O
showed O
probable O
inhibitory O
activity O
against O
Src O
kinase O
. O

Giant O
cell O
tumor O
of O
bone O
: O
a O
basic O
science O
perspective O
. O

Comprehending O
the O
pathogenesis O
of O
giant O
cell O
tumor O
of O
bone O
( O
GCT O
) O
is O
of O
critical O
importance O
for O
developing O
novel O
targeted O
treatments O
for O
this O
locally O
- O
aggressive O
primary O
bone O
tumor O
. O

GCT O
is O
characterized O
by O
the O
presence O
of O
large O
multinucleated O
osteoclast O
- O
like O
giant O
cells O
distributed O
amongst O
mononuclear O
spindle O
- O
like O
stromal O
cells O
and O
other O
monocytes O
. O

The O
giant O
cells O
are O
principally O
responsible O
for O
the O
extensive O
bone O
resorption O
by O
the O
tumor O
. O

However O
, O
the O
spindle O
- O
like O
stromal O
cells O
chiefly O
direct O
the O
pathology O
of O
the O
tumor O
by O
recruiting O
monocytes O
and O
promoting O
their O
fusion O
into O
giant O
cells O
. O

The O
stromal O
cells O
also O
enhance O
the O
resorptive O
ability O
of O
the O
giant O
cells O
. O

This O
review O
encompasses O
many O
of O
the O
attributes O
of O
GCT O
, O
including O
the O
process O
of O
giant O
cell O
formation O
and O
the O
mechanisms O
of O
bone O
resorption O
. O

The O
significance O
of O
the O
receptor O
activator O
of O
nuclear O
factor O
- O
kappa O
B O
ligand O
( O
RANKL O
) O
in O
the O
development O
of O
GCT O
and O
the O
importance O
of O
proteases O
, O
including O
numerous O
matrix O
metalloproteinases O
, O
are O
highlighted O
. O

The O
mesenchymal O
lineage O
of O
the O
stromal O
cells O
and O
the O
origin O
of O
the O
hematopoietic O
monocytes O
are O
also O
discussed O
. O

Several O
aspects O
of O
GCT O
that O
require O
further O
understanding O
, O
including O
the O
etiology O
of O
the O
tumor O
, O
the O
mechanisms O
of O
metastases O
, O
and O
the O
development O
of O
an O
appropriate O
animal O
model O
, O
are O
also O
considered O
. O

By O
exploring O
the O
current O
status O
of O
GCT O
research O
, O
this O
review O
accentuates O
the O
significant O
progress O
made O
in O
understanding O
the O
biology O
of O
the O
tumor O
, O
and O
discusses O
important O
areas O
for O
future O
investigation O
. O

NCTC O
2544 O
and O
IL O
- O
18 O
production O
: O
a O
tool O
for O
the O
identification O
of O
contact O
allergens O
. O

Progress O
in O
understanding O
the O
mechanisms O
of O
skin O
sensitization O
, O
provides O
us O
with O
the O
opportunity O
to O
develop O
in O
vitro O
tests O
as O
an O
alternative O
to O
in O
vivo O
sensitization O
testing O
. O

Keratinocytes O
play O
a O
key O
role O
in O
all O
phases O
of O
skin O
sensitization O
. O

We O
have O
recently O
identified O
interleukin O
- O
18 O
( O
IL O
- O
18 O
) O
production O
in O
keratinocyte O
as O
a O
potentially O
useful O
endpoint O
for O
determination O
of O
contact O
sensitization O
potential O
of O
low O
molecular O
weight O
chemicals O
. O

The O
aim O
of O
the O
present O
article O
is O
to O
further O
exploit O
the O
performance O
of O
the O
NCTC O
2544 O
assay O
. O

NCTC O
2544 O
is O
a O
commercially O
available O
skin O
epithelial O
- O
like O
cell O
line O
originating O
from O
normal O
human O
skin O
, O
which O
posses O
a O
good O
expression O
of O
cytochrome O
P450 O
- O
dependent O
enzymatic O
activities O
. O

Cells O
were O
exposed O
to O
contact O
allergens O
( O
2 B
- I
bromo I
- I
2 I
- I
bromomethyl I
glutaronitrile I
, O
cinnamaldehyde B
, O
citral B
, O
diethylmaleate B
, O
dinitrochlorobenzene B
, O
glyoxal B
, O
2 B
- I
mercaptobenzothiazol I
, O
nickel B
sulfate I
, O
4 B
- I
nitrobenzylbromide I
, O
oxazolone B
, O
penicillin B
G I
, O
resorcinol B
, O
tetramethylthiuram B
disulfide I
) O
, O
to O
pre O
- O
pro O
- O
haptens O
( O

cinnamyl B
alcohol I
, O
eugenol B
, O
isoeugenol B
, O
p B
- I
phenylediamine I
) O
, O
to O
respiratory O
allergens O
( O
ammonium B
hexachloroplatinate I
, O
diphenylmethane B
diisocyanate I
, O
glutaraldehyde B
, O
hexamethylenediisocy B
, O
maleic B
anhydride I
, O
trimellitic B
anhydride I
) O
and O
to O
irritants O
( O
benzaldehyde B
, O
cholorobenzene B
, O
diethylphtalate B
, O
hydrobenzoic B
acid I
, O
lactic B
acid I
, O
octanoic B
acid I
, O

phenol B
, O
salicylic B
acid I
, O
sodium B
lauryl I
sulphate I
, O
sulfamic B
acid I
) O
. O

Cell O
associated O
IL O
- O
18 O
was O
evaluated O
24 O
later O
by O
ELISA O
. O

At O
not O
- O
cytotoxic O
concentrations O
( O
cell O
viability O
higher O
of O
80 O
% O
, O
as O
assessed O
by O
MTT B
reduction O
assay O
) O
, O
all O
contact O
sensitizers O
, O
including O
pre O
- O
pro O
- O
haptens O
, O
induced O
a O
dose O
- O
related O
increase O
in O
IL O
- O
18 O
, O
whereas O
both O
irritants O
, O
with O
the O
exception O
of O
sulfamic B
acid I
, O
and O
respiratory O
allergens O
failed O
. O

A O
total O
of O
33 O
chemicals O
were O
tested O
, O
with O
an O
overall O
accuracy O
of O
97 O
% O
. O

Overall O
, O
results O
obtained O
indicated O
that O
cell O
- O
associated O
IL O
- O
18 O
might O
provide O
an O
in O
vitro O
tool O
for O
identification O
and O
discrimination O
of O
contact O
vs O
. O
respiratory O
allergens O
and O
/ O
or O
irritants O
. O

Application O
of O
the O
acquired O
knowledge O
and O
implementation O
of O
the O
Sens O
- O
it O
- O
iv O
toolbox O
for O
identification O
and O
classification O
of O
skin O
and O
respiratory O
sensitizers O
. O

The O
contribution O
of O
the O
Sens O
- O
it O
- O
iv O
project O
to O
the O
reduction O
and O
replacement O
of O
animal O
experimentation O
is O
3 O
- O
fold O
. O

The O
funding O
of O
basic O
research O
has O
expanded O
the O
existing O
scientific O
knowledge O
thereby O
strengthening O
the O
understanding O
of O
the O
cellular O
and O
molecular O
mechanisms O
driving O
skin O
and O
respiratory O
sensitization O
. O

Examples O
are O
given O
on O
how O
a O
better O
understanding O
was O
used O
to O
improve O
existing O
test O
concepts O
. O

This O
knowledge O
was O
also O
applied O
to O
develop O
novel O
test O
systems O
. O

While O
some O
of O
test O
systems O
did O
not O
reach O
sufficient O
maturity O
for O
being O
considered O
for O
pre O
- O
validation O
others O
did O
and O
entered O
into O
the O
Sens O
- O
it O
- O
iv O
toolbox O
. O

In O
the O
process O
, O
developments O
outside O
the O
Sens O
- O
it O
- O
iv O
orbit O
were O
carefully O
followed O
and O
assessed O
in O
order O
to O
avoid O
duplication O
and O
to O
assure O
synergy O
between O
the O
ongoing O
activities O
( O
e O
. O
g O
. O
Cosmetics O
Europe O
Task O
Force O
for O
Sensitization O
) O
. O

Tests O
from O
the O
Sens O
- O
it O
- O
iv O
toolbox O
were O
submitted O
to O
the O
European O
Reference O
Laboratory O
for O
Alternative O
Methods O
( O
EuRL O
- O
ECVAM O
) O
to O
initiate O
the O
rigid O
procedures O
for O
regulatory O
acceptance O
by O
national O
and O
international O
authorities O
. O

In O
spite O
of O
not O
being O
validated O
yet O
, O
selected O
tests O
were O
already O
applied O
in O
a O
weight O
- O
of O
- O
evidence O
approach O
in O
the O
context O
of O
REACH O
. O

Furthermore O
, O
several O
chemical O
, O
pharmaceutical O
, O
cosmetic O
and O
consumer O
product O
companies O
are O
currently O
assessing O
selected O
tests O
and O
testing O
strategies O
for O
their O
value O
as O
tools O
for O
screening O
and O
hazard O
identification O
using O
in O
house O
compounds O
and O
mixtures O
. O

The O
main O
points O
of O
concern O
related O
to O
transfer O
to O
and O
implementation O
by O
industry O
were O
cost O
, O
through O
- O
put O
and O
applicability O
domain O
, O
rather O
than O
regulatory O
acceptance O
. O

These O
issues O
are O
currently O
addressed O
in O
applied O
research O
projects O
which O
are O
financially O
supported O
by O
individual O
companies O
, O
or O
consortia O
of O
companies O
, O
representing O
the O
various O
industry O
sectors O
. O

Assay O
of O
vtg O
, O
ERs O
and O
PPARs O
as O
endpoint O
for O
the O
rapid O
in O
vitro O
screening O
of O
the O
harmful O
effect O
of O
Di B
- I
( I
2 I
- I
ethylhexyl I
) I
- I
phthalate I
( O
DEHP B
) O
and O
phthalic B
acid I
( O
PA O
) O
in O
zebrafish O
primary O
hepatocyte O
cultures O
. O

In O
the O
last O
years O
the O
concern O
about O
the O
negative O
effects O
of O
phthalates B
on O
reproduction O
significantly O
increased O
. O

Considering O
that O
, O
at O
date O
data O
available O
dealing O
with O
the O
adverse O
outcome O
of O
Di B
- I
( I
2 I
- I
ethylhexyl I
) I
- I
phthalate I
( O
DEHP B
) O
on O
the O
reproduction O
of O
several O
species O
are O
still O
contrasting O
, O
in O
this O
study O
, O
the O
effects O
induced O
by O
DEHP B
( O
0 O
. O
05 O
, O
0 O
. O
1 O
, O
1 O
, O
10 O
and O
100 O
nM O
) O
and O
its O
active O
metabolite O
, O
phthalic B
acid I
( O
PA O
) O
( O
0 O
. O
01 O
, O
0 O
. O
1 O
, O
1 O
and O
10 O
mu O
M O
) O
, O
were O
analyzed O
in O
zebrafish O
, O
Danio O
rerio O
, O
primary O
hepatocyte O
cultures O
, O
using O
target O
molecules O

involved O
in O
fish O
reproduction O
( O
vitellogenin O
- O
- O
vtg O
and O
estrogen B
receptors O
- O
- O
ER O
alpha O
, O
beta O
1 O
and O
beta O
2 O
) O
and O
metabolism O
( O
peroxisome O
proliferators O
activated O
receptors O
- O
- O
PPAR O
alpha O
, O
beta O
, O
gamma O
) O
. O

The O
use O
of O
in O
vitro O
culture O
, O
in O
fact O
, O
has O
the O
potential O
to O
significantly O
reduce O
the O
number O
of O
animals O
sacrificed O
for O
research O
allowing O
a O
precise O
control O
of O
the O
physical O
and O
chemical O
parameters O
that O
is O
often O
not O
possible O
in O
vivo O
. O

Moreover O
, O
since O
many O
toxicological O
studies O
revealed O
a O
sex O
specific O
response O
to O
toxicants O
, O
male O
and O
female O
primary O
hepatocyte O
cultures O
were O
set O
up O
to O
elucidate O
the O
possible O
gender O
specific O
effects O
of O
two O
common O
environmental O
phthalates B
. O

The O
increase O
of O
vtg B
levels O
observed O
in O
the O
culture O
media O
of O
male O
or O
female O
hepatocytes O
strongly O
evidenced O
the O
phthalates B
E2 O
- O
like O
action O
. O

Moreover O
, O
the O
data O
obtained O
suggested O
that O
the O
observed O
different O
ERs O
isoforms O
modulation O
is O
otherwise O
associated O
with O
the O
vtg O
increase O
, O
depending O
on O
fish O
gender O
. O

Regarding O
PPARs O
, O
a O
similar O
trend O
of O
expression O
was O
found O
in O
both O
males O
and O
females O
. O

In O
conclusion O
, O
this O
study O
enforces O
the O
role O
of O
vtg O
as O
biomarker O
for O
evaluate O
the O
presence O
of O
environmental O
doses O
of O
DEHP B
and O
PA O
. O

Considering O
the O
similar O
gender O
modulation O
observed O
for O
vtg O
and O
PPARs O
, O
these O
molecules O
could O
be O
used O
for O
the O
rapid O
screening O
of O
the O
presence O
of O
DEHP B
and O
PA O
. O

Noteworthy O
the O
gender O
specific O
modulation O
observed O
for O
ERs O
opens O
a O
debate O
on O
the O
estrogenic O
mechanism O
of O
action O
of O
DEHP B
and O
PA O
and O
their O
role O
on O
vtg O
induction O
. O

Inhibition O
of O
EGF O
/ O
EGFR O
activation O
with O
naphtho B
[ I
1 I
, I
2 I
- I
b I
] I
furan I
- I
4 I
, I
5 I
- I
dione I
blocks O
migration O
and O
invasion O
of O
MDA O
- O
MB O
- O
231 O
cells O
. O

Naphtho B
[ I
1 I
, I
2 I
- I
b I
] I
furan I
- I
4 I
, I
5 I
- I
dione I
( O
NFD B
) O
, O
a O
bioactive O
component O
of O
Avicennia O
marina O
, O
has O
been O
demonstrated O
to O
display O
anti O
- O
cancer O
activity O
. O

Activation O
of O
epidermal O
growth O
factor O
receptor O
( O
EGFR O
) O
- O
induced O
signaling O
pathway O
has O
been O
correlated O
with O
cancer O
metastasis O
in O
various O
tumors O
, O
including O
breast O
carcinoma O
. O

We O
use O
EGF O
as O
a O
metastatic O
inducer O
of O
MDA O
- O
MB O
- O
231 O
cells O
to O
investigate O
the O
effect O
of O
NFD O
on O
cell O
migration O
and O
invasion O
. O

NFD O
suppressed O
EGF O
- O
mediated O
protein O
levels O
of O
c O
- O
Jun O
and O
c O
- O
Fos O
, O
and O
reduced O
MMP O
- O
9 O
expression O
and O
activity O
, O
concomitantly O
with O
a O
marked O
inhibition O
on O
cell O
migration O
and O
invasion O
without O
obvious O
cellular O
cytotoxicity O
. O

NFD O
abrogated O
EGF O
- O
induced O
phosphorylation O
of O
EGF O
receptor O
( O
EGFR O
) O
and O
phosphatidylinositol B
3 O
- O
kinase O
( O
PI3K O
) O
/ O
Akt O
. O

The O
specific O
PI3K O
inhibitor O
, O
wortmannin B
, O
blocked O
significantly O
EGF O
- O
induced O
cell O
migration O
and O
invasion O
. O

Furthermore O
, O
the O
EGFR O
inhibitor O
AG1478 B
inhibited O
EGF O
- O
induced O
MMP O
- O
9 O
expression O
, O
cell O
migration O
and O
invasion O
, O
as O
well O
as O
the O
activation O
of O
PI3K O
/ O
Akt O
, O
suggesting O
that O
PI3K O
/ O
Akt O
activation O
occur O
downstream O
of O
EGFR O
activation O
. O

These O
findings O
suggest O
that O
NFD O
inhibited O
the O
EGF O
- O
induced O
invasion O
and O
migration O
of O
MDA O
- O
MB O
- O
231 O
cells O
via O
EGFR O
- O
dependent O
PI3K O
/ O
Akt O
signaling O
, O
leading O
to O
the O
down O
- O
regulation O
of O
MMP O
- O
9 O
expression O
. O

These O
results O
provide O
a O
novel O
mechanism O
to O
explain O
the O
role O
of O
NFD O
as O
a O
potent O
anti O
- O
metastatic O
agent O
in O
MDA O
- O
MB O
- O
231 O
cells O
. O

The O
association O
of O
serum O
25 B
- I
hydroxyvitamin I
D I
and O
vertebral O
fractures O
in O
patients O
with O
type O
2 O
diabetes O
. O

Vitamin B
D I
is O
an O
important O
regulator O
of O
bone O
health O
. O

Previous O
studies O
examining O
the O
association O
between O
vitamin B
D I
deficiency O
and O
osteoporotic O
fractures O
have O
reported O
conflicting O
results O
. O

The O
relationship O
between O
vitamin B
D I
status O
and O
risk O
of O
vertebral O
fractures O
in O
diabetic O
patients O
is O
unknown O
. O

The O
objective O
of O
this O
study O
was O
to O
examine O
whether O
low O
serum O
25 B
- I
hydroxyvitamin I
D I
[ O
25 B
( I
OH I
) I
D I
] O
levels O
were O
associated O
with O
vertebral O
fractures O
in O
patients O
with O
type O
2 O
diabetes O
. O

This O
cross O
- O
sectional O
study O
was O
conducted O
among O
161 O
postmenopausal O
women O
and O
180 O
men O
with O
type O
2 O
diabetes O
. O

Serum O
concentrations O
of O
25 B
( I
OH I
) I
D I
were O
measured O
and O
the O
presence O
of O
vertebral O
fracture O
was O
assessed O
using O
lateral O
plain O
radiographs O
of O
the O
thoracolumbar O
spine O
. O

Women O
had O
lower O
25 B
( I
OH I
) I
D I
levels O
than O
men O
( O
31 O
. O
3 O
+ O
/ O
- O
17 O
. O
7 O
vs O
. O
41 O
. O
3 O
+ O
/ O
- O
26 O
. O
5 O
ng O
/ O
mL O
, O
p O
< O
0 O
. O
001 O
) O
. O

Vertebral O
fractures O
were O
found O
in O
16 O
% O
of O
patients O
. O

Men O
with O
a O
serum O
25 B
( I
OH I
) I
D I
concentration O
greater O
than O
30 O
ng O
/ O
mL O
showed O
a O
lower O
prevalence O
of O
vertebral O
fractures O
compared O
to O
those O
with O
20 O
- O
29 O
. O
9 O
ng O
/ O
mL O
or O
those O
with O
less O
than O
20 O
ng O
/ O
mL O
( O
9 O
. O
4 O
% O
vs O
. O
17 O
. O
9 O
% O
vs O
. O
21 O
. O
7 O
% O
, O
p O
for O
trend O
= O
0 O
. O
036 O
) O
. O

However O
, O
there O
was O
no O
significant O
association O
between O
vitamin B
D I
status O
and O
the O
prevalence O
of O
vertebral O
fractures O
in O
women O
( O
14 O
. O
4 O
% O
vs O
. O
19 O
. O
2 O
% O
vs O
. O
26 O
. O
6 O
% O
, O
p O
for O
trend O
= O
0 O
. O
111 O
) O
. O

After O
adjusting O
for O
multiple O
confounding O
factors O
, O
men O
with O
a O
serum O
25 B
( I
OH I
) I
D I
concentration O
of O
less O
than O
20 O
ng O
/ O
mL O
were O
associated O
with O
an O
increased O
risk O
of O
vertebral O
fractures O
( O
OR O
7 O
. O
87 O
; O
95 O
% O
CI O
1 O
. O
69 O
- O
36 O
. O
71 O
) O
, O
but O
not O
women O
. O

In O
conclusion O
, O
serum O
25 B
( I
OH I
) I
D I
levels O
below O
20 O
ng O
/ O
mL O
were O
associated O
with O
an O
increased O
vertebral O
fracture O
risk O
in O
men O
with O
type O
2 O
diabetes O
. O

Chiral O
and O
chemical O
oscillations O
in O
a O
simple O
dimerization O
model O
. O

We O
consider O
the O
APED O
model O
( O
activation O
- O
polymerization O
- O
epimerization O
- O
depolymerization O
) O
for O
describing O
the O
emergence O
of O
chiral O
solutions O
within O
a O
non O
- O
catalytic O
framework O
for O
chiral O
polymerization O
. O

The O
minimal O
APED O
model O
for O
dimerization O
can O
lead O
to O
the O
spontaneous O
appearance O
of O
chiral O
oscillations O
and O
we O
describe O
in O
detail O
the O
nature O
of O
these O
oscillations O
in O
the O
enantiomeric O
excess O
, O
which O
are O
the O
consequence O
of O
oscillations O
of O
the O
concentrations O
of O
the O
associated O
chemical O
species O
. O

Ketamine B
- O
induced O
neuronal O
damage O
and O
altered O
N B
- I
methyl I
- I
D I
- I
aspartate I
receptor O
function O
in O
rat O
primary O
forebrain O
culture O
. O

Ketamine B
, O
a O
noncompetitive O
N B
- I
methyl I
- I
D I
- I
aspartate I
( O
NMDA B
) O
receptor O
antagonist O
, O
is O
frequently O
used O
in O
pediatric O
general O
anesthesia O
. O

Accumulating O
evidence O
from O
animal O
experiments O
has O
demonstrated O
that O
ketamine B
causes O
neuronal O
cell O
death O
during O
the O
brain O
growth O
spurt O
. O

To O
elucidate O
the O
underlying O
mechanisms O
associated O
with O
ketamine B
- O
induced O
neuronal O
toxicity O
and O
search O
for O
approaches O
or O
agents O
to O
prevent O
ketamine B
' O
s O
adverse O
effects O
on O
the O
developing O
brain O
, O
a O
primary O
nerve O
cell O
culture O
system O
was O
utilized O
. O

Neurons O
harvested O
from O
the O
forebrain O
of O
newborn O
rats O
were O
maintained O
under O
normal O
control O
conditions O
or O
exposed O
to O
either O
ketamine B
( O
10 O
micro O
M O
) O
or O
ketamine B
plus O
L B
- I
carnitine I
( O
an O
antioxidant O
; O
1 O
- O
100 O
micro O
M O
) O
for O
24h O
, O
followed O
by O
a O
24 O
- O
h O
withdrawal O
period O
. O

Ketamine B
exposure O
resulted O
in O
elevated O
NMDA B
receptor O
( O
NR1 O
) O
expression O
, O
increased O
generation O
of O
reactive O
oxygen B
species O
( O
ROS O
) O
as O
indicated O
by O
higher O
levels O
of O
8 B
- I
oxoguanine I
production O
, O
and O
enhanced O
neuronal O
damage O
. O

Coadministration O
of O
L B
- I
carnitine I
significantly O
diminished O
ROS O
generation O
and O
provided O
near O
complete O
protection O
of O
neurons O
from O
ketamine B
- O
induced O
cell O
death O
. O

NMDA B
receptors O
regulate O
channels O
that O
are O
highly O
permeable O
to O
calcium B
, O
and O
calcium B
imaging O
data O
demonstrated O
that O
neurons O
exposed O
to O
ketamine B
had O
a O
significantly O
elevated O
amplitude O
of O
calcium B
influx O
and O
higher O
intracellular O
free O
calcium B
concentrations O
( O
[ O
Ca B
( I
2 I
+ I
) I
] O
i O
) O
evoked O
by O
NMDA B
( O
50 O
micro O
M O
) O
, O
compared O
with O
control O
neurons O
. O

These O
findings O
suggest O
that O
prolonged O
ketamine B
exposure O
produces O
an O
increase O
in O
NMDA B
receptor O
expression O
( O
compensatory O
upregulation O
) O
, O
which O
allows O
for O
a O
higher O
/ O
toxic O
influx O
of O
calcium B
into O
neurons O
once O
ketamine B
is O
removed O
from O
the O
system O
, O
leading O
to O
elevated O
ROS O
generation O
and O
neuronal O
cell O
death O
. O

L B
- I
Carnitine I
appears O
to O
be O
a O
promising O
agent O
in O
preventing O
or O
reversing O
ketamine B
' O
s O
toxic O
effects O
on O
neurons O
at O
an O
early O
developmental O
stage O
. O

Resonance O
Raman O
spectral O
imaging O
of O
intracellular O
uptake O
of O
beta B
- I
carotene I
loaded O
poly B
( I
D I
, I
L I
- I
lactide I
- I
co I
- I
glycolide I
) I
nanoparticles O
. O

The O
use O
of O
nanoparticles O
for O
drug O
delivery O
has O
been O
drawing O
considerable O
attention O
in O
pharmaceutical O
research O
. O

With O
increasing O
diversity O
and O
potential O
of O
various O
carrier O
systems O
, O
it O
is O
important O
to O
study O
the O
impact O
of O
nanocarriers O
on O
sub O
- O
cellular O
metabolic O
processes O
and O
organelles O
, O
since O
the O
delivery O
of O
a O
drug O
usually O
involves O
intra O
- O
cellular O
internalization O
. O

Herein O
, O
we O
employ O
Raman O
microscopy O
as O
a O
non O
- O
invasive O
method O
for O
cellular O
and O
sub O
- O
cellular O
imaging O
, O
to O
monitor O
the O
uptake O
and O
translocation O
patterns O
of O
particles O
based O
on O
poly B
( I
D I
, I
L I
- I
lactide I
- I
co I
- I
glycolide I
) I
over O
time O
. O

As O
the O
technique O
detects O
inherent O
signals O
from O
the O
molecules O
of O
interest O
, O
it O
does O
not O
rely O
on O
external O
labels O
or O
dyes O
, O
which O
is O
an O
advantage O
over O
fluorescence O
labeling O
. O

For O
this O
purpose O
, O
the O
particles O
were O
loaded O
with O
beta B
- I
carotene I
. O

The O
conjugated O
pi O
- O
system O
of O
the O
molecule O
has O
a O
large O
Raman O
scattering O
cross O
- O
section O
and O
gives O
rise O
to O
resonance O
Raman O
effects O
, O
which O
can O
enhance O
the O
sensitivity O
by O
orders O
of O
magnitude O
. O

beta B
- I
Carotene I
as O
a O
provitamin O
is O
not O
soluble O
in O
water O
and O
is O
thus O
usually O
of O
low O
bioavailability O
, O
which O
is O
enhanced O
by O
encapsulation O
into O
the O
nanoparticles O
. O

Activation O
of O
group O
I O
metabotropic O
glutamate B
receptors O
potentiates O
heteromeric O
kainate B
receptors O
. O

Kainate B
receptors O
( O
KARs O
) O
, O
a O
family O
of O
ionotropic O
glutamate B
receptors O
, O
are O
widely O
expressed O
in O
the O
central O
nervous O
system O
and O
are O
critically O
involved O
in O
synaptic O
transmission O
. O

KAR O
activation O
is O
influenced O
by O
metabotropic O
glutamate B
receptor O
( O
mGlu O
) O
signaling O
, O
but O
the O
underlying O
mechanisms O
are O
not O
understood O
. O

We O
undertook O
studies O
to O
examine O
how O
mGlu O
modulation O
affects O
activation O
of O
KARs O
. O

Confocal O
immunohistochemistry O
of O
rat O
hippocampus O
and O
cultured O
rat O
cortex O
revealed O
colocalization O
of O
the O
high O
- O
affinity O
KAR O
subunits O
with O
group O
I O
mGlu O
receptors O
. O

In O
hippocampal O
and O
cortical O
cultures O
, O
the O
calcium B
signal O
caused O
by O
activation O
of O
native O
KARs O
was O
potentiated O
by O
activation O
of O
group O
I O
mGlu O
receptors O
. O

In O
Xenopus O
laevis O
oocytes O
, O
activation O
of O
group O
I O
mGlu O
receptors O
potentiated O
heteromeric O
but O
not O
homomeric O
KAR O
- O
mediated O
currents O
, O
with O
no O
change O
in O
agonist O
potency O
. O

The O
potentiation O
of O
heteromeric O
KARs O
by O
mGlu1 O
activation O
was O
attenuated O
by O
GDP B
beta I
S I
, O
blocked O
by O
an O
inhibitor O
of O
phospholipase O
C O
or O
the O
calcium B
chelator O
1 B
, I
2 I
- I
bis I
( I
o I
- I
aminophenoxy I
) I
ethane I
- I
N I
, I
N I
, I
N I
' I
, I
N I
' I
- I
tetraacetic I
acid I
( O
BAPTA B
) O
, O
prolonged O
by O
the O
phosphatase O
inhibitor O
okadaic B
acid I
, O
but O
unaffected O
by O
the O
tyrosine B
kinase O
inhibitor O
lavendustin B
A I
. O

Protein O
kinase O
C O
( O
PKC O
) O
inhibition O
reduced O
the O
potentiation O
by O
mGlu1 O
of O
GluK2 O
/ O
GluK5 O
, O
and O
conversely O
, O
direct O
activation O
of O
PKC O
by O
phorbol B
12 I
- I
myristate I
, I
13 I
- I
acetate I
potentiated O
GluK2 O
/ O
GluK5 O
. O

Using O
site O
- O
directed O
mutagenesis O
, O
we O
identified O
three O
serines B
( O
Ser833 B
, O
Ser836 B
, O
and O
Ser840 B
) O
within O
the O
membrane O
proximal O
region O
of O
the O
GluK5 O
C B
- O
terminal O
domain O
that O
, O
in O
combination O
, O
are O
required O
for O
mGlu1 O
- O
mediated O
potentiation O
of O
KARs O
. O

Together O
, O
these O
data O
suggest O
that O
phosphorylation O
of O
key O
residues O
in O
the O
C B
- O
terminal O
domain O
changes O
the O
overall O
charge O
of O
this O
domain O
, O
resulting O
in O
potentiated O
agonist O
responses O
. O

beta O
- O
Adrenergic O
agonists O
mediate O
enhancement O
of O
beta O
1 O
- O
adrenergic O
receptor O
N B
- O
terminal O
cleavage O
and O
stabilization O
in O
vivo O
and O
in O
vitro O
. O

The O
beta O
( O
1 O
) O
- O
adrenergic O
receptor O
( O
beta O
( O
1 O
) O
AR O
) O
is O
the O
predominant O
beta O
AR O
in O
the O
heart O
and O
is O
the O
main O
target O
for O
beta O
- O
adrenergic O
antagonists O
, O
widely O
used O
in O
the O
treatment O
of O
cardiovascular O
diseases O
. O

Previously O
, O
we O
have O
shown O
that O
the O
human O
( O
h O
) O
beta O
( O
1 O
) O
AR O
is O
cleaved O
in O
its O
N B
terminus O
by O
a O
metalloproteinase O
, O
both O
constitutively O
and O
in O
a O
receptor O
activation O
- O
dependent O
manner O
. O

In O
this O
study O
, O
we O
investigated O
the O
specific O
events O
involved O
in O
beta O
( O
1 O
) O
AR O
regulation O
, O
focusing O
on O
the O
effects O
of O
long O
- O
term O
treatment O
with O
beta O
- O
adrenergic O
ligands O
on O
receptor O
processing O
in O
stably O
transfected O
human O
embryonic O
kidney O
293 O
( O
i O
) O
cells O
. O

The O
key O
findings O
were O
verified O
using O
the O
transiently O
transfected O
h O
beta O
( O
1 O
) O
AR O
and O
the O
endogenously O
expressed O
receptor O
in O
neonatal O
rat O
cardiomyocytes O
. O

By O
using O
flow O
cytometry O
and O
Western O
blotting O
, O
we O
demonstrated O
that O
isoproterenol B
, O
S B
- I
propranolol I
, O
CGP B
- I
12177 I
[ O
4 B
- I
[ I
3 I
- I
[ I
( I
1 I
, I
1 I
- I
dimethylethyl I
) I
amino I
] I
2 I
- I
hydroxypropoxy I
] I
- I
1 I
, I
3 I
- I
dihydro I
- I
2H I
- I
benzimidazol I
- I
2 I
- I
one I
] O
, O
pindolol B
, O
and O
timolol B
, O
which O
displayed O
agonistic O
properties O
toward O
the O
beta O
( O
1 O
) O
AR O
in O
either O
the O
adenylyl O
cyclase O
or O

the O
mitogen O
- O
activated O
protein O
kinase O
signaling O
pathways O
, O
induced O
cleavage O
of O
the O
mature O
cell O
- O
surface O
receptor O
. O

In O
contrast O
, O
metoprolol B
, O
bisoprolol B
, O
and O
CGP B
- I
20712 I
[ O
1 B
- I
[ I
2 I
- I
( I
( I
3 I
- I
carbamoyl I
- I
4 I
- I
hydroxy I
) I
phenoxy I
) I
ethylamino I
] I
- I
3 I
- I
[ I
4 I
- I
( I
1 I
- I
methyl I
- I
4 I
- I
trifluoromethyl I
- I
2 I
- I
imidazolyl I
) I
phenoxy I
] I
- I
2 I
- I
propanol I
] O
, O
which O
showed O
no O
agonistic O
activity O
, O
had O
only O
a O
marginal O
or O
no O
effect O
. O

Importantly O
, O
the O
agonists O
also O
stabilized O
intracellular O
receptor O
precursors O
, O
possibly O
via O
their O
pharmacological O
chaperone O
action O
, O
and O
they O
stabilized O
the O
receptor O
in O
vitro O
. O

The O
opposing O
effects O
on O
the O
two O
receptor O
forms O
thus O
led O
to O
an O
increase O
in O
the O
amount O
of O
cleaved O
receptor O
fragments O
at O
the O
plasma O
membrane O
. O

The O
results O
underscore O
the O
pluridimensionality O
of O
beta O
- O
adrenergic O
ligands O
and O
extend O
this O
property O
from O
receptor O
activation O
and O
signaling O
to O
the O
regulation O
of O
beta O
( O
1 O
) O
AR O
levels O
. O

This O
phenomenon O
may O
contribute O
to O
the O
exceptional O
resistance O
of O
beta O
( O
1 O
) O
ARs O
to O
downregulation O
and O
tendency O
toward O
upregulation O
following O
long O
- O
term O
ligand O
treatments O
. O

The O
biarylpyrazole B
compound O
AM251 B
alters O
mitochondrial O
physiology O
via O
proteolytic O
degradation O
of O
ERR O
alpha O
. O

The O
orphan O
nuclear O
receptor O
estrogen B
- O
related O
receptor O
alpha O
( O
ERR O
alpha O
) O
directs O
the O
transcription O
of O
nuclear O
genes O
involved O
in O
energy O
homeostasis O
control O
and O
the O
regulation O
of O
mitochondrial O
mass O
and O
function O
. O

A O
crucial O
role O
for O
controlling O
ERR O
alpha O
- O
mediated O
target O
gene O
expression O
has O
been O
ascribed O
to O
the O
biarylpyrazole B
compound O
1 B
- I
( I
2 I
, I
4 I
- I
dichlorophenyl I
) I
- I
5 I
- I
( I
4 I
- I
iodophenyl I
) I
- I
4 I
- I
methyl I
- I
N I
- I
1 I
- I
piperidinyl I
- I
1H I
- I
pyrazole I
- I
3 I
- I
carboxamide I
( O
AM251 B
) O
through O
direct O
binding O
to O
and O
destabilization O
of O
ERR O
alpha O
protein O
. O

Here O
, O
we O
provide O
evidence O
that O
structurally O
related O
AM251 B
analogs O
also O
have O
negative O
impacts O
on O
ERR O
alpha O
protein O
levels O
in O
a O
cell O
- O
type O
- O
dependent O
manner O
while O
having O
no O
deleterious O
actions O
on O
ERR O
gamma O
. O

We O
show O
that O
these O
off O
- O
target O
cellular O
effects O
of O
AM251 O
are O
mediated O
by O
proteasomal O
degradation O
of O
nuclear O
ERR O
alpha O
. O

Cell O
treatment O
with O
the O
nuclear O
export O
inhibitor O
leptomycin B
B I
did O
not O
prevent O
AM251 B
- O
induced O
destabilization O
of O
ERR O
alpha O
protein O
, O
whereas O
proteasome O
inhibition O
with O
MG132 B
stabilized O
and O
maintained O
its O
DNA O
- O
binding O
function O
, O
indicative O
of O
ERR O
alpha O
being O
a O
target O
of O
nuclear O
proteasomal O
complexes O
. O

NativePAGE O
analysis O
revealed O
that O
ERR O
alpha O
formed O
a O
~ O
220 O
- O
kDa O
multiprotein O
nuclear O
complex O
that O
was O
devoid O
of O
ERR O
gamma O
and O
the O
coregulator O
peroxisome O
proliferator O
- O
activated O
receptor O
gamma O
coactivator O
- O
1 O
. O

AM251 B
induced O
SUMO O
- O
2 O
, O
3 O
incorporation O
in O
ERR O
alpha O
in O
conjunction O
with O
increased O
protein O
kinase O
C O
activity O
, O
whose O
activation O
by O
phorbol B
ester I
also O
promoted O
ERR O
alpha O
protein O
loss O
. O

Down O
- O
regulation O
of O
ERR O
alpha O
by O
AM251 O
or O
small O
interfering O
RNA O
led O
to O
increased O
mitochondria O
biogenesis O
while O
negatively O
impacting O
mitochondrial O
membrane O
potential O
. O

These O
results O
reveal O
a O
novel O
molecular O
mechanism O
by O
which O
AM251 B
and O
related O
compounds O
alter O
mitochondrial O
physiology O
through O
destabilization O
of O
ERR O
alpha O
. O

Metformin B
directly O
inhibits O
ghrelin O
secretion O
through O
AMP B
- O
activated O
protein O
kinase O
in O
rat O
primary O
gastric O
cells O
. O

The O
antidiabetic O
drug O
Metformin B
causes O
weight O
loss O
in O
both O
diabetic O
and O
non O
- O
diabetic O
individuals O
. O

Metformin B
treatment O
is O
also O
associated O
with O
lower O
circulating O
levels O
of O
the O
orexigenic O
hormone O
ghrelin O
. O

To O
test O
whether O
Metformin B
directly O
affects O
ghrelin O
cells O
, O
rat O
primary O
stomach O
cells O
were O
treated O
with O
Metformin B
and O
the O
levels O
of O
ghrelin O
secretion O
, O
proghrelin O
gene O
expression O
and O
activation O
of O
adenosine B
monophosphate I
- O
activated O
protein O
kinase O
( O
AMPK O
) O
were O
examined O
. O

Metformin B
significantly O
reduced O
ghrelin O
secretion O
and O
proghrelin O
mRNA O
production O
and O
both O
these O
effects O
were O
blocked O
by O
co O
- O
incubation O
with O
the O
AMPK O
inhibitor O
compound B
C I
. O

Furthermore O
, O
the O
AMPK O
activator O
5 B
- I
amino I
- I
1 I
- I
beta I
- I
D I
- I
ribofuranosyl I
- I
imidazole I
- I
4 I
- I
carboxamide I
( O
AICAR B
) O
significantly O
inhibited O
ghrelin O
secretion O
. O

Additionally O
, O
ghrelin O
cells O
were O
shown O
to O
express O
AMPK O
. O

Finally O
, O
Metformin B
treatment O
caused O
a O
significant O
increase O
in O
the O
level O
of O
phosphorylated O
( O
active O
) O
AMPK O
. O

Our O
results O
show O
that O
Metformin B
directly O
inhibits O
stomach O
ghrelin O
production O
and O
secretion O
through O
AMPK O
. O

This O
reduction O
in O
ghrelin O
secretion O
may O
be O
one O
of O
the O
key O
components O
in O
Metformin B
' O
s O
mechanism O
of O
weight O
loss O
. O

A O
hybrid O
method O
employing O
breakdown O
anodization O
and O
electrophoretic O
deposition O
for O
superhydrophilic O
surfaces O
. O

A O
fabrication O
method O
is O
developed O
for O
superhydrophilic O
surfaces O
with O
high O
capillary O
pressure O
and O
fast O
spreading O
speed O
. O

The O
fabrication O
method O
consists O
of O
electrophoretic O
deposition O
( O
EPD O
) O
and O
breakdown O
anodization O
( O
BDA O
) O
. O

Nanopores O
and O
micropores O
were O
produced O
on O
titanium B
plates O
by O
EPD O
and O
BDA B
, O
respectively O
. O

In O
EPD O
, O
TiO B
( I
2 I
) I
nanoparticles O
were O
used O
to O
enhance O
the O
surface O
energy O
and O
create O
nanoporous O
structures O
, O
while O
BDA B
was O
employed O
to O
produce O
microporous O
structures O
. O

Capillary O
rise O
measurements O
( O
CRM O
) O
were O
utilized O
to O
characterize O
superhydrophilic O
surfaces O
in O
terms O
of O
capillary O
pressure O
and O
spreading O
speed O
. O

From O
CRM O
, O
it O
was O
revealed O
that O
microporous O
structures O
play O
a O
dominant O
role O
in O
determining O
transport O
properties O
, O
and O
nanoporous O
structures O
affect O
local O
wettability O
without O
significantly O
reducing O
spreading O
speed O
. O

By O
combining O
BDA B
and O
EPD O
into O
a O
hybrid O
method O
, O
dual O
- O
scale O
( O
nano O
and O
micro O
) O
porous O
structures O
were O
produced O
on O
titanium B
plates O
. O

The O
methods O
presented O
offer O
the O
potential O
to O
vary O
the O
transport O
characteristics O
of O
superhydrophilic O
surfaces O
by O
altering O
the O
nanoscale O
and O
microscale O
features O
independently O
. O

As O
an O
example O
, O
surfaces O
with O
unconventional O
capillary O
flows O
were O
produced O
by O
the O
hybrid O
method O
. O

This O
method O
provides O
additional O
opportunities O
to O
investigate O
wetting O
phenomena O
while O
offering O
a O
potentially O
low O
cost O
process O
for O
industrial O
applications O
. O

Genetic O
approaches O
in O
Drosophila O
for O
the O
study O
neurodevelopmental O
disorders O
. O

The O
fruit O
fly O
Drosophila O
melanogaster O
is O
one O
of O
the O
premier O
genetic O
model O
organisms O
used O
in O
biomedical O
research O
today O
owing O
to O
the O
extraordinary O
power O
of O
its O
genetic O
tool O
- O
kit O
. O

Made O
famous O
by O
numerous O
seminal O
discoveries O
of O
basic O
developmental O
mechanisms O
and O
behavioral O
genetics O
, O
the O
power O
of O
fruit O
fly O
genetics O
is O
becoming O
increasingly O
applied O
to O
questions O
directly O
relevant O
to O
human O
health O
. O

In O
this O
review O
we O
discuss O
how O
Drosophila O
research O
is O
applied O
to O
address O
major O
questions O
in O
neurodevelopmental O
disorders O
. O

This O
article O
is O
part O
of O
the O
Special O
Issue O
entitled O
' O
Neurodevelopmental O
Disorders O
' O
. O

Voluntary O
exercise O
does O
not O
ameliorate O
spatial O
learning O
and O
memory O
deficits O
induced O
by O
chronic O
administration O
of O
nandrolone B
decanoate I
in O
rats O
. O

Chronic O
exposure O
to O
the O
anabolic O
androgenic O
steroids O
( O
AAS O
) O
nandrolone B
decanoate I
( O
ND O
) O
in O
supra O
- O
physiological O
doses O
is O
associated O
with O
learning O
and O
memory O
impairments O
. O

Given O
the O
well O
- O
known O
beneficial O
effects O
of O
voluntary O
exercise O
on O
cognitive O
functions O
, O
we O
examined O
whether O
voluntary O
exercise O
would O
improve O
the O
cognitive O
deficits O
induced O
by O
chronic O
administration O
of O
ND O
. O

We O
also O
investigated O
the O
effects O
of O
ND O
and O
voluntary O
exercise O
on O
hippocampal O
BDNF O
levels O
. O

The O
rats O
were O
randomly O
distributed O
into O
4 O
experimental O
groups O
: O
the O
vehicle O
- O
sedentary O
group O
, O
the O
ND O
- O
sedentary O
group O
, O
the O
vehicle O
- O
exercise O
group O
, O
and O
the O
ND O
- O
exercise O
group O
. O

The O
vehicle O
- O
exercise O
and O
the O
ND O
- O
exercise O
groups O
were O
allowed O
to O
freely O
exercise O
in O
a O
running O
wheel O
for O
15 O
days O
. O

The O
vehicle O
- O
sedentary O
and O
the O
ND O
- O
sedentary O
groups O
were O
kept O
sedentary O
for O
the O
same O
period O
. O

Vehicle O
or O
ND O
injections O
were O
started O
14 O
days O
prior O
to O
the O
voluntary O
exercise O
and O
continued O
throughout O
the O
15 O
days O
of O
voluntary O
exercise O
. O

After O
the O
15 O
- O
day O
period O
, O
the O
rats O
were O
trained O
and O
tested O
on O
a O
water O
maze O
spatial O
task O
using O
four O
trials O
per O
day O
for O
5 O
consecutive O
days O
followed O
by O
a O
probe O
trial O
two O
days O
later O
. O

Exercise O
significantly O
improved O
performance O
during O
both O
the O
training O
and O
retention O
of O
the O
water O
maze O
task O
, O
and O
enhanced O
hippocampal O
BDNF O
. O

ND O
impaired O
spatial O
learning O
and O
memory O
, O
and O
this O
effect O
was O
not O
rescued O
by O
exercise O
. O

ND O
also O
potentiated O
the O
exercise O
- O
induced O
increase O
in O
hippocampal O
BDNF O
levels O
. O

These O
results O
seem O
to O
indicate O
that O
voluntary O
exercise O
is O
unable O
to O
improve O
the O
disruption O
of O
cognitive O
functions O
by O
chronic O
ND O
. O

Moreover O
, O
increased O
levels O
of O
BDNF O
may O
play O
a O
role O
in O
ND O
- O
induced O
impairments O
in O
learning O
and O
memory O
. O

The O
harmful O
effects O
of O
ND O
and O
other O
AAS B
on O
learning O
and O
memory O
should O
be O
taken O
into O
account O
when O
athletes O
decide O
to O
use O
AAS B
for O
performance O
or O
body O
image O
improvement O
. O

Rosiglitazone B
disrupts O
endosteal O
bone O
formation O
during O
distraction O
osteogenesis O
by O
local O
adipocytic O
infiltration O
. O

Rosiglitazone B
( O
Rosi B
) O
is O
a O
drug O
in O
the O
thiazolidinedione B
class O
for O
treatment O
of O
type O
2 O
diabetes O
mellitus O
( O
T2DM O
) O
, O
which O
binds O
and O
activates O
PPAR O
gamma O
nuclear O
receptor O
in O
fat O
cells O
, O
sensitizing O
them O
to O
insulin O
. O

Despite O
proven O
antidiabetic O
efficacy O
, O
Rosi O
therapy O
may O
be O
associated O
with O
trabecular O
bone O
loss O
and O
an O
increased O
risk O
of O
fractures O
. O

To O
examine O
the O
potential O
side O
effects O
of O
Rosi O
treatment O
on O
bone O
formation O
, O
we O
delivered O
Rosi O
to O
mice O
using O
a O
combined O
model O
of O
distraction O
osteogenesis O
( O
DO O
) O
and O
type O
2 O
diabetes O
mellitus O
( O
T2DM O
) O
. O

DO O
provides O
a O
unique O
method O
to O
isolate O
the O
sequence O
of O
intramembranous O
bone O
formation O
, O
an O
important O
component O
of O
both O
fracture O
healing O
and O
bone O
homeostasis O
. O

Four O
groups O
of O
n O
= O
6 O
mice O
were O
used O
to O
compare O
the O
effects O
of O
Rosi O
on O
bone O
formation O
and O
cellular O
composition O
in O
both O
diabetic O
( O
Avy O
/ O
a O
strain O
) O
and O
non O
- O
diabetic O
mice O
( O
a O
/ O
a O
strain O
) O
. O

New O
bone O
formation O
was O
examined O
by O
high O
resolution O
radiographs O
, O
micro O
- O
computed O
tomography O
, O
and O
histology O
. O

Precursor O
cells O
in O
the O
distraction O
gap O
were O
quantitated O
using O
immunohistochemical O
stains O
for O
proliferating O
cell O
nuclear O
antigen O
. O

Committed O
osteoblasts O
and O
adipocytes O
in O
the O
gap O
were O
identified O
and O
quantitated O
by O
immunostaining O
for O
osteocalcin O
and O
FABP4 O
/ O
aP2 O
, O
respectively O
. O

The O
diabetic O
model O
developed O
obesity O
, O
hyperglycemia O
, O
hyperinsulinemia O
and O
insulin O
resistance O
, O
while O
the O
control O
littermates O
remained O
lean O
, O
normoglycemic O
and O
insulin O
sensitive O
. O

Rosi O
treatment O
decreased O
levels O
of O
non O
- O
fasted O
glucose B
and O
insulin O
and O
improved O
insulin O
sensitivity O
in O
the O
A O
( O
vy O
) O
/ O
a O
mice O
, O
but O
had O
no O
effect O
in O
a O
/ O
a O
mice O
, O
indicating O
antidiabetic O
efficacy O
of O
Rosi O
at O
the O
tested O
dose O
. O

Despite O
the O
diabetic O
, O
obese O
mice O
having O
twice O
the O
number O
of O
fat O
cells O
in O
their O
marrow O
than O
the O
non O
- O
diabetic O
mice O
, O
bone O
formation O
using O
DO O
was O
not O
adversely O
affected O
by O
the O
diabetes O
itself O
. O

However O
, O
Rosi O
treatment O
significantly O
diminished O
intramembranous O
endosteal O
bone O
formation O
, O
while O
increasing O
adipogenesis O
in O
and O
adjacent O
to O
the O
distraction O
gap O
up O
to O
3 O
. O
5 O
- O
to O
3 O
. O
8 O
- O
fold O
in O
both O
diabetic O
and O
non O
- O
diabetic O
models O
. O

This O
effect O
was O
independent O
of O
the O
anti O
- O
diabetic O
therapeutic O
response O
. O

These O
results O
raise O
the O
question O
of O
whether O
osteoblast O
precursors O
are O
inhibited O
in O
their O
development O
or O
actually O
converted O
to O
adipocytic O
phenotypes O
, O
possibly O
via O
marrow O
fat O
PPAR O
gamma O
nuclear O
receptor O
. O

Pharmacological O
management O
of O
ocular O
hypertension O
: O
current O
approaches O
and O
future O
prospective O
. O

Elevated O
eye O
pressure O
is O
the O
main O
risk O
factor O
for O
glaucoma O
, O
and O
intraocular O
pressure O
rises O
when O
the O
balance O
between O
aqueous O
humor O
formation O
and O
outflow O
resistance O
is O
compromised O
. O

In O
a O
normal O
eye O
there O
is O
a O
precise O
tune O
of O
aqueous O
outflow O
under O
the O
fine O
control O
of O
ciliary O
body O
and O
trabecular O
meshwork O
. O

Current O
pharmacological O
therapies O
for O
lowering O
the O
intraocular O
pressure O
in O
glaucoma O
include O
increasing O
aqueous O
humor O
outflow O
and O
suppression O
of O
aqueous O
humor O
production O
. O

However O
, O
most O
of O
antiglaucoma O
drugs O
currently O
on O
the O
market O
do O
not O
target O
the O
trabecular O
meshwork O
that O
represents O
the O
site O
of O
the O
pathology O
. O

This O
review O
focuses O
on O
pharmacological O
management O
of O
ocular O
hypertension O
with O
a O
particular O
attention O
to O
the O
future O
pharmacotherapy O
scenario O
. O

Perfluorooctane B
sulfonate I
( O
PFOS B
) O
affects O
hormone O
receptor O
activity O
, O
steroidogenesis O
, O
and O
expression O
of O
endocrine O
- O
related O
genes O
in O
vitro O
and O
in O
vivo O
. O

Perfluorooctane B
sulfonate I
( O
PFOS B
) O
is O
a O
widespread O
and O
persistent O
chemical O
in O
the O
environment O
. O

We O
investigated O
the O
endocrine O
- O
disrupting O
effects O
of O
PFOS B
using O
a O
combination O
of O
in O
vitro O
and O
in O
vivo O
assays O
. O

Reporter O
gene O
assays O
were O
used O
to O
detect O
receptor O
- O
mediated O
( O
anti O
- O
) O
estrogenic O
, O
( O
anti O
- O
) O
androgenic O
, O
and O
( O
anti O
- O
) O
thyroid O
hormone O
activities O
. O

The O
effect O
of O
PFOS B
on O
steroidogenesis O
was O
assessed O
both O
at O
hormone O
levels O
in O
the O
supernatant O
and O
at O
expression O
levels O
of O
hormone O
- O
induced O
genes O
in O
the O
H295R O
cell O
. O

A O
zebrafish O
- O
based O
short O
- O
term O
screening O
method O
was O
developed O
to O
detect O
the O
effect O
of O
PFOS B
on O
endocrine O
function O
in O
vivo O
. O

The O
results O
indicate O
that O
PFOS B
can O
act O
as O
an O
estrogen B
receptor O
agonist O
and O
thyroid O
hormone O
receptor O
antagonist O
. O

Exposure O
to O
PFOS B
decreased O
supernatant O
testosterone B
( O
T O
) O
, O
increased O
estradiol B
( O
E2 O
) O
concentrations O
in O
H295R O
cell O
medium O
and O
altered O
the O
expression O
of O
several O
genes O
involved O
in O
steroidogenesis O
. O

In O
addition O
, O
PFOS B
increased O
early O
thyroid O
development O
gene O
( O
hhex O
and O
pax8 O
) O
expression O
in O
a O
concentration O
- O
dependent O
manner O
, O
decreased O
steroidogenic O
enzyme O
gene O
( O
CYP17 O
, O
CYP19a O
, O
CYP19b O
) O
expression O
, O
and O
changed O
the O
expression O
pattern O
of O
estrogen B
receptor O
production O
genes O
( O
esr1 O
, O
esr2b O
) O
after O
500 O
micro O
g O
/ O
L O
PFOS B
treatment O
in O
zebrafish O
embryos O
. O

These O
results O
indicate O
that O
PFOS B
has O
the O
ability O
to O
act O
as O
an O
endocrine O
disruptor O
both O
in O
vitro O
and O
in O
vivo O
by O
disrupting O
the O
function O
of O
nuclear O
hormone O
receptors O
, O
interfering O
with O
steroidogenesis O
, O
and O
altering O
the O
expression O
of O
endocrine O
- O
related O
genes O
in O
zebrafish O
embryo O
. O

Solid O
- O
state O
nanopore O
detection O
of O
protein O
complexes O
: O
applications O
in O
healthcare O
and O
protein O
kinetics O
. O

Protein O
conjugation O
provides O
a O
unique O
look O
into O
many O
biological O
phenomena O
and O
has O
been O
used O
for O
decades O
for O
molecular O
recognition O
purposes O
. O

In O
this O
study O
, O
the O
use O
of O
solid O
- O
state O
nanopores O
for O
the O
detection O
of O
gp120 O
- O
associated O
complexes O
are O
investigated O
. O

They O
exhibit O
monovalent O
and O
multivalent O
binding O
to O
anti O
- O
gp120 O
antibody O
monomer O
and O
dimers O
. O

In O
order O
to O
investigate O
the O
feasibility O
of O
many O
practical O
applications O
related O
to O
nanopores O
, O
detection O
of O
specific O
protein O
complexes O
is O
attempted O
within O
a O
heterogeneous O
protein O
sample O
, O
and O
the O
role O
of O
voltage O
on O
complexed O
proteins O
is O
researched O
. O

It O
is O
found O
that O
the O
electric O
field O
within O
the O
pore O
can O
result O
in O
unbinding O
of O
a O
freely O
translocating O
protein O
complex O
within O
the O
transient O
event O
durations O
measured O
experimentally O
. O

The O
strong O
dependence O
of O
the O
unbinding O
time O
with O
voltage O
can O
be O
used O
to O
improve O
the O
detection O
capability O
of O
the O
nanopore O
system O
by O
adding O
an O
additional O
level O
of O
specificity O
that O
can O
be O
probed O
. O

These O
data O
provide O
a O
strong O
framework O
for O
future O
protein O
- O
specific O
detection O
schemes O
, O
which O
are O
shown O
to O
be O
feasible O
in O
the O
realm O
of O
a O
' O
real O
- O
world O
' O
sample O
and O
an O
automated O
multidimensional O
method O
of O
detecting O
events O
. O

Multicenter O
precision O
of O
cortical O
and O
trabecular O
bone O
quality O
measures O
assessed O
by O
high O
- O
resolution O
peripheral O
quantitative O
computed O
tomography O
. O

High O
- O
resolution O
peripheral O
quantitative O
computed O
tomography O
( O
HR O
- O
pQCT O
) O
has O
recently O
been O
introduced O
as O
a O
clinical O
research O
tool O
for O
in O
vivo O
assessment O
of O
bone O
quality O
. O

The O
utility O
of O
this O
technology O
to O
address O
important O
skeletal O
health O
questions O
requires O
translation O
to O
standardized O
multicenter O
data O
pools O
. O

Our O
goal O
was O
to O
evaluate O
the O
feasibility O
of O
pooling O
data O
in O
multicenter O
HR O
- O
pQCT O
imaging O
trials O
. O

Reproducibility O
imaging O
experiments O
were O
performed O
using O
structure O
and O
composition O
- O
realistic O
phantoms O
constructed O
from O
cadaveric O
radii O
. O

Single O
- O
center O
precision O
was O
determined O
by O
repeat O
scanning O
over O
short O
- O
term O
( O
< O
72 O
hours O
) O
, O
intermediate O
- O
term O
( O
3 O
- O
5 O
months O
) O
, O
and O
long O
- O
term O
intervals O
( O
28 O
months O
) O
. O

Multicenter O
precision O
was O
determined O
by O
imaging O
the O
phantoms O
at O
nine O
different O
HR O
- O
pQCT O
centers O
. O

Least O
significant O
change O
( O
LSC O
) O
and O
root O
mean O
squared O
coefficient O
of O
variation O
( O
RMSCV O
) O
for O
each O
interval O
and O
across O
centers O
was O
calculated O
for O
bone O
density O
, O
geometry O
, O
microstructure O
, O
and O
biomechanical O
parameters O
. O

Single O
- O
center O
short O
- O
term O
RMSCVs O
were O
< O
1 O
% O
for O
all O
parameters O
except O
cortical O
thickness O
( O
Ct O
. O
Th O
) O
( O
1 O
. O
1 O
% O
) O
, O
spatial O
variability O
in O
cortical O
thickness O
( O
Ct O
. O
Th O
. O
SD O
) O
( O
2 O
. O
6 O
% O
) O
, O
standard O
deviation O
of O
trabecular O
separation O
( O
Tb O
. O
Sp O
. O
SD O
) O
( O
1 O
. O
8 O
% O
) O
, O
and O
porosity O
measures O
( O
6 O
% O
to O
8 O
% O
) O
. O

Intermediate O
- O
term O
RMSCVs O
were O
generally O
not O
statistically O
different O
from O
short O
- O
term O
values O
. O

Long O
- O
term O
variability O
was O
significantly O
greater O
for O
all O
density O
measures O
( O
0 O
. O
7 O
% O
to O
2 O
. O
0 O
% O
; O
p O
< O
0 O
. O
05 O
versus O
short O
- O
term O
) O
and O
several O
structure O
measures O
: O
cortical O
thickness O
( O
Ct O
. O
Th O
) O
( O
3 O
. O
4 O
% O
; O
p O
< O
0 O
. O
01 O
versus O
short O
- O
term O
) O
, O
cortical O
porosity O
( O
Ct O
. O
Po O
) O
( O
15 O
. O
4 O
% O
; O
p O
< O
0 O
. O
01 O
versus O
short O
- O
term O
) O
, O
and O
trabecular O
thickness O
( O
Tb O
. O
Th O
) O
( O
2 O
. O
2 O
% O
; O
p O
< O
0 O
. O
01 O
versus O
short O
- O
term O
) O
. O

Multicenter O
RMSCVs O
were O
also O
significantly O
higher O
than O
short O
- O
term O
values O
: O
2 O
% O
to O
4 O
% O
for O
density O
and O
micro O
- O
finite O
element O
analysis O
( O
micro O
FE O
) O
measures O
( O
p O
< O
0 O
. O
0001 O
) O
, O
2 O
. O
6 O
% O
to O
5 O
. O
3 O
% O
for O
morphometric O
measures O
( O
p O
< O
0 O
. O
001 O
) O
, O
whereas O
Ct O
. O
Po O
was O
16 O
. O
2 O
% O
( O
p O
< O
0 O
. O
001 O
) O
. O

In O
the O
absence O
of O
subject O
motion O
, O
multicenter O
precision O
errors O
for O
HR O
- O
pQCT O
parameters O
were O
generally O
less O
than O
5 O
% O
. O

Phantom O
- O
based O
multicenter O
precision O
was O
comparable O
to O
previously O
reported O
in O
in O
vivo O
single O
- O
center O
precision O
errors O
, O
although O
this O
was O
approximately O
two O
to O
five O
times O
worse O
than O
ex O
vivo O
short O
- O
term O
precision O
. O

The O
data O
generated O
from O
this O
study O
will O
contribute O
to O
the O
future O
design O
and O
validation O
of O
standardized O
procedures O
that O
are O
broadly O
translatable O
to O
multicenter O
study O
designs O
. O

Pharmacokinetics O
and O
metabolism O
of O
[ B
( I
14 I
) I
C I
] I
anagliptin I
, O
a O
novel O
dipeptidyl O
peptidase O
- O
4 O
inhibitor O
, O
in O
humans O
. O

1 O
. O
The O
disposition O
of O
anagliptin B
, O
an O
orally O
active O
, O
highly O
selective O
dipeptidyl O
peptidase O
- O
4 O
inhibitor O
, O
was O
investigated O
after O
a O
single O
oral O
dose O
of O
100 O
mg O
/ O
1 O
. O
92 O
MBq O
[ B
( I
14 I
) I
C I
] I
anagliptin I
to O
six O
healthy O
men O
. O

Almost O
all O
the O
dose O
( O
98 O
. O
2 O
% O
) O
was O
recovered O
within O
168 O
h O
: O
73 O
. O
2 O
% O
in O
urine O
and O
25 O
. O
0 O
% O
in O
faeces O
. O

2 O
. O
Anagliptin B
was O
rapidly O
absorbed O
, O
with O
peak O
plasma O
concentrations O
of O
unchanged O
drug O
attained O
at O
a O
mean O
time O
of O
1 O
. O
8 O
- O
h O
postdose O
. O

Mean O
fraction O
of O
the O
dose O
absorbed O
was O
> O
73 O
% O
. O

Unchanged O
drug O
and O
a O
carboxylate B
metabolite O
( O
M1 O
) O
were O
the O
major O
components O
in O
plasma O
, O
accounting O
for O
66 O
. O
0 O
and O
23 O
. O
4 O
% O
of O
total O
plasma O
radioactivity O
area O
under O
the O
curve O
, O
respectively O
. O

3 O
. O
Anagliptin B
was O
incompletely O
metabolized O
, O
with O
about O
50 O
% O
dose O
eliminated O
as O
unchanged O
drug O
( O
46 O
. O
6 O
% O
in O
urine O
and O
4 O
. O
1 O
% O
in O
faeces O
) O
. O

Metabolism O
to O
M1 O
accounted O
for O
29 O
. O
2 O
% O
of O
the O
dose O
. O

No O
other O
metabolite O
accounted O
for O
> O
1 O
% O
dose O
in O
excreta O
or O
yielded O
measurable O
systemic O
exposure O
. O

Terminal O
half O
- O
life O
of O
anagliptin B
and O
M1 O
was O
4 O
. O
37 O
and O
9 O
. O
88 O
h O
, O
respectively O
. O

Renal O
clearance O
of O
unbound O
anagliptin B
and O
unbound O
M1 O
far O
exceeded O
glomerular O
filtration O
rate O
, O
indicating O
active O
renal O
elimination O
: O
that O
might O
reflect O
the O
fact O
that O
anagliptin B
may O
be O
a O
substrate O
of O
OAT1 O
, O
OAT3 O
, O
MDR1 O
and O
MRP2 O
, O
and O
M1 O
a O
substrate O
of O
OAT3 O
, O
BCRP O
, O
MRP2 O
and O
MRP4 O
. O

Substrate O
effect O
on O
the O
plasmonic O
sensing O
ability O
of O
hollow O
nanoparticles O
of O
different O
shapes O
. O

Gold O
hollow O
nanospheres O
( O
AuHSs O
) O
and O
gold O
hollow O
nanocubes O
( O
AuHCs O
) O
were O
synthesized O
by O
the O
galvanic O
replacement O
technique O
using O
silver B
nano O
templates O
. O

Colloidal O
AuHSs B
are O
found O
to O
have O
a O
higher O
sensitivity O
factor O
than O
that O
of O
AuHCs B
. O

This O
value O
decreases O
for O
both O
shapes O
when O
the O
nanoparticles O
are O
assembled O
on O
a O
quartz B
substrate O
by O
using O
the O
Langmuir O
- O
Blodgett O
technique O
. O

AuHSs O
are O
observed O
to O
have O
the O
larger O
effect O
. O

It O
is O
observed O
that O
as O
the O
separation O
gap O
between O
AuHCs B
nanoparticles O
decreases O
, O
their O
localized O
surface O
plasmon O
resonance O
band O
red O
shifts O
more O
than O
AuHSs B
. O

This O
is O
accounted O
for O
by O
the O
discrete O
dipole O
approximation O
( O
DDA O
) O
calculations O
. O

The O
coupling O
between O
the O
plasmon O
fields O
of O
the O
AuHCs B
pair O
is O
stronger O
than O
that O
between O
AuHSs B
pair O
. O

Using O
the O
DDA O
calculation O
, O
this O
is O
found O
to O
be O
due O
to O
geometric O
factors O
, O
as O
well O
as O
to O
the O
difference O
in O
the O
plasmonic O
field O
intensity O
. O

The O
calculation O
also O
showed O
that O
the O
plasmon O
field O
distributions O
of O
both O
AuHCs B
and O
AuHSs B
were O
distorted O
by O
the O
quartz B
substrate O
in O
a O
different O
manner O
. O

It O
is O
also O
observed O
that O
the O
surface O
- O
enhanced O
Raman O
spectrum O
of O
thiophenol B
is O
stronger O
when O
measured O
on O
AuHCs B
than O
on O
AuHSs B
. O

This O
is O
due O
to O
the O
difference O
in O
the O
plasmon O
field O
distribution O
as O
well O
as O
the O
fact O
that O
the O
AuHCs B
have O
a O
higher O
scattering O
/ O
absorption O
yield O
ratio O
. O

Noncanonical O
suppression O
of O
GH O
- O
dependent O
isoforms O
of O
cytochrome O
P450 O
by O
the O
somatostatin B
analog O
octreotide B
. O

Octreotide O
is O
a O
potent O
somatostatin B
analog O
therapeutically O
used O
to O
treat O
several O
conditions O
including O
hyper O
GH O
secretion O
in O
patients O
with O
acromegaly O
. O

We O
infused O
, O
over O
30 O
s O
, O
octreotide O
into O
male O
rats O
every O
12 O
h O
for O
6 O
days O
at O
levels O
considerably O
greater O
than O
typical O
human O
therapeutic O
doses O
. O

Unexpectedly O
, O
resulting O
circulating O
GH O
profile O
was O
characterized O
by O
pulses O
of O
higher O
amplitudes O
, O
longer O
durations O
, O
and O
greater O
total O
content O
than O
normal O
, O
but O
still O
contained O
an O
otherwise O
male O
- O
like O
episodic O
secretory O
profiles O
. O

In O
apparent O
disaccord O
, O
the O
normally O
elevated O
masculine O
expression O
levels O
( O
protein O
and O
/ O
or O
mRNA O
) O
of O
CYP2C11 O
( O
accounting O
for O
> O
50 O
% O
of O
the O
total O
hepatic O
cytochrome O
P450 O
content O
) O
, O
CYP3A2 O
, O
CYP2C7 O
, O
and O
IGF1 O
, O
dependent O
on O
the O
episodic O
GH O
profile O
, O
were O
considerably O
downregulated O
. O

We O
explain O
this O
contradiction O
by O
proposing O
that O
the O
requisite O
minimal O
GH O
- O
devoid O
interpulse O
durations O
in O
the O
masculine O
profile O
that O
solely O
regulate O
expression O
of O
at O
least O
CYP2C11 O
and O
IGF1 O
may O
be O
sufficiently O
reduced O
to O
suppress O
transcription O
of O
the O
hepatic O
genes O
. O

Alternatively O
, O
we O
observed O
that O
octreotide B
infusion O
may O
have O
acted O
directly O
on O
the O
hepatocytes O
to O
induce O
expression O
of O
immune O
response O
factors O
postulated O
to O
suppress O
CYP O
transcription O
and O
/ O
or O
upregulate O
expression O
of O
several O
negative O
regulators O
( O
e O
. O
g O
. O
phosphatases O
and O
SOCS O
proteins O
) O
of O
the O
JAK2 O
/ O
STAT5B O
signaling O
pathway O
that O
normally O
mediates O
the O
upregulation O
of O
CYP2C11 O
and O
IGF1 O
by O
the O
masculine O
episodic O
GH O
profile O
. O

Effects O
of O
alpha O
7 O
positive O
allosteric O
modulators O
in O
murine O
inflammatory O
and O
chronic O
neuropathic O
pain O
models O
. O

Agonists O
and O
positive O
allosteric O
modulators O
( O
PAMs O
) O
of O
alpha O
7 O
nicotinic O
acetylcholine B
receptors O
( O
nAChRs O
) O
are O
currently O
being O
considered O
as O
novel O
therapeutic O
approaches O
for O
managing O
cognitive O
deficits O
in O
schizophrenia O
and O
Alzheimer O
' O
s O
disease O
. O

Though O
alpha O
7 O
agonists O
were O
recently O
found O
to O
possess O
antinociceptive O
and O
anti O
- O
inflammatory O
properties O
in O
rodent O
models O
of O
chronic O
neuropathic O
pain O
and O
inflammation O
, O
the O
effects O
of O
alpha O
7 O
nAChRs O
PAMs O
on O
chronic O
pain O
and O
inflammation O
remain O
largely O
unknown O
. O

The O
present O
study O
investigated O
whether O
PAMs O
, O
by O
increasing O
endogenous O
cholinergic O
tone O
, O
potentiate O
alpha O
7 O
nAChRs O
function O
to O
attenuate O
inflammatory O
and O
chronic O
neuropathic O
pain O
in O
mice O
. O

We O
tested O
two O
types O
of O
PAMS O
, O
type O
I O
( O
NS1738 B
) O
and O
type O
II O
( O
PNU B
- I
120596 I
) O
in O
carrageenan O
- O
induced O
inflammatory O
pain O
and O
chronic O
constriction O
injury O
( O
CCI O
) O
neuropathic O
pain O
models O
. O

We O
found O
that O
both O
NS1738 B
and O
PNU B
- I
120596 I
significantly O
reduced O
thermal O
hyperalgesia O
, O
while O
only O
PNU B
- I
120596 I
significantly O
reduced O
edema O
caused O
by O
a O
hind O
paw O
infusion O
of O
carrageenan O
. O

Importantly O
, O
PNU B
- I
120596 I
reversed O
established O
thermal O
hyperalgesia O
and O
edema O
induced O
by O
carrageenan O
. O

In O
the O
CCI O
model O
, O
PNU B
- I
120596 I
had O
long O
- O
lasting O
( O
up O
to O
6 O
h O
) O
, O
dose O
- O
dependent O
anti O
- O
hyperalgesic O
and O
anti O
- O
allodynic O
effects O
after O
a O
single O
injection O
, O
while O
NS1738 B
was O
inactive O
. O

Systemic O
administration O
of O
the O
alpha O
7 O
nAChR O
antagonist O
MLA B
reversed O
PNU B
- I
120596 I
' O
s O
effects O
, O
suggesting O
the O
involvement O
of O
central O
and O
peripheral O
alpha O
7 O
nAChRs O
. O

Furthermore O
, O
PNU B
- I
120596 I
enhanced O
an O
ineffective O
dose O
of O
selective O
agonist O
PHA B
- I
543613 I
to O
produce O
anti O
- O
allodynic O
effects O
in O
the O
CCI O
model O
. O

Our O
results O
indicate O
that O
the O
type O
II O
alpha O
7 O
nAChRs O
PAM O
PNU B
- I
120596 I
, O
but O
not O
the O
type O
I O
alpha O
7 O
nAChRs O
PAM O
NS1738 B
, O
shows O
significant O
anti O
- O
edematous O
and O
anti O
- O
allodynic O
effects O
in O
inflammatory O
and O
CCI O
pain O
models O
in O
mice O
. O

Tandem O
inverse O
- O
electron O
- O
demand O
hetero O
- O
/ O
retro O
- O
Diels O
- O
Alder O
reactions O
for O
aromatic O
nitrogen B
heterocycle O
synthesis O
. O

The O
merged O
inverse O
- O
electron O
- O
demand O
hetero O
- O
Diels O
- O
Alder O
( O
ihDA O
) O
/ O
retro O
- O
Diels O
- O
Alder O
( O
rDA O
) O
reaction O
sequence O
can O
be O
used O
to O
rapidly O
synthesise O
highly O
functionalised O
nitrogen B
heteroaromatics O
. O

The O
reaction O
offers O
many O
advantages O
: O
high O
atom O
economy O
, O
high O
levels O
of O
regioselectivity O
, O
it O
rarely O
requires O
a O
catalyst O
and O
, O
in O
some O
cases O
, O
can O
be O
performed O
in O
the O
absence O
of O
solvent O
. O

In O
this O
tutorial O
review O
we O
discuss O
the O
range O
of O
commonly O
used O
dienophiles B
and O
aza B
- I
dienes I
for O
this O
process O
whilst O
highlighting O
the O
reactivity O
trends O
, O
and O
illustrating O
their O
applications O
. O

Use O
of O
transgenic O
GFP O
reporter O
strains O
of O
the O
nematode O
Caenorhabditis O
elegans O
to O
investigate O
the O
patterns O
of O
stress O
responses O
induced O
by O
pesticides O
and O
by O
organic O
extracts O
from O
agricultural O
soils O
. O

As O
a O
free O
- O
living O
nematode O
, O
C O
. O
elegans O
is O
exposed O
to O
various O
pesticides O
used O
in O
agriculture O
, O
as O
well O
as O
to O
persistent O
organic O
residues O
which O
may O
contaminate O
the O
soil O
for O
long O
periods O
. O

Following O
on O
from O
our O
previous O
study O
of O
metal O
effects O
on O
24 O
GFP O
- O
reporter O
strains O
representing O
four O
different O
stress O
- O
response O
pathways O
in O
C O
. O
elegans O
( O
Anbalagan O
et O
al O
. O
Ecotoxicology O
21 O
: O
439 O
- O
455 O
, O
2012 O
) O
, O
we O
now O
present O
parallel O
data O
on O
the O
responses O
of O
these O
same O
strains O
to O
several O
commonly O
used O
pesticides O
. O

Some O
of O
these O
, O
like O
dichlorvos B
, O
induced O
multiple O
stress O
genes O
in O
a O
concentration O
- O
dependent O
manner O
. O

Unusually O
, O
endosulfan B
induced O
only O
one O
gene O
( O
cyp O
- O
34A9 O
) O
to O
very O
high O
levels O
( O
8 O
- O
10 O
- O
fold O
) O
even O
at O
the O
lowest O
test O
concentration O
, O
with O
a O
clear O
plateau O
at O
higher O
doses O
. O

Other O
pesticides O
, O
like O
diuron B
, O
did O
not O
alter O
reporter O
gene O
expression O
detectably O
even O
at O
the O
highest O
test O
concentration O
attainable O
, O
while O
others O
( O
such O
as O
glyphosate B
) O
did O
so O
only O
at O
very O
high O
concentrations O
. O

We O
have O
also O
used O
five O
responsive O
GFP O
reporters O
to O
investigate O
the O
toxicity O
of O
soil O
pore O
water O
from O
two O
agricultural O
sites O
in O
south O
- O
east O
Spain O
, O
designated O
P74 O
( O
used O
for O
cauliflower O
production O
, O
but O
significantly O
metal O
contaminated O
) O
and O
P73 O
( O
used O
for O
growing O
lettuce O
, O
but O
with O
only O
background O
levels O
of O
metals O
) O
. O

Both O
soil O
pore O
water O
samples O
induced O
all O
five O
test O
genes O
to O
varying O
extents O
, O
yet O
artificial O
mixtures O
containing O
all O
major O
metals O
present O
had O
essentially O
no O
effect O
on O
these O
same O
transgenes O
. O

Soluble O
organic O
contaminants O
present O
in O
the O
pore O
water O
were O
extracted O
with O
acetone B
and O
dichloromethane B
, O
then O
after O
evaporation O
of O
the O
solvents O
, O
the O
organic O
residues O
were O
redissolved O
in O
ultrapure O
water O
to O
reconstitute O
the O
soluble O
organic O
components O
of O
the O
original O
soil O
pore O
water O
. O

These O
organic O
extracts O
induced O
transgene O
expression O
at O
similar O
or O
higher O
levels O
than O
the O
original O
pore O
water O
. O

Addition O
of O
the O
corresponding O
metal O
mixtures O
had O
either O
no O
effect O
, O
or O
reduced O
transgene O
expression O
towards O
the O
levels O
seen O
with O
soil O
pore O
water O
only O
. O

We O
conclude O
that O
the O
main O
toxicants O
present O
in O
these O
soil O
pore O
water O
samples O
are O
organic O
rather O
than O
metallic O
in O
nature O
. O

Organic O
extracts O
from O
a O
control O
standard O
soil O
( O
Lufa O
2 O
. O
2 O
) O
had O
negligible O
effects O
on O
expression O
of O
these O
genes O
, O
and O
similarly O
several O
pesticides O
had O
little O
effect O
on O
the O
expression O
of O
a O
constitutive O
myo O
- O
3 O
: O
: O
GFP O
transgene O
. O

Both O
the O
P73 O
and O
P74 O
sites O
have O
been O
treated O
regularly O
with O
( O
undisclosed O
) O
pesticides O
, O
as O
permitted O
under O
EU O
regulations O
, O
though O
other O
( O
e O
. O
g O
. O
industrial O
) O
organic O
residues O
may O
also O
be O
present O
. O

Mineralocorticoid O
receptor O
antagonists O
and O
renal O
involvement O
in O
primary O
aldosteronism O
: O
opening O
of O
a O
new O
era O
. O

Primary O
aldosteronism O
( O
PA O
) O
is O
one O
of O
the O
commonest O
forms O
of O
curable O
hypertension O
, O
and O
use O
of O
the O
plasma O
aldosterone B
- O
to O
- O
renin O
ratio O
as O
a O
screening O
test O
has O
led O
to O
a O
more O
efficient O
identification O
of O
this O
condition O
. O

Both O
animal O
and O
human O
studies O
have O
indicated O
that O
PA O
is O
associated O
with O
a O
variety O
of O
cardiovascular O
and O
renal O
complications O
that O
reflect O
the O
capability O
of O
elevated O
aldosterone B
to O
induce O
tissue O
damage O
exceeding O
that O
induced O
by O
hypertension O
itself O
. O

Involvement O
of O
the O
kidney O
in O
PA O
is O
highly O
relevant O
because O
structural O
renal O
damage O
is O
associated O
with O
less O
favorable O
outcome O
, O
both O
in O
terms O
of O
blood O
pressure O
response O
to O
treatment O
and O
possibility O
to O
develop O
progressive O
renal O
failure O
. O

However O
, O
early O
involvement O
of O
the O
kidney O
in O
PA O
is O
characterized O
by O
functional O
changes O
that O
are O
largely O
reversible O
with O
treatment O
. O

Unilateral O
adrenalectomy O
or O
administration O
of O
mineralocorticoid O
receptor O
antagonists O
are O
the O
current O
options O
for O
treating O
an O
aldosterone B
- O
producing O
adenoma O
or O
idiopathic O
adrenal O
hyperplasia O
. O

Both O
treatments O
are O
effective O
in O
correcting O
hypertension O
and O
hypokalemia O
, O
and O
currently O
available O
information O
on O
their O
capability O
to O
prevent O
deterioration O
of O
renal O
function O
indicates O
that O
both O
surgery O
and O
medical O
treatment O
are O
of O
considerable O
value O
. O

Immune O
regulation O
toward O
immunomodulation O
for O
neuroprotection O
in O
glaucoma O
. O

Although O
the O
immune O
system O
functions O
to O
preserve O
and O
restore O
tissue O
homeostasis O
, O
accumulating O
risk O
factors O
, O
prolonged O
glial O
activation O
, O
and O
sustained O
release O
of O
pro O
- O
inflammatory O
mediators O
in O
glaucoma O
may O
lead O
to O
a O
failure O
in O
the O
regulation O
of O
stress O
- O
induced O
immune O
response O
, O
and O
innate O
immune O
cells O
, O
autoreactive O
T O
cells O
, O
autoantibodies O
, O
and O
excess O
complement O
attack O
may O
exhibit O
potent O
stimuli O
that O
harm O
retinal O
ganglion O
cell O
somas O
, O
axons O
, O
and O
synapses O
. O

Identification O
of O
the O
cellular O
and O
molecular O
components O
of O
immune O
response O
pathways O
can O
provide O
immunomodulatory O
treatment O
strategies O
to O
attenuate O
neuroinflammation O
, O
protect O
neural O
tissue O
from O
collateral O
injury O
, O
and O
enhance O
endogenous O
recovery O
processes O
. O

This O
review O
highlights O
the O
current O
knowledge O
of O
molecular O
mechanisms O
regulating O
neuroinflammation O
in O
glaucoma O
. O

Bis B
( I
12 I
) I
- I
hupyridone I
, O
a O
novel O
acetylcholinesterase O
inhibitor O
, O
protects O
against O
glutamate B
- O
induced O
neuronal O
excitotoxicity O
via O
activating O
alpha O
7 O
nicotinic O
acetylcholine B
receptor O
/ O
phosphoinositide O
3 O
- O
kinase O
/ O
Akt O
cascade O
. O

Bis B
( I
12 I
) I
- I
hupyridone I
( O
B12H B
) O
, O
derived O
from O
the O
Chinese O
medicinal O
component O
huperzine B
A I
, O
was O
originally O
designed O
as O
a O
novel O
acetylcholinesterase O
( O
AChE O
) O
inhibitor O
. O

In O
this O
paper O
, O
we O
report O
that O
B12H B
( O
24 O
- O
h O
pretreatment O
) O
effectively O
blocked O
glutamate B
- O
induced O
neuronal O
excitotoxicity O
in O
cerebellar O
granule O
neurons O
( O
CGNs O
) O
. O

However O
, O
the O
huge O
discrepancy O
between O
the O
EC50 O
value O
and O
IC50 O
value O
of O
B12H B
, O
to O
protect O
against O
neuronal O
toxicity O
( O
0 O
. O
09 O
mu O
M O
) O
and O
to O
block O
the O
NMDA B
receptor O
( O
21 O
. O
8 O
mu O
M O
) O
respectively O
, O
suggests O
that O
the O
neuroprotection O
of O
B12H B
might O
be O
not O
primarily O
due O
to O
the O
blockade O
of O
the O
NMDA B
receptor O
. O

Pretreatment O
by O
specific O
antagonists O
of O
alpha7 O
- O
nicotinic O
acetylcholine B
receptor O
( O
alpha O
7nAChR O
) O
, O
but O
not O
muscarinic O
acetylcholine B
receptor O
( O
mAChR O
) O
or O
alpha O
4 O
beta O
2nAChR O
, O
decreased O
the O
neuroprotection O
of O
B12H O
. O

The O
neuroprotection O
of O
B12H O
could O
also O
be O
abolished O
by O
the O
pretreatment O
of O
specific O
PI3 O
- O
K O
inhibitors O
. O

Furthermore O
, O
B12H O
restored O
the O
suppressed O
activation O
of O
the O
Akt O
pathway O
caused O
by O
glutamate B
as O
evidenced O
by O
the O
decreased O
expressions O
of O
pSer473 O
- O
Akt O
and O
pSer9 O
- O
GSK3 O
beta O
. O

All O
these O
results O
suggest O
that O
B12H O
substantially O
protected O
CGNs O
against O
glutamate B
- O
induced O
neuronal O
excitotoxicity O
via O
activating O
alpha O
7nAChR O
/ O
PI3 O
- O
K O
/ O
Akt O
cascade O
. O

Ts6 O
and O
Ts2 O
from O
Tityus O
serrulatus O
venom O
induce O
inflammation O
by O
mechanisms O
dependent O
on O
lipid O
mediators O
and O
cytokine O
production O
. O

Inflammatory O
mediators O
are O
thought O
to O
be O
involved O
in O
the O
systemic O
and O
local O
immune O
response O
induced O
by O
the O
Tityus O
serrulatus O
scorpion O
envenomation O
. O

New O
functional O
aspects O
of O
lipid O
mediators O
have O
recently O
been O
described O
. O

Here O
, O
we O
examine O
the O
unreported O
role O
of O
lipid O
mediators O
in O
cell O
recruitment O
to O
the O
peritoneal O
cavity O
after O
an O
injection O
with O
Ts2 O
or O
Ts6 O
toxins O
isolated O
from O
the O
T O
. O
serrulatus O
scorpion O
venom O
. O

In O
this O
report O
, O
we O
demonstrate O
that O
following O
a O
single O
intraperitoneal O
( O
i O
. O
p O
. O
) O
injection O
of O
Ts2 O
or O
Ts6 O
( O
250 O
mu O
g O
/ O
kg O
) O
in O
mice O
, O
there O
was O
an O
induction O
of O
leukocytosis O
with O
a O
predominance O
of O
neutrophils O
observed O
at O
4 O
, O
24 O
, O
48 O
and O
96 O
h O
. O

Moreover O
, O
total O
protein O
, O
leukotriene B
( I
LT I
) I
B I
( I
4 I
) I
, O
prostaglandin B
( I
PG I
) I
E I
( I
2 I
) I
and O
pro O
- O
inflammatory O
cytokine O
levels O
were O
increased O
. O

We O
also O
observed O
an O
increase O
of O
regulatory O
cytokines O
, O
including O
interleukin O
( O
IL O
) O
- O
10 O
, O
after O
the O
Ts2 O
injection O
. O

Finally O
, O
we O
observed O
that O
Ts2 O
or O
Ts6 O
injection O
in O
5 O
- O
lipoxygenase O
( O
LO O
) O
deficient O
mice O
and O
in O
wild O
type O
( O
WT O
) O
129sv O
mice O
pre O
- O
treated O
with O
LTs O
and O
PGs O
inhibitors O
( O
MK B
- I
886 I
and O
celecoxib B
, O
respectively O
) O
a O
reduction O
the O
influx O
of O
leukocytes O
occurs O
in O
comparison O
to O
WT O
. O

The O
recruitment O
of O
these O
cells O
demonstrated O
a O
phenotype O
characteristic O
of O
neutrophils O
, O
macrophages O
, O
CD4 O
and O
CD8 O
lymphocytes O
expressing O
GR1 O
+ O
, O
F4 O
/ O
80 O
+ O
, O
CD3 O
+ O
/ O
CD4 O
+ O
and O
CD3 O
+ O
/ O
CD8 O
+ O
, O
respectively O
. O

In O
conclusion O
, O
our O
data O
demonstrate O
that O
Ts2 O
and O
Ts6 O
induce O
inflammation O
by O
mechanisms O
dependent O
on O
lipid O
mediators O
and O
cytokine O
production O
. O

Ts2 O
may O
play O
a O
regulatory O
role O
whereas O
Ts6 O
exhibits O
pro O
- O
inflammatory O
activity O
exclusively O
. O

Xanthohumol B
induces O
phase O
II O
enzymes O
via O
Nrf2 O
in O
human O
hepatocytes O
in O
vitro O
. O

The O
aim O
of O
this O
study O
was O
to O
investigate O
whether O
xanthohumol B
may O
exert O
chemoprotective O
activity O
through O
the O
modulation O
of O
the O
nuclear O
factor O
erythroid O
- O
2 O
- O
related O
factor O
2 O
( O
Nrf2 O
) O
pathway O
in O
immortalized O
normal O
THLE O
- O
2 O
hepatocytes O
and O
a O
hepatocellular O
carcinoma O
HepG2 O
cell O
line O
. O

Cells O
were O
incubated O
in O
the O
presence O
of O
xanthohumol B
and O
the O
activation O
of O
Nrf2 O
and O
expression O
of O
genes O
controlled O
by O
this O
transcription O
factor O
were O
evaluated O
. O

Additionally O
, O
p53 O
level O
was O
assessed O
. O

Xanthohumol B
increased O
the O
expression O
and O
led O
to O
the O
activation O
of O
Nrf2 O
in O
both O
cell O
lines O
. O

However O
, O
in O
contrast O
to O
normal O
cells O
the O
expression O
of O
genes O
controlled O
by O
this O
transcription O
factor O
was O
not O
affected O
in O
HepG2 O
cells O
, O
except O
for O
GSTA O
and O
GSTP O
. O

Xanthohumol B
, O
beside O
the O
induction O
of O
GSTs O
and O
HO O
- O
1 O
, O
significantly O
elevated O
NQO1 O
expression O
in O
concert O
with O
p53 O
level O
in O
normal O
hepatocytes O
. O

The O
activation O
of O
Nrf2 O
pathway O
and O
subsequently O
phase O
II O
enzymes O
in O
concert O
with O
p53 O
induction O
in O
normal O
hepatocytes O
may O
account O
for O
the O
molecular O
mechanism O
of O
the O
chemopreventive O
activity O
of O
xanthohumol B
. O

On O
the O
other O
hand O
its O
cytotoxicity O
towards O
HCC O
cells O
shown O
in O
this O
study O
indicates O
that O
it O
may O
also O
be O
considered O
as O
potentially O
chemotherapeutic O
. O

Deriving O
an O
explicit O
hepatic O
clearance O
equation O
accounting O
for O
plasma O
protein O
binding O
and O
hepatocellular O
uptake O
. O

High O
throughput O
in O
vitro O
biochemical O
and O
cell O
- O
based O
assays O
have O
the O
promise O
to O
provide O
more O
mechanism O
- O
based O
assessments O
of O
the O
adverse O
effects O
of O
large O
numbers O
of O
chemicals O
. O

One O
of O
the O
most O
challenging O
hurdles O
for O
interpreting O
in O
vitro O
toxicity O
findings O
is O
the O
need O
for O
reverse O
dosimetry O
tools O
that O
estimate O
the O
exposures O
that O
will O
give O
concentrations O
in O
vivo O
similar O
to O
the O
active O
concentrations O
in O
vitro O
. O

Recent O
experience O
using O
IVIVE O
approaches O
to O
estimate O
in O
vivo O
pharmacokinetics O
( O
Wetmore O
et O
al O
. O
, O
2012 O
) O
identified O
the O
need O
to O
develop O
a O
hepatic O
clearance O
equation O
that O
explicitly O
accounted O
for O
a O
broader O
set O
of O
protein O
binding O
and O
membrane O
transport O
processes O
and O
did O
not O
depend O
on O
a O
well O
- O
mixed O
description O
of O
the O
liver O
compartment O
. O

Here O
we O
derive O
an O
explicit O
steady O
- O
state O
hepatic O
clearance O
equation O
that O
includes O
these O
factors O
. O

In O
addition O
to O
the O
derivation O
, O
we O
provide O
simple O
computer O
code O
to O
calculate O
steady O
- O
state O
extraction O
for O
any O
combination O
of O
blood O
flow O
, O
membrane O
transport O
processes O
and O
plasma O
protein O
- O
chemical O
binding O
rates O
. O

This O
expanded O
equation O
provides O
a O
tool O
to O
estimate O
hepatic O
clearance O
for O
a O
more O
diverse O
array O
of O
compounds O
. O

Growth O
differentiation O
factor O
15 O
stimulates O
rapamycin B
- O
sensitive O
ovarian O
cancer O
cell O
growth O
and O
invasion O
. O

Identification O
of O
novel O
molecular O
markers O
and O
therapeutic O
targets O
may O
improve O
survival O
rates O
for O
patients O
with O
ovarian O
cancer O
. O

In O
the O
current O
study O
, O
immunohistochemical O
( O
IHC O
) O
analysis O
of O
two O
human O
ovarian O
tumor O
tissue O
arrays O
showed O
high O
staining O
for O
GDF15 O
in O
a O
majority O
of O
tissues O
. O

Exogenous O
stimulation O
of O
ovarian O
cancer O
cell O
lines O
with O
recombinant O
human O
GDF15 O
( O
rhGDF15 O
) O
or O
stable O
over O
- O
expression O
of O
a O
GDF15 O
expression O
plasmid O
promoted O
anchorage O
- O
independent O
growth O
, O
increased O
invasion O
, O
and O
up O
- O
regulation O
of O
matrix O
metalloproteinases O
( O
MMPs O
) O
and O
vascular O
endothelial O
growth O
factor O
( O
VEGF O
) O
. O

MMP O
inhibition O
suppressed O
GDF15 O
- O
mediated O
invasion O
. O

In O
addition O
, O
IHC O
analysis O
of O
human O
ovarian O
tumor O
tissue O
arrays O
indicated O
that O
GDF15 O
expression O
correlated O
significantly O
with O
high O
MMP2 O
and O
MMP9 O
expression O
. O

Exogenous O
and O
endogenous O
GDF15 O
over O
- O
expression O
stimulated O
phosphorylation O
of O
p38 O
, O
Erk1 O
/ O
2 O
, O
and O
Akt O
. O

Pharmacologic O
inhibition O
of O
p38 O
, O
MEK O
, O
or O
PI3K O
suppressed O
GDF15 O
- O
stimulated O
growth O
. O

Further O
, O
proliferation O
, O
growth O
, O
and O
invasion O
of O
GDF15 O
stable O
clones O
were O
blocked O
by O
rapamycin B
. O

IHC O
analysis O
demonstrated O
significant O
correlation O
between O
GDF15 O
expression O
and O
phosphorylation O
of O
mTOR O
. O

Finally O
, O
knockdown O
of O
endogenous O
GDF15 O
or O
neutralization O
of O
secreted O
GDF15 O
suppressed O
invasion O
and O
growth O
of O
a O
GDF15 O
- O
over O
- O
expressing O
ovarian O
cancer O
cell O
line O
. O

These O
data O
indicate O
that O
GDF15 O
over O
- O
expression O
, O
which O
occurred O
in O
a O
majority O
of O
human O
ovarian O
cancers O
, O
promoted O
rapamycin B
- O
sensitive O
invasion O
and O
growth O
of O
ovarian O
cancer O
cells O
. O

Inhibition O
of O
mTOR O
may O
be O
an O
effective O
therapeutic O
strategy O
for O
ovarian O
cancers O
that O
over O
- O
express O
GDF15 O
. O

Future O
studies O
should O
examine O
GDF15 O
as O
a O
novel O
molecular O
target O
for O
blocking O
ovarian O
cancer O
progression O
. O

Solid O
- O
state O
dependent O
dissolution O
and O
oral O
bioavailability O
of O
piroxicam B
in O
rats O
. O

The O
aim O
of O
this O
study O
was O
to O
gain O
understanding O
about O
the O
effects O
of O
different O
solid O
- O
state O
forms O
of O
a O
poorly O
water O
- O
soluble O
piroxicam B
on O
drug O
dissolution O
and O
oral O
bioavailability O
in O
rats O
. O

Three O
different O
solid O
- O
state O
forms O
of O
piroxicam B
were O
studied O
: O
anhydrate O
I O
( O
AH O
) O
, O
monohydrate B
( O
MH O
) O
, O
and O
amorphous O
form O
in O
solid O
dispersion O
( O
SD O
) O
. O

In O
addition O
, O
the O
effect O
of O
a O
new O
polymeric O
excipient O
Soluplus B
( O
R O
) O
( O
polyvinyl B
caprolactam I
- O
polyvinyl B
acetate I
- O
polyethylene B
glycol I
graft O
copolymer O
) O
on O
oral O
bioavailability O
of O
piroxicam B
was O
investigated O
. O

Significant O
differences O
in O
the O
dissolution O
and O
oral O
bioavailability O
were O
found O
between O
the O
solid O
- O
state O
forms O
of O
piroxicam B
. O

Amorphous O
piroxicam B
in O
SD O
showed O
the O
fastest O
dissolution O
in O
vitro O
and O
a O
solid O
- O
state O
transformation O
to O
MH O
in O
the O
dissolution O
medium O
. O

Despite O
the O
presence O
of O
solid O
- O
state O
transformation O
, O
SD O
exhibited O
the O
highest O
rate O
and O
extent O
of O
oral O
absorption O
in O
rats O
. O

Oral O
bioavailability O
of O
other O
two O
solid O
- O
state O
forms O
decreased O
in O
the O
order O
AH O
and O
MH O
. O

The O
use O
of O
Soluplus B
( O
R O
) O
was O
found O
to O
enhance O
the O
dissolution O
and O
oral O
bioavailability O
of O
piroxicam B
in O
rats O
. O

The O
present O
study O
shows O
the O
importance O
of O
solid O
- O
state O
form O
selection O
for O
oral O
bioavailability O
of O
a O
poorly O
water O
- O
soluble O
drug O
. O

Fetal O
muscle O
- O
type O
nicotinic O
acetylcholine B
receptor O
activation O
in O
TE O
- O
671 O
cells O
and O
inhibition O
of O
fetal O
movement O
in O
a O
day O
40 O
pregnant O
goat O
model O
by O
optical O
isomers O
of O
the O
piperidine B
alkaloid I
coniine B
. O

Coniine B
is O
an O
optically O
active O
toxic O
piperidine B
alkaloid I
and O
nicotinic O
acetylcholine B
receptor O
( O
nAChR O
) O
agonist O
found O
in O
poison O
hemlock O
( O
Conium O
maculatum O
L O
. O
) O
. O

Coniine B
teratogenicity O
is O
hypothesized O
to O
be O
attributable O
to O
the O
binding O
, O
activation O
, O
and O
prolonged O
desensitization O
of O
fetal O
muscle O
- O
type O
nAChR O
, O
which O
results O
in O
the O
complete O
inhibition O
of O
fetal O
movement O
. O

However O
, O
pharmacological O
evidence O
of O
coniine B
actions O
at O
fetal O
muscle O
- O
type O
nAChR O
is O
lacking O
. O

The O
present O
study O
compared O
( B
- I
) I
- I
coniine I
, O
( B
+ I
) I
- I
coniine I
, O
and O
nicotine B
for O
the O
ability O
to O
inhibit O
fetal O
movement O
in O
a O
day O
40 O
pregnant O
goat O
model O
and O
in O
TE O
- O
671 O
cells O
that O
express O
fetal O
muscle O
- O
type O
nAChR O
. O

Furthermore O
, O
alpha O
- O
conotoxins O
( O
CTx O
) O
EI O
and O
GI O
were O
used O
to O
antagonize O
the O
actions O
of O
( B
+ I
) I
- I
and I
( I
- I
) I
- I
coniine I
in O
TE O
- O
671 O
cells O
. O

( B
- I
) I
- I
Coniine I
was O
more O
effective O
at O
eliciting O
electrical O
changes O
in O
TE O
- O
671 O
cells O
and O
inhibiting O
fetal O
movement O
than O
was O
( B
+ I
) I
- I
coniine I
, O
suggesting O
stereoselectivity O
by O
the O
receptor O
. O

The O
pyridine B
alkaloid O
nicotine B
did O
not O
inhibit O
fetal O
movement O
in O
a O
day O
40 O
pregnant O
goat O
model O
, O
suggesting O
agonist O
specificity O
for O
the O
inhibition O
of O
fetal O
movement O
. O

Low O
concentrations O
of O
both O
CTxs O
potentiated O
the O
TE O
- O
671 O
cell O
response O
and O
higher O
concentrations O
of O
CTx O
EI O
, O
and O
GI O
antagonized O
the O
actions O
of O
both O
coniine B
enantiomers O
demonstrating O
concentration O
- O
dependent O
coagonism O
and O
selective O
antagonism O
. O

These O
results O
provide O
pharmacological O
evidence O
that O
the O
piperidine B
alkaloid I
coniine B
is O
acting O
at O
fetal O
muscle O
- O
type O
nAChR O
in O
a O
concentration O
- O
dependent O
manner O
. O

Review O
and O
discussion O
of O
tubular O
biomarkers O
in O
the O
diagnosis O
and O
management O
of O
diabetic O
nephropathy O
. O

The O
prevalence O
of O
diabetic O
nephropathy O
has O
tremendously O
increased O
with O
the O
relentless O
rise O
in O
the O
incidence O
of O
diabetes O
over O
the O
last O
couple O
decades O
. O

Diabetic O
nephropathy O
is O
a O
leading O
cause O
of O
morbidity O
and O
mortality O
, O
and O
it O
invariably O
leads O
to O
an O
end O
- O
stage O
renal O
disease O
( O
ESRD O
) O
. O

In O
an O
effort O
to O
delay O
the O
onset O
of O
ESRD O
systematic O
screening O
and O
appropriate O
management O
are O
needed O
to O
evaluate O
the O
progression O
of O
renal O
damage O
in O
diabetic O
nephropathy O
. O

The O
reliability O
of O
current O
tests O
in O
predicting O
the O
onset O
, O
progression O
and O
response O
to O
various O
regimens O
for O
diabetic O
nephropathy O
is O
still O
under O
debate O
; O
and O
it O
has O
engendered O
a O
search O
for O
more O
sensitive O
and O
specific O
urinary O
biomarkers O
, O
especially O
those O
reflective O
of O
tubular O
dysfunctions O
. O

It O
is O
well O
- O
known O
that O
there O
is O
a O
good O
correlation O
between O
the O
degree O
of O
damage O
to O
the O
tubulo O
- O
interstitial O
compartment O
and O
the O
deterioration O
of O
renal O
functions O
. O

In O
view O
of O
this O
, O
the O
utility O
of O
urinary O
biomarkers O
, O
reflective O
of O
tubular O
injury O
, O
reported O
in O
the O
literature O
is O
discussed O
in O
this O
brief O
review O
. O

Density O
functional O
conformational O
study O
of O
2 B
- I
O I
- I
sulfated I
3 I
, I
6 I
anhydro I
- I
alpha I
- I
D I
- I
galactose I
and O
of O
neo B
- I
kappa I
- I
and I
iota I
- I
carrabiose I
molecules O
in O
gas O
phase O
and O
water O
. O

We O
examined O
the O
conformational O
preferences O
of O
the O
2 B
- I
O I
- I
sulfated I
- I
3 I
, I
6 I
- I
alpha I
- I
D I
- I
anhydrogalactose I
( O
compound O
I O
) O
and O
two O
1 O
, O
3 O
linked O
disaccharides B
constituting O
- O
kappa O
or O
iota O
- O
carrageenans O
using O
density O
functional O
and O
ab O
initio O
methods O
in O
gas O
phase O
and O
aqueous O
solution O
. O

Systematic O
modifications O
of O
two O
torsion O
angles O
leading O
to O
324 O
and O
144 O
starting O
geometries O
for O
the O
compound O
I O
and O
each O
disaccharide B
were O
used O
to O
generate O
adiabatic O
maps O
using O
B3LYP O
/ O
6 O
- O
31G O
( O
d O
) O
. O

The O
lower O
energy O
conformers O
were O
then O
fully O
optimized O
using O
B3LYP O
, O
B3PW91 O
and O
MP2 O
with O
several O
basis O
sets O
. O

Overall O
, O
we O
discuss O
the O
impact O
of O
full O
relaxation O
on O
the O
energy O
and O
structure O
of O
the O
dominant O
conformations O
, O
present O
the O
performance O
comparison O
with O
previous O
molecular O
mechanics O
calculations O
if O
available O
, O
and O
determine O
whether O
our O
results O
are O
impacted O
, O
when O
polarization O
and O
diffuse O
functions O
are O
added O
to O
the O
6 O
- O
31G O
( O
d O
) O
basis O
set O
, O
or O
when O
the O
MP2 O
level O
of O
theory O
is O
used O
. O

Effects O
of O
silver B
nanoparticles O
on O
the O
liver O
and O
hepatocytes O
in O
vitro O
. O

With O
the O
increasing O
use O
and O
incorporation O
of O
nanoparticles O
( O
NPs O
) O
into O
consumer O
products O
, O
screening O
for O
potential O
toxicity O
is O
necessary O
to O
ensure O
customer O
safety O
. O

NPs O
have O
been O
shown O
to O
translocate O
to O
the O
bloodstream O
following O
inhalation O
and O
ingestion O
, O
and O
such O
studies O
demonstrate O
that O
the O
liver O
is O
an O
important O
organ O
for O
accumulation O
. O

Silver B
( O
Ag B
) O
NPs O
are O
highly O
relevant O
for O
human O
exposure O
due O
to O
their O
use O
in O
food O
contact O
materials O
, O
dietary O
supplements O
, O
and O
antibacterial O
wound O
treatments O
. O

Due O
to O
the O
large O
number O
of O
different O
NPs O
already O
used O
in O
various O
products O
and O
being O
developed O
for O
new O
applications O
, O
it O
is O
essential O
that O
relevant O
, O
quick O
, O
and O
cheap O
methods O
of O
in O
vitro O
risk O
assessment O
suitable O
for O
these O
new O
materials O
are O
established O
. O

Therefore O
, O
this O
study O
used O
a O
simple O
hepatocytes O
model O
combined O
with O
an O
in O
vivo O
injection O
model O
to O
simulate O
the O
passage O
of O
a O
small O
amount O
of O
NPs O
into O
the O
bloodstream O
following O
exposure O
, O
e O
. O
g O
. O
, O
via O
ingestion O
or O
inhalation O
, O
and O
examined O
the O
potential O
of O
Ag B
NPs O
of O
20 O
nm O
diameter O
to O
cause O
toxicity O
, O
inflammation O
, O
and O
oxidative O
stress O
in O
the O
liver O
following O
in O
vivo O
exposures O
of O
female O
Wistar O
rats O
via O
iv O
injection O
to O
50 O
mu O
g O
of O
NPs O
and O
in O
vitro O
exposures O
using O
the O
human O
hepatocyte O
cell O
line O

C3A O
. O

We O
found O
that O
Ag B
NPs O
were O
highly O
cytotoxic O
to O
hepatocytes O
( O
LC O
( O
50 O
) O
lactate B
dehydrogenase O
: O
2 O
. O
5 O
mu O
g O
/ O
cm O
( O
2 O
) O
) O
and O
affected O
hepatocyte O
homeostasis O
by O
reducing O
albumin O
release O
. O

At O
sublethal O
concentrations O
with O
normal O
cell O
or O
tissue O
morphology O
, O
Ag B
NPs O
were O
detected O
in O
cytoplasm O
and O
nuclei O
of O
hepatocytes O
. O

We O
observed O
similar O
effects O
of O
Ag B
NPs O
on O
inflammatory O
mediator O
expression O
in O
vitro O
and O
in O
vivo O
with O
increase O
of O
interleukin O
- O
8 O
( O
IL O
- O
8 O
) O
/ O
macrophage O
inflammatory O
protein O
2 O
, O
IL O
- O
1RI O
, O
and O
tumor O
necrosis O
factor O
- O
alpha O
expression O
in O
both O
models O
and O
increased O
IL O
- O
8 O
protein O
release O
in O
vitro O
. O

This O
article O
presents O
evidence O
of O
the O
potential O
toxicity O
and O
inflammogenic O
potential O
of O
Ag B
NPs O
in O
the O
liver O
following O
ingestion O
. O

In O
addition O
, O
the O
similarities O
between O
in O
vitro O
and O
in O
vivo O
responses O
are O
striking O
and O
encouraging O
for O
future O
reduction O
, O
refinement O
, O
and O
replacement O
of O
animal O
studies O
by O
the O
use O
of O
hepatocyte O
cell O
lines O
in O
particle O
risk O
assessment O
. O

Comment O
on O
real O
- O
time O
observation O
on O
dynamic O
growth O
/ O
dissolution O
of O
conductive O
filaments O
in O
oxide B
- O
electrolyte O
- O
based O
ReRAM O
. O

Filament O
formation O
and O
dissolution O
in O
the O
system O
Ag B
( I
Cu I
) I
/ O
ZrO B
( I
2 I
) I
/ O
Pt B
were O
observed O
by O
Liu O
et O
al O
. O

[ O
Adv O
. O
Mater O
. O
2012 O
, O
24 O
, O
1844 O
] O
. O

Their O
explanation O
of O
the O
phenomena O
is O
shown O
here O
to O
be O
inappropriate O
. O

Various O
situations O
, O
including O
the O
" O
bipolar O
electrode O
" O
shown O
in O
the O
figure O
, O
are O
considered O
and O
the O
difference O
between O
the O
behavior O
in O
electrochemical O
metallization O
memories O
( O
ECMs O
) O
and O
valence O
change O
memories O
( O
VCMs O
) O
outlined O
. O

Of O
crucial O
importance O
for O
distinguishing O
ECM O
from O
VCM O
behavior O
, O
that O
is O
, O
the O
effects O
of O
cation O
and O
anion O
migration O
, O
is O
the O
choice O
of O
the O
solid O
materials O
used O
to O
transport O
metal O
cations O
. O

A O
possible O
explanation O
of O
the O
phenomena O
is O
proposed O
. O

Extracellular O
loop O
II O
modulates O
GTP B
sensitivity O
of O
the O
prostaglandin B
EP3 O
receptor O
. O

Unlike O
the O
majority O
of O
G O
protein O
- O
coupled O
receptors O
, O
the O
prostaglandin B
E I
( I
2 I
) I
( O
PGE B
( I
2 I
) I
) O
E O
- O
prostanoid O
3 O
( O
EP3 O
) O
receptor O
binds O
agonist O
with O
high O
affinity O
that O
is O
insensitive O
to O
the O
presence O
of O
guanosine B
5 I
[ I
prime I
] I
- I
O I
- I
( I
3 I
- I
thio I
) I
triphosphate I
( O
GTP B
gamma I
S I
) O
. O

We O
report O
the O
identification O
of O
mutations O
that O
confer O
GTP O
gamma O
S O
sensitivity O
to O
agonist O
binding O
. O

Seven O
point O
mutations O
were O
introduced O
into O
the O
conserved O
motif O
in O
the O
second O
extracellular O
loop O
( O
ECII O
) O
of O
EP3 O
, O
resulting O
in O
acquisition O
of O
GTP B
- O
sensitive O
agonist O
binding O
. O

One O
receptor O
mutation O
W203A O
was O
studied O
in O
detail O
. O

Loss O
of O
agonist O
binding O
was O
observed O
on O
intact O
human O
embryonic O
kidney O
293 O
cells O
expressing O
the O
W203A O
receptor O
, O
conditions O
where O
high O
GTP B
levels O
are O
present O
; O
however O
, O
high O
affinity O
binding O
[ B
( I
3 I
) I
H I
] I
PGE I
( I
2 I
) I
was O
observed O
in O
broken O
cell O
preparations O
washed O
free O
of O
GTP B
. O

The O
[ B
( I
3 I
) I
H I
] I
PGE I
( I
2 I
) I
binding O
of O
W203A O
in O
broken O
cell O
membrane O
fractions O
was O
inhibited O
by O
addition O
of O
GTP B
gamma I
S I
( O
IC O
( O
50 O
) O
21 O
+ O
/ O
- O
1 O
. O
8 O
nM O
) O
. O

Taken O
together O
, O
these O
results O
suggest O
that O
the O
wild O
- O
type O
EP3 O
receptor O
displays O
unusual O
characteristics O
of O
the O
complex O
coupled O
equilibria O
between O
agonist O
- O
receptor O
and O
receptor O
- O
G O
protein O
interaction O
. O

Moreover O
, O
mutation O
of O
ECII O
can O
alter O
this O
coupled O
equilibrium O
from O
GTP B
- O
insensitive O
agonist O
binding O
to O
more O
conventional O
GTP B
- O
sensitive O
binding O
. O

This O
suggests O
that O
for O
the O
mutant O
receptors O
, O
ECII O
plays O
a O
critical O
role O
in O
linking O
the O
agonist O
bound O
receptor O
conformation O
to O
the O
G O
protein O
nucleotide B
bound O
state O
. O

Mesoscopic O
model O
parametrization O
of O
hydrogen B
bonds O
and O
stacking O
interactions O
of O
RNA O
from O
melting O
temperatures O
. O

Information O
about O
molecular O
interactions O
in O
DNA O
can O
be O
obtained O
from O
experimental O
melting O
temperature O
data O
by O
using O
mesoscopic O
statistical O
physics O
models O
. O

Here O
, O
we O
extend O
the O
technique O
to O
RNA O
and O
show O
that O
the O
new O
parameters O
correctly O
reproduce O
known O
properties O
such O
as O
the O
stronger O
hydrogen B
bonds O
of O
AU B
base O
pairs O
. O

We O
also O
were O
able O
to O
calculate O
a O
complete O
set O
of O
elastic O
constants O
for O
all O
10 O
irreducible O
combinations O
of O
nearest O
neighbours O
( O
NNs O
) O
. O

We O
believe O
that O
this O
is O
particularly O
useful O
as O
experimentally O
derived O
information O
about O
RNA O
elasticity O
is O
relatively O
scarce O
. O

The O
melting O
temperature O
prediction O
using O
the O
present O
model O
improves O
over O
those O
from O
traditional O
NN O
model O
, O
providing O
thus O
an O
alternative O
way O
to O
calculate O
these O
temperatures O
for O
RNA O
. O

Additionally O
, O
we O
calculated O
the O
site O
- O
dependent O
base O
pair O
oscillation O
to O
explain O
why O
RNA O
shows O
larger O
oscillation O
amplitudes O
despite O
having O
stronger O
AU B
hydrogen B
bonds O
. O

Carbaryl B
exposure O
and O
recovery O
modify O
the O
interrenal O
and O
thyroidal O
activities O
and O
the O
mitochondria O
- O
rich O
cell O
function O
in O
the O
climbing O
perch O
Anabas O
testudineus O
Bloch O
. O

We O
examined O
the O
effects O
of O
carbaryl B
( O
1 B
- I
naphthyl I
methylcarbamate I
; O
sevin B
) O
, O
a O
carbamate B
pesticide O
, O
on O
interrenal O
and O
thyroid O
activities O
and O
mitochondrial O
rich O
( O
MR O
) O
cell O
function O
in O
climbing O
perch O
to O
understand O
the O
physiological O
basis O
of O
toxicity O
acclimation O
in O
this O
fish O
to O
the O
chemical O
stressor O
. O

Carbaryl B
exposure O
( O
5 O
- O
20 O
mg O
L O
( O
- O
1 O
) O
) O
for O
48 O
h O
increased O
cortisol B
and O
glucose B
, O
but O
decreased O
the O
T O
( O
3 O
) O
level O
without O
affecting O
T O
( O
4 O
) O
concentration O
in O
the O
plasma O
. O

These O
responses O
of O
the O
carbaryl B
- O
exposed O
fish O
were O
nullified O
and O
a O
rise O
in O
plasma O
T O
( O
4 O
) O
occurred O
in O
these O
fish O
when O
they O
were O
kept O
for O
96 O
h O
recovery O
in O
clean O
water O
. O

A O
tight O
plasma O
mineral O
control O
was O
indicated O
in O
the O
carbaryl B
- O
exposed O
fish O
as O
reflected O
by O
the O
unchanged O
plasma O
Na B
, O
K B
, O
Ca B
and O
inorganic O
phosphate B
levels O
. O

The O
ouabain B
- O
sensitive O
Na B
( I
+ I
) I
, O
K B
( I
+ I
) I
- O
ATPase O
activity O
showed O
an O
increase O
in O
the O
gills O
but O
the O
intestinal O
and O
renal O
tissues O
showed O
little O
response O
to O
carbaryl B
treatment O
. O

However O
, O
substantial O
increases O
in O
the O
intestinal O
and O
renal O
Na B
( I
+ I
) I
, O
K B
( I
+ I
) I
- O
ATPase O
activities O
occurred O
in O
the O
recovery O
fish O
. O

The O
MR O
cells O
in O
the O
branchial O
epithelia O
showed O
a O
strong O
Na B
( I
+ I
) I
, O
K B
( I
+ I
) I
- O
ATPase O
immunoreactivity O
to O
carbaryl B
treatment O
indicating O
an O
activated O
MR O
cell O
function O
. O

The O
numerical O
MR O
cell O
density O
remained O
unchanged O
, O
but O
stretching O
of O
secondary O
gill O
lamellae O
as O
part O
of O
gill O
remodeling O
occurred O
during O
carbaryl B
exposure O
. O

The O
increased O
surface O
of O
these O
lamellae O
with O
abundant O
MR O
cells O
as O
a O
result O
of O
its O
migration O
into O
the O
lamellar O
surface O
points O
to O
marked O
structural O
and O
functional O
modifications O
of O
these O
cells O
in O
the O
carbaryl B
- O
treated O
fish O
which O
is O
likely O
to O
a O
target O
for O
carbaryl B
action O
. O

The O
rise O
in O
plasma O
T O
( O
4 O
) O
and O
the O
restoration O
of O
normal O
branchial O
epithelia O
in O
the O
recovery O
fish O
indicate O
a O
thyroidal O
involvement O
in O
the O
recovery O
response O
and O
survival O
. O

Our O
data O
thus O
provide O
evidence O
that O
carbaryl B
exposure O
and O
its O
recovery O
evoke O
interrenal O
and O
thyroid O
disruption O
in O
this O
fish O
leading O
to O
a O
modified O
osmotic O
response O
including O
an O
altered O
MR O
cell O
function O
. O

Liquid O
crystal O
pump O
. O

We O
report O
a O
dielectrically O
actuated O
liquid O
crystal O
( O
LC O
) O
pump O
. O

A O
small O
volume O
of O
LC O
forms O
a O
pillar O
- O
like O
droplet O
in O
a O
cylindrical O
hole O
which O
partially O
touches O
the O
bottom O
substrate O
with O
embedded O
interdigitated O
electrodes O
. O

By O
applying O
a O
voltage O
, O
the O
LC O
droplet O
can O
be O
largely O
stretched O
along O
the O
electrode O
direction O
by O
the O
generated O
dielectric O
force O
, O
which O
in O
turn O
exerts O
a O
pressure O
to O
displace O
a O
small O
volume O
of O
fluid O
on O
the O
opposite O
side O
of O
the O
chamber O
. O

Once O
the O
voltage O
is O
removed O
, O
the O
LC O
droplet O
returns O
to O
its O
initial O
state O
. O

The O
LC O
droplet O
with O
such O
a O
reciprocating O
movement O
behaves O
like O
a O
pump O
. O

In O
this O
work O
, O
the O
actuation O
mechanism O
of O
the O
LC O
pump O
is O
presented O
and O
the O
performance O
evaluated O
experimentally O
. O

Our O
LC O
pump O
has O
the O
following O
advantages O
: O
simple O
structure O
, O
easy O
fabrication O
, O
compact O
size O
, O
high O
precision O
, O
low O
power O
consumption O
, O
and O
relatively O
fast O
response O
time O
. O

It O
is O
promising O
for O
applications O
in O
lens O
actuators O
, O
biotechnology O
, O
drug O
delivery O
, O
and O
other O
lab O
- O
on O
- O
a O
- O
chip O
devices O
. O

Costs O
of O
living O
in O
metal O
polluted O
areas O
: O
respiration O
rate O
of O
the O
ground O
beetle O
Pterostichus O
oblongopunctatus O
from O
two O
gradients O
of O
metal O
pollution O
. O

To O
address O
the O
question O
about O
costs O
of O
living O
in O
polluted O
areas O
, O
biomarkers O
linked O
to O
metabolism O
were O
measured O
in O
Pterostichus O
oblongopunctatus O
( O
Coleoptera O
: O
Carabidae O
) O
collected O
along O
two O
metal O
- O
pollution O
gradients O
in O
the O
vicinity O
of O
the O
two O
largest O
Polish O
zinc B
smelters O
: O
' O
Boles O
l O
aw O
' O
and O
' O
Miasteczko O
S O
l O
a O
skie O
' O
in O
southern O
Poland O
. O

Both O
gradients O
covered O
a O
broad O
range O
of O
Zn B
and O
Cd B
concentrations O
in O
the O
humus O
layer O
( O
109 O
- O
6151 O
and O
1 O
. O
48 O
- O
71 O
. O
4 O
mg O
kg O
( O
- O
1 O
) O
, O
respectively O
) O
and O
body O
metal O
concentrations O
increased O
with O
increasing O
soil O
metal O
concentrations O
. O

The O
whole O
- O
organism O
respiration O
rate O
was O
measured O
as O
oxygen B
consumption O
with O
Micro O
- O
Oxymax O
respirometer O
, O
and O
cellular O
energy O
consumption O
- O
as O
the O
activity O
of O
electron O
transport O
system O
, O
which O
is O
linked O
to O
cellular O
respiration O
rate O
. O

The O
significant O
increase O
in O
the O
whole O
- O
organism O
respiration O
rate O
with O
the O
body O
metal O
concentration O
was O
found O
when O
taking O
into O
account O
other O
factors O
such O
as O
body O
mass O
, O
gradient O
( O
or O
year O
of O
sampling O
as O
the O
beetles O
were O
collected O
on O
the O
gradients O
in O
different O
years O
) O
and O
the O
interactions O
: O
body O
metal O
concentrations O
x O
collection O
date O
, O
body O
metal O
concentrations O
x O
body O
mass O
, O
and O
body O
mass O
x O
gradient O
/ O
sampling O
year O
. O

However O
, O
no O
relationships O
between O
metal O
concentrations O
in O
soil O
or O
body O
metal O
concentrations O
and O
the O
whole O
- O
organism O
or O
cellular O
respiration O
rate O
could O
be O
detected O
when O
using O
mean O
values O
per O
site O
, O
underlining O
the O
crucial O
importance O
of O
incorporating O
individual O
variability O
in O
such O
analyses O
. O

The O
observed O
increase O
of O
the O
whole O
- O
organism O
respiration O
rate O
with O
increasing O
body O
contamination O
with O
metals O
suggests O
that O
P O
. O
oblongopunctatus O
incurs O
energetic O
expenditures O
resulting O
from O
the O
necessity O
to O
facilitate O
metal O
elimination O
or O
repair O
of O
toxicant O
- O
induced O
damage O
. O

Pharmacologic O
properties O
, O
metabolism O
, O
and O
disposition O
of O
linaclotide B
, O
a O
novel O
therapeutic O
peptide O
approved O
for O
the O
treatment O
of O
irritable O
bowel O
syndrome O
with O
constipation O
and O
chronic O
idiopathic O
constipation O
. O

Linaclotide B
, O
a O
potent O
guanylate O
cyclase O
C O
agonist O
, O
is O
a O
therapeutic O
peptide O
approved O
in O
the O
United O
States O
for O
the O
treatment O
of O
irritable O
bowel O
syndrome O
with O
constipation O
and O
chronic O
idiopathic O
constipation O
. O

We O
present O
for O
the O
first O
time O
the O
metabolism O
, O
degradation O
, O
and O
disposition O
of O
linaclotide B
in O
animals O
and O
humans O
. O

We O
examined O
the O
metabolic O
stability O
of O
linaclotide B
in O
conditions O
that O
mimic O
the O
gastrointestinal O
tract O
and O
characterized O
the O
metabolite O
MM B
- I
419447 I
( O
CCEYCCNPACTGC B
) O
, O
which O
contributes O
to O
the O
pharmacologic O
effects O
of O
linaclotide B
. O

Systemic O
exposure O
to O
these O
active O
peptides O
is O
low O
in O
rats O
and O
humans O
, O
and O
the O
low O
systemic O
and O
portal O
vein O
concentrations O
of O
linaclotide B
and O
MM B
- I
419447 I
observed O
in O
the O
rat O
confirmed O
both O
peptides O
are O
minimally O
absorbed O
after O
oral O
administration O
. O

Linaclotide B
is O
stable O
in O
the O
acidic O
environment O
of O
the O
stomach O
and O
is O
converted O
to O
MM B
- I
419447 I
in O
the O
small O
intestine O
. O

The O
disulfide B
bonds O
of O
both O
peptides O
are O
reduced O
in O
the O
small O
intestine O
, O
where O
they O
are O
subsequently O
proteolyzed O
and O
degraded O
. O

After O
oral O
administration O
of O
linaclotide B
, O
< O
1 O
% O
of O
the O
dose O
was O
excreted O
as O
active O
peptide O
in O
rat O
feces O
and O
a O
mean O
of O
3 O
- O
5 O
% O
in O
human O
feces O
; O
in O
both O
cases O
MM B
- I
419447 I
was O
the O
predominant O
peptide O
recovered O
. O

MM B
- I
419447 I
exhibits O
high O
- O
affinity O
binding O
in O
vitro O
to O
T84 O
cells O
, O
resulting O
in O
a O
significant O
, O
concentration O
- O
dependent O
accumulation O
of O
intracellular O
cyclic B
guanosine I
- I
3 I
' I
, I
5 I
' I
- I
monophosphate I
( O
cGMP B
) O
. O

In O
rat O
models O
of O
gastrointestinal O
function O
, O
orally O
dosed O
MM B
- I
419447 I
significantly O
increased O
fluid O
secretion O
into O
small O
intestinal O
loops O
, O
increased O
intraluminal O
cGMP B
, O
and O
caused O
a O
dose O
- O
dependent O
acceleration O
in O
gastrointestinal O
transit O
. O

These O
results O
demonstrate O
the O
importance O
of O
the O
active O
metabolite O
in O
contributing O
to O
linaclotide B
' O
s O
pharmacology O
. O

Lanthanum B
( I
III I
) I
regulates O
the O
nitrogen B
assimilation O
in O
soybean O
seedlings O
under O
ultraviolet O
- O
B O
radiation O
. O

Ultraviolet O
- O
B O
( O
UV O
- O
B O
, O
280 O
- O
320 O
nm O
) O
radiation O
has O
seriously O
affected O
the O
growth O
of O
plants O
. O

Finding O
the O
technology O
/ O
method O
to O
alleviate O
the O
damage O
of O
UV O
- O
B O
radiation O
has O
become O
a O
frontal O
topic O
in O
the O
field O
of O
environmental O
science O
. O

The O
pretreatment O
with O
rare O
earth O
elements O
( O
REEs O
) O
is O
an O
effective O
method O
, O
but O
the O
regulation O
mechanism O
of O
REEs O
is O
unknown O
. O

Here O
, O
the O
regulation O
effects O
of O
lanthanum B
( O
La B
( I
III I
) I
) O
on O
nitrogen B
assimilation O
in O
soybean O
seedlings O
( O
Glycine O
max O
L O
. O
) O
under O
ultraviolet O
- O
B O
radiation O
were O
investigated O
to O
elucidate O
the O
regulation O
mechanism O
of O
REEs O
on O
plants O
under O
UV O
- O
B O
radiation O
. O

UV O
- O
B O
radiation O
led O
to O
the O
inhibition O
in O
the O
activities O
of O
the O
key O
enzymes O
( O
nitrate B
reductase O
, O
glutamine B
synthetase O
, O
glutamate B
synthase O
) O
in O
the O
nitrogen B
assimilation O
, O
the O
decrease O
in O
the O
contents O
of O
nitrate B
and O
soluble O
proteins O
, O
as O
well O
as O
the O
increase O
in O
the O
content O
of O
amino B
acid I
in O
soybean O
seedlings O
. O

The O
change O
degree O
of O
UV O
- O
B O
radiation O
at O
the O
high O
level O
( O
0 O
. O
45 O
W O
m O
( O
- O
2 O
) O
) O
was O
higher O
than O
that O
of O
UV O
- O
B O
radiation O
at O
the O
low O
level O
( O
0 O
. O
15 O
W O
m O
( O
- O
2 O
) O
) O
. O

The O
pretreatment O
with O
20 O
mg O
L O
( O
- O
1 O
) O
La B
( I
III I
) I
could O
alleviate O
the O
effects O
of O
UV O
- O
B O
radiation O
on O
the O
activities O
of O
nitrate B
reductase O
, O
glutamine B
synthetase O
, O
glutamate B
synthase O
, O
and O
glutamate B
dehydrogenase O
, O
promoting O
amino B
acid I
conversion O
and O
protein O
synthesis O
in O
soybean O
seedlings O
. O

The O
regulation O
effect O
of O
La B
( I
III I
) I
under O
UV O
- O
B O
radiation O
at O
the O
low O
level O
was O
better O
than O
that O
of O
UV O
- O
B O
radiation O
at O
the O
high O
level O
. O

The O
results O
indicated O
that O
the O
pretreatment O
with O
20 O
mg O
L O
( O
- O
1 O
) O
La B
( I
III I
) I
could O
alleviate O
the O
inhibition O
of O
UV O
- O
B O
radiation O
on O
nitrogen B
assimilation O
in O
soybean O
seedlings O
. O

Neutrophil O
and O
eosinophil O
granulocytes O
as O
key O
players O
in O
a O
mouse O
model O
of O
chemical O
- O
induced O
asthma O
. O

Diisocyanates B
are O
an O
important O
cause O
of O
chemical O
- O
induced O
occupational O
asthma O
. O

This O
type O
of O
immunologically O
mediated O
asthma O
is O
often O
characterized O
by O
a O
predominant O
granulocytic O
inflammation O
in O
the O
airways O
, O
rather O
than O
an O
infiltration O
by O
lymphocytes O
. O

We O
sought O
to O
determine O
the O
contribution O
of O
granulocytes O
in O
the O
outcome O
of O
chemical O
- O
induced O
asthma O
using O
general O
and O
specific O
leukocyte O
depletion O
strategies O
in O
an O
established O
mouse O
model O
of O
isocyanate B
asthma O
. O

On O
days O
1 O
and O
8 O
, O
BALB O
/ O
c O
mice O
received O
dermal O
applications O
with O
toluene B
- I
2 I
, I
4 I
- I
diisocyanate I
( O
TDI B
) O
or O
vehicle O
( O
acetone B
olive O
oil O
) O
, O
followed O
by O
two O
ip O
injections O
of O
cyclophosphamide B
( O
CP O
, O
days O
11 O
and O
13 O
) O
, O
or O
one O
iv O
injection O
of O
antigranulocyte O
receptor O
1 O
( O
aGR1 O
, O
day O
13 O
) O
monoclonal O
antibody O
( O
mAb O
) O
, O
or O
two O
ip O
injections O
of O
Ly6G O
- O
specific O
mAb O
( O
1A8 O
, O
days O
13 O
and O
14 O
) O

. O

On O
day O
15 O
, O
the O
mice O
were O
challenged O
( O
oropharyngeal O
administration O
) O
with O
TDI B
or O
vehicle O
. O

The O
next O
day O
, O
we O
assessed O
methacholine B
airway O
hyperreactivity O
( O
AHR O
) O
; O
bronchoalveolar O
lavage O
differential O
cell O
count O
; O
histopathology O
and O
total O
serum O
IgE O
; O
and O
auricular O
lymphocyte O
subpopulations O
and O
release O
of O
interleukin O
( O
IL O
) O
- O
2 O
, O
IL O
- O
4 O
, O
IL O
- O
10 O
, O
IL O
- O
13 O
, O
and O
gamma O
interferon O
by O
these O
lymphocytes O
. O

CP O
depleted O
all O
leukocyte O
types O
and O
completely O
prevented O
AHR O
and O
airway O
inflammation O
. O

aGR1 O
depleted O
granulocytes O
and O
CD8 O
( O
+ O
) O
lymphocytes O
, O
which O
resulted O
in O
a O
partial O
prevention O
in O
AHR O
but O
no O
decrease O
in O
airway O
inflammation O
. O

Depletion O
of O
Ly6G O
- O
positive O
granulocytes O
, O
i O
. O
e O
. O
, O
both O
neutrophils O
and O
eosinophils O
, O
prevented O
AHR O
and O
lung O
epithelial O
damage O
and O
significantly O
reduced O
airway O
inflammation O
. O

Injection O
of O
aGR1 O
or O
1A8 O
led O
to O
significantly O
changed O
cytokine O
release O
patterns O
in O
TDI B
- O
treated O
mice O
. O

Granulocytes O
, O
both O
neutrophils O
and O
eosinophils O
, O
are O
key O
cellular O
players O
in O
this O
model O
of O
chemical O
- O
induced O
asthma O
. O

Thermosensitive O
polymeric O
hydrogels O
as O
drug O
delivery O
systems O
. O

Thermosensitive O
hydrogels O
are O
very O
important O
biomaterials O
used O
in O
drug O
delivery O
systems O
( O
DDSs O
) O
, O
which O
gained O
increasing O
attention O
of O
researchers O
. O

Thermosensitive O
hydrogels O
have O
great O
potential O
in O
various O
applications O
, O
such O
as O
drug O
delivery O
, O
cell O
encapsulation O
, O
tissue O
engineering O
, O
and O
etc O
. O

Especially O
, O
injectable O
thermosensitive O
hydrogels O
with O
lower O
sol O
- O
gel O
transition O
temperature O
around O
physiological O
temperature O
have O
been O
extensively O
studied O
. O

By O
in O
vivo O
injection O
, O
the O
hydrogels O
formed O
non O
- O
flowing O
gel O
at O
body O
temperature O
. O

Upon O
incorporation O
of O
pharmaceutical O
agents O
, O
the O
hydrogel O
systems O
could O
act O
as O
sustained O
drug O
release O
depot O
in O
situ O
. O

Injectable O
thermosensitive O
hydrogel O
systems O
have O
a O
number O
of O
advantages O
, O
including O
simplicity O
of O
drug O
formulation O
, O
protective O
environment O
for O
drugs O
, O
prolonged O
and O
localized O
drug O
delivery O
, O
and O
ease O
of O
application O
. O

The O
objective O
of O
this O
review O
is O
to O
summarize O
fundamentals O
, O
applications O
, O
and O
recent O
advances O
of O
injectable O
thermosensitive O
hydrogel O
as O
DDSs O
, O
including O
chitosan O
and O
related O
derivatives O
, O
poly B
( I
N I
- I
isopropylacrylamide I
) I
- O
based O
( O
PNIPAAM B
) O
copolymers O
, O
poly B
( I
ethylene I
oxide I
) I
/ O
poly B
( I
propylene I
oxide I
) I
( O
PEO B
/ O
PPO B
) O
copolymers O
and O
its O
derivatives O
, O
and O
poly B
( I
ethylene I
glycol I
) I
/ O
biodegradable O
polyester B
copolymers O
. O

New O
insights O
in O
the O
pathogenesis O
and O
treatment O
of O
normal O
tension O
glaucoma O
. O

Increased O
intraocular O
pressure O
( O
IOP O
) O
is O
a O
major O
risk O
factor O
for O
glaucomatous O
damage O
and O
reducing O
IOP O
improves O
prognosis O
. O

Nevertheless O
, O
there O
is O
little O
doubt O
that O
other O
risk O
factors O
besides O
IOP O
such O
as O
unstable O
ocular O
perfusion O
are O
involved O
. O

Blood O
flow O
is O
unstable O
if O
either O
the O
IOP O
fluctuates O
at O
a O
high O
level O
( O
or O
blood O
pressure O
fluctuates O
at O
a O
low O
level O
) O
or O
if O
the O
autoregulation O
of O
blood O
flow O
disturbed O
. O

A O
common O
cause O
for O
a O
disturbed O
OBF O
autoregulation O
is O
a O
primary O
vascular O
dysregulation O
( O
PVD O
) O
frequently O
observed O
in O
normal O
tension O
glaucoma O
patients O
. O

An O
unstable O
blood O
flow O
leads O
to O
recurrent O
mild O
reperfusion O
injury O
( O
chronic O
oxidative O
stress O
) O
affecting O
particularly O
the O
mitochondria O
of O
the O
optic O
nerve O
head O
. O

OBF O
regulation O
can O
be O
improved O
by O
magnesium B
, O
calcium B
channel O
blockers O
as O
well O
as O
with O
carbonic O
anhydrase O
inhibitors O
. O

Upregulation O
of O
phagocyte O
- O
like O
NADPH B
oxidase O
by O
cytokines O
in O
pancreatic O
beta O
- O
cells O
: O
attenuation O
of O
oxidative O
and O
nitrosative O
stress O
by O
2 B
- I
bromopalmitate I
. O

Phagocyte O
- O
like O
NADPH B
oxidase O
( O
Nox2 O
) O
has O
been O
shown O
to O
play O
regulatory O
roles O
in O
the O
metabolic O
dysfunction O
of O
the O
islet O
beta O
- O
cell O
under O
the O
duress O
of O
glucolipotoxic O
conditions O
and O
exposure O
to O
proinflammatory O
cytokines O
. O

However O
, O
the O
precise O
mechanisms O
underlying O
Nox2 O
activation O
by O
these O
stimuli O
remain O
less O
understood O
. O

To O
this O
end O
, O
we O
report O
a O
time O
- O
dependent O
phosphorylation O
of O
p47phox O
, O
a O
cytosolic O
subunit O
of O
Nox2 O
, O
by O
cytomix B
( O
IL O
- O
1 O
beta O
+ O
TNF O
alpha O
+ O
IFN O
gamma O
) O
in O
insulin O
- O
secreting O
INS O
- O
1 O
832 O
/ O
13 O
cells O
. O

Furthermore O
, O
cytomix B
induced O
the O
expression O
of O
gp91phox O
, O
a O
membrane O
component O
of O
Nox2 O
. O

2 B
- I
Bromopalmitate I
( O
2 B
- I
BP I
) O
, O
a O
known O
inhibitor O
of O
protein O
palmitoylation O
, O
markedly O
attenuated O
cytokine O
- O
induced O
, O
Nox2 O
- O
mediated O
reactive O
oxygen B
species O
( O
ROS O
) O
generation O
and O
inducible O
nitric B
oxide I
synthase O
( O
iNOS O
) O
- O
mediated O
nitric B
oxide I
( O
NO B
) O
generation O
. O

However O
, O
2 B
- I
BP I
failed O
to O
exert O
any O
significant O
effects O
on O
cytomix O
- O
induced O
CHOP O
expression O
, O
a O
marker O
for O
endoplasmic O
reticulum O
stress O
. O

Together O
, O
our O
findings O
identify O
palmitoyltransferase O
as O
a O
target O
for O
inhibition O
of O
cytomix B
- O
induced O
oxidative O
( O
ROS O
generation O
) O
and O
nitrosative O
( O
NO B
generation O
) O
stress O
in O
the O
pancreatic O
beta O
- O
cell O
. O

mTOR O
inhibition O
modulates O
epileptogenesis O
, O
seizures O
and O
depressive O
behavior O
in O
a O
genetic O
rat O
model O
of O
absence O
epilepsy O
. O

Several O
signaling O
pathways O
are O
believed O
to O
be O
involved O
in O
the O
epileptogenic O
process O
that O
triggers O
the O
subsequent O
changes O
in O
the O
brain O
causing O
epilepsy O
. O

The O
mammalian O
target O
of O
rapamycin B
( O
mTOR O
) O
is O
a O
serine B
/ O
threonine B
kinase O
that O
in O
the O
brain O
, O
regulates O
several O
important O
physiological O
functions O
such O
as O
neuronal O
development O
and O
synaptic O
plasticity O
, O
and O
also O
seems O
to O
be O
involved O
in O
many O
pathologies O
, O
including O
epilepsy O
and O
psychiatric O
disorders O
. O

Previous O
work O
in O
animal O
models O
of O
both O
genetic O
and O
acquired O
generalized O
convulsive O
epilepsies O
, O
has O
suggested O
that O
modulators O
of O
the O
mTOR O
signaling O
pathway O
may O
have O
beneficial O
neuroprotective O
and O
antiepileptogenic O
effects O
. O

Here O
, O
we O
investigated O
for O
the O
first O
time O
, O
the O
effect O
of O
some O
treatment O
schedules O
( O
i O
. O
e O
. O
early O
chronic O
, O
sub O
- O
chronic O
and O
acute O
) O
with O
the O
specific O
mTOR O
inhibitor O
rapamycin B
, O
on O
the O
development O
of O
absence O
seizures O
and O
seizure O
parameters O
as O
well O
as O
depressive O
- O
like O
behavior O
in O
WAG O
/ O
Rij O
rats O
, O
a O
genetic O
model O
of O
absence O
epilepsy O
, O
epileptogenesis O
and O
mild O
- O
depression O
comorbidity O
. O

In O
addition O
, O
we O
studied O
the O
possible O
interaction O
between O
rapamycin B
treatment O
and O
the O
effects O
of O
bacterial O
lipopolysaccharide O
( O
LPS O
) O
endotoxin O
administration O
, O
which O
is O
known O
to O
aggravate O
absence O
seizures O
through O
generation O
of O
increased O
neuroinflammatory O
responses O
. O

We O
found O
that O
rapamycin B
( O
early O
chronic O
treatment O
for O
17 O
weeks O
, O
starting O
at O
P45 O
) O
exhibited O
clear O
antiepileptogenic O
properties O
also O
in O
this O
animal O
epilepsy O
model O
; O
however O
, O
this O
effect O
was O
accompanied O
by O
unexpected O
prodepressant O
effects O
. O

Both O
acute O
and O
sub O
- O
chronic O
( O
7 O
day O
) O
treatments O
also O
had O
anti O
- O
absence O
properties O
, O
but O
the O
sub O
- O
chronic O
treatment O
produced O
contrasting O
antidepressant O
properties O
in O
the O
WAG O
/ O
Rij O
rats O
that O
were O
not O
seen O
in O
control O
Wistar O
rats O
. O

The O
rapamycin B
/ O
LPS O
co O
- O
administration O
studies O
showed O
that O
rapamycin B
blocked O
or O
prevented O
the O
LPS O
- O
dependent O
increase O
in O
absence O
seizures O
, O
suggesting O
an O
anti O
- O
inflammatory O
- O
like O
protective O
action O
. O

In O
conclusion O
, O
we O
have O
demonstrated O
a O
novel O
antiepileptogenic O
effect O
of O
rapamycin B
in O
a O
well O
- O
established O
animal O
model O
of O
absence O
epilepsy O
, O
and O
we O
suggest O
that O
this O
effect O
may O
be O
mediated O
by O
the O
inhibition O
of O
inflammatory O
processes O
that O
are O
developed O
in O
the O
brain O
of O
these O
specific O
animals O
during O
epileptogenesis O
and O
during O
seizures O
. O

Our O
experiments O
here O
suggest O
new O
insights O
into O
this O
intriguing O
field O
, O
which O
deserves O
to O
be O
further O
explored O
. O

This O
article O
is O
part O
of O
the O
Special O
Issue O
entitled O
' O
New O
Targets O
and O
Approaches O
to O
the O
Treatment O
of O
Epilepsy O
' O
. O

The O
pyridyl B
group O
in O
ligand O
design O
for O
selective O
metal O
ion O
complexation O
and O
sensing O
. O

Factors O
in O
polypyridyl B
ligands O
that O
control O
their O
thermodynamic O
metal O
ion O
selectivity O
in O
aqueous O
solution O
, O
and O
their O
use O
in O
selective O
fluorescent O
sensing O
, O
are O
examined O
. O

Preorganization O
of O
polypyridyl B
ligands O
ranging O
from O
bidentate O
to O
tetradentate O
by O
bridging O
benzo B
groups O
, O
as O
are O
present O
in O
1 B
, I
10 I
- I
phenanthroline I
( O
phen B
) O
compared O
to O
2 B
, I
2 I
' I
- I
bipyridyl I
( O
bpy B
) O
, O
is O
discussed O
. O

The O
role O
of O
solvation O
is O
considered O
in O
relation O
to O
the O
relative O
affinity O
of O
ligands O
containing O
pyridyl B
groups O
for O
divalent O
and O
trivalent O
metal O
ions O
in O
aqueous O
solution O
. O

The O
effects O
of O
steric O
clashes O
between O
H B
atoms O
on O
polypyridyl B
ligands O
in O
decreasing O
complex O
stability O
are O
evaluated O
, O
as O
well O
as O
the O
effect O
of O
chelate O
ring O
size O
on O
metal O
ion O
selectivity O
. O

Phen B
ligands O
with O
other O
donor O
groups O
present O
at O
the O
2 O
and O
9 O
positions O
, O
such O
as O
alcohols B
, O
amides B
, O
carboxylates B
, O
and O
oximes B
are O
discussed O
. O

The O
design O
of O
pyridyl B
- O
based O
ligands O
for O
the O
separation O
of O
Am B
( I
III I
) I
from O
lanthanide B
( I
III I
) I
ions O
is O
considered O
, O
as O
well O
as O
ligands O
for O
the O
removal O
of O
metal O
ions O
such O
as O
Cu B
( I
II I
) I
or O
Zn B
( I
II I
) I
in O
neurological O
diseases O
such O
as O
Alzheimer O
' O
s O
. O

The O
design O
of O
pyridyl B
- O
based O
fluorescent O
sensors O
for O
selective O
sensing O
of O
metal O
ions O
is O
examined O
in O
terms O
of O
the O
role O
of O
spin O
- O
orbit O
coupling O
constants O
( O
zeta O
) O
, O
paramagnetism O
, O
and O
steric O
effects O
in O
the O
development O
of O
selective O
fluorescent O
sensors O
that O
operate O
via O
chelation O
enhanced O
fluorescence O
( O
CHEF O
) O
. O

It O
is O
concluded O
that O
for O
lighter O
metal O
ions O
with O
smaller O
zeta O
values O
such O
as O
Zn B
( I
II I
) I
and O
Ca B
( I
II I
) I
, O
and O
to O
a O
lesser O
extent O
Cd B
( I
II I
) I
, O
that O
the O
CHEF O
effect O
can O
be O
achieved O
with O
pyridyl B
- O
containing O
fluorophores O
that O
coordinate O
directly O
to O
the O
metal O
ion O
. O

The O
way O
in O
which O
steric O
effects O
can O
be O
used O
to O
decrease O
the O
CHEF O
effect O
in O
Zn B
( I
II I
) I
relative O
to O
Cd B
( I
II I
) I
to O
enable O
selective O
sensing O
of O
the O
latter O
is O
analyzed O
. O

For O
heavier O
metal O
ions O
such O
as O
Hg B
( I
II I
) I
and O
Pb B
( I
II I
) I
, O
because O
of O
their O
large O
zeta O
values O
which O
quench O
fluorescence O
, O
it O
is O
concluded O
that O
the O
fluorophore O
should O
be O
tethered O
to O
the O
metal O
- O
binding O
part O
of O
the O
sensor O
, O
and O
prevented O
from O
binding O
to O
the O
metal O
ion O
by O
steric O
and O
electronic O
factors O
. O

How O
Hg B
( I
II I
) I
can O
quench O
the O
CHEF O
effect O
by O
pi O
- O
contact O
with O
fluorophores O
such O
as O
the O
anthracenyl B
group O
, O
which O
at O
first O
sight O
might O
not O
seem O
able O
to O
bond O
with O
metal O
ions O
, O
is O
examined O
. O

Positive O
selection O
within O
a O
diatom O
species O
acts O
on O
putative O
protein O
interactions O
and O
transcriptional O
regulation O
. O

Diatoms O
are O
the O
most O
species O
- O
rich O
group O
of O
microalgae O
, O
and O
their O
contribution O
to O
marine O
primary O
production O
is O
important O
on O
a O
global O
scale O
. O

Diatoms O
can O
form O
dense O
blooms O
through O
rapid O
asexual O
reproduction O
; O
mutations O
acquired O
and O
propagated O
during O
blooms O
likely O
provide O
the O
genetic O
, O
and O
thus O
phenotypic O
, O
variability O
upon O
which O
natural O
selection O
may O
act O
. O

Positive O
selection O
was O
tested O
using O
genome O
and O
transcriptome O
- O
wide O
pair O
- O
wise O
comparisons O
of O
homologs O
in O
three O
genera O
of O
diatoms O
( O
Pseudo O
- O
nitzschia O
, O
Ditylum O
, O
and O
Thalassiosira O
) O
that O
represent O
decreasing O
phylogenetic O
distances O
. O

The O
signal O
of O
positive O
selection O
was O
greatest O
between O
two O
strains O
of O
Thalassiosira O
pseudonana O
. O

Further O
testing O
among O
seven O
strains O
of O
T O
. O
pseudonana O
yielded O
809 O
candidate O
genes O
of O
positive O
selection O
, O
which O
are O
7 O
% O
of O
the O
protein O
- O
coding O
genes O
. O

Orphan O
genes O
and O
genes O
encoding O
protein O
- O
binding O
domains O
and O
transcriptional O
regulators O
were O
enriched O
within O
the O
set O
of O
positively O
selected O
genes O
relative O
to O
the O
genome O
as O
a O
whole O
. O

Positively O
selected O
genes O
were O
linked O
to O
the O
potential O
selective O
pressures O
of O
nutrient O
limitation O
and O
sea O
surface O
temperature O
based O
on O
analysis O
of O
gene O
expression O
profiles O
and O
identification O
of O
positively O
selected O
genes O
in O
subsets O
of O
strains O
from O
locations O
with O
similar O
environmental O
conditions O
. O

The O
identification O
of O
positively O
selected O
genes O
presents O
an O
opportunity O
to O
test O
new O
hypotheses O
in O
natural O
populations O
and O
the O
laboratory O
that O
integrate O
selected O
genotypes O
in O
T O
. O
pseudonana O
with O
their O
associated O
phenotypes O
and O
selective O
forces O
. O

Negative O
regulation O
of O
inflammation O
by O
SIRT1 O
. O

Sirtuin O
1 O
( O
SIRT1 O
) O
, O
the O
mammalian O
Sir2 O
homologue O
, O
is O
a O
class O
III O
histone O
deacetylase O
shown O
to O
act O
on O
a O
wide O
range O
of O
histones O
and O
non O
- O
histone O
substrates O
. O

Numerous O
studies O
have O
demonstrated O
that O
SIRT1 O
regulates O
critical O
metabolic O
and O
physiological O
processes O
including O
senescence O
, O
stress O
resistance O
, O
metabolism O
and O
apoptosis O
. O

Recently O
, O
SIRT1 O
was O
also O
found O
to O
play O
an O
important O
role O
in O
modulating O
the O
development O
and O
progression O
of O
inflammation O
through O
deacetylating O
histones O
and O
critical O
transcription O
factor O
such O
as O
nuclear O
factor O
kappa O
B O
( O
NF O
- O
kappa O
B O
) O
and O
activator O
protein O
1 O
( O
AP O
- O
1 O
) O
, O
thus O
leading O
to O
transcriptional O
repression O
of O
various O
inflammation O
- O
related O
genes O
. O

There O
is O
increasing O
evidence O
that O
reduction O
of O
SIRT1 O
levels O
is O
closely O
correlated O
with O
many O
inflammatory O
diseases O
while O
pharmacologic O
activation O
of O
SIRT1 O
would O
be O
a O
promising O
therapeutic O
strategy O
for O
inflammation O
- O
related O
diseases O
. O

Four O
disruptive O
strategies O
for O
removing O
drug O
discovery O
bottlenecks O
. O

Drug O
discovery O
is O
shifting O
focus O
from O
industry O
to O
outside O
partners O
and O
, O
in O
the O
process O
, O
creating O
new O
bottlenecks O
. O

Technologies O
like O
high O
throughput O
screening O
( O
HTS O
) O
have O
moved O
to O
a O
larger O
number O
of O
academic O
and O
institutional O
laboratories O
in O
the O
USA O
, O
with O
little O
coordination O
or O
consideration O
of O
the O
outputs O
and O
creating O
a O
translational O
gap O
. O

Although O
there O
have O
been O
collaborative O
public O
- O
private O
partnerships O
in O
Europe O
to O
share O
pharmaceutical O
data O
, O
the O
USA O
has O
seemingly O
lagged O
behind O
and O
this O
may O
hold O
it O
back O
. O

Sharing O
precompetitive O
data O
and O
models O
may O
accelerate O
discovery O
across O
the O
board O
, O
while O
finding O
the O
best O
collaborators O
, O
mining O
social O
media O
and O
mobile O
approaches O
to O
open O
drug O
discovery O
should O
be O
evaluated O
in O
our O
efforts O
to O
remove O
drug O
discovery O
bottlenecks O
. O

We O
describe O
four O
strategies O
to O
rectify O
the O
current O
unsustainable O
situation O
. O

Converging O
levels O
of O
analysis O
on O
a O
genomic O
hotspot O
for O
psychosis O
: O
insights O
from O
22q11 O
. O
2 O
deletion O
syndrome O
. O

Schizophrenia O
is O
a O
devastating O
neurodevelopmental O
disorder O
that O
, O
despite O
extensive O
research O
, O
still O
poses O
a O
considerable O
challenge O
to O
attempts O
to O
unravel O
its O
heterogeneity O
, O
and O
the O
complex O
biochemical O
mechanisms O
by O
which O
it O
arises O
. O

While O
the O
majority O
of O
cases O
are O
of O
unknown O
etiology O
, O
accumulating O
evidence O
suggests O
that O
rare O
genetic O
mutations O
, O
such O
as O
22q11 O
. O
2 O
Deletion O
Syndrome O
( O
22qDS O
) O
, O
can O
play O
a O
significant O
role O
in O
predisposition O
to O
the O
illness O
. O

Up O
to O
25 O
% O
of O
individuals O
with O
22qDS O
eventually O
develop O
schizophrenia O
; O
conversely O
, O
this O
deletion O
is O
estimated O
to O
account O
for O
1 O
- O
2 O
% O
of O
schizophrenia O
cases O
overall O
. O

This O
locus O
of O
Chromosome O
22q11 O
. O
2 O
contains O
genes O
that O
encode O
for O
proteins O
and O
enzymes O
involved O
in O
regulating O
neurotransmission O
, O
neuronal O
development O
, O
myelination O
, O
microRNA O
processing O
, O
and O
post O
- O
translational O
protein O
modifications O
. O

As O
a O
consequence O
of O
the O
deletion O
, O
affected O
individuals O
exhibit O
cognitive O
dysfunction O
, O
structural O
and O
functional O
brain O
abnormalities O
, O
and O
neurodevelopmental O
anomalies O
that O
parallel O
many O
of O
the O
phenotypic O
characteristics O
of O
schizophrenia O
. O

As O
an O
illustration O
of O
the O
value O
of O
rare O
, O
highly O
penetrant O
genetic O
subtypes O
for O
elucidating O
pathological O
mechanisms O
of O
complex O
neuropsychiatric O
disorders O
, O
we O
provide O
here O
an O
overview O
of O
the O
cellular O
, O
network O
, O
and O
systems O
- O
level O
anomalies O
found O
in O
22qDS O
, O
and O
review O
the O
intriguing O
evidence O
for O
this O
disorder O
' O
s O
association O
with O
schizophrenia O
. O

This O
article O
is O
part O
of O
the O
Special O
Issue O
entitled O
' O
Neurodevelopmental O
Disorders O
' O
. O

Pharmacokinetic O
study O
of O
Growth O
Hormone O
- O
Releasing O
Peptide O
6 O
( O
GHRP O
- O
6 O
) O
in O
nine O
male O
healthy O
volunteers O
. O

GHRP O
- O
6 O
is O
a O
growth O
hormone O
secretagogue O
that O
also O
enhances O
tissue O
viability O
in O
different O
organs O
. O

In O
the O
present O
work O
, O
we O
studied O
the O
pharmacokinetics O
of O
this O
short O
therapeutic O
hexapeptide B
( O
His B
- I
( I
D I
- I
Trp I
) I
- I
Ala I
- I
Trp I
- I
( I
D I
- I
Phe I
) I
- I
Lys I
- I
NH I
( I
2 I
, I
) I
MW O
= O
872 O
. O
44 O
Da O
) O
in O
nine O
male O
healthy O
volunteers O
after O
a O
single O
intravenous O
bolus O
administration O
of O
100 O
, O
200 O
and O
400 O
mu O
g O
/ O
kg O
of O
body O
weight O
. O

GHRP O
- I
6 O
was O
quantified O
in O
human O
plasma O
by O
a O
specific O
LC O
- O
MS O
method O
, O
previously O
developed O
and O
validated O
following O
FDA O
guidelines O
, O
using O
( B
13 I
) I
C I
( I
3 I
) I
Ala I
- I
GHRP I
- I
6 I
as O
internal O
standard O
( O
Gil O
et O
al O
. O
, O
2012 O
, O
J O
. O
Pharm O
. O
Biomed O
. O
Anal O
. O
60 O
, O
19 O
- O
25 O
) O
. O

The O
Lower O
Limit O
of O
Quantification O
( O
5 O
ng O
/ O
mL O
) O
was O
reached O
in O
all O
subjects O
at O
12h O
post O
- O
administration O
, O
which O
was O
sufficient O
for O
modeling O
a O
pharmacokinetic O
profile O
including O
over O
85 O
% O
of O
the O
Area O
under O
the O
Curve O
( O
AUC O
) O
. O

Disposition O
of O
GHRP O
- O
6 O
best O
fitted O
a O
bi O
- O
exponential O
function O
with O
R O
( O
2 O
) O
higher O
than O
0 O
. O
99 O
, O
according O
to O
a O
mathematic O
modeling O
and O
confirmed O
by O
an O
Akaike O
index O
( O
AIC O
) O
lower O
than O
that O
of O
the O
corresponding O
one O
- O
compartment O
model O
for O
all O
subjects O
. O

Averaging O
all O
three O
dose O
levels O
, O
the O
distribution O
and O
elimination O
half O
- O
life O
of O
GHRP O
- O
6 O
were O
7 O
. O
6 O
+ O
/ O
- O
1 O
. O
9 O
min O
and O
2 O
. O
5 O
+ O
/ O
- O
1 O
. O
1h O
, O
respectively O
. O

These O
values O
are O
coherent O
with O
existing O
data O
for O
other O
drugs O
whose O
disposition O
also O
fits O
this O
model O
. O

Dose O
dependence O
analysis O
revealed O
a O
noticeable O
trend O
for O
AUC O
to O
increase O
proportionally O
with O
administered O
dose O
. O

Atypical O
GHRP B
- I
6 I
concentration O
spikes O
were O
observed O
during O
the O
elimination O
phase O
in O
four O
out O
of O
the O
nine O
subjects O
studied O
. O

Apoptosis O
initiation O
of O
beta B
- I
ionone I
in O
SGC O
- O
7901 O
gastric O
carcinoma O
cancer O
cells O
via O
a O
PI3K O
- O
AKT O
pathway O
. O

beta B
- I
ionone I
has O
been O
shown O
to O
hold O
potent O
anti O
- O
proliferative O
and O
apoptosis O
induction O
properties O
in O
vitro O
and O
in O
vivo O
. O

To O
investigate O
the O
effects O
of O
beta B
- I
ionone I
on O
apoptosis O
initiation O
and O
its O
possible O
mechanisms O
of O
action O
, O
we O
qualified O
cell O
apoptosis O
, O
proteins O
related O
to O
apoptosis O
and O
a O
phosphatidylinositol B
3 O
- O
kinase O
( O
PI3K O
) O
- O
AKT O
pathway O
in O
human O
gastric O
adenocarcinoma O
cancer O
SGC O
- O
7901 O
cells O
. O

The O
results O
demonstrated O
that O
beta B
- I
ionone I
- O
induced O
apoptosis O
in O
a O
dose O
- O
dependent O
manner O
in O
SGC O
- O
7901 O
cells O
treated O
with O
beta B
- I
ionone I
( O
25 O
, O
50 O
, O
100 O
and O
200 O
mu O
mol O
/ O
L O
) O
for O
24 O
h O
. O

beta B
- I
ionone I
was O
also O
shown O
to O
induce O
the O
expression O
of O
cleaved O
- O
caspase O
- O
3 O
and O
inhibit O
bcl O
- O
2 O
expression O
in O
SGC O
- O
7901 O
cells O
in O
a O
dose O
- O
dependent O
manner O
. O

The O
significantly O
decreased O
levels O
of O
p O
- O
PI3K O
and O
p O
- O
AKT O
expression O
were O
observed O
in O
SGC O
- O
7901 O
cells O
after O
beta B
- I
ionone I
treatments O
in O
a O
time O
- O
and O
dose O
- O
dependent O
manner O
( O
P O
< O
0 O
. O
01 O
) O
. O

Thus O
, O
the O
apoptosis O
induction O
in O
SGC O
- O
7901 O
cells O
by O
beta B
- I
ionone I
may O
be O
regulated O
through O
a O
PI3K O
- O
AKT O
pathway O
. O

These O
results O
demonstrate O
a O
potential O
mechanism O
by O
which O
beta B
- I
ionone I
to O
induce O
apoptosis O
initiation O
in O
SGC O
- O
7901 O
cells O
. O

Enhanced O
carcinogenicity O
by O
coexposure O
to O
arsenic B
and O
iron B
and O
a O
novel O
remediation O
system O
for O
the O
elements O
in O
well O
drinking O
water O
. O

Various O
carcinomas O
including O
skin O
cancer O
are O
explosively O
increasing O
in O
arsenicosis O
patients O
who O
drink O
arsenic B
- O
polluted O
well O
water O
, O
especially O
in O
Bangladesh O
. O

Although O
well O
drinking O
water O
in O
the O
cancer O
- O
prone O
areas O
contains O
various O
elements O
, O
very O
little O
is O
known O
about O
the O
effects O
of O
elements O
except O
arsenic B
on O
carcinogenicity O
. O

In O
order O
to O
clarify O
the O
carcinogenic O
effects O
of O
coexposure O
to O
arsenic B
and O
iron B
, O
anchorage O
- O
independent O
growth O
and O
invasion O
in O
human O
untransformed O
HaCaT O
and O
transformed O
A431 O
keratinocytes O
were O
examined O
. O

Since O
the O
mean O
ratio O
of O
arsenic B
and O
iron B
in O
well O
water O
was O
1 O
: O
10 O
in O
cancer O
- O
prone O
areas O
of O
Bangladesh O
, O
effects O
of O
1 O
mu O
M O
arsenic B
and O
10 O
mu O
M O
iron B
were O
investigated O
. O

Iron B
synergistically O
promoted O
arsenic B
- O
mediated O
anchorage O
- O
independent O
growth O
in O
untransformed O
and O
transformed O
keratinocytes O
. O

Iron B
additionally O
increased O
invasion O
in O
both O
types O
of O
keratinocytes O
. O

Activities O
of O
c O
- O
SRC O
and O
ERK O
that O
regulate O
anchorage O
- O
independent O
growth O
and O
invasion O
were O
synergistically O
enhanced O
in O
both O
types O
of O
keratinocytes O
. O

Our O
results O
suggest O
that O
iron B
promotes O
arsenic B
- O
mediated O
transformation O
of O
untransformed O
keratinocytes O
and O
progression O
of O
transformed O
keratinocytes O
. O

We O
then O
developed O
a O
low O
- O
cost O
and O
high O
- O
performance O
adsorbent O
composed O
of O
a O
hydrotalcite O
- O
like O
compound O
for O
arsenic B
and O
iron B
. O

The O
adsorbent O
rapidly O
reduced O
concentrations O
of O
both O
elements O
from O
well O
drinking O
water O
in O
cancer O
- O
prone O
areas O
of O
Bangladesh O
to O
levels O
less O
than O
those O
in O
WHO O
health O
- O
based O
guidelines O
for O
drinking O
water O
. O

Thus O
, O
we O
not O
only O
demonstrated O
for O
the O
first O
time O
increased O
carcinogenicity O
by O
coexposure O
to O
arsenic B
and O
iron B
but O
also O
proposed O
a O
novel O
remediation O
system O
for O
well O
drinking O
water O
. O

The O
effect O
of O
oxygen B
heteroatoms O
on O
the O
single O
molecule O
conductance O
of O
saturated O
chains O
. O

Single O
molecule O
conductance O
measurements O
on O
alkanedithiols B
and O
alkoxydithiols B
( O
dithiolated B
oligoethers I
) O
were O
performed O
using O
the O
STM O
- O
controlled O
break O
junction O
method O
in O
order O
to O
ascertain O
how O
the O
oxygen B
heteroatoms O
in O
saturated O
linear O
chains O
impact O
the O
molecular O
conductance O
. O

The O
experimental O
results O
show O
that O
the O
difference O
in O
conductance O
increases O
with O
chain O
length O
, O
over O
the O
range O
studied O
. O

Comparisons O
with O
electronic O
structure O
calculations O
and O
previous O
work O
on O
alkanes B
indicate O
that O
the O
conductance O
of O
the O
oligoethers B
is O
lower O
than O
that O
of O
alkane B
chains O
with O
the O
same O
length O
. O

Electronic O
structure O
calculations O
allow O
the O
difference O
in O
the O
conductance O
of O
these O
two O
families O
of O
molecules O
to O
be O
traced O
to O
differences O
in O
the O
spatial O
distribution O
of O
the O
molecular O
orbitals O
that O
contribute O
most O
to O
the O
conductance O
. O

A O
pathway O
analysis O
of O
the O
electronic O
coupling O
through O
the O
chain O
is O
used O
to O
explain O
how O
the O
difference O
in O
conductance O
between O
the O
alkane O
and O
oligoether O
molecules O
depends O
on O
the O
chain O
length O
. O

Efficacy O
of O
asiatic B
acid I
, O
a O
pentacyclic B
triterpene I
on O
attenuating O
the O
key O
enzymes O
activities O
of O
carbohydrate B
metabolism O
in O
streptozotocin B
- O
induced O
diabetic O
rats O
. O

Asiatic B
acid I
( O
AA O
) O
, O
a O
triterpenoid B
derivative O
of O
Centella O
asiatica O
, O
has O
shown O
significant O
biological O
effects O
of O
antioxidant O
and O
anti O
- O
inflammatory O
activities O
. O

Aim O
of O
this O
investigation O
was O
to O
evaluate O
the O
antihyperglycemic O
effect O
of O
AA O
on O
the O
activities O
of O
hepatic O
enzymes O
of O
carbohydrate B
metabolism O
in O
streptozotocin B
( O
STZ B
) O
- O
induced O
diabetic O
rats O
. O

To O
induce O
diabetes O
mellitus O
, O
rats O
were O
injected O
with O
streptozotocin B
intraperitoneally O
at O
a O
single O
dose O
of O
40 O
mg O
/ O
kg O
b O
. O
w O
. O

Diabetic O
rats O
showed O
significant O
( O
p O
< O
0 O
. O
05 O
) O
increased O
in O
plasma O
glucose B
, O
glycosylated O
hemoglobin O
and O
significant O
( O
p O
< O
0 O
. O
05 O
) O
decreased O
in O
circulating O
insulin O
and O
hemoglobin O
. O

The O
altered O
activities O
of O
key O
enzymes O
such O
as O
glucose B
- O
6 O
- O
phosphatase O
and O
fructose B
- O
1 O
, O
6 O
- O
bisphosphatase O
of O
carbohydrate B
metabolism O
significantly O
( O
p O
< O
0 O
. O
05 O
) O
increased O
whereas O
hexokinase O
, O
pyruvate B
kinase O
, O
glucose B
- I
6 I
- I
phosphate I
dehydrogenase O
and O
glycogen O
content O
significantly O
( O
p O
< O
0 O
. O
05 O
) O
decreased O
in O
the O
liver O
of O
diabetic O
rats O
and O
also O
increased O
activities O
of O
aspartate B
transaminase O
( O
AST O
) O
, O
alanine B
transaminase O
( O
ALT O
) O
and O
alkaline O

phosphatase O
( O
ALP O
) O
. O

Oral O
administration O
of O
AA O
( O
5 O
, O
10 O
and O
20 O
mg O
/ O
kg O
b O
. O
w O
. O
) O
and O
glibenclamide B
( O
600 O
mu O
g O
/ O
kg O
b O
. O
w O
. O
) O
to O
diabetic O
rats O
for O
45 O
days O
prevented O
the O
above O
alteration O
and O
reverted O
to O
near O
normalcy O
. O

Protection O
of O
body O
weight O
loss O
of O
diabetic O
rats O
by O
AA O
was O
also O
observed O
. O

No O
significant O
effect O
was O
observed O
in O
normal O
rats O
treated O
with O
AA O
( O
20 O
mg O
/ O
kg O
b O
. O
w O
. O
) O
. O

In O
this O
search O
, O
AA O
found O
to O
be O
potential O
bioactive O
compound O
to O
regulate O
the O
carbohydrate B
metabolism O
by O
modulating O
the O
key O
regulatory O
enzymes O
in O
diabetic O
rats O
. O

These O
findings O
merit O
further O
research O
in O
this O
field O
. O

Mancozeb B
- O
induced O
behavioral O
deficits O
precede O
structural O
neural O
degeneration O
. O

Manganese B
- O
containing O
fungicides O
like O
Mancozeb B
have O
been O
associated O
with O
neurodegenerative O
conditions O
like O
Parkinson O
' O
s O
disease O
. O

We O
examined O
the O
behavioral O
damage O
and O
differential O
neuronal O
vulnerability O
resulting O
from O
Mancozeb B
exposure O
using O
Caenorhabditis O
elegans O
, O
an O
important O
mid O
- O
trophic O
level O
soil O
organism O
that O
is O
also O
a O
powerful O
model O
for O
studying O
mechanisms O
of O
environmental O
pollutant O
- O
induced O
neurodegenerative O
disease O
. O

The O
dopamine B
- O
mediated O
swim O
to O
crawl O
locomotory O
transition O
behavior O
is O
exquisitely O
vulnerable O
to O
Mancozeb B
, O
with O
functional O
impairment O
preceding O
markers O
of O
neuronal O
structural O
damage O
. O

The O
damage O
is O
partially O
rescued O
in O
mutants O
lacking O
the O
divalent O
metal O
transporter O
, O
SMF O
- O
1 O
, O
demonstrating O
that O
some O
, O
but O
not O
all O
, O
of O
the O
damage O
is O
mediated O
by O
manganese B
. O

Increasing O
concentrations O
of O
Mancozeb B
recruit O
additional O
behavioral O
dysfunction O
, O
notably O
serotonin B
- O
mediated O
egg O
- O
laying O
behavior O
, O
but O
without O
evident O
serotonergic O
neuronal O
structural O
damage O
. O

Thus O
, O
measurements O
of O
behavioral O
dysfunction O
are O
a O
sensitive O
early O
marker O
of O
fungicide O
toxicity O
that O
could O
be O
exploited O
to O
examine O
further O
mechanisms O
of O
neuron O
damage O
and O
possible O
therapeutic O
interventions O
. O

These O
results O
also O
provide O
important O
insight O
into O
the O
consequences O
of O
fungicide O
use O
on O
the O
ecological O
behavior O
of O
nematodes O
. O

In O
vitro O
metabolism O
, O
permeation O
, O
and O
brain O
availability O
of O
six O
major O
boswellic B
acids I
from O
Boswellia O
serrata O
gum O
resins O
. O

Boswellia O
serrata O
gum O
resin O
extracts O
( O
BSE O
) O
revealed O
potent O
anti O
- O
inflammatory O
actions O
in O
preclinical O
and O
clinical O
studies O
. O

In O
2002 O
BSE O
was O
assigned O
an O
orphan O
drug O
status O
by O
the O
European O
Medicines O
Agency O
( O
EMA O
) O
for O
the O
treatment O
of O
peritumoral O
edema O
. O

In O
the O
past O
pharmacological O
effects O
of O
BSE O
were O
mainly O
attributed O
to O
11 B
- I
keto I
- I
beta I
- I
boswellic I
acid I
( O
KBA B
) O
and O
3 B
- I
acetyl I
- I
11 I
- I
keto I
- I
beta I
- I
boswellic I
acid I
( O
AKBA B
) O
. O

Therefore O
pharmacokinetic O
and O
pharmacodynamic O
studies O
focused O
mainly O
on O
these O
two O
boswellic B
acids I
( O
BAs B
) O
. O

However O
, O
other O
BAs O
, O
like O
beta B
- I
boswellic I
acid I
( O
beta B
BA I
) O
, O
might O
also O
contribute O
to O
the O
anti O
- O
inflammatory O
actions O
of O
BSE O
. O

Here O
, O
we O
determined O
the O
metabolic O
stability O
, O
permeability O
and O
brain O
availability O
of O
six O
major O
BAs B
, O
that O
is O
, O
KBA O
, O
AKBA O
, O
beta O
BA O
, O
3 B
- I
acetyl I
- I
beta I
- I
boswellic I
acid I
( O
A O
beta O
BA O
) O
, O
alpha B
- I
boswellic I
acid I
( O
alpha B
BA O
) O
, O
and O
3 B
- I
acetyl I
- I
alpha I
- I
boswellic I
acid I
( O
A O
alpha O
BA O
) O
. O

For O
permeability O
studies O
, O
the O
Caco O
- O
2 O
model O
was O
adapted O
to O
physiological O
conditions O
by O
the O
addition O
of O
bovine O
serum O
albumin O
( O
BSA O
) O
to O
the O
basolateral O
side O
and O
the O
use O
of O
modified O
fasted O
state O
simulated O
intestinal O
fluid O
( O
FaSSIF O
) O
on O
the O
apical O
side O
. O

Under O
these O
conditions O
the O
four O
BAs B
lacking O
the O
11 B
- I
keto I
moiety O
revealed O
moderate O
permeability O
. O

Furthermore O
the O
permeability O
of O
AKBA O
and O
KBA O
was O
improved O
compared O
to O
earlier O
studies O
. O

In O
contrast O
to O
A O
alpha O
- O
and O
A O
beta O
BA O
, O
beta O
BA O
and O
alpha O
BA O
were O
intensively O
metabolized O
after O
incubation O
with O
human O
and O
rat O
liver O
microsomes O
. O

Finally O
, O
the O
availability O
of O
all O
six O
major O
BAs O
could O
be O
confirmed O
in O
rat O
brain O
8h O
after O
oral O
administration O
of O
240mg O
/ O
kg O
BSE O
to O
rats O
showing O
mean O
concentrations O
of O
11 O
. O
6ng O
/ O
g O
for O
KBA O
, O
37 O
. O
5ng O
/ O
g O
for O
AKBA O
, O
485 O
. O
1ng O
/ O
g O
for O
alpha O
BA O
, O
1066 O
. O
6ng O
/ O
g O
for O
beta O
BA O
, O
43 O
. O
0ng O
/ O
g O
for O
A O
alpha O
BA O
and O
163 O
. O
7ng O
/ O
g O
for O
A O
beta O
BA O
. O

Possible O
ways O
of O
fagopyrin B
biosynthesis O
and O
production O
in O
buckwheat O
plants O
. O

The O
present O
work O
extends O
knowledge O
about O
possible O
biosynthesis O
of O
fagopyrin B
in O
buckwheat O
plants O
by O
providing O
possible O
candidate O
genes O
for O
its O
biosynthesis O
and O
the O
role O
of O
type O
III O
polyketide O
synthases O
( O
PKSs O
) O
. O

Moreover O
, O
new O
information O
is O
presented O
about O
the O
possible O
connection O
between O
naphthodianthrones B
and O
phenolic O
biosynthesis O
. O

Possible O
regulation O
of O
fagopyrin B
biosynthesis O
and O
production O
under O
different O
growth O
conditions O
is O
also O
discussed O
. O

Adolescent O
male O
rats O
are O
less O
sensitive O
than O
adults O
to O
the O
anxiogenic O
and O
serotonin B
- O
releasing O
effects O
of O
fenfluramine B
. O

Risk O
taking O
behavior O
increases O
during O
adolescence O
, O
which O
is O
also O
a O
critical O
period O
for O
the O
onset O
of O
drug O
abuse O
. O

The O
central O
serotonergic O
system O
matures O
during O
the O
adolescent O
period O
, O
and O
its O
immaturity O
during O
early O
adolescence O
may O
contribute O
to O
adolescent O
risk O
taking O
, O
as O
deficits O
in O
central O
serotonergic O
function O
have O
been O
associated O
with O
impulsivity O
, O
aggression O
, O
and O
risk O
taking O
. O

We O
investigated O
serotonergic O
modulation O
of O
behavior O
and O
presynaptic O
serotonergic O
function O
in O
adult O
( O
67 O
- O
74 O
days O
old O
) O
and O
adolescent O
( O
28 O
- O
34 O
days O
old O
) O
male O
rats O
. O

Fenfluramine B
( O
2 O
mg O
/ O
kg O
, O
i O
. O
p O
. O
) O
produced O
greater O
anxiogenic O
effects O
in O
adult O
rats O
in O
both O
the O
light O
/ O
dark O
and O
elevated O
plus O
maze O
tests O
for O
anxiety O
- O
like O
behavior O
, O
and O
stimulated O
greater O
increases O
in O
extracellular O
serotonin B
in O
the O
adult O
medial O
prefrontal O
cortex O
( O
mPFC O
) O
( O
1 O
, O
2 O
. O
5 O
, O
and O
10 O
mg O
/ O
kg O
, O
i O
. O
p O
. O
) O
. O

Local O
infusion O
of O
100 O
mM O
potassium B
chloride I
into O
the O
mPFC O
also O
stimulated O
greater O
serotonin B
efflux O
in O
adult O
rats O
. O

Adult O
rats O
had O
higher O
tissue O
serotonin B
content O
than O
adolescents O
in O
the O
prefrontal O
cortex O
, O
amygdala O
, O
and O
hippocampus O
, O
but O
the O
rate O
of O
serotonin B
synthesis O
was O
similar O
between O
age O
groups O
. O

Serotonin B
transporter O
( O
SERT O
) O
immunoreactivity O
and O
SERT O
radioligand O
binding O
were O
comparable O
between O
age O
groups O
in O
all O
three O
brain O
regions O
. O

These O
data O
suggest O
that O
lower O
tissue O
serotonin B
stores O
in O
adolescents O
limit O
fenfluramine B
- O
stimulated O
serotonin B
release O
and O
so O
contribute O
to O
the O
lesser O
anxiogenic O
effects O
of O
fenfluramine B
. O

Arsenic B
trioxide I
- O
induced O
hERG O
K B
( I
+ I
) I
channel O
deficiency O
can O
be O
rescued O
by O
matrine B
and O
oxymatrine B
through O
up O
- O
regulating O
transcription O
factor O
Sp1 O
expression O
. O

The O
human O
ether O
- O
a O
- O
go O
- O
go O
- O
related O
gene O
( O
hERG O
) O
encodes O
the O
rapidly O
activating O
, O
delayed O
rectifier O
potassium B
channel O
( O
IKr O
) O
important O
for O
cardiac O
repolarization O
. O

Dysfunction O
of O
the O
hERG O
channel O
can O
cause O
Long O
QT O
Syndrome O
( O
LQTS O
) O
. O

A O
wide O
variety O
of O
structurally O
diverse O
therapeutic O
compounds O
reduce O
the O
hERG O
current O
by O
acute O
direct O
inhibition O
of O
the O
hERG O
current O
or O
/ O
and O
selective O
disruption O
of O
hERG O
protein O
expression O
. O

Arsenic B
trioxide I
( O
As B
( I
2 I
) I
O I
( I
3 I
) I
) O
, O
which O
is O
used O
to O
treat O
acute O
promyelocytic O
leukemia O
, O
can O
cause O
LQTS O
type O
2 O
( O
LQT2 O
) O
by O
reducing O
the O
hERG O
current O
through O
the O
diversion O
of O
hERG O
trafficking O
to O
the O
cytoplasmic O
membrane O
. O

This O
cardiotoxicity O
limits O
its O
clinical O
applications O
. O

Our O
aim O
was O
to O
develop O
cardioprotective O
agents O
to O
decrease O
As B
( I
2 I
) I
O I
( I
3 I
) I
- O
induced O
cardiotoxicity O
. O

We O
reported O
that O
superfusion O
of O
hERG O
- O
expressing O
HEK293 O
( O
hERG O
- O
HEK O
) O
cells O
with O
matrine O
( O
1 O
, O
10 O
mu O
M O
) O
increased O
the O
hERG O
current O
by O
promoting O
hERG O
channel O
activation O
. O

Long O
- O
term O
treatment O
with O
1 O
mu O
M O
matrine O
or O
oxymatrine B
increased O
expression O
of O
the O
hERG O
protein O
and O
rescued O
the O
hERG O
surface O
expression O
disrupted O
by O
As B
( I
2 I
) I
O I
( I
3 I
) I
. O

In O
addition O
, O
Matrine B
and O
oxymatrine B
significantly O
shortened O
action O
potential O
duration O
prolonged O
by O
As B
( I
2 I
) I
O I
( I
3 I
) I
in O
guinea O
pig O
ventricular O
myocytes O
. O

These O
results O
were O
ascribed O
to O
the O
up O
- O
regulation O
of O
hERG O
at O
both O
mRNA O
and O
protein O
levels O
via O
an O
increase O
in O
the O
expression O
of O
transcription O
factor O
Sp1 O
, O
an O
established O
transactivator O
of O
the O
hERG O
gene O
. O

Therefore O
, O
matrine B
and O
oxymatrine B
may O
have O
the O
potential O
to O
cure O
LQT2 O
as O
a O
potassium B
channel O
activator O
by O
promoting O
hERG O
channel O
activation O
and O
increasing O
hERG O
channel O
expression O
. O

TNF O
- O
alpha O
- O
mediated O
NF O
- O
kappa O
B O
survival O
signaling O
impairment O
by O
cisplatin B
enhances O
JNK O
activation O
allowing O
synergistic O
apoptosis O
of O
renal O
proximal O
tubular O
cells O
. O

Cisplatin B
- O
induced O
nephrotoxicity O
is O
an O
important O
limiting O
factor O
for O
cisplatin B
use O
. O

Tumor O
necrosis O
factor O
- O
alpha O
( O
TNF O
- O
alpha O
) O
is O
known O
to O
contribute O
to O
cisplatin B
- O
induced O
nephrotoxicity O
by O
inducing O
an O
inflammatory O
process O
aggravating O
the O
primary O
injury O
, O
thereby O
resulting O
in O
acute O
kidney O
injury O
( O
AKI O
) O
. O

The O
present O
study O
investigates O
the O
pathways O
synergistically O
activated O
by O
cisplatin B
and O
TNF O
- O
alpha O
responsible O
for O
TNF O
- O
alpha O
- O
enhanced O
cisplatin B
- O
induced O
renal O
cell O
injury O
. O

To O
do O
so O
, O
immortalized O
renal O
proximal O
tubular O
epithelial O
cells O
( O
IM O
- O
PTECs O
) O
were O
co O
- O
treated O
with O
TNF O
- O
alpha O
and O
cisplatin B
. O

Under O
these O
conditions O
, O
cisplatin B
induced O
dose O
- O
dependent O
apoptosis O
in O
IM O
- O
PTECs O
, O
which O
was O
significantly O
enhanced O
by O
TNF O
- O
alpha O
. O

Transcriptomic O
analysis O
revealed O
that O
cisplatin B
inhibited O
the O
typical O
TNF O
- O
alpha O
response O
and O
cisplatin B
/ O
TNF O
- O
alpha O
treatment O
up O
- O
regulated O
cell O
death O
pathways O
while O
it O
down O
- O
regulated O
survival O
pathways O
compared O
to O
cisplatin B
alone O
. O

In O
concordance O
, O
the O
gene O
expression O
levels O
of O
kidney O
injury O
markers O
combined O
with O
activation O
of O
specific O
inflammatory O
mediators O
were O
enhanced O
by O
cisplatin B
/ O
TNF O
- O
alpha O
treatment O
, O
resembling O
the O
in O
vivo O
cisplatin B
- O
induced O
nephrotoxicity O
response O
. O

Furthermore O
, O
combined O
cisplatin B
/ O
TNF O
- O
alpha O
treatment O
inhibited O
NF O
- O
kappa O
B O
nuclear O
translocation O
and O
NF O
- O
kappa O
B O
- O
mediated O
gene O
transcription O
leading O
to O
enhanced O
and O
prolonged O
JNK O
and O
c O
- O
Jun O
phosphorylation O
. O

JNK O
sustained O
activation O
further O
inhibited O
NF O
- O
kappa O
B O
signaling O
via O
a O
feedback O
loop O
mechanism O
. O

This O
led O
to O
an O
alteration O
in O
the O
transcription O
of O
the O
NF O
- O
kappa O
B O
- O
induced O
anti O
- O
apoptotic O
genes O
c O
- O
IAP2 O
, O
Bcl O
- O
XL O
, O
Bruce O
and O
Bcl2 O
and O
pro O
- O
apoptotic O
genes O
Bfk O
and O
Xaf1 O
and O
consequently O
to O
sensitization O
of O
the O
IM O
- O
PTECs O
toward O
cisplatin B
/ O
TNF O
- O
alpha O
- O
induced O
toxicity O
. O

In O
conclusion O
, O
our O
findings O
support O
a O
model O
whereby O
renal O
cells O
exposed O
to O
both O
cisplatin B
and O
TNF O
- O
alpha O
switch O
into O
a O
more O
pro O
- O
apoptotic O
and O
inflammatory O
program O
by O
altering O
their O
NF O
- O
kappa O
B O
/ O
JNK O
/ O
c O
- O
Jun O
balance O
. O

Ibandronate B
increases O
the O
expression O
of O
the O
pro O
- O
apoptotic O
gene O
FAS O
by O
epigenetic O
mechanisms O
in O
tumor O
cells O
. O

There O
is O
growing O
evidence O
that O
aminobisphosphonates B
like O
ibandronate B
show O
anticancer O
activity O
by O
an O
unknown O
mechanism O
. O

Biochemically O
, O
they O
prevent O
posttranslational O
isoprenylation O
of O
small O
GTPases O
, O
thus O
inhibiting O
their O
activity O
. O

In O
tumor O
cells O
, O
activated O
RAS O
- O
GTPase O
, O
the O
founding O
member O
of O
the O
gene O
family O
, O
down O
- O
regulates O
the O
expression O
of O
the O
pro O
- O
apoptotic O
gene O
FAS O
via O
epigenetic O
DNA O
- O
methylation O
by O
DNMT1 O
. O

We O
compared O
ibandronate B
treatment O
in O
neoplastic O
human O
U O
- O
2 O
osteosarcoma O
and O
in O
mouse O
CCL O
- O
51 O
breast O
cancer O
cells O
as O
well O
as O
in O
the O
immortalized O
non O
- O
neoplastic O
MC3T3 O
- O
E1 O
osteoblastic O
cells O
. O

Ibandronate B
attenuated O
cell O
proliferation O
in O
all O
cell O
lines O
tested O
. O

In O
the O
neoplastic O
cells O
we O
found O
up O
- O
regulation O
of O
caspases O
suggesting O
apoptosis O
. O

Further O
we O
found O
stimulation O
of O
FAS O
- O
expression O
as O
a O
result O
of O
epigenetic O
DNA O
demethylation O
that O
was O
due O
to O
down O
- O
regulation O
of O
DNMT1 O
, O
which O
was O
rescued O
by O
re O
- O
isoprenylation O
by O
both O
geranylgeranyl B
- I
pyrophosphate I
and O
farnesylpyrophosphat B
. O

In O
contrast O
, O
ibandronate B
did O
not O
affect O
FAS O
and O
DNMT1 O
expression O
in O
MC3T3 O
- O
E1 O
non O
- O
neoplastic O
cells O
. O

Data O
suggest O
that O
bisphosphonates B
via O
modulation O
of O
the O
activity O
of O
small O
- O
GTPases O
induce O
apoptosis O
in O
neoplastic O
cells O
by O
DNA O
- O
CpG B
- O
demethylation O
and O
stimulation O
of O
FAS O
- O
expression O
. O

In O
conclusion O
the O
shown O
epigenetic O
mechanism O
underlying O
the O
anti O
- O
neoplastic O
activity O
of O
farnesyl B
- O
transferase O
- O
inhibition O
, O
also O
explains O
the O
clinical O
success O
of O
other O
drugs O
, O
which O
target O
this O
pathway O
. O

Interorgan O
metabolism O
of O
ornithine B
phenylacetate I
( O
OP O
) O
- O
- O
a O
novel O
strategy O
for O
treatment O
of O
hyperammonemia O
. O

Combined O
administration O
of O
ornithine B
and O
phenylacetate B
( O
OP O
) O
is O
proposed O
as O
a O
novel O
treatment O
of O
hyperammonemia O
and O
hepatic O
encephalopathy O
. O

Ornithine B
is O
believed O
to O
increase O
ammonia B
fixation O
into O
glutamine B
in O
muscle O
tissue O
and O
glutamine B
is O
subsequently O
thought O
to O
react O
with O
phenylacetate B
forming O
phenylacetylglutamin B
( O
PAGN B
) O
which O
is O
excreted O
in O
urine O
. O

The O
aim O
of O
the O
present O
study O
was O
to O
elucidate O
the O
interorgan O
metabolism O
of O
ornithine B
and O
ammonia B
in O
cirrhotic O
rats O
treated O
with O
OP O
in O
order O
to O
obtain O
an O
understanding O
of O
the O
underlying O
mechanisms O
of O
the O
beneficial O
effect O
of O
the O
treatment O
, O
which O
are O
largely O
unknown O
. O

Bile O
duct O
ligated O
cirrhotic O
rats O
and O
SHAM O
rats O
were O
treated O
with O
OP O
or O
saline O
for O
five O
days O
. O

[ B
2 I
, I
5 I
- I
( I
15 I
) I
N I
] I
Ornithine I
or O
( B
15 I
) I
NH I
( I
4 I
) I
( I
+ I
) I
were O
administered O
intravenously O
and O
the O
incorporation O
of O
( B
15 I
) I
N I
in O
amino B
acids I
as O
well O
as O
the O
content O
of O
the O
amino B
acids I
were O
subsequently O
determined O
in O
plasma O
, O
skeletal O
muscle O
, O
liver O
and O
kidney O
. O

In O
BDL O
rats O
, O
OP O
treatment O
reduced O
arterial O
ammonia B
concentration O
and O
increased O
that O
of O
glutamine B
30 O
min O
after O
the O
treatment O
but O
not O
after O
15 O
h O
. O

OP O
treatment O
did O
not O
increase O
( B
15 I
) I
N I
labeling O
in O
glutamine B
from O
[ B
2 I
, I
5 I
- I
( I
15 I
) I
N I
] I
ornithine I
and O
( B
15 I
) I
NH I
( I
4 I
) I
( I
+ I
) I
in O
skeletal O
muscle O
or O
liver O
. O

However O
, O
the O
extent O
of O
glutamine B
labeling O
from O
[ B
2 I
, I
5 I
- I
( I
15 I
) I
N I
] I
ornithine I
or O
( B
15 I
) I
NH I
( I
4 I
) I
( I
+ I
) I
was O
similar O
in O
arterial O
blood O
and O
liver O
and O
higher O
than O
that O
in O
skeletal O
muscle O
. O

These O
findings O
suggest O
that O
the O
effect O
of O
OP O
was O
related O
to O
hepatic O
metabolism O
of O
ornithine B
. O

PAGN O
could O
not O
be O
detected O
in O
urine O
or O
blood O
in O
any O
of O
the O
rats O
which O
may O
explain O
why O
OP O
treatment O
only O
reduced O
arterial O
ammonia B
transiently O
. O

Platelet O
- O
derived O
growth O
factor O
triggers O
PKA O
- O
mediated O
signalling O
by O
a O
redox O
- O
dependent O
mechanism O
in O
rat O
renal O
mesangial O
cells O
. O

Inflammatory O
glomerular O
kidney O
diseases O
are O
often O
accompanied O
with O
a O
massive O
production O
of O
reactive O
oxygen B
species O
( O
ROS O
) O
that O
affect O
the O
function O
of O
the O
glomerular O
filtration O
barrier O
and O
contribute O
to O
mesangiolysis O
via O
the O
induction O
of O
cell O
death O
in O
mesangial O
cells O
. O

Intriguingly O
, O
ROS O
also O
trigger O
fine O
- O
tuned O
signalling O
processes O
that O
affect O
gene O
expression O
and O
cell O
proliferation O
or O
migration O
. O

To O
define O
such O
redox O
- O
driven O
signalling O
devices O
, O
a O
proteomics O
approach O
was O
performed O
to O
identify O
the O
formation O
of O
protein O
complexes O
induced O
by O
ROS O
. O

To O
this O
end O
, O
protein O
lysates O
of O
human O
podocytes O
were O
treated O
with O
or O
without O
hydrogen B
peroxide I
( O
250 O
mu O
M O
) O
. O

Thereafter O
cell O
lysates O
were O
subjected O
to O
diagonal O
2D O
gel O
electrophoresis O
and O
putative O
redox O
- O
affected O
proteins O
were O
analysed O
by O
MS O
/ O
MS O
analysis O
. O

Among O
others O
, O
the O
regulatory O
subunit O
of O
protein O
kinase O
A O
( O
PKA O
) O
could O
be O
identified O
that O
forms O
homodimers O
under O
oxidative O
conditions O
. O

To O
evaluate O
whether O
ROS O
dependent O
dimerization O
of O
PKA O
also O
occurs O
in O
a O
more O
physiological O
setting O
, O
rat O
mesangial O
cells O
were O
treated O
with O
platelet O
- O
derived O
growth O
factor O
- O
BB O
( O
PDGF O
- O
BB O
) O
to O
induce O
ROS O
formation O
. O

This O
regimen O
resulted O
in O
a O
redox O
dependent O
dimerization O
of O
the O
R O
- O
subunits O
of O
PKA O
. O

To O
demonstrate O
whether O
PDGF O
- O
BB O
induced O
ROS O
formation O
affects O
PKA O
dependent O
pathways O
, O
the O
effects O
of O
PDGF O
- O
BB O
on O
phosphorylation O
of O
serine B
157 O
of O
vasodilator O
stimulated O
protein O
( O
VASP O
) O
a O
classical O
target O
of O
PKA O
were O
analysed O
. O

Interestingly O
PDGF O
- O
BB O
induced O
VASP O
phosphorylation O
in O
a O
ROS O
dependent O
manner O
but O
independent O
of O
changes O
in O
cAMP B
levels O
. O

Taken O
together O
, O
we O
demonstrate O
a O
redox O
- O
mediated O
activation O
of O
PKA O
by O
PDGF O
- O
BB O
thus O
highlighting O
a O
physiological O
role O
of O
ROS O
as O
regulator O
of O
PKA O
activity O
in O
rat O
mesangial O
cells O
. O

Chloroacetic B
acid I
induced O
neuronal O
cells O
death O
through O
oxidative O
stress O
- O
mediated O
p38 O
- O
MAPK O
activation O
pathway O
regulated O
mitochondria O
- O
dependent O
apoptotic O
signals O
. O

Chloroacetic B
acid I
( O
CA O
) O
, O
a O
toxic O
chlorinated O
analog O
of O
acetic B
acid I
, O
is O
widely O
used O
in O
chemical O
industries O
as O
an O
herbicide O
, O
detergent O
, O
and O
disinfectant O
, O
and O
chemical O
intermediates O
that O
are O
formed O
during O
the O
synthesis O
of O
various O
products O
. O

In O
addition O
, O
CA O
has O
been O
found O
as O
a O
by O
- O
product O
of O
chlorination O
disinfection O
of O
drinking O
water O
. O

However O
, O
there O
is O
little O
known O
about O
neurotoxic O
injuries O
of O
CA O
on O
the O
mammalian O
, O
the O
toxic O
effects O
and O
molecular O
mechanisms O
of O
CA O
- O
induced O
neuronal O
cell O
injury O
are O
mostly O
unknown O
. O

In O
this O
study O
, O
we O
examined O
the O
cytotoxicity O
of O
CA O
on O
cultured O
Neuro O
- O
2a O
cells O
and O
investigated O
the O
possible O
mechanisms O
of O
CA O
- O
induced O
neurotoxicity O
. O

Treatment O
of O
Neuro O
- O
2a O
cells O
with O
CA O
significantly O
reduced O
the O
number O
of O
viable O
cells O
( O
in O
a O
dose O
- O
dependent O
manner O
with O
a O
range O
from O
0 O
. O
1 O
to O
3mM O
) O
, O
increased O
the O
generation O
of O
ROS O
, O
and O
reduced O
the O
intracellular O
levels O
of O
glutathione B
depletion O
. O

CA O
also O
increased O
the O
number O
of O
sub O
- O
G1 O
hypodiploid O
cells O
; O
increased O
mitochondrial O
dysfunction O
( O
loss O
of O
MMP O
, O
cytochrome O
c O
release O
, O
and O
accompanied O
by O
Bcl O
- O
2 O
and O
Mcl O
- O
1 O
down O
- O
regulation O
and O
Bax O
up O
- O
regulation O
) O
, O
and O
activated O
the O
caspase O
cascades O
activations O
, O
which O
displayed O
features O
of O
mitochondria O
- O
dependent O
apoptosis O
pathway O
. O

These O
CA O
- O
induced O
apoptosis O
- O
related O
signals O
were O
markedly O
prevented O
by O
the O
antioxidant O
N B
- I
acetylcysteine I
( O
NAC B
) O
. O

Moreover O
, O
CA O
activated O
the O
JNK O
and O
p38 O
- O
MAPK O
pathways O
, O
but O
did O
not O
that O
ERK1 O
/ O
2 O
pathway O
, O
in O
treated O
Neuro O
- O
2a O
cells O
. O

Pretreatment O
with O
NAC B
and O
specific O
p38 O
- O
MAPK O
inhibitor O
( O
SB203580 B
) O
, O
but O
not O
JNK O
inhibitor O
( O
SP600125 B
) O
effectively O
abrogated O
the O
phosphorylation O
of O
p38 O
- O
MAPK O
and O
attenuated O
the O
apoptotic O
signals O
( O
including O
: O
decrease O
in O
cytotoxicity O
, O
caspase O
- O
3 O
/ O
- O
7 O
activation O
, O
the O
cytosolic O
cytochrome O
c O
release O
, O
and O
the O
reversed O
alteration O
of O
Bcl O
- O
2 O
and O
Bax O
mRNA O
) O
in O
CA O
- O
treated O
Neuro O
- O
2a O
cells O
. O

Taken O
together O
, O
these O
data O
suggest O
that O
oxidative O
stress O
- O
induced O
p38 O
- O
MAPK O
activated O
pathway O
- O
regulated O
mitochondria O
- O
dependent O
apoptosis O
plays O
an O
important O
role O
in O
CA O
- O
caused O
neuronal O
cell O
death O
. O

Bioassay O
- O
guided O
isolation O
of O
urease O
and O
alpha O
- O
chymotrypsin O
inhibitory O
constituents O
from O
the O
stems O
of O
Lawsonia O
alba O
Lam O
. O

( O
Henna O
) O
. O

Seven O
constituents O
were O
isolated O
from O
the O
stems O
of O
Lawsonia O
alba O
Lam O
. O
, O
following O
an O
activity O
- O
guided O
isolation O
, O
which O
include O
two O
new O
constituents O
, O
namely O
lawsorosemarinol B
( O
1 O
) O
and O
lawsofructose B
( O
2 O
) O
, O
one O
known O
compound O
2 B
- I
( I
beta I
- I
d I
- I
glucopyranosyloxy I
) I
- I
1 I
, I
4 I
- I
naphthoquinone I
( O
3 O
) O
and O
four O
compounds O
, O
4 B
- I
hydroxy I
coumarine I
( O
4 O
) O
, O
3 B
- I
( I
4 I
- I
hyroxyphenyl I
) I
- I
triacontyl I
- I
( I
Z I
) I
- I
propenoate I
( O
5 O
) O
, O

3 B
- I
( I
4 I
- I
hydroxy I
- I
3 I
- I
methoxyphenyl I
) I
- I
triacontyl I
- I
( I
Z I
) I
- I
propenoate I
( O
6 O
) O
and O
7 B
- I
hydroxy I
- I
4 I
- I
methyl I
coumarin I
( O
7 O
) O
first O
time O
isolated O
from O
Lawsonia O
alba O
. O

Their O
structure O
elucidation O
was O
based O
on O
spectroscopic O
data O
analyses O
. O

Compounds O
3 O
and O
7 O
showed O
a O
moderate O
inhibition O
of O
urease O
activity O
, O
while O
rest O
of O
them O
showed O
less O
than O
50 O
% O
inhibition O
. O

These O
compounds O
did O
not O
show O
any O
significant O
inhibition O
against O
alpha O
- O
chymotrypsin O
. O

Active O
self O
- O
healing O
encapsulation O
of O
vaccine O
antigens O
in O
PLGA B
microspheres O
. O

Herein O
, O
we O
describe O
the O
detailed O
development O
of O
a O
simple O
and O
effective O
method O
to O
microencapsulate O
vaccine O
antigens O
in O
poly B
( I
lactic I
- I
co I
- I
glycolic I
acid I
) I
( O
PLGA B
) O
by O
simple O
mixing O
of O
preformed O
active O
self O
- O
microencapsulating O
( O
SM O
) O
PLGA B
microspheres O
in O
a O
low O
concentration O
aqueous O
antigen O
solution O
at O
modest O
temperature O
( O
10 O
- O
38 O
degrees O
C O
) O
. O

Co O
- O
encapsulating O
protein O
- O
sorbing O
vaccine O
adjuvants O
and O
polymer O
plasticizers O
were O
used O
to O
" O
actively O
" O
load O
the O
protein O
in O
the O
polymer O
pores O
and O
facilitate O
polymer O
self O
- O
healing O
at O
a O
temperature O
> O
the O
hydrated O
polymer O
glass O
transition O
temperature O
, O
respectively O
. O

The O
microsphere O
formulation O
parameters O
and O
loading O
conditions O
to O
provide O
optimal O
active O
self O
- O
healing O
microencapsulation O
of O
vaccine O
antigens O
in O
PLGA B
was O
investigated O
. O

Active O
self O
- O
healing O
encapsulation O
of O
two O
antigens O
, O
ovalbumin O
and O
tetanus O
toxoid O
( O
TT O
) O
, O
in O
PLGA B
microspheres O
was O
adjusted O
by O
preparing O
blank O
microspheres O
containing O
different O
vaccine O
adjuvants O
( O
aluminum B
hydroxide I
( O
Al B
( I
OH I
) I
3 I
) O
or O
calcium B
phosphate I
) O
. O

Active O
loading O
of O
vaccine O
antigen O
in O
Al B
( I
OH I
) I
3 I
- O
PLGA I
microspheres O
was O
found O
to O
: O
a O
) O
increase O
with O
an O
increasing O
loading O
of O
Al B
( I
OH I
) I
3 I
( O
0 O
. O
88 O
- O
3 O
wt O
. O
% O
) O
and O
addition O
of O
porosigen O
, O
b O
) O
decrease O
when O
the O
inner O
Al B
( I
OH I
) I
3 I
/ O
trehalose B
phase O
to O
1 O
mL O
outer O
oil O
phase O
and O
size O
of O
microspheres O
was O
respectively O
> O
0 O
. O
2 O
mL O
and O
63 O
mu O
m O
, O
and O
c O
) O
change O
negligibly O
by O
PLGA B
concentration O
and O
initial O
incubation O
( O
loading O
) O
temperature O
. O

Encapsulation O
of O
protein O
sorbing O
Al B
( I
OH I
) I
3 I
in O
PLGA B
microspheres O
resulted O
in O
suppression O
of O
self O
- O
healing O
of O
PLGA B
pores O
, O
which O
was O
then O
overcome O
by O
improving O
polymer O
chain O
mobility O
, O
which O
in O
turn O
was O
accomplished O
by O
coincorporating O
hydrophobic O
plasticizers O
in O
PLGA B
. O

Active O
self O
- O
healing O
microencapsulation O
of O
manufacturing O
process O
- O
labile O
TT O
in O
PLGA B
was O
found O
to O
: O
a O
) O
obviate O
micronization O
- O
and O
organic O
solvent O
- O
induced O
TT O
degradation O
, O
b O
) O
improve O
antigen O
loading O
( O
1 O
. O
4 O
- O
1 O
. O
8 O
wt O
. O
% O
TT O
) O
and O
encapsulation O
efficiency O
( O
~ O
97 O
% O
) O
, O
c O
) O
provide O
nearly O
homogeneous O
distribution O
and O
stabilization O
of O
antigen O
in O
polymer O
, O
and O
d O
) O
provide O
improved O
in O
vitro O
controlled O
release O
of O
antigenic O
TT O
. O

N B
- I
Arachidonyl I
glycine I
does O
not O
activate O
G O
protein O
- O
coupled O
receptor O
18 O
signaling O
via O
canonical O
pathways O
. O

Recent O
studies O
propose O
that O
N B
- I
arachidonyl I
glycine I
( O
NAGly B
) O
, O
a O
carboxylic B
analogue O
of O
anandamide B
, O
is O
an O
endogenous O
ligand O
of O
the O
G O
alpha O
( O
i O
/ O
o O
) O
protein O
- O
coupled O
receptor O
18 O
( O
GPR18 O
) O
. O

However O
, O
a O
high O
- O
throughput O
beta O
- O
arrestin O
- O
based O
screen O
failed O
to O
detect O
activation O
of O
GPR18 O
by O
NAGly O
( O
Yin O
et O
al O
. O
, O
2009 O
; O
JBC O
, O
18 O
: O
12328 O
) O
. O

To O
address O
this O
inconsistency O
, O
this O
study O
investigated O
GPR18 O
coupling O
in O
a O
native O
neuronal O
system O
with O
endogenous O
signaling O
pathways O
and O
effectors O
. O

GPR18 O
was O
heterologously O
expressed O
in O
rat O
sympathetic O
neurons O
, O
and O
the O
modulation O
of O
N B
- O
type O
( O
Ca B
( O
v O
) O
2 O
. O
2 O
) O
calcium B
channels O
was O
examined O
. O

Proper O
expression O
and O
trafficking O
of O
receptor O
were O
confirmed O
by O
the O
" O
rim O
- O
like O
" O
fluorescence O
of O
fluorescently O
tagged O
receptor O
and O
the O
positive O
staining O
of O
external O
hemagglutinin O
- O
tagged O
GPR18 O
- O
expressing O
cells O
. O

Application O
of O
NAGly O
on O
GPR18 O
- O
expressing O
neurons O
did O
not O
inhibit O
calcium B
currents O
but O
instead O
potentiated O
currents O
in O
a O
voltage O
- O
dependent O
manner O
, O
similar O
to O
what O
has O
previously O
been O
reported O
( O
Guo O
et O
al O
. O
, O
2008 O
; O
J O
Neurophysiol O
, O
100 O
: O
1147 O
) O
. O

Other O
proposed O
agonists O
of O
GPR18 O
, O
including O
anandamide B
and O
abnormal O
cannabidiol B
, O
also O
failed O
to O
induce O
inhibition O
of O
calcium B
currents O
. O

Mutants O
of O
GPR18 O
, O
designed O
to O
constitutively O
activate O
receptors O
, O
did O
not O
tonically O
inhibit O
calcium B
currents O
, O
indicating O
a O
lack O
of O
GPR18 O
activation O
or O
coupling O
to O
endogenous O
G O
proteins O
. O

Other O
downstream O
effectors O
of O
G O
alpha O
( O
i O
/ O
o O
) O
- O
coupled O
receptors O
, O
G O
protein O
- O
coupled O
inwardly O
rectifying O
potassium B
channels O
and O
adenylate O
cyclase O
, O
were O
not O
modulated O
by O
GPR18 O
signaling O
. O

Furthermore O
, O
GPR18 O
did O
not O
couple O
to O
other O
G O
proteins O
tested O
: O
G O
alpha O
( O
s O
) O
, O
G O
alpha O
( O
z O
) O
, O
and O
G O
alpha O
( O
15 O
) O
. O

These O
results O
suggest O
NAGly B
is O
not O
an O
agonist O
for O
GPR18 O
or O
that O
GPR18 O
signaling O
involves O
noncanonical O
pathways O
not O
examined O
in O
these O
studies O
. O

Effects O
of O
Korean O
red O
ginseng O
extracts O
on O
neural O
tube O
defects O
and O
impairment O
of O
social O
interaction O
induced O
by O
prenatal O
exposure O
to O
valproic B
acid I
. O

Ginseng O
is O
one O
of O
the O
most O
widely O
used O
medicinal O
plants O
, O
which O
belongs O
to O
the O
genus O
Panax O
. O

Compared O
to O
uncured O
white O
ginseng O
, O
red O
ginseng O
has O
been O
generally O
regarded O
to O
produce O
superior O
pharmacological O
effects O
with O
lesser O
side O
/ O
adverse O
effects O
, O
which O
made O
it O
popular O
in O
a O
variety O
of O
formulation O
from O
tea O
to O
oriental O
medicine O
. O

Using O
the O
prenatal O
valproic B
acid I
( O
VPA B
) O
- O
injection O
model O
of O
autism O
spectrum O
disorder O
( O
ASD O
) O
in O
rats O
, O
which O
produces O
social O
impairrment O
and O
altered O
seizure O
susceptibility O
as O
in O
human O
ASD O
patients O
as O
well O
as O
mild O
neural O
tube O
defects O
like O
crooked O
tail O
phenotype O
, O
we O
examined O
whether O
chronic O
administration O
of O
red O
ginseng O
extract O
may O
rescue O
the O
social O
impairment O
and O
crooked O
tail O
phenotype O
in O
prenatally O
VPA B
- O
exposed O
rat O
offspring O
. O

VPA B
- O
induced O
impairment O
in O
social O
interactions O
tested O
using O
sociability O
and O
social O
preference O
paradigms O
as O
well O
as O
crooked O
tail O
phenotypes O
were O
significantly O
improved O
by O
administration O
of O
Korean O
red O
ginseng O
( O
KRG O
) O
in O
a O
dose O
dependent O
manner O
. O

Rat O
offspring O
prenatally O
exposed O
to O
VPA B
showed O
higher O
sensitivity O
to O
electric O
shock O
seizure O
and O
increased O
locomotor O
activity O
in O
open O
- O
field O
test O
. O

KRG O
treatment O
reversed O
abnormal O
locomotor O
activity O
and O
sensitivity O
to O
electric O
shock O
to O
control O
level O
. O

These O
results O
suggest O
that O
KRG O
may O
modulate O
neurobehavioral O
and O
structural O
organization O
of O
nervous O
system O
adversely O
affected O
by O
prenatal O
exposure O
to O
VPA B
. O

The O
crystal O
structure O
of O
human O
telomeric O
DNA O
complexed O
with O
berberine B
: O
an O
interesting O
case O
of O
stacked O
ligand O
to O
G O
- O
tetrad O
ratio O
higher O
than O
1 O
: O
1 O
. O

The O
first O
crystal O
structure O
of O
human O
telomeric O
DNA O
in O
complex O
with O
the O
natural O
alkaloid O
berberine B
, O
produced O
by O
different O
plant O
families O
and O
used O
in O
folk O
medicine O
for O
millennia O
, O
was O
solved O
by O
X O
- O
ray O
diffraction O
method O
. O

The O
G O
- O
quadruplex O
unit O
features O
all O
- O
parallel O
strands O
. O

The O
overall O
folding O
assumed O
by O
DNA O
is O
the O
same O
found O
in O
previously O
reported O
crystal O
structures O
. O

Similarly O
to O
previously O
reported O
structures O
the O
ligand O
molecules O
were O
found O
to O
be O
stacked O
onto O
the O
external O
5 O
' O
and O
3 O
' O
- O
end O
G O
- O
tetrads O
. O

However O
, O
the O
present O
crystal O
structure O
highlighted O
for O
the O
first O
time O
, O
the O
presence O
of O
two O
berberine B
molecules O
in O
the O
two O
binding O
sites O
, O
directly O
interacting O
with O
each O
tetrad O
. O

As O
a O
consequence O
, O
our O
structural O
data O
point O
out O
a O
2 O
: O
1 O
ligand O
to O
G O
- O
tetrad O
molar O
ratio O
, O
which O
has O
never O
been O
reported O
before O
in O
a O
telomeric O
intramolecular O
quadruplex O
structure O
. O

Arsenic B
increases O
Pi O
- O
mediated O
vascular O
calcification O
and O
induces O
premature O
senescence O
in O
vascular O
smooth O
muscle O
cells O
. O

Several O
mechanisms O
have O
been O
proposed O
to O
explain O
the O
vascular O
toxicity O
of O
arsenic B
. O

Some O
of O
them O
are O
described O
in O
this O
work O
, O
such O
as O
stress O
- O
induced O
premature O
senescence O
( O
SIPS O
) O
, O
dedifferentiation O
, O
and O
medial O
vascular O
calcification O
, O
and O
they O
all O
affect O
vascular O
smooth O
muscle O
cells O
( O
VSMC O
) O
. O

Rat O
aortic O
VSMC O
were O
treated O
with O
1 O
- O
100 O
micro O
M O
of O
either O
sodium B
arsenate I
( O
As B
( I
V I
) I
) O
, O
sodium B
arsenite I
( O
As B
( I
III I
) I
) O
, O
monomethylarsonic B
acid I
, O
or O
dimethylarsinic B
acid I
. O

None O
of O
the O
treatments O
induced O
VSMC O
calcification O
in O
the O
presence O
of O
1mM O
inorganic O
phosphate B
( O
Pi O
) O
, O
but O
1 O
micro O
M O
As B
( I
III I
) I
did O
increase O
calcification O
when O
induced O
with O
2 O
. O
5mM O
Pi O
. O

A O
lactate B
dehydrogenase O
assay O
revealed O
that O
this O
increase O
was O
explained O
by O
a O
rise O
in O
cytotoxicity O
due O
to O
simultaneous O
incubation O
with O
1 O
micro O
M O
As B
( I
III I
) I
and O
2 O
. O
5mM O
Pi O
. O

This O
calcification O
increase O
was O
also O
observed O
in O
the O
aortas O
of O
a O
vascular O
calcification O
model O
: O
5 O
/ O
6 O
nephrectomized O
rats O
fed O
with O
a O
high O
Pi O
diet O
and O
treated O
with O
vitamin B
D I
( I
3 I
) I
. O

Several O
known O
mechanisms O
that O
might O
explain O
arsenic B
toxicity O
in O
our O
experimental O
model O
were O
discarded O
: O
apoptosis O
, O
oxidative O
stress O
, O
and O
inflammasome O
activation O
. O

Nevertheless O
, O
both O
senescence O
- O
associated O
beta O
- O
galactosidase O
activity O
and O
p21 O
expression O
were O
increased O
by O
As B
( I
III I
) I
, O
which O
reveals O
the O
induction O
of O
SIPS O
. O

As B
( I
III I
) I
also O
caused O
dedifferentiation O
of O
VSMC O
, O
as O
shown O
by O
the O
reduced O
expression O
of O
the O
VSMC O
markers O
SM22 O
alpha O
and O
calponin O
. O

Senescence O
and O
gene O
expression O
were O
also O
observed O
in O
the O
aortas O
of O
healthy O
rats O
treated O
with O
50 O
ppm O
As B
( I
V I
) I
in O
drinking O
water O
for O
1 O
month O
. O

In O
conclusion O
, O
both O
premature O
senescence O
in O
aortic O
VSMC O
with O
phenotypic O
dedifferentiation O
and O
the O
increase O
of O
Pi O
- O
induced O
calcification O
are O
novel O
mechanisms O
of O
arsenic B
vasculotoxicity O
. O

Consideration O
of O
rat O
chronic O
progressive O
nephropathy O
in O
regulatory O
evaluations O
for O
carcinogenicity O
. O

Chronic O
progressive O
nephropathy O
( O
CPN O
) O
is O
a O
spontaneous O
renal O
disease O
of O
rats O
which O
can O
be O
a O
serious O
confounder O
in O
toxicology O
studies O
. O

It O
is O
a O
progressive O
disease O
with O
known O
physiological O
factors O
that O
modify O
disease O
progression O
, O
such O
as O
high O
dietary O
protein O
. O

The O
weight O
of O
evidence O
supports O
an O
absence O
of O
a O
renal O
counterpart O
in O
humans O
. O

There O
is O
extensive O
evidence O
that O
advanced O
CPN O
, O
particularly O
end O
- O
stage O
kidney O
, O
is O
a O
risk O
factor O
for O
development O
of O
a O
background O
incidence O
of O
atypical O
tubule O
hyperplasia O
and O
renal O
tubule O
tumors O
( O
RTT O
) O
. O

The O
likely O
cause O
underlying O
this O
association O
with O
tubule O
neoplasia O
is O
the O
long O
- O
term O
increased O
tubule O
cell O
proliferation O
that O
occurs O
throughout O
CPN O
progression O
. O

As O
a O
variety O
of O
chemicals O
are O
able O
to O
exacerbate O
CPN O
, O
there O
is O
a O
potential O
for O
those O
exacerbating O
the O
severity O
up O
to O
and O
including O
end O
- O
stage O
kidney O
to O
cause O
a O
marginal O
increase O
in O
RTT O
and O
their O
precursor O
lesions O
. O

Extensive O
statistical O
analysis O
of O
National O
Toxicology O
Program O
studies O
shows O
a O
strong O
correlation O
between O
high O
- O
grade O
CPN O
, O
especially O
end O
- O
stage O
CPN O
, O
and O
renal O
tumor O
development O
. O

CPN B
as O
a O
mode O
of O
action O
( O
MOA O
) O
for O
rat O
RTT O
has O
received O
attention O
from O
regulatory O
authorities O
only O
recently O
. O

In O
the O
absence O
of O
toxic O
effects O
elsewhere O
, O
this O
does O
not O
constitute O
a O
carcinogenic O
effect O
of O
the O
chemical O
but O
can O
be O
addressed O
through O
a O
proposed O
MOA O
approach O
for O
regulatory O
purposes O
to O
reach O
a O
decision O
that O
RTT O
, O
developing O
as O
a O
result O
of O
CPN B
exacerbation O
in O
rats O
, O
have O
no O
relevance O
for O
human O
risk O
assessment O
. O

Guidelines O
are O
proposed O
for O
evaluation O
of O
exacerbation O
of O
CPN O
and O
RTT O
as O
a O
valid O
MOA O
for O
a O
given O
chemical O
. O

Differential O
influences O
of O
ethanol B
on O
early O
exposure O
to O
racemic B
methylphenidate I
compared O
with O
dexmethylphenidate B
in O
humans O
. O

Enantioselective O
hydrolysis O
of O
oral O
racemic O
methylphenidate B
( O
dl B
- I
MPH I
) O
by O
carboxylesterase O
1 O
( O
CES1 O
) O
limits O
the O
absolute O
bioavailability O
of O
the O
pharmacologically O
active O
d B
- I
MPH I
isomer O
to O
approximately O
30 O
% O
and O
that O
of O
the O
inactive O
l B
- I
MPH I
to O
only O
1 O
- O
2 O
% O
. O

Coadministration O
of O
dl B
- I
MPH I
with O
ethanol B
results O
in O
elevated O
d B
- I
MPH I
plasma O
concentrations O
accompanied O
by O
CES1 O
- O
mediated O
enantioselective O
transesterification O
of O
l B
- I
MPH I
to O
l B
- I
ethylphenidate I
( O
EPH B
) O
. O

The O
present O
study O
tested O
the O
hypothesis O
that O
administration O
of O
the O
pure O
isomer O
dexmethylphenidate B
( O
d B
- I
MPH I
) O
will O
overcome O
the O
influence O
of O
ethanol B
on O
d B
- I
MPH I
absorption O
by O
eliminating O
competitive O
CES1 O
- O
mediated O
presystemic O
metabolism O
of O
l B
- I
MPH I
to O
l B
- I
EPH I
. O

Twenty O
- O
four O
healthy O
volunteers O
received O
dl B
- I
MPH I
( O
0 O
. O
3 O
mg O
/ O
kg O
) O
or O
d B
- I
MPH I
( O
0 O
. O
15 O
mg O
/ O
kg O
) O
, O
with O
or O
without O
ethanol B
( O
0 O
. O
6 O
g O
/ O
kg O
) O
. O

During O
the O
absorption O
phase O
of O
dl B
- I
MPH I
, O
concomitant O
ethanol B
significantly O
elevated O
d B
- I
MPH I
plasma O
concentrations O
( O
44 O
- O
99 O
% O
; O
P O
< O
0 O
. O
005 O
) O
. O

Furthermore O
, O
immediately O
following O
the O
ethanol B
drink O
the O
subjective O
effects O
of O
" O
high O
, O
" O
" O
good O
, O
" O
" O
like O
, O
" O
" O
stimulated O
, O
" O
and O
overall O
" O
effect O
" O
were O
significantly O
potentiated O
( O
P O
< O
= O
0 O
. O
01 O
) O
. O

Plasma O
l B
- I
EPH I
concentrations O
exceeded O
those O
of O
l B
- I
MPH I
. O

Ethanol B
combined O
with O
pure O
d B
- I
MPH I
did O
not O
elevate O
plasma O
d B
- I
MPH I
concentrations O
during O
the O
absorption O
phase O
, O
and O
the O
ethanol B
- O
induced O
potentiation O
of O
subjective O
effects O
was O
delayed O
relative O
to O
dl B
- I
MPH I
- O
ethanol B
. O

These O
findings O
are O
consistent O
with O
l B
- I
MPH I
competitively O
inhibiting O
presystemic O
CES1 O
metabolism O
of O
d B
- I
MPH I
. O

Ethanol B
increased O
the O
d O
- O
MPH I
area O
under O
the O
curve O
( O
AUC O
) O
( O
0 O
- O
inf O
) O
by O
21 O
% O
following O
dl O
- O
MPH O
( O
P O
< O
0 O
. O
001 O
) O
and O
14 O
% O
for O
d O
- O
MPH I
( O
P O
= O
0 O
. O
001 O
) O
. O

In O
men O
receiving O
d B
- I
MPH I
- O
ethanol B
, O
the O
d B
- I
MPH I
absorption O
partial O
AUC O
( O
0 O
. O
5 O
- O
2 O
hours O
) O
was O
2 O
. O
1 O
times O
greater O
and O
the O
time O
to O
maximum O
concentration O
( O
T O
( O
max O
) O
) O
occurred O
1 O
. O
1 O
hours O
earlier O
than O
in O
women O
, O
consistent O
with O
an O
increased O
rate O
of O
d B
- I
MPH I
absorption O
reducing O
hepatic O
extraction O
. O

More O
rapid O
absorption O
of O
d B
- I
MPH I
carries O
implications O
for O
increased O
abuse O
liability O
. O

Evolution O
and O
diversity O
of O
Arsenophonus O
endosymbionts O
in O
aphids O
. O

Endosymbiotic O
bacteria O
are O
important O
drivers O
of O
insect O
evolutionary O
ecology O
, O
acting O
both O
as O
partners O
that O
contribute O
to O
host O
adaptation O
and O
as O
subtle O
parasites O
that O
manipulate O
host O
reproduction O
. O

Among O
them O
, O
the O
genus O
Arsenophonus O
is O
emerging O
as O
one O
of O
the O
most O
widespread O
lineages O
. O

Its O
biology O
is O
, O
however O
, O
entirely O
unknown O
in O
most O
cases O
, O
and O
it O
is O
therefore O
unclear O
how O
infections O
spread O
through O
insect O
populations O
. O

Here O
we O
examine O
the O
incidence O
and O
evolutionary O
history O
of O
Arsenophonus O
in O
aphid O
populations O
from O
86 O
species O
, O
characterizing O
the O
processes O
that O
shape O
their O
diversity O
. O

We O
identify O
aphids O
as O
harbouring O
an O
important O
diversity O
of O
Arsenophonus O
strains O
. O

Present O
in O
7 O
% O
of O
the O
sampled O
species O
, O
incidence O
was O
especially O
high O
in O
the O
Aphis O
genus O
with O
more O
than O
31 O
% O
of O
the O
infected O
species O
. O

Phylogenetic O
investigations O
revealed O
that O
these O
Arseno O
- O
phonus O
strains O
do O
not O
cluster O
within O
an O
aphid O
- O
specific O
clade O
but O
rather O
exhibit O
distinct O
evolutionary O
origins O
showing O
that O
they O
undergo O
repeated O
horizontal O
transfers O
( O
HT O
) O
between O
distantly O
related O
host O
species O
. O

Their O
diversity O
pattern O
strongly O
suggests O
that O
ecological O
interactions O
, O
such O
as O
plant O
mediation O
and O
parasitism O
, O
are O
major O
drivers O
for O
Arsenophonus O
dispersal O
, O
dictating O
global O
incidence O
across O
insect O
communities O
. O

Notably O
, O
plants O
hosting O
aphids O
may O
be O
important O
ecological O
arenas O
for O
global O
exchange O
of O
Arsenophonus B
, O
serving O
as O
reservoirs O
for O
HT O
. O

Methotrexate B
- O
conjugated O
and O
hyperbranched O
polyglycerol B
- O
grafted O
Fe B
3 I
O I
4 I
magnetic O
nanoparticles O
for O
targeted O
anticancer O
effects O
. O

Superparamagnetic O
nanoparticles O
grafted O
with O
hyperbranched O
polyglycerol B
( O
HPG B
) O
and O
conjugated O
with O
methotrexate B
( O
MTX B
) O
( O
MNP O
- O
g O
- O
HPG B
- O
MTX B
) O
were O
synthesized O
via O
a O
sol O
- O
gel O
reaction O
followed O
by O
thiol B
- O
ene O
click O
chemistry O
and O
esterification O
reaction O
. O

The O
successful O
grafting O
of O
MTX B
and O
HPG B
onto O
the O
nanoparticles O
was O
confirmed O
by O
X O
- O
ray O
photoelectron O
spectroscopy O
( O
XPS O
) O
, O
Fourier O
transform O
infrared O
( O
FT O
- O
IR O
) O
spectroscopy O
, O
and O
UV O
- O
visible O
spectroscopy O
. O

The O
HPG O
- O
graft O
layer O
confers O
the O
magnetic O
nanoparticles O
with O
good O
dispersibility O
and O
stability O
in O
aqueous O
medium O
and O
macrophage O
- O
evasive O
property O
while O
the O
MTX B
acts O
as O
a O
chemotherapeutic O
drug O
as O
well O
as O
a O
tumor O
targeting O
ligand O
. O

The O
dose O
- O
dependent O
targeting O
and O
anticancer O
effect O
of O
the O
MNP O
- O
g O
- O
HPG I
- O
MTX B
nanoparticles O
were O
evaluated O
, O
and O
the O
results O
showed O
that O
depending O
on O
the O
amount O
of O
conjugated O
MTX B
and O
the O
concentration O
of O
the O
incubated O
nanoparticles O
, O
the O
uptake O
of O
MNP O
- O
g O
- O
HPG I
- O
MTX B
nanoparticles O
by O
human O
head O
and O
neck O
cancer O
( O
KB O
) O
cells O
can O
be O
eight O
times O
or O
more O
higher O
than O
those O
by O
3T3 O
fibroblasts O
and O
RAW O
macrophages O
. O

As O
a O
result O
, O
the O
MNP O
- O
g O
- O
HPG O
- O
MTX B
nanoparticles O
are O
capable O
of O
killing O
~ O
50 O
% O
of O
the O
KB O
cells O
while O
at O
the O
same O
time O
exhibiting O
low O
cytotoxicity O
towards O
3T3 O
fibroblasts O
and O
RAW O
macrophages O
. O

Thus O
, O
such O
nanoparticles O
can O
potentially O
be O
used O
as O
active O
targeting O
anticancer O
agents O
. O

Promoting O
effect O
of O
polysaccharide O
isolated O
from O
Mori O
fructus O
on O
dendritic O
cell O
maturation O
. O

Maturation O
of O
dendritic O
cells O
( O
DCs O
) O
is O
usually O
attenuated O
in O
the O
tumor O
microenvironment O
, O
which O
is O
an O
important O
immunological O
problem O
in O
DC O
- O
based O
immunotherapy O
of O
cancer O
. O

In O
this O
study O
, O
we O
report O
the O
effect O
of O
a O
Mori O
fructus O
polysaccharide O
( O
MFP O
) O
on O
DC O
maturation O
. O

MFP O
was O
treated O
to O
DCs O
generated O
from O
mouse O
BM O
cells O
. O

MFP O
induced O
phenotypic O
maturation O
of O
DCs O
, O
as O
proven O
by O
the O
increased O
expression O
of O
CD40 O
, O
CD80 O
/ O
86 O
, O
and O
MHC O
- O
I O
/ O
II O
molecules O
. O

MFP O
induced O
functional O
maturation O
of O
DCs O
, O
in O
that O
MFP O
increased O
the O
expression O
of O
IL O
- O
12 O
, O
IL O
- O
1 O
beta O
, O
TNF O
- O
alpha O
, O
and O
IFN O
- O
beta O
, O
decreased O
antigen O
capture O
capacity O
, O
and O
enhanced O
allogenic O
T O
cell O
stimulation O
. O

MFP O
efficiently O
induced O
maturation O
of O
DCs O
from O
C3H O
/ O
HeN O
mice O
having O
normal O
toll O
- O
like O
receptor4 O
( O
TLR4 O
) O
, O
but O
not O
DCs O
from O
C3H O
/ O
HeJ O
mice O
having O
mutated O
TLR4 O
, O
suggesting O
that O
TLR4 O
might O
be O
one O
of O
the O
membrane O
receptors O
of O
MFP O
. O

As O
a O
mechanism O
of O
action O
, O
MFP B
increased O
phosphorylation O
of O
mitogen O
- O
activated O
protein O
kinase O
( O
MAPKs O
) O
, O
and O
nuclear O
translocation O
of O
NF O
- O
kappa O
B O
p65 O
subunit O
, O
which O
were O
important O
signal O
molecules O
downstream O
from O
TLR4 O
. O

These O
data O
suggest O
that O
MFP O
induces O
DC O
maturation O
through O
TLR4 O
and O
MFP O
can O
be O
used O
as O
an O
adjuvant O
in O
DC O
- O
based O
cancer O
immunotherapy O
. O

The O
hypothalamus O
- O
adipose O
axis O
is O
a O
key O
target O
of O
developmental O
programming O
by O
maternal O
nutritional O
manipulation O
. O

Epidemiological O
studies O
initially O
demonstrated O
that O
maternal O
undernutrition O
leading O
to O
low O
birth O
weight O
may O
predispose O
for O
energy O
balance O
disorders O
throughout O
life O
. O

High O
birth O
weight O
due O
to O
maternal O
obesity O
or O
diabetes O
, O
inappropriate O
early O
post O
- O
natal O
nutrition O
and O
rapid O
catch O
- O
up O
growth O
may O
also O
sensitise O
to O
increased O
risk O
of O
obesity O
. O

As O
stated O
by O
the O
Developmental O
Origin O
of O
Health O
and O
Disease O
concept O
, O
the O
perinatal O
perturbation O
of O
foetus O
/ O
neonate O
nutrient O
supply O
might O
be O
a O
crucial O
determinant O
of O
individual O
programming O
of O
body O
weight O
set O
point O
. O

The O
hypothalamus O
- O
adipose O
axis O
plays O
a O
pivotal O
role O
in O
the O
maintenance O
of O
energy O
homoeostasis O
controlling O
the O
nutritional O
status O
and O
energy O
storage O
level O
. O

The O
perinatal O
period O
largely O
corresponds O
to O
the O
period O
of O
brain O
maturation O
, O
neuronal O
differentiation O
and O
active O
adipogenesis O
in O
rodents O
. O

Numerous O
dams O
and O
/ O
or O
foetus O
/ O
neonate O
dietary O
manipulation O
models O
were O
developed O
to O
investigate O
the O
mechanisms O
underlying O
perinatal O
programming O
in O
rodents O
. O

These O
models O
showed O
several O
common O
offspring O
hypothalamic O
consequences O
such O
as O
impaired O
neurogenesis O
, O
neuronal O
functionality O
, O
nuclei O
structural O
organisation O
and O
feeding O
circuitry O
hardwiring O
. O

These O
alterations O
led O
to O
a O
persistent O
reprogrammed O
appetite O
system O
that O
favoured O
the O
orexigenic O
pathways O
, O
leptin O
/ O
insulin O
resistance O
and O
hyperphagia O
. O

Impaired O
hypothalamic O
sympathetic O
outflow O
to O
adipose O
tissue O
and O
/ O
or O
reduced O
innervation O
may O
also O
account O
for O
modified O
fat O
cell O
metabolism O
. O

Thus O
, O
enhanced O
adipogenesis O
and O
/ O
or O
lipogenesis O
capacities O
may O
predispose O
the O
offspring O
to O
fat O
accumulation O
. O

Abnormal O
hypothalamus O
- O
adipose O
axis O
circadian O
rhythms O
were O
also O
evidenced O
. O

This O
review O
mainly O
focuses O
on O
studies O
in O
rodents O
. O

It O
highlights O
hormonal O
and O
epigenetic O
mechanisms O
responsible O
for O
long O
- O
lasting O
programming O
of O
energy O
balance O
in O
the O
offspring O
. O

Dietary O
supplementation O
may O
provide O
a O
therapeutic O
option O
using O
a O
specific O
regimen O
for O
reversing O
adverse O
programming O
outcomes O
in O
humans O
. O

Large O
- O
area O
fabrication O
of O
periodic O
sub O
- O
15 O
nm O
- O
width O
single O
- O
layer O
graphene B
nanorings O
. O

A O
periodically O
aligned O
array O
of O
graphene B
nanorings O
( O
GRNRs O
) O
with O
a O
sub O
- O
15 O
nm O
linewidth O
at O
a O
pitch O
of O
450 O
nm O
is O
fabricated O
with O
a O
large O
area O
, O
9 O
cm O
( O
2 O
) O
, O
through O
conventional O
nanoimprint O
lithography O
coupled O
with O
sophisticated O
metal O
deposition O
and O
plasma O
- O
etching O
processes O
. O

The O
existence O
of O
the O
single O
- O
layer O
GRNRs O
is O
verified O
by O
various O
techniques O
. O

Flexible O
and O
stretchable O
polymers O
with O
embedded O
magnetic O
nanostructures O
. O

A O
novel O
pathway O
is O
presented O
to O
transfer O
and O
embed O
functional O
patterned O
magnetic O
nanostructures O
into O
flexible O
and O
stretchable O
polymeric O
membranes O
. O

The O
geometrical O
and O
magnetic O
properties O
are O
maintained O
through O
the O
process O
, O
realized O
even O
directly O
inside O
a O
microfluidic O
channel O
. O

These O
results O
pave O
the O
way O
to O
the O
realization O
of O
smart O
biomedical O
systems O
and O
devices O
based O
on O
the O
integration O
of O
magnetic O
nanostructures O
into O
new O
classes O
of O
substrates O
. O

Sclerostin O
antibody O
inhibits O
skeletal O
deterioration O
due O
to O
reduced O
mechanical O
loading O
. O

Sclerostin O
, O
a O
product O
of O
the O
SOST O
gene O
produced O
mainly O
by O
osteocytes O
, O
is O
a O
potent O
negative O
regulator O
of O
bone O
formation O
that O
appears O
to O
be O
responsive O
to O
mechanical O
loading O
, O
with O
SOST O
expression O
increasing O
following O
mechanical O
unloading O
. O

We O
tested O
the O
ability O
of O
a O
murine O
sclerostin O
antibody O
( O
SclAbII O
) O
to O
prevent O
bone O
loss O
in O
adult O
mice O
subjected O
to O
hindlimb O
unloading O
( O
HLU O
) O
via O
tail O
suspension O
for O
21 O
days O
. O

Mice O
( O
n O
= O
11 O
- O
17 O
/ O
group O
) O
were O
assigned O
to O
control O
( O
CON O
, O
normal O
weight O
bearing O
) O
or O
HLU O
and O
injected O
with O
either O
SclAbII O
( O
subcutaneously O
, O
25 O
mg O
/ O
kg O
) O
or O
vehicle O
( O
VEH O
) O
twice O
weekly O
. O

SclAbII O
completely O
inhibited O
the O
bone O
deterioration O
due O
to O
disuse O
, O
and O
induced O
bone O
formation O
such O
that O
bone O
properties O
in O
HLU O
- O
SclAbII O
were O
at O
or O
above O
values O
of O
CON O
- O
VEH O
mice O
. O

For O
example O
, O
hindlimb O
bone O
mineral O
density O
( O
BMD O
) O
decreased O
- O
9 O
. O
2 O
% O
+ O
/ O
- O
1 O
. O
0 O
% O
in O
HLU O
- O
VEH O
, O
whereas O
it O
increased O
4 O
. O
2 O
% O
+ O
/ O
- O
0 O
. O
7 O
% O
, O
13 O
. O
1 O
% O
+ O
/ O
- O
1 O
. O
0 O
% O
, O
and O
30 O
. O
6 O
% O
+ O
/ O
- O
3 O
. O
0 O
% O
in O
CON O
- O
VEH O
, O
HLU O
- O
SclAbII O
, O
and O
CON O
- O
SclAbII O
, O
respectively O
( O
p O
< O
0 O
. O
0001 O
) O
. O

Trabecular O
bone O
volume O
, O
assessed O
by O
micro O
- O
computed O
tomography O
( O
micro O
CT O
) O
imaging O
of O
the O
distal O
femur O
, O
was O
lower O
in O
HLU O
- O
VEH O
versus O
CON O
- O
VEH O
( O
p O
< O
0 O
. O
05 O
) O
, O
and O
was O
2 O
- O
to O
3 O
- O
fold O
higher O
in O
SclAbII O
groups O
versus O
VEH O
( O
p O
< O
0 O
. O
001 O
) O
. O

Midshaft O
femoral O
strength O
, O
assessed O
by O
three O
- O
point O
bending O
, O
and O
distal O
femoral O
strength O
, O
assessed O
by O
micro O
- O
finite O
element O
analysis O
( O
micro O
FEA O
) O
, O
were O
significantly O
higher O
in O
SclAbII O
versus O
VEH O
- O
groups O
in O
both O
loading O
conditions O
. O

Serum O
sclerostin O
was O
higher O
in O
HLU O
- O
VEH O
( O
134 O
+ O
/ O
- O
5 O
pg O
/ O
mL O
) O
compared O
to O
CON O
- O
VEH O
( O
116 O
+ O
/ O
- O
6 O
pg O
/ O
mL O
, O
p O
< O
0 O
. O
05 O
) O
. O

Serum O
osteocalcin O
was O
decreased O
by O
hindlimb O
suspension O
and O
increased O
by O
SclAbII O
treatment O
. O

Interestingly O
, O
the O
anabolic O
effects O
of O
sclerostin O
inhibition O
on O
some O
bone O
outcomes O
appeared O
to O
be O
enhanced O
by O
normal O
mechanical O
loading O
. O

Altogether O
, O
these O
results O
confirm O
the O
ability O
of O
SclAbII O
to O
abrogate O
disuse O
- O
induced O
bone O
loss O
and O
demonstrate O
that O
sclerostin O
antibody O
treatment O
increases O
bone O
mass O
by O
increasing O
bone O
formation O
in O
both O
normally O
loaded O
and O
underloaded O
environments O
. O

Effects O
of O
bisphenol B
A I
on O
growth O
and O
nitrogen B
nutrition O
of O
roots O
of O
soybean O
seedlings O
. O

Bisphenol B
A I
( O
BPA B
) O
is O
an O
environmental O
endocrine O
disruptor O
that O
seriously O
threatens O
ecological O
systems O
. O

Plants O
are O
the O
primary O
producers O
in O
ecological O
systems O
, O
but O
little O
information O
is O
available O
concerning O
the O
toxic O
effect O
of O
BPA B
on O
plants O
. O

In O
the O
present O
study O
, O
the O
effects O
of O
BPA B
on O
the O
growth O
and O
nitrogen B
nutrition O
of O
roots O
of O
soybean O
seedlings O
were O
investigated O
by O
using O
a O
root O
automatic O
scan O
apparatus O
and O
biochemical O
methods O
. O

It O
was O
found O
that O
when O
soybean O
seedlings O
were O
treated O
with O
1 O
. O
5 O
mg O
/ O
L O
BPA B
, O
the O
growth O
of O
roots O
was O
improved O
, O
the O
content O
of O
nitrate B
in O
roots O
was O
increased O
, O
the O
content O
of O
ammonium B
in O
roots O
was O
decreased O
, O
and O
the O
activities O
of O
nitrate B
reductase O
and O
nitrite B
reductase O
in O
roots O
were O
not O
changed O
. O

The O
opposite O
effects O
were O
observed O
in O
roots O
treated O
with O
17 O
. O
2 O
mg O
/ O
L O
and O
50 O
. O
0 O
mg O
/ O
L O
BPA B
, O
except O
for O
an O
increase O
in O
the O
content O
of O
nitrate B
in O
roots O
treated O
with O
17 O
. O
2 O
mg O
/ O
L O
BPA B
and O
a O
decrease O
in O
the O
activities O
of O
nitrate B
reductase O
and O
nitrite B
reductase O
in O
roots O
of O
soybeans O
seedlings O
. O

Statistical O
analysis O
indicated O
that O
the O
change O
in O
the O
nitrogen B
nutrition O
of O
roots O
of O
soybean O
seedlings O
treated O
with O
BPA B
was O
one O
reason O
why O
the O
growth O
of O
roots O
was O
changed O
. O

The O
authors O
suggest O
that O
the O
potential O
environmental O
and O
ecological O
risk O
of O
BPA B
to O
plants O
should O
receive O
more O
consideration O
. O

Piccolo O
NuA4 O
- O
catalyzed O
acetylation O
of O
nucleosomal O
histones O
: O
critical O
roles O
of O
an O
Esa1 O
Tudor O
/ O
chromo O
barrel O
loop O
and O
an O
Epl1 O
enhancer O
of O
polycomb O
A O
( O
EPcA O
) O
basic O
region O
. O

Piccolo O
NuA4 O
is O
an O
essential O
yeast O
histone O
acetyltransferase O
( O
HAT O
) O
complex O
that O
targets O
histones O
H4 O
and O
H2A O
in O
nucleosome O
substrates O
. O

While O
Piccolo O
NuA4 O
' O
s O
catalytic O
subunit O
Esa1 O
alone O
is O
unable O
to O
acetylate O
nucleosomal O
histones O
, O
its O
accessory O
subunits O
, O
Yng2 O
and O
Epl1 O
, O
enable O
Esa1 O
to O
bind O
to O
and O
to O
act O
on O
nucleosomes O
. O

We O
previously O
determined O
that O
the O
Tudor O
domain O
of O
Esa1 O
and O
the O
EPcA O
homology O
domain O
of O
Epl1 O
play O
critical O
roles O
in O
Piccolo O
NuA4 O
' O
s O
ability O
to O
act O
on O
the O
nucleosome O
. O

In O
this O
work O
, O
we O
pinpoint O
a O
loop O
within O
the O
Esa1 O
Tudor O
domain O
and O
a O
short O
basic O
region O
at O
the O
N B
terminus O
of O
the O
Epl1 O
EPcA O
domain O
as O
necessary O
for O
this O
nucleosomal O
HAT O
activity O
. O

We O
also O
show O
that O
this O
Esa1 O
Tudor O
domain O
loop O
region O
is O
positioned O
close O
to O
nucleosomal O
DNA O
and O
that O
the O
Epl1 O
EPcA O
basic O
region O
is O
in O
proximity O
to O
the O
N B
- O
terminal O
histone O
H2A O
tail O
, O
the O
globular O
region O
of O
histone O
H4 O
, O
and O
also O
to O
nucleosomal O
DNA O
when O
Piccolo O
NuA4 O
interacts O
with O
the O
nucleosome O
. O

Since O
neither O
region O
identified O
is O
required O
for O
Piccolo O
NuA4 O
to O
bind O
to O
nucleosomes O
and O
yet O
both O
are O
needed O
to O
acetylate O
nucleosomes O
, O
these O
regions O
may O
function O
after O
the O
enzyme O
binds O
nucleosomes O
to O
disengage O
substrate O
histone O
tails O
from O
nucleosomal O
DNA O
. O

Highly O
predictive O
ligand O
- O
based O
pharmacophore O
and O
homology O
models O
of O
ABHD6 O
. O

alpha O
/ O
beta O
- O
Hydrolase O
domain O
- O
containing O
6 O
( O
ABHD6 O
) O
represents O
a O
potentially O
attractive O
therapeutic O
target O
for O
indirectly O
potentiating O
2 B
- I
arachidonoylglycerol I
signaling O
; O
however O
, O
the O
enzyme O
is O
currently O
largely O
uncharacterized O
. O

Here O
, O
we O
describe O
a O
five O
element O
, O
ligand O
- O
based O
pharmacophore O
model O
along O
with O
a O
refined O
homology O
model O
of O
ABHD6 O
. O

Following O
a O
virtual O
screen O
of O
a O
modest O
database O
, O
both O
the O
pharmacophore O
and O
homology O
models O
were O
found O
to O
be O
highly O
predictive O
, O
preferentially O
identifying O
ABHD6 O
inhibitors O
over O
drug O
- O
like O
non O
- O
inhibitors O
. O

The O
models O
yield O
insight O
into O
the O
features O
required O
for O
optimal O
ligand O
binding O
to O
ABHD6 O
and O
the O
atomic O
structure O
of O
the O
binding O
site O
. O

In O
combination O
, O
the O
two O
models O
should O
be O
very O
helpful O
not O
only O
in O
high O
- O
throughput O
virtual O
screening O
, O
but O
also O
in O
lead O
optimization O
, O
and O
will O
facilitate O
the O
development O
of O
novel O
, O
selective O
ABHD6 O
inhibitors O
as O
potential O
drugs O
. O

Toosendanin B
induces O
apoptosis O
through O
suppression O
of O
JNK O
signaling O
pathway O
in O
HL O
- O
60 O
cells O
. O

Toosendanin B
( O
TSN B
) O
, O
a O
triterpenoid B
isolated O
from O
Melia O
toosendan O
Sieb O
. O

et O
Zucc O
. O
, O
has O
been O
found O
to O
suppress O
proliferation O
and O
induce O
apoptosis O
in O
a O
variety O
of O
human O
cancer O
cells O
. O

However O
, O
the O
mechanism O
how O
TSN B
induces O
apoptosis O
remains O
poorly O
understood O
. O

In O
this O
study O
, O
we O
examined O
the O
effects O
of O
TSN B
on O
the O
growth O
, O
cell O
cycle O
arrest O
, O
induction O
of O
apoptosis O
and O
the O
involved O
signaling O
pathway O
in O
human O
promyelocytic O
leukemia O
HL O
- O
60 O
cells O
. O

Proliferation O
of O
HL O
- O
60 O
cells O
was O
inhibited O
in O
a O
dose O
- O
dependent O
manner O
with O
the O
IC O
( O
50 O
( O
48 O
h O
) O
) O
of O
28 O
ng O
/ O
mL O
. O

The O
growth O
inhibition O
was O
due O
primarily O
to O
the O
S O
phase O
arrest O
and O
cell O
apoptosis O
. O

Cell O
apoptosis O
induced O
by O
TSN O
was O
confirmed O
by O
Annexin O
V O
- O
FITC B
/ O
propidium B
iodide I
staining O
. O

The O
increase O
of O
the O
pro O
- O
apoptotic O
protein O
Bax O
, O
cleaved O
PARP O
and O
caspase O
- O
3 O
, O
and O
the O
decrease O
of O
anti O
- O
apoptotic O
protein O
Bcl O
- O
2 O
were O
observed O
. O

Western O
blot O
analysis O
indicated O
that O
TSN O
inhibits O
the O
CDC42 O
/ O
MEKK1 O
/ O
JNK O
pathway O
. O

Taken O
together O
, O
our O
study O
suggested O
, O
for O
the O
first O
time O
, O
that O
the O
pro O
- O
apoptotic O
effects O
of O
TSN O
on O
HL O
- O
60 O
cells O
were O
mediated O
through O
JNK O
signaling O
pathway O
. O

Griseofulvin B
inhibits O
the O
growth O
of O
adrenocortical O
cancer O
cells O
in O
vitro O
. O

Supernumerary O
centrosomes O
and O
aneuploidy O
are O
associated O
with O
a O
malignant O
phenotype O
of O
tumor O
cells O
. O

Centrosomal O
clustering O
is O
a O
mechanism O
used O
by O
cancer O
cells O
with O
supernumerary O
centrosomes O
to O
solve O
the O
threatening O
problem O
of O
multipolar O
spindles O
. O

Griseofulvin B
is O
an O
antifungal O
substance O
that O
interferes O
with O
the O
microtubule O
apparatus O
and O
inhibits O
centrosomal O
clustering O
. O

It O
has O
also O
been O
demonstrated O
that O
griseofulvin B
inhibits O
the O
growth O
of O
tumor O
cells O
in O
vitro O
and O
in O
vivo O
. O

However O
, O
it O
is O
not O
yet O
known O
whether O
treatment O
with O
griseofulvin B
inhibits O
growth O
of O
adrenocortical O
tumor O
cells O
. O

We O
studied O
the O
viability O
and O
antiproliferative O
effects O
of O
griseofulvin B
on O
cultured O
NCI O
- O
H295R O
adrenocortical O
carcinoma O
cells O
using O
Wst O
- O
1 O
- O
, O
BrdUrd O
- O
, O
and O
[ B
3H I
] I
- I
thymidine I
assays O
. O

For O
the O
detection O
of O
apoptosis O
we O
used O
a O
caspase O
3 O
/ O
7 O
cleavage O
assay O
and O
light O
microscopy O
techniques O
. O

We O
observed O
that O
incubation O
with O
griseofulvin B
for O
24 O
- O
48 O
h O
leads O
to O
a O
decrease O
in O
the O
viability O
and O
proliferation O
of O
NCI O
- O
H295R O
cells O
in O
a O
dose O
- O
dependent O
manner O
. O

Significant O
effects O
could O
be O
observed O
after O
incubation O
with O
griseofulvin B
as O
measured O
by O
Wst O
- O
1 O
- O
, O
BrdUrd O
- O
, O
and O
[ B
3H I
] I
dT I
- O
uptake O
assays O
. O

Apoptosis O
of O
NCI O
- O
H295R O
cells O
was O
increased O
in O
a O
dose O
- O
dependent O
manner O
up O
to O
4 O
. O
5 O
- O
fold O
after O
incubation O
with O
griseofulvin B
40 O
mu O
M O
for O
24 O
h O
as O
shown O
by O
caspase O
3 O
/ O
7 O
cleavage O
assay O
and O
light O
microscopy O
. O

With O
regard O
to O
new O
treatment O
strategies O
for O
adrenocortical O
cancer O
, O
griseofulvin B
, O
and O
possibly O
other O
agents O
, O
which O
interfere O
with O
the O
microtubule O
apparatus O
and O
inhibit O
centrosomal O
clustering O
, O
may O
turn O
out O
to O
be O
interesting O
targets O
for O
further O
research O
. O

Nano O
- O
titanium B
dioxide I
induces O
genotoxicity O
and O
apoptosis O
in O
human O
lung O
cancer O
cell O
line O
, O
A549 O
. O

The O
increased O
inhaled O
application O
of O
titanium B
dioxide I
nanoparticles O
( O
TiO B
( I
2 I
) I
NPs O
) O
increases O
the O
potential O
pulmonary O
health O
risks O
. O

The O
present O
investigations O
were O
carried O
out O
to O
study O
the O
TiO B
( I
2 I
) I
NPs O
- O
induced O
apoptosis O
, O
oxidative O
stress O
and O
genotoxicity O
in O
the O
human O
lung O
cancer O
cell O
line O
, O
A549 O
, O
a O
widely O
used O
cell O
system O
for O
pulmonary O
toxicity O
studies O
. O

Tetrazolium B
bromide I
salt I
and O
lactate B
dehydrogenase O
release O
assays O
were O
used O
to O
study O
the O
cytotoxicity O
. O

The O
genotoxicity O
studies O
were O
carried O
out O
using O
cytokinesis O
block O
micronucleus O
assay O
. O

Apoptosis O
was O
confirmed O
by O
the O
formation O
of O
apoptotic O
bodies O
and O
altered O
expression O
( O
messenger O
RNA O
( O
mRNA O
) O
and O
protein O
) O
of O
markers O
such O
as O
P O
( O
53 O
) O
, O
P O
( O
21 O
) O
, O
Bax O
, O
Bcl O
( O
2 O
) O
and O
cleaved O
caspase O
- O
3 O
. O

Cells O
exposed O
to O
TiO B
( I
2 I
) I
NPs O
( O
10 O
and O
50 O
mu O
g O
/ O
ml O
) O
for O
6 O
- O
24 O
h O
shows O
significant O
induction O
in O
oxidative O
stress O
, O
that O
is O
, O
the O
production O
of O
reactive O
oxygen B
species O
and O
malondialdehyde B
and O
decrease O
in O
the O
activity O
of O
catalase O
and O
glutathione B
. O

TiO B
( I
2 I
) I
NPs O
exposure O
also O
induces O
the O
formation O
of O
apoptotic O
bodies O
and O
micronucleus O
as O
marker O
of O
genotoxicity O
. O

A O
significant O
up O
- O
regulation O
in O
the O
expression O
of O
apoptosis O
markers O
such O
as O
P O
( O
53 O
) O
, O
P O
( O
21 O
) O
and O
cleaved O
caspase O
- O
3 O
was O
observed O
, O
while O
the O
levels O
were O
down O
- O
regulated O
for O
Bcl O
( O
2 O
) O
at O
both O
mRNA O
and O
protein O
levels O
. O

TiO B
( I
2 I
) I
NPs O
exposure O
could O
not O
pose O
significant O
effects O
on O
Bax O
expression O
. O

Data O
indicate O
that O
nano O
- O
TiO B
( I
2 I
) I
induces O
oxidative O
stress O
, O
genotoxicity O
and O
apoptosis O
in O
human O
lung O
cancer O
cell O
line O
, O
A549 O
. O

Our O
result O
also O
identifies O
the O
mechanisms O
involved O
in O
TiO B
( I
2 I
) I
NP O
- O
induced O
changes O
in O
A549 O
cells O
. O

Perhaps O
, O
reporting O
for O
the O
first O
time O
, O
the O
association O
of O
TiO B
( I
2 I
) I
NPs O
- O
induced O
genotoxicity O
and O
apoptosis O
at O
transcriptional O
and O
translational O
level O
in O
the O
human O
lung O
cancer O
cell O
line O
, O
A549 O
cells O
. O

The O
antinociceptive O
effects O
of O
nicotinic O
receptors O
alpha O
7 O
- O
positive O
allosteric O
modulators O
in O
murine O
acute O
and O
tonic O
pain O
models O
. O

The O
alpha O
7 O
nicotinic O
acetylcholine B
receptor O
( O
nAChR O
) O
subtype O
is O
abundantly O
expressed O
in O
the O
central O
nervous O
system O
and O
in O
the O
periphery O
. O

Recent O
evidence O
suggests O
that O
alpha O
7 O
nAChR O
subtypes O
, O
which O
can O
be O
activated O
by O
an O
endogenous O
cholinergic O
tone O
, O
comprising O
acetylcholine B
and O
the O
alpha O
7 O
nAChR O
agonist O
choline B
, O
play O
an O
important O
role O
in O
subchronic O
pain O
and O
inflammation O
. O

This O
study O
' O
s O
objective O
was O
to O
test O
whether O
alpha O
7 O
nAChR O
positive O
allosteric O
modulators O
( O
PAMs O
) O
produce O
antinociception O
in O
in O
vivo O
mouse O
models O
of O
acute O
and O
persistent O
pain O
. O

Testing O
type O
I O
[ O
N B
- I
( I
5 I
- I
chloro I
- I
2 I
- I
hydroxyphenyl I
) I
- I
N I
' I
- I
[ I
2 I
- I
chloro I
- I
5 I
- I
( I
trifluoromethyl I
) I
phenyl I
] I
( O
NS1738 B
) O
] O
and O
type O
II O
[ O
1 B
- I
( I
5 I
- I
chloro I
- I
2 I
, I
4 I
- I
dimethoxy I
- I
phenyl I
) I
- I
3 I
- I
( I
5 I
- I
methyl I
- I
isoxazol I
- I
3 I
- I
yl I
) I
( O
PNU B
- I
120596 I
) O
] O
alpha O
7 O
nAChR O
PAMs O
in O
acute O
and O
persistent O
pain O
, O
we O
found O

that O
, O
although O
neither O
reduced O
acute O
thermal O
pain O
, O
only O
PNU B
- I
120596 I
dose O
- O
dependently O
attenuated O
paw O
- O
licking O
behavior O
in O
the O
formalin B
test O
. O

The O
long O
- O
acting O
effect O
of O
PNU B
- I
120596 I
in O
this O
test O
was O
in O
discordance O
with O
its O
pharmacokinetic O
profile O
in O
mice O
, O
which O
suggests O
the O
involvement O
of O
postreceptor O
signaling O
mechanisms O
. O

Our O
results O
with O
selective O
mitogen O
- O
activated O
protein O
kinase O
kinase O
inhibitor O
1 B
, I
4 I
- I
diamino I
- I
2 I
, I
3 I
- I
dicyano I
- I
1 I
, I
4 I
- I
bis I
( I
o I
- I
aminophenylmercapto I
) I
butadiene I
monoethanolate I
( O
U0126 B
) O
argues O
for O
an O
important O
role O
of O
extracellular O
signal O
- O
regulated O
kinase O
- O
1 O
/ O
2 O
pathways O
activation O
in O
PNU B
- I
120596 I
' O
s O
antinociceptive O
effects O
. O

The O
alpha O
7 O
antagonist O
MLA B
, O
administered O
intrathecally O
, O
reversed O
PNU B
- I
120596 I
' O
s O
effects O
, O
confirming O
PNU B
- I
120596 I
' O
s O
action O
, O
in O
part O
, O
through O
central O
alpha O
7 O
nAChRs O
. O

Importantly O
, O
tolerance O
to O
PNU B
- I
120596 I
was O
not O
developed O
after O
subchronic O
treatment O
of O
the O
drug O
. O

Surprisingly O
, O
PNU B
- I
120596 I
' O
s O
antinociceptive O
effects O
were O
blocked O
by O
NS1738 B
. O

Our O
results O
indicate O
that O
type O
II O
alpha O
7 O
nAChR O
PAM O
PNU B
- I
120596 I
, O
but O
not O
type O
I O
alpha O
7 O
nAChR O
PAM O
NS1738 B
, O
shows O
significant O
antinociception O
effects O
in O
persistent O
pain O
models O
in O
mice O
. O

A O
cyclometallated B
iridium I
( I
III I
) I
complex O
as O
a O
c O
- O
myc O
G O
- O
quadruplex O
stabilizer O
and O
down O
- O
regulator O
of O
c O
- O
myc O
oncogene O
expression O
. O

A O
new O
cyclometallated O
iridium I
( I
III I
) I
complex O
with O
the O
2 B
, I
2 I
' I
- I
biquinoline I
N B
- O
donor O
ligand O
has O
been O
synthesized O
and O
characterized O
. O

The O
interaction O
and O
affinity O
of O
the O
complex O
towards O
c O
- O
myc O
G O
- O
quadruplex O
and O
duplex O
DNA O
have O
been O
investigated O
using O
UV O
/ O
Vis O
spectroscopy O
and O
gel O
mobility O
shift O
assay O
. O

These O
studies O
revealed O
that O
complex O
1 O
binds O
to O
c O
- O
myc O
G O
- O
quadruplexes O
( O
Pu22 O
and O
Pu27 O
) O
with O
high O
affinity O
but O
does O
not O
interact O
with O
duplex O
DNA O
either O
by O
intercalation O
or O
groove O
binding O
. O

The O
ability O
of O
1 O
to O
stabilize O
c O
- O
myc O
G O
- O
quadruplex O
DNA O
in O
vitro O
has O
also O
been O
examined O
through O
a O
PCR O
stop O
assay O
and O
a O
cell O
- O
based O
luciferase O
reporter O
assay O
. O

Complex O
1 O
displays O
promising O
cytotoxic O
activity O
against O
the O
HeLa O
cell O
line O
with O
sub O
- O
micromolar O
potency O
. O

Platycodin B
D I
attenuates O
bile O
duct O
ligation O
- O
induced O
hepatic O
injury O
and O
fibrosis O
in O
mice O
. O

Platycodin B
D I
( O
PD O
) O
is O
the O
major O
triterpene B
saponin I
in O
the O
root O
of O
Platycodon O
grandiflorum O
. O

The O
aim O
of O
the O
present O
study O
was O
to O
evaluate O
the O
protective O
effects O
of O
PD O
on O
bile O
duct O
ligation O
( O
BDL O
) O
- O
induced O
cholestasis O
in O
mice O
. O

Mice O
were O
allocated O
to O
five O
groups O
: O
sham O
, O
BDL O
alone O
, O
and O
BDL O
with O
PD O
treatment O
at O
1 O
, O
2 O
, O
and O
4mg O
/ O
kg O
. O

PD O
was O
administered O
to O
the O
mice O
for O
28 O
consecutive O
days O
after O
the O
BDL O
operation O
. O

PD O
treatment O
of O
BDL O
- O
operated O
mice O
decreased O
serum O
alanine B
aminotransferase O
, O
serum O
aspartate B
aminotransferase O
, O
and O
total O
bilirubin B
levels O
by O
up O
to O
37 O
% O
, O
31 O
% O
, O
and O
41 O
% O
, O
respectively O
, O
in O
comparison O
with O
the O
levels O
in O
mice O
that O
underwent O
BDL O
alone O
. O

PD O
treatment O
attenuated O
oxidative O
stress O
, O
as O
evidenced O
by O
an O
increase O
in O
anti O
- O
oxidative O
enzyme O
levels O
glutathione B
and O
superoxide B
dismutase O
together O
with O
a O
decrease O
in O
lipid O
peroxidation O
and O
oxidative O
stress O
indices O
levels O
of O
malondialdehyde B
and O
nitric B
oxide I
. O

Histopathological O
studies O
further O
confirmed O
the O
protective O
effects O
of O
PD O
on O
cholestasis O
- O
induced O
hepatic O
injury O
and O
liver O
fibrosis O
in O
mice O
. O

In O
addition O
, O
nuclear O
factor O
- O
kappa O
B O
and O
inducible O
nitric B
oxide I
synthase O
levels O
significantly O
decreased O
after O
PD O
treatment O
, O
as O
did O
the O
levels O
of O
hepatocyte O
apoptosis O
. O

Taken O
together O
, O
these O
results O
suggest O
that O
PD O
treatment O
might O
be O
beneficial O
in O
cholestasis O
- O
induced O
hepatotoxicity O
. O

Endocrine O
disruptive O
potential O
of O
endosulfan B
on O
the O
reproductive O
axis O
of O
Cichlasoma O
dimerus O
( O
Perciformes O
, O
Cichlidae O
) O
. O

Endosulfan B
( O
ES O
) O
, O
a O
persistent O
organochlorine B
pesticide O
, O
is O
widely O
used O
despite O
its O
toxicity O
to O
non O
- O
target O
animals O
. O

Upon O
reaching O
water O
bodies O
, O
ES O
can O
cause O
negative O
effects O
on O
aquatic O
animals O
, O
including O
disruption O
of O
hormonal O
systems O
. O

However O
, O
the O
action O
of O
ES O
on O
fish O
reproductive O
axis O
has O
been O
hardly O
studied O
thus O
far O
. O

The O
aim O
of O
the O
present O
work O
was O
to O
assess O
the O
endocrine O
disruptive O
potential O
of O
endosulfan B
on O
the O
pituitary O
gonadotropins O
levels O
and O
on O
the O
testes O
function O
due O
to O
ES O
in O
the O
South O
American O
freshwater O
fish O
Cichlasoma O
dimerus O
, O
using O
in O
vitro O
and O
in O
vivo O
approaches O
. O

In O
vitro O
experiments O
showed O
that O
ES O
inhibited O
the O
LH O
- O
stimulated O
steroidogenesis O
in O
gonads O
; O
no O
change O
was O
observed O
in O
gonadotropins O
release O
from O
pituitaries O
in O
culture O
. O

Laboratory O
waterborne O
ES O
( O
0 O
. O
1 O
, O
0 O
. O
3 O
and O
1 O
mu O
g O
/ O
L O
) O
exposure O
for O
two O
months O
caused O
decrease O
in O
beta O
FSH O
pituitary O
content O
and O
gamma O
GT O
activity O
in O
the O
testes O
( O
Sertoli O
cell O
function O
marker O
) O
. O

Testicular O
histology O
revealed O
pathologies O
such O
as O
scarce O
intermediate O
stages O
of O
spermatogenesis O
, O
release O
of O
immature O
germ O
cells O
into O
the O
lobular O
lumen O
, O
presence O
of O
foam O
cells O
and O
interstitial O
fibrosis O
. O

As O
FSH O
and O
FSH O
- O
mediated O
steroidogenesis O
regulate O
spermatogenesis O
and O
Sertoli O
cell O
function O
, O
the O
effect O
of O
ES O
on O
FSH O
could O
be O
responsible O
for O
the O
morphological O
alterations O
observed O
in O
testes O
. O

In O
vitro O
, O
ES O
disrupted O
steroidogenesis O
in O
gonads O
, O
therefore O
similar O
effects O
in O
vivo O
cannot O
be O
ruled O
out O
. O

Based O
on O
this O
evidence O
, O
ES O
exhibits O
an O
endocrine O
disruptive O
action O
on O
the O
reproductive O
axis O
of O
C O
. O
dimerus O
, O
causing O
disruption O
at O
the O
pituitary O
and O
/ O
or O
at O
the O
gonad O
level O
. O

These O
effects O
could O
acquire O
ecological O
significance O
under O
prolonged O
exposure O
to O
the O
pesticide O
in O
nature O
. O

Antiarrhythmic O
effects O
of O
( B
- I
) I
- I
epicatechin I
- I
3 I
- I
gallate I
, O
a O
novel O
sodium B
channel O
agonist O
in O
cultured O
neonatal O
rat O
ventricular O
myocytes O
. O

( B
- I
) I
- I
Epicatechin I
- I
3 I
- I
gallate I
( O
ECG B
) O
, O
a O
polyphenol B
extracted O
from O
green O
tea O
, O
has O
been O
proposed O
as O
an O
effective O
compound O
for O
improving O
cardiac O
contractility O
. O

However O
, O
the O
therapeutic O
potential O
of O
ECG O
on O
the O
treatment O
of O
arrhythmia O
remains O
unknown O
. O

We O
investigated O
the O
direct O
actions O
of O
ECG O
on O
the O
modulation O
of O
ion O
currents O
and O
cardiac O
cell O
excitability O
in O
the O
primary O
culture O
of O
neonatal O
rat O
ventricular O
myocyte O
( O
NRVM O
) O
, O
which O
is O
considered O
a O
hypertrophic O
model O
for O
analysis O
of O
myocardial O
arrhythmias O
. O

By O
using O
the O
whole O
- O
cell O
patch O
- O
clamp O
configurations O
, O
we O
found O
ECG O
enhanced O
the O
slowly O
inactivating O
component O
of O
voltage O
- O
gated O
Na B
( I
+ I
) I
currents O
( O
I O
( O
Na B
) O
) O
in O
a O
concentration O
- O
dependent O
manner O
( O
0 O
. O
1 O
- O
100 O
mu O
M O
) O
with O
an O
EC O
( O
50 O
) O
value O
of O
3 O
. O
8 O
mu O
M O
. O

ECG O
not O
only O
shifted O
the O
current O
- O
voltage O
relationship O
of O
peak O
I O
( O
Na B
) O
to O
the O
hyperpolarizing O
direction O
but O
also O
accelerated O
I O
( O
Na B
) O
recovery O
kinetics O
. O

Working O
at O
a O
concentration O
level O
of O
I O
( O
Na B
) O
enhancement O
, O
ECG O
has O
no O
notable O
effect O
on O
voltage O
- O
gated O
K B
( I
+ I
) I
currents O
and O
L O
- O
type O
Ca B
( I
2 I
+ I
) I
currents O
. O

With O
culture O
time O
increment O
, O
the O
firing O
rate O
of O
spontaneous O
action O
potential O
( O
sAP O
) O
in O
NRVMs O
was O
gradually O
decreased O
until O
spontaneous O
early O
after O
- O
depolarization O
( O
EAD O
) O
was O
observed O
after O
about O
one O
week O
culture O
. O

ECG O
increased O
the O
firing O
rate O
of O
normal O
sAP O
about O
two O
- O
fold O
without O
waveform O
alteration O
. O

Interestingly O
, O
the O
bradycardia O
- O
dependent O
EAD O
could O
be O
significantly O
restored O
by O
ECG O
in O
fast O
firing O
rate O
to O
normal O
sAP O
waveform O
. O

The O
expression O
of O
dominant O
cardiac O
sodium B
channel O
subunit O
, O
Nav1 O
. O
5 O
, O
was O
consistently O
detected O
throughout O
the O
culture O
periods O
. O

Our O
results O
reveal O
how O
ECG O
, O
the O
novel O
I O
( O
Na B
) O
agonist O
, O
may O
act O
as O
a O
promising O
candidate O
in O
clinical O
applications O
on O
cardiac O
arrhythmias O
. O

Acetylcholinesterase O
and O
agrin O
: O
Different O
functions O
, O
similar O
expression O
patterns O
, O
multiple O
roles O
. O

Acetylcholinesterase O
( O
AChE O
) O
and O
agrin O
play O
unique O
functional O
roles O
in O
the O
neuromuscular O
junction O
( O
NMJ O
) O
. O

AChE O
is O
a O
cholinergic O
and O
agrin O
a O
synaptogenetic O
component O
. O

In O
spite O
of O
their O
different O
functions O
, O
they O
share O
several O
common O
features O
: O
their O
targeting O
is O
determined O
by O
alternative O
splicing O
; O
unlike O
most O
other O
NMJ O
components O
they O
are O
expressed O
in O
both O
, O
muscle O
and O
motor O
neuron O
and O
both O
reside O
on O
the O
synaptic O
basal O
lamina O
of O
the O
NMJ O
. O

Also O
, O
both O
were O
reported O
to O
play O
various O
nonjunctional O
roles O
. O

However O
, O
while O
the O
origin O
of O
basal O
lamina O
bound O
agrin O
is O
undoubtedly O
neural O
, O
the O
neural O
origin O
of O
AChE O
, O
which O
is O
anchored O
to O
the O
basal O
lamina O
with O
collagenic O
tail O
ColQ O
, O
is O
elusive O
. O

Hypothesizing O
that O
motor O
neuron O
proteins O
targeted O
to O
the O
NMJ O
basal O
lamina O
share O
common O
temporal O
pattern O
of O
expression O
, O
which O
is O
coordinated O
with O
the O
formation O
of O
basal O
lamina O
, O
we O
compared O
expression O
of O
agrin O
isoforms O
with O
the O
expression O
of O
AChE O
- O
T O
and O
ColQ O
in O
the O
developing O
rat O
spinal O
cord O
at O
the O
stages O
before O
and O
after O
the O
formation O
of O
NMJ O
basal O
lamina O
. O

Cellular O
origin O
of O
AChE O
- O
T O
and O
agrin O
was O
determined O
by O
in O
situ O
hybridization O
and O
their O
quantitative O
levels O
by O
RT O
PCR O
. O

We O
found O
parallel O
increase O
in O
expression O
of O
the O
synaptogenetic O
( O
agrin O
8 O
) O
isoform O
of O
agrin O
and O
ColQ O
after O
the O
formation O
of O
basal O
lamina O
supporting O
the O
view O
that O
ColQ O
bound O
AChE O
and O
agrin O
8 O
isoform O
are O
destined O
to O
the O
basal O
lamina O
. O

Catalytic O
AChE O
- O
T O
subunit O
and O
agrin O
isoforms O
19 O
and O
0 O
followed O
different O
expression O
patterns O
. O

In O
accordance O
with O
the O
reports O
of O
other O
authors O
, O
our O
investigations O
also O
revealed O
various O
alternative O
functions O
for O
AChE O
and O
agrin O
. O

We O
have O
already O
demonstrated O
participation O
of O
AChE O
in O
myoblast O
apoptosis O
; O
here O
we O
present O
the O
evidence O
that O
agrin O
promotes O
the O
maturation O
of O
heavy O
myosin O
chains O
and O
the O
excitation O
- O
contraction O
coupling O
. O

These O
results O
show O
that O
common O
features O
of O
AChE O
and O
agrin O
extend O
to O
their O
capacity O
to O
play O
multiple O
roles O
in O
muscle O
development O
. O

Sodium B
/ I
iodide I
symporter O
is O
expressed O
in O
the O
majority O
of O
seminomas O
and O
embryonal O
testicular O
carcinomas O
. O

Testicular O
cancer O
is O
the O
most O
frequent O
cancer O
in O
young O
men O
. O

The O
large O
majority O
of O
patients O
have O
a O
good O
prognosis O
, O
but O
in O
a O
small O
group O
of O
tumors O
, O
the O
current O
treatments O
are O
not O
effective O
. O

Radioiodine B
is O
routinely O
used O
in O
the O
treatment O
of O
thyroid O
cancer O
and O
is O
currently O
investigated O
as O
a O
potential O
therapeutic O
tool O
even O
for O
extra O
- O
thyroid O
tumors O
able O
to O
concentrate O
this O
radioisotope O
. O

Expression O
of O
Na B
( I
+ I
) I
/ O
I B
( I
- I
) I
symporter O
( O
NIS O
( O
SLC5A5 O
) O
) O
, O
the O
glycoprotein O
responsible O
for O
iodide B
transport O
, O
has O
been O
demonstrated O
in O
normal O
testicular O
tissue O
. O

In O
this O
study O
, O
we O
analyzed O
NIS O
expression O
in O
a O
large O
series O
of O
testicular O
carcinomas O
. O

Our O
retrospective O
series O
included O
107 O
patients O
operated O
for O
testicular O
tumors O
: O
98 O
typical O
seminomas O
, O
six O
embryonal O
carcinomas O
, O
one O
mixed O
embryonal O
choriocarcinoma O
, O
and O
two O
Leydig O
cells O
tumors O
. O

Expression O
and O
regulation O
of O
NIS O
mRNA O
and O
protein O
levels O
were O
also O
investigated O
in O
human O
embryonal O
testicular O
carcinoma O
cells O
( O
NTERA O
) O
by O
real O
- O
time O
RT O
- O
PCR O
and O
western O
blotting O
respectively O
. O

Immunohistochemical O
analysis O
showed O
the O
presence O
of O
NIS O
in O
the O
large O
majority O
of O
seminomas O
( O
90 O
/ O
98 O
) O
and O
embryonal O
carcinomas O
( O
5 O
/ O
7 O
) O
of O
the O
testis O
but O
not O
in O
Leydig O
cell O
carcinomas O
. O

Expression O
of O
NIS O
protein O
was O
significantly O
associated O
with O
lymphovascular O
invasion O
. O

In O
NTERA O
cells O
treated O
with O
the O
histone O
deacetylase O
inhibitors O
SAHA B
and O
valproic B
acid I
, O
a O
significant O
increase O
in O
NIS O
mRNA O
( O
about O
60 O
- O
and O
30 O
- O
fold O
vs O
control O
, O
P O
< O
0 O
. O
001 O
and O
P O
< O
0 O
. O
01 O
respectively O
) O
and O
protein O
levels O
, O
resulting O
in O
enhanced O
ability O
to O
uptake O
radioiodine B
, O
was O
observed O
. O

Finally O
, O
NIS O
expression O
in O
testicular O
tumors O
with O
the O
more O
aggressive O
behavior O
is O
of O
interest O
for O
the O
potential O
use O
of O
targeting O
NIS O
to O
deliver O
radioiodine O
in O
malignant O
cells O
. O

Evaluation O
of O
the O
relationship O
between O
sex O
, O
polymorphisms O
in O
CYP2C8 O
and O
CYP2C9 O
, O
and O
pharmacokinetics O
of O
angiotensin O
receptor O
blockers O
. O

Angiotensin O
II O
receptor O
blockers O
( O
ARBs O
) O
are O
used O
to O
treat O
hypertension O
. O

Most O
ARBs O
are O
metabolized O
by O
CYP2C9 O
. O

The O
aim O
of O
this O
study O
is O
to O
evaluate O
the O
possible O
association O
between O
sex O
, O
polymorphisms O
in O
the O
CYP2C8 O
and O
CYP2C9 O
genes O
, O
and O
the O
pharmacokinetics O
of O
losartan B
, O
valsartan B
, O
candesartan B
, O
and O
telmisartan B
. O

The O
study O
population O
comprised O
246 O
healthy O
volunteers O
from O
seven O
single O
- O
dose O
clinical O
trials O
: O
64 O
from O
two O
candesartan B
studies O
, O
43 O
from O
a O
telmisartan B
study O
, O
36 O
from O
a O
losartan B
study O
, O
and O
103 O
from O
three O
valsartan B
studies O
. O

DNA O
was O
extracted O
from O
blood O
samples O
and O
single O
- O
nucleotide O
polymorphisms O
in O
the O
CYP2C8 O
( O
CYP2C8 O
* O
2 O
, O
CYP2C8 O
* O
3 O
, O
CYP2C8 O
* O
4 O
, O
CYP2C8 O
* O
5 O
) O
and O
CYP2C9 O
( O
CYP2C9 O
* O
2 O
, O
CYP2C9 O
* O
3 O
) O
genes O
were O
evaluated O
using O
real O
- O
time O
polymerase O
chain O
reaction O
. O

Sex O
only O
affected O
telmisartan B
pharmacokinetics O
, O
since O
women O
showed O
a O
higher O
telmisartan B
C O
( O
max O
) O
than O
men O
( O
590 O
. O
5 O
+ O
/ O
- O
75 O
. O
8 O
ng O
/ O
ml O
versus O
282 O
. O
1 O
+ O
/ O
- O
30 O
. O
8 O
ng O
/ O
ml O
; O
P O
< O
= O
0 O
. O
01 O
) O
. O

CYP2C9 O
variants O
were O
associated O
only O
with O
losartan B
pharmacokinetics O
: O
the O
half O
- O
life O
of O
losartan B
was O
higher O
in O
CYP2C9 O
* O
3 O
allele O
carriers O
( O
3 O
. O
1 O
+ O
/ O
- O
0 O
. O
4 O
hours O
) O
than O
in O
volunteers O
with O
the O
wild O
- O
type O
genotype O
( O
2 O
. O
3 O
+ O
/ O
- O
0 O
. O
1 O
hours O
) O
( O
P O
< O
= O
0 O
. O
05 O
) O
. O

CYP2C8 O
polymorphisms O
were O
associated O
only O
with O
valsartan B
pharmacokinetics O
, O
since O
* O
2 O
allele O
carriers O
showed O
faster O
clearance O
( O
1 O
. O
07 O
+ O
/ O
- O
0 O
. O
57 O
l O
/ O
h O
. O
kg O
) O
than O
those O
with O
the O
wild O
- O
type O
genotype O
( O
0 O
. O
48 O
+ O
/ O
- O
0 O
. O
72 O
l O
/ O
h O
. O
kg O
; O
P O
< O
= O
0 O
. O
01 O
) O
and O
carriers O
of O
the O
* O
3 O
allele O
( O
0 O
. O
35 O
+ O
/ O
- O
0 O
. O
49 O
l O
/ O
h O
. O
kg O
; O
P O
< O
= O
0 O
. O
001 O
) O
. O

These O
results O
suggest O
that O
genotypes O
for O
CYP2C9 O
and O
CYP2C8 O
are O
relevant O
to O
the O
pharmacokinetics O
of O
losartan B
and O
valsartan B
, O
respectively O
, O
but O
not O
the O
pharmacokinetics O
of O
candesartan B
or O
telmisartan B
. O

SpliceAid O
- O
F O
: O
a O
database O
of O
human O
splicing O
factors O
and O
their O
RNA O
- O
binding O
sites O
. O

A O
comprehensive O
knowledge O
of O
all O
the O
factors O
involved O
in O
splicing O
, O
both O
proteins O
and O
RNAs O
, O
and O
of O
their O
interaction O
network O
is O
crucial O
for O
reaching O
a O
better O
understanding O
of O
this O
process O
and O
its O
functions O
. O

A O
large O
part O
of O
relevant O
information O
is O
buried O
in O
the O
literature O
or O
collected O
in O
various O
different O
databases O
. O

By O
hand O
- O
curated O
screenings O
of O
literature O
and O
databases O
, O
we O
retrieved O
experimentally O
validated O
data O
on O
71 O
human O
RNA O
- O
binding O
splicing O
regulatory O
proteins O
and O
organized O
them O
into O
a O
database O
called O
' O
SpliceAid O
- O
F O
' O
( O
http O
: O
/ O
/ O
www O
. O
caspur O
. O
it O
/ O
SpliceAidF O
/ O
) O
. O

For O
each O
splicing O
factor O
( O
SF O
) O
, O
the O
database O
reports O
its O
functional O
domains O
, O
its O
protein O
and O
chemical O
interactors O
and O
its O
expression O
data O
. O

Furthermore O
, O
we O
collected O
experimentally O
validated O
RNA O
- O
SF O
interactions O
, O
including O
relevant O
information O
on O
the O
RNA O
- O
binding O
sites O
, O
such O
as O
the O
genes O
where O
these O
sites O
lie O
, O
their O
genomic O
coordinates O
, O
the O
splicing O
effects O
, O
the O
experimental O
procedures O
used O
, O
as O
well O
as O
the O
corresponding O
bibliographic O
references O
. O

We O
also O
collected O
information O
from O
experiments O
showing O
no O
RNA O
- O
SF O
binding O
, O
at O
least O
in O
the O
assayed O
conditions O
. O

In O
total O
, O
SpliceAid O
- O
F O
contains O
4227 O
interactions O
, O
2590 O
RNA O
- O
binding O
sites O
and O
1141 O
' O
no O
- O
binding O
' O
sites O
, O
including O
information O
on O
cellular O
contexts O
and O
conditions O
where O
binding O
was O
tested O
. O

The O
data O
collected O
in O
SpliceAid O
- O
F O
can O
provide O
significant O
information O
to O
explain O
an O
observed O
splicing O
pattern O
as O
well O
as O
the O
effect O
of O
mutations O
in O
functional O
regulatory O
elements O
. O

Mapping O
of O
Saccharomyces O
cerevisiae O
metabolites O
in O
fermenting O
wheat O
straight O
- O
dough O
reveals O
succinic B
acid I
as O
pH O
- O
determining O
factor O
. O

Fermenting O
yeast O
does O
not O
merely O
cause O
dough O
leavening O
, O
but O
also O
contributes O
to O
the O
bread O
aroma O
and O
might O
alter O
dough O
rheology O
. O

Here O
, O
the O
yeast O
carbon B
metabolism O
was O
mapped O
during O
bread O
straight O
- O
dough O
fermentation O
. O

The O
concentration O
of O
most O
metabolites O
changed O
quasi O
linearly O
as O
a O
function O
of O
fermentation O
time O
. O

Ethanol B
and O
carbon B
dioxide I
concentrations O
reached O
up O
to O
60 O
mmol O
/ O
100g O
flour O
. O

Interestingly O
, O
high O
levels O
of O
glycerol B
( O
up O
to O
10 O
mmol O
/ O
100g O
flour O
) O
and O
succinic B
acid I
( O
up O
to O
1 O
. O
6 O
mmol O
/ O
100g O
flour O
) O
were O
produced O
during O
dough O
fermentation O
. O

Further O
tests O
showed O
that O
, O
contrary O
to O
current O
belief O
, O
the O
pH O
decrease O
in O
fermenting O
dough O
is O
primarily O
caused O
by O
the O
production O
of O
succinic B
acid I
by O
the O
yeast O
instead O
of O
carbon B
dioxide I
dissolution O
or O
bacterial O
organic O
acids O
. O

Together O
, O
our O
results O
provide O
a O
comprehensive O
overview O
of O
metabolite O
production O
during O
dough O
fermentation O
and O
yield O
insight O
into O
the O
importance O
of O
some O
of O
these O
metabolites O
for O
dough O
properties O
. O

Preparative O
separation O
and O
purification O
of O
sulforaphene B
from O
radish O
seeds O
by O
high O
- O
speed O
countercurrent O
chromatography O
. O

Sulforaphene B
, O
a O
kind O
of O
isothiocyanates B
, O
derived O
from O
glucoraphenin B
which O
is O
the O
important O
ingredient O
of O
radish O
( O
Raphanus O
sativus O
L O
. O
) O
seeds O
, O
has O
shown O
significant O
pharmacological O
activities O
. O

In O
this O
paper O
, O
the O
separation O
and O
purification O
of O
sulforaphene B
from O
radish O
seeds O
, O
was O
achieved O
by O
high O
- O
speed O
countercurrent O
chromatography O
( O
HSCCC O
) O
. O

A O
two O
- O
phase O
solvent O
system O
consisted O
of O
n B
- I
hexane I
- O
ethyl B
acetate I
- O
methanol B
- O
water O
( O
35 O
: O
100 O
: O
35 O
: O
100 O
, O
v O
/ O
v O
/ O
v O
/ O
v O
) O
was O
applied O
. O

The O
revolution O
speed O
of O
the O
separation O
column O
, O
flow O
rate O
of O
the O
mobile O
phase O
and O
separation O
temperature O
were O
800 O
rpm O
, O
2 O
ml O
/ O
min O
and O
30 O
degrees O
C O
, O
respectively O
. O

From O
about O
1000 O
mg O
amount O
of O
the O
crude O
plant O
extract O
, O
249 O
. O
4 O
mg O
of O
pure O
sulforaphene B
was O
obtained O
by O
one O
- O
step O
separation O
on O
a O
280 O
ml O
HSCCC O
column O
. O

The O
purified O
sulforaphene B
was O
at O
a O
high O
purity O
of O
96 O
. O
9 O
% O
and O
the O
mass O
recovery O
was O
more O
than O
95 O
% O
. O

The O
purity O
of O
sulforaphene B
was O
determined O
by O
HPLC O
analysis O
and O
its O
chemical O
structure O
was O
assessed O
by O
MS O
, O
( B
1 I
) I
H I
NMR O
, O
( B
13 I
) I
C I
NMR O
and O
DEPT O
- O
135 O
NMR O
. O

Separation O
and O
quantification O
of O
water O
buffalo O
milk O
protein O
fractions O
and O
genetic O
variants O
by O
RP O
- O
HPLC O
. O

A O
RP O
- O
HPLC O
method O
, O
developed O
for O
the O
separation O
and O
quantification O
of O
the O
most O
common O
genetic O
variants O
of O
bovine O
milk O
proteins O
, O
was O
successfully O
applied O
to O
the O
analysis O
of O
water O
buffalo O
milk O
. O

All O
the O
most O
common O
buffalo O
casein O
and O
whey O
proteins O
fractions O
, O
as O
well O
as O
their O
genetic O
variants O
, O
were O
detected O
and O
separated O
simultaneously O
in O
40 O
min O
. O

Purified O
buffalo O
proteins O
were O
used O
as O
calibration O
standards O
and O
a O
total O
of O
536 O
individual O
milk O
samples O
were O
analysed O
for O
protein O
composition O
. O

alpha O
( O
S1 O
) O
- O
, O
alpha O
( O
S2 O
) O
- O
, O
beta O
gamma O
- O
, O
and O
kappa O
- O
casein O
were O
32 O
. O
2 O
% O
, O
15 O
. O
8 O
% O
, O
36 O
. O
5 O
% O
, O
and O
15 O
. O
5 O
% O
, O
respectively O
, O
of O
total O
casein O
content O
, O
whereas O
content O
of O
beta O
- O
Lactoglobulin O
was O
approximately O
1 O
. O
3 O
times O
as O
high O
as O
that O
of O
alpha O
- O
Lactalbumin O
. O

The O
existence O
of O
a O
polymorphism O
of O
kappa O
- O
casein O
was O
demonstrated O
in O
Mediterranean O
water O
buffalo O
and O
alpha O
( O
S1 O
) O
- O
and O
kappa O
- O
casein O
genetic O
variants O
were O
successfully O
detected O
by O
RP O
- O
HPLC O
. O

Lead O
and O
cadmium B
concentrations O
in O
goat O
, O
cow O
, O
sheep O
, O
and O
buffalo O
milks O
from O
different O
regions O
of O
Iran O
. O

In O
total O
, O
137 O
goat O
, O
cow O
, O
sheep O
, O
and O
buffalo O
milk O
samples O
were O
collected O
in O
different O
regions O
of O
Iran O
and O
analysed O
to O
determine O
concentrations O
of O
lead O
and O
cadmium B
by O
a O
graphite B
furnace O
atomic O
absorption O
spectrometric O
method O
. O

The O
mean O
recovery O
of O
the O
analytical O
method O
was O
96 O
. O
3 O
% O
and O
104 O
% O
for O
cadmium B
and O
lead O
, O
respectively O
. O

The O
mean O
lead O
and O
cadmium B
contents O
obtained O
from O
137 O
samples O
were O
1 O
. O
93 O
+ O
/ O
- O
1 O
. O
48 O
( O
range O
: O
0 O
. O
18 O
- O
6 O
. O
11 O
ng O
/ O
ml O
) O
and O
9 O
. O
51 O
+ O
/ O
- O
4 O
. O
93 O
ng O
/ O
ml O
( O
range O
: O
1 O
. O
84 O
ng O
/ O
ml O
- O
30 O
. O
50 O
ng O
/ O
ml O
) O
, O
respectively O
. O

Lead O
concentration O
in O
8 O
. O
1 O
% O
of O
sheep O
and O
1 O
. O
9 O
% O
of O
cow O
milk O
samples O
was O
higher O
than O
the O
newly O
established O
Codex O
standard O
. O

The O
mean O
concentrations O
of O
cadmium B
and O
lead O
in O
animals O
aged O
< O
= O
3 O
years O
( O
n O
= O
80 O
; O
1 O
. O
40 O
+ O
/ O
- O
1 O
. O
05 O
ng O
/ O
ml O
and O
7 O
. O
91 O
+ O
/ O
- O
3 O
. O
60 O
ng O
/ O
ml O
, O
respectively O
) O
were O
lower O
than O
in O
animals O
aged O
> O
3 O
years O
( O
n O
= O
58 O
; O
2 O
. O
69 O
+ O
/ O
- O
1 O
. O
67 O
ng O
/ O
ml O
and O
11 O
. O
8 O
+ O
/ O
- O
5 O
. O
71 O
ng O
/ O
ml O
, O
respectively O
) O
. O

Purification O
and O
characterization O
of O
membrane O
- O
bound O
polyphenoloxidase O
( O
mPPO O
) O
from O
Snake O
fruit O
[ O
Salacca O
zalacca O
( O
Gaertn O
. O
) O
Voss O
] O
. O

Membrane O
- O
bound O
polyphenoloxidase O
( O
mPPO O
) O
an O
oxidative O
enzyme O
which O
is O
responsible O
for O
the O
undesirable O
browning O
reaction O
in O
Snake O
fruit O
( O
Salacca O
zalacca O
( O
Gaertn O
. O
) O
Voss O
) O
was O
investigated O
. O

The O
enzyme O
was O
extracted O
using O
a O
non O
- O
ionic O
detergent O
( O
Triton B
X I
- I
114 I
) O
, O
followed O
by O
temperature O
- O
induced O
phase O
partitioning O
technique O
which O
resulted O
in O
two O
separate O
layers O
( O
detergent O
- O
poor O
phase O
at O
the O
upper O
layer O
and O
detergent O
- O
rich O
phase O
at O
the O
lower O
layer O
) O
. O

The O
upper O
detergent O
- O
poor O
phase O
extract O
was O
subsequently O
fractionated O
by O
40 O
- O
80 O
% O
ammonium B
sulfate I
and O
chromatographed O
on O
HiTrap O
Phenyl B
Sepharose O
and O
Superdex O
200 O
HR O
10 O
/ O
30 O
. O

The O
mPPO O
was O
purified O
to O
14 O
. O
1 O
folds O
with O
a O
recovery O
of O
12 O
. O
35 O
% O
. O

A O
single O
prominent O
protein O
band O
appeared O
on O
native O
- O
PAGE O
and O
SDS O
- O
PAGE O
implying O
that O
the O
mPPO O
is O
a O
monomeric O
protein O
with O
estimated O
molecular O
weight O
of O
38kDa O
. O

Characterization O
study O
showed O
that O
mPPO O
from O
Snake O
fruit O
was O
optimally O
active O
at O
pH O
6 O
. O
5 O
, O
temperature O
30 O
degrees O
C O
and O
active O
towards O
diphenols B
as O
substrates O
. O

The O
K O
( O
m O
) O
and O
V O
( O
max O
) O
values O
were O
calculated O
to O
be O
5 O
. O
46 O
mM O
and O
0 O
. O
98 O
U O
/ O
ml O
/ O
min O
, O
respectively O
, O
when O
catechol B
was O
used O
as O
substrate O
. O

Among O
the O
chemical O
inhibitors O
tested O
, O
l B
- I
cysteine I
showed O
the O
best O
inhibitory O
effect O
, O
with O
an O
IC O
( O
50 O
) O
of O
1 O
. O
3 O
+ O
/ O
- O
0 O
. O
002 O
mM O
followed O
by O
ascorbic B
acid I
( O
1 O
. O
5 O
+ O
/ O
- O
0 O
. O
06 O
mM O
) O
, O
glutathione B
( O
1 O
. O
5 O
+ O
/ O
- O
0 O
. O
07 O
mM O
) O
, O
EDTA B
( O
100 O
+ O
/ O
- O
0 O
. O
02 O
mM O
) O
and O
citric B
acid I
( O
186 O
+ O
/ O
- O
0 O
. O
16 O
mM O
) O
. O

Toona O
sinensis O
and O
its O
major O
bioactive O
compound O
gallic B
acid I
inhibit O
LPS O
- O
induced O
inflammation O
in O
nuclear O
factor O
- O
kappa O
B O
transgenic O
mice O
as O
evaluated O
by O
in O
vivo O
bioluminescence O
imaging O
. O

In O
the O
present O
study O
, O
we O
investigated O
the O
anti O
- O
inflammatory O
effects O
of O
a O
nutritious O
vegetable O
Toona O
sinensis O
( O
leaf O
extracts O
, O
TS O
) O
and O
its O
major O
bioactive O
compound O
gallic B
acid I
( O
GA O
) O
by O
analysing O
LPS O
- O
induced O
NF O
- O
kappa O
B O
activation O
in O
transgenic O
mice O
, O
using O
bioluminescence O
imaging O
. O

Mice O
were O
challenged O
intraperitoneally O
with O
LPS O
( O
1mg O
/ O
kg O
) O
and O
treated O
orally O
with O
TS O
or O
GA O
( O
100 O
or O
5mg O
/ O
kg O
, O
respectively O
) O
. O

In O
vivo O
and O
ex O
vivo O
imaging O
showed O
that O
LPS O
increased O
NF O
- O
kappa O
B O
luminescence O
in O
the O
abdominal O
region O
, O
which O
was O
significantly O
inhibited O
by O
TS O
or O
GA O
. O

Immunohistochemical O
and O
ELISA O
analyses O
confirmed O
that O
TS O
and O
GA O
inhibited O
LPS O
- O
induced O
NF O
- O
kappa O
B O
, O
interleukin O
- O
1 O
beta O
, O
and O
tumour O
necrosis O
factor O
- O
alpha O
expression O
. O

Microarray O
analysis O
revealed O
that O
biological O
pathways O
associated O
with O
metabolism O
and O
the O
immune O
responses O
were O
affected O
by O
TS O
or O
GA O
. O

Particularly O
, O
LPS O
- O
induced O
thioredoxin O
- O
like O
4B O
( O
TXNL4B O
) O
2 O
expression O
in O
the O
small O
intestine O
, O
and O
TXNL4B O
, O
iNOS O
, O
and O
COX O
- O
2 O
expression O
in O
RAW O
264 O
. O
7 O
cells O
were O
significantly O
inhibited O
by O
TS O
or O
GA O
. O

Thus O
, O
the O
anti O
- O
inflammatory O
potential O
of O
TS O
was O
mediated O
by O
the O
downregulation O
of O
NF O
- O
kappa O
B O
pathway O
. O

HPLC O
confirmatory O
method O
development O
for O
the O
determination O
of O
seven O
quinolones B
in O
salmon O
tissue O
( O
Salmo O
salar O
L O
. O
) O
validated O
according O
to O
the O
European O
Union O
Decision O
2002 O
/ O
657 O
/ O
EC O
. O

A O
confirmatory O
high O
pressure O
liquid O
chromatographic O
method O
for O
the O
determination O
of O
seven O
quinolone B
antibiotics O
in O
tissue O
of O
Atlantic O
salmon O
( O
Salmo O
salar O
L O
. O
) O
was O
developed O
. O

Ciprofloxacin B
( O
CIP B
) O
, O
danofloxacin B
( O
DAN B
) O
, O
enrofloxacin B
( O
ENR B
) O
, O
sarafloxacin B
( O
SAR B
) O
, O
oxolinic B
acid I
( O
OXO B
) O
, O
nalidixic B
acid I
( O
NAL B
) O
and O
flumequine B
( O
FLU B
) O
were O
separated O
on O
a O
Perfectsil O
ODS O
- O
2 O
120 O
( O
250 O
mm O
x O
4 O
mm O
, O
5 O
mu O
m O
) O
column O
by O
gradient O
elution O
with O
a O
mobile O
phase O
consisting O
of O
0 O
. O
1 O
% O
trifluoroacetic B
acid I
( O
pH O
= O
1 O
) O

, O
acetonitrile B
and O
methanol B
at O
25 O
degrees O
C O
within O
22 O
min O
. O

Analytes O
were O
monitored O
at O
255 O
nm O
( O
for O
the O
determination O
of O
OXO B
, O
NAL B
and O
FLU B
) O
and O
275 O
nm O
( O
for O
CIP B
, O
DAN B
, O
ENR B
and O
SAR B
) O
by O
means O
of O
photodiode O
array O
detector O
. O

Examined O
quinolones B
were O
isolated O
from O
salmon O
tissue O
by O
extraction O
with O
citrate B
buffer O
solution O
( O
pH O
= O
4 O
. O
7 O
) O
and O
purified O
by O
solid O
phase O
extraction O
using O
Oasis O
HLB O
( O
200mg O
/ O
6 O
mL O
) O
cartridges O
. O

The O
developed O
method O
was O
fully O
validated O
in O
terms O
of O
selectivity O
, O
linearity O
, O
accuracy O
, O
precision O
, O
stability O
and O
sensitivity O
according O
to O
the O
European O
Union O
Decision O
2002 O
/ O
657 O
/ O
EC O
. O

The O
accuracy O
of O
the O
method O
was O
additionally O
proved O
by O
its O
application O
to O
certified O
reference O
material O
of O
salmon O
tissue O
( O
BCR O
( O
R O
) O
725 O
) O
. O

Chemical O
analysis O
and O
anti O
- O
inflammatory O
comparison O
of O
the O
cell O
culture O
of O
Glycyrrhiza O
with O
its O
field O
cultivated O
variety O
. O

Suspended O
cells O
of O
Glycyrrhiza O
( O
CG O
) O
possessed O
a O
similar O
content O
of O
flavonoids B
and O
a O
lower O
content O
of O
triterpenes B
, O
when O
compared O
with O
its O
field O
cultivated O
equivalent O
( O
NG O
) O
. O

Xylene B
- O
induced O
ear O
oedema O
and O
ovalbumin O
- O
induced O
mouse O
paw O
oedema O
were O
applied O
, O
to O
compare O
the O
effects O
of O
CG O
and O
NG O
on O
the O
acute O
inflammatory O
response O
. O

Extracts O
of O
the O
cell O
culture O
of O
Glycyrrhiza O
possessed O
a O
similar O
anti O
- O
inflammatory O
effect O
to O
those O
of O
NG O
, O
through O
the O
enhancement O
of O
the O
SOD O
activity O
of O
plasma O
and O
liver O
tissues O
. O

The O
use O
of O
a O
cell O
culture O
of O
liquorice O
instead O
of O
field O
cultivation O
would O
be O
potentially O
profitable O
. O

Antiproliferative O
and O
immunoactivatory O
ability O
of O
an O
enzymatic O
extract O
from O
rice O
bran O
. O

The O
validation O
of O
natural O
products O
as O
source O
of O
functional O
foods O
or O
nutraceuticals O
has O
become O
an O
important O
issue O
in O
current O
health O
research O
. O

Thus O
, O
the O
present O
work O
has O
tested O
on O
MOLT O
- O
4 O
cells O
( O
human O
T O
cell O
acute O
lymphoblastic O
leukemic O
) O
the O
antiproliferative O
effect O
of O
a O
water O
- O
soluble O
enzymatic O
extract O
from O
rice O
bran O
( O
EERB O
) O
. O

Present O
work O
shows O
that O
EERB B
induces O
cellular O
death O
in O
MOLT O
- O
4 O
cells O
in O
a O
dose O
- O
dependent O
way O
( O
0 O
- O
10mg O
/ O
mL O
) O
but O
not O
in O
non O
- O
tumoral O
lymphocytes O
. O

Flow O
cytometric O
analysis O
of O
MOLT O
- O
4 O
cells O
treated O
with O
EERB B
showed O
the O
presence O
of O
death O
cells O
by O
apoptosis O
rather O
than O
necrosis O
. O

Additionally O
, O
EERB O
also O
exerts O
an O
immunoactivatory O
effect O
on O
N13 O
microglia O
cells O
, O
by O
inducing O
TNF O
- O
alpha O
( O
tumour O
necrosis O
factor O
- O
alpha O
) O
expression O
, O
which O
plays O
a O
key O
role O
in O
the O
innate O
immune O
response O
to O
infection O
. O

Accordingly O
, O
we O
can O
propose O
EERB O
as O
a O
useful O
natural O
standardized O
extract O
with O
antiproliferative O
and O
immunoactivatory O
ability O
that O
would O
be O
beneficial O
to O
apply O
in O
the O
functional O
food O
field O
. O

Effect O
of O
extrusion O
conditions O
on O
physicochemical O
and O
sensorial O
properties O
of O
corn O
- O
broad O
beans O
( O
Vicia O
faba O
) O
spaghetti O
type O
pasta O
. O

Corn O
- O
broad O
bean O
spaghetti O
type O
pasta O
was O
made O
with O
a O
corn O
/ O
broad O
bean O
flour O
blend O
in O
a O
70 O
: O
30 O
ratio O
, O
through O
an O
extrusion O
- O
cooking O
process O
( O
Brabender O
10 O
DN O
single O
- O
screw O
extruder O
with O
a O
3 O
: O
1 O
compression O
ratio O
) O
. O

The O
effect O
of O
temperature O
( O
T O
= O
80 O
, O
90 O
and O
100 O
degrees O
C O
) O
and O
moisture O
( O
M O
= O
28 O
% O
, O
31 O
% O
and O
34 O
% O
) O
on O
the O
extrusion O
responses O
( O
specific O
consumption O
of O
mechanical O
energy O
and O
pressure O
) O
and O
the O
quality O
of O
this O
pasta O
- O
like O
product O
( O
expansion O
, O
cooking O
- O
related O
losses O
, O
water O
absorption O
, O
firmness O
and O
stickiness O
) O
was O
assessed O
. O

The O
structural O
changes O
of O
starch O
were O
studied O
by O
means O
of O
DSC O
and O
XRD O
. O

The O
extrusion O
- O
cooking O
process O
, O
at O
M O
= O
28 O
% O
and O
T O
= O
100 O
degrees O
C O
, O
is O
appropriate O
to O
obtain O
corn O
- O
broad O
bean O
spaghetti O
- O
type O
pasta O
with O
high O
protein O
and O
dietary O
fibre O
content O
and O
adequate O
quality O
. O

The O
cooking O
characteristics O
and O
resistance O
to O
overcooking O
depended O
on O
the O
degree O
of O
gelatinisation O
and O
formation O
of O
amylose O
- O
lipid O
complexes O
. O

The O
critical O
gelatinisation O
point O
was O
46 O
. O
55 O
% O
; O
beyond O
that O
point O
, O
the O
quality O
of O
the O
product O
declines O
. O

Quantitative O
determination O
of O
fatty B
acid I
chain O
composition O
in O
pork O
meat O
products O
by O
high O
resolution O
1H B
NMR O
spectroscopy O
. O

High O
resolution O
( B
1 I
) I
H I
NMR O
spectroscopy O
was O
proposed O
for O
the O
determination O
of O
the O
fatty B
acid I
chain O
profile O
of O
lipids O
in O
pork O
meat O
products O
during O
ripening O
. O

Two O
typical O
Mediterranean O
PDO O
salami O
produced O
in O
Calabria O
, O
a O
region O
in O
the O
Southern O
Italy O
, O
were O
chosen O
as O
a O
case O
of O
study O
. O

Quantitative O
NMR O
analysis O
provided O
the O
fatty B
acid I
chain O
profiles O
of O
total O
lipid O
extracts O
. O

The O
transesterification O
of O
total O
lipid O
extracts O
furnished O
FAME B
mixtures O
that O
enabled O
quantitation O
of O
fatty B
acid I
acyl B
chains O
in O
the O
acylglycerol B
and O
FFA O
portions O
. O

In O
all O
cases O
, O
oleyl B
chains O
were O
predominant O
, O
and O
high O
amounts O
of O
polyunsaturated B
fatty I
acid I
chains O
were O
observed O
. O

The O
proposed O
spectroscopic O
method O
allowed O
also O
the O
estimation O
of O
the O
most O
important O
nutritional O
parameters O
of O
dry O
fermented O
meat O
products O
. O

Identification O
of O
a O
novel O
phenolic B
compound O
in O
litchi O
( O
Litchi O
chinensis O
Sonn O
. O
) O
pericarp O
and O
bioactivity O
evaluation O
. O

Litchi O
( O
Litchi O
chinensis O
Sonn O
. O
) O
is O
a O
delicious O
fruit O
widely O
accepted O
by O
consumers O
all O
over O
the O
world O
. O

In O
this O
work O
, O
phytochemical O
investigation O
of O
litchi O
pericarp O
methanol B
extracts O
led O
to O
the O
isolation O
of O
a O
novel O
phenolic O
, O
2 B
- I
( I
2 I
- I
hydroxyl I
- I
5 I
- I
( I
methoxycarbonyl I
) I
phenoxy I
) I
benzoic I
acid I
, O
together O
with O
kaempferol B
, O
isolariciresinol B
, O
stigmasterol B
, O
butylated B
hydroxytoluene I
, O
3 B
, I
4 I
- I
dihydroxyl I
benzoate I
, O
methyl B
shikimate I
and O
ethyl B
shikimate I
. O

Most O
were O
found O
in O
litchi O
pericarp O
for O
the O
first O
time O
. O

Their O
structures O
were O
mainly O
elucidated O
by O
NMR O
and O
MS O
evidences O
. O

Antioxidant O
activities O
of O
the O
eight O
compounds O
were O
determined O
by O
a O
DPPH B
radical O
scavenging O
assay O
and O
the O
results O
showed O
that O
2 B
- I
( I
2 I
- I
hydroxy I
- I
5 I
- I
( I
methoxycarbonyl I
) I
phenoxy I
) I
benzoic I
acid I
, O
kaempferol B
, O
isolariciresinol B
, O
butylated B
hydroxytoluene I
and O
3 B
, I
4 I
- I
dihydroxy I
benzoate I
exhibited O
good O
antioxidant O
activities O
. O

An O
interesting O
finding O
was O
that O
butylated B
hydroxytoluene I
was O
detected O
as O
a O
natural O
antioxidant O
in O
this O
work O
, O
which O
was O
usually O
taken O
as O
a O
synthesized O
antioxidant O
. O

Furthermore O
, O
the O
novel O
compound O
exhibited O
no O
inhibitory O
effects O
against O
tyrosinase O
and O
alpha O
- O
glucosidase O
activities O
. O

Rapid O
resolution O
liquid O
chromatography O
- O
electrospray O
ionisation O
tandem O
mass O
spectrometry O
method O
for O
identification O
of O
chemical O
constituents O
in O
Citri O
Reticulatae O
Pericarpium O
. O

Citri O
Reticulatae O
Pericarpium O
( O
CRP O
) O
is O
one O
of O
the O
most O
commonly O
used O
traditional O
Chinese O
medicines O
with O
great O
medicinal O
and O
dietary O
values O
. O

In O
this O
work O
, O
we O
developed O
an O
approach O
utilising O
rapid O
resolution O
liquid O
chromatography O
/ O
electrospray O
ionisation O
tandem O
mass O
spectrometry O
( O
RRLC O
- O
ESI O
- O
MS O
/ O
MS O
) O
for O
the O
identification O
and O
profiling O
of O
chemical O
composition O
in O
CRP O
. O

On O
the O
basis O
of O
RRLC O
retention O
times O
, O
cochromatography O
with O
available O
authentic O
standards O
, O
mass O
spectral O
fragmentation O
patterns O
and O
literature O
information O
, O
a O
total O
of O
41 O
chemical O
compounds O
, O
including O
4 O
flavone B
- I
C I
- I
glycosides I
, O
7 O
flavonoid B
- I
O I
- I
glycosides I
and O
19 O
polymethoxyflavones B
were O
unambiguously O
identified O
or O
tentatively O
characterised O
in O
CRP O
. O

The O
occurrence O
of O
1 O
flavone B
- I
C I
- I
glycoside I
and O
3 O
cyclic O
peptides O
in O
particular O
has O
not O
yet O
been O
described O
. O

The O
results O
indicated O
that O
the O
developed O
method O
could O
serve O
as O
a O
rapid O
, O
effective O
tool O
for O
structural O
characterisation O
of O
chemical O
constituents O
in O
CRP O
. O

Resveratrols B
in O
Vitis O
berry O
skins O
and O
leaves O
: O
their O
extraction O
and O
analysis O
by O
HPLC O
. O

An O
orthogonal O
L O
( O
36 O
) O
( O
6 O
) O
( O
5 O
) O
test O
design O
was O
applied O
to O
select O
the O
optimum O
conditions O
for O
extracting O
resveratrols B
from O
grape O
berry O
skins O
and O
leaves O
. O

Solvent O
choice O
was O
the O
most O
important O
factor O
in O
the O
extraction O
of O
resveratrols B
, O
and O
mixed O
methanol B
and O
ethyl B
acetate I
[ O
50 O
: O
50 O
( O
v O
/ O
v O
) O
] O
had O
much O
higher O
extraction O
efficiency O
than O
the O
other O
five O
solvents O
tested O
. O

For O
extracting O
resveratrols B
, O
1g O
of O
berry O
skins O
or O
leaf O
tissue O
extracted O
in O
10 O
mL O
methanol B
and O
ethyl B
acetate I
[ O
50 O
: O
50 O
( O
v O
/ O
v O
) O
] O
for O
24h O
at O
25 O
degrees O
C O
in O
darkness O
was O
the O
optimized O
extraction O
condition O
. O

The O
optimized O
analytical O
method O
for O
HPLC O
was O
a O
multi O
- O
step O
gradient O
elution O
using O
acetonitrile B
and O
water O
. O

The O
optimized O
method O
was O
used O
to O
determine O
resveratrols B
among O
three O
different O
cultivars O
. O

The O
cultivar O
' O
Zhi O
168 O
' O
had O
the O
highest O
total O
resveratrols B
in O
berry O
skins O
while O
' O
Saint O
- O
Emilion O
' O
had O
the O
lowest O
resveratrols B
. O

The O
resveratrol B
content O
of O
' O
Beta O
' O
was O
between O
that O
of O
' O
Zhi O
168 O
' O
and O
' O
Saint O
- O
Emilion O
' O
. O

Electronic O
nose O
and O
GC O
- O
MS O
analysis O
of O
volatile O
compounds O
in O
Tuber O
magnatum O
Pico O
: O
evaluation O
of O
different O
storage O
conditions O
. O

The O
characteristic O
aromatic O
composition O
of O
white O
truffles O
( O
Tuber O
magnatum O
Pico O
) O
determines O
its O
culinary O
and O
commercial O
value O
. O

However O
modifications O
of O
truffle O
organoleptic O
proprieties O
occur O
during O
preservation O
. O

A O
study O
of O
headspace O
of O
white O
truffles O
by O
using O
Electronic O
nose O
( O
E O
- O
nose O
) O
, O
gas O
chromatography O
- O
mass O
spectrometry O
( O
GC O
- O
MS O
) O
and O
sensory O
analyses O
was O
performed O
. O

Truffles O
were O
stored O
at O
different O
conditions O
for O
7 O
days O
: O
+ O
4 O
and O
+ O
8 O
degrees O
C O
wrapped O
in O
blotting O
paper O
or O
covered O
by O
rice O
or O
none O
of O
the O
above O
. O

Headspace O
E O
- O
nose O
measurements O
and O
sensory O
analyses O
were O
performed O
each O
day O
. O

Statistical O
multivariate O
analysis O
of O
the O
data O
showed O
the O
capability O
of O
E O
- O
nose O
to O
predict O
sensorial O
analysis O
scores O
and O
to O
monitor O
aroma O
profile O
changes O
during O
storage O
. O

Truffle O
' O
s O
volatile O
molecules O
were O
also O
extracted O
by O
headspace O
solid O
phase O
microextraction O
technique O
and O
separated O
and O
identified O
by O
GC O
- O
MS O
. O

Partial O
Components O
Analysis O
of O
data O
was O
performed O
. O

E O
- O
nose O
and O
GC O
- O
MS O
results O
were O
in O
agreement O
and O
showed O
that O
truffle O
storage O
in O
paper O
at O
+ O
8 O
degrees O
C O
seemed O
to O
be O
the O
best O
storage O
condition O
. O

Comparison O
of O
different O
methods O
to O
quantify O
fat O
classes O
in O
bakery O
products O
. O

The O
definition O
of O
fat O
differs O
in O
different O
countries O
; O
thus O
whether O
fat O
is O
listed O
on O
food O
labels O
depends O
on O
the O
country O
. O

Some O
countries O
list O
crude O
fat O
content O
in O
the O
' O
Fat O
' O
section O
on O
the O
food O
label O
, O
whereas O
other O
countries O
list O
total O
fat O
. O

In O
this O
study O
, O
three O
methods O
were O
used O
for O
determining O
fat O
classes O
and O
content O
in O
bakery O
products O
: O
the O
Folch O
method O
, O
the O
automated O
Soxhlet O
method O
, O
and O
the O
AOAC O
996 O
. O
06 O
method O
. O

The O
results O
using O
these O
methods O
were O
compared O
. O

Fat O
( O
crude O
) O
extracted O
by O
the O
Folch O
and O
Soxhlet O
methods O
was O
gravimetrically O
determined O
and O
assessed O
by O
fat O
class O
using O
capillary O
gas O
chromatography O
( O
GC O
) O
. O

In O
most O
samples O
, O
fat O
( O
total O
) O
content O
determined O
by O
the O
AOAC O
996 O
. O
06 O
method O
was O
lower O
than O
the O
fat O
( O
crude O
) O
content O
determined O
by O
the O
Folch O
or O
automated O
Soxhlet O
methods O
. O

Furthermore O
, O
monounsaturated O
fat O
or O
saturated O
fat O
content O
determined O
by O
the O
AOAC O
996 O
. O
06 O
method O
was O
lowest O
. O

Almost O
no O
difference O
was O
observed O
between O
fat O
( O
crude O
) O
content O
determined O
by O
the O
Folch O
method O
and O
that O
determined O
by O
the O
automated O
Soxhlet O
method O
for O
nearly O
all O
samples O
. O

In O
three O
samples O
( O
wheat O
biscuits O
, O
butter O
cookies O
- O
1 O
, O
and O
chocolate O
chip O
cookies O
) O
, O
monounsaturated O
fat O
, O
saturated O
fat O
, O
and O
trans O
fat O
content O
obtained O
by O
the O
automated O
Soxhlet O
method O
was O
higher O
than O
that O
obtained O
by O
the O
Folch O
method O
. O

The O
polyunsaturated B
fat O
content O
obtained O
by O
the O
automated O
Soxhlet O
method O
was O
not O
higher O
than O
that O
obtained O
by O
the O
Folch O
method O
in O
any O
sample O
. O

Nutrients O
, O
phytochemicals O
and O
bioactivity O
of O
wild O
Roman O
chamomile O
: O
a O
comparison O
between O
the O
herb O
and O
its O
preparations O
. O

Roman O
chamomile O
, O
Chamaemelum O
nobile O
L O
. O

( O
Asteraceae O
) O
, O
has O
been O
used O
for O
medicinal O
applications O
, O
mainly O
through O
oral O
dosage O
forms O
( O
decoctions O
and O
infusions O
) O
. O

Herein O
, O
the O
nutritional O
characterisation O
of O
C O
. O
nobile O
was O
performed O
, O
and O
herbal O
material O
and O
its O
decoction O
and O
infusion O
were O
submitted O
to O
an O
analysis O
of O
phytochemicals O
and O
bioactivity O
evaluation O
. O

The O
antioxidant O
activity O
was O
determined O
by O
free O
radicals O
scavenging O
activity O
, O
reducing O
power O
and O
inhibition O
of O
lipid O
peroxidation O
, O
the O
antitumour O
potential O
was O
tested O
in O
human O
tumour O
cell O
lines O
( O
breast O
, O
lung O
, O
colon O
, O
cervical O
and O
hepatocellular O
carcinomas O
) O
, O
and O
the O
hepatotoxicity O
was O
evaluated O
using O
a O
porcine O
liver O
primary O
cell O
culture O
. O

C O
. O
nobile O
proved O
to O
be O
an O
equilibrated O
valuable O
herb O
rich O
in O
carbohydrates B
and O
proteins O
, O
and O
poor O
in O
fat O
, O
providing O
tocopherols B
, O
carotenoids O
and O
essential O
fatty B
acids I
( O
C18 B
: I
2n6 I
and O
C18 B
: I
3n3 I
) O
. O

Moreover O
, O
the O
herb O
and O
its O
infusion O
are O
a O
source O
of O
phenolic O
compounds O
( O
flavonoids B
such O
as O
flavonols B
and O
flavones B
, O
phenolic B
acids I
and O
derivatives O
) O
and O
organic O
acids O
( O
oxalic B
, I
quinic I
, I
malic I
, I
citric I
and I
fumaric I
acids I
) O
that O
showed O
antioxidant O
and O
antitumour O
activities O
, O
without O
hepatotoxicity O
. O

The O
most O
abundant O
compounds O
in O
the O
plant O
extract O
and O
infusion O
were O
5 B
- I
O I
- I
caffeoylquinic I
acid I
and O
an O
apigenin B
derivative O
. O

These O
, O
as O
well O
as O
other O
bioactive O
compounds O
, O
are O
affected O
in O
C O
. O
nobile O
decoction O
, O
leading O
to O
a O
lower O
antioxidant O
potential O
and O
absence O
of O
antitumour O
potential O
. O

The O
plant O
bioactivity O
could O
be O
explored O
in O
the O
medicine O
, O
food O
, O
and O
cosmetic O
industries O
. O

' O
Emerging O
' O
mycotoxins O
in O
cereals O
processing O
chains O
: O
changes O
of O
enniatins B
during O
beer O
and O
bread O
making O
. O

Enniatins B
represent O
an O
emerging O
food O
safety O
issue O
because O
of O
their O
extensive O
incidence O
, O
documented O
in O
recent O
decades O
, O
in O
various O
small O
grain O
cereals O
. O

This O
study O
was O
concerned O
with O
the O
fate O
of O
these O
Fusarium O
mycotoxins O
within O
malting O
, O
brewing O
, O
milling O
and O
baking O
, O
when O
employed O
for O
the O
processing O
of O
contaminated O
barley O
and O
wheat O
. O

Besides O
enniatins B
A I
, I
A1 I
, I
B I
and I
B1 I
, O
also O
deoxynivalenol B
and O
its O
conjugated O
form O
( O
deoxynivalenol B
- I
3 I
- I
glucoside I
) O
were O
determined O
in O
almost O
all O
tested O
cereal O
- O
based O
samples O
. O

Significant O
decline O
of O
enniatins B
occurred O
within O
all O
technologies O
, O
with O
the O
largest O
drop O
in O
their O
concentrations O
observed O
in O
the O
brewing O
process O
. O

While O
enniatins B
were O
not O
detectable O
in O
final O
beers O
, O
they O
were O
almost O
quantitatively O
transferred O
to O
spent O
grains O
, O
probably O
because O
of O
their O
limited O
water O
solubility O
. O

Regarding O
bread O
baking O
, O
levels O
of O
enniatins B
decreased O
down O
to O
30 O
% O
of O
their O
concentration O
in O
the O
initial O
flour O
used O
for O
baking O
. O

In O
this O
case O
, O
degradation O
at O
higher O
temperatures O
might O
be O
assumed O
. O

Dietary O
Monascus O
adlay O
supplements O
facilitate O
suppression O
of O
cigarette O
smoke O
- O
induced O
pulmonary O
endoplasmic O
reticulum O
stress O
, O
autophagy O
, O
apoptosis O
and O
emphysema O
- O
related O
PLGF O
in O
the O
rat O
. O

Cigarette O
smoke O
( O
CS O
) O
exposure O
may O
cause O
oxidative O
stress O
in O
the O
lung O
, O
leading O
to O
cell O
death O
and O
long O
- O
term O
injury O
. O

Monascus O
adlay O
( O
MA O
) O
with O
antioxidant O
components O
produced O
by O
inoculating O
adlay O
( O
Cois O
lachrymal O
- O
jobi O
L O
. O
var O
. O
ma O
- O
yuen O
Stapf O
) O
with O
Monascus O
purpureus O
may O
protect O
lung O
against O
CS O
- O
induced O
lung O
injuries O
in O
rats O
. O

MA O
and O
lovastatin B
had O
higher O
antioxidant O
activities O
than O
either O
M O
. O
purpureus O
or O
adlay O
. O

CS O
exposure O
caused O
significant O
lung O
damage O
, O
as O
evidenced O
by O
higher O
levels O
of O
reactive O
oxygen B
species O
( O
ROS O
) O
, O
neutrophil O
infiltration O
, O
dityrosine B
and O
4 B
- I
HNE I
, O
as O
well O
as O
lower O
levels O
of O
Mn B
- O
superoxide B
dismutase O
and O
catalase O
expression O
. O

Lung O
tissues O
with O
CS O
exposure O
had O
higher O
levels O
of O
ER O
stress O
, O
apoptosis O
, O
autophagy O
and O
emphysema O
- O
related O
placenta O
growth O
factor O
( O
PlGF O
) O
expressions O
. O

All O
CS O
- O
induced O
injuries O
were O
significantly O
suppressed O
by O
MA O
supplements O
. O

MA O
would O
be O
a O
beneficial O
nutritional O
therapy O
to O
ameliorate O
CS O
- O
induced O
lung O
injury O
via O
preserving O
antioxidant O
defense O
mechanisms O
, O
decreasing O
oxidative O
stress O
and O
inhibiting O
ER O
stress O
, O
autophagy O
, O
apoptosis O
and O
emphysema O
- O
related O
risk O
factor O
. O

An O
extract O
procedure O
for O
studying O
the O
free O
and O
glycosilated O
aroma O
compounds O
in O
grapes O
. O

In O
this O
study O
seven O
published O
methods O
of O
extraction O
of O
skin O
free O
and O
bound O
volatile O
compounds O
have O
been O
compared O
. O

The O
free O
and O
bound O
volatiles O
were O
separated O
by O
solid O
phase O
extraction O
( O
SPE O
) O
and O
then O
analysed O
by O
gas O
chromatography O
coupled O
with O
mass O
spectrometry O
( O
GC O
- O
MS O
) O
. O

The O
results O
showed O
that O
the O
extraction O
of O
volatile O
compounds O
from O
grapes O
is O
highly O
affected O
by O
extraction O
solution O
features O
. O

The O
solution O
at O
pH O
3 O
. O
2 O
and O
0 O
% O
ethanol B
resulted O
the O
most O
effective O
as O
it O
led O
to O
the O
extraction O
of O
a O
higher O
number O
and O
amount O
of O
free O
and O
glycosilated O
volatile O
compounds O
. O

The O
selected O
extraction O
method O
of O
grape O
skin O
and O
the O
process O
of O
pulp O
juice O
were O
validated O
for O
quantitative O
determination O
of O
a O
wide O
range O
of O
grape O
aroma O
compounds O
. O

A O
total O
of O
37 O
free O
and O
bound O
grape O
aroma O
compounds O
were O
quantified O
by O
GC O
- O
MS O
in O
selective O
ion O
monitoring O
modality O
( O
SIM O
) O
. O

Among O
them O
, O
26 O
volatile O
compounds O
resulted O
validated O
in O
grape O
skin O
and O
pulp O
juice O
. O

One O
- O
step O
purification O
of O
lactoperoxidase O
from O
bovine O
milk O
by O
affinity O
chromatography O
. O

Sulphanilamide B
was O
determined O
to O
be O
a O
new O
inhibitor O
of O
lactoperoxidase O
( O
LPO O
) O
with O
an O
IC O
( O
50 O
) O
of O
0 O
. O
848 O
. O
10 O
( O
- O
5 O
) O
M O
. O

The O
K O
( O
i O
) O
for O
sulphanilamide B
was O
determined O
to O
be O
3 O
. O
57 O
. O
10 O
( O
- O
5 O
) O
M O
and O
sulphanilamide B
showed O
competitive O
inhibition O
, O
which O
makes O
it O
a O
suitable O
ligand O
for O
constructing O
a O
Sepharose O
4B O
- O
L B
- I
tyrosine I
affinity O
matrix O
. O

The O
affinity O
matrix O
was O
synthesised O
by O
coupling O
sulphanilamide B
as O
the O
ligand O
and O
L B
- I
tyrosine I
as O
the O
spacer O
arm O
to O
a O
cyanogen B
bromide I
( O
CNBr B
) O
- O
activated O
- O
Sepharose B
4B I
matrix O
. O

Lactoperoxidase O
was O
purified O
409 O
- O
fold O
from O
the O
synthesized O
affinity O
matrix O
in O
a O
single O
step O
, O
with O
a O
yield O
of O
62 O
. O
3 O
% O
and O
a O
specific O
activity O
of O
40 O
. O
9 O
EU O
/ O
mg O
protein O
. O

The O
enzyme O
activity O
was O
measured O
using O
ABTS B
as O
a O
chromogenic O
substrate O
( O
pH O
6 O
. O
0 O
) O
. O

The O
degree O
of O
LPO O
purification O
was O
monitored O
by O
SDS B
- O
PAGE O
and O
its O
R O
( O
z O
) O
( O
A O
( O
412 O
) O
/ O
A O
( O
280 O
) O
) O
value O
. O

The O
R O
( O
z O
) O
value O
for O
the O
purified O
LPO O
was O
found O
to O
be O
0 O
. O
7 O
. O

Maximum O
binding O
was O
achieved O
and O
K O
( O
m O
) O
and O
V O
( O
max O
) O
values O
were O
determined O
. O

Infusion O
and O
decoction O
of O
wild O
German O
chamomile O
: O
bioactivity O
and O
characterization O
of O
organic O
acids O
and O
phenolic B
compounds O
. O

Natural O
products O
represent O
a O
rich O
source O
of O
biologically O
active O
compounds O
and O
are O
an O
example O
of O
molecular O
diversity O
, O
with O
recognised O
potential O
in O
drug O
discovery O
. O

Herein O
, O
the O
methanol B
extract O
of O
Matricaria O
recutita O
L O
. O

( O
German O
chamomile O
) O
and O
its O
decoction O
and O
infusion O
( O
the O
most O
consumed O
preparations O
of O
this O
herb O
) O
were O
submitted O
to O
an O
analysis O
of O
phytochemicals O
and O
bioactivity O
evaluation O
. O

The O
antioxidant O
activity O
was O
determined O
by O
free O
radicals O
scavenging O
activity O
, O
reducing O
power O
and O
inhibition O
of O
lipid O
peroxidation O
; O
the O
antitumour O
potential O
was O
tested O
in O
human O
tumour O
cell O
lines O
( O
breast O
, O
lung O
, O
colon O
, O
cervical O
and O
hepatocellular O
carcinomas O
) O
, O
and O
the O
hepatotoxicity O
was O
evaluated O
using O
a O
porcine O
liver O
primary O
cell O
culture O
( O
non O
- O
tumour O
cells O
) O
. O

All O
the O
samples O
revealed O
antioxidant O
properties O
. O

The O
decoction O
exhibited O
no O
antitumour O
activity O
( O
GI O
( O
50 O
) O
> O
400 O
mu O
g O
/ O
mL O
) O
which O
could O
indicate O
that O
this O
bioactivity O
might O
be O
related O
to O
compounds O
( O
including O
phenolic B
compounds O
) O
that O
were O
not O
extracted O
or O
that O
were O
affected O
by O
the O
decoction O
procedure O
. O

Both O
plant O
methanol B
extract O
and O
infusion O
showed O
inhibitory O
activity O
to O
the O
growth O
of O
HCT O
- O
15 O
( O
GI O
( O
50 O
) O
250 O
. O
24 O
and O
298 O
. O
23 O
mu O
g O
/ O
mL O
, O
respectively O
) O
and O
HeLa O
( O
GI O
( O
50 O
) O
259 O
. O
36 O
and O
277 O
. O
67 O
mu O
g O
/ O
mL O
, O
respectively O
) O
cell O
lines O
, O
without O
hepatotoxicity O
( O
GI O
( O
50 O
) O
> O
400 O
mu O
g O
/ O
mL O
) O
. O

Infusion O
and O
decoction O
gave O
higher O
contents O
of O
organic O
acids O
( O
24 O
. O
42 O
and O
23 O
. O
35 O
g O
/ O
100g O
dw O
) O
. O

Otherwise O
, O
the O
plant O
methanol B
extract O
contained O
the O
highest O
amounts O
of O
both O
phenolic B
acids I
( O
3 O
. O
99 O
g O
/ O
100g O
dw O
) O
and O
flavonoids B
( O
2 O
. O
59 O
g O
/ O
100g O
dw O
) O
. O

The O
major O
compound O
found O
in O
all O
the O
preparations O
was O
luteolin B
O I
- I
acylhexoside I
. O

Overall O
, O
German O
chamomile O
contains O
important O
phytochemicals O
with O
bioactive O
properties O
( O
mainly O
antitumour O
potential O
selective O
to O
colon O
and O
cervical O
carcinoma O
cell O
lines O
) O
to O
be O
explored O
in O
the O
pharmaceutical O
, O
food O
and O
cosmetics O
industries O
. O

Authentication O
of O
beeswax O
( O
Apis O
mellifera O
) O
by O
high O
- O
temperature O
gas O
chromatography O
and O
chemometric O
analysis O
. O

Chemical O
characterization O
and O
authentication O
of O
beeswax O
of O
Apis O
mellifera O
was O
performed O
by O
high O
temperature O
capillary O
gas O
chromatography O
coupled O
to O
electron O
impact O
mass O
spectrometry O
or O
to O
flame O
ionisation O
detection O
and O
chemometric O
analysis O
. O

Many O
major O
components O
( O
> O
50 O
) O
of O
beeswax O
, O
odd O
and O
even O
hydrocarbons B
, O
oleofin B
, O
palmitate B
, O
oleate B
and O
hydroxypalmitate B
monoesters I
were O
detected O
, O
and O
for O
the O
first O
time O
palmitate B
and I
oleate I
monoesters I
esterified O
with O
1 B
- I
octadecanol I
and O
1 B
- I
eicosanol I
are O
reported O
to O
be O
present O
in O
beeswax O
. O

Unsupervised O
pattern O
recognition O
procedures O
, O
cluster O
analysis O
and O
principal O
component O
analysis O
, O
were O
used O
to O
find O
data O
patterns O
and O
successfully O
differentiate O
authentic O
and O
paraffin B
adulterated O
beeswax O
based O
on O
the O
chemical O
profile O
obtained O
. O

Independent O
assessment O
of O
beeswax O
quality O
and O
performance O
of O
the O
unsupervised O
classification O
methods O
were O
performed O
using O
classical O
analytical O
parameters O
. O

The O
discrimination O
power O
of O
the O
chemometric O
unsupervised O
methods O
for O
detection O
of O
paraffin B
adulterated O
beeswax O
was O
superior O
to O
the O
discriminating O
power O
of O
classical O
analytical O
parameters O
. O

Using O
linear O
discriminant O
analysis O
, O
classification O
rules O
for O
authentic O
and O
paraffin B
adulterated O
beeswax O
samples O
were O
developed O
. O

The O
model O
was O
validated O
by O
leave O
- O
one O
- O
out O
cross O
validation O
and O
showed O
good O
recognition O
and O
prediction O
abilities O
, O
100 O
% O
and O
99 O
% O
, O
respectively O
. O

Antioxidant O
activity O
comparison O
between O
[ B
6S I
] I
- I
5 I
- I
methyltetrahydrofoli I
acid I
calcium I
salt O
and O
the O
related O
racemate O
form O
. O

Folates B
, O
such O
as O
[ B
6S I
] I
- I
5 I
- I
methyltetrahydrofoli I
acid I
, O
have O
been O
introduced O
in O
the O
market O
both O
in O
vitamin O
pills O
and O
in O
fortified O
foods O
. O

Their O
antioxidant O
activity O
has O
been O
evaluated O
, O
but O
stereoisomer O
influence O
on O
activity O
has O
not O
been O
proven O
. O

In O
this O
study O
, O
a O
comparison O
between O
[ B
6S I
] I
- I
5 I
- I
methyltetrahydrofoli I
acid I
( O
5 B
- I
MTHF I
) O
and O
its O
racemate O
[ O
6R O
, O
S O
] O
form O
was O
made O
by O
TEAC O
assay O
at O
different O
pHs O
, O
FRAP O
assay O
, O
and O
ORAC O
assay O
. O

The O
results O
showed O
that O
the O
[ O
6S O
] O
form O
had O
higher O
antioxidant O
activity O
than O
its O
racemate O
form O
in O
the O
TEAC O
assay O
at O
all O
pHs O
, O
with O
similar O
values O
in O
the O
FRAP O
and O
ORAC O
assays O
. O

Results O
suggest O
that O
stereoisomeric O
difference O
could O
influence O
the O
antioxidant O
activity O
of O
5 B
- I
MTHF I
and O
hence O
should O
be O
taken O
into O
account O
when O
folates B
are O
added O
to O
foodstuffs O
to O
improve O
their O
nutritional O
value O
. O

Use O
of O
viscera O
extract O
from O
hybrid O
catfish O
( O
Clarias O
macrocephalus O
x O
Clarias O
gariepinus O
) O
for O
the O
production O
of O
protein O
hydrolysate O
from O
toothed O
ponyfish O
( O
Gazza O
minuta O
) O
muscle O
. O

Proteolytic O
activity O
of O
viscera O
extract O
from O
hybrid O
catfish O
( O
Clarias O
macrocephalus O
x O
Clarias O
gariepinus O
) O
was O
studied O
. O

The O
optimal O
pH O
and O
temperature O
were O
9 O
. O
0 O
and O
50 O
degrees O
C O
, O
respectively O
, O
when O
toothed O
ponyfish O
( O
Gazza O
minuta O
) O
muscle O
was O
used O
as O
a O
substrate O
. O

When O
viscera O
extract O
from O
hybrid O
catfish O
was O
used O
for O
the O
production O
of O
protein O
hydrolysate O
from O
toothed O
ponyfish O
muscle O
, O
extract O
concentration O
, O
reaction O
time O
, O
and O
fish O
muscle O
/ O
buffer O
ratio O
affected O
the O
hydrolysis O
and O
nitrogen B
recovery O
( O
NR O
) O
( O
p O
< O
0 O
. O
05 O
) O
. O

Optimum O
conditions O
for O
toothed O
ponyfish O
muscle O
hydrolysis O
were O
3 O
. O
5 O
% O
hybrid O
catfish O
viscera O
extract O
, O
15 O
min O
reaction O
time O
and O
fish O
muscle O
/ O
buffer O
ratio O
of O
1 O
: O
3 O
( O
w O
/ O
v O
) O
. O

High O
correlation O
between O
the O
degree O
of O
hydrolysis O
( O
DH O
) O
and O
NR O
( O
R O
( O
2 O
) O
= O
0 O
. O
974 O
) O
was O
observed O
. O

Freeze O
- O
dried O
hydrolysate O
had O
a O
high O
protein O
content O
( O
89 O
. O
02 O
% O
, O
dry O
weight O
basis O
) O
and O
it O
was O
brownish O
yellow O
in O
colour O
( O
L O
( O
* O
) O
= O
63 O
. O
67 O
, O
a O
( O
* O
) O
= O
6 O
. O
33 O
, O
b O
( O
* O
) O
= O
22 O
. O
41 O
) O
. O

The O
protein O
hydrolysate O
contained O
a O
high O
amount O
of O
essential O
amino B
acids I
( O
48 O
. O
22 O
% O
) O
and O
had O
arginine B
and O
lysine B
as O
the O
dominant O
amino B
acids I
. O

Simultaneous O
separation O
and O
purification O
of O
total O
polyphenols B
, O
chlorogenic B
acid I
and O
phlorizin B
from O
thinned O
young O
apples O
. O

An O
efficient O
preparative O
separation O
of O
polyphenols B
from O
thinned O
young O
apples O
( O
TYA O
) O
has O
been O
developed O
in O
the O
present O
study O
. O

X O
- O
5 O
resin O
was O
verified O
to O
offer O
the O
best O
adsorption O
capacity O
and O
desorption O
ratio O
for O
total O
polyphenols B
among O
the O
eight O
macroporous O
resins O
investigated O
. O

Influential O
factors O
, O
such O
as O
pH O
value O
and O
concentration O
of O
feeding O
solution O
, O
strippant O
, O
and O
adsorption O
isotherm O
to O
the O
separation O
of O
total O
polyphenols B
, O
were O
successively O
investigated O
on O
X O
- O
5 O
resin O
. O

After O
one O
run O
treatment O
, O
the O
phenolic O
content O
was O
increased O
2 O
. O
12 O
- O
fold O
from O
35 O
. O
17 O
% O
to O
74 O
. O
64 O
% O
, O
with O
a O
recovery O
yield O
of O
89 O
. O
35 O
% O
. O

Chlorogenic B
acid I
and O
phlorizin B
were O
selectively O
purified O
using O
X O
- O
5 O
and O
polyamide B
resins O
. O

The O
contents O
of O
chlorogenic B
acid I
and O
phlorizin B
were O
15 O
. O
20 O
% O
and O
97 O
. O
52 O
% O
with O
recovery O
yields O
of O
89 O
. O
16 O
% O
and O
64 O
. O
95 O
% O
, O
respectively O
. O

The O
method O
developed O
will O
provide O
a O
potential O
approach O
for O
its O
wide O
industrial O
and O
pharmaceutical O
use O
. O

Antioxidant O
and O
antihypertensive O
properties O
of O
liquid O
and O
solid O
state O
fermented O
lentils O
. O

The O
effect O
of O
liquid O
( O
LSF O
) O
and O
solid O
state O
fermentation O
( O
SSF O
) O
of O
lentils O
for O
production O
of O
water O
- O
soluble O
fractions O
with O
antioxidant O
and O
antihypertensive O
properties O
was O
studied O
. O

LSF O
was O
performed O
either O
spontaneously O
( O
NF O
) O
or O
by O
Lactobacillus O
plantarum O
( O
LP O
) O
while O
SSF O
was O
performed O
by O
Bacillus O
subtilis O
( O
BS O
) O
. O

Native O
lactic O
flora O
in O
NF O
adapted O
better O
than O
L O
. O
plantarum O
to O
fermentative O
broth O
and O
BS O
counts O
increased O
4 O
. O
0 O
logCFU O
/ O
g O
up O
to O
48 O
h O
of O
SSF O
. O

LSF O
water O
- O
soluble O
fractions O
had O
higher O
( O
P O
< O
= O
0 O
. O
05 O
) O
free O
amino B
groups O
, O
GABA B
content O
, O
antioxidant O
and O
angiotensin O
I O
- O
converting O
enzyme O
inhibitory O
( O
ACEI O
) O
activities O
than O
SSF O
. O

In O
addition O
, O
GABA B
and O
ACEI O
activity O
of O
LSF O
increased O
in O
a O
time O
- O
dependent O
manner O
. O

Proteolysis O
by O
BS O
was O
limited O
, O
with O
slight O
changes O
in O
free O
amino B
groups O
, O
while O
GABA B
, O
total O
phenolic B
compounds O
and O
antioxidant O
capacity O
increased O
throughout O
fermentation O
. O

Higher O
antihypertensive O
potential O
was O
observed O
in O
NF O
( O
96 O
h O
) O
characterised O
by O
the O
highest O
GABA B
content O
( O
10 O
. O
42 O
mg O
/ O
g O
extract O
) O
, O
ACE O
- O
inhibitory O
potency O
( O
expressed O
as O
IC O
( O
50 O
) O
) O
of O
0 O
. O
18 O
mg O
protein O
/ O
ml O
and O
antioxidant O
capacity O
of O
0 O
. O
26 O
mmol O
Trolox B
equivalents O
/ O
g O
extract O
. O

Therefore O
, O
water O
- O
soluble O
fermented O
lentil O
extracts O
obtained O
by O
LSF O
are O
particularly O
promising O
as O
functional O
ingredients O
in O
preventing O
hypertension O
. O

Fucoxanthin B
content O
and O
antioxidant O
properties O
of O
Undaria O
pinnatifida O
. O

This O
study O
investigated O
the O
fucoxanthin B
content O
of O
New O
Zealand O
( O
NZ O
) O
Undaria O
pinnatifida O
harvested O
from O
two O
locations O
in O
the O
Marlborough O
Sounds O
, O
New O
Zealand O
across O
its O
growing O
season O
. O

Fucoxanthin B
content O
and O
antioxidant O
properties O
of O
processed O
New O
Zealand O
U O
. O
pinnatifida O
and O
commercial O
wakame O
from O
Japan O
and O
Korea O
were O
further O
compared O
. O

Results O
showed O
that O
U O
. O
pinnatifida O
harvested O
from O
Port O
Underwood O
had O
higher O
fucoxanthin B
content O
in O
the O
blade O
compared O
to O
Pelorus O
Sound O
. O

The O
sporophyll O
also O
contained O
a O
significant O
amount O
of O
fucoxanthin B
throughout O
the O
harvest O
season O
, O
although O
lower O
than O
in O
the O
blade O
. O

Two O
antioxidant O
measurement O
methods O
, O
DPPH B
and O
CUPRAC B
, O
were O
utilised O
to O
measure O
antioxidant O
activities O
. O

Processed O
NZ O
U O
. O
pinnatifida O
had O
a O
lower O
fucoxanthin B
content O
and O
antioxidant O
activity O
than O
freeze O
- O
dried O
Undaria O
. O

Fucoxanthin B
content O
and O
antioxidant O
activities O
of O
NZ O
processed O
U O
. O
pinnatifida O
were O
not O
significantly O
different O
from O
other O
commercial O
samples O
from O
Japan O
and O
Korea O
. O

In O
conclusion O
, O
U O
. O
pinnatifida O
in O
New O
Zealand O
has O
a O
great O
potential O
to O
be O
a O
food O
and O
nutraceutical O
resource O
. O

Structure O
and O
composition O
of O
model O
cheeses O
influence O
sodium B
NMR O
mobility O
, O
kinetics O
of O
sodium B
release O
and O
sodium B
partition O
coefficients O
. O

The O
mobility O
and O
release O
of O
sodium B
ions O
were O
assessed O
in O
model O
cheeses O
with O
three O
different O
lipid O
/ O
protein O
ratios O
, O
with O
or O
without O
added O
NaCl B
. O

The O
rheological O
properties O
of O
the O
cheeses O
were O
analysed O
using O
uniaxial O
compression O
tests O
. O

Microstructure O
was O
characterised O
by O
confocal O
laser O
scanning O
microscopy O
. O

( B
23 I
) I
Na I
nuclear O
magnetic O
resonance O
( O
NMR O
) O
spectroscopy O
was O
used O
to O
study O
the O
molecular O
mobility O
of O
sodium B
ions O
in O
model O
cheeses O
through O
measurements O
of O
the O
relaxation O
and O
creation O
times O
. O

Greater O
mobility O
was O
observed O
in O
cheeses O
containing O
a O
lower O
protein O
content O
and O
with O
added O
NaCl B
. O

The O
kinetics O
of O
sodium B
release O
from O
the O
cheese O
to O
an O
aqueous O
phase O
was O
correlated O
with O
the O
mobility O
of O
sodium B
ions O
. O

The O
highest O
rates O
of O
sodium B
release O
were O
observed O
with O
a O
lower O
protein O
content O
and O
with O
added O
NaCl B
. O

The O
water O
/ O
cheese O
partition O
coefficients O
of O
sodium B
increased O
when O
NaCl B
was O
added O
or O
the O
protein O
content O
was O
higher O
. O

The O
study O
highlighted O
the O
effect O
of O
model O
cheese O
characteristics O
on O
molecular O
and O
macroscopic O
behaviours O
of O
sodium B
. O

A O
combination O
of O
[ B
+ I
] I
and I
[ I
- I
] I
- I
Huperzine I
A I
improves O
protection O
against O
soman O
toxicity O
compared O
to O
[ B
+ I
] I
- I
Huperzine I
A I
in O
guinea O
pigs O
. O

The O
neuropathologic O
mechanisms O
after O
exposure O
to O
lethal O
doses O
of O
nerve O
agent O
are O
complex O
and O
involve O
multiple O
biochemical O
pathways O
. O

Effective O
treatment O
requires O
drugs O
that O
can O
simultaneously O
protect O
by O
reversible O
binding O
to O
the O
acetylcholinesterase O
( O
AChE O
) O
and O
blocking O
cascades O
of O
seizure O
related O
brain O
damage O
, O
inflammation O
, O
neuronal O
degeneration O
as O
well O
as O
promoting O
induction O
of O
neuroregeneration O
. O

[ B
- I
] I
- I
Huperzine I
A I
( O
[ B
- I
] I
- I
Hup I
A I
) O
, O
is O
a O
naturally O
occurring O
potent O
reversible O
AChE O
inhibitor O
that O
penetrates O
the O
blood O
- O
brain O
barrier O
. O

It O
also O
has O
several O
neuroprotective O
effects O
including O
modification O
of O
beta O
- O
amyloid O
peptide O
, O
reduction O
of O
oxidative O
stress O
, O
anti O
- O
inflammatory O
, O
anti O
- O
apoptotic O
and O
induction O
and O
regulation O
of O
nerve O
growth O
factor O
. O

Toxicities O
at O
higher O
doses O
restrict O
the O
neuroporotective O
ability O
of O
[ B
- I
] I
- I
Hup I
A I
for O
treatment O
. O

The O
synthetic O
stereoisomer O
, O
[ B
+ I
] I
- I
Hup I
A I
, O
is O
less O
toxic O
due O
to O
poor O
AChE O
inhibition O
and O
is O
suitable O
for O
both O
pre O
- O
/ O
post O
- O
exposure O
treatments O
of O
nerve O
agent O
toxicity O
. O

[ B
+ I
] I
- I
Hup I
A I
block O
the O
N B
- I
methyl I
- I
d I
- I
aspartate I
( O
NMDA B
) O
- O
induced O
seizure O
in O
rats O
, O
reduce O
excitatory O
amino B
acid I
induced O
neurotoxicity O
and O
also O
prevent O
soman O
induced O
toxicity O
with O
minimum O
performance O
decrement O
. O

Unique O
combinations O
of O
two O
stereo O
- O
isomers O
of O
Hup B
A I
may O
provide O
an O
excellent O
pre O
/ O
post O
- O
treatment O
drug O
for O
the O
nerve O
agent O
induced O
seizure O
/ O
status O
epilepticus O
. O

We O
investigated O
a O
combination O
of O
[ B
+ I
] I
- I
Hup I
A O
with O
a O
small O
dose O
of O
[ B
- I
] I
- I
Hup I
A O
( O
[ B
+ I
] I
and I
[ I
- I
] I
- I
Hup I
A O
) O
against O
soman B
toxicity O
. O

Our O
data O
showed O
that O
pretreatment O
with O
a O
combination O
[ B
+ I
] I
and I
[ I
- I
] I
- I
Hup I
A I
significantly O
increased O
the O
survival O
rate O
and O
reduced O
behavioral O
abnormalities O
after O
exposure O
to O
1 O
. O
2 O
x O
LD50 O
soman O
compared O
to O
[ B
+ I
] I
- I
Hup I
A I
in O
guinea O
pigs O
. O

In O
addition O
, O
[ B
+ I
] I
and I
[ I
- I
] I
- I
Hup I
A O
pretreatment O
inhibited O
the O
development O
of O
high O
power O
of O
EEG O
better O
than O
[ B
+ I
] I
- I
Hup I
A O
pretreatment O
alone O
. O

These O
data O
suggest O
that O
a O
combination O
of O
[ O
+ O
] O
and O
[ O
- O
] O
- O
Hup O
A O
offers O
better O
protection O
than O
[ O
+ O
] O
- O
Hup O
A O
and O
serves O
as O
a O
potent O
medical O
countermeasure O
against O
lethal O
dose O
nerve O
agent O
toxicity O
in O
guinea O
pigs O
. O

Organophosphorus B
compound O
esterase O
profiles O
as O
predictors O
of O
therapeutic O
and O
toxic O
effects O
. O

Certain O
organophosphorus B
compounds O
( O
OPCs O
) O
inhibit O
various O
serine B
esterases O
( O
EOHs O
) O
via O
phosphorylation O
of O
their O
active O
site O
serines B
. O

We O
focused O
on O
4 O
EOHs O
of O
particular O
toxicological O
interest O
: O
acetylcholinesterase O
( O
AChE O
: O
acute O
neurotoxicity O
; O
cognition O
enhancement O
) O
, O
butyrylcholinesteras O
( O
BChE O
: O
inhibition O
of O
drug O
metabolism O
and O
/ O
or O
stoichiometric O
scavenging O
of O
EOH O
inhibitors O
; O
cognition O
enhancement O
) O
, O
carboxylesterase O
( O
CaE O
: O
inhibition O
of O
drug O
metabolism O
and O
/ O
or O
stoichiometric O
scavenging O
of O
EOH O
inhibitors O
) O
, O
and O
neuropathy O
target O
esterase O
( O
NTE O
: O
delayed O

neurotoxicity O
, O
OPIDN O
) O
. O

The O
relative O
degree O
of O
inhibition O
of O
these O
EOHs O
constitutes O
the O
" O
esterase O
profile O
" O
of O
an O
OPC O
and O
serves O
as O
a O
major O
determinant O
of O
its O
net O
physiological O
effects O
. O

Thus O
, O
understanding O
and O
controlling O
the O
esterase O
profile O
of O
OPC O
activity O
and O
selectivity O
toward O
these O
4 O
target O
enzymes O
is O
a O
significant O
undertaking O
. O

In O
the O
present O
study O
, O
we O
analyzed O
the O
inhibitor O
properties O
of O
52 O
OPCs O
against O
the O
4 O
EOHs O
, O
along O
with O
pairwise O
and O
multitarget O
selectivities O
between O
them O
, O
using O
2 O
QSAR O
approaches O
: O
Hansch O
modeling O
and O
Molecular O
Field O
Topology O
Analysis O
( O
MFTA O
) O
. O

The O
general O
formula O
of O
the O
OPCs O
was O
( B
RO I
) I
2P I
( I
O I
) I
X I
, O
where O
R O
= O
alkyl B
, O
X O
= O
- O
SCH B
( I
Hal I
) I
COOEt I
( O
Hal B
= O
Cl B
, O
Br B
) O
, O
- O
SCHCl2 B
, O
- O
SCH2Br B
, O
- O
OCH B
( I
CF3 I
) I
R I
( I
1 I
) I
( O
R O
( O
1 O
) O
= O
C6H5 B
, O
CF3 B
, O
COOEt B
, O
COOMe B
) O
. O

The O
Hansch O
model O
showed O
that O
increasing O
neuropathic O
potential O
correlated O
with O
rising O
R O
hydrophobicity O
; O
moreover O
, O
OPC O
binding O
to O
scavenger O
EOHs O
( O
BChE O
and O
CaE O
) O
had O
different O
effects O
on O
potential O
acute O
and O
delayed O
neurotoxicity O
. O

Predicted O
protective O
roles O
of O
BChE O
and O
CaE O
against O
acute O
toxicity O
were O
enhanced O
with O
increasing O
hydrophobicity O
, O
but O
projected O
protection O
against O
OPIDN O
was O
decreased O
. O

Next O
, O
Molecular O
Field O
Topology O
Analysis O
( O
MFTA O
) O
models O
were O
built O
, O
considering O
atomic O
descriptors O
, O
e O
. O
g O
. O
, O
effective O
charge O
, O
van O
der O
Waals O
radius O
of O
environment O
, O
and O
group O
lipophilicity O
. O

Activity O
/ O
selectivity O
maps O
confirmed O
predictions O
from O
Hansch O
models O
and O
revealed O
other O
structural O
factors O
affecting O
activity O
and O
selectivity O
. O

Virtual O
screening O
based O
on O
multitarget O
selectivity O
MFTA O
models O
was O
used O
to O
design O
libraries O
of O
OPCs O
with O
favorable O
esterase O
profiles O
for O
potential O
application O
as O
selective O
inhibitors O
of O
CaE O
without O
untoward O
side O
effects O
. O

New O
tools O
in O
diagnosis O
and O
biomonitoring O
of O
intoxications O
with O
organophosphorothioa B
: O
Case O
studies O
with O
chlorpyrifos B
and O
diazinon B
. O

Organophosphate B
( O
OP O
) O
pesticides O
are O
neurotoxic O
compounds O
that O
are O
widely O
used O
in O
agriculture O
. O

Classical O
methods O
for O
monitoring O
OP O
exposure O
comprise O
the O
measurement O
of O
intact O
OP O
, O
its O
metabolites O
or O
cholinesterase O
activity O
. O

Newly O
developed O
methods O
focus O
on O
the O
analysis O
of O
the O
OP O
adduct O
bound O
to O
proteins O
such O
as O
butyrylcholinesteras O
( O
BuChE O
) O
and O
albumin O
. O

These O
adducts O
can O
be O
analyzed O
by O
means O
of O
fluoride B
reactivation O
or O
by O
analysis O
with O
LC O
- O
MS O
/ O
MS O
of O
the O
pepsin O
or O
pronase O
digest O
of O
butyrylcholinesteras O
and O
albumin O
, O
respectively O
. O

The O
utility O
of O
these O
methods O
is O
illustrated O
through O
the O
analysis O
of O
plasma O
samples O
obtained O
from O
patients O
taken O
1 O
- O
49days O
after O
ingestion O
of O
the O
organophosphate B
pesticides O
chlorpyrifos B
and O
/ O
or O
diazinon B
. O

Thus O
, O
in O
this O
particular O
case O
several O
independent O
methodologies O
were O
applied O
to O
the O
biomedical O
samples O
, O
all O
pointing O
to O
the O
same O
exposure O
. O

Strategies O
for O
the O
selection O
of O
catalytic O
antibodies O
against O
organophosphorus B
nerve O
agents O
. O

Among O
the O
strategies O
aimed O
at O
biocompatible O
means O
for O
organophosphorus B
nerve O
agents O
neutralization O
, O
immunoglobulins O
have O
attracted O
attention O
in O
the O
1990 O
' O
s O
and O
2000 O
' O
s O
both O
for O
their O
ability O
to O
immobilize O
the O
toxicants O
, O
but O
also O
for O
their O
ability O
to O
be O
turned O
into O
enzymatically O
active O
antibodies O
known O
as O
catalytic O
antibodies O
or O
abzymes O
( O
antibodies O
- O
enzymes O
) O
. O

We O
will O
present O
here O
a O
critical O
review O
of O
the O
successive O
strategies O
used O
for O
the O
selection O
of O
these O
nerve O
agent O
- O
hydrolyzing O
abzymes O
, O
based O
on O
hapten O
design O
, O
namely O
antibodies O
raised O
against O
a O
wide O
variety O
of O
transition O
state O
analogs O
, O
and O
eventually O
the O
strategies O
based O
on O
anti O
- O
idiotypic O
antibodies O
and O
reactibodies O
. O

Reduced O
in O
vitro O
and O
in O
vivo O
toxicity O
of O
siRNA O
- O
lipoplexes O
with O
addition O
of O
polyglutamate B
. O

We O
previously O
designed O
a O
new O
siRNA O
vector O
that O
efficiently O
silences O
genes O
in O
vitro O
and O
in O
vivo O
. O

The O
vector O
originality O
is O
based O
on O
the O
fact O
that O
, O
in O
addition O
to O
the O
siRNA O
molecule O
, O
it O
contains O
two O
components O
: O
1 O
) O
a O
cationic O
liposome O
that O
auto O
- O
associates O
with O
the O
siRNA O
to O
form O
particles O
called O
" O
lipoplexes O
" O
and O
, O
2 O
) O
an O
anionic O
polymer O
which O
enhances O
the O
lipoplex O
' O
s O
efficiency O
. O

This O
anionic O
polymer O
can O
be O
a O
nucleic O
acid O
, O
a O
polypeptide O
or O
a O
polysaccharide O
. O

We O
show O
here O
how O
the O
nature O
of O
the O
added O
anionic O
polymer O
into O
our O
siRNA O
delivery O
system O
impacts O
the O
toxic O
effects O
induced O
by O
siRNA O
lipoplexes O
. O

We O
first O
observed O
that O
: O
( O
i O
) O
siRNA O
lipoplexes O
- O
induced O
toxicity O
was O
cell O
line O
dependent O
, O
tumoral O
cell O
lines O
being O
the O
more O
sensitive O
; O
and O
( O
ii O
) O
plasmid O
DNA O
- O
containing O
siRNA O
lipoplexes O
were O
more O
toxic O
than O
polyglutamate B
- O
containing O
ones O
or O
cationic O
liposomes O
. O

We O
next O
determined O
that O
the O
toxicity O
induced O
by O
plasmid O
- O
containing O
lipoplexes O
is O
a O
long O
- O
lasting O
effect O
that O
decreased O
cell O
survival O
capacity O
for O
several O
generations O
. O

We O
also O
found O
that O
treated O
cells O
underwent O
death O
following O
apoptosis O
pathway O
. O

Systemic O
injection O
to O
mice O
of O
siRNA O
lipoplexes O
, O
rather O
than O
of O
cationic O
liposome O
, O
triggered O
a O
production O
of O
several O
cytokines O
in O
mice O
and O
replacement O
of O
plasmid O
by O
polyglutamate B
reduced O
the O
elevation O
of O
all O
assayed O
cytokines O
. O

In O
order O
to O
enhance O
siRNA O
lipoplexes O
efficiency O
, O
the O
addition O
of O
polyglutamate B
as O
anionic O
polymer O
should O
be O
preferred O
to O
plasmid O
DNA O
as O
far O
as O
in O
vitro O
as O
well O
as O
in O
vivo O
toxicity O
is O
concerned O
. O

Helenalin B
- O
induced O
apoptosis O
is O
dependent O
on O
production O
of O
reactive O
oxygen B
species O
and O
independent O
of O
induction O
of O
endoplasmic O
reticulum O
stress O
in O
renal O
cell O
carcinoma O
. O

Helenalin B
, O
a O
sesquiterpene B
lactone I
, O
exhibits O
anti O
- O
inflammatory O
and O
anti O
- O
tumor O
activities O
. O

Here O
, O
we O
investigated O
whether O
helenalin B
could O
induce O
apoptosis O
in O
human O
renal O
carcinoma O
Caki O
cells O
. O

Helenalin B
increased O
apoptosis O
in O
dose O
dependent O
manner O
in O
Caki O
cells O
, O
and O
also O
induced O
apoptosis O
in O
other O
carcinoma O
cells O
, O
such O
as O
human O
renal O
carcinoma O
ACHN O
cells O
, O
human O
colon O
carcinoma O
HT29 O
and O
HCT116 O
cells O
. O

We O
found O
that O
helenalin B
markedly O
induced O
endoplasmic O
reticulum O
( O
ER O
) O
stress O
- O
related O
genes O
, O
such O
as O
regulated O
in O
development O
and O
DNA O
damage O
responses O
( O
REDD O
) O
1 O
, O
activating O
transcription O
factor O
- O
4 O
( O
ATF4 O
) O
and O
/ O
or O
the O
CCAAT O
enhancer O
- O
binding O
protein O
- O
homologous O
protein O
( O
CHOP O
) O
. O

However O
, O
down O
- O
regulation O
of O
ATF4 O
and O
/ O
or O
CHOP O
expression O
by O
siRNA O
had O
no O
effect O
on O
helenalin B
- O
induced O
apoptosis O
in O
Caki O
and O
HCT116 O
cells O
. O

Helenalin B
increased O
production O
of O
intracellular O
reactive O
oxygen B
species O
( O
ROS O
) O
. O

Furthermore O
, O
ROS O
scavengers O
, O
N B
- I
acetylcystine I
( O
NAC B
) O
, O
and O
glutathione B
ethyl I
ester I
( O
GEE B
) O
, O
reduced O
helenalin B
- O
induced O
apoptosis O
. O

Taken O
together O
, O
helenalin B
induced O
apoptosis O
via O
ROS O
generation O
in O
human O
renal O
carcinoma O
Caki O
cells O
. O

Dietary O
quercetin B
ameliorates O
nonalcoholic O
steatohepatitis O
induced O
by O
a O
high O
- O
fat O
diet O
in O
gerbils O
. O

Dietary O
quercetin B
is O
highly O
abundant O
in O
edible O
plants O
, O
which O
possesses O
a O
wide O
range O
of O
pharmacological O
properties O
. O

This O
study O
was O
to O
investigate O
hepatoprotective O
effects O
of O
quercetin B
in O
the O
nonalcoholic O
steatohepatitis O
( O
NASH O
) O
gerbils O
induced O
by O
a O
high O
- O
fat O
diet O
( O
HFD O
) O
, O
and O
to O
evaluate O
its O
regulatory O
mechanism O
on O
hepatic O
inflammatory O
response O
. O

The O
gerbils O
were O
fed O
with O
HFD O
for O
28 O
days O
to O
induce O
NASH O
. O

From O
15th O
day O
to O
28th O
day O
, O
the O
treated O
drugs O
were O
given O
daily O
to O
each O
animal O
, O
respectively O
. O

The O
lipid O
profiles O
and O
biochemical O
markers O
were O
determined O
at O
the O
end O
of O
the O
experiment O
. O

The O
expressions O
of O
Sirt1 O
, O
NF O
- O
kappa O
B O
p65 O
and O
iNOS O
were O
detected O
by O
immunohistochemistry O
and O
Western O
blot O
analysis O
. O

The O
results O
showed O
that O
oral O
administration O
of O
quercetin B
at O
doses O
of O
30 O
- O
60 O
mg O
/ O
kg O
to O
hyperlipidemia O
rats O
for O
14 O
days O
were O
highly O
effective O
in O
decreasing O
the O
levels O
of O
serum O
total O
cholesterol B
( O
TC O
) O
, O
triglycerides B
( O
TG B
) O
, O
low O
- O
density O
lipoprotein O
cholesterol B
( O
LDL O
- O
C O
) O
, O
alanine B
aminotransferase O
( O
ALT O
) O
and O
aspartate B
aminotransferase O
( O
AST O
) O
. O

It O
could O
decrease O
lipid O
accumulation O
in O
the O
hepatocytes O
, O
and O
reduce O
serum O
levels O
of O
pro O
- O
inflammatory O
cytokines O
TNF O
- O
alpha O
and O
IL O
- O
6 O
via O
regulating O
the O
expressions O
of O
Sirt1 O
, O
NF O
- O
kappa O
B O
p65 O
and O
iNOS O
. O

Thus O
, O
dietary O
quercetin B
had O
significant O
therapeutic O
benefits O
and O
could O
be O
explored O
as O
a O
potential O
promising O
candidate O
for O
the O
prevention O
of O
NASH O
. O

Neuroprotective O
role O
of O
ATP B
- O
sensitive O
potassium B
channels O
in O
cerebral O
ischemia O
. O

ATP B
- O
sensitive O
potassium B
( O
K B
( O
ATP B
) O
) O
channels O
are O
weak O
, O
inward O
rectifiers O
that O
couple O
metabolic O
status O
to O
cell O
membrane O
electrical O
activity O
, O
thus O
modulating O
many O
cellular O
functions O
. O

An O
increase O
in O
the O
ADP B
/ O
ATP B
ratio O
opens O
K B
( O
ATP B
) O
channels O
, O
leading O
to O
membrane O
hyperpolarization O
. O

K B
( O
ATP B
) O
channels O
are O
ubiquitously O
expressed O
in O
neurons O
located O
in O
different O
regions O
of O
the O
brain O
, O
including O
the O
hippocampus O
and O
cortex O
. O

Brief O
hypoxia O
triggers O
membrane O
hyperpolarization O
in O
these O
central O
neurons O
. O

In O
vivo O
animal O
studies O
confirmed O
that O
knocking O
out O
the O
Kir6 O
. O
2 O
subunit O
of O
the O
K B
( O
ATP B
) O
channels O
increases O
ischemic O
infarction O
, O
and O
overexpression O
of O
the O
Kir6 O
. O
2 O
subunit O
reduces O
neuronal O
injury O
from O
ischemic O
insults O
. O

These O
findings O
provide O
the O
basis O
for O
a O
practical O
strategy O
whereby O
activation O
of O
endogenous O
K B
( O
ATP B
) O
channels O
reduces O
cellular O
damage O
resulting O
from O
cerebral O
ischemic O
stroke O
. O

K B
( O
ATP B
) O
channel O
modulators O
may O
prove O
to O
be O
clinically O
useful O
as O
part O
of O
a O
combination O
therapy O
for O
stroke O
management O
in O
the O
future O
. O

The O
kinase O
activity O
of O
EphA4 O
mediates O
homeostatic O
scaling O
- O
down O
of O
synaptic O
strength O
via O
activation O
of O
Cdk5 O
. O

Neurons O
within O
a O
network O
have O
the O
ability O
to O
homeostatically O
scale O
- O
down O
their O
excitatory O
synaptic O
strength O
under O
conditions O
of O
persistent O
neuronal O
activity O
elevation O
, O
a O
process O
pivotal O
to O
neural O
circuit O
stability O
. O

How O
this O
homeostatic O
regulation O
is O
achieved O
at O
the O
molecular O
level O
in O
developing O
neural O
circuits O
, O
which O
face O
gradually O
elevated O
neuronal O
activity O
as O
part O
of O
circuit O
wiring O
, O
is O
not O
well O
- O
understood O
. O

Using O
dissociated O
hippocampal O
neuronal O
cultures O
, O
we O
identified O
a O
critical O
and O
cell O
autonomous O
role O
for O
the O
receptor O
tyrosine B
kinase O
EphA4 O
in O
mediating O
activity O
- O
induced O
homeostatic O
down O
- O
regulation O
of O
excitatory O
synaptic O
strength O
. O

Reducing O
the O
endogenous O
level O
of O
EphA4 O
in O
individual O
neurons O
by O
RNAi O
effectively O
blocked O
activity O
- O
induced O
scaling O
- O
down O
of O
excitatory O
synaptic O
strength O
, O
while O
co O
- O
transfection O
of O
RNAi O
resistant O
EphA4 O
rescued O
this O
effect O
. O

Furthermore O
, O
interfering O
with O
EphA4 O
forward O
signaling O
using O
EphA4 O
- O
Fc O
blocked O
activity O
- O
induced O
homeostatic O
synaptic O
scaling O
- O
down O
, O
while O
direct O
activation O
of O
EphA4 O
with O
its O
ligand O
EphrinA1 O
weakened O
excitatory O
synaptic O
strength O
. O

Up O
- O
or O
down O
- O
regulating O
EphA4 O
function O
in O
individual O
neurons O
also O
did O
not O
affect O
the O
density O
of O
excitatory O
synapses O
. O

The O
kinase O
activities O
of O
EphA4 O
and O
its O
downstream O
effector O
Cdk5 O
were O
both O
required O
for O
homeostatic O
synaptic O
scaling O
, O
as O
overexpression O
of O
EphA4 O
with O
constitutively O
active O
kinase O
activity O
reduced O
excitatory O
synaptic O
strength O
, O
while O
interfering O
with O
either O
the O
kinase O
activity O
of O
EphA4 O
or O
Cdk5 O
blocked O
activity O
- O
induced O
synaptic O
scaling O
. O

Consistently O
, O
the O
activities O
of O
EphA4 O
and O
Cdk5 O
increased O
significantly O
during O
global O
and O
persistent O
activity O
elevation O
. O

Together O
, O
our O
work O
demonstrated O
that O
the O
kinase O
activity O
of O
EphA4 O
, O
via O
activation O
of O
downstream O
Cdk5 O
activity O
, O
mediates O
the O
scaling O
- O
down O
of O
excitatory O
synaptic O
strength O
under O
conditions O
of O
global O
activity O
elevation O
. O

A O
missense O
polymorphism O
( O
rs11466653 O
, O
Met326Thr O
) O
of O
toll O
- O
like O
receptor O
10 O
( O
TLR10 O
) O
is O
associated O
with O
tumor O
size O
of O
papillary O
thyroid O
carcinoma O
in O
the O
Korean O
population O
. O

Toll O
- O
like O
receptors O
( O
TLRs O
) O
are O
important O
components O
of O
innate O
immune O
response O
. O

The O
aim O
of O
this O
study O
was O
to O
investigate O
whether O
TLR O
gene O
cluster O
( O
TLR10 O
- O
TLR1 O
- O
TLR6 O
) O
polymorphisms O
are O
associated O
with O
the O
etiology O
of O
papillary O
thyroid O
carcinoma O
( O
PTC O
) O
and O
its O
clinicopathologic O
characteristics O
. O

We O
recruited O
94 O
PTC O
patients O
and O
325 O
control O
subjects O
. O

Genotypes O
for O
each O
SNP O
were O
determined O
by O
direct O
sequencing O
. O

SNPStats O
and O
SPSS O
18 O
. O
0 O
were O
used O
to O
evaluate O
odds O
ratios O
( O
ORs O
) O
, O
95 O
% O
confidence O
intervals O
( O
CIs O
) O
, O
and O
P O
values O
. O

Multiple O
logistic O
regression O
analyzes O
of O
genetic O
data O
were O
performed O
. O

The O
missense O
SNP O
rs11466653 O
was O
associated O
with O
small O
tumor O
size O
( O
< O
1 O
cm O
) O
in O
PTC O
. O

The O
frequency O
of O
the O
rs11466653 O
T O
allele O
was O
higher O
in O
PTC O
patients O
with O
tumors O
< O
1 O
cm O
in O
size O
than O
in O
the O
control O
group O
( O
95 O
. O
8 O
vs O
. O
87 O
. O
2 O
% O
; O
P O
= O
0 O
. O
021 O
, O
OR O
= O
0 O
. O
30 O
, O
95 O
% O
CI O
= O
0 O
. O
11 O
- O
0 O
. O
83 O
) O
. O

The O
T O
allele O
of O
rs11466653 O
( O
T O
/ O
C O
, O
Met326Thr O
) O
in O
TLR10 O
may O
be O
a O
risk O
factor O
for O
the O
development O
of O
tumors O
in O
PTC O
in O
the O
Korean O
population O
. O

First O
- O
principles O
calculations O
of O
lithium B
- O
ion O
migration O
at O
a O
coherent O
grain O
boundary O
in O
a O
cathode O
material O
, O
LiCoO B
( I
2 I
) I
. O

Results O
of O
theoretical O
calculations O
are O
reported O
, O
examining O
the O
effect O
of O
a O
coherent O
twin O
boundary O
on O
the O
electrical O
properties O
of O
LiCoO B
( I
2 I
) I
. O

This O
study O
suggests O
that O
internal O
interfaces O
in O
LiCoO B
( I
2 I
) I
strongly O
affect O
the O
battery O
voltage O
, O
battery O
capacity O
, O
and O
power O
density O
of O
this O
material O
, O
which O
is O
of O
particular O
concern O
if O
it O
is O
used O
in O
all O
- O
solid O
- O
state O
Li B
- O
ion O
batteries O
. O

Cross O
- O
species O
transcriptomic O
analysis O
of O
mouse O
and O
rat O
lung O
exposed O
to O
chloroprene B
. O

beta B
- I
Chloroprene I
( O
2 B
- I
chloro I
- I
1 I
, I
3 I
- I
butadiene I
) O
, O
a O
monomer O
used O
in O
the O
production O
of O
neoprene B
elastomers O
, O
is O
of O
regulatory O
interest O
due O
to O
the O
production O
of O
multiorgan O
tumors O
in O
mouse O
and O
rat O
cancer O
bioassays O
. O

A O
significant O
increase O
in O
female O
mouse O
lung O
tumors O
was O
observed O
at O
the O
lowest O
exposure O
concentration O
of O
12 O
. O
8 O
ppm O
, O
whereas O
a O
small O
, O
but O
not O
statistically O
significant O
increase O
was O
observed O
in O
female O
rats O
only O
at O
the O
highest O
exposure O
concentration O
of O
80 O
ppm O
. O

The O
metabolism O
of O
chloroprene B
results O
in O
the O
generation O
of O
reactive O
epoxides B
, O
and O
the O
rate O
of O
overall O
chloroprene B
metabolism O
is O
highly O
species O
dependent O
. O

To O
identify O
potential O
key O
events O
in O
the O
mode O
of O
action O
of O
chloroprene B
lung O
tumorigenesis O
, O
dose O
- O
response O
and O
time O
- O
course O
gene O
expression O
microarray O
measurements O
were O
made O
in O
the O
lungs O
of O
female O
mice O
and O
female O
rats O
. O

The O
gene O
expression O
changes O
were O
analyzed O
using O
both O
a O
traditional O
ANOVA O
approach O
followed O
by O
pathway O
enrichment O
analysis O
and O
a O
pathway O
- O
based O
benchmark O
dose O
( O
BMD O
) O
analysis O
approach O
. O

Pathways O
related O
to O
glutathione B
biosynthesis O
and O
metabolism O
were O
the O
primary O
pathways O
consistent O
with O
cross O
- O
species O
differences O
in O
tumor O
incidence O
. O

Transcriptional O
BMD O
values O
for O
the O
pathway O
were O
more O
similar O
to O
differences O
in O
tumor O
response O
than O
were O
estimated O
target O
tissue O
dose O
surrogates O
based O
on O
the O
total O
amount O
of O
chloroprene B
metabolized O
per O
unit O
mass O
of O
lung O
tissue O
per O
day O
. O

The O
closer O
correspondence O
of O
the O
transcriptional O
changes O
with O
the O
tumor O
response O
is O
likely O
due O
to O
their O
reflection O
of O
the O
overall O
balance O
between O
metabolic O
activation O
and O
detoxication O
reactions O
, O
whereas O
the O
current O
tissue O
dose O
surrogate O
reflects O
only O
oxidative O
metabolism O
. O

Trans O
- O
chromosomic O
mice O
containing O
a O
human O
CYP3A O
cluster O
for O
prediction O
of O
xenobiotic O
metabolism O
in O
humans O
. O

Human O
CYP3A O
is O
the O
most O
abundant O
P450 O
isozyme O
present O
in O
the O
human O
liver O
and O
small O
intestine O
, O
and O
metabolizes O
around O
50 O
% O
of O
medical O
drugs O
on O
the O
market O
. O

The O
human O
CYP3A O
subfamily O
comprises O
four O
members O
( O
CYP3A4 O
, O
CYP3A5 O
, O
CYP3A7 O
, O
CYP3A43 O
) O
encoded O
on O
human O
chromosome O
7 O
. O

However O
, O
transgenic O
mouse O
lines O
carrying O
the O
entire O
human O
CYP3A O
cluster O
have O
not O
been O
constructed O
because O
of O
limitations O
in O
conventional O
cloning O
techniques O
. O

Here O
, O
we O
show O
that O
the O
introduction O
of O
a O
human O
artificial O
chromosome O
( O
HAC O
) O
containing O
the O
entire O
genomic O
human O
CYP3A O
locus O
recapitulates O
tissue O
- O
and O
stage O
- O
specific O
expression O
of O
human O
CYP3A O
genes O
and O
xenobiotic O
metabolism O
in O
mice O
. O

About O
700 O
kb O
of O
the O
entire O
CYP3A O
genomic O
segment O
was O
cloned O
into O
a O
HAC O
( O
CYP3A O
- O
HAC O
) O
, O
and O
trans O
- O
chromosomic O
( O
Tc O
) O
mice O
carrying O
a O
single O
copy O
of O
germline O
- O
transmittable O
CYP3A O
- O
HAC O
were O
generated O
via O
a O
chromosome O
- O
engineering O
technique O
. O

The O
tissue O
- O
and O
stage O
- O
specific O
expression O
profiles O
of O
CYP3A O
genes O
were O
consistent O
with O
those O
seen O
in O
humans O
. O

We O
further O
generated O
mice O
carrying O
the O
CYP3A O
- O
HAC O
in O
the O
background O
homozygous O
for O
targeted O
deletion O
of O
most O
endogenous O
Cyp3a O
genes O
. O

In O
this O
mouse O
strain O
with O
' O
fully O
humanized O
' O
CYP3A O
genes O
, O
the O
kinetics O
of O
triazolam B
metabolism O
, O
CYP3A O
- O
mediated O
mechanism O
- O
based O
inactivation O
effects O
and O
formation O
of O
fetal O
- O
specific O
metabolites O
of O
dehydroepiandrostero B
observed O
in O
humans O
were O
well O
reproduced O
. O

Thus O
, O
these O
mice O
are O
likely O
to O
be O
valuable O
in O
evaluating O
novel O
drugs O
metabolized O
by O
CYP3A O
enzymes O
and O
in O
studying O
the O
regulation O
of O
human O
CYP3A O
gene O
expression O
. O

Furthermore O
, O
this O
system O
can O
also O
be O
used O
for O
generating O
Tc O
mice O
carrying O
other O
human O
metabolic O
genes O
. O

FlyBase O
: O
improvements O
to O
the O
bibliography O
. O

An O
accurate O
, O
comprehensive O
, O
non O
- O
redundant O
and O
up O
- O
to O
- O
date O
bibliography O
is O
a O
crucial O
component O
of O
any O
Model O
Organism O
Database O
( O
MOD O
) O
. O

Principally O
, O
the O
bibliography O
provides O
a O
set O
of O
references O
that O
are O
specific O
to O
the O
field O
served O
by O
the O
MOD O
. O

Moreover O
, O
it O
serves O
as O
a O
backbone O
to O
which O
all O
curated O
biological O
data O
can O
be O
attributed O
. O

Here O
, O
we O
describe O
the O
organization O
and O
main O
features O
of O
the O
bibliography O
in O
FlyBase O
( O
flybase O
. O
org O
) O
, O
the O
MOD O
for O
Drosophila O
melanogaster O
. O

We O
present O
an O
overview O
of O
the O
current O
content O
of O
the O
bibliography O
, O
the O
pipeline O
for O
identifying O
and O
adding O
new O
references O
, O
the O
presentation O
of O
data O
within O
Reference O
Reports O
and O
effective O
methods O
for O
searching O
and O
retrieving O
bibliographic O
data O
. O

We O
highlight O
recent O
improvements O
in O
these O
areas O
and O
describe O
the O
advantages O
of O
using O
the O
FlyBase O
bibliography O
over O
alternative O
literature O
resources O
. O

Although O
this O
article O
is O
focused O
on O
bibliographic O
data O
, O
many O
of O
the O
features O
and O
tools O
described O
are O
applicable O
to O
browsing O
and O
querying O
other O
datasets O
in O
FlyBase O
. O

Enhancement O
on O
oral O
absorption O
of O
paclitaxel B
by O
multifunctional O
pluronic B
micelles O
. O

The O
aim O
of O
the O
present O
study O
is O
to O
synthesize O
Pluronic B
F127 I
- I
polyethylenimine I
- I
folate I
( O
PF127 B
- I
PEI I
- I
FA I
) O
copolymer O
, O
construct O
a O
mixed O
micelle O
system O
with O
PF127 B
- I
PEI I
- I
FA I
copolymer O
and O
Pluronic B
P123 I
( O
PP123 B
) O
and O
to O
evaluate O
the O
potential O
of O
these O
mixed O
micelles O
as O
an O
oral O
drug O
delivery O
system O
for O
paclitaxel B
( O
PTX B
) O
. O

The O
results O
of O
intestinal O
absorption O
revealed O
that O
the O
PTX B
- O
loaded O
micelles O
displayed O
superior O
permeability O
across O
intestinal O
barrier O
than O
free O
drug O
and O
PF127 B
- I
PEI I
- I
FA I
/ O
PP123 B
mixed O
micelles O
exhibited O
the O
strongest O
permeability O
across O
intestinal O
barrier O
. O

These O
results O
were O
also O
proved O
by O
the O
studies O
on O
cytotoxicity O
and O
cell O
uptake O
tests O
. O

The O
mechanism O
was O
demonstrated O
in O
connection O
with O
inhibition O
of O
the O
efflux O
mediated O
by O
intestinal O
P O
- O
glycoprotein O
( O
P O
- O
gp O
) O
and O
enhancement O
of O
the O
electrostatic O
interaction O
of O
positive O
micelles O
with O
the O
negative O
intestinal O
epithelial O
cells O
, O
thereby O
promoting O
the O
permeation O
across O
the O
intestinal O
wall O
. O

The O
presence O
of O
verapamil B
and O
Pluronic B
both O
improved O
the O
intestinal O
absorption O
of O
PTX B
, O
which O
further O
certified O
the O
effect O
of O
Pluronic B
on O
P O
- O
gp O
inhibition O
. O

Pharmacokinetic O
study O
demonstrated O
that O
the O
area O
under O
the O
plasma O
concentration O
- O
time O
curve O
( O
AUC O
( O
0 O
- O
- O
> O
36 O
h O
) O
) O
of O
PTX B
- O
loaded O
micelles O
was O
three O
times O
greater O
than O
the O
PTX B
solution O
( O
dissolved O
in O
a O
50 O
/ O
50 O
( O
vol O
/ O
vol O
) O
mixture O
of O
Cremophore O
EL O
/ O
dehydrated O
ethanol B
) O
( O
p O
< O
0 O
. O
05 O
) O
. O

In O
general O
PF127 B
- I
PEI I
- I
FA I
/ O
PP123 B
mixed O
micelles O
were O
proved O
to O
be O
potential O
oral O
drug O
delivery O
system O
for O
PTX B
. O

Is O
polycystic O
ovary O
syndrome O
, O
a O
state O
of O
relative O
estrogen B
excess O
, O
a O
real O
risk O
factor O
for O
estrogen B
- O
dependant O
malignancies O
? O

Polycystic O
ovary O
syndrome O
( O
PCOS O
) O
is O
a O
common O
endocrinopathy O
affecting O
women O
of O
fertile O
age O
. O

It O
is O
associated O
with O
several O
risk O
factors O
and O
long O
- O
term O
health O
consequences O
. O

Chronic O
anovulation O
combined O
with O
relative O
estrogen B
excess O
and O
consequent O
prolonged O
stimulatory O
effect O
on O
the O
endometrium O
can O
lead O
to O
the O
pathogenesis O
of O
hormonal O
dependant O
carcinoma O
. O

PCOS O
is O
thus O
traditionally O
reported O
to O
be O
associated O
with O
increased O
risk O
of O
endometrial O
, O
as O
well O
as O
breast O
and O
ovarian O
cancers O
. O

This O
article O
provides O
a O
critical O
literature O
review O
of O
the O
relationship O
between O
PCOS O
and O
the O
incidence O
of O
estrogen B
- O
dependant O
gynecological O
tumours O
, O
and O
it O
then O
discusses O
whether O
the O
commonly O
cited O
risk O
factor O
association O
can O
be O
substantiated O
by O
high O
quality O
studies O
which O
comply O
with O
the O
requirements O
of O
" O
evidence O
- O
based O
medicine O
. O
" O

Distribution O
, O
fate O
and O
histopathological O
effects O
of O
ethion B
insecticide O
on O
selected O
organs O
of O
the O
crayfish O
, O
Procambarus O
clarkii O
. O

This O
study O
aims O
to O
investigate O
the O
fate O
and O
histopathological O
effects O
of O
ethion B
on O
selected O
organs O
of O
the O
crayfish O
, O
Procamabrus O
clarkii O
. O

Crayfish O
were O
exposed O
to O
1 O
mg O
l O
( O
- O
1 O
) O
( B
14 I
) I
C I
- I
ethion I
and O
the O
concentrations O
of O
ethion B
and O
its O
possible O
degradation O
products O
were O
measured O
in O
water O
and O
different O
organs O
of O
the O
crayfish O
over O
both O
the O
exposure O
and O
recovery O
periods O
. O

Chromatographic O
analysis O
revealed O
that O
ethion B
was O
degraded O
into O
ethion B
monooxon I
, O
ethion B
dioxon I
, O
O B
, I
O I
- I
diethyl I
phosphorothioate I
, O
O B
- I
ethyl I
phosphorothioate I
and O
one O
unknown O
compound O
. O

At O
the O
end O
of O
exposure O
period O
, O
ethion B
was O
accumulated O
in O
different O
organs O
of O
the O
crayfish O
especially O
in O
the O
hepatopancreas O
and O
gills O
. O

Following O
the O
transfer O
of O
crayfish O
to O
clean O
water O
for O
seven O
days O
, O
the O
concentration O
of O
insecticide O
residues O
were O
decreased O
in O
both O
the O
hepatopancreas O
and O
gills O
suggesting O
that O
these O
organs O
play O
an O
important O
role O
in O
elimination O
of O
ethion B
. O

On O
the O
other O
hand O
, O
the O
exposure O
of O
the O
crayfish O
to O
( O
1 O
/ O
4 O
) O
96 O
h O
- O
LC O
( O
50 O
) O
( O
0 O
. O
36 O
mg O
l O
( O
- O
1 O
) O
) O
of O
ethion B
caused O
extensive O
ultrastructural O
alterations O
to O
both O
hepatopancreas O
and O
gill O
epithelial O
cells O
. O

In O
the O
hepatopancreas O
, O
the O
most O
notable O
pathological O
features O
included O
vacuolation O
, O
degradation O
and O
distinct O
cell O
lysis O
. O

In O
the O
gill O
epithelium O
, O
the O
histopathological O
alterations O
included O
infiltration O
of O
hemocytes O
, O
cytoplasmic O
vacuolation O
and O
a O
decrease O
in O
the O
number O
of O
basal O
plasma O
membrane O
infoldings O
. O

Synthesis O
and O
antitumor O
activity O
of O
N B
- I
sulfonyl I
- I
3 I
, I
7 I
- I
dioxo I
- I
5 I
beta I
- I
cholan I
- I
24 I
- I
amides I
, O
ursodeoxycholic B
acid I
derivatives O
. O

A O
series O
of O
N B
- I
sulfonyl I
- I
3 I
, I
7 I
- I
dioxo I
- I
5 I
beta I
- I
cholan I
- I
24 I
- I
amides I
, O
ursodeoxycholic B
acid I
derivatives O
, O
have O
been O
designed O
and O
synthesized O
in O
nine O
steps O
starting O
from O
ursodeoxycholic B
acid I
. O

The O
in O
vitro O
antitumor O
activity O
of O
the O
target O
compounds O
has O
been O
evaluated O
against O
HCT O
- O
116 O
, O
MCF O
- O
7 O
, O
K562 O
, O
and O
SGC O
- O
7901 O
cell O
lines O
. O

The O
pharmacological O
results O
showed O
that O
most O
of O
the O
prepared O
compounds O
display O
excellent O
selective O
cytotoxicity O
toward O
HCT O
- O
116 O
, O
MCF O
- O
7 O
, O
and O
K562 O
cell O
lines O
. O

Particularly O
, O
compounds O
10c O
, O
10f O
and O
10g O
show O
high O
inhibitory O
activity O
on O
these O
human O
cancer O
cell O
lines O
( O
IC50 O
: O
2 O
. O
39 O
- O
9 O
. O
34 O
mu O
M O
) O
. O

Conversely O
, O
all O
compounds O
are O
generally O
inactive O
against O
SGC O
- O
7901 O
, O
with O
only O
10b O
having O
IC O
5 O
0 O
below O
50 O
mu O
M O
. O

Precipitation O
of O
Ibuprofen B
Sodium I
using O
compressed O
carbon B
dioxide I
as O
antisolvent O
. O

Precipitation O
with O
compressed O
antisolvent O
( O
PCA O
) O
process O
was O
used O
to O
produce O
fine O
particles O
of O
Ibuprofen B
Sodium I
with O
the O
ultimate O
goal O
of O
obtaining O
controlled O
particle O
size O
and O
size O
distribution O
of O
this O
non O
- O
steroidal O
anti O
- O
inflammatory O
drug O
. O

This O
systematic O
investigation O
shows O
that O
particle O
size O
and O
size O
distribution O
of O
the O
final O
product O
can O
be O
controlled O
reproducibly O
by O
varying O
a O
number O
operating O
parameters O
such O
as O
antisolvent O
addition O
rate O
, O
temperature O
, O
concentration O
, O
and O
solution O
addition O
rate O
. O

The O
mechanisms O
that O
control O
particle O
size O
and O
particle O
size O
distribution O
were O
explained O
by O
invoking O
the O
differences O
in O
the O
relative O
weight O
of O
primary O
, O
secondary O
nucleation O
and O
growth O
kinetic O
phenomena O
. O

A O
number O
of O
techniques O
were O
used O
for O
the O
characterization O
of O
the O
generated O
particles O
. O

In O
addition O
to O
scanning O
electron O
microscope O
( O
SEM O
) O
, O
dynamic O
light O
scattering O
measurements O
were O
conducted O
to O
determine O
the O
size O
of O
the O
particles O
in O
terms O
of O
number O
- O
weighted O
size O
distribution O
. O

The O
influence O
of O
process O
parameters O
on O
the O
Ibuprofen B
Sodium I
crystallinity O
was O
investigated O
using O
X O
- O
ray O
diffraction O
( O
XRD O
) O
. O

Moreover O
, O
the O
' O
' O
in O
vitro O
' O
' O
drug O
performance O
was O
tested O
. O

The O
results O
showed O
an O
improvement O
of O
the O
PCA O
processed O
Ibuprofen B
Sodium I
' O
' O
in O
vitro O
' O
' O
drug O
activity O
. O

In O
addition O
, O
dissolution O
investigations O
demonstrated O
that O
the O
flow O
rate O
, O
in O
combination O
with O
the O
particle O
size O
distribution O
, O
substantially O
influence O
the O
drug O
" O
in O
vitro O
" O
dissolution O
. O

Angiotensin O
- O
( O
1 O
- O
7 O
) O
modulates O
renin O
- O
angiotensin O
system O
associated O
with O
reducing O
oxidative O
stress O
and O
attenuating O
neuronal O
apoptosis O
in O
the O
brain O
of O
hypertensive O
rats O
. O

Angiotensin O
- O
( O
1 O
- O
7 O
) O
[ O
Ang O
- O
( O
1 O
- O
7 O
) O
] O
has O
beneficial O
effects O
against O
hypertension O
- O
induced O
damage O
in O
heart O
and O
kidney O
, O
but O
its O
effects O
in O
brain O
are O
not O
clear O
as O
yet O
. O

The O
present O
study O
aimed O
to O
investigate O
the O
protective O
effects O
of O
Ang O
- O
( O
1 O
- O
7 O
) O
on O
the O
physiopathologic O
changes O
caused O
by O
hypertension O
in O
brain O
of O
spontaneously O
hypertensive O
rats O
( O
SHRs O
) O
. O

Wistar O
- O
Kyoto O
rats O
received O
intracerebroventricu O
( O
I O
. O
C O
. O
V O
. O
) O
infusion O
of O
artificial O
cerebrospinal O
fluid O
( O
aCSF O
) O
while O
SHRs O
received O
I O
. O
C O
. O
V O
. O
infusion O
of O
Ang O
- O
( O
1 O
- O
7 O
) O
, O
Mas O
receptor O
antagonist O
A B
- I
779 I
and O
aCSF B
for O
4 O
weeks O
. O

Brain O
tissues O
were O
collected O
and O
analyzed O
by O
western O
blot O
, O
enzyme O
immunoassay O
, O
spectrophotometric O
assays O
and O
terminal O
deoxynucleotidyl O
transferase O
- O
mediated O
dUTP B
end O
- O
labeling O
( O
TUNEL O
) O
staining O
. O

Our O
study O
showed O
that O
infusion O
of O
Ang O
- O
( O
1 O
- O
7 O
) O
for O
4 O
weeks O
significantly O
reduced O
the O
expression O
of O
Angiotensin O
II O
and O
Angiotensin O
II O
type O
1 O
receptors O
in O
SHR O
brain O
. O

Additionally O
, O
it O
decreased O
the O
levels O
of O
malondialdehyde B
and O
elevated O
total O
superoxide B
dismutase O
activity O
, O
which O
was O
accompanied O
by O
reductions O
of O
NADPH B
oxidase O
subunit O
gp91 O
( O
phox O
) O
and O
inducible O
nitric B
oxide I
synthase O
in O
the O
brain O
of O
SHR O
. O

The O
increases O
of O
the O
percentage O
of O
TUNEL O
- O
positive O
neurons O
and O
Bax O
to O
Bcl O
- O
2 O
ratio O
in O
SHR O
brain O
were O
also O
attenuated O
by O
Ang O
- O
( O
1 O
- O
7 O
) O
. O

The O
anti O
- O
oxidative O
and O
anti O
- O
apoptosis O
effects O
of O
Ang O
- O
( O
1 O
- O
7 O
) O
are O
independent O
of O
blood O
pressure O
reduction O
and O
can O
be O
partially O
abolished O
by O
A B
- I
779 I
. O

These O
findings O
suggest O
that O
chronic O
treatment O
with O
Ang O
- O
( O
1 O
- O
7 O
) O
is O
beneficial O
to O
attenuate O
hypertension O
- O
induced O
physiopathologic O
changes O
in O
brain O
and O
may O
be O
helpful O
to O
prevent O
hypertension O
- O
related O
cerebrovascular O
diseases O
. O

Cell O
cycle O
regulation O
by O
glucosamine B
in O
human O
pulmonary O
epithelial O
cells O
. O

Airway O
epithelial O
cells O
play O
an O
important O
role O
against O
intruding O
pathogens O
. O

Glucosamine B
, O
a O
commonly O
used O
supplemental O
compound O
, O
has O
recently O
begun O
to O
be O
regarded O
as O
a O
potential O
anti O
- O
inflammatory O
molecule O
. O

This O
study O
aimed O
to O
uncover O
how O
glucosamine B
impacts O
on O
cellular O
proliferation O
in O
human O
alveolar O
epithelial O
cells O
( O
A549 O
) O
and O
bronchial O
epithelial O
cells O
( O
HBECs O
) O
. O

With O
trypan B
blue I
- O
exclusion O
assay O
, O
we O
observed O
that O
glucosamine B
( O
10 O
, O
20 O
, O
50 O
mM O
) O
caused O
a O
decrease O
in O
cell O
number O
at O
24 O
and O
48 O
h O
; O
with O
a O
flow O
cytometric O
analysis O
, O
we O
also O
noted O
an O
enhanced O
cell O
accumulation O
within O
the O
G O
( O
0 O
) O
/ O
G O
( O
1 O
) O
phase O
at O
24 O
h O
and O
induction O
of O
late O
apoptosis O
at O
24 O
and O
48 O
h O
by O
glucosamine B
( O
10 O
, O
20 O
, O
50 O
mM O
) O
in O
A549 O
cells O
and O
HBECs O
. O

Examination O
of O
phosphorylation O
in O
retinoblastoma O
( O
Rb O
) O
protein O
, O
we O
found O
an O
inhibitory O
effect O
by O
glucosamine B
at O
20 O
and O
50 O
mM O
. O

Glucosamine B
at O
50 O
mM O
was O
demonstrated O
to O
elevate O
both O
the O
mRNA O
and O
protein O
expression O
of O
p53 O
and O
heme O
oxygenase O
- O
1 O
( O
HO O
- O
1 O
) O
, O
but O
also O
caused O
a O
reduction O
in O
p21 O
protein O
expression O
. O

In O
addition O
, O
glucosamine B
attenuated O
p21 O
protein O
stability O
via O
the O
proteasomal O
proteolytic O
pathway O
, O
as O
well O
as O
inducing O
p21 O
nuclear O
accumulation O
. O

Altogether O
, O
our O
results O
suggest O
that O
a O
high O
dose O
of O
glucosamine B
may O
inhibit O
cell O
proliferation O
through O
apoptosis O
and O
disturb O
cell O
cycle O
progression O
with O
a O
halt O
at O
G O
( O
0 O
) O
/ O
G O
( O
1 O
) O
phase O
, O
and O
that O
this O
occurs O
, O
at O
least O
in O
part O
, O
by O
a O
reduction O
in O
Rb O
phosphorylation O
together O
with O
modulation O
of O
p21 O
, O
p53 O
and O
HO O
- O
1 O
expression O
, O
and O
nuclear O
p21 O
accumulation O
. O

Symmetrically O
reduced O
stiffness O
and O
increased O
extensibility O
in O
compression O
and O
tension O
at O
the O
mineralized O
fibrillar O
level O
in O
rachitic O
bone O
. O

In O
metabolic O
bone O
diseases O
, O
the O
alterations O
in O
fibrillar O
level O
bone O
- O
material O
quality O
affecting O
macroscopic O
mechanical O
competence O
are O
not O
well O
- O
understood O
quantitatively O
. O

Here O
, O
we O
quantify O
the O
fibrillar O
level O
deformation O
in O
cantilever O
bending O
in O
a O
mouse O
model O
for O
hereditary O
rickets O
( O
Hpr O
) O
. O

Microfocus O
in O
- O
situ O
synchrotron O
small O
- O
angle O
X O
- O
ray O
scattering O
( O
SAXS O
) O
combined O
with O
cantilever O
bending O
was O
used O
to O
resolve O
nanoscale O
fibril O
strain O
in O
tensile O
- O
and O
compressive O
tissue O
regions O
separately O
, O
with O
quantitative O
backscattered O
scanning O
electron O
microscopy O
used O
to O
measure O
microscale O
mineralization O
. O

Tissue O
- O
level O
flexural O
moduli O
for O
Hpr O
mice O
were O
significantly O
( O
p O
< O
0 O
. O
01 O
) O
smaller O
compared O
to O
wild O
- O
type O
( O
~ O
5 O
to O
10 O
- O
fold O
reduction O
) O
. O

At O
the O
fibrillar O
level O
, O
the O
fibril O
moduli O
within O
the O
tensile O
and O
compressive O
zones O
were O
significantly O
( O
p O
< O
0 O
. O
05 O
) O
lower O
by O
~ O
3 O
- O
to O
5 O
- O
fold O
in O
Hpr O
mice O
compared O
to O
wild O
- O
type O
mice O
. O

Hpr O
mice O
have O
a O
lower O
mineral O
content O
( O
24 O
. O
2 O
+ O
/ O
- O
2 O
. O
1Cawt O
. O
% O
versus O
27 O
. O
4 O
+ O
/ O
- O
3 O
. O
3Ca O
wt O
. O
% O
) O
and O
its O
distribution O
was O
more O
heterogeneous O
compared O
to O
wild O
- O
type O
animals O
. O

However O
, O
the O
average O
effective O
fibril O
modulus O
did O
not O
differ O
significantly O
( O
p O
> O
0 O
. O
05 O
) O
over O
ages O
( O
4 O
, O
7 O
and O
10weeks O
) O
between O
tensile O
and O
compressive O
zones O
. O

Our O
results O
indicate O
that O
incompletely O
mineralized O
fibrils O
in O
Hpr O
mice O
have O
greater O
deformability O
and O
lower O
moduli O
in O
both O
compression O
and O
tension O
, O
and O
those O
compressive O
and O
tensile O
zones O
have O
similar O
moduli O
at O
the O
fibrillar O
level O
. O

Prediction O
of O
crizotinib B
- O
midazolam B
interaction O
using O
the O
Simcyp O
population O
- O
based O
simulator O
: O
comparison O
of O
CYP3A O
time O
- O
dependent O
inhibition O
between O
human O
liver O
microsomes O
versus O
hepatocytes O
. O

Crizotinib B
( O
Xalkori B
) O
is O
an O
orally O
available O
potent O
inhibitor O
of O
multiple O
tyrosine B
kinases O
, O
including O
anaplastic O
lymphoma O
kinase O
and O
mesenchymal O
- O
epithelial O
transition O
factor O
. O

Objectives O
of O
the O
present O
study O
were O
as O
follows O
: O
1 O
) O
to O
characterize O
crizotinib B
time O
- O
dependent O
inhibition O
( O
TDI O
) O
potency O
for O
CYP3A O
in O
human O
liver O
microsomes O
( O
HLM O
) O
and O
cryopreserved O
human O
hepatocytes O
suspended O
in O
human O
plasma O
( O
HSP O
) O
; O
2 O
) O
to O
characterize O
crizotinib B
enzyme O
induction O
potency O
on O
CYP3A4 O
in O
cryopreserved O
human O
hepatocytes O
; O
3 O
) O
to O
predict O
crizotinib B
steady O
- O
state O
plasma O
concentrations O
in O
patients O
( O
e O
. O
g O
. O
, O
autoinhibition O

and O
autoinduction O
) O
using O
the O
mechanistic O
dynamic O
model O
, O
Simcyp O
population O
- O
based O
simulator O
; O
and O
4 O
) O
to O
predict O
a O
clinical O
crizotinib B
- O
midazolam B
interaction O
using O
the O
dynamic O
model O
as O
well O
as O
the O
static O
mathematical O
model O
. O

Crizotinib B
inactivation O
constant O
( O
K O
( O
I O
) O
) O
and O
maximum O
inactivation O
rate O
constant O
( O
k O
( O
inact O
) O
) O
for O
TDI B
were O
estimated O
as O
, O
respectively O
, O
0 O
. O
37 O
micro O
M O
and O
6 O
. O
9 O
h O
( O
- O
1 O
) O
in O
HLM O
and O
0 O
. O
89 O
micro O
M O
and O
0 O
. O
78 O
h O
( O
- O
1 O
) O
in O
HSP O
. O

Thus O
, O
crizotinib B
inactivation O
efficiency O
( O
k O
( O
inact O
) O
/ O
K O
( O
I O
) O
) O
was O
~ O
20 O
- O
fold O
lower O
in O
HSP O
relative O
to O
HLM O
. O

Crizotinib B
E O
( O
max O
) O
and O
EC O
( O
50 O
) O
for O
CYP3A4 O
induction O
( O
measured O
as O
mRNA O
expression O
) O
were O
estimated O
as O
6 O
. O
4 O
- O
to O
29 O
- O
fold O
and O
0 O
. O
47 O
to O
3 O
. O
1 O
micro O
M O
, O
respectively O
. O

Based O
on O
these O
in O
vitro O
parameters O
, O
the O
predicted O
crizotinib B
steady O
- O
state O
area O
under O
plasma O
concentration O
- O
time O
curve O
( O
AUC O
) O
with O
HLM O
- O
TDI B
was O
2 O
. O
1 O
- O
fold O
higher O
than O
the O
observed O
AUC O
, O
whereas O
that O
with O
HSP O
- O
TDI B
was O
consistent O
with O
the O
observed O
result O
( O
< O
= O
1 O
. O
1 O
- O
fold O
) O
. O

The O
increase O
in O
midazolam B
AUC O
with O
coadministration O
of O
crizotinib B
( O
21 O
- O
fold O
) O
was O
significantly O
overpredicted O
using O
HLM O
- O
TDI O
, O
whereas O
the O
prediction O
using O
HSP O
- O
TDI O
( O
3 O
. O
6 O
- O
fold O
) O
was O
consistent O
with O
the O
observed O
result O
( O
3 O
. O
7 O
- O
fold O
) O
. O

Collectively O
, O
the O
present O
study O
demonstrated O
the O
value O
of O
HSP O
to O
predict O
in O
vivo O
CYP3A O
- O
mediated O
drug O
- O
drug O
interaction O
. O

Arsenic B
and O
arsenic B
species O
in O
cultured O
oyster O
( O
Crassostrea O
gigas O
and O
C O
. O
corteziensis O
) O
from O
coastal O
lagoons O
of O
the O
SE O
Gulf O
of O
California O
, O
Mexico O
. O

The O
aim O
of O
this O
study O
was O
to O
evaluate O
the O
bioavailability O
of O
arsenic B
( O
As B
) O
through O
cultured O
oyster O
Crassostrea O
gigas O
and O
Crassostrea O
corteziensis O
from O
four O
coastal O
lagoons O
( O
SE O
Gulf O
of O
California O
) O
. O

Organisms O
were O
collected O
in O
two O
seasons O
( O
rainy O
and O
dry O
season O
) O
, O
and O
they O
were O
analyzed O
for O
total O
arsenic B
and O
chemical O
speciation O
of O
this O
element O
. O

The O
concentrations O
of O
As B
in O
oyster O
soft O
tissue O
fluctuated O
between O
5 O
. O
44 O
and O
9 O
. O
56 O
mu O
g O
/ O
g O
for O
rainy O
season O
and O
6 O
. O
46 O
and O
8 O
. O
33 O
mu O
g O
/ O
g O
for O
dry O
season O
( O
dry O
weight O
) O
in O
C O
. O
gigas O
. O

In O
C O
. O
corteziensis O
, O
the O
As B
concentrations O
were O
< O
5 O
mu O
g O
/ O
g O
for O
both O
seasons O
( O
dry O
weight O
) O
. O

Arsenic B
speciation O
indicated O
arsenobetaine B
as O
the O
major O
arseno B
- O
compound O
accounting O
for O
43 O
. O
2 O
- O
76 O
. O
3 O
% O
of O
total O
content O
of O
As B
. O

Lower O
contributions O
were O
obtained O
for O
non O
- O
extractable O
As B
( O
11 O
. O
3 O
- O
17 O
. O
5 O
% O
) O
and O
other O
molecules O
such O
as O
arsenocholine B
and O
methyl B
- I
arsonate I
( O
< O
5 O
% O
) O
. O

Inorganic O
arsenic B
was O
detectable O
in O
only O
two O
samples O
, O
at O
concentrations O
lower O
than O
< O
0 O
. O
1 O
mu O
g O
/ O
g O
. O

These O
As O
data O
are O
the O
first O
generated O
for O
these O
mollusks O
in O
NW O
Mexico O
and O
indicate O
that O
C O
. O
gigas O
and O
C O
. O
corteziensis O
farmed O
in O
this O
area O
are O
safe O
for O
human O
consumption O
in O
terms O
of O
arseno B
- O
compounds O
. O

Probing O
the O
binding O
of O
cationic O
lipids O
with O
dendrimers O
. O

Polycationic O
polymers O
are O
used O
extensively O
in O
biology O
to O
disrupt O
cell O
membranes O
and O
thus O
enhance O
the O
transport O
of O
materials O
into O
the O
cell O
. O

We O
report O
the O
bindings O
of O
several O
lipids O
cholesterol B
( O
Chol B
) O
, O
1 B
, I
2 I
- I
dioleoyl I
- I
3 I
- I
trimethylammonium I
- I
propane I
( O
DOTAP B
) O
, O
dioctadecyldimethyla B
( O
DDAB B
) O
, O
and O
dioleoylphosphatidyl B
( O
DOPE B
) O
to O
dendrimers O
of O
different O
compositions O
such O
as O
mPEG B
- I
PAMAM I
( O
G3 O
) O
, O
mPEG B
- I
PAMAM I
( O
G4 O
) O
, O
and O
PAMAM B
( O
G4 O
) O
under O
physiological O
conditions O
. O

FTIR O
, O
UV O
- O
visible O
spectroscopic O
, O
methods O
and O
molecular O
modeling O
were O
used O
to O
analyze O
the O
lipid O
binding O
mode O
, O
the O
binding O
constant O
, O
and O
the O
effects O
of O
lipid O
complexation O
on O
the O
dendrimer O
structure O
. O

The O
structural O
analysis O
showed O
that O
lipids O
bind O
dendrimers O
through O
both O
hydrophilic O
and O
hydrophobic O
contacts O
with O
overall O
binding O
constants O
of O
K O
( O
chol B
- O
mPEG I
- O
G3 O
) O
= O
1 O
. O
7 O
x O
10 O
( O
3 O
) O
M O
( O
- O
1 O
) O
, O
K O
( O
chol B
- I
mPEG I
- O
PAMAM I
- O
G4 O
) O
= O
2 O
. O
7 O
x O
10 O
( O
3 O
) O
M O
( O
- O
1 O
) O
, O
K O
( O
chol B
- O
PAMAM I
- O
G4 O
) O
= O
1 O
. O
0 O
x O
10 O
( O
3 O
) O
M O
( O
- O
1 O
) O
, O
K O
( O
DOPE B
- O
mPEG I
- O
G3 O

) O
= O
1 O
. O
5 O
x O
10 O
( O
3 O
) O
M O
( O
- O
1 O
) O
, O
K O
( O
DOPE B
- O
mPEG I
- O
PAMAM B
- O
G4 O
) O
= O
1 O
. O
6 O
x O
10 O
( O
3 O
) O
M O
( O
- O
1 O
) O
, O
K O
( O
DOPE B
- O
PAMAM I
- O
G4 O
) O
= O
5 O
. O
3 O
x O
10 O
( O
2 O
) O
M O
( O
- O
1 O
) O
, O
K O
( O
DDAB B
- O
mPEG I
- O
G3 O
) O
= O
1 O
. O
5 O
x O
10 O
( O
3 O
) O
M O
( O
- O
1 O
) O
, O
K O
( O
DDAB B
- O
mPEG I
- O
PAMAM I
- O
G4 O
) O
= O
1 O
. O
9 O
x O
10 O
( O

2 O
) O
M O
( O
- O
1 O
) O
, O
K O
( O
DDAB B
- O
PAMAM I
- O
G4 O
) O
= O
7 O
. O
0 O
x O
10 O
( O
2 O
) O
M O
( O
- O
1 O
) O
, O
K O
( O
DOTAP B
- O
mPEG I
- O
G3 O
) O
= O
1 O
. O
9 O
x O
10 O
( O
3 O
) O
M O
( O
- O
1 O
) O
, O
K O
( O
DOTAP B
- O
mPEG I
- O
PAMAM I
- O
G4 O
) O
= O
1 O
. O
5 O
x O
10 O
( O
3 O
) O
M O
( O
- O
1 O
) O
, O
and O
K O
( O
DOTAP B
- O
PAMAM B
- O
G4 O
) O
= O
5 O
. O
7 O
x O
10 O
( O
2 O
) O
M O
( O
- O
1 O
) O
. O

Weaker O
interaction O
was O
observed O
as O
dendrimer O
cationic O
charges O
increased O
. O

The O
free O
binding O
energies O
from O
docking O
were O
- O
5 O
. O
15 O
( O
cholesterol B
) O
, O
- O
5 O
. O
79 O
( O
DDAB B
) O
, O
and O
- O
5 O
. O
36 O
kcal O
/ O
mol O
( O
DOTAP B
) O
with O
the O
order O
of O
stability O
DDAB B
- O
PAMAM B
- O
G O
- O
4 O
> O
DOTAP B
- O
PAMAM B
- O
G4 O
> O
cholesterol B
- O
PAMAM B
- O
G4 O
, O
consistent O
with O
the O
spectroscopic O
results O
. O

Dendrimers O
might O
act O
as O
carriers O
to O
transport O
lipids O
in O
vitro O
. O

Glycolytic O
enzymes O
PGK1 O
and O
PKM2 O
as O
novel O
transcriptional O
targets O
of O
PPAR O
gamma O
in O
breast O
cancer O
pathophysiology O
. O

Peroxisome O
proliferator O
- O
activated O
receptor O
gamma O
( O
PPAR O
gamma O
) O
is O
a O
nuclear O
receptor O
and O
plays O
important O
roles O
in O
breast O
cancer O
cell O
proliferation O
. O

The O
complexity O
of O
the O
underlying O
biochemical O
and O
molecular O
mechanisms O
of O
breast O
cancer O
and O
the O
involvement O
of O
PPAR O
gamma O
in O
breast O
cancer O
pathophysiology O
are O
unclear O
. O

In O
this O
study O
, O
we O
carried O
out O
prediction O
of O
the O
peroxisome O
proliferator O
response O
element O
( O
PPRE O
) O
motifs O
in O
2332 O
genes O
reported O
to O
be O
involved O
in O
breast O
cancer O
in O
literature O
. O

A O
total O
of O
178 O
genes O
were O
found O
to O
have O
PPRE O
( O
DR1 O
/ O
DR2 O
) O
and O
/ O
or O
PPAR O
- O
associated O
conserved O
motif O
( O
PACM O
) O
motifs O
. O

We O
further O
constructed O
protein O
- O
protein O
interaction O
network O
, O
disease O
gene O
network O
and O
gene O
ontology O
( O
GO O
) O
analyses O
to O
identify O
novel O
key O
genes O
for O
experimental O
validation O
. O

We O
identified O
two O
genes O
in O
the O
glycolytic O
pathway O
( O
phosphoglycerate B
kinase O
1 O
( O
PGK1 O
) O
and O
pyruvate B
kinase O
M2 O
( O
PKM2 O
) O
) O
at O
the O
ATP B
production O
steps O
and O
experimentally O
validated O
their O
repression O
by O
PPAR O
gamma O
in O
two O
breast O
cancer O
cell O
lines O
MDA O
- O
MB O
- O
231 O
and O
MCF O
- O
7 O
. O

Further O
analysis O
suggested O
that O
this O
repression O
leads O
to O
decrease O
in O
ATP B
levels O
and O
apoptosis O
. O

These O
investigations O
will O
help O
us O
in O
understanding O
the O
molecular O
mechanisms O
by O
which O
PPAR O
gamma O
regulates O
the O
cellular O
energy O
pathway O
and O
the O
use O
of O
its O
ligands O
in O
human O
breast O
cancer O
therapeutics O
. O

Evaluation O
of O
the O
metabolism O
and O
hepatotoxicity O
of O
xenobiotics O
utilizing O
precision O
- O
cut O
slices O
. O

1 O
. O

Precision O
- O
cut O
liver O
slices O
are O
a O
valuable O
in O
vitro O
model O
system O
to O
study O
the O
metabolism O
and O
toxicity O
of O
xenobiotics O
. O

Liver O
slices O
retain O
tissue O
architecture O
so O
that O
all O
cell O
types O
are O
present O
and O
intercellular O
communication O
between O
the O
various O
cell O
types O
is O
retained O
. O

2 O
. O

Precision O
- O
cut O
liver O
slices O
from O
humans O
and O
other O
species O
have O
been O
used O
to O
study O
pathways O
of O
phase O
I O
( O
e O
. O
g O
. O
cytochrome O
P450 O
- O
dependent O
biotransformations O
) O
and O
II O
( O
e O
. O
g O
. O
conjugation O
with O
D B
- I
glucuronic I
acid I
, O
sulphate B
and O
glutathione B
) O
metabolism O
of O
a O
wide O
range O
of O
xenobiotics O
. O

3 O
. O

Liver O
slices O
can O
also O
be O
employed O
to O
investigate O
the O
induction O
and O
inhibition O
of O
xenobiotic O
metabolizing O
enzymes O
and O
to O
obtain O
kinetic O
data O
on O
the O
rates O
of O
metabolism O
of O
xenobiotics O
. O

4 O
. O

Precision O
- O
cut O
liver O
slices O
from O
humans O
and O
other O
species O
have O
been O
used O
to O
study O
the O
toxicity O
of O
a O
wide O
variety O
of O
xenobiotics O
. O

Toxicity O
can O
be O
assessed O
by O
various O
techniques O
including O
gene O
expression O
, O
morphological O
examination O
and O
a O
wide O
range O
of O
biochemical O
endpoints O
. O

5 O
. O

Precision O
- O
cut O
liver O
slices O
can O
be O
utilized O
to O
examine O
species O
differences O
in O
hepatic O
xenobiotic O
metabolism O
and O
xenobiotic O
- O
induced O
toxicity O
, O
thus O
permitting O
comparisons O
between O
animal O
species O
and O
humans O
. O

In O
vitro O
and O
in O
vivo O
evaluation O
of O
an O
in O
situ O
gel O
forming O
system O
for O
the O
delivery O
of O
PEGylated O
octreotide O
. O

The O
objective O
of O
this O
study O
was O
to O
develop O
a O
controlled O
delivery O
system O
for O
PEGylated O
octreotide O
using O
a O
Poloxamer B
based O
in O
situ O
gel O
forming O
polymer O
. O

PEGylated O
octreotide B
kept O
its O
full O
biological O
activity O
and O
higher O
serum O
half O
- O
life O
compared O
to O
the O
original O
octreotide B
. O

The O
designed O
drug O
delivery O
system O
contained O
low O
concentration O
of O
Poloxamer B
407 I
( O
P407 B
) O
( O
< O
0 O
. O
16 O
% O
) O
with O
polyvinyl B
alcohol I
( O
PVA B
) O
as O
a O
polymeric O
additive O
. O

Rheological O
measurements O
of O
gel O
vehicle O
formulations O
indicated O
that O
the O
in O
situ O
gel O
forming O
system O
with O
optimum O
sol O
- O
gel O
transition O
temperature O
of O
28 O
. O
7 O
degrees O
C O
could O
be O
formed O
using O
a O
combination O
of O
P407 B
and O
PVA B
at O
ratio O
of O
15 O
- O
10 O
% O
( O
w O
/ O
v O
) O
. O

The O
effect O
of O
formulation O
additives O
such O
as O
buffering O
agents O
on O
rheological O
behavior O
demonstrated O
that O
sodium B
bicarbonate I
and O
lactic B
acid I
have O
opposite O
effect O
on O
sol O
- O
gel O
transition O
temperature O
of O
the O
system O
. O

Using O
buffering O
agents O
, O
it O
was O
possible O
to O
shift O
the O
sol O
- O
gel O
transition O
to O
lower O
or O
higher O
temperatures O
. O

The O
in O
vitro O
release O
profiles O
of O
octreotide O
and O
PEGylated O
octreotide O
from O
the O
selected O
P407 B
/ O
PVA B
formulations O
were O
measured O
using O
a O
membrane O
- O
less O
device O
. O

PEGylated O
octreotide B
showed O
slower O
release O
rate O
from O
the O
gel O
system O
with O
different O
release O
kinetic O
compared O
to O
octreotide B
. O

In O
animal O
studies O
, O
a O
sustained O
release O
rate O
was O
achieved O
with O
both O
PEGylated O
and O
non O
- O
PEGylated O
octreotide B
, O
but O
longer O
delivery O
was O
observed O
for O
PEGylated O
octreotide B
. O

Tissue O
histopathological O
studies O
confirmed O
the O
biocompatibility O
of O
the O
delivery O
system O
for O
PEGylated O
octreotide O
, O
supporting O
the O
suitability O
of O
P407 B
/ O
PVA B
mixture O
as O
an O
injectable O
drug O
delivery O
system O
. O

The O
total O
effects O
of O
increasing O
PEGylated O
peptide O
half O
- O
life O
and O
prolonged O
release O
from O
thermoresponsive O
gel O
system O
offer O
the O
potential O
for O
sustained O
delivery O
of O
PEGylated O
octreotide B
. O

Regulation O
of O
glycogen O
synthase O
from O
mammalian O
skeletal O
muscle O
- O
- O
a O
unifying O
view O
of O
allosteric O
and O
covalent O
regulation O
. O

It O
is O
widely O
accepted O
that O
insufficient O
insulin O
- O
stimulated O
activation O
of O
muscle O
glycogen O
synthesis O
is O
one O
of O
the O
major O
components O
of O
non O
- O
insulin O
- O
dependent O
( O
type O
2 O
) O
diabetes O
mellitus O
. O

Glycogen O
synthase O
, O
a O
key O
enzyme O
in O
muscle O
glycogen O
synthesis O
, O
is O
extensively O
regulated O
, O
both O
allosterically O
( O
by O
glucose B
- I
6 I
- I
phosphate I
, O
ATP B
, O
and O
others O
) O
and O
covalently O
( O
by O
phosphorylation O
) O
. O

Although O
glycogen O
synthase O
has O
been O
a O
topic O
of O
intense O
study O
for O
more O
than O
50 O
years O
, O
its O
kinetic O
characterization O
has O
been O
confounded O
by O
its O
large O
number O
of O
phosphorylation O
states O
. O

Questions O
remain O
regarding O
the O
function O
of O
glycogen O
synthase O
regulation O
and O
the O
relative O
importance O
of O
allosteric O
and O
covalent O
modification O
in O
fulfilling O
this O
function O
. O

In O
this O
review O
, O
we O
consider O
both O
earlier O
kinetic O
studies O
and O
more O
recent O
site O
- O
directed O
mutagenesis O
and O
crystal O
structure O
studies O
in O
a O
detailed O
qualitative O
discussion O
of O
the O
effects O
of O
regulation O
on O
the O
kinetics O
of O
glycogen O
synthase O
. O

We O
propose O
that O
both O
allosteric O
and O
covalent O
modification O
of O
glycogen O
synthase O
may O
be O
described O
by O
a O
Monod O
- O
Wyman O
- O
Changeux O
model O
in O
terms O
of O
apparent O
changes O
to O
L O
, O
the O
equilibrium O
constant O
for O
transition O
between O
the O
T O
and O
R O
conformers O
. O

As O
, O
with O
the O
exception O
of O
L O
, O
all O
parameters O
of O
this O
model O
are O
independent O
of O
the O
glycogen O
synthase O
phosphorylation O
state O
, O
the O
need O
to O
determine O
kinetic O
parameters O
for O
all O
possible O
states O
is O
eliminated O
; O
only O
the O
relationship O
between O
a O
particular O
state O
and O
L O
must O
be O
established O
. O

We O
conclude O
by O
suggesting O
that O
renewed O
efforts O
to O
characterize O
the O
relationship O
between O
phosphorylation O
and O
the O
kinetics O
of O
glycogen O
synthase O
are O
essential O
in O
order O
to O
obtain O
a O
better O
quantitative O
understanding O
of O
the O
function O
of O
glycogen O
synthesis O
regulation O
. O

The O
model O
we O
propose O
may O
prove O
useful O
in O
this O
regard O
. O

LARGE2 O
generates O
the O
same O
xylose B
- O
and O
glucuronic B
acid I
- O
containing O
glycan O
structures O
as O
LARGE O
. O

LARGE O
( O
like O
- O
glycosyltransferase O
) O
and O
LARGE2 O
( O
glycosyltransferase O
- O
like O
1B O
( O
GYLTL1B O
) O
) O
are O
homologous O
Golgi O
glycosyltransferases O
possessing O
two O
catalytic O
domains O
with O
homology O
to O
members O
of O
glycosyltransferase O
families O
GT8 O
and O
GT49 O
. O

Mutations O
in O
human O
and O
mouse O
Large O
result O
in O
muscular O
dystrophy O
due O
to O
underglycosylation O
of O
dystroglycan O
. O

The O
systemic O
function O
of O
LARGE2 O
is O
unknown O
, O
but O
at O
a O
cellular O
level O
the O
enzyme O
can O
substitute O
for O
LARGE O
in O
glycosylating O
dystroglycan O
. O

Here O
, O
we O
show O
that O
LARGE2 O
catalyzes O
the O
same O
glycosylation O
reaction O
as O
LARGE O
. O

It O
is O
a O
bifunctional O
glycosyltransferase O
using O
uridine B
diphosphate I
( O
UDP B
) O
- O
xylose B
( O
Xyl B
) O
and O
UDP B
- O
glucuronic B
acid I
( O
GlcA B
) O
as O
donor O
sugars B
to O
produce O
a O
xyloglucuronan O
with O
alternating O
Xyl B
and O
GlcA B
residues O
. O

Electric O
field O
- O
induced O
dipole O
switching O
at O
the O
donor O
/ O
acceptor O
interface O
in O
organic O
solar O
cells O
. O

Order O
of O
dipole O
moment O
layers O
at O
donor O
and O
acceptor O
interfaces O
in O
bilayer O
organic O
solar O
cells O
is O
manipulated O
reversibly O
by O
applying O
bias O
voltages O
. O

The O
energy O
level O
shifts O
at O
the O
interfaces O
induce O
reversible O
changes O
in O
the O
open O
circuit O
voltage O
and O
the O
diode O
properties O
. O

This O
finding O
could O
lead O
to O
a O
better O
understanding O
of O
the O
structure O
- O
property O
relationship O
at O
the O
materials O
interfaces O
in O
organic O
optoelectronic O
devices O
. O

Reversible O
and O
cyclical O
transformations O
between O
solid O
and O
hollow O
nanostructures O
in O
confined O
reactions O
of O
manganese B
oxide I
and O
silica B
within O
nanosized O
spheres O
. O

Annealing O
of O
MnO B
@ O
SiO B
( I
2 I
) I
nanospheres O
in O
a O
reducing O
gas O
environment O
resulted O
in O
the O
transformation O
of O
the O
core O
- O
shell O
structure O
into O
a O
hollow O
structure O
as O
a O
result O
of O
outward O
diffusion O
of O
MnO B
species O
into O
the O
thermodynamically O
more O
stable O
silicate B
phase O
. O

When O
the O
hollow O
silicate B
nanospheres O
were O
oxidized O
, O
the O
interior O
cavities O
were O
refilled O
with O
a O
Mn B
( I
3 I
) I
O I
( I
4 I
) I
phase O
segregated O
from O
the O
silicate B
phase O
, O
and O
the O
hollow O
structure O
reverted O
to O
the O
initial O
core O
- O
shell O
structure O
. O

More O
interestingly O
, O
when O
catalytically O
active O
Pt B
nanocrystals O
were O
introduced O
into O
the O
manganese B
oxide I
/ O
silica B
system O
, O
the O
Mn B
( I
3 I
) I
O I
( I
4 I
) I
was O
readily O
reduced O
to O
the O
chemically O
reactive O
MnO B
, O
even O
at O
low O
temperature O
, O
which O
enabled O
reconversion O
of O
the O
solid O
nanospheres O
with O
a O
Mn B
( I
3 I
) I
O I
( I
4 I
) I
core O
to O
hollow O
nanostructures O
during O
reductive O
annealing O
. O

Therefore O
, O
when O
MnO B
@ O
SiO B
( I
2 I
) I
/ O
Pt B
( I
II I
) I
nanospheres O
were O
subjected O
to O
an O
oxidation O
/ O
reduction O
cycle O
by O
repeatedly O
switching O
the O
flowing O
gas O
between O
air O
and O
hydrogen B
, O
the O
nanospheres O
underwent O
a O
reversible O
change O
between O
solid O
and O
hollow O
structures O
, O
depending O
on O
the O
gas O
environment O
. O

The O
solid O
- O
to O
- O
hollow O
- O
to O
- O
solid O
transformation O
was O
successfully O
cycled O
many O
times O
simply O
by O
repeatedly O
switching O
the O
flowing O
gas O
during O
annealing O
. O

Polydatin B
ameliorates O
renal O
injury O
by O
attenuating O
oxidative O
stress O
- O
related O
inflammatory O
responses O
in O
fructose B
- O
induced O
urate B
nephropathic O
mice O
. O

A O
series O
of O
studies O
have O
recently O
demonstrated O
that O
the O
oxidative O
stress O
, O
nuclear O
factor O
- O
kappa O
B O
( O
NF O
- O
kappa O
B O
) O
activation O
and O
the O
subsequent O
coordinated O
inflammatory O
responses O
played O
an O
important O
role O
in O
the O
pathogenesis O
of O
urate B
nephropathy O
( O
UN O
) O
. O

Polydatin B
has O
been O
suggested O
to O
have O
the O
properties O
of O
anti O
- O
oxidative O
, O
anti O
- O
inflammatory O
and O
nephroprotective O
effects O
. O

However O
, O
the O
possible O
protective O
and O
beneficial O
effects O
of O
polydatin B
on O
UN O
are O
not O
fully O
elucidated O
. O

Therefore O
, O
we O
investigated O
the O
potential O
beneficial O
effects O
and O
possible O
mechanisms O
of O
polydatin B
on O
UN O
. O

In O
this O
study O
, O
polydatin B
showed O
inhibitory O
activities O
on O
xanthine B
oxidase O
to O
repress O
the O
level O
of O
serum O
uric B
acid I
in O
vivo O
and O
in O
vitro O
. O

Further O
investigations O
revealed O
that O
polydatin B
displayed O
little O
toxic O
effects O
and O
significantly O
ameliorated O
the O
renal O
function O
in O
fructose B
- O
induced O
UN O
mice O
. O

The O
nephroprotective O
activities O
of O
polydatin B
was O
not O
only O
due O
to O
the O
effects O
on O
remarkably O
attenuating O
the O
oxidative O
stress O
induced O
by O
uric B
acid I
, O
but O
also O
on O
markedly O
suppressing O
the O
oxidative O
stress O
- O
related O
inflammatory O
cascade O
, O
including O
decreasing O
the O
expressions O
of O
NF O
- O
kappa O
B O
p65 O
, O
COX O
- O
2 O
and O
iNOS O
proteins O
and O
inhibiting O
the O
productions O
of O
TNF O
- O
alpha O
, O
PGE B
( I
2 I
) I
and O
IL O
- O
1 O
beta O
. O

These O
findings O
elucidated O
that O
polydatin B
exhibited O
prominent O
nephroprotective O
activities O
and O
low O
toxic O
effects O
. O

Alleviation O
effects O
of O
magnesium B
on O
copper B
toxicity O
and O
accumulation O
in O
grapevine O
roots O
evaluated O
with O
biotic O
ligand O
models O
. O

Copper B
toxicity O
and O
accumulation O
in O
plants O
are O
affected O
by O
physicochemical O
characteristics O
of O
soil O
solutions O
such O
as O
the O
concentrations O
of O
coexistent O
cations O
( O
e O
. O
g O
. O
, O
Ca B
( I
2 I
+ I
) I
, O
Mg B
( I
2 I
+ I
) I
, O
K B
( I
+ I
) I
, O
Na B
( I
+ I
) I
, O
and O
H B
( I
+ I
) I
) O
. O

The O
biotic O
ligand O
model O
( O
BLM O
) O
approach O
has O
been O
proposed O
to O
predict O
metal O
phyto O
- O
toxicity O
and O
- O
accumulation O
by O
taking O
into O
account O
the O
effects O
of O
coexistent O
cations O
, O
given O
the O
assumption O
of O
the O
partition O
equilibrium O
of O
metal O
ions O
between O
soil O
solution O
and O
solid O
phase O
. O

The O
alleviation O
effects O
of O
Mg B
on O
Cu B
toxicity O
and O
accumulation O
in O
grapevine O
roots O
were O
the O
main O
concerns O
in O
this O
study O
and O
were O
investigated O
by O
using O
a O
hydroponic O
experiment O
of O
grapevine O
cuttings O
. O

The O
BLM O
approach O
, O
which O
incorporated O
competition O
of O
Mg B
( I
2 I
+ I
) I
with O
Cu B
( I
2 I
+ I
) I
to O
occupy O
the O
biotic O
ligands O
on O
root O
surfaces O
, O
was O
developed O
to O
predict O
Cu B
rhizotoxicity O
and O
accumulation O
by O
grapevine O
roots O
. O

In O
the O
results O
, O
the O
effective O
activity O
of O
Cu B
, O
{ O
Cu B
( I
2 I
+ I
) I
} O
, O
resulting O
in O
a O
50 O
% O
reduction O
of O
root O
elongation O
( O
EA O
( O
50 O
) O
) O
, O
linearly O
increased O
with O
increments O
of O
Mg B
activity O
, O
{ O
Mg B
( I
2 I
+ I
) I
} O
. O

In O
addition O
, O
the O
Cu B
concentration O
in O
root O
, O
Cu B
( O
root O
) O
, O
was O
retarded O
by O
an O
increase O
of O
{ O
Mg B
( I
2 I
+ I
) I
} O
. O

The O
linear O
model O
was O
significantly O
fitted O
to O
the O
relationship O
between O
{ O
Cu B
( I
2 I
+ I
) I
} O
/ O
Cu B
( O
root O
) O
and O
{ O
Mg B
( I
2 I
+ I
) I
} O
. O

According O
to O
the O
concept O
of O
BLM O
, O
the O
present O
results O
revealed O
that O
the O
amelioration O
effects O
of O
Mg B
on O
Cu B
toxicity O
and O
accumulation O
in O
roots O
could O
arise O
from O
competition O
between O
Mg B
( I
2 I
+ I
) I
and O
Cu B
( I
2 I
+ I
) I
on O
the O
binding O
sites O
( O
i O
. O
e O
. O
, O
the O
biotic O
ligands O
) O
. O

Then O
, O
the O
developed O
Cu B
- O
BLMs O
incorporating O
the O
Mg B
( I
2 I
+ I
) I
competition O
effectiveness O
were O
validated O
provide O
accurate O
predictions O
of O
Cu B
toxicity O
and O
accumulation O
in O
grapevine O
roots O
. O

To O
our O
knowledge O
this O
is O
the O
first O
report O
of O
the O
successful O
development O
of O
BLMs O
for O
a O
woody O
plant O
. O

This O
BLM O
approach O
shows O
promise O
of O
being O
widely O
applicable O
for O
various O
terrestrial O
plants O
. O

High O
yield O
, O
reproducible O
and O
quasi O
- O
automated O
bilayer O
formation O
in O
a O
microfluidic O
format O
. O

A O
microfluidic O
platform O
is O
reported O
for O
various O
experimentation O
schemes O
on O
cell O
membrane O
models O
and O
membrane O
proteins O
using O
a O
combination O
of O
electrical O
and O
optical O
measurements O
, O
including O
confocal O
microscopy O
. O

Bilayer O
lipid O
membranes O
( O
BLMs O
) O
are O
prepared O
in O
the O
device O
upon O
spontaneous O
and O
instantaneous O
thinning O
of O
the O
lipid O
solution O
in O
a O
100 O
- O
mu O
m O
dry O
- O
etched O
aperture O
in O
a O
12 O
. O
5 O
- O
mu O
m O
thick O
Teflon B
foil O
. O

Using O
this O
quasi O
- O
automated O
approach O
, O
a O
remarkable O
100 O
% O
membrane O
formation O
yield O
is O
reached O
( O
including O
reflushing O
in O
4 O
% O
of O
the O
cases O
) O
, O
and O
BLMs O
are O
stable O
for O
up O
to O
36 O
h O
. O

Furthermore O
, O
the O
potential O
of O
this O
platform O
is O
demonstrated O
for O
( O
i O
) O
the O
in O
- O
depth O
characterization O
of O
BLMs O
comprising O
both O
synthetic O
and O
natural O
lipids O
( O
1 B
, I
2 I
- I
diphytanoyl I
- I
sn I
- I
glycero I
- I
3 I
- I
phosphocholine I
( O
DPhPC B
) O
and O
L B
- I
alpha I
- I
phosphatidylcholine I
( O
L B
- I
alpha I
- I
PC I
) O
/ O
cholesterol B
, O
respectively O
) O
in O
terms O
of O
seal O
resistance O
, O
capacitance O
, O
surface O
area O
, O
specific O
capacitance O
, O
and O
membrane O
hydrophobic O
thickness O
; O
( O
ii O
) O
confocal O
microscopy O
imaging O

of O
phase O
separation O
in O
sphingomyelin B
/ O
L B
- I
alpha I
- I
PC I
/ O
cholesterol B
ternary O
membranes O
; O
( O
iii O
) O
electrical O
measurements O
of O
individual O
nanopores O
( O
alpha O
- O
hemolysin O
, O
gramicidin O
) O
; O
and O
( O
iv O
) O
indirect O
assessment O
of O
the O
alteration O
of O
membrane O
properties O
upon O
exposure O
to O
chemical O
stimuli O
using O
the O
natural O
nanopore O
gramicidin O
as O
a O
sensor O
. O

Hierarchical O
porous O
materials O
: O
catalytic O
applications O
. O

In O
this O
review O
, O
we O
discuss O
the O
phenomenon O
of O
complementary O
macropore O
incorporation O
into O
mesoporous O
and O
/ O
or O
microporous O
solids O
in O
order O
to O
enhance O
their O
catalytic O
performance O
in O
fuels O
and O
chemicals O
synthesis O
. O

C3 O
' O
/ O
C4 O
' O
- O
Stereochemical O
Effects O
of O
Digitoxigenin B
alpha I
- I
L I
- I
/ I
alpha I
- I
D I
- I
Glycoside I
in O
Cancer O
Cytotoxicity O
. O

Sweet O
' O
n O
low O
in O
stereo O
: O
A O
Wharton O
reaction O
was O
employed O
along O
with O
a O
diastereoselective O
palladium B
- O
catalyzed O
glycosylation O
and O
other O
post O
- O
glycosylation O
transformations O
to O
synthesize O
digitoxin B
analogues O
. O

Cytotoxic O
evaluation O
against O
a O
panel O
of O
cancer O
cell O
lines O
uncovered O
the O
stereochemical O
and O
substitutional O
limits O
of O
the O
C3 O
' I
/ I
C4 O
' O
- O
hydroxy B
functionality O
in O
digitoxin O
monosaccharide B
. O

Investigating O
the O
motion O
of O
diblock O
copolymer O
assemblies O
in O
ionic O
liquids O
by O
in O
situ O
electron O
microscopy O
. O

The O
movement O
of O
individual O
block O
copolymer O
micelles O
in O
free O
- O
standing O
films O
of O
ionic O
liquids O
is O
investigated O
by O
transmission O
electron O
microscopy O
with O
the O
aim O
of O
providing O
an O
easily O
accessible O
high O
- O
resolution O
imaging O
tool O
for O
the O
in O
situ O
observation O
of O
particle O
movement O
in O
a O
liquid O
environment O
. O

A O
proof O
of O
concept O
and O
first O
studies O
on O
the O
behavior O
of O
individual O
particles O
in O
the O
fluid O
are O
demonstrated O
. O

The O
peri O
- O
islet O
basement O
membrane O
, O
a O
barrier O
to O
infiltrating O
leukocytes O
in O
type O
1 O
diabetes O
in O
mouse O
and O
human O
. O

We O
provide O
the O
first O
comprehensive O
analysis O
of O
the O
extracellular O
matrix O
( O
ECM O
) O
composition O
of O
peri O
- O
islet O
capsules O
, O
composed O
of O
the O
peri O
- O
islet O
basement O
membrane O
( O
BM O
) O
and O
subjacent O
interstitial O
matrix O
( O
IM O
) O
, O
in O
development O
of O
type O
1 O
diabetes O
in O
NOD O
mice O
and O
in O
human O
type O
1 O
diabetes O
. O

Our O
data O
demonstrate O
global O
loss O
of O
peri O
- O
islet O
BM O
and O
IM O
components O
only O
at O
sites O
of O
leukocyte O
infiltration O
into O
the O
islet O
. O

Stereological O
analyses O
reveal O
a O
correlation O
between O
incidence O
of O
insulitis O
and O
the O
number O
of O
islets O
showing O
loss O
of O
peri O
- O
islet O
BM O
versus O
islets O
with O
intact O
BMs O
, O
suggesting O
that O
leukocyte O
penetration O
of O
the O
peri O
- O
islet O
BM O
is O
a O
critical O
step O
. O

Protease O
- O
and O
protease O
inhibitor O
- O
specific O
microarray O
analyses O
( O
CLIP O
- O
CHIP O
) O
of O
laser O
- O
dissected O
leukocyte O
infiltrated O
and O
noninfiltrated O
pancreatic O
islets O
and O
confirmatory O
quantitative O
real O
time O
PCR O
and O
protein O
analyses O
identified O
cathepsin O
S O
, O
W O
, O
and O
C O
activity O
at O
sites O
of O
leukocyte O
penetration O
of O
the O
peri O
- O
islet O
BM O
in O
association O
with O
a O
macrophage O
subpopulation O
in O
NOD O
mice O
and O
human O
type O
1 O
diabetic O
samples O
and O
, O
hence O
, O
potentially O
a O
novel O
therapeutic O
target O
specifically O
acting O
at O
the O
islet O
penetration O

stage O
. O

Interestingly O
, O
the O
peri O
- O
islet O
BM O
and O
underlying O
IM O
are O
reconstituted O
once O
inflammation O
subsides O
, O
indicating O
that O
the O
peri O
- O
islet O
BM O
- O
producing O
cells O
are O
not O
lost O
due O
to O
the O
inflammation O
, O
which O
has O
important O
ramifications O
to O
islet O
transplantation O
studies O
. O

Neuronal O
androgen B
receptor O
regulates O
insulin O
sensitivity O
via O
suppression O
of O
hypothalamic O
NF O
- O
kappa O
B O
- O
mediated O
PTP1B O
expression O
. O

Clinical O
investigations O
highlight O
the O
increased O
incidence O
of O
metabolic O
syndrome O
in O
prostate O
cancer O
( O
PCa O
) O
patients O
receiving O
androgen B
deprivation O
therapy O
( O
ADT O
) O
. O

Studies O
using O
global O
androgen B
receptor O
( O
AR O
) O
knockout O
mice O
demonstrate O
that O
AR O
deficiency O
results O
in O
the O
development O
of O
insulin O
resistance O
in O
males O
. O

However O
, O
mechanisms O
by O
which O
AR O
in O
individual O
organs O
coordinately O
regulates O
insulin O
sensitivity O
remain O
unexplored O
. O

Here O
we O
tested O
the O
hypothesis O
that O
functional O
AR O
in O
the O
brain O
contributes O
to O
whole O
- O
body O
insulin O
sensitivity O
regulation O
and O
to O
the O
metabolic O
abnormalities O
developed O
in O
AR O
- O
deficient O
male O
mice O
. O

The O
mouse O
model O
selectively O
lacking O
AR O
in O
the O
central O
nervous O
system O
and O
AR O
- O
expressing O
GT1 O
- O
7 O
neuronal O
cells O
were O
established O
and O
used O
to O
delineate O
molecular O
mechanisms O
in O
insulin O
signaling O
modulated O
by O
AR O
. O

Neuronal O
AR O
deficiency O
leads O
to O
reduced O
insulin O
sensitivity O
in O
middle O
- O
aged O
mice O
. O

Neuronal O
AR O
regulates O
hypothalamic O
insulin O
signaling O
by O
repressing O
nuclear O
factor O
- O
kappa O
B O
( O
NF O
- O
kappa O
B O
) O
- O
mediated O
induction O
of O
protein O
- O
tyrosine B
phosphatase O
1B O
( O
PTP1B O
) O
. O

Hypothalamic O
insulin O
resistance O
leads O
to O
hepatic O
insulin O
resistance O
, O
lipid O
accumulation O
, O
and O
visceral O
obesity O
. O

The O
functional O
deficiency O
of O
AR O
in O
the O
hypothalamus O
leads O
to O
male O
mice O
being O
more O
susceptible O
to O
the O
effects O
of O
high O
- O
fat O
diet O
consumption O
on O
PTP1B O
expression O
and O
NF O
- O
kappa O
B O
activation O
. O

These O
findings O
suggest O
that O
in O
men O
with O
PCa O
undergoing O
ADT O
, O
reduction O
of O
AR O
function O
in O
the O
brain O
may O
contribute O
to O
insulin O
resistance O
and O
visceral O
obesity O
. O

Pharmacotherapies O
targeting O
neuronal O
AR O
and O
NF O
- O
kappa O
B O
may O
be O
developed O
to O
combat O
the O
metabolic O
syndrome O
in O
men O
receiving O
ADT O
and O
in O
elderly O
men O
with O
age O
- O
associated O
hypogonadism O
. O

Identification O
of O
cross O
- O
species O
shared O
transcriptional O
networks O
of O
diabetic O
nephropathy O
in O
human O
and O
mouse O
glomeruli O
. O

Murine O
models O
are O
valuable O
instruments O
in O
defining O
the O
pathogenesis O
of O
diabetic O
nephropathy O
( O
DN O
) O
, O
but O
they O
only O
partially O
recapitulate O
disease O
manifestations O
of O
human O
DN O
, O
limiting O
their O
utility O
. O

To O
define O
the O
molecular O
similarities O
and O
differences O
between O
human O
and O
murine O
DN O
, O
we O
performed O
a O
cross O
- O
species O
comparison O
of O
glomerular O
transcriptional O
networks O
. O

Glomerular O
gene O
expression O
was O
profiled O
in O
patients O
with O
early O
type O
2 O
DN O
and O
in O
three O
mouse O
models O
( O
streptozotocin B
DBA O
/ O
2 O
, O
C57BLKS O
db O
/ O
db O
, O
and O
eNOS O
- O
deficient O
C57BLKS O
db O
/ O
db O
mice O
) O
. O

Species O
- O
specific O
transcriptional O
networks O
were O
generated O
and O
compared O
with O
a O
novel O
network O
- O
matching O
algorithm O
. O

Three O
shared O
human O
- O
mouse O
cross O
- O
species O
glomerular O
transcriptional O
networks O
containing O
143 O
( O
Human O
- O
DBA O
STZ B
) O
, O
97 O
( O
Human O
- O
BKS O
db O
/ O
db O
) O
, O
and O
162 O
( O
Human O
- O
BKS O
eNOS O
( O
- O
/ O
- O
) O
db O
/ O
db O
) O
gene O
nodes O
were O
generated O
. O

Shared O
nodes O
across O
all O
networks O
reflected O
established O
pathogenic O
mechanisms O
of O
diabetes O
complications O
, O
such O
as O
elements O
of O
Janus O
kinase O
( O
JAK O
) O
/ O
signal O
transducer O
and O
activator O
of O
transcription O
( O
STAT O
) O
and O
vascular O
endothelial O
growth O
factor O
receptor O
( O
VEGFR O
) O
signaling O
pathways O
. O

In O
addition O
, O
novel O
pathways O
not O
previously O
associated O
with O
DN O
and O
cross O
- O
species O
gene O
nodes O
and O
pathways O
unique O
to O
each O
of O
the O
human O
- O
mouse O
networks O
were O
discovered O
. O

The O
human O
- O
mouse O
shared O
glomerular O
transcriptional O
networks O
will O
assist O
DN O
researchers O
in O
selecting O
mouse O
models O
most O
relevant O
to O
the O
human O
disease O
process O
of O
interest O
. O

Moreover O
, O
they O
will O
allow O
identification O
of O
new O
pathways O
shared O
between O
mice O
and O
humans O
. O

Metabolite O
profiling O
reveals O
normal O
metabolic O
control O
in O
carriers O
of O
mutations O
in O
the O
glucokinase O
gene O
( O
MODY2 O
) O
. O

Mutations O
in O
the O
gene O
encoding O
glucokinase O
( O
GCK O
) O
cause O
a O
mild O
hereditary O
form O
of O
diabetes O
termed O
maturity O
- O
onset O
diabetes O
of O
the O
young O
( O
MODY O
) O
2 O
or O
GCK O
- O
MODY O
. O

The O
disease O
does O
not O
progress O
over O
time O
, O
and O
diabetes O
complications O
rarely O
develop O
. O

It O
has O
therefore O
been O
suggested O
that O
GCK O
- O
MODY O
represents O
a O
metabolically O
compensated O
condition O
, O
but O
experimental O
support O
for O
this O
notion O
is O
lacking O
. O

Here O
, O
we O
profiled O
metabolites O
in O
serum O
from O
patients O
with O
MODY1 O
( O
HNF4A O
) O
, O
MODY2 O
( O
GCK O
) O
, O
MODY3 O
( O
HNF1A O
) O
, O
and O
type O
2 O
diabetes O
and O
from O
healthy O
individuals O
to O
characterize O
metabolic O
perturbations O
caused O
by O
specific O
mutations O
. O

Analysis O
of O
four O
GCK O
- O
MODY O
patients O
revealed O
a O
metabolite O
pattern O
similar O
to O
that O
of O
healthy O
individuals O
, O
while O
other O
forms O
of O
diabetes O
differed O
markedly O
in O
their O
metabolite O
profiles O
. O

Furthermore O
, O
despite O
elevated O
glucose B
concentrations O
, O
carriers O
of O
GCK O
mutations O
showed O
lower O
levels O
of O
free O
fatty B
acids I
and O
triglycerides B
than O
healthy O
control O
subjects O
. O

The O
metabolite O
profiling O
was O
confirmed O
by O
enzymatic O
assays O
and O
replicated O
in O
a O
cohort O
of O
11 O
GCK O
- O
MODY O
patients O
. O

Elevated O
levels O
of O
fatty B
acids I
are O
known O
to O
associate O
with O
beta O
- O
cell O
dysfunction O
, O
insulin O
resistance O
, O
and O
increased O
incidence O
of O
late O
complications O
. O

Our O
results O
show O
that O
GCK O
- O
MODY O
represents O
a O
metabolically O
normal O
condition O
, O
which O
may O
contribute O
to O
the O
lack O
of O
late O
complications O
and O
the O
nonprogressive O
nature O
of O
the O
disease O
. O

Intrahypothalamic O
estradiol B
regulates O
glucose B
metabolism O
via O
the O
sympathetic O
nervous O
system O
in O
female O
rats O
. O

Long O
- O
term O
reduced O
hypothalamic O
estrogen B
signaling O
leads O
to O
increased O
food O
intake O
and O
decreased O
locomotor O
activity O
and O
energy O
expenditure O
, O
and O
ultimately O
results O
in O
obesity O
and O
insulin O
resistance O
. O

In O
the O
current O
study O
, O
we O
aimed O
to O
determine O
the O
acute O
obesity O
- O
independent O
effects O
of O
hypothalamic O
estrogen B
signaling O
on O
glucose B
metabolism O
. O

We O
studied O
endogenous O
glucose B
production O
( O
EGP O
) O
and O
insulin O
sensitivity O
during O
selective O
modulation O
of O
systemic O
or O
intrahypothalamic O
estradiol B
( O
E2 O
) O
signaling O
in O
rats O
1 O
week O
after O
ovariectomy O
( O
OVX O
) O
. O

OVX O
caused O
a O
17 O
% O
decrease O
in O
plasma O
glucose B
, O
which O
was O
completely O
restored O
by O
systemic O
E2 O
. O

Likewise O
, O
the O
administration O
of O
E2 O
by O
microdialysis O
, O
either O
in O
the O
hypothalamic O
paraventricular O
nucleus O
( O
PVN O
) O
or O
in O
the O
ventromedial O
nucleus O
( O
VMH O
) O
, O
restored O
plasma O
glucose B
. O

The O
infusion O
of O
an O
E2 O
antagonist O
via O
reverse O
microdialysis O
into O
the O
PVN O
or O
VMH O
attenuated O
the O
effect O
of O
systemic O
E2 O
on O
plasma O
glucose B
. O

Furthermore O
, O
E2 O
administration O
in O
the O
VMH O
, O
but O
not O
in O
the O
PVN O
, O
increased O
EGP O
and O
induced O
hepatic O
insulin O
resistance O
. O

E2 O
administration O
in O
both O
the O
PVN O
and O
the O
VMH O
resulted O
in O
peripheral O
insulin O
resistance O
. O

Finally O
, O
sympathetic O
, O
but O
not O
parasympathetic O
, O
hepatic O
denervation O
blunted O
the O
effect O
of O
E2 O
in O
the O
VMH O
on O
both O
EGP O
and O
hepatic O
insulin O
sensitivity O
. O

In O
conclusion O
, O
intrahypothalamic O
estrogen B
regulates O
peripheral O
and O
hepatic O
insulin O
sensitivity O
via O
sympathetic O
signaling O
to O
the O
liver O
. O

Comparative O
analysis O
of O
four O
oxidized O
guanine B
lesions O
from O
reactions O
of O
DNA O
with O
peroxynitrite B
, O
singlet O
oxygen B
, O
and O
gamma O
- O
radiation O
. O

Oxidative O
damage O
to O
DNA O
has O
many O
origins O
, O
including O
irradiation O
, O
inflammation O
, O
and O
oxidative O
stress O
, O
but O
the O
chemistries O
are O
not O
the O
same O
. O

The O
most O
oxidizable O
base O
in O
DNA O
is O
2 B
- I
deoxyguanosine I
( O
dG O
) O
, O
and O
the O
primary O
oxidation O
products O
are O
8 B
- I
oxodG I
and O
2 B
- I
amino I
- I
imidazolone I
. O

The O
latter O
rapidly O
converts O
to O
2 B
, I
2 I
- I
diamino I
- I
oxazolone I
( O
Ox O
) O
, O
and O
8 B
- I
oxodG I
is O
further O
oxidized O
to O
spiroiminodihydantoi B
( O
Sp O
) O
and O
guanidinohydantoin B
( O
Gh O
) O
. O

In O
this O
study O
, O
we O
have O
examined O
the O
dose O
- O
response O
relationship O
for O
the O
formation O
of O
the O
above O
four O
products O
arising O
in O
calf O
thymus O
DNA O
exposed O
to O
gamma O
irradiation O
, O
photoactivated O
rose O
bengal O
, O
and O
two O
sources O
of O
peroxynitrite B
. O

In O
order O
to O
carry O
out O
these O
experiments O
, O
we O
developed O
a O
chromatographic O
system O
and O
synthesized O
isotopomeric O
internal O
standards O
to O
enable O
accurate O
and O
precise O
analysis O
based O
upon O
selected O
reaction O
monitoring O
mass O
spectrometry O
. O

8 B
- I
OxodG I
was O
the O
most O
abundant O
products O
in O
all O
cases O
, O
but O
its O
accumulation O
was O
highly O
dependent O
on O
the O
nature O
of O
the O
oxidizing O
agent O
and O
the O
subsequent O
conversion O
to O
Sp O
and O
Gh O
. O

Among O
the O
other O
oxidation O
products O
, O
Ox O
was O
the O
most O
abundant O
, O
and O
Sp O
was O
formed O
in O
significantly O
greater O
yield O
than O
Gh O
. O

Inactivation O
of O
Escherichia O
coli O
by O
sonoelectrocatalytic O
disinfection O
using O
TiO2 B
as O
electrode O
. O

This O
is O
the O
first O
study O
to O
demonstrate O
sonoelectrocatalytic O
disinfection O
using O
titanium B
dioxide I
( O
TiO B
( I
2 I
) I
) O
as O
an O
anode O
for O
effective O
inactivation O
of O
Escherichia O
coli O
. O

In O
brief O
, O
a O
non O
- O
woven O
TiO B
( I
2 I
) I
fabric O
used O
as O
an O
anode O
and O
a O
platinum B
cathode O
were O
immersed O
in O
an O
E O
. O
coli O
suspension O
in O
which O
a O
positive O
potential O
was O
applied O
to O
TiO B
( I
2 I
) I
concomitant O
with O
ultrasound O
( O
US O
) O
irradiation O
. O

Two O
control O
experiments O
were O
performed O
using O
E O
. O
coli O
suspensions O
to O
exhibit O
the O
effects O
of O
the O
sonoelectrocatalytic O
disinfection O
. O

One O
was O
disinfection O
by O
applying O
a O
positive O
potential O
to O
a O
TiO B
( I
2 I
) I
electrode O
, O
but O
without O
US O
irradiation O
( O
electrochemical O
disinfection O
) O
. O

The O
other O
was O
disinfection O
without O
applying O
a O
potential O
, O
but O
with O
US O
irradiation O
in O
the O
presence O
of O
TiO B
( I
2 I
) I
( O
sonocatalytic O
disinfection O
) O
. O

The O
cell O
inactivation O
rate O
in O
sonoelectrocatalytic O
disinfection O
was O
synergistically O
much O
more O
enhanced O
than O
the O
combined O
inactivation O
rates O
in O
electrochemical O
disinfection O
and O
sonocatalytic O
disinfection O
. O

This O
synergistically O
enhanced O
inactivation O
rate O
of O
E O
. O
coli O
cells O
was O
attributable O
to O
effective O
reaction O
of O
the O
sonocatalytically O
generated O
OH B
radicals O
with O
E O
. O
coli O
cells O
at O
the O
surface O
of O
the O
TiO B
( I
2 I
) I
anode O
, O
which O
resulted O
from O
the O
electroadsorption O
of O
E O
. O
coli O
cells O
toward O
the O
TiO B
( I
2 I
) I
anode O
. O

Recurrent O
major O
depressive O
disorder O
: O
Imbalance O
of O
neurokinin O
( O
NK O
) O
- O
1 O
and O
NK O
- O
2 O
receptor O
expression O
in O
monocytes O
. O

Increasing O
evidence O
suggests O
that O
tachykinins O
are O
involved O
in O
the O
control O
of O
different O
pathological O
conditions O
, O
including O
psychiatric O
disorders O
. O

In O
this O
study O
we O
evaluated O
the O
expression O
of O
NK O
( O
1 O
) O
and O
NK O
( O
2 O
) O
receptors O
( O
NK O
- O
1R O
and O
NK O
- O
2R O
) O
, O
as O
well O
as O
the O
effects O
of O
substance O
P O
( O
SP O
) O
and O
neurokinin O
A O
( O
NKA O
) O
, O
in O
monocytes O
isolated O
from O
15 O
healthy O
subjects O
and O
15 O
patients O
with O
recurrent O
major O
depressive O
disorder O
( O
RMDD O
) O
, O
under O
stable O
antidepressant O
therapy O
. O

NK O
- O
1R O
expression O
in O
monocytes O
from O
RMDD O
patients O
was O
significantly O
decreased O
as O
compared O
to O
healthy O
subjects O
, O
whereas O
NK O
- O
2R O
expression O
was O
markedly O
increased O
. O

Both O
NK O
- O
1R O
and O
NK O
- O
2R O
expression O
correlated O
with O
HAM O
- O
D O
, O
but O
not O
HAM O
- O
A O
, O
score O
. O

SP O
, O
NKA O
and O
selective O
NK O
- O
1R O
and O
NK O
- O
2R O
agonists O
stimulated O
TNF O
- O
alpha O
release O
in O
monocytes O
of O
both O
groups O
, O
with O
a O
significant O
higher O
effect O
observed O
in O
RMDD O
. O

Moreover O
they O
induced O
NF O
- O
kappa O
B O
activation O
, O
which O
was O
reversed O
by O
selective O
NK O
- O
1R O
and O
NK O
- O
2R O
antagonists O
, O
so O
demonstrating O
that O
it O
was O
receptor O
- O
mediated O
. O

The O
occurrence O
of O
a O
profound O
alteration O
in O
NK O
receptor O
expression O
in O
RMDD O
is O
a O
novel O
finding O
that O
suggests O
NK O
- O
1R O
and O
NK O
- O
2R O
pathways O
as O
possible O
relevant O
players O
in O
major O
depressive O
disorder O
, O
so O
improving O
our O
understanding O
of O
the O
complex O
pathogenesis O
of O
the O
disease O
. O

The O
role O
of O
mitochondria O
and O
biotransformation O
in O
abamectin B
- O
induced O
cytotoxicity O
in O
isolated O
rat O
hepatocytes O
. O

Abamectin B
( O
ABA B
) O
, O
which O
belongs O
to O
the O
family O
of O
avermectins B
, O
is O
used O
as O
a O
parasiticide O
; O
however O
, O
ABA B
poisoning O
can O
impair O
liver O
function O
. O

In O
a O
previous O
study O
using O
isolated O
rat O
liver O
mitochondria O
, O
we O
observed O
that O
ABA O
inhibited O
the O
activity O
of O
adenine B
nucleotide I
translocator O
and O
FoF1 O
- O
ATPase O
. O

The O
aim O
of O
this O
study O
was O
to O
characterize O
the O
mechanism O
of O
ABA O
toxicity O
in O
isolated O
rat O
hepatocytes O
and O
to O
evaluate O
whether O
this O
effect O
is O
dependent O
on O
its O
metabolism O
. O

The O
toxicity O
of O
ABA O
was O
assessed O
by O
monitoring O
oxygen B
consumption O
and O
mitochondrial O
membrane O
potential O
, O
intracellular O
ATP B
concentration O
, O
cell O
viability O
, O
intracellular O
Ca B
( I
2 I
+ I
) I
homeostasis O
, O
release O
of O
cytochrome O
c O
, O
caspase O
3 O
activity O
and O
necrotic O
cell O
death O
. O

ABA O
reduces O
cellular O
respiration O
in O
cells O
energized O
with O
glutamate B
and O
malate B
or O
succinate B
. O

The O
hepatocytes O
that O
were O
previously O
incubated O
with O
proadifen B
, O
a O
cytochrome O
P450 O
inhibitor O
, O
are O
more O
sensitive O
to O
the O
compound O
as O
observed O
by O
a O
rapid O
decrease O
in O
the O
mitochondrial O
membrane O
potential O
accompanied O
by O
reductions O
in O
ATP B
concentration O
and O
cell O
viability O
and O
a O
disruption O
of O
intracellular O
Ca B
( I
2 I
+ I
) I
homeostasis O
followed O
by O
necrosis O
. O

Our O
results O
indicate O
that O
ABA B
biotransformation O
reduces O
its O
toxicity O
, O
and O
its O
toxic O
action O
is O
related O
to O
the O
inhibition O
of O
mitochondrial O
activity O
, O
which O
leads O
to O
decreased O
synthesis O
of O
ATP B
followed O
by O
cell O
death O
. O

4 B
- I
( I
Methylnitrosamino I
) I
- I
1 I
- I
( I
3 I
- I
pyridyl I
) I
- I
1 I
- I
butanone I
( O
NNK B
) O
metabolism O
- O
related O
enzymes O
gene O
polymorphisms O
, O
NNK B
metabolites O
levels O
and O
urothelial O
carcinoma O
. O

Gene O
polymorphisms O
of O
the O
4 B
- I
( I
methylnitrosamino I
) I
- I
1 I
- I
( I
3 I
- I
pyridyl I
) I
- I
1 I
- I
butanone I
( O
NNK B
) O
metabolism O
- O
related O
enzymes O
- O
cytochrome O
P450 O
( O
CYP O
) O
monooxygenase O
2A13 O
( O
CYP2A13 O
) O
and O
UDP B
- O
glucuronosyltransfer O
( O
UGT O
) O
- O
2B7 O
could O
contribute O
to O
the O
levels O
of O
NNK B
- O
related O
metabolites O
in O
urine O
, O
thereby O
increasing O
the O
susceptibility O
to O
urothelial O

carcinoma O
( O
UC O
) O
. O

Therefore O
, O
our O
study O
aimed O
to O
evaluate O
the O
roles O
of O
two O
gene O
polymorphisms O
( O
CYP2A13 O
and O
UGT2B7 O
) O
of O
NNK B
metabolism O
- O
related O
enzymes O
in O
the O
carcinogenesis O
of O
UC O
in O
Taiwan O
. O

A O
hospital O
- O
based O
pilot O
case O
- O
control O
study O
was O
conducted O
. O

There O
were O
121 O
UC O
cases O
and O
121 O
age O
- O
and O
sex O
- O
matched O
healthy O
participants O
recruited O
from O
March O
2007 O
to O
April O
2009 O
. O

Urine O
samples O
were O
analyzed O
for O
NNK B
- O
related O
metabolites O
using O
the O
liquid O
chromatography O
- O
tandem O
mass O
spectrometry O
method O
. O

Genotyping O
was O
conducted O
using O
a O
polymerase O
chain O
reaction O
- O
restriction O
fragment O
length O
polymorphism O
technique O
. O

ANCOVA O
and O
multivariate O
logistic O
regression O
were O
applied O
for O
data O
analyses O
. O

In O
healthy O
controls O
, O
former O
smokers O
had O
significantly O
higher O
total O
NNAL B
and O
higher O
NNAL B
- I
Gluc I
than O
never O
smokers O
or O
current O
smokers O
. O

Subjects O
carrying O
the O
UGT2B7 O
268 O
His B
/ O
Tyr B
or O
Tyr B
/ O
Tyr B
genotype O
had O
significantly O
lower O
total O
NNAL O
than O
those O
carrying O
His B
/ O
His B
genotype O
. O

However O
, O
no O
association O
was O
seen O
between O
gene O
polymorphisms O
of O
CYP2A13 O
and O
UGT2B7 O
and O
UC O
risk O
after O
adjustment O
for O
age O
and O
sex O
. O

Significant O
dose O
- O
response O
associations O
between O
total O
NNAL O
, O
free O
NNAL B
, O
the O
ratios O
of O
free O
NNAL B
/ O
total O
NNAL B
and O
NNAL O
- O
Gluc O
/ O
total O
NNAL B
and O
UC O
risk O
were O
observed O
. O

In O
the O
future O
, O
large O
- O
scale O
studies O
will O
be O
required O
to O
verify O
the O
association O
between O
the O
single O
nucleotide O
polymorphisms O
of O
NNK O
metabolism O
- O
related O
enzymes O
and O
UC O
risk O
. O

Novel O
potassium B
channel O
blocker O
venom O
peptides O
from O
Mesobuthus O
gibbosus O
( O
Scorpiones O
: O
Buthidae O
) O
. O

In O
the O
present O
study O
, O
we O
report O
for O
the O
first O
time O
, O
the O
molecular O
, O
biochemical O
and O
electrophysiological O
characterization O
of O
the O
components O
present O
in O
the O
soluble O
venom O
from O
Mesobuthus O
gibbosus O
( O
Brull O
e O
, O
1832 O
) O
. O

According O
to O
the O
epidemiological O
and O
clinical O
situation O
of O
scorpion O
envenomation O
cases O
M O
. O
gibbosus O
scorpion O
is O
one O
of O
the O
most O
important O
health O
- O
threatening O
species O
of O
Turkey O
. O

Despite O
the O
medical O
importance O
reported O
for O
M O
. O
gibbosus O
, O
there O
is O
no O
additional O
information O
on O
toxin O
peptides O
and O
venom O
components O
to O
clarify O
the O
toxic O
effect O
of O
the O
M O
. O
gibbosus O
sting O
. O

Biochemical O
characterization O
of O
the O
venom O
was O
performed O
using O
different O
protocols O
and O
techniques O
following O
a O
bioassay O
- O
guided O
strategy O
( O
HPLC O
, O
mass O
spectrometry O
and O
Edman O
degradation O
sequencing O
) O
. O

Venom O
fractions O
were O
tested O
in O
electrophysiological O
assays O
on O
a O
panel O
of O
six O
K B
( I
+ I
) I
channels O
( O
K B
( O
v O
) O
1 O
. O
1 O
- O
1 O
. O
6 O
) O
by O
using O
the O
two O
- O
electrode O
voltage O
clamp O
technique O
. O

Three O
new O
alpha B
- I
KTx I
peptides O
were O
found O
and O
called O
MegKTx1 O
, O
MegKTx2 O
and O
MegKTx3 O
( O
M O
. O
gibbosus O
, O
K B
( I
+ I
) I
channel O
toxin O
number O
1 O
- O
3 O
) O
. O

A O
cDNA O
library O
from O
the O
telson O
was O
constructed O
and O
specific O
screening O
of O
transcripts O
was O
performed O
. O

Biochemical O
and O
molecular O
characterization O
of O
MegKTx O
peptides O
and O
transcripts O
shows O
a O
relation O
with O
toxins O
of O
three O
different O
alpha O
- O
KTx O
subfamilies O
( O
alpha O
- O
KTx3 O
. O
x O
, O
alpha O
- O
KTx9 O
. O
x O
and O
alpha O
- O
KTx16 O
. O
x O
) O
. O

Use O
of O
high O
content O
image O
analyses O
to O
detect O
chemical O
- O
mediated O
effects O
on O
neurite O
sub O
- O
populations O
in O
primary O
rat O
cortical O
neurons O
. O

Traditional O
developmental O
neurotoxicity O
tests O
performed O
in O
vivo O
are O
costly O
, O
time O
- O
consuming O
and O
utilize O
a O
large O
number O
of O
animals O
. O

In O
order O
to O
address O
these O
inefficiencies O
, O
in O
vitro O
models O
of O
neuronal O
development O
have O
been O
used O
in O
a O
first O
tier O
screening O
approach O
for O
developmental O
neurotoxicity O
hazard O
identification O
. O

One O
commonly O
used O
endpoint O
for O
assessing O
developmental O
neurotoxicity O
in O
vitro O
is O
measurement O
of O
neurite O
outgrowth O
. O

This O
biological O
process O
is O
amenable O
to O
high O
- O
throughput O
measurement O
using O
high O
content O
imaging O
( O
HCI O
) O
based O
methodologies O
. O

To O
date O
, O
a O
majority O
of O
HCI O
studies O
of O
neurite O
outgrowth O
have O
focused O
on O
measurements O
of O
total O
neurite O
outgrowth O
without O
examining O
whether O
stereotypic O
neuronal O
growth O
patterns O
are O
disrupted O
or O
whether O
specific O
sub O
- O
populations O
of O
neurites O
( O
i O
. O
e O
. O
axons O
or O
dendrites O
) O
are O
selectively O
affected O
. O

The O
present O
study O
describes O
the O
development O
and O
implementation O
of O
two O
HCI O
based O
analysis O
methods O
for O
assessing O
chemical O
effects O
on O
neuronal O
maturation O
. O

These O
methods O
utilize O
the O
stereotypical O
growth O
pattern O
of O
primary O
rat O
cortical O
neurons O
in O
culture O
( O
i O
. O
e O
. O
the O
Staging O
Method O
) O
, O
as O
well O
as O
the O
differential O
cytoplasmic O
distribution O
of O
beta O
( O
III O
) O
- O
tubulin O
and O
MAP2 O
( O
i O
. O
e O
. O
the O
Subtraction O
Method O
) O
, O
to O
quantify O
inhibition O
of O
neurite O
initiation O
, O
axon O
outgrowth O
and O
secondary O
neurite O
( O
or O
dendrite O
) O
outgrowth O
in O
response O
to O
chemical O
exposure O
. O

Results O
demonstrate O
that O
these O
distinct O
maturational O
processes O
are O
differentially O
affected O
by O
pharmacological O
compounds O
( O
K252a O
, O
Na B
( I
3 I
) I
VO I
( I
4 I
) I
, O
Bis B
- I
1 I
) O
known O
to O
inhibit O
neurite O
outgrowth O
. O

Furthermore O
, O
a O
group O
of O
known O
developmental O
neurotoxicants O
also O
differentially O
affected O
the O
growth O
of O
axons O
and O
secondary O
neurites O
in O
primary O
cortical O
culture O
. O

This O
work O
improves O
upon O
previous O
HCI O
methods O
by O
providing O
a O
means O
in O
which O
to O
rapidly O
and O
specifically O
quantify O
chemical O
effects O
on O
the O
growth O
of O
axons O
and O
dendrites O
in O
vitro O
. O

Therapeutic O
RNA O
aptamers O
in O
clinical O
trials O
. O

RNA O
aptamers O
can O
fold O
into O
complex O
structures O
and O
bind O
with O
high O
affinity O
and O
selectivity O
to O
various O
macromolecules O
, O
viruses O
, O
and O
cells O
. O

They O
are O
isolated O
from O
a O
large O
pool O
of O
nucleic O
acids O
by O
a O
conceptually O
straightforward O
iterative O
selection O
process O
called O
SELEX O
. O

Aptamers O
have O
enormous O
potential O
as O
therapeutics O
due O
to O
their O
ability O
to O
bind O
to O
proteins O
and O
specifically O
inhibit O
their O
functions O
with O
minimal O
or O
no O
harmful O
side O
- O
effects O
. O

The O
first O
aptamer O
therapeutic O
was O
FDA O
approved O
in O
2005 O
and O
a O
number O
of O
novel O
aptamer O
- O
based O
therapeutics O
are O
currently O
undergoing O
clinical O
trials O
for O
treating O
diseases O
such O
as O
macular O
degeneration O
, O
choroidal O
neovascularization O
, O
intravascular O
thrombus O
, O
acute O
coronary O
syndrome O
, O
von O
Willebrand O
factor O
related O
disorders O
, O
von O
Hippel O
- O
Lindau O
syndrome O
( O
VHL O
) O
, O
angiomas O
, O
acute O
myeloid O
leukemia O
, O
renal O
cell O
carcinoma O
, O
non O
- O
small O
cell O
lung O
cancer O
, O
thrombotic O
thrombocytopenic O
purpura O
, O
and O
several O
others O
. O

In O
this O
review O
, O
we O
present O
aptamers O
in O
on O
- O
going O
, O
completed O
, O
and O
terminated O
clinical O
studies O
highlighting O
their O
mechanism O
of O
action O
as O
well O
as O
the O
inherent O
challenges O
of O
aptamer O
production O
and O
use O
. O

Superoxide B
anion O
mediates O
the O
L O
- O
selectin O
down O
- O
regulation O
induced O
by O
non O
- O
steroidal O
anti O
- O
inflammatory O
drugs O
in O
human O
neutrophils O
. O

Non O
- O
steroidal O
anti O
- O
inflammatory O
drugs O
( O
NSAIDs O
) O
induce O
the O
shedding O
of O
L O
- O
selectin O
in O
human O
neutrophils O
through O
a O
mechanism O
still O
not O
well O
understood O
. O

In O
this O
work O
we O
studied O
both O
the O
functional O
effect O
of O
NSAIDs O
on O
the O
neutrophils O
/ O
endothelial O
cells O
dynamic O
interaction O
, O
and O
the O
potential O
involvement O
of O
reactive O
oxygen B
species O
( O
ROS O
) O
in O
the O
NSAIDs O
- O
mediated O
down O
- O
regulation O
of O
L O
- O
selectin O
. O

When O
human O
neutrophils O
were O
incubated O
with O
diclofenac B
, O
a O
significant O
reduction O
in O
the O
number O
of O
cells O
that O
rolled O
on O
activated O
endothelial O
cells O
was O
observed O
. O

Different O
NSAIDs O
( O
flufenamic B
acid I
, O
meclofenamic B
acid I
, O
diclofenac B
, O
indomethacin B
, O
nimesulide B
, O
flurbiprofen B
, O
meloxicam B
, O
phenylbutazone B
, O
piroxicam B
, O
ketoprofen B
and O
aspirin B
) O
caused O
variable O
increase O
in O
neutrophil O
intracellular O
ROS O
concentration O
, O
which O
was O
inversely O
proportional O
to O
the O
change O
produced O
in O
L O
- O
selectin O
surface O
expression O
. O

Pre O
- O
incubation O
of O
neutrophils O
with O
superoxide B
dismutase O
, O
but O
not O
with O
catalase O
, O
showed O
both O
a O
significant O
protective O
effect O
on O
the O
L O
- O
selectin O
down O
- O
regulation O
induced O
by O
several O
NSAIDs O
and O
a O
diminished O
effect O
of O
diclofenac B
on O
neutrophil O
rolling O
. O

Interestingly O
, O
diclofenac B
and O
flufenamic B
acid I
but O
not O
piroxicam B
significantly O
increased O
the O
extracellular O
superoxide B
anion O
production O
by O
neutrophils O
, O
and O
inhibition O
of O
nicotinamide B
adenine I
dinucleotide I
phosphate I
( O
NADPH B
) O
- O
oxidase O
activity O
with O
diphenyleneiodonium B
prevented O
the O
down O
- O
regulation O
of O
L O
- O
selectin O
by O
diclofenac B
. O

In O
accordance O
with O
these O
results O
, O
neutrophils O
from O
patients O
with O
chronic O
granulomatous O
disease O
, O
a O
hereditary O
disease O
in O
which O
neutrophils O
show O
a O
reduced O
capacity O
to O
form O
superoxide B
radicals O
, O
exhibited O
a O
lower O
down O
- O
regulation O
of O
L O
- O
selectin O
( O
IC50 O
: O
15 O
. O
3 O
mu O
g O
/ O
ml O
) O
compared O
to O
normal O
controls O
( O
IC50 O
: O
5 O
. O
6 O
mu O
g O
/ O
ml O
) O
in O
response O
to O
diclofenac B
. O

CONCLUSION O
: O
A O
group O
of O
NSAIDs O
is O
capable O
of O
interfering O
with O
the O
ability O
of O
neutrophils O
to O
interact O
with O
endothelial O
cells O
by O
triggering O
L O
- O
selectin O
- O
shedding O
through O
the O
NADPH B
- O
oxidase O
- O
dependent O
generation O
of O
superoxide B
anion O
at O
the O
plasma O
membrane O
. O

Proteasome O
inhibition O
attenuates O
heart O
failure O
during O
the O
late O
stages O
of O
pressure O
overload O
through O
alterations O
in O
collagen O
expression O
. O

Although O
the O
role O
of O
the O
ubiquitin O
- O
proteasome O
system O
( O
UPS O
) O
in O
cardiac O
hypertrophy O
induced O
by O
pressure O
overload O
has O
been O
consistently O
studied O
, O
the O
fundamental O
importance O
of O
the O
UPS O
in O
cardiac O
fibrosis O
has O
received O
much O
less O
attention O
. O

Our O
previous O
study O
found O
that O
proteasome O
inhibitor O
( O
MG132 B
) O
treatment O
attenuated O
cardiac O
fibrosis O
and O
heart O
failure O
during O
the O
early O
and O
middle O
stages O
of O
pressure O
overload O
. O

However O
, O
the O
effects O
of O
this O
inhibitor O
on O
late O
- O
stage O
pressure O
overload O
hearts O
remain O
unclear O
and O
controversial O
. O

The O
present O
study O
was O
designed O
to O
investigate O
the O
effects O
and O
possible O
mechanisms O
of O
MG132 B
on O
cardiac O
fibrosis O
and O
dysfunction O
during O
the O
late O
stages O
of O
pressure O
overload O
. O

Male O
Sprague O
Dawley O
rats O
with O
abdominal O
aortic O
constriction O
( O
AAC O
) O
or O
a O
sham O
operation O
received O
an O
intraperitoneal O
injection O
of O
MG132 B
( O
0 O
. O
1 O
mg O
kg O
- O
( O
1 O
) O
day O
- O
( O
1 O
) O
) O
or O
vehicle O
for O
16 O
weeks O
. O

Left O
ventricular O
( O
LV O
) O
function O
, O
collagen O
deposition O
and O
Ang O
II O
levels O
were O
evaluated O
at O
study O
termination O
. O

Ang O
II O
- O
stimulated O
adult O
rat O
cardiac O
fibroblasts O
were O
utilized O
to O
examine O
the O
effects O
of O
MG132 B
on O
collagen O
synthesis O
and O
the O
relationship O
between O
the O
renin O
- O
angiotensin O
- O
aldosterone B
system O
( O
RAAS O
) O
and O
the O
UPS O
. O

MG132 B
treatment O
attenuated O
ventricular O
dysfunction O
by O
suppressing O
cardiac O
fibrosis O
rather O
than O
inhibiting O
cardiac O
hypertrophy O
during O
the O
late O
- O
stages O
of O
pressure O
overload O
. O

We O
also O
found O
that O
Ang O
II O
activates O
UPS O
in O
the O
heart O
and O
MG132 B
attenuates O
Ang O
II O
- O
induced O
collagen O
synthesis O
via O
suppression O
of O
the O
NF O
- O
kappa O
B O
/ O
TGF O
- O
beta O
/ O
Smad2 O
signaling O
pathways O
. O

Proteasome O
inhibition O
therefore O
could O
provide O
a O
new O
promising O
therapeutic O
strategy O
to O
prevent O
cardiac O
fibrosis O
and O
progression O
of O
heart O
failure O
even O
during O
the O
late O
- O
stages O
of O
pressure O
overload O
. O

Yuwen02f1 O
suppresses O
LPS O
- O
induced O
endotoxemia O
and O
adjuvant O
- O
induced O
arthritis O
primarily O
through O
blockade O
of O
ROS O
formation O
, O
NFkB O
and O
MAPK O
activation O
. O

Phagocytes O
release O
inflammatory O
mediators O
to O
defense O
harmful O
stimuli O
upon O
bacterial O
invasion O
, O
however O
, O
excessive O
inflammatory O
reaction O
leads O
to O
tissue O
damage O
and O
manifestation O
of O
pathological O
states O
. O

Therefore O
, O
targeting O
on O
uncontrolled O
inflammation O
seems O
feasible O
to O
control O
numerous O
inflammation O
- O
associated O
diseases O
. O

Under O
the O
drug O
screening O
process O
of O
synthetic O
diphenylpyrazole B
derivatives O
, O
we O
discovered O
compound O
yuwen02f1 B
possesses O
anti O
- O
inflammatory O
effects O
in O
decreasing O
the O
release O
of O
pro O
- O
inflammatory O
cytokines O
including O
TNF O
alpha O
and O
IL O
- O
6 O
, O
nitric B
oxide I
, O
reactive O
oxygen B
species O
( O
ROS O
) O
as O
well O
as O
inhibiting O
migration O
of O
LPS O
- O
stimulated O
phagocytes O
. O

In O
addition O
, O
we O
observed O
that O
the O
molecular O
mechanism O
of O
yuwen02f1 O
- O
mediated O
anti O
- O
inflammation O
is O
associated O
with O
decreasing O
phosphorylation O
of O
MAPK O
molecules O
including O
ERK1 O
/ O
2 O
, O
JNK O
and O
p38 O
, O
and O
attenuating O
translocation O
of O
p47 O
( O
phox O
) O
and O
p67 O
( O
phox O
) O
to O
the O
cell O
membrane O
. O

Yuwen02f1 O
also O
reverses O
I O
kappa O
B O
alpha O
degradation O
and O
attenuates O
the O
expression O
of O
NF O
kappa O
B O
- O
related O
downstream O
inducible O
enzymes O
like O
iNOS O
and O
COX O
- O
2 O
. O

Furthermore O
, O
we O
found O
that O
yuwen02f1 O
attenuates O
some O
pathological O
syndromes O
of O
LPS O
- O
induced O
sepsis O
and O
adjuvant O
- O
induced O
arthritis O
in O
mice O
, O
as O
evidenced O
by O
decreasing O
the O
cytokine O
production O
, O
reversing O
thrombocytopenic O
syndrome O
, O
protecting O
the O
mice O
from O
tissue O
injury O
in O
septic O
mice O
, O
and O
attenuating O
paw O
edema O
in O
arthritic O
mice O
as O
well O
. O

These O
results O
suggest O
that O
yuwen02f1 B
is O
a O
potential O
anti O
- O
inflammatory O
agent O
for O
alleviating O
syndromes O
of O
acute O
and O
chronic O
inflammatory O
diseases O
as O
evidenced O
by O
attenuating O
the O
generation O
of O
cytokines O
and O
down O
- O
regulating O
the O
expression O
of O
iNOS O
and O
COX O
- O
2 O
through O
the O
blockade O
of O
ROS O
generation O
and O
NADPH B
oxidase O
, O
NF O
kappa O
B O
and O
MAPK O
activation O
pathways O
in O
LPS O
- O
stimulated O
phagocytes O
. O

Protective O
effects O
of O
erythropoietin O
on O
astrocytic O
swelling O
after O
oxygen B
- O
glucose B
deprivation O
and O
reoxygenation O
: O
mediation O
through O
AQP4 O
expression O
and O
MAPK O
pathway O
. O

Recent O
in O
vivo O
studies O
have O
shown O
that O
erythropoietin O
( O
EPO O
) O
offers O
strong O
protection O
against O
brain O
edema O
. O

However O
, O
the O
intracellular O
and O
molecular O
mechanisms O
behind O
this O
beneficial O
effect O
have O
not O
been O
specified O
. O

The O
aim O
of O
this O
study O
was O
to O
determine O
whether O
human O
erythropoietin O
( O
rhEPO O
) O
reduces O
the O
astrocytic O
swelling O
created O
by O
oxygen B
- O
glucose B
deprivation O
followed O
by O
reoxygenation O
( O
OGD O
/ O
Reox O
) O
in O
vitro O
and O
whether O
this O
effect O
can O
be O
mediated O
through O
the O
modulation O
of O
aquaporin4 O
( O
AQP4 O
) O
expression O
in O
the O
plasma O
membrane O
( O
PM O
) O
and O
phosphorylation O
of O
the O
mitogen O
- O
activated O
protein O
kinase O
pathway O
( O
MAPK O
) O
pathway O
. O

Our O
results O
showed O
that O
OGD O
/ O
Reox O
produced O
increase O
in O
cell O
volume O
, O
morphological O
swelling O
, O
and O
mitochondrial O
swelling O
. O

These O
changes O
were O
associated O
with O
the O
up O
- O
regulation O
of O
AQP4 O
in O
PM O
and O
the O
over O
- O
activation O
of O
MAPK O
. O

Silencing O
AQP4 O
expression O
using O
small O
interfering O
ribonucleic O
acid O
for O
AQP4 O
was O
found O
to O
block O
astrocytic O
swelling O
. O

Inhibition O
of O
the O
over O
- O
activation O
of O
MAPK O
mitigated O
the O
PM O
AQP4 O
overabundance O
and O
cellular O
swelling O
. O

As O
expected O
, O
treatment O
with O
rhEPO O
significantly O
reduced O
the O
OGD O
/ O
Reox O
- O
induced O
increase O
in O
cell O
volume O
, O
morphological O
swelling O
, O
and O
mitochondrial O
swelling O
as O
well O
as O
the O
up O
- O
regulation O
of O
AQP4 O
in O
PM O
. O

In O
addition O
, O
cultures O
treated O
with O
the O
neutralizing O
anti O
- O
EPO O
antibody O
worsened O
the O
PM O
AQP4 O
abundance O
and O
cellular O
swelling O
, O
abolishing O
the O
protective O
effects O
mediated O
by O
rhEPO O
treatment O
. O

Furthermore O
, O
the O
over O
- O
activation O
of O
these O
MAPK O
after O
OGD O
/ O
Reox O
was O
attenuated O
by O
rhEPO O
treatment O
significantly O
. O

In O
conclusion O
, O
our O
data O
strongly O
suggest O
that O
rhEPO O
can O
protect O
astrocytes O
from O
swelling O
caused O
by O
ischemia O
and O
reperfusion O
- O
like O
injury O
. O

This O
neuroprotective O
capacity O
is O
partially O
mediated O
by O
diminishing O
the O
MAPK O
- O
activity O
- O
dependent O
overabundance O
of O
AQP4 O
in O
PM O
. O

Toxicogenomic O
biomarkers O
for O
renal O
papillary O
injury O
in O
rats O
. O

Renal O
papillary O
injury O
is O
a O
common O
side O
effect O
observed O
during O
nonclinical O
and O
clinical O
investigations O
in O
drug O
development O
. O

The O
present O
study O
aimed O
to O
identify O
genomic O
biomarkers O
for O
early O
and O
sensitive O
detection O
of O
renal O
papillary O
injury O
in O
rats O
. O

We O
hypothesized O
that O
previously O
identified O
genomic O
biomarkers O
for O
tubular O
injury O
might O
be O
applicable O
for O
the O
sensitive O
detection O
of O
papillary O
injury O
in O
rats O
. O

We O
selected O
18 O
genes O
as O
candidate O
biomarkers O
for O
papillary O
injury O
based O
on O
previously O
published O
studies O
and O
analyzed O
their O
expression O
profiles O
by O
RT O
- O
PCR O
in O
each O
kidney O
region O
, O
namely O
the O
cortex O
, O
cortico O
- O
medullary O
junction O
, O
and O
papilla O
in O
various O
nephrotoxicity O
models O
. O

Comparative O
analysis O
of O
gene O
expression O
profiles O
revealed O
that O
some O
genes O
were O
commonly O
upregulated O
or O
downregulated O
in O
the O
renal O
papilla O
, O
reflecting O
papillary O
injuries O
induced O
by O
2 B
- I
bromoethylamine I
hydrobromide I
, O
phenylbutazone B
, O
or O
n B
- I
phenylanthranilic I
acid I
. O

By O
applying O
receiver O
operator O
characteristics O
analysis O
, O
six O
candidate O
biomarkers O
were O
identified O
and O
their O
usefulness O
was O
confirmed O
by O
using O
an O
independent O
data O
set O
. O

The O
three O
top O
- O
ranked O
genes O
, O
Timp1 O
, O
Igf1 O
, O
and O
Lamc2 O
, O
exhibited O
the O
best O
prediction O
performance O
in O
an O
external O
data O
set O
with O
area O
under O
the O
curve O
( O
AUC O
) O
values O
of O
greater O
than O
0 O
. O
91 O
. O

An O
optimized O
support O
vector O
machine O
model O
consisting O
of O
three O
genes O
achieved O
the O
highest O
AUC O
value O
of O
0 O
. O
99 O
. O

In O
conclusion O
, O
even O
though O
definitive O
validation O
studies O
are O
required O
for O
the O
establishment O
of O
their O
usefulness O
and O
reliability O
, O
these O
identified O
genes O
may O
prove O
to O
be O
the O
most O
promising O
candidate O
genomic O
biomarkers O
of O
renal O
papillary O
injury O
in O
rats O
. O

Differential O
responses O
in O
ammonia B
excretion O
, O
sodium B
fluxes O
and O
gill O
permeability O
explain O
different O
sensitivities O
to O
acute O
high O
environmental O
ammonia B
in O
three O
freshwater O
teleosts O
. O

We O
examined O
the O
acute O
physiological O
responses O
to O
high O
environmental O
ammonia B
( O
HEA O
) O
, O
particularly O
the O
linkages O
between O
branchial O
ammonia B
fluxes O
and O
unidirectional O
Na B
( I
+ I
) I
fluxes O
, O
as O
well O
as O
urea B
excretion O
, O
cortisol B
, O
and O
indicators O
of O
gill O
permeability O
in O
three O
freshwater O
teleosts O
differing O
in O
their O
sensitivities O
to O
ammonia B
; O
the O
highly O
sensitive O
salmonid O
Oncorhynchus O
mykiss O
( O
rainbow O
trout O
) O
, O
the O
less O
sensitive O
cyprinid O
Cyprinus O
carpio O
( O
common O
carp O
) O
and O
the O
highly O
resistant O
cyprinid O

Carassius O
auratus O
( O
goldfish O
) O
. O

Fish O
were O
acutely O
exposed O
to O
two O
sub O
- O
lethal O
ammonia B
concentrations O
( O
as O
NH B
( I
4 I
) I
HCO I
( I
3 I
) I
) O
at O
pH O
7 O
. O
9 O
: O
1 O
mM O
for O
a O
period O
of O
12 O
h O
, O
identical O
for O
all O
species O
, O
and O
5 O
mM O
for O
the O
cyprinids O
and O
1 O
. O
4 O
mM O
for O
the O
trout O
for O
3 O
h O
. O

Elevation O
of O
plasma O
cortisol B
at O
both O
levels O
of O
HEA O
was O
apparent O
in O
all O
species O
. O

At O
1 O
mM O
, O
ammonia B
excretion O
( O
J O
( O
amm O
) O
) O
was O
inhibited O
to O
a O
greater O
extent O
in O
trout O
than O
cyprinids O
and O
concurrently O
a O
significantly O
higher O
plasma O
ammonia B
level O
was O
evident O
in O
trout O
. O

However O
J O
( O
amm O
) O
was O
reversed O
in O
all O
species O
at O
5 O
or O
1 O
. O
4 O
mM O
. O

Goldfish O
showed O
a O
significant O
increase O
in O
urea B
excretion O
rate O
( O
J O
( O
urea B
) O
) O
during O
HEA O
exposure O
. O

In O
carp O
and O
trout O
, O
neither O
level O
of O
HEA O
elevated O
J O
( O
urea B
) O
but O
urea B
production O
was O
increased O
as O
evidenced O
by O
a O
considerable O
elevation O
of O
plasma O
urea B
. O

At O
1mM O
HEA O
, O
Na B
( I
+ I
) I
imbalance O
became O
progressively O
more O
severe O
in O
trout O
and O
carp O
due O
to O
a O
stimulation O
of O
unidirectional O
Na B
( I
+ I
) I
efflux O
( O
J O
( O
out O
) O
( O
Na B
) O
) O
without O
a O
concomitant O
increase O
in O
unidirectional O
Na B
( I
+ I
) I
influx O
( O
J O
( O
in O
) O
( O
Na B
) O
) O
. O

Additionally O
, O
a O
transient O
reduction O
of O
J O
( O
in O
) O
( O
Na O
) O
was O
evident O
in O
trout O
. O

Goldfish O
showed O
an O
opposite O
trend O
for O
J O
( O
out O
) O
( O
Na B
) O
with O
reduced O
efflux O
rates O
and O
a O
positive O
Na B
( I
+ I
) I
balance O
during O
the O
first O
few O
hours O
of O
HEA O
. O

However O
, O
after O
12 O
h O
of O
exposure O
, O
both O
J O
( O
in O
) O
( O
Na B
) O
and O
J O
( O
out O
) O
( O
Na B
) O
were O
also O
increased O
in O
both O
carp O
and O
goldfish O
, O
whereas O
only O
J O
( O
out O
) O
( O
Na B
) O
was O
increased O
in O
trout O
, O
leading O
to O
a O
net O
Na B
( I
+ I
) I
loss O
. O

Na B
( I
+ I
) I
homeostasis O
was O
entirely O
disrupted O
in O
all O
three O
species O
when O
subjected O
to O
the O
5 O
or O
1 O
. O
4 O
mM O
ammonia B
for O
3 O
h O
: O
J O
( O
in O
) O
( O
Na B
) O
was O
significantly O
inhibited O
while O
considerable O
activation O
of O
J O
( O
out O
) O
( O
Na B
) O
was O
observed O
. O

Diffusive O
water O
efflux O
rates O
and O
net O
K B
( I
+ I
) I
loss O
rates O
across O
the O
gills O
were O
enhanced O
during O
HEA O
only O
in O
trout O
, O
indicating O
an O
increment O
in O
gill O
transcellular O
permeability O
. O

Transepithelial O
potential O
was O
increased O
in O
all O
the O
species O
during O
ammonia B
exposure O
, O
but O
to O
the O
least O
extent O
in O
goldfish O
. O

Overall O
, O
for O
several O
different O
physiological O
systems O
, O
trout O
were O
most O
disturbed O
, O
and O
goldfish O
were O
least O
disturbed O
by O
HEA O
, O
helping O
to O
explain O
the O
differential O
ammonia B
tolerance O
of O
the O
three O
species O
. O

Metabolic O
pathways O
of O
inhaled O
glucocorticoids O
by O
the O
CYP3A O
enzymes O
. O

Asthma O
is O
one O
of O
the O
most O
prevalent O
diseases O
in O
the O
world O
, O
for O
which O
the O
mainstay O
treatment O
has O
been O
inhaled O
glucocorticoids O
( O
GCs O
) O
. O

Despite O
the O
widespread O
use O
of O
these O
drugs O
, O
approximately O
30 O
% O
of O
asthma O
sufferers O
exhibit O
some O
degree O
of O
steroid O
insensitivity O
or O
are O
refractory O
to O
inhaled O
GCs O
. O

One O
hypothesis O
to O
explain O
this O
phenomenon O
is O
interpatient O
variability O
in O
the O
clearance O
of O
these O
compounds O
. O

The O
objective O
of O
this O
research O
is O
to O
determine O
how O
metabolism O
of O
GCs O
by O
the O
CYP3A O
family O
of O
enzymes O
could O
affect O
their O
effectiveness O
in O
asthmatic O
patients O
. O

In O
this O
work O
, O
the O
metabolism O
of O
four O
frequently O
prescribed O
inhaled O
GCs O
, O
triamcinolone B
acetonide I
, O
flunisolide B
, O
budesonide B
, O
and O
fluticasone B
propionate I
, O
by O
the O
CYP3A O
family O
of O
enzymes O
was O
studied O
to O
identify O
differences O
in O
their O
rates O
of O
clearance O
and O
to O
identify O
their O
metabolites O
. O

Both O
interenzyme O
and O
interdrug O
variability O
in O
rates O
of O
metabolism O
and O
metabolic O
fate O
were O
observed O
. O

CYP3A4 O
was O
the O
most O
efficient O
metabolic O
catalyst O
for O
all O
the O
compounds O
, O
and O
CYP3A7 O
had O
the O
slowest O
rates O
. O

CYP3A5 O
, O
which O
is O
particularly O
relevant O
to O
GC O
metabolism O
in O
the O
lungs O
, O
was O
also O
shown O
to O
efficiently O
metabolize O
triamcinolone B
acetonide I
, O
budesonide B
, O
and O
fluticasone B
propionate I
. O

In O
contrast O
, O
flunisolide B
was O
only O
metabolized O
via O
CYP3A4 O
, O
with O
no O
significant O
turnover O
by O
CYP3A5 O
or O
CYP3A7 O
. O

Common O
metabolites O
included O
6 O
beta O
- O
hydroxylation O
and O
Delta O
( O
6 O
) O
- O
dehydrogenation O
for O
triamcinolone B
acetonide I
, O
budesonide B
, O
and O
flunisolide B
. O

The O
structure O
of O
Delta B
( I
6 I
) I
- I
flunisolide I
was O
unambiguously O
established O
by O
NMR O
analysis O
. O

Metabolism O
also O
occurred O
on O
the O
D O
- O
ring O
substituents O
, O
including O
the O
21 B
- I
carboxy I
metabolites O
for O
triamcinolone B
acetonide I
and O
flunisolide B
. O

The O
novel O
metabolite O
21 B
- I
nortriamcinolone I
acetonide I
was O
also O
identified O
by O
liquid O
chromatography O
- O
mass O
spectrometry O
and O
NMR O
analysis O
. O

IsoDGR O
- O
tagged O
albumin O
: O
a O
new O
alpha O
v O
beta O
3 O
selective O
carrier O
for O
nanodrug O
delivery O
to O
tumors O
. O

A O
new O
cyclic O
peptide O
containing O
the O
isoDGR O
motif O
that O
, O
after O
coupling O
to O
albumin O
, O
selectively O
binds O
alpha O
v O
beta O
3 O
, O
an O
integrin O
overexpressed O
in O
the O
tumor O
vasculature O
. O

IsoDGR O
- O
tagged O
albumin O
binds O
tumor O
vessels O
and O
can O
be O
exploited O
as O
a O
carrier O
for O
the O
preparation O
of O
tumor O
vasculature O
- O
selective O
nanomedicines O
, O
such O
as O
gold O
nanoparticles O
( O
Au B
) O
carrying O
tumor O
necrosis O
factor O
alpha O
( O
TNF O
) O
, O
a O
potent O
vascular O
damaging O
agent O
. O

Enhancing O
the O
photocatalytic O
activity O
of O
anatase O
TiO2 B
by O
improving O
the O
specific O
facet O
- O
induced O
spontaneous O
separation O
of O
photogenerated O
electrons O
and O
holes O
. O

Recently O
, O
it O
has O
been O
proven O
that O
directional O
flow O
of O
photogenerated O
charge O
carriers O
occurs O
on O
specific O
facets O
of O
TiO B
( I
2 I
) I
nanocrystals O
. O

Herein O
, O
we O
demonstrate O
that O
the O
photocatalytic O
activity O
of O
anatase O
TiO B
( I
2 I
) I
nanocrystals O
in O
both O
photoreduction O
and O
photooxidation O
processes O
can O
be O
enhanced O
by O
selectively O
depositing O
Pt B
nanoparticles O
on O
the O
{ O
101 O
} O
facets O
, O
which O
strengthens O
spontaneously O
surface O
- O
induced O
separation O
between O
photogenerated O
electrons O
and O
holes O
in O
the O
photocatalysis O
process O
. O

An O
optimal O
ratio O
of O
the O
oxidative O
{ O
001 O
} O
facets O
to O
the O
reductive O
{ O
101 O
} O
facets O
exists O
with O
regard O
to O
the O
photocatalysis O
of O
the O
faceted O
TiO B
( I
2 I
) I
nanocrystals O
, O
and O
this O
is O
crucial O
for O
balancing O
the O
recombination O
and O
redox O
reaction O
rates O
of O
photogenerated O
electrons O
and O
holes O
. O

The O
present O
work O
might O
help O
us O
gain O
deeper O
insight O
into O
the O
relation O
between O
the O
specific O
surface O
of O
semiconductor O
photocatalysts O
and O
their O
photocatalytic O
activities O
and O
provides O
us O
with O
a O
new O
route O
to O
design O
photocatalysts O
with O
high O
photocatalytic O
activity O
. O

Noncompetitive O
, O
voltage O
- O
dependent O
NMDA B
receptor O
antagonism O
by O
hydrophobic O
anions O
. O

NMDA B
receptor O
( O
NMDAR O
) O
antagonists O
are O
dissociative O
anesthetics O
, O
drugs O
of O
abuse O
, O
and O
are O
of O
therapeutic O
interest O
in O
neurodegeneration O
and O
neuropsychiatric O
disease O
. O

Many O
well O
- O
known O
NMDAR O
antagonists O
are O
positively O
charged O
, O
voltage O
- O
dependent O
channel O
blockers O
. O

We O
recently O
showed O
that O
the O
hydrophobic O
anion O
dipicrylamine B
( O
DPA B
) O
negatively O
regulates O
GABA B
( O
A O
) O
receptor O
function O
by O
a O
mechanism O
indistinguishable O
from O
that O
of O
sulfated O
neurosteroids O
. O

Because O
sulfated B
neurosteroids O
also O
modulate O
NMDARs O
, O
here O
we O
examined O
the O
effects O
of O
DPA B
on O
NMDAR O
function O
. O

In O
rat O
hippocampal O
neurons O
DPA O
inhibited O
currents O
gated O
by O
300 O
micro O
M O
NMDA B
with O
an O
IC O
( O
50 O
) O
of O
2 O
. O
3 O
micro O
M O
. O

Neither O
onset O
nor O
offset O
of O
antagonism O
exhibited O
dependence O
on O
channel O
activation O
but O
exhibited O
a O
noncompetitive O
profile O
. O

DPA B
antagonism O
was O
independent O
of O
NMDAR O
subunit O
composition O
and O
was O
similar O
at O
extrasynaptic O
and O
total O
receptor O
populations O
. O

Surprisingly O
, O
similar O
to O
cationic O
channel O
blockers O
but O
unlike O
sulfated B
neurosteroids I
, O
DPA B
antagonism O
was O
voltage O
dependent O
. O

Onset O
and O
offset O
of O
DPA B
antagonism O
were O
nearly O
10 O
- O
fold O
faster O
than O
DPA B
- O
induced O
increases O
in O
membrane O
capacitance O
, O
suggesting O
that O
membrane O
interactions O
do O
not O
directly O
explain O
antagonism O
. O

Furthermore O
, O
voltage O
dependence O
did O
not O
derive O
from O
association O
of O
DPA B
with O
a O
site O
on O
NMDARs O
directly O
accessible O
to O
the O
outer O
membrane O
leaflet O
, O
assessed O
by O
DPA B
translocation O
experiments O
. O

Consistent O
with O
the O
expected O
lack O
of O
channel O
block O
, O
DPA B
antagonism O
did O
not O
interact O
with O
permeant O
ions O
. O

Therefore O
, O
we O
speculate O
that O
voltage O
dependence O
may O
arise O
from O
interactions O
of O
DPA B
with O
the O
inherent O
voltage O
dependence O
of O
channel O
gating O
. O

Overall O
, O
we O
conclude O
that O
DPA B
noncompetitively O
inhibits O
NMDA B
- O
induced O
current O
by O
a O
novel O
voltage O
- O
dependent O
mechanism O
and O
represents O
a O
new O
class O
of O
anionic O
NMDAR O
antagonists O
. O

Structural O
optimization O
of O
2 B
, I
5 I
- I
thiophene I
amides I
as O
highly O
potent O
and O
selective O
17 B
beta I
- I
hydroxysteroid I
dehydrogenase O
type O
2 O
inhibitors O
for O
the O
treatment O
of O
osteoporosis O
. O

Inhibition O
of O
17 O
beta O
- O
HSD2 O
is O
an O
attractive O
mechanism O
for O
the O
treatment O
of O
osteoporosis O
. O

We O
report O
here O
the O
optimization O
of O
human O
17 O
beta O
- O
HSD2 O
inhibitors O
in O
the O
2 B
, I
5 I
- I
thiophene I
amide I
class O
by O
varying O
the O
size O
of O
the O
linker O
( O
n O
equals O
0 O
and O
2 O
) O
between O
the O
amide B
moiety O
and O
the O
phenyl B
group O
. O

While O
none O
of O
the O
phenethylamides B
( O
n O
= O
2 O
) O
were O
active O
, O
most O
of O
the O
anilides B
( O
n O
= O
0 O
) O
turned O
out O
to O
moderately O
or O
strongly O
inhibit O
17 O
beta O
- O
HSD2 O
. O

The O
four O
most O
active O
compounds O
showed O
an O
IC O
5 O
0 O
of O
around O
60 O
nM O
and O
a O
very O
good O
selectivity O
toward O
17 O
beta O
- O
HSD1 O
, O
17 O
beta O
- O
HSD4 O
, O
17 O
beta O
- O
HSD5 O
, O
11 O
beta O
- O
HSD1 O
, O
11 O
beta O
- O
HSD2 O
and O
the O
estrogen B
receptors O
alpha O
and O
beta O
. O

The O
investigated O
compounds O
inhibited O
monkey O
17 O
beta O
- O
HSD2 O
moderately O
, O
and O
one O
of O
them O
showed O
good O
inhibitory O
activity O
on O
mouse O
17 O
beta O
- O
HSD2 O
. O

SAR O
studies O
allowed O
a O
first O
characterization O
of O
the O
human O
17 O
beta O
- O
HSD2 O
active O
site O
, O
which O
is O
predicted O
to O
be O
considerably O
larger O
than O
that O
of O
17 O
beta O
- O
HSD1 O
. O

P2Y O
purinergic O
receptors O
: O
new O
targets O
for O
analgesic O
and O
antimigraine O
drugs O
. O

Millions O
of O
individuals O
worldwide O
suffer O
from O
acute O
and O
, O
more O
severely O
, O
chronic O
pain O
conditions O
( O
e O
. O
g O
. O
, O
neuropathic O
pain O
, O
and O
migraine O
) O
. O

The O
latter O
bear O
tremendous O
personal O
, O
familial O
, O
and O
social O
costs O
, O
since O
sufferers O
and O
their O
relatives O
undergo O
a O
complete O
turnaround O
of O
their O
lives O
with O
the O
search O
of O
relief O
from O
pain O
becoming O
their O
pivotal O
thought O
. O

Sadly O
, O
to O
date O
no O
effective O
pharmacological O
approaches O
are O
available O
which O
can O
alleviate O
chronic O
pain O
significantly O
or O
in O
the O
long O
run O
in O
all O
patients O
. O

The O
current O
central O
strategy O
for O
the O
development O
of O
new O
and O
effective O
painkillers O
lies O
in O
the O
hypothesis O
that O
cellular O
and O
/ O
or O
molecular O
players O
in O
nociception O
must O
exists O
that O
are O
not O
targeted O
by O
" O
classical O
" O
analgesics O
, O
and O
therefore O
researchers O
have O
put O
tremendous O
efforts O
into O
the O
in O
- O
depth O
analysis O
of O
the O
pathways O
leading O
to O
pain O
development O
and O
maintenance O
over O
time O
. O

In O
this O
complex O
scenario O
, O
two O
outsiders O
are O
now O
taking O
the O
center O
stage O
: O
glial O
cells O
in O
sensory O
ganglia O
and O
in O
the O
central O
nervous O
system O
, O
thanks O
to O
their O
ability O
to O
communicate O
with O
neurons O
and O
to O
modulate O
their O
firing O
, O
and O
the O
purinergic O
system O
. O

Extracellular O
purine B
and O
pyrimidine B
nucleotides B
are O
involved O
in O
the O
physiology O
of O
virtually O
every O
body O
district O
, O
and O
their O
extracellular O
concentrations O
massively O
increase O
under O
pathological O
situations O
, O
suggesting O
that O
they O
might O
represent O
potential O
targets O
for O
the O
modulation O
of O
disease O
- O
associated O
symptoms O
, O
like O
pain O
. O

Here O
, O
we O
provide O
an O
overview O
of O
the O
present O
knowledge O
of O
the O
role O
of O
nucleotides B
in O
nociception O
, O
with O
a O
particular O
emphasis O
on O
G O
protein O
- O
coupled O
P2Y O
receptors O
and O
their O
involvement O
in O
the O
communication O
between O
first O
- O
and O
second O
- O
order O
neurons O
in O
sensory O
nerve O
pathways O
and O
surrounding O
glial O
cells O
. O

Answers O
to O
critics O
: O
Why O
there O
is O
a O
long O
term O
toxicity O
due O
to O
a O
Roundup B
- O
tolerant O
genetically O
modified O
maize O
and O
to O
a O
Roundup B
herbicide O
. O

Our O
recent O
work O
( O
S O
e O
ralini O
et O
al O
. O
, O
2012 O
) O
remains O
to O
date O
the O
most O
detailed O
study O
involving O
the O
life O
- O
long O
consumption O
of O
an O
agricultural O
genetically O
modified O
organism O
( O
GMO O
) O
. O

This O
is O
true O
especially O
for O
NK603 O
maize O
for O
which O
only O
a O
90 O
- O
day O
test O
for O
commercial O
release O
was O
previously O
conducted O
using O
the O
same O
rat O
strain O
( O
Hammond O
et O
al O
. O
, O
2004 O
) O
. O

It O
is O
also O
the O
first O
long O
term O
detailed O
research O
on O
mammals O
exposed O
to O
a O
highly O
diluted O
pesticide O
in O
its O
total O
formulation O
with O
adjuvants O
. O

This O
may O
explain O
why O
75 O
% O
of O
our O
first O
criticisms O
arising O
within O
a O
week O
, O
among O
publishing O
authors O
, O
come O
from O
plant O
biologists O
, O
some O
developing O
patents O
on O
GMOs O
, O
even O
if O
it O
was O
a O
toxicological O
paper O
on O
mammals O
, O
and O
from O
Monsanto O
Company O
who O
owns O
both O
the O
NK603 O
GM O
maize O
and O
Roundup B
herbicide O
( O
R O
) O
. O

Our O
study O
has O
limits O
like O
any O
one O
, O
and O
here O
we O
carefully O
answer O
to O
all O
criticisms O
from O
agencies O
, O
consultants O
and O
scientists O
, O
that O
were O
sent O
to O
the O
Editor O
or O
to O
ourselves O
. O

At O
this O
level O
, O
a O
full O
debate O
is O
biased O
if O
the O
toxicity O
tests O
on O
mammals O
of O
NK603 O
and O
R O
obtained O
by O
Monsanto O
Company O
remain O
confidential O
and O
thus O
unavailable O
in O
an O
electronic O
format O
for O
the O
whole O
scientific O
community O
to O
conduct O
independent O
scrutiny O
of O
the O
raw O
data O
. O

In O
our O
article O
, O
the O
conclusions O
of O
long O
- O
term O
NK603 B
and O
Roundup B
toxicities O
came O
from O
the O
statistically O
highly O
discriminant O
findings O
at O
the O
biochemical O
level O
in O
treated O
groups O
in O
comparison O
to O
controls O
, O
because O
these O
findings O
do O
correspond O
in O
an O
blinded O
analysis O
to O
the O
pathologies O
observed O
in O
organs O
, O
that O
were O
in O
turn O
linked O
to O
the O
deaths O
by O
anatomopathologists O
. O

GM O
NK603 O
and O
R O
cannot O
be O
regarded O
as O
safe O
to O
date O
. O

Decreased O
levels O
of O
AKR1B1 O
and O
AKR1B10 O
in O
cancerous O
endometrium O
compared O
to O
adjacent O
non O
- O
cancerous O
tissue O
. O

Endometrial O
cancer O
is O
associated O
with O
enhanced O
cell O
proliferation O
due O
to O
high O
concentrations O
of O
estrogens B
, O
and O
decreased O
cell O
differentiation O
due O
to O
low O
levels O
of O
progesterone B
and O
retinoic B
acid I
. O

It O
is O
also O
associated O
with O
aberrant O
inflammatory O
responses O
and O
concomitant O
increased O
production O
of O
prostaglandins B
. O

The O
human O
members O
of O
the O
aldo O
- O
keto O
reductase O
1B O
( O
AKR1B O
) O
subfamily O
, O
AKR1B1 O
and O
AKR1B10 O
, O
have O
roles O
in O
these O
processes O
and O
can O
thus O
be O
implicated O
in O
endometrial O
cancer O
. O

To O
date O
, O
there O
have O
been O
no O
reports O
on O
the O
expression O
of O
AKR1B1 O
in O
endometrial O
cancer O
, O
while O
AKR1B10 O
has O
only O
been O
studied O
at O
the O
cellular O
level O
. O

To O
evaluate O
the O
roles O
of O
these O
AKR1B O
enzymes O
, O
we O
investigated O
expression O
of O
AKR1B1 O
and O
AKR1B10 O
in O
47 O
paired O
samples O
of O
cancerous O
and O
adjacent O
control O
endometrium O
at O
the O
mRNA O
and O
protein O
levels O
, O
by O
quantitative O
PCR O
, O
Western O
blotting O
and O
immunohistochemistry O
staining O
. O

There O
were O
significantly O
lower O
mRNA O
and O
protein O
levels O
of O
AKR1B1 O
in O
cancerous O
tissues O
compared O
to O
adjacent O
endometrium O
. O

The O
gene O
expression O
of O
AKR1B10 O
at O
the O
mRNA O
level O
was O
significantly O
increased O
, O
while O
there O
were O
significantly O
decreased O
protein O
levels O
. O

Immunohistochemistry O
revealed O
that O
both O
of O
these O
enzymes O
were O
present O
in O
all O
of O
the O
samples O
, O
and O
are O
located O
in O
epithelial O
cells O
of O
cancerous O
and O
control O
endometrial O
glands O
. O

Elevated O
levels O
in O
adjacent O
non O
- O
cancerous O
tissues O
imply O
that O
these O
enzymes O
are O
more O
important O
in O
the O
initiation O
of O
endometrial O
cancer O
than O
in O
its O
progression O
. O

To O
the O
best O
of O
our O
knowledge O
, O
this O
is O
the O
first O
report O
on O
the O
expression O
of O
AKR1B1 O
and O
AKR1B10 O
in O
endometrial O
cancer O
. O

Further O
studies O
are O
needed O
to O
define O
the O
precise O
roles O
of O
these O
enzymes O
in O
the O
pathogenesis O
of O
endometrial O
cancer O
. O

Effects O
of O
arsenite B
in O
astrocytes O
on O
neuronal O
signaling O
transduction O
. O

The O
main O
purpose O
of O
this O
study O
was O
to O
test O
the O
hypothesis O
that O
arsenite B
induces O
neurotoxicity O
via O
effects O
on O
astrocytes O
. O

Astrocytes O
were O
exposed O
to O
0 O
, O
5 O
or O
10 O
mu O
M O
arsenite B
in O
medium O
for O
24 O
h O
, O
and O
then O
astrocyte O
- O
conditioned O
medium O
( O
ACM O
) O
was O
collected O
after O
incubation O
with O
fresh O
medium O
for O
6 O
h O
. O

Primary O
neuron O
cultures O
were O
divided O
into O
four O
groups O
due O
to O
ACM B
, O
which O
were O
neurons O
without O
ACM B
exposure O
( O
group O
I O
) O
and O
neurons O
exposed O
to O
ACM B
from O
0 O
, O
5 O
or O
10 O
mu O
M O
arsenite B
treated O
astrocytes O
( O
group O
II O
- O
IV O
) O
. O

Protein O
expression O
of O
N B
- I
methyl I
- I
d I
- I
aspartate I
receptors O
( O
NR1 O
, O
NR2A O
, O
NR2B O
) O
, O
calmodulin O
- O
dependent O
protein O
kinase O
II O
( O
CaMKII O
) O
and O
adenylate O
cyclase O
( O
AC O
) O
in O
neurons O
were O
measured O
after O
incubation O
with O
ACM O
for O
4 O
, O
8 O
or O
12 O
h O
. O

Morphological O
changes O
and O
synaptic O
formation O
were O
observed O
after O
a O
72 O
h O
- O
incubation O
with O
ACM B
. O

Compared O
to O
group O
II O
, O
synaptic O
formation O
and O
protein O
expression O
of O
NR2A O
, O
NR2B O
, O
CaMKII O
and O
AC O
in O
group O
III O
and O
IV O
were O
significantly O
suppressed O
. O

Moreover O
, O
synaptic O
formation O
and O
protein O
expression O
of O
CaMKII O
and O
AC O
in O
group O
II O
were O
significantly O
enhanced O
when O
compared O
with O
group O
I O
. O

Taken O
together O
, O
findings O
from O
this O
study O
suggested O
that O
arsenic B
in O
astrocytes O
might O
impair O
synaptic O
formation O
through O
disturbing O
astrocytic O
effects O
on O
neuronal O
signal O
transduction O
. O

Toxicity O
of O
the O
synthetic O
polymeric B
3 I
- I
alkylpyridinium I
salt I
( O
APS3 B
) O
is O
due O
to O
specific O
block O
of O
nicotinic O
acetylcholine B
receptors O
. O

The O
in O
vivo O
and O
in O
vitro O
toxic O
effects O
of O
the O
synthetic O
polymeric O
3 B
- I
alkylpyridinium I
salt I
( O
APS3 B
) O
, O
from O
the O
Mediterranean O
marine O
sponge O
Reniera O
sarai O
, O
were O
evaluated O
on O
mammals O
, O
with O
emphasis O
to O
determine O
its O
mode O
of O
action O
. O

The O
median O
lethal O
doses O
of O
APS3 O
were O
7 O
. O
25 O
and O
higher O
that O
20mg O
/ O
kg O
in O
mouse O
and O
rat O
, O
respectively O
. O

Intravenous O
administration O
of O
7 O
. O
25 O
and O
20mg O
/ O
kg O
APS3 B
to O
rat O
caused O
a O
significant O
fall O
followed O
by O
an O
increase O
in O
mean O
arterial O
blood O
pressure O
accompanied O
by O
tachycardia O
. O

In O
addition O
, O
cumulative O
doses O
of O
APS3 B
( O
up O
to O
60 O
mg O
/ O
kg O
) O
inhibited O
rat O
nerve O
- O
evoked O
skeletal O
muscle O
contraction O
in O
vivo O
, O
with O
a O
median O
inhibitory O
dose O
( O
ID O
( O
50 O
) O
) O
of O
37 O
. O
25mg O
/ O
kg O
. O

When O
administrated O
locally O
by O
intramuscular O
injection O
to O
mouse O
, O
APS3 B
decreased O
the O
compound O
muscle O
action O
potential O
recorded O
in O
response O
to O
in O
vivo O
nerve O
stimulation O
, O
with O
an O
ID O
( O
50 O
) O
of O
0 O
. O
5mg O
/ O
kg O
. O

In O
vitro O
experiments O
confirmed O
the O
inhibitory O
effect O
of O
APS3 B
on O
mouse O
hemidiaphragm O
nerve O
- O
evoked O
muscle O
contraction O
with O
a O
median O
inhibitory O
concentration O
( O
IC O
( O
50 O
) O
) O
of O
20 O
. O
3 O
mu O
M O
, O
without O
affecting O
directly O
elicited O
muscle O
contraction O
. O

The O
compound O
inhibited O
also O
miniature O
endplate O
potentials O
and O
nerve O
- O
evoked O
endplate O
potentials O
with O
an O
IC O
( O
50 O
) O
of O
7 O
. O
28 O
mu O
M O
in O
mouse O
hemidiaphragm O
. O

Finally O
, O
APS3 B
efficiently O
blocked O
acetylcholine B
- O
activated O
membrane O
inward O
currents O
flowing O
through O
Torpedo O
nicotinic O
acetylcholine B
receptors O
( O
nAChRs O
) O
incorporated O
to O
Xenopus O
oocytes O
, O
with O
an O
IC O
( O
50 O
) O
of O
0 O
. O
19 O
mu O
M O
. O

In O
conclusion O
, O
our O
results O
strongly O
suggest O
that O
APS3 B
blocks O
muscle O
- O
type O
nAChRs O
, O
and O
show O
for O
the O
first O
time O
that O
in O
vivo O
toxicity O
of O
APS3 B
is O
likely O
to O
occur O
through O
an O
antagonist O
action O
of O
the O
compound O
on O
these O
receptors O
. O

Characteristic O
molecular O
signature O
for O
the O
early O
detection O
and O
prediction O
of O
polycyclic B
aromatic I
hydrocarbons I
in O
rat O
liver O
. O

Predictions O
of O
toxicity O
are O
central O
for O
the O
assessment O
of O
chemical O
toxicity O
, O
and O
the O
effects O
of O
environmental O
toxic O
compounds O
are O
still O
a O
major O
issue O
for O
predicting O
potential O
human O
health O
risks O
. O

Among O
the O
various O
environmental O
toxicants O
, O
polycyclic B
aromatic I
hydrocarbons I
( O
PAHs B
) O
are O
an O
important O
class O
of O
environmental O
pollutant O
, O
and O
many O
PAHs B
are O
known O
or O
suspected O
carcinogens O
. O

In O
the O
present O
study O
, O
to O
investigate O
whether O
characteristic O
expression O
profiles O
of O
PAHs B
exist O
in O
rat O
liver O
and O
whether O
a O
characteristic O
molecular O
signature O
can O
discriminate O
and O
predict O
among O
different O
PAHs B
at O
an O
early O
exposure O
time O
, O
we O
analyzed O
the O
genome O
- O
wide O
expression O
profiles O
of O
rat O
livers O
exposed O
to O
PAHs B
[ O
benzo B
[ I
a I
] I
anthracene I
( O
BA O
) O
, O
benzo B
[ I
a I
] I
pyrene I
( O
BP O
) O
, O
phenanthrene B
( O
PA O
) O
and O
naphthalene B
( O
NT O
) O
] O
. O

At O
early O
time O
- O
point O
PAH B
exposure O
, O
large O
- O
scale O
gene O
expression O
analysis O
resulted O
in O
characteristic O
molecular O
signatures O
for O
each O
PAH B
, O
and O
supervised O
analysis O
identified O
1183 O
outlier O
genes O
as O
a O
distinct O
molecular O
signature O
discerning O
PAHs B
from O
the O
normal O
control O
group O
. O

We O
identified O
158 O
outlier O
genes O
as O
early O
predictive O
and O
surrogate O
markers O
for O
predicting O
each O
tested O
PAH O
by O
combination O
of O
two O
different O
multi O
- O
classification O
algorithms O
with O
100 O
% O
accuracy O
through O
a O
leave O
- O
one O
out O
cross O
- O
validation O
method O
. O

In O
conclusion O
, O
the O
characteristic O
gene O
expression O
signatures O
from O
a O
rat O
model O
system O
could O
be O
used O
as O
predictable O
and O
discernible O
gene O
- O
based O
biomarkers O
for O
the O
detection O
and O
prediction O
of O
PAHs B
, O
and O
these O
molecular O
markers O
may O
provide O
insights O
into O
the O
underlying O
mechanisms O
for O
genotoxicity O
of O
exposure O
to O
PAHs B
from O
environmental O
aspect O
. O

Combined O
and O
interactive O
effects O
of O
global O
climate O
change O
and O
toxicants O
on O
populations O
and O
communities O
. O

Increased O
temperature O
and O
other O
environmental O
effects O
of O
global O
climate O
change O
( O
GCC O
) O
have O
documented O
impacts O
on O
many O
species O
( O
e O
. O
g O
. O
, O
polar O
bears O
, O
amphibians O
, O
coral O
reefs O
) O
as O
well O
as O
on O
ecosystem O
processes O
and O
species O
interactions O
( O
e O
. O
g O
. O
, O
the O
timing O
of O
predator O
- O
prey O
interactions O
) O
. O

A O
challenge O
for O
ecotoxicologists O
is O
to O
predict O
how O
joint O
effects O
of O
climatic O
stress O
and O
toxicants O
measured O
at O
the O
individual O
level O
( O
e O
. O
g O
. O
, O
reduced O
survival O
and O
reproduction O
) O
will O
be O
manifested O
at O
the O
population O
level O
( O
e O
. O
g O
. O
, O
population O
growth O
rate O
, O
extinction O
risk O
) O
and O
community O
level O
( O
e O
. O
g O
. O
, O
species O
richness O
, O
food O
- O
web O
structure O
) O
. O

The O
authors O
discuss O
how O
population O
- O
and O
community O
- O
level O
responses O
to O
toxicants O
under O
GCC O
are O
likely O
to O
be O
influenced O
by O
various O
ecological O
mechanisms O
. O

Stress O
due O
to O
GCC O
may O
reduce O
the O
potential O
for O
resistance O
to O
and O
recovery O
from O
toxicant O
exposure O
. O

Long O
- O
term O
toxicant O
exposure O
can O
result O
in O
acquired O
tolerance O
to O
this O
stressor O
at O
the O
population O
or O
community O
level O
, O
but O
an O
associated O
cost O
of O
tolerance O
may O
be O
the O
reduced O
potential O
for O
tolerance O
to O
subsequent O
climatic O
stress O
( O
or O
vice O
versa O
) O
. O

Moreover O
, O
GCC O
can O
induce O
large O
- O
scale O
shifts O
in O
community O
composition O
, O
which O
may O
affect O
the O
vulnerability O
of O
communities O
to O
other O
stressors O
. O

Ecological O
modeling O
based O
on O
species O
traits O
( O
representing O
life O
- O
history O
traits O
, O
population O
vulnerability O
, O
sensitivity O
to O
toxicants O
, O
and O
sensitivity O
to O
climate O
change O
) O
can O
be O
a O
promising O
approach O
for O
predicting O
combined O
impacts O
of O
GCC O
and O
toxicants O
on O
populations O
and O
communities O
. O

Linking O
GABA B
( O
A O
) O
receptor O
subunits O
to O
alcohol B
- O
induced O
conditioned O
taste O
aversion O
and O
recovery O
from O
acute O
alcohol B
intoxication O
. O

GABA B
type O
A O
receptors O
( O
GABA B
( O
A O
) O
- O
R O
) O
are O
important O
for O
ethanol B
actions O
and O
it O
is O
of O
interest O
to O
link O
individual O
subunits O
with O
specific O
ethanol B
behaviors O
. O

We O
studied O
null O
mutant O
mice O
for O
six O
different O
GABA B
( O
A O
) O
- O
R O
subunits O
( O
alpha O
1 O
, O
alpha O
2 O
, O
alpha O
3 O
, O
alpha O
4 O
, O
alpha O
5 O
and O
delta O
) O
. O

Only O
mice O
lacking O
the O
alpha O
2 O
subunit O
showed O
reduction O
of O
conditioned O
taste O
aversion O
( O
CTA O
) O
to O
ethanol B
. O

These O
results O
are O
in O
agreement O
with O
data O
from O
knock O
- O
in O
mice O
with O
mutation O
of O
the O
ethanol B
- O
sensitive O
site O
in O
the O
alpha O
2 O
- O
subunit O
( O
Blednov O
et O
al O
. O
, O
2011 O
) O
. O

All O
together O
, O
they O
indicate O
that O
aversive O
property O
of O
ethanol B
is O
dependent O
on O
ethanol B
action O
on O
alpha O
2 O
- O
containing O
GABA B
( O
A O
) O
- O
R O
. O

Deletion O
of O
the O
alpha O
2 O
- O
subunit O
led O
to O
faster O
recovery O
whereas O
absence O
of O
the O
alpha O
3 O
- O
subunit O
slowed O
recovery O
from O
ethanol B
- O
induced O
incoordination O
( O
rotarod O
) O
. O

Deletion O
of O
the O
other O
four O
subunits O
did O
not O
affect O
this O
behavior O
. O

Similar O
changes O
in O
this O
behavior O
for O
the O
alpha O
2 O
and O
alpha O
3 O
null O
mutants O
were O
found O
for O
flurazepam B
motor O
incoordination O
. O

However O
, O
no O
differences O
in O
recovery O
were O
found O
in O
motor O
- O
incoordinating O
effects O
of O
an O
alpha O
1 O
- O
selective O
modulator O
( O
zolpidem B
) O
or O
an O
alpha O
4 O
- O
selective O
agonist O
( O
gaboxadol B
) O
. O

Therefore O
, O
recovery O
of O
rotarod O
incoordination O
is O
under O
control O
of O
two O
GABA B
( O
A O
) O
- O
R O
subunits O
: O
alpha O
2 O
and O
alpha O
3 O
. O

For O
motor O
activity O
, O
alpha O
3 O
null O
mice O
demonstrated O
higher O
activation O
by O
ethanol B
( O
1 O
g O
/ O
kg O
) O
whereas O
both O
alpha O
2 O
( O
- O
/ O
- O
) O
and O
alpha O
3 O
( O
- O
/ O
Y O
) O
knockout O
mice O
were O
less O
sensitive O
to O
ethanol B
- O
induced O
reduction O
of O
motor O
activity O
( O
1 O
. O
5 O
g O
/ O
kg O
) O
. O

These O
studies O
demonstrate O
that O
the O
effects O
of O
ethanol B
at O
GABAergic O
synapses O
containing O
alpha O
2 O
subunit O
are O
important O
for O
specific O
behavioral O
effects O
of O
ethanol B
which O
may O
be O
relevant O
to O
the O
genetic O
linkage O
of O
the O
alpha O
2 O
subunit O
with O
human O
alcoholism O
. O

Orexin O
A O
regulates O
cardiovascular O
responses O
in O
stress O
- O
induced O
hypertensive O
rats O
. O

Several O
pieces O
of O
evidence O
indicate O
that O
the O
rostral O
ventrolateral O
medulla O
( O
RVLM O
) O
is O
probably O
one O
of O
the O
key O
neural O
structures O
mediating O
the O
pressor O
effects O
of O
orexins O
in O
the O
brain O
. O

Nitric B
oxide I
synthase O
/ O
nitric B
oxide I
( O
NOS O
/ O
NO B
) O
system O
in O
the O
RVLM O
modulates O
cardiovascular O
activities O
. O

Our O
experiments O
were O
designed O
to O
test O
the O
hypothesis O
that O
orexin O
- O
A O
( O
OXA O
) O
is O
involved O
in O
the O
mechanism O
of O
stress O
- O
induced O
hypertension O
( O
SIH O
) O
by O
adjusting O
NOS O
/ O
NO B
system O
in O
the O
RVLM O
. O

The O
stress O
- O
induced O
hypertensive O
rats O
( O
SIHR O
) O
model O
was O
established O
by O
electric O
foot O
- O
shocks O
and O
noises O
. O

Here O
we O
examined O
the O
expression O
of O
OXA B
immunoreactive O
( O
OXA B
- O
IR O
) O
cells O
in O
the O
lateral O
hypothalamus O
( O
LH O
) O
and O
the O
protein O
level O
of O
orexin O
1 O
receptor O
( O
OX1R O
) O
in O
the O
RVLM O
of O
SIHR O
, O
and O
we O
found O
that O
the O
expressions O
of O
OXA B
- O
IR O
and O
OX1R O
were O
higher O
than O
those O
of O
the O
control O
group O
. O

The O
double O
- O
staining O
immunohistochemical O
evidence O
showed O
that O
OX1R O
immunoreactive O
( O
OX1R O
- O
IR O
) O
cells O
and O
neuronal O
nitric B
oxide I
synthase O
( O
nNOS O
) O
or O
inducible O
nitric B
oxide I
synthase O
( O
iNOS O
) O
immunoreactive O
( O
IR O
) O
cells O
were O
co O
- O
localizated O
in O
the O
RVLM O
. O

Microinjection O
of O
OXA B
( O
10 O
, O
50 O
, O
100 O
pmol O
/ O
100 O
nl O
) O
into O
the O
unilateral O
( O
right O
) O
RVLM O
of O
control O
rats O
or O
SIHR O
produced O
pressor O
and O
tachycardiac O
effects O
in O
a O
dose O
- O
dependent O
manner O
. O

SB B
- I
408124 I
( O
100 O
pmol O
/ O
100 O
nl O
, O
an O
antagonist O
of O
OX1R O
) O
or O
TCS B
OX2 I
29 O
( O
100 O
pmol O
/ O
100 O
nl O
, O
an O
antagonist O
of O
OX2R O
) O
partly O
abolished O
the O
cardiovascular O
effects O
of O
exogenously O
- O
administrated O
OXA B
into O
the O
RVLM O
of O
control O
rats O
and O
SIHR O
, O
and O
lowered O
the O
increased O
systolic O
blood O
pressure O
( O
SBP O
) O
and O
heart O
rate O
( O
HR O
) O
of O
SIHR O
, O
with O
no O
difference O
in O
statistical O
significance O
between O
the O
two O
antagonists O
' O
effects O
. O

Microinjection O
into O
the O
RVLM O
of O
both O
control O
and O
SIHR O
groups O
of O
7 B
- I
Ni I
( O
0 O
. O
05 O
pmol O
/ O
100 O
nl O
, O
nNOS O
inhibitor O
) O
or O
Methylene B
Blue I
[ O
100 O
pmol O
/ O
100 O
nl O
, O
an O
inhibitor O
of O
soluble O
guanylate B
cyclase O
( O
sGC O
) O
] O
suppressed O
the O
OXA B
- O
induced O
increase O
of O
SBP O
and O
HR O
, O
whereas O
microinjection O
of O
AG O
( O
1 O
, O
10 O
, O
100 O
pmol O
/ O
100 O
nl O
) O
had O
no O
obvious O
effects O
on O
the O
OXA B
- O
induced O
increase O
of O
SBP O
and O
HR O
. O

Our O
results O
indicate O
that O
OXA B
in O
the O
RVLM O
may O
participate O
in O
the O
central O
regulation O
of O
cardiovascular O
activities O
in O
SIHR O
, O
and O
OX1R O
and O
OX2R O
both O
have O
important O
roles O
in O
it O
. O

The O
cardiovascular O
effects O
of O
OXA B
in O
the O
RVLM O
may O
be O
induced O
by O
nNOS O
- O
derived O
NO B
, O
which O
activated O
sGC O
- O
associated O
signaling O
pathway O
. O

Implications O
of O
global O
climate O
change O
for O
the O
assessment O
and O
management O
of O
human O
health O
risks O
of O
chemicals O
in O
the O
natural O
environment O
. O

Global O
climate O
change O
( O
GCC O
) O
is O
likely O
to O
alter O
the O
degree O
of O
human O
exposure O
to O
pollutants O
and O
the O
response O
of O
human O
populations O
to O
these O
exposures O
, O
meaning O
that O
risks O
of O
pollutants O
could O
change O
in O
the O
future O
. O

The O
present O
study O
, O
therefore O
, O
explores O
how O
GCC O
might O
affect O
the O
different O
steps O
in O
the O
pathway O
from O
a O
chemical O
source O
in O
the O
environment O
through O
to O
impacts O
on O
human O
health O
and O
evaluates O
the O
implications O
for O
existing O
risk O
- O
assessment O
and O
management O
practices O
. O

In O
certain O
parts O
of O
the O
world O
, O
GCC O
is O
predicted O
to O
increase O
the O
level O
of O
exposure O
of O
many O
environmental O
pollutants O
due O
to O
direct O
and O
indirect O
effects O
on O
the O
use O
patterns O
and O
transport O
and O
fate O
of O
chemicals O
. O

Changes O
in O
human O
behavior O
will O
also O
affect O
how O
humans O
come O
into O
contact O
with O
contaminated O
air O
, O
water O
, O
and O
food O
. O

Dietary O
changes O
, O
psychosocial O
stress O
, O
and O
coexposure O
to O
stressors O
such O
as O
high O
temperatures O
are O
likely O
to O
increase O
the O
vulnerability O
of O
humans O
to O
chemicals O
. O

These O
changes O
are O
likely O
to O
have O
significant O
implications O
for O
current O
practices O
for O
chemical O
assessment O
. O

Assumptions O
used O
in O
current O
exposure O
- O
assessment O
models O
may O
no O
longer O
apply O
, O
and O
existing O
monitoring O
methods O
may O
not O
be O
robust O
enough O
to O
detect O
adverse O
episodic O
changes O
in O
exposures O
. O

Organizations O
responsible O
for O
the O
assessment O
and O
management O
of O
health O
risks O
of O
chemicals O
therefore O
need O
to O
be O
more O
proactive O
and O
consider O
the O
implications O
of O
GCC O
for O
their O
procedures O
and O
processes O
. O

Biological O
network O
inference O
for O
drug O
discovery O
. O

A O
better O
understanding O
of O
the O
pathophysiology O
should O
help O
deliver O
drugs O
whose O
targets O
are O
involved O
in O
the O
causative O
processes O
underlying O
a O
disease O
. O

Biological O
network O
inference O
uses O
computational O
methods O
for O
deducing O
from O
high O
- O
throughput O
experimental O
data O
, O
the O
topology O
and O
the O
causal O
structure O
of O
the O
interactions O
among O
the O
drugs O
and O
their O
targets O
. O

Therefore O
, O
biological O
network O
inference O
can O
support O
and O
contribute O
to O
the O
experimental O
identification O
of O
both O
gene O
and O
protein O
networks O
causing O
a O
disease O
as O
well O
as O
the O
biochemical O
networks O
of O
drugs O
metabolism O
and O
mechanisms O
of O
action O
. O

The O
resulting O
high O
- O
level O
networks O
serve O
as O
a O
foundational O
basis O
for O
more O
detailed O
mechanistic O
models O
and O
are O
increasingly O
used O
in O
drug O
discovery O
by O
pharmaceutical O
and O
biotechnology O
companies O
. O

We O
review O
and O
compare O
recent O
computational O
technologies O
for O
network O
inference O
applied O
to O
drug O
discovery O
. O

Spontaneous O
electric O
fields O
in O
films O
of O
CF3Cl B
, O
CF2Cl2 B
and O
CFCl3 B
. O

Data O
are O
presented O
showing O
the O
spontaneous O
formation O
of O
electric O
fields O
within O
solid O
films O
of O
the O
chlorofluorocarbons B
( O
CFCs B
) O
CF B
( I
3 I
) I
Cl I
, O
CF B
( I
2 I
) I
Cl I
( I
2 I
) I
and O
CFCl B
( I
3 I
) I
as O
a O
function O
of O
film O
deposition O
temperature O
from O
40 O
K O
and O
above O
. O

Electric O
fields O
, O
which O
arise O
through O
dipole O
alignment O
and O
lie O
in O
the O
range O
of O
a O
few O
times O
10 O
( O
7 O
) O
V O
m O
( O
- O
1 O
) O
to O
a O
few O
times O
10 O
( O
6 O
) O
V O
m O
( O
- O
1 O
) O
, O
decrease O
as O
the O
degree O
of O
chlorination O
increases O
. O

Maximum O
deposition O
temperatures O
for O
display O
of O
an O
electric O
field O
lie O
at O
~ O
50 O
K O
, O
~ O
65 O
K O
and O
~ O
52 O
K O
for O
CF B
( I
3 I
) I
Cl I
, O
CF B
( I
2 I
) I
Cl I
( I
2 I
) I
and O
CFCl B
( I
3 I
) I
respectively O
. O

CFCl B
( I
3 I
) I
films O
possess O
electric O
fields O
which O
show O
an O
onset O
of O
temporal O
metastability O
between O
deposition O
temperatures O
of O
46 O
K O
and O
50 O
K O
. O

CF B
( I
3 I
) I
Cl I
and O
CF B
( I
2 I
) I
Cl I
( I
2 I
) I
demonstrate O
temperatures O
of O
~ O
65 O
K O
and O
~ O
80 O
K O
at O
which O
the O
electric O
field O
in O
the O
film O
is O
removed O
by O
heating O
, O
so O
- O
called O
Curie O
points O
, O
with O
decay O
of O
the O
field O
spread O
over O
more O
than O
10 O
K O
. O

CFCl B
( I
3 I
) I
displays O
a O
comparatively O
sharp O
Curie O
point O
at O
55 O
K O
. O

This O
variety O
of O
behaviour O
arises O
despite O
the O
resemblance O
of O
these O
three O
species O
in O
terms O
of O
electronic O
structure O
and O
gas O
phase O
dipole O
moment O
, O
emphasising O
the O
requirement O
for O
detailed O
chemical O
models O
of O
this O
phenomenon O
. O

Toxicity O
of O
diesel O
contaminated O
soils O
to O
the O
subantarctic O
earthworm O
Microscolex O
macquariensis O
. O

Several O
fuel O
spills O
have O
occurred O
on O
subantarctic O
Macquarie O
Island O
( O
54 O
degrees O
30 O
' O
S O
158 O
degrees O
57 O
' O
E O
) O
associated O
with O
storing O
fuel O
and O
generating O
power O
for O
the O
island O
' O
s O
research O
station O
. O

The O
Australian O
Antarctic O
Division O
began O
full O
- O
scale O
, O
on O
- O
site O
remediation O
of O
these O
sites O
in O
2009 O
. O

To O
develop O
appropriate O
target O
concentrations O
for O
remediation O
, O
acute O
and O
chronic O
tests O
were O
developed O
with O
the O
endemic O
earthworm O
, O
Microscolex O
macquariensis O
, O
using O
avoidance O
, O
survival O
, O
and O
reproduction O
as O
endpoints O
. O

Uncontaminated O
low O
( O
3 O
% O
) O
, O
medium O
( O
11 O
% O
) O
, O
and O
high O
( O
38 O
- O
48 O
% O
) O
carbon B
content O
soils O
from O
Macquarie O
Island O
were O
used O
to O
examine O
the O
influence O
of O
soil O
carbon B
on O
toxicity O
. O

Soils O
were O
spiked O
with O
Special O
Antarctic O
Blend O
( O
SAB O
) O
diesel O
and O
used O
either O
immediately O
to O
simulate O
a O
fresh O
spill O
or O
after O
four O
weeks O
to O
simulate O
an O
aged O
spill O
. O

Earthworms O
were O
sensitive O
to O
fresh O
SAB O
, O
with O
significant O
avoidance O
at O
181 O
mg O
/ O
kg O
; O
acute O
14 O
- O
d O
survival O
median O
lethal O
concentration O
( O
LC50 O
) O
of O
103 O
mg O
/ O
kg O
for O
low O
carbon B
soil O
; O
and O
juvenile O
production O
median O
effective O
concentration O
( O
EC50 O
) O
of O
317 O
mg O
/ O
kg O
for O
high O
carbon B
soil O
. O

Earthworms O
were O
less O
sensitive O
to O
aged O
SAB O
than O
to O
fresh O
SAB O
in O
high O
carbon B
soil O
for O
juvenile O
production O
( O
EC50 O
of O
1 O
, O
753 O
and O
317 O
mg O
/ O
kg O
, O
respectively O
) O
, O
but O
were O
more O
sensitive O
for O
adult O
survival O
( O
LC50 O
of O
2 O
, O
322 O
and O
1 O
, O
364 O
mg O
/ O
kg O
, O
respectively O
) O
. O

Using O
M O
. O
macquariensis O
as O
a O
surrogate O
for O
soil O
quality O
, O
approximately O
50 O
to O
200 O
mg O
SAB O
/ O
kg O
soil O
would O
be O
a O
sufficiently O
protective O
remediation O
target O
. O

Extraction O
of O
sediment O
- O
associated O
polycyclic B
aromatic I
hydrocarbons I
with O
granular O
activated O
carbon B
. O

Addition O
of O
activated O
carbon B
( O
AC O
) O
to O
sediments O
has O
been O
proposed O
as O
a O
method O
to O
reduce O
ecotoxicological O
risks O
of O
sediment O
- O
bound O
contaminants O
. O

The O
present O
study O
explores O
the O
effectiveness O
of O
granular O
AC O
( O
GAC O
) O
in O
extracting O
polycyclic B
aromatic I
hydrocarbon I
( O
PAH B
) O
from O
highly O
contaminated O
sediments O
. O

Four O
candidate O
GAC O
materials O
were O
screened O
in O
terms O
of O
PAH O
extraction O
efficiency O
using O
single O
- O
step O
24 O
- O
h O
GAC O
extractions O
, O
with O
traditional O
24 O
- O
h O
Tenax O
extraction O
as O
a O
reference O
. O

Subsequently O
, O
sorption O
of O
native O
PAHs B
to O
the O
best O
performing O
GAC O
1240W O
( O
0 O
. O
45 O
- O
1 O
. O
70 O
mm O
) O
was O
studied O
for O
sediment O
only O
and O
for O
GAC O
- O
sediment O
mixtures O
at O
different O
GAC O
- O
sediment O
weight O
ratios O
, O
using O
76 O
- O
micro O
m O
polyoxymethylene B
( O
POM B
) O
passive O
samplers O
. O

Granular O
AC O
sorption O
parameters O
for O
PAHs B
were O
determined O
by O
subtracting O
the O
contribution O
of O
PAH B
sorption O
to O
sediment O
from O
PAH B
sorption O
to O
the O
GAC O
- O
sediment O
mixture O
. O

It O
appears O
that O
the O
binding O
of O
PAHs B
and O
the O
effectiveness O
of O
GAC O
to O
reduce O
sediment O
porewater O
concentrations O
were O
highly O
dependent O
on O
the O
GAC O
- O
sediment O
mixing O
ratio O
and O
hydrophobicity O
of O
the O
PAH B
. O

Despite O
the O
considerable O
fouling O
of O
GAC O
by O
organic O
matter O
and O
oil O
, O
50 O
to O
90 O
% O
of O
the O
most O
available O
PAH B
was O
extracted O
by O
the O
GAC O
during O
a O
28 O
- O
d O
contact O
time O
, O
at O
a O
dose O
as O
low O
as O
4 O
% O
, O
which O
also O
is O
a O
feasible O
dose O
in O
field O
- O
scale O
applications O
aimed O
at O
cleaning O
the O
sediment O
by O
GAC O
addition O
and O
removal O
. O

Runt O
- O
related O
transcription O
factor O
1 O
( O
RUNX1 O
) O
stimulates O
tumor O
suppressor O
p53 O
protein O
in O
response O
to O
DNA O
damage O
through O
complex O
formation O
and O
acetylation O
. O

Representative O
tumor O
suppressor O
p53 O
plays O
a O
critical O
role O
in O
the O
regulation O
of O
proper O
DNA O
damage O
response O
. O

In O
this O
study O
, O
we O
have O
found O
for O
the O
first O
time O
that O
Runt O
- O
related O
transcription O
factor O
1 O
( O
RUNX1 O
) O
contributes O
to O
p53 O
- O
dependent O
DNA O
damage O
response O
. O

Upon O
adriamycin B
( O
ADR B
) O
exposure O
, O
p53 O
as O
well O
as O
RUNX1 O
were O
strongly O
induced O
in O
p53 O
- O
proficient O
HCT116 O
and O
U2OS O
cells O
, O
which O
were O
closely O
associated O
with O
significant O
transactivation O
of O
p53 O
target O
genes O
, O
such O
as O
p21 O
( O
WAF O
) O
( O
1 O
) O
, O
BAX O
, O
NOXA O
, O
and O
PUMA O
. O

RUNX1 O
was O
exclusively O
expressed O
in O
the O
cell O
nucleus O
and O
formed O
a O
complex O
with O
p53 O
in O
response O
to O
ADR B
. O

Chromatin O
immunoprecipitation O
assay O
demonstrated O
that O
p53 O
together O
with O
RUNX1 O
are O
efficiently O
recruited O
onto O
p53 O
target O
gene O
promoters O
following O
ADR B
exposure O
, O
indicating O
that O
RUNX1 O
is O
involved O
in O
p53 O
- O
mediated O
transcriptional O
regulation O
. O

Indeed O
, O
forced O
expression O
of O
RUNX1 O
stimulated O
the O
transcriptional O
activity O
of O
p53 O
in O
response O
to O
ADR B
. O

Consistent O
with O
these O
observations O
, O
knockdown O
of O
RUNX1 O
attenuated O
ADR B
- O
mediated O
induction O
of O
p53 O
target O
genes O
and O
suppressed O
ADR B
- O
dependent O
apoptosis O
. O

Furthermore O
, O
RUNX1 O
was O
associated O
with O
p300 O
histone O
acetyltransferase O
, O
and O
ADR O
- O
dependent O
acetylation O
of O
p53 O
at O
Lys B
- O
373 O
/ O
382 O
was O
markedly O
inhibited O
in O
RUNX1 O
knockdown O
cells O
. O

In O
addition O
, O
knockdown O
of O
RUNX1 O
resulted O
in O
a O
significant O
decrease O
in O
the O
amount O
of O
p53 O
- O
p300 O
complex O
following O
ADR B
exposure O
. O

Taken O
together O
, O
our O
present O
results O
strongly O
suggest O
that O
RUNX1 O
is O
required O
for O
the O
stimulation O
of O
p53 O
in O
response O
to O
DNA O
damage O
and O
also O
provide O
novel O
insight O
into O
understanding O
the O
molecular O
mechanisms O
behind O
p53 O
- O
dependent O
DNA O
damage O
response O
. O

Control O
of O
stem O
cells O
and O
cancer O
stem O
cells O
by O
Hedgehog O
signaling O
: O
pharmacologic O
clues O
from O
pathway O
dissection O
. O

Hedgehog O
is O
a O
key O
morphogen O
regulating O
embryonic O
development O
and O
tissue O
repair O
. O

Remarkably O
, O
when O
misregulated O
, O
it O
leads O
to O
tumorigenesis O
. O

Hedgehog O
signaling O
is O
triggered O
by O
binding O
of O
ligands O
with O
transmembrane O
receptor O
Ptch O
and O
is O
subsequently O
mediated O
by O
transcriptional O
effectors O
belonging O
to O
the O
Gli O
family O
, O
whose O
functions O
is O
tuned O
by O
a O
number O
of O
molecular O
interactions O
and O
post O
- O
synthetic O
modifications O
. O

The O
complex O
of O
these O
regulatory O
circuitries O
provides O
a O
tight O
control O
of O
developmental O
processes O
, O
mainly O
involving O
the O
modulation O
of O
genes O
determining O
the O
fate O
of O
stem O
cells O
. O

Similarly O
, O
Hedgehog O
regulates O
cancer O
stem O
cells O
fostering O
tumorigenesis O
. O

To O
this O
regard O
, O
these O
processes O
represent O
promising O
targets O
for O
novel O
therapeutic O
strategies O
aiming O
at O
the O
control O
of O
stemness O
reactivation O
and O
maintenance O
in O
cancer O
. O

Hydrogen B
sulfide I
increases O
nitric B
oxide I
production O
with O
calcium B
- O
dependent O
activation O
of O
endothelial O
nitric B
oxide I
synthase O
in O
endothelial O
cells O
. O

Hydrogen B
sulfide I
( O
H B
( I
2 I
) I
S I
) O
was O
recently O
discovered O
to O
be O
synthesized O
in O
mammalian O
tissues O
by O
several O
different O
enzymes O
. O

Numerous O
studies O
have O
shown O
that O
H B
( I
2 I
) I
S I
has O
vasodilator O
and O
antihypertensive O
effects O
in O
the O
cardiovascular O
system O
. O

However O
, O
intracellular O
mechanisms O
of O
the O
H B
( I
2 I
) I
S I
- O
induced O
vasodilation O
and O
its O
interactions O
with O
other O
endothelium O
- O
derived O
relaxing O
factors O
, O
such O
as O
nitric B
oxide I
( O
NO B
) O
, O
remain O
unclear O
. O

We O
investigated O
whether O
H B
( I
2 I
) I
S I
directly O
regulates O
endothelial O
NO B
synthase O
( O
eNOS O
) O
activity O
and O
NO B
production O
in O
endothelial O
cells O
. O

NaHS B
, O
a O
H B
( I
2 I
) I
S I
donor O
, O
dose O
- O
dependently O
increased O
NO B
production O
in O
cultured O
endothelial O
cells O
. O

This O
effect O
was O
abolished O
by O
a O
calcium B
chelator O
( O
BAPTA B
- I
AM I
) O
, O
but O
not O
by O
the O
absence O
of O
extracellular O
calcium B
. O

The O
NaHS B
- O
induced O
NO B
production O
was O
partially O
blocked O
by O
inhibitors O
of O
ryanodine B
receptor O
( O
dantrolene B
) O
or O
inositol B
1 I
, I
4 I
, I
5 I
- I
triphosphate I
receptor O
( O
xestospongin B
C I
) O
. O

NaHS B
significantly O
increased O
intracellular O
calcium B
concentrations O
, O
and O
this O
effect O
was O
attenuated O
by O
dantrolene B
or O
xestospongin B
C I
. O

NaHS B
induced O
phosphorylation O
of O
eNOS O
at O
the O
activating O
phosphoserine B
residue O
1179 O
. O

The O
NaHS B
- O
induced O
eNOS O
phosphorylation O
and O
NO B
production O
were O
not O
affected O
by O
a O
PI3K O
/ O
Akt O
inhibitor O
( O
wortmannin B
) O
. O

The O
data O
of O
this O
study O
suggest O
that O
H B
( I
2 I
) I
S I
directly O
acts O
on O
endothelial O
cells O
to O
induce O
eNOS O
activation O
and O
NO B
production O
by O
releasing O
calcium B
from O
the O
intracellular O
store O
in O
endoplasmic O
reticulum O
, O
which O
may O
explain O
one O
of O
mechanisms O
of O
its O
vasodilator O
function O
. O

Efficient O
serum O
- O
resistant O
lipopolyplexes O
targeted O
to O
the O
folate B
receptor O
. O

In O
this O
work O
, O
we O
have O
developed O
and O
evaluated O
a O
new O
targeted O
lipopolyplex O
( O
LPP O
) O
, O
by O
combining O
polyethylenimine B
( O
PEI B
) O
, O
1 B
, I
2 I
- I
dioleoyl I
- I
3 I
- I
( I
trimethylammonium I
) I
propane I
( O
DOTAP B
) O
/ O
Chol B
liposomes O
, O
the O
plasmids O
pCMVLuc O
/ O
pCMVIL O
- O
12 O
, O
and O
the O
ligand O
folic B
acid I
( O
FA O
) O
, O
able O
to O
transfect O
HeLa O
and O
B16 O
- O
F10 O
cells O
in O
the O
presence O
of O
very O
high O
concentration O
of O
serum O
( O
60 O
% O
FBS O
) O
. O

These O
complexes O
( O
Fol O
- O
LPP O
) O
have O
a O
net O
positive O
surface O
charge O
. O

The O
combination O
of O
folic B
acid I
with O
lipopolyplexes O
also O
enhanced O
significantly O
the O
transfection O
activity O
of O
the O
therapeutic O
gene O
interleukin O
- O
12 O
( O
IL O
- O
12 O
) O
, O
without O
any O
significant O
cytotoxicity O
. O

The O
specificity O
of O
the O
folate B
receptor O
( O
FR O
) O
- O
mediated O
gene O
transfer O
was O
corroborated O
by O
employing O
a O
folate B
receptor O
deficient O
cell O
line O
( O
HepG2 O
) O
. O

This O
formulation O
improved O
gene O
delivery O
showed O
by O
conventional O
lipoplexes O
or O
polyplexes O
resulting O
an O
efficient O
, O
simple O
, O
and O
nontoxic O
method O
for O
gene O
delivery O
of O
therapeutic O
genes O
in O
vitro O
and O
very O
probably O
in O
vivo O
. O

Ferulic B
acid I
modulates O
fluoride B
- O
induced O
oxidative O
hepatotoxicity O
in O
male O
Wistar O
rats O
. O

The O
present O
study O
is O
aimed O
to O
evaluate O
the O
protective O
effect O
of O
ferulic B
acid I
( O
FA O
) O
on O
fluoride B
- O
induced O
oxidative O
hepatotoxicity O
in O
male O
Wistar O
rats O
. O

Fluoride B
( O
25 O
mg O
/ O
L O
) O
was O
given O
orally O
to O
induce O
hepatotoxicity O
for O
12 O
weeks O
. O

Hepatic O
damage O
were O
assessed O
using O
status O
of O
pathophysiological O
markers O
like O
serum O
marker O
enzymes O
like O
aspartate B
transaminase O
, O
alanine B
transaminase O
, O
alkaline O
phosphatase O
, O
acid O
phosphatase O
, O
gamma B
glutamyl I
transferase O
, O
lactate B
dehydrogenase O
, O
bilirubin B
, O
lipid O
profile O
, O
total O
protein O
content O
levels O
, O
and O
histopathological O
studies O
. O

Treatment O
with O
FA O
significantly O
reduced O
the O
degree O
of O
histological O
aberrations O
and O
rescued O
lipid O
peroxidation O
, O
as O
observed O
from O
reduced O
levels O
of O
lipid O
hydroperoxides B
, O
nitric B
oxide I
, O
restored O
levels O
of O
enzymic O
and O
non O
- O
enzymic O
antioxidants O
, O
and O
total O
protein O
content O
, O
with O
a O
concomitant O
decline O
in O
the O
levels O
of O
marker O
enzymes O
and O
lipid O
profile O
in O
fluoride B
- O
induced O
rats O
. O

These O
results O
suggest O
that O
ferulic B
acid I
has O
the O
ability O
to O
protect O
fluoride B
- O
induced O
hepatic O
damage O
. O

The O
clinical O
relevance O
of O
plasma O
protein O
binding O
changes O
. O

Controversy O
reigns O
as O
to O
how O
protein O
binding O
changes O
alter O
the O
time O
course O
of O
unbound O
drug O
concentrations O
in O
patients O
. O

Given O
that O
the O
unbound O
concentration O
is O
responsible O
for O
drug O
efficacy O
and O
potential O
drug O
toxicity O
, O
this O
area O
is O
of O
significant O
interest O
to O
clinicians O
and O
academics O
worldwide O
. O

The O
present O
uncertainty O
means O
that O
many O
questions O
relating O
to O
this O
area O
exist O
, O
including O
" O
How O
important O
is O
protein O
binding O
? O
" O
, O
" O
Is O
protein O
binding O
always O
constant O
? O
" O
, O
" O
Do O
pH O
and O
temperature O
changes O
alter O
binding O
? O
" O
and O
" O
How O
do O
protein O
binding O
changes O
affect O
dosing O
requirements O
? O
" O
. O

In O
this O
paper O
, O
we O
seek O
to O
address O
these O
questions O
and O
consider O
the O
data O
associated O
with O
altered O
pharmacokinetics O
in O
the O
presence O
of O
changes O
in O
protein O
binding O
and O
the O
clinical O
consequences O
that O
these O
may O
have O
on O
therapy O
, O
using O
examples O
from O
the O
critical O
care O
area O
. O

The O
published O
literature O
consistently O
indicates O
that O
a O
change O
in O
the O
protein O
binding O
and O
unbound O
concentrations O
of O
some O
drugs O
are O
common O
in O
certain O
specific O
patient O
groups O
such O
as O
the O
critically O
ill O
. O

Changes O
in O
pharmacokinetic O
parameters O
, O
including O
clearance O
and O
apparent O
volume O
of O
distribution O
( O
V O
( O
d O
) O
) O
, O
may O
be O
dramatic O
. O

Drugs O
with O
high O
protein O
binding O
, O
high O
intrinsic O
clearance O
( O
e O
. O
g O
. O
clearance O
by O
glomerular O
filtration O
) O
and O
where O
dosing O
is O
not O
titrated O
to O
effect O
are O
most O
likely O
to O
be O
affected O
in O
a O
clinical O
context O
. O

Drugs O
such O
as O
highly O
protein O
bound O
antibacterials O
with O
multiple O
half O
- O
lives O
within O
a O
dosing O
interval O
and O
that O
have O
some O
level O
of O
renal O
clearance O
, O
such O
as O
ertapenem B
, O
teicoplanin B
, O
ceftriaxone B
and O
flucloxacillin B
, O
are O
commonly O
affected O
. O

In O
response O
to O
these O
challenges O
, O
clinicians O
need O
to O
adapt O
dosing O
regimens O
rationally O
based O
on O
the O
pharmacokinetic O
/ O
pharmacodynamic O
characteristics O
of O
the O
drug O
. O

We O
propose O
that O
further O
pharmacokinetic O
modelling O
- O
based O
research O
is O
required O
to O
enable O
the O
design O
of O
robust O
dosing O
regimens O
for O
drugs O
affected O
by O
altered O
protein O
binding O
. O

In O
vitro O
cytochrome O
p450 O
activity O
decreases O
in O
children O
with O
high O
pediatric O
end O
- O
stage O
liver O
disease O
scores O
. O

To O
improve O
the O
modeling O
and O
simulation O
of O
pharmacokinetics O
in O
pediatric O
patients O
, O
research O
into O
developmental O
and O
disease O
- O
specific O
determinants O
is O
needed O
. O

This O
article O
describes O
the O
evaluation O
of O
the O
activity O
of O
in O
vitro O
cytochrome O
P450 O
( O
P450 O
) O
, O
an O
important O
enzyme O
family O
in O
drug O
metabolism O
, O
in O
children O
with O
hepatic O
dysfunction O
. O

The O
activity O
of O
six O
P450 O
isoforms O
( O
CYP1A2 O
, O
2C9 O
, O
2C19 O
, O
2D6 O
, O
2E1 O
, O
and O
3A4 O
) O
was O
evaluated O
in O
31 O
patients O
with O
different O
pathologies O
, O
predominantly O
biliary O
atresia O
( O
n O
= O
23 O
) O
. O

Hypervariable O
activity O
was O
observed O
for O
all O
the O
isoforms O
. O

Compared O
with O
average O
adult O
activity O
, O
low O
activity O
levels O
were O
seen O
for O
CYP1A2 O
, O
2C19 O
, O
2E1 O
, O
and O
3A4 O
. O

For O
CYP2E1 O
and O
3A4 O
, O
a O
positive O
correlation O
between O
activity O
and O
abundance O
was O
observed O
. O

Age O
, O
comedication O
, O
and O
genotype O
could O
not O
be O
used O
as O
predictors O
for O
P450 O
activity O
in O
this O
patient O
population O
. O

In O
contrast O
, O
the O
pediatric O
end O
- O
stage O
liver O
disease O
score O
was O
negatively O
correlated O
with O
the O
ln O
( O
activity O
) O
. O

This O
finding O
suggests O
a O
decrease O
in O
P450 O
activity O
with O
deteriorating O
hepatic O
function O
. O

Moreover O
, O
the O
activity O
of O
all O
isoforms O
was O
correlated O
, O
demonstrating O
a O
concomitant O
decrease O
of O
all O
isoforms O
in O
young O
patients O
with O
liver O
disease O
. O

To O
our O
knowledge O
, O
this O
is O
the O
first O
study O
to O
evaluate O
P450 O
activity O
in O
children O
with O
hepatic O
impairment O
. O

The O
presented O
data O
may O
provide O
support O
in O
the O
further O
optimization O
of O
a O
disease O
- O
specific O
model O
in O
this O
patient O
population O
. O

Induction O
of O
multidrug O
resistance O
transporter O
ABCG2 O
by O
prolactin O
in O
human O
breast O
cancer O
cells O
. O

The O
multidrug O
transporter O
, O
breast O
cancer O
resistance O
protein O
, O
ABCG2 O
, O
is O
up O
- O
regulated O
in O
certain O
chemoresistant O
cancer O
cells O
and O
in O
the O
mammary O
gland O
during O
lactation O
. O

We O
investigated O
the O
role O
of O
the O
lactogenic O
hormone O
prolactin O
( O
PRL O
) O
in O
the O
regulation O
of O
ABCG2 O
. O

PRL O
dose O
- O
dependently O
induced O
ABCG2 O
expression O
in O
T O
- O
47D O
human O
breast O
cancer O
cells O
. O

This O
induction O
was O
significantly O
reduced O
by O
short O
- O
interfering O
RNA O
- O
mediated O
knockdown O
of O
Janus O
kinase O
2 O
( O
JAK2 O
) O
. O

Knockdown O
or O
pharmacologic O
inhibition O
of O
the O
down O
- O
stream O
signal O
transducer O
and O
activator O
of O
transcription O
- O
5 O
( O
STAT5 O
) O
also O
blunted O
the O
induction O
of O
ABCG2 O
by O
PRL O
, O
suggesting O
a O
role O
for O
the O
JAK2 O
/ O
STAT5 O
pathway O
in O
PRL O
- O
induced O
ABCG2 O
expression O
. O

Corroborating O
these O
findings O
, O
we O
observed O
PRL O
- O
stimulated O
STAT5 O
recruitment O
to O
a O
region O
containing O
a O
putative O
gamma O
- O
interferon O
activation O
sequence O
( O
GAS O
) O
element O
at O
- O
434 O
base O
pairs O
upstream O
of O
the O
ABCG2 O
transcription O
start O
site O
. O

Introduction O
of O
a O
single O
mutation O
to O
the O
- O
434 O
GAS O
element O
significantly O
attenuated O
PRL O
- O
stimulated O
activity O
of O
a O
luciferase O
reporter O
driven O
by O
the O
ABCG2 O
gene O
promoter O
and O
5 O
' O
- O
flanking O
region O
containing O
the O
- O
434 O
GAS O
motif O
. O

In O
addition O
, O
this O
GAS O
element O
showed O
strong O
copy O
number O
dependency O
in O
its O
response O
to O
PRL O
treatment O
. O

Interestingly O
, O
inhibitors O
against O
the O
mitogen O
- O
activated O
protein O
kinase O
and O
phosphoinositide O
- O
3 O
- O
kinase O
signaling O
pathways O
significantly O
decreased O
the O
induction O
of O
ABCG2 O
by O
PRL O
without O
altering O
STAT5 O
recruitment O
to O
the O
GAS O
element O
. O

We O
conclude O
that O
the O
JAK2 O
/ O
STAT5 O
pathway O
is O
required O
but O
not O
sufficient O
for O
the O
induction O
of O
ABCG2 O
by O
PRL O
. O

Obtusilactone B
B I
from O
Machilus O
Thunbergii O
targets O
barrier O
- O
to O
- O
autointegration O
factor O
to O
treat O
cancer O
. O

Targeting O
specific O
molecules O
is O
a O
promising O
cancer O
treatment O
because O
certain O
types O
of O
cancer O
cells O
are O
dependent O
on O
specific O
oncogenes O
. O

This O
strategy O
led O
to O
the O
development O
of O
therapeutics O
that O
use O
monoclonal O
antibodies O
or O
small O
- O
molecule O
inhibitors O
. O

However O
, O
the O
continued O
development O
of O
novel O
molecular O
targeting O
inhibitors O
is O
required O
to O
target O
the O
various O
oncogenes O
associated O
with O
the O
diverse O
types O
and O
stages O
of O
cancer O
. O

Obtusilactone B
B I
is O
a O
butanolide B
derivative O
purified O
from O
Machilus O
thunbergii O
. O

In O
this O
study O
, O
we O
show O
that O
obtusilactone B
B I
functions O
as O
a O
small O
- O
molecule O
inhibitor O
that O
causes O
abnormal O
nuclear O
envelope O
dynamics O
and O
inhibits O
growth O
by O
suppressing O
vaccinia O
- O
related O
kinase O
1 O
( O
VRK1 O
) O
- O
mediated O
phosphorylation O
of O
barrier O
- O
to O
- O
autointegration O
factor O
( O
BAF O
) O
. O

BAF O
is O
important O
in O
maintaining O
lamin O
integrity O
, O
which O
is O
closely O
associated O
with O
diseases O
that O
include O
cancer O
. O

Specific O
binding O
of O
obtusilactone B
B I
to O
BAF O
suppressed O
VRK1 O
- O
mediated O
BAF O
phosphorylation O
and O
the O
subsequent O
dissociation O
of O
the O
nuclear O
envelope O
from O
DNA O
that O
allows O
cells O
to O
progress O
through O
the O
cell O
cycle O
. O

Obtusilactone B
B I
potently O
induced O
tumor O
cell O
death O
in O
vitro O
, O
indicating O
that O
specific O
targeting O
of O
BAF O
to O
block O
cell O
cycle O
progression O
can O
be O
an O
effective O
anticancer O
strategy O
. O

Our O
results O
demonstrate O
that O
targeting O
a O
major O
constituent O
of O
the O
nuclear O
envelope O
may O
be O
a O
novel O
and O
promising O
alternative O
approach O
to O
cancer O
treatment O
. O

Synthesis O
and O
antitubercular O
activity O
of O
2 B
- I
( I
substituted I
phenyl I
/ I
benzyl I
- I
amino I
) I
- I
6 I
- I
( I
4 I
- I
chlorophenyl I
) I
- I
5 I
- I
( I
methoxycarbonyl I
) I
- I
4 I
- I
methyl I
- I
3 I
, I
6 I
- I
dihydropyrimidin I
- I
1 I
- I
ium I
chlorides I
. O

A O
series O
of O
2 B
- I
( I
substituted I
phenyl I
/ I
benzyl I
- I
amino I
) I
- I
6 I
- I
( I
4 I
- I
chlorophenyl I
) I
- I
5 I
- I
( I
methoxycarbonyl I
) I
- I
4 I
- I
methyl I
- I
3 I
, I
6 I
- I
dihydropyrimidin I
- I
1 I
- I
ium I
chlorides I
7 O
- O
13 O
and O
15 O
was O
synthesized O
in O
their O
hydrochloride B
salt O
form O
. O

The O
title O
compounds O
were O
characterized O
by O
FT O
- O
IR O
, O
NMR O
( O
( B
1 I
) I
H I
and O
( B
13 I
) I
C I
) O
and O
elemental O
analysis O
. O

They O
were O
evaluated O
for O
their O
in O
vitro O
antitubercular O
activity O
against O
Mycobacterium O
tuberculosis O
H37Rv O
, O
multidrug O
resistance O
tuberculosis O
and O
extensively O
drug O
resistance O
tuberculosis O
by O
agar O
diffusion O
method O
and O
tested O
for O
the O
cytotoxic O
action O
on O
peripheral O
blood O
mononuclear O
cells O
by O
MTT B
assay O
. O

Among O
all O
the O
tested O
compounds O
in O
the O
series O
, O
compounds O
7 O
and O
11 O
emerged O
as O
promising O
antitubercular O
agents O
at O
16 O
mu O
g O
/ O
mL O
against O
multidrug O
resistance O
tuberculosis O
and O
over O
64 O
mu O
g O
/ O
mL O
against O
extensively O
drug O
resistance O
tuberculosis O
. O

The O
conformational O
features O
and O
supramolecular O
assembly O
of O
the O
promising O
compounds O
7 O
and O
11 O
were O
determined O
by O
single O
crystal O
X O
- O
ray O
study O
. O

A O
dual O
role O
of O
Se B
on O
Cd B
toxicity O
: O
evidences O
from O
the O
uptake O
of O
Cd B
and O
some O
essential O
elements O
and O
the O
growth O
responses O
in O
paddy O
rice O
. O

This O
study O
was O
carried O
out O
to O
investigate O
the O
effects O
of O
selenium B
( O
Se B
) O
on O
the O
uptake O
and O
translocation O
of O
cadmium B
( O
Cd B
) O
and O
essential O
elements O
in O
paddy O
rice O
( O
Oryza O
sativa O
L O
. O
, O
Shuangyou O
998 O
) O
. O

Selenium B
could O
alleviate O
/ O
aggravate O
Cd B
toxicity O
in O
paddy O
rice O
, O
which O
depended O
on O
the O
dosages O
of O
Se B
and O
/ O
or O
Cd B
. O

When O
Cd B
treatment O
level O
was O
as O
low O
as O
35 O
. O
6 O
mu O
M O
, O
< O
= O
12 O
. O
7 O
mu O
M O
Se B
could O
inhibit O
the O
uptake O
of O
Cd B
in O
paddy O
rice O
and O
increase O
the O
biomass O
of O
paddy O
rice O
; O
however O
, O
with O
Cd B
levels O
reaching O
89 O
- O
178 O
mu O
M O
, O
the O
addition O
of O
Se B
resulted O
in O
increases O
in O
Cd B
uptake O
and O
exacerbated O
the O
growth O
of O
paddy O
rice O
. O

Cd B
always O
inhibited O
the O
uptake O
of O
Se B
. O

Cd B
alone O
suppressed O
the O
uptake O
of O
Ca B
, O
Mg B
, O
Mn B
, O
Cu B
, O
and O
Zn B
; O
however O
, O
Se B
reversed O
the O
decreases O
in O
the O
concentrations O
of O
the O
said O
elements O
, O
suggesting O
an O
element O
regulation O
mechanism O
to O
relieve O
Cd B
toxicity O
. O

Without O
Cd B
in O
the O
solution O
, O
low O
doses O
of O
Se B
increased O
the O
biomasses O
of O
shoots O
and O
roots O
at O
the O
expense O
of O
the O
more O
or O
less O
decreases O
in O
the O
concentrations O
of O
Ca B
, O
Mg B
, O
K B
, O
Fe B
, O
Mn B
, O
Cu B
, O
and O
shoot O
Zn B
, O
indicating O
an O
antagonistic O
effect O
of O
Se B
on O
these O
cations O
. O

The O
presence O
of O
Cd B
could O
also O
reverse O
these O
decreases O
especially O
at O
the O
highest O
treatment O
levels O
for O
both O
Se B
and O
Cd B
, O
also O
suggesting O
an O
element O
regulation O
mechanism O
responsible O
for O
the O
detoxification O
of O
high O
dosages O
of O
Se B
. O

Consequently O
, O
when O
Se B
is O
used O
to O
alleviate O
Cd B
toxicity O
, O
attention O
must O
be O
paid O
to O
the O
Cd B
pollution O
extent O
and O
doses O
of O
Se B
supplement O
. O

Diatom O
frustules O
as O
light O
traps O
enhance O
DSSC O
efficiency O
. O

Diatoms O
are O
one O
of O
the O
most O
successful O
photosynthetic O
organisms O
and O
given O
the O
important O
role O
that O
their O
shells O
( O
frustules O
) O
play O
in O
light O
trapping O
we O
explored O
their O
use O
in O
multilayered O
materials O
for O
application O
as O
photoanodes O
in O
dye O
sensitised O
solar O
cells O
( O
DSSCs O
) O
. O

We O
find O
a O
substantial O
improvement O
in O
energy O
conversion O
efficiency O
of O
30 O
% O
, O
increasing O
from O
3 O
. O
5 O
% O
to O
4 O
. O
6 O
% O
with O
diatom O
incorporation O
. O

Involvement O
of O
lysosomal O
exocytosis O
in O
the O
excretion O
of O
mesoporous O
silica B
nanoparticles O
and O
enhancement O
of O
the O
drug O
delivery O
effect O
by O
exocytosis O
inhibition O
. O

The O
exocytosis O
of O
phosphonate B
modified O
mesoporous O
silica B
nanoparticles O
( O
P O
- O
MSNs O
) O
is O
demonstrated O
and O
lysosomal O
exocytosis O
is O
identified O
as O
the O
mechanism O
responsible O
for O
this O
event O
. O

Regulation O
of O
P O
- O
MSN O
exocytosis O
can O
be O
achieved O
by O
inhibiting O
or O
accelerating O
lysosomal O
exocytosis O
. O

Slowing O
down O
P O
- O
MSN O
exocytosis O
enhances O
the O
drug O
delivery O
effect O
of O
CPT B
- O
loaded O
P O
- O
MSNs O
by O
improving O
cell O
killing O
. O

Overexpression O
of O
ATP B
- O
binding O
cassette O
transporter O
ABCG2 O
as O
a O
potential O
mechanism O
of O
acquired O
resistance O
to O
vemurafenib B
in O
BRAF O
( O
V600E O
) O
mutant O
cancer O
cells O
. O

Melanoma O
is O
the O
most O
serious O
type O
of O
skin O
cancer O
with O
a O
high O
potential O
for O
metastasis O
and O
very O
low O
survival O
rates O
. O

The O
discovery O
of O
constitutive O
activation O
of O
the O
BRAF O
kinase O
caused O
by O
activating O
BRAF O
( O
V600E O
) O
kinase O
mutation O
in O
most O
melanoma O
patients O
led O
to O
the O
discovery O
of O
the O
first O
potent O
BRAF O
( O
V600E O
) O
signaling O
inhibitor O
, O
vemurafenib B
. O

Vemurafenib B
was O
effective O
in O
treating O
advanced O
melanoma O
patients O
and O
was O
proposed O
for O
the O
treatment O
of O
other O
BRAF O
( O
V600E O
) O
mutant O
cancers O
as O
well O
. O

Unfortunately O
, O
the O
success O
of O
vemurafenib B
was O
hampered O
by O
the O
rapid O
development O
of O
acquired O
resistance O
in O
different O
types O
of O
BRAF O
( O
V600E O
) O
mutant O
cancer O
cells O
. O

It O
becomes O
important O
to O
identify O
and O
evaluate O
all O
of O
the O
potential O
mechanisms O
of O
cellular O
resistance O
to O
vemurafenib B
. O

In O
this O
study O
, O
we O
characterized O
the O
interactions O
of O
vemurafenib B
with O
three O
major O
ATP B
- O
binding O
cassette O
( O
ABC O
) O
transporters O
, O
ABCB1 O
, O
ABCC1 O
and O
ABCG2 O
. O

We O
found O
that O
vemurafenib B
stimulated O
the O
ATPase O
activity O
and O
potently O
inhibited O
drug O
efflux O
mediated O
by O
ABCB1 O
and O
ABCG2 O
. O

Vemurafenib B
also O
restored O
drug O
sensitivity O
in O
ABCG2 O
- O
overexpressing O
cells O
. O

Moreover O
, O
we O
revealed O
that O
in O
the O
presence O
of O
functional O
ABCG2 O
, O
BRAF O
kinase O
inhibition O
by O
vemurafenib B
is O
reduced O
in O
BRAF O
( O
V600E O
) O
mutant O
A375 O
cells O
. O

Taken O
together O
, O
our O
findings O
indicate O
that O
ABCG2 O
confers O
resistance O
to O
vemurafenib B
in O
A375 O
cells O
, O
suggesting O
involvement O
of O
this O
transporter O
in O
acquired O
resistance O
to O
vemurafenib B
. O

Thus O
, O
combination O
chemotherapy O
targeting O
multiple O
pathways O
could O
be O
an O
effective O
therapeutic O
strategy O
to O
overcome O
acquired O
resistance O
to O
vemurafenib B
for O
cancers O
harboring O
the O
BRAF O
( O
V600E O
) O
mutation O
. O

New O
developments O
in O
the O
pharmacological O
modulation O
of O
wound O
healing O
after O
glaucoma O
filtration O
surgery O
. O

Despite O
the O
advent O
of O
many O
new O
devices O
for O
glaucoma O
surgery O
, O
scarring O
is O
the O
main O
cause O
of O
suboptimal O
pressure O
control O
and O
surgical O
failure O
in O
all O
forms O
of O
surgery O
. O

The O
cytotoxic O
antimetabolites O
, O
5 B
- I
flurouracil I
and O
mitomycin B
C I
both O
prolong O
success O
but O
with O
the O
increased O
risk O
of O
blinding O
complications O
. O

A O
greater O
understanding O
of O
the O
cellular O
mechanisms O
of O
the O
wound O
healing O
response O
has O
led O
to O
the O
identification O
and O
modulation O
of O
potential O
therapeutic O
targets O
. O

These O
include O
transforming O
factor O
beta O
, O
inflammatory O
mediators O
, O
the O
acute O
phase O
protein O
serum O
amyloid O
P O
, O
vascular O
endothelial O
growth O
factor O
and O
the O
matrix O
metallaproteinases O
. O

While O
optimal O
drug O
delivery O
is O
still O
a O
major O
challenge O
, O
modulating O
these O
effects O
either O
directly O
or O
through O
downstream O
signalling O
promises O
to O
yield O
anti O
- O
scarring O
efficacy O
, O
while O
minimising O
side O
effects O
. O

An O
antioxidant O
regenerating O
system O
for O
continuous O
quenching O
of O
free O
radicals O
in O
chronic O
wounds O
. O

A O
novel O
antioxidant O
regenerating O
system O
consisting O
of O
cellobiose B
dehydrogenase O
( O
CDH O
) O
, O
cellobiose B
, O
and O
phenolic B
antioxidants O
with O
potential O
application O
for O
continuous O
quenching O
of O
free O
radical O
species O
in O
chronic O
wounds O
was O
developed O
. O

This O
antioxidant O
regenerating O
system O
, O
continuously O
quenched O
in O
situ O
produced O
. O
NO B
, O
O B
( I
2 I
) I
( I
. I
- I
) I
and O
OH B
. I
radicals O
and O
the O
produced O
oxidized O
phenolic B
antioxidants O
were O
regenerated O
back O
to O
their O
original O
parent O
compounds O
by O
CDH B
using O
cellobiose B
as O
electron O
donor O
. O

This O
system O
therefore O
prevented O
the O
accumulation O
of O
oxidized O
phenolic B
antioxidants O
. O

Interestingly O
, O
this O
study O
also O
challenges O
the O
relevance O
of O
using O
total O
antioxidant O
capacities O
values O
of O
plant O
crude O
extracts O
obtained O
using O
biologically O
none O
relevant O
radical O
species O
like O
( O
2 B
, I
2 I
- I
diphenyl I
- I
1 I
- I
picrylhydrazyl I
( O
DPPH B
) O
) O
, O
Trolox B
Equivalent O
Antioxidant O
Capacity O
( O
TEAC O
) O
, O
etc O
. O
when O
applied O
as O
medicinal O
remedies O
. O

This O
is O
because O
methoxylated O
phenolic O
antioxidants O
like O
sinapic B
acid I
, O
ferulic B
acid I
; O
2 B
, I
6 I
- I
dimethoxyphenol I
readily O
donate O
their O
electrons O
to O
these O
radicals O
( O
DPPH B
, O
TEAC O
, O
etc O
. O
) O
, O
thereby O
greatly O
influencing O
the O
total O
antioxidant O
values O
although O
this O
study O
showed O
that O
they O
are O
not O
at O
all O
effective O
in O
quenching O
O B
( I
2 I
) I
( I
. I
- I
) I
radicals O
and O
again O
are O
not O
the O
most O
effective O
quenchers O
of O
NO B
and O
OH B
radicals O
as O
demonstrated O
during O
this O
study O
. O

Combination O
treatment O
with O
progesterone B
and O
vitamin B
D I
hormone O
is O
more O
effective O
than O
monotherapy O
in O
ischemic O
stroke O
: O
The O
role O
of O
BDNF O
/ O
TrkB O
/ O
Erk1 O
/ O
2 O
signaling O
in O
neuroprotection O
. O

We O
investigated O
whether O
combinatorial O
post O
- O
injury O
treatment O
with O
progesterone B
( O
P4 O
) O
and O
vitamin B
D I
hormone I
( O
VDH B
) O
would O
reduce O
ischemic O
injury O
more O
effectively O
than O
P4 O
alone O
in O
an O
oxygen B
glucose B
deprivation O
( O
OGD O
) O
model O
in O
primary O
cortical O
neurons O
and O
in O
a O
transient O
middle O
cerebral O
artery O
occlusion O
( O
tMCAO O
) O
model O
in O
rats O
. O

In O
the O
OGD O
model O
, O
P4 O
and O
VDH B
each O
showed O
neuroprotection O
individually O
, O
but O
combination O
of O
the O
" O
best O
" O
doses O
did O
not O
show O
substantial O
efficacy O
; O
instead O
, O
the O
lower O
dose O
of O
VDH B
in O
combination O
with O
P4 O
was O
the O
most O
effective O
. O

In O
the O
tMCAO O
model O
, O
P4 O
and O
VDH O
were O
given O
alone O
or O
in O
combination O
at O
different O
times O
post O
- O
occlusion O
for O
7 O
days O
. O

In O
vivo O
data O
confirmed O
the O
in O
vitro O
findings O
and O
showed O
better O
infarct O
reduction O
at O
day O
7 O
and O
functional O
outcomes O
( O
at O
3 O
, O
5 O
and O
7 O
days O
post O
- O
occlusion O
) O
after O
combinatorial O
treatment O
than O
when O
either O
agent O
was O
given O
alone O
. O

VDH B
, O
but O
not O
P4 O
, O
upregulated O
heme O
oxygenase O
- O
1 O
, O
suggesting O
a O
pathway O
for O
the O
neuroprotective O
effects O
of O
VDH B
differing O
from O
that O
of O
P4 O
. O

The O
combination O
of O
P4 O
and O
VDH B
activated O
brain O
- O
derived O
neurotrophic O
factor O
and O
its O
specific O
receptor O
, O
tyrosine B
kinase O
receptor O
- O
B O
. O

Under O
specific O
conditions O
VDH O
potentiates O
P4 O
' O
s O
neuroprotective O
efficacy O
and O
should O
be O
considered O
as O
a O
potential O
partner O
of O
P4 O
in O
a O
low O
- O
cost O
, O
safe O
and O
effective O
combinatorial O
treatment O
for O
stroke O
. O

The O
nonfermentable O
dietary O
fiber O
hydroxypropyl B
methylcellulose O
modulates O
intestinal O
microbiota O
. O

Diet O
influences O
host O
metabolism O
and O
intestinal O
microbiota O
; O
however O
, O
detailed O
understanding O
of O
this O
tripartite O
interaction O
is O
limited O
. O

To O
determine O
whether O
the O
nonfermentable O
fiber O
hydroxypropyl O
methylcellulose O
( O
HPMC O
) O
could O
alter O
the O
intestinal O
microbiota O
and O
whether O
such O
changes O
correlated O
with O
metabolic O
improvements O
, O
C57B O
/ O
L6 O
mice O
were O
normalized O
to O
a O
high O
- O
fat O
diet O
( O
HFD O
) O
, O
then O
either O
maintained O
on O
HFD O
( O
control O
) O
, O
or O
switched O
to O
HFD O
supplemented O
with O
10 O
% O
HPMC O
, O
or O
a O
low O
- O
fat O
diet O
( O
LFD O
) O
. O

Compared O
to O
control O
treatment O
, O
both O
LFD O
and O
HPMC O
reduced O
weight O
gain O
( O
11 O
. O
8 O
and O
5 O
. O
7 O
g O
, O
respectively O
) O
, O
plasma O
cholesterol B
( O
23 O
. O
1 O
and O
19 O
. O
6 O
% O
) O
, O
and O
liver O
triglycerides B
( O
73 O
. O
1 O
and O
44 O
. O
6 O
% O
) O
, O
and O
, O
as O
revealed O
by O
454 O
- O
pyrosequencing O
of O
the O
microbial O
16S O
rRNA O
gene O
, O
decreased O
microbial O
alpha O
- O
diversity O
and O
differentially O
altered O
intestinal O
microbiota O
. O

Both O
LFD O
and O
HPMC O
increased O
intestinal O
Erysipelotrichaceae O
( O
7 O
. O
3 O
- O
and O
12 O
. O
4 O
- O
fold O
) O
and O
decreased O
Lachnospiraceae O
( O
2 O
. O
0 O
- O
and O
2 O
. O
7 O
- O
fold O
) O
, O
while O
only O
HPMC O
increased O
Peptostreptococcacea O
( O
3 O
. O
4 O
- O
fold O
) O
and O
decreased O
Ruminococcaceae O
( O
2 O
. O
7 O
- O
fold O
) O
. O

Specific O
microorganisms O
were O
directly O
linked O
with O
weight O
change O
and O
metabolic O
parameters O
in O
HPMC O
and O
HFD O
mice O
, O
but O
not O
in O
LFD O
mice O
, O
indicating O
that O
the O
intestinal O
microbiota O
may O
play O
differing O
roles O
during O
the O
two O
dietary O
modulations O
. O

This O
work O
indicates O
that O
HPMC O
is O
a O
potential O
prebiotic O
fiber O
that O
influences O
intestinal O
microbiota O
and O
improves O
host O
metabolism O
. O

Inhibition O
of O
glycogen O
synthase O
kinase O
- O
3 O
ameliorates O
beta O
- O
amyloid O
pathology O
and O
restores O
lysosomal O
acidification O
and O
mammalian O
target O
of O
rapamycin B
activity O
in O
the O
Alzheimer O
disease O
mouse O
model O
: O
in O
vivo O
and O
in O
vitro O
studies O
. O

Accumulation O
of O
beta O
- O
amyloid O
( O
A O
beta O
) O
deposits O
is O
a O
primary O
pathological O
feature O
of O
Alzheimer O
disease O
that O
is O
correlated O
with O
neurotoxicity O
and O
cognitive O
decline O
. O

The O
role O
of O
glycogen O
synthase O
kinase O
- O
3 O
( O
GSK O
- O
3 O
) O
in O
Alzheimer O
disease O
pathogenesis O
has O
been O
debated O
. O

To O
study O
the O
role O
of O
GSK O
- O
3 O
in O
A O
beta O
pathology O
, O
we O
used O
5XFAD O
mice O
co O
- O
expressing O
mutated O
amyloid O
precursor O
protein O
and O
presenilin O
- O
1 O
that O
develop O
massive O
cerebral O
A O
beta O
loads O
. O

Both O
GSK O
- O
3 O
isozymes O
( O
alpha O
/ O
beta O
) O
were O
hyperactive O
in O
this O
model O
. O

Nasal O
treatment O
of O
5XFAD O
mice O
with O
a O
novel O
substrate O
competitive O
GSK O
- O
3 O
inhibitor O
, O
L803 B
- O
mts O
, O
reduced O
A O
beta O
deposits O
and O
ameliorated O
cognitive O
deficits O
. O

Analyses O
of O
5XFAD O
hemi O
- O
brain O
samples O
indicated O
that O
L803 O
- O
mts O
restored O
the O
activity O
of O
mammalian O
target O
of O
rapamycin B
( O
mTOR O
) O
and O
inhibited O
autophagy O
. O

Lysosomal O
acidification O
was O
impaired O
in O
the O
5XFAD O
brains O
as O
indicated O
by O
reduced O
cathepsin O
D O
activity O
and O
decreased O
N B
- O
glycoyslation O
of O
the O
vacuolar O
ATPase O
subunit O
V0a1 O
, O
a O
modification O
required O
for O
lysosomal O
acidification O
. O

Treatment O
with O
L803 O
- O
mts O
restored O
lysosomal O
acidification O
in O
5XFAD O
brains O
. O

Studies O
in O
SH O
- O
SY5Y O
cells O
confirmed O
that O
GSK O
- O
3 O
alpha O
and O
GSK O
- O
3 O
beta O
impair O
lysosomal O
acidification O
and O
that O
treatment O
with O
L803 B
- O
mts O
enhanced O
the O
acidic O
lysosomal O
pool O
as O
demonstrated O
in O
LysoTracker O
Red O
- O
stained O
cells O
. O

Furthermore O
, O
L803 O
- O
mts O
restored O
impaired O
lysosomal O
acidification O
caused O
by O
dysfunctional O
presenilin O
- O
1 O
. O

We O
provide O
evidence O
that O
mTOR O
is O
a O
target O
activated O
by O
GSK O
- O
3 O
but O
inhibited O
by O
impaired O
lysosomal O
acidification O
and O
elevation O
in O
amyloid O
precursor O
protein O
/ O
A O
beta O
loads O
. O

Taken O
together O
, O
our O
data O
indicate O
that O
GSK O
- O
3 O
is O
a O
player O
in O
A O
beta O
pathology O
. O

Inhibition O
of O
GSK O
- O
3 O
restores O
lysosomal O
acidification O
that O
in O
turn O
enables O
clearance O
of O
A O
beta O
burdens O
and O
reactivation O
of O
mTOR O
. O

These O
changes O
facilitate O
amelioration O
in O
cognitive O
function O
. O

MetalPDB O
: O
a O
database O
of O
metal O
sites O
in O
biological O
macromolecular O
structures O
. O

We O
present O
here O
MetalPDB O
( O
freely O
accessible O
at O
http O
: O
/ O
/ O
metalweb O
. O
cerm O
. O
unifi O
. O
it O
) O
, O
a O
novel O
resource O
aimed O
at O
conveying O
the O
information O
available O
on O
the O
three O
- O
dimensional O
( O
3D O
) O
structures O
of O
metal O
- O
binding O
biological O
macromolecules O
in O
a O
consistent O
and O
effective O
manner O
. O

This O
is O
achieved O
through O
the O
systematic O
and O
automated O
representation O
of O
metal O
- O
binding O
sites O
in O
proteins O
and O
nucleic O
acids O
by O
way O
of O
Minimal O
Functional O
Sites O
( O
MFSs O
) O
. O

MFSs O
are O
3D O
templates O
that O
describe O
the O
local O
environment O
around O
the O
metal O
( O
s O
) O
independently O
of O
the O
larger O
context O
of O
the O
macromolecular O
structure O
embedding O
the O
site O
( O
s O
) O
, O
and O
are O
the O
central O
objects O
of O
MetalPDB O
design O
. O

MFSs O
are O
grouped O
into O
equistructural O
( O
broadly O
defined O
as O
sites O
found O
in O
corresponding O
positions O
in O
similar O
structures O
) O
and O
equivalent O
sites O
( O
equistructural O
sites O
that O
contain O
the O
same O
metals O
) O
, O
allowing O
users O
to O
easily O
analyse O
similarities O
and O
variations O
in O
metal O
- O
macromolecule O
interactions O
, O
and O
to O
link O
them O
to O
functional O
information O
. O

The O
web O
interface O
of O
MetalPDB O
allows O
access O
to O
a O
comprehensive O
overview O
of O
metal O
- O
containing O
biological O
structures O
, O
providing O
a O
basis O
to O
investigate O
the O
basic O
principles O
governing O
the O
properties O
of O
these O
systems O
. O

MetalPDB O
is O
updated O
monthly O
in O
an O
automated O
manner O
. O

Influence O
of O
coadministration O
of O
artemether B
and O
lumefantrine B
on O
selected O
plasma O
biochemical O
and O
erythrocyte O
oxidative O
stress O
indices O
in O
female O
Wistar O
rats O
. O

Among O
the O
artemisinin B
- O
based O
combination O
therapy O
( O
ACT O
) O
regimens O
, O
artemisinin B
derivative O
, O
artemether B
in O
combination O
with O
lumefantrine B
( O
artemether B
- O
lumefantrine B
, O
AL O
) O
has O
achieved O
excellent O
results O
in O
the O
fight O
against O
malarial O
scourge O
. O

In O
this O
study O
, O
we O
evaluated O
the O
toxic O
potential O
of O
these O
drugs O
at O
the O
therapeutic O
doses O
in O
female O
Wistar O
rats O
. O

Animals O
were O
randomly O
divided O
into O
four O
groups O
: O
those O
administered O
1 O
% O
Tween B
80 I
( O
control O
) O
, O
those O
administered O
artemether B
( O
4 O
mg O
/ O
kg O
body O
weight O
) O
, O
those O
administered O
lumefantrine B
( O
24 O
mg O
/ O
kg O
body O
weight O
) O
, O
and O
those O
coadministered O
artemether B
( O
4 O
mg O
/ O
kg O
body O
weight O
) O
and O
lumefantrine B
( O
24 O
mg O
/ O
kg O
body O
weight O
) O
. O

The O
drugs O
were O
orally O
administered O
twice O
daily O
for O
3 O
days O
by O
gastric O
intubation O
after O
which O
selected O
plasma O
biochemical O
indices O
, O
and O
erythrocytes O
antioxidant O
defence O
and O
lipid O
peroxidation O
markers O
were O
evaluated O
. O

Coadministration O
of O
artemether B
and O
lumefantrine B
raised O
liver O
and O
renal O
function O
markers O
and O
increased O
atherogenic O
index O
. O

While O
reduced B
glutathione I
, O
glucose B
- I
6 I
- I
phosphate I
dehydrogenase O
( O
G6PD O
) O
and O
catalase O
activities O
were O
reduced O
, O
glutathione B
peroxidase O
and O
glutathione B
- O
s B
- O
transferase O
activities O
increased O
in O
all O
the O
treated O
groups O
compared O
to O
the O
control O
group O
. O

The O
drugs O
caused O
significant O
( O
p O
< O
0 O
. O
05 O
) O
elevation O
of O
malondialdehyde B
( O
MDA B
) O
levels O
compared O
to O
the O
control O
group O
. O

These O
results O
imply O
that O
coadministration O
of O
artemether B
and O
lumefantrine B
may O
increase O
the O
risks O
of O
atherosclerosis O
as O
well O
as O
liver O
and O
renal O
function O
impairments O
in O
the O
users O
. O

In O
addition O
, O
the O
drugs O
may O
also O
promote O
oxidative O
stress O
in O
the O
erythrocytes O
. O

Different O
fates O
of O
Alzheimer O
' O
s O
disease O
amyloid O
- O
beta O
fibrils O
remodeled O
by O
biocompatible O
small O
molecules O
. O

Amyloid O
fibrils O
implicated O
in O
numerous O
human O
diseases O
are O
thermodynamically O
very O
stable O
. O

Stringent O
conditions O
that O
would O
not O
be O
possible O
in O
a O
physiological O
environment O
are O
often O
required O
to O
disrupt O
the O
stable O
fibrils O
. O

Recently O
, O
there O
is O
increasing O
evidence O
that O
small O
molecules O
can O
remodel O
amyloid O
fibrils O
in O
a O
physiologically O
relevant O
manner O
. O

In O
order O
to O
investigate O
possible O
fibril O
remodeling O
mechanisms O
using O
this O
approach O
, O
we O
performed O
comparative O
studies O
on O
the O
structural O
features O
of O
the O
different O
amyloid O
- O
beta O
( O
A O
beta O
) O
aggregates O
remodeled O
from O
A O
beta O
fibrils O
by O
three O
biocompatible O
small O
molecules O
: O
methylene B
blue I
; O
brilliant B
blue I
G I
; O
and O
erythrosine B
B I
. O

Combined O
with O
circular O
dichroism O
( O
CD O
) O
, O
immuno O
- O
blotting O
, O
transmission O
electron O
microscopy O
( O
TEM O
) O
, O
and O
atomic O
force O
microscopy O
( O
AFM O
) O
results O
, O
it O
was O
found O
that O
brilliant B
blue I
G I
- O
and O
erythrosine B
B I
- O
treatment O
generate O
fragmented O
A O
beta O
fibrils O
and O
protofibrils O
, O
respectively O
. O

In O
contrast O
, O
incubation O
of O
the O
A O
beta O
fibrils O
with O
methylene B
blue I
perturbs O
fibrillar O
structure O
, O
leading O
to O
amorphous O
A O
beta O
aggregates O
. O

Our O
findings O
provide O
insights O
on O
the O
molecular O
mechanism O
of O
amyloid O
fibril O
formation O
and O
remodeling O
and O
also O
illustrate O
the O
possibility O
of O
controlled O
changes O
in O
biomolecule O
nanostructures O
. O

Neurotransmitters O
, O
psychotropic O
drugs O
and O
microglia O
: O
clinical O
implications O
for O
psychiatry O
. O

Psychiatric O
disorders O
have O
long O
and O
dominantly O
been O
regarded O
to O
be O
induced O
by O
disturbances O
of O
neuronal O
networks O
including O
synapses O
and O
neurotransmitters O
. O

Thus O
, O
the O
effects O
of O
psychotropic O
drugs O
such O
as O
antipsychotics O
and O
antidepressants O
have O
been O
understood O
to O
modulate O
synaptic O
regulation O
via O
receptors O
and O
transporters O
of O
neurotransmitters O
such O
as O
dopamine B
and O
serotonin B
. O

Recently O
, O
microglia O
, O
immunological O
/ O
inflammatory O
cells O
in O
the O
brain O
, O
have O
been O
indicated O
to O
have O
positive O
links O
to O
psychiatric O
disorders O
. O

Positron O
emission O
tomography O
( O
PET O
) O
imaging O
and O
postmortem O
studies O
have O
revealed O
microglial O
activation O
in O
the O
brain O
of O
neuropsychiatric O
disorders O
such O
as O
schizophrenia O
, O
depression O
and O
autism O
. O

Animal O
models O
of O
neuropsychiatric O
disorders O
have O
revealed O
the O
underlying O
microglial O
pathologies O
. O

In O
addition O
, O
various O
psychotropic O
drugs O
have O
been O
suggested O
to O
have O
direct O
effects O
on O
microglia O
. O

Until O
now O
, O
the O
relationship O
between O
microglia O
, O
neurotransmitters O
and O
psychiatric O
disorders O
has O
not O
been O
well O
understood O
. O

Therefore O
, O
in O
this O
review O
, O
at O
first O
, O
we O
summarize O
recent O
findings O
of O
interaction O
between O
microglia O
and O
neurotransmitters O
such O
as O
dopamine B
, O
serotonin B
, O
norepinephrine B
, O
acetylcholine B
and O
glutamate B
. O

Next O
, O
we O
introduce O
up O
- O
to O
- O
date O
knowledge O
of O
the O
effects O
of O
psychotropic O
drugs O
such O
as O
antipsychotics O
, O
antidepressants O
and O
antiepileptics O
on O
microglial O
modulation O
. O

Finally O
, O
we O
propose O
the O
possibility O
that O
modulating O
microglia O
may O
be O
a O
key O
target O
in O
the O
treatment O
of O
various O
psychiatric O
disorders O
. O

Further O
investigations O
and O
clinical O
trials O
should O
be O
conducted O
to O
clarify O
this O
perspective O
, O
using O
animal O
in O
vivo O
studies O
and O
imaging O
studies O
with O
human O
subjects O
. O

Recent O
developments O
in O
neurochemical O
imaging O
in O
schizophrenia O
: O
an O
update O
. O

The O
advent O
of O
neurochemical O
brain O
imaging O
methods O
has O
provided O
an O
opportunity O
to O
study O
the O
neurochemistry O
of O
the O
human O
brain O
in O
normal O
and O
abnormal O
development O
. O

The O
aim O
of O
this O
article O
is O
to O
provide O
an O
update O
on O
recent O
major O
developments O
in O
neurochemical O
imaging O
in O
schizophrenia O
research O
. O

In O
this O
concise O
review O
, O
we O
discuss O
the O
major O
findings O
on O
three O
neurotransmitters O
, O
namely O
dopamine B
, O
serotonin B
and O
glutamate B
. O

The O
most O
promising O
radioligand O
for O
D O
( O
2 O
) O
/ O
D O
( O
3 O
) O
neuroreceptor O
imaging O
is O
the O
agonist O
[ B
( I
11 I
) I
C I
] I
PHNO I
, O
with O
higher O
in O
vivo O
affinity O
for O
D O
( O
3 O
) O
than O
D O
( O
2 O
) O
receptors O
, O
which O
can O
be O
used O
to O
measure O
amphetamine B
- O
induced O
release O
of O
dopamine B
, O
and O
therefore O
a O
potential O
model O
of O
dopaminergic O
alterations O
in O
schizophrenia O
. O

Recent O
development O
of O
selective O
radiotracers O
allow O
imaging O
of O
the O
serotonin B
transporter O
( O
SERT O
) O
using O
positron O
emission O
tomography O
( O
PET O
) O
with O
selective O
tracers O
such O
as O
[ B
( I
11 I
) I
C I
] I
DASB I
. O

Additionally O
, O
the O
glutamatergic O
hypothesis O
has O
evolved O
from O
theory O
to O
phase O
III O
clinical O
trials O
of O
newer O
agents O
with O
novel O
mechanisms O
. O

With O
the O
development O
of O
newer O
radioligands O
and O
the O
in O
vivo O
application O
of O
magnetic O
resonance O
spectroscopy O
( O
MRS O
) O
at O
relatively O
high O
magnetic O
field O
strengths O
, O
there O
is O
ample O
scope O
for O
further O
neuroimaging O
advances O
. O

Serotonin B
receptors O
of O
type O
6 O
( O
5 O
- O
HT6 O
) O
: O
from O
neuroscience O
to O
clinical O
pharmacology O
. O

The O
serotonin B
( O
5 B
- I
HT I
) O
receptors O
of O
type O
6 O
( O
5 O
- O
HT6 O
) O
are O
quite O
different O
from O
all O
other O
5 B
- I
HT I
receptors O
, O
as O
they O
include O
a O
short O
third O
cytoplasmatic O
loop O
and O
a O
long O
C B
- O
terminal O
tail O
, O
and O
one O
intron O
located O
in O
the O
middle O
of O
the O
third O
cytoplasmatic O
loop O
. O

A O
lot O
of O
controversies O
still O
exist O
regarding O
their O
binding O
affinity O
, O
effects O
of O
5 O
- O
HT6 O
ligands O
on O
brain O
catecholamines B
, O
behavioral O
syndromes O
regulated O
by O
them O
, O
and O
brain O
distribution O
. O

In O
spite O
of O
the O
lack O
of O
information O
on O
metabolic O
pattern O
of O
the O
various O
compounds O
, O
some O
of O
5 O
- O
HT6 O
receptor O
ligands O
entered O
the O
clinical O
development O
as O
potential O
anti O
- O
dementia O
, O
antipsychotic O
, O
antidepressant O
and O
anti O
- O
obese O
drugs O
. O

The O
present O
paper O
is O
a O
comprehensive O
review O
on O
the O
state O
of O
art O
of O
the O
5 O
- O
HT6 O
receptors O
, O
while O
highlighting O
the O
potential O
clinical O
applications O
of O
5 O
- O
HT6 O
receptor O
agonists O
/ O
antagonists O
. O

Transcranial O
brain O
stimulation O
in O
schizophrenia O
: O
targeting O
cortical O
excitability O
, O
connectivity O
and O
plasticity O
. O

Transcranial O
magnetic O
stimulation O
( O
TMS O
) O
is O
a O
very O
popular O
tool O
used O
within O
neuroscience O
. O

This O
and O
other O
associated O
techniques O
allow O
the O
in O
vivo O
investigation O
of O
cortical O
excitability O
, O
cortical O
connectivity O
and O
cortical O
plasticity O
. O

Schizophrenia O
is O
a O
brain O
disorder O
and O
various O
theories O
other O
than O
the O
dopamine B
hypothesis O
have O
been O
developed O
to O
describe O
its O
underlying O
neurobiology O
. O

Supported O
by O
animal O
and O
post O
mortem O
studies O
, O
findings O
from O
TMS O
studies O
indicate O
that O
schizophrenia O
is O
a O
disease O
of O
reduced O
cortical O
inhibition O
and O
impaired O
intra O
- O
and O
intercortical O
connectivity O
. O

Further O
studies O
using O
repetitive O
TMS O
and O
other O
plasticity O
- O
inducing O
techniques O
have O
shown O
that O
cortical O
plasticity O
is O
altered O
in O
schizophrenia O
patients O
, O
supporting O
the O
recently O
discussed O
plasticity O
deficiency O
theory O
of O
schizophrenia O
. O

This O
review O
gives O
an O
introduction O
to O
the O
most O
frequently O
applied O
techniques O
, O
describes O
findings O
in O
schizophrenia O
patients O
and O
discusses O
these O
findings O
with O
regard O
to O
the O
neurotransmitters O
and O
associated O
receptors O
involved O
. O

In O
summary O
, O
there O
is O
emerging O
evidence O
of O
an O
important O
pathophysiological O
interplay O
between O
reduced O
inhibition O
, O
impaired O
connectivity O
and O
reduced O
plasticity O
in O
schizophrenia O
patients O
. O

Gamma B
- I
aminobutyric I
- I
acid I
- O
receptors O
and O
glutamtergic O
N B
- I
Methyl I
- I
D I
- I
aspartic I
- I
acid I
- O
receptors O
are O
most O
likely O
to O
be O
involved O
in O
this O
complex O
interplay O
, O
which O
may O
reflect O
a O
disturbed O
signal O
- O
to O
- O
noise O
ratio O
in O
schizophrenia O
patients O
. O

This O
review O
will O
discuss O
this O
issue O
with O
regard O
to O
the O
available O
treatment O
options O
and O
will O
give O
implications O
for O
future O
research O
and O
therapeutic O
strategies O
regarding O
disinhibition O
and O
neuroplasticity O
in O
schizophrenia O
. O

A O
general O
approach O
for O
combining O
voxel O
- O
based O
meta O
- O
analyses O
conducted O
in O
different O
neuroimaging O
modalities O
. O

Meta O
- O
analyses O
are O
useful O
to O
summarize O
the O
exponential O
amount O
of O
inconsistent O
and O
conflicting O
neuroimaging O
data O
. O

However O
, O
they O
are O
usually O
separately O
conducted O
for O
each O
different O
neuroimaging O
modality O
, O
preventing O
the O
multimodal O
integration O
of O
different O
imaging O
findings O
in O
a O
given O
neuropsychiatric O
disorder O
. O

Here O
, O
we O
describe O
an O
innovative O
method O
to O
meta O
- O
analytically O
combine O
the O
results O
of O
different O
imaging O
modalities O
, O
such O
as O
structural O
and O
functional O
paradigms O
. O

The O
method O
accounts O
for O
the O
presence O
of O
noise O
in O
the O
estimation O
of O
the O
p O
- O
values O
, O
and O
can O
be O
easily O
applied O
to O
any O
meta O
- O
analytical O
software O
. O

We O
hope O
that O
with O
this O
advanced O
imaging O
tool O
, O
researchers O
will O
be O
able O
to O
provide O
more O
complete O
multimodal O
pictures O
of O
the O
brain O
regions O
affected O
in O
different O
neuropsychiatric O
disorders O
. O

Distinct O
roles O
of O
methamphetamine B
in O
modulating O
spatial O
memory O
consolidation O
, O
retrieval O
, O
reconsolidation O
and O
the O
accompanying O
changes O
of O
ERK O
and O
CREB O
activation O
in O
hippocampus O
and O
prefrontal O
cortex O
. O

Drugs O
of O
abuse O
modulated O
learning O
and O
memory O
in O
humans O
yet O
the O
underlying O
mechanism O
remained O
unclear O
. O

The O
extracellular O
signal O
- O
regulated O
kinase O
( O
ERK O
) O
and O
the O
transcription O
factor O
cAMP B
response O
element O
- O
binding O
protein O
( O
CREB O
) O
were O
involved O
in O
neuroplastic O
changes O
associated O
with O
learning O
and O
memory O
. O

In O
the O
current O
study O
, O
we O
used O
a O
Morris O
water O
maze O
to O
examine O
the O
effect O
of O
methamphetamine B
( O
METH B
) O
on O
different O
processes O
of O
spatial O
memory O
in O
mice O
. O

We O
then O
investigated O
the O
status O
of O
ERK O
and O
CREB O
in O
the O
hippocampus O
and O
prefrontal O
cortex O
( O
PFC O
) O
. O

We O
found O
that O
1 O
. O
0 O
mg O
/ O
kg O
dose O
of O
METH B
facilitated O
spatial O
memory O
consolidation O
when O
it O
was O
injected O
immediately O
after O
the O
last O
learning O
trial O
. O

In O
contrast O
, O
the O
same O
dose O
of O
METH B
had O
no O
effect O
on O
spatial O
memory O
retrieval O
when O
it O
was O
injected O
30 O
min O
before O
the O
test O
. O

Furthermore O
, O
1 O
. O
0 O
mg O
/ O
kg O
dose O
of O
METH B
injected O
immediately O
after O
retrieval O
had O
no O
effect O
on O
spatial O
memory O
reconsolidation O
. O

Activation O
of O
both O
ERK O
and O
CREB O
in O
the O
hippocampus O
was O
found O
following O
memory O
consolidation O
but O
not O
after O
retrieval O
or O
reconsolidation O
in O
METH B
- O
treated O
mouse O
groups O
. O

In O
contrast O
, O
activation O
of O
both O
ERK O
and O
CREB O
in O
the O
PFC O
was O
found O
following O
memory O
retrieval O
but O
not O
other O
processes O
in O
METH B
- O
treated O
mouse O
groups O
. O

These O
results O
suggested O
that O
METH B
facilitated O
spatial O
memory O
consolidation O
but O
not O
retrieval O
or O
reconsolidation O
. O

Moreover O
, O
activation O
of O
the O
ERK O
and O
CREB O
signaling O
pathway O
in O
the O
hippocampus O
might O
be O
involved O
in O
METH B
- O
induced O
spatial O
memory O
changes O
. O

Development O
of O
a O
repeated O
exposure O
protocol O
of O
human O
bronchial O
epithelium O
in O
vitro O
to O
study O
the O
long O
- O
term O
effects O
of O
atmospheric O
particles O
. O

Chronic O
exposure O
to O
atmospheric O
particles O
is O
suspected O
of O
exacerbating O
chronic O
inflammatory O
respiratory O
diseases O
but O
the O
underlying O
mechanisms O
remain O
poorly O
understood O
. O

An O
experimental O
strategy O
using O
human O
bronchial O
epithelial O
cells O
( O
NHBE O
) O
known O
to O
be O
one O
of O
the O
main O
target O
cells O
of O
particles O
in O
the O
lung O
was O
developed O
to O
investigate O
the O
long O
term O
effects O
of O
repeated O
exposure O
to O
particles O
. O

Primary O
cultures O
of O
NHBE O
cells O
were O
grown O
at O
an O
air O
- O
liquid O
interface O
and O
subjected O
to O
repeated O
treatments O
to O
particles O
. O

Fate O
of O
particles O
, O
pro O
inflammatory O
response O
and O
epithelial O
differentiation O
were O
studied O
during O
the O
5 O
weeks O
following O
the O
final O
treatment O
. O

Ultrastructural O
observations O
revealed O
the O
biopersistence O
of O
particles O
in O
the O
bronchial O
epithelium O
. O

The O
expression O
of O
cytochrome O
P450 O
1A1 O
, O
was O
transiently O
induced O
, O
suggesting O
that O
organic O
compounds O
could O
have O
been O
metabolized O
. O

The O
release O
of O
GM O
- O
CSF O
and O
IL O
- O
6 O
( O
biomarkers O
of O
pro O
- O
inflammatory O
response O
) O
, O
was O
induced O
by O
particle O
treatments O
and O
was O
maintained O
up O
to O
5weeks O
after O
treatments O
. O

The O
release O
of O
amphiregulin O
and O
TGF O
alpha O
( O
Growth O
Factor O
) O
was O
induced O
after O
each O
treatment O
. O

The O
number O
of O
cells O
expressing O
the O
mucin O
MUC5AC O
, O
a O
differentiation O
marker O
, O
was O
increased O
in O
particle O
- O
exposed O
epithelium O
. O

The O
experimental O
strategy O
we O
developed O
is O
suitable O
for O
investigating O
in O
greater O
depth O
the O
long O
term O
effects O
of O
particles O
on O
bronchial O
epithelial O
cells O
repeatedly O
exposed O
to O
atmospheric O
particles O
in O
vitro O
. O

Nano O
and O
microparticulate O
chitosan O
- O
based O
systems O
for O
antiviral O
topical O
delivery O
. O

Acyclovir B
( O
ACV B
) O
is O
one O
of O
the O
drugs O
of O
choice O
for O
the O
treatment O
of O
epidermal O
, O
ocular O
or O
systemic O
herpetic O
infections O
. O

Nevertheless O
, O
its O
trans O
- O
mucosal O
limited O
absorption O
and O
the O
scarce O
contact O
time O
of O
the O
formulation O
with O
the O
mucosal O
surface O
- O
especially O
in O
the O
ocular O
mucosa O
- O
constitute O
a O
big O
limitation O
of O
the O
antiviral O
efficiency O
. O

The O
most O
effective O
way O
to O
solve O
these O
problems O
is O
to O
increase O
the O
quantity O
and O
the O
residence O
time O
of O
the O
drug O
over O
the O
ocular O
surface O
. O

In O
order O
to O
cope O
with O
all O
these O
requirements O
, O
micro O
- O
particles O
( O
MPs O
) O
and O
nano O
- O
particles O
( O
NPs O
) O
containing O
ACV B
have O
been O
developed O
using O
cross O
- O
linked O
chitosan O
with O
tripolyphosphate B
( O
TPP B
) O
due O
to O
the O
biocompatibility O
, O
bio O
- O
adhesion O
ability O
and O
the O
potential O
power O
as O
penetration O
enhancer O
of O
this O
polymer O
. O

Particles O
were O
characterized O
by O
Fourier O
- O
transformed O
infrared O
( O
FTIR O
) O
spectroscopy O
, O
X O
- O
ray O
diffraction O
, O
SEM O
, O
Zeta O
potential O
and O
particle O
size O
. O

Encapsulation O
efficiency O
and O
release O
profiles O
in O
flow O
through O
diffusion O
cells O
were O
also O
determined O
. O

Besides O
the O
Slug O
Mucosal O
Irritation O
( O
SMI O
) O
assay O
has O
been O
applied O
as O
an O
alternative O
to O
the O
Draize O
test O
to O
predict O
the O
mucosal O
irritation O
of O
the O
selected O
formulation O
. O

FTIR O
and O
X O
- O
ray O
results O
suggested O
an O
electrostatic O
interaction O
ACV B
- O
Chitosan O
that O
made O
ACV B
be O
molecularly O
dispersed O
within O
the O
polymer O
matrix O
. O

Encapsulation O
efficiency O
was O
75 O
% O
for O
MP O
and O
16 O
% O
for O
NP O
. O

Release O
profiles O
in O
flow O
through O
diffusion O
cells O
were O
also O
determined O
. O

From O
the O
diffusion O
profiles O
, O
it O
was O
found O
that O
the O
amounts O
of O
ACV B
effectively O
diffused O
in O
24h O
were O
30 O
, O
430 O
and O
80 O
mu O
g O
for O
the O
ACV B
solution O
, O
MP O
and O
NP O
respectively O
. O

SMI O
results O
showed O
that O
chitosan O
- O
based O
particles O
induced O
moderate O
irritation O
and O
mild O
tissue O
damage O
, O
what O
supposes O
that O
ACV B
- O
MP O
constitute O
a O
promising O
alternative O
for O
further O
development O
of O
an O
antiviral O
formulation O
. O

A O
novel O
permeation O
enhancer O
: O
N B
- I
succinyl I
chitosan O
on O
the O
intranasal O
absorption O
of O
isosorbide B
dinitrate I
in O
rats O
. O

The O
purpose O
of O
this O
paper O
is O
to O
study O
the O
potential O
of O
N B
- I
succinyl I
chitosan O
as O
a O
novel O
permeation O
enhancer O
for O
the O
intranasal O
absorption O
of O
isosorbide B
dinitrate I
( O
ISDN B
) O
. O

A O
series O
of O
N B
- I
succinyl I
chitosan O
( O
NSCS O
) O
with O
different O
degree O
of O
succinylation O
( O
DS O
) O
and O
molecular O
weight O
were O
synthesized O
. O

An O
in O
situ O
nasal O
perfusion O
technique O
in O
rats O
was O
utilized O
to O
investigate O
the O
effect O
of O
NSCS O
substitution O
degree O
, O
NSCS O
molecular O
weight O
and O
concentration O
on O
the O
intranasal O
absorption O
of O
ISDN B
. O

The O
absorption O
enhancing O
effect O
of O
NSCS O
was O
compared O
with O
that O
of O
chitosan O
. O

It O
was O
found O
that O
all O
the O
NSCS O
investigated O
improved O
the O
intranasal O
absorption O
of O
ISDN B
remarkably O
. O

Better O
promoting O
effect O
was O
observed O
for O
0 O
. O
1 O
% O
NSCS O
50 O
( O
63 O
) O
compared O
with O
0 O
. O
5 O
% O
chitosan O
50 O
. O

In O
nasal O
ciliotoxicity O
test O
, O
both O
NSCS O
and O
chitosan O
investigated O
showed O
good O
safety O
profiles O
. O

Thereafter O
, O
in O
vivo O
studies O
of O
the O
selected O
formulations O
were O
carried O
out O
in O
rats O
and O
the O
pharmacokinetic O
parameters O
were O
calculated O
and O
compared O
with O
that O
of O
intravenous O
injection O
. O

Both O
in O
situ O
and O
in O
vivo O
studies O
demonstrated O
that O
NSCS O
is O
more O
effective O
than O
chitosan O
in O
promoting O
intranasal O
absorption O
of O
ISDN B
. O

Taking O
both O
absorption O
enhancing O
and O
safety O
reason O
into O
account O
, O
we O
suggest O
NSCS O
is O
a O
promising O
intranasal O
absorption O
enhancer O
. O

Implementation O
and O
evaluation O
of O
an O
optical O
fiber O
system O
as O
novel O
process O
monitoring O
tool O
during O
lyophilization O
. O

Lyophilization O
is O
an O
important O
and O
well O
- O
established O
pharmaceutical O
drying O
process O
. O

Product O
temperature O
is O
the O
most O
critical O
process O
parameter O
during O
lyophilization O
as O
it O
impacts O
both O
product O
quality O
and O
process O
efficiency O
. O

Traditionally O
, O
thermocouples O
( O
TCs O
) O
or O
resistance O
temperature O
detectors O
( O
RTDs O
) O
and O
recently O
, O
manometric O
temperatures O
measurements O
( O
MTMs O
) O
have O
been O
used O
to O
monitor O
the O
product O
temperature O
. O

But O
, O
all O
of O
these O
techniques O
have O
several O
drawbacks O
. O

The O
objective O
of O
this O
study O
was O
the O
implementation O
and O
evaluation O
of O
an O
optical O
fiber O
system O
as O
novel O
process O
monitoring O
tool O
during O
lyophilization O
. O

Therefore O
, O
temperature O
profiles O
of O
mannitol B
, O
sucrose B
, O
or O
trehalose B
were O
recorded O
with O
various O
prototypes O
of O
the O
optical O
fiber O
sensors O
( O
OFSs O
) O
and O
compared O
to O
data O
obtained O
with O
conventional O
TCs O
or O
Pirani O
/ O
capacitance O
manometry O
with O
respect O
to O
the O
endpoint O
of O
primary O
drying O
. O

The O
OFS O
allowed O
easy O
handling O
and O
easy O
center O
bottom O
positioning O
. O

Data O
obtained O
with O
the O
OFS O
in O
contact O
with O
product O
were O
in O
good O
agreement O
with O
data O
obtained O
via O
TCs O
or O
Pirani O
/ O
capacitance O
manometry O
. O

The O
OFSs O
showed O
significantly O
higher O
sensitivity O
, O
faster O
response O
, O
and O
better O
resolution O
compared O
to O
TCs B
. O

This O
allowed O
for O
the O
detection O
of O
additional O
excipient O
crystallization O
events O
. O

It O
was O
found O
that O
force O
effects O
on O
unshielded O
sensors O
enabled O
to O
detect O
glass O
transitions O
. O

Three O
- O
dimensional O
temperature O
profiles O
were O
obtained O
with O
an O
OFS O
helix O
configuration O
. O

The O
possible O
integration O
of O
a O
glass O
fiber O
with O
several O
OFSs O
in O
series O
into O
the O
shelf O
surface O
enables O
non O
- O
invasive O
, O
automatic O
loading O
compatible O
monitoring O
of O
the O
drying O
process O
. O

In O
conclusion O
, O
these O
advantages O
turn O
the O
novel O
optical O
fiber O
systems O
into O
a O
highly O
attractive O
process O
monitoring O
tool O
during O
lyophilization O
. O

Establishment O
of O
a O
triple O
co O
- O
culture O
in O
vitro O
cell O
models O
to O
study O
intestinal O
absorption O
of O
peptide O
drugs O
. O

In O
vitro O
cell O
culture O
models O
for O
studying O
oral O
drug O
absorption O
during O
early O
stages O
of O
drug O
development O
have O
become O
a O
useful O
tool O
in O
drug O
discovery O
and O
development O
, O
with O
respect O
to O
substance O
throughput O
and O
reproducibility O
. O

The O
aim O
of O
this O
study O
was O
to O
establish O
an O
in O
vitro O
cellular O
model O
based O
on O
human O
colon O
carcinoma O
Caco O
- O
2 O
, O
mucus O
- O
producing O
HT29 O
, O
and O
Raji O
B O
cells O
in O
order O
to O
design O
a O
model O
that O
more O
accurately O
mimics O
the O
small O
intestinal O
epithelial O
layer O
. O

Normal O
oriented O
model O
was O
set O
up O
by O
seeding O
co O
- O
cultures O
of O
Caco O
- O
2 O
and O
HT29 O
cells O
into O
Transwell O
filters O
and O
maintained O
under O
identical O
conditions O
following O
addition O
of O
Raji O
B O
to O
the O
basolateral O
chamber O
. O

Inverted O
model O
was O
set O
up O
seeding O
Caco O
- O
2 O
and O
HT29 O
cells O
on O
the O
basolateral O
chamber O
and O
then O
transferred O
in O
the O
Transwell O
device O
with O
the O
epithelial O
cells O
facing O
the O
basolateral O
chamber O
following O
Raji O
B O
addition O
to O
the O
apical O
compartment O
. O

Morphological O
differences O
on O
size O
and O
thickness O
of O
cell O
membranes O
were O
detected O
between O
the O
models O
studied O
by O
using O
fluorescence O
microscopy O
. O

On O
the O
triple O
co O
- O
culture O
models O
, O
cell O
membranes O
were O
increasing O
in O
size O
and O
thickness O
from O
the O
Caco O
- O
2 O
to O
Caco O
- O
2 O
/ O
HT29 O
and O
Caco O
- O
2 O
/ O
Raji O
B O
. O
Also O
, O
the O
nuclei O
seem O
to O
be O
larger O
than O
in O
the O
other O
studied O
models O
. O

Insulin O
permeation O
was O
higher O
on O
the O
triple O
co O
- O
culture O
model O
when O
compared O
to O
the O
Caco O
- O
2 O
/ O
HT29 O
co O
- O
culture O
model O
. O

Also O
, O
insulin O
permeation O
as O
mediated O
by O
nanoparticles O
and O
insulin O
solution O
permeation O
was O
higher O
on O
the O
normal O
oriented O
Caco O
- O
2 O
/ O
HT29 O
/ O
Raji O
B O
model O
as O
compared O
to O
the O
inverted O
model O
. O

Overall O
, O
our O
results O
suggest O
that O
Caco O
- O
2 O
/ O
HT29 O
/ O
Raji O
B O
triple O
co O
- O
culture O
normal O
oriented O
cellular O
model O
may O
be O
reliable O
to O
obtain O
a O
more O
physiological O
, O
functional O
, O
and O
reproducible O
in O
vitro O
model O
of O
the O
intestinal O
barrier O
to O
study O
protein O
absorption O
, O
both O
in O
solution O
and O
when O
delivered O
by O
nanocarriers O
. O

Triclosan B
exposure O
alters O
postembryonic O
development O
in O
a O
Pacific O
tree O
frog O
( O
Pseudacris O
regilla O
) O
Amphibian O
Metamorphosis O
Assay O
( O
TREEMA O
) O
. O

The O
Amphibian O
Metamorphosis O
Assay O
( O
AMA O
) O
, O
developed O
for O
Xenopus O
laevis O
, O
is O
designed O
to O
identify O
chemicals O
that O
disrupt O
thyroid O
hormone O
( O
TH O
) O
- O
mediated O
biological O
processes O
. O

We O
adapted O
the O
AMA O
for O
use O
on O
an O
ecologically O
- O
relevant O
North O
American O
species O
, O
the O
Pacific O
tree O
frog O
( O
Pseudacris O
regilla O
) O
, O
and O
applied O
molecular O
endpoints O
to O
evaluate O
the O
effects O
of O
the O
antibacterial O
agent O
, O
triclosan B
( O
TCS B
) O
. O

Premetamorphic O
( O
Gosner O
stage O
26 O
- O
28 O
) O
tadpoles O
were O
immersed O
for O
21 O
days O
in O
solvent O
control O
, O
1 O
. O
5 O
mu O
g O
/ O
L O
thyroxine B
( O
T O
( O
4 O
) O
) O
, O
0 O
. O
3 O
, O
3 O
and O
30 O
mu O
g O
/ O
L O
( O
nominal O
) O
TCS B
, O
or O
combined O
T O
( O
4 O
) O
/ O
TCS B
treatments O
. O

Exposure O
effects O
were O
scored O
by O
morphometric O
( O
developmental O
stage O
, O
wet O
weight O
, O
and O
body O
, O
snout O
- O
vent O
and O
hindlimb O
lengths O
) O
and O
molecular O
( O
mRNA O
abundance O
using O
quantitative O
real O
time O
polymerase O
chain O
reaction O
) O
criteria O
. O

T O
( O
4 O
) O
treatment O
alone O
accelerated O
development O
concomitant O
with O
altered O
levels O
of O
TH O
receptors O
alpha O
and O
beta O
, O
proliferating O
cell O
nuclear O
antigen O
, O
and O
gelatinase O
B O
mRNAs O
in O
the O
brain O
and O
tail O
. O

We O
observed O
TCS B
- O
induced O
perturbations O
in O
all O
of O
the O
molecular O
and O
morphological O
endpoints O
indicating O
that O
TCS B
exposure O
disrupts O
coordination O
of O
postembryonic O
tadpole O
development O
. O

Clear O
alterations O
in O
molecular O
endpoints O
were O
evident O
at O
day O
2 O
whereas O
the O
earliest O
morphological O
effects O
appeared O
at O
day O
4 O
and O
were O
most O
evident O
at O
day O
21 O
. O

Although O
TCS B
alone O
( O
3 O
and O
30 O
mu O
g O
/ O
L O
) O
was O
protective O
against O
tadpole O
mortality O
, O
this O
protection O
was O
lost O
in O
the O
presence O
of O
T O
( O
4 O
) O
. O

The O
Pacific O
tree O
frog O
is O
the O
most O
sensitive O
species O
examined O
to O
date O
displaying O
disruption O
of O
TH O
- O
mediated O
development O
by O
a O
common O
antimicrobial O
agent O
. O

Human O
paraoxonase O
double O
mutants O
hydrolyze O
V O
and O
G O
class O
organophosphorus B
nerve O
agents O
. O

Variants O
of O
human O
paraoxonase O
1 O
( O
PON1 O
) O
are O
being O
developed O
as O
catalytic O
bioscavengers O
for O
the O
organophosphorus B
chemical O
warfare O
agents O
( O
OP O
) O
. O

It O
is O
preferable O
that O
the O
new O
PON1 O
variants O
have O
broad O
spectrum O
hydrolase O
activities O
to O
hydrolyze O
both O
G O
- O
and O
V O
- O
class O
OPs O
. O

H115W O
PON1 O
has O
shown O
improvements O
over O
wild O
type O
PON1 O
in O
its O
capacity O
to O
hydrolyze O
some O
OP O
compounds O
. O

We O
improved O
upon O
these O
activities O
either O
by O
substituting O
a O
tryptophan B
( O
F347W O
) O
near O
the O
putative O
active O
site O
residues O
for O
enhanced O
substrate O
binding O
or O
by O
reducing O
a O
bulky O
group O
( O
Y71A O
) O
at O
the O
periphery O
of O
the O
putative O
enzyme O
active O
site O
. O

When O
compared O
to O
H115W O
alone O
, O
we O
found O
that O
H115W O
/ O
Y71A O
and O
H115W O
/ O
F347W O
maintained O
VX O
catalytic O
efficiency O
but O
showed O
mixed O
results O
for O
the O
capacity O
to O
hydrolyze O
paraoxon B
. O

Testing O
our O
double O
mutants O
against O
racemic B
sarin I
, O
we O
observed O
reduced O
values O
of O
KM O
for O
H115W O
/ O
F347W O
that O
modestly O
improved O
catalytic O
efficiency O
over O
wild O
type O
and O
H115W O
. O

Contrary O
to O
previous O
reports O
, O
we O
show O
that O
H115W O
can O
hydrolyze O
soman B
, O
and O
the O
double O
mutant O
H115W O
/ O
Y71A O
is O
nearly O
4 O
- O
fold O
more O
efficient O
than O
H115W O
for O
paraoxon B
hydrolysis O
. O

We O
also O
observed O
modest O
stereoselectivity O
for O
hydrolysis O
of O
the O
P O
( O
- O
) O
stereoisomer O
of O
tabun B
by O
H115W O
/ O
F347W O
. O

These O
data O
demonstrate O
enhancements O
made O
in O
PON1 O
for O
the O
purpose O
of O
developing O
an O
improved O
catalytic O
bioscavenger O
to O
protect O
cholinesterase O
against O
chemical O
warfare O
agents O
. O

Expression O
of O
cAMP B
- O
responsive O
element O
binding O
proteins O
( O
CREBs O
) O
in O
fast O
- O
and O
slow O
- O
twitch O
muscles O
: O
A O
signaling O
pathway O
to O
account O
for O
the O
synaptic O
expression O
of O
collagen O
- O
tailed O
subunit O
( O
ColQ O
) O
of O
acetylcholinesterase O
at O
the O
rat O
neuromuscular O
junction O
. O

The O
gene O
encoding O
the O
collagen O
- O
tailed O
subunit O
( O
ColQ O
) O
of O
acetylcholinesterase O
( O
AChE O
) O
contains O
two O
distinct O
promoters O
that O
drive O
the O
production O
of O
two O
ColQ O
mRNAs O
, O
ColQ O
- O
1 O
and O
ColQ O
- O
1a O
, O
in O
slow O
- O
and O
fast O
- O
twitch O
muscles O
, O
respectively O
. O

ColQ O
- O
1a O
is O
expressed O
at O
the O
neuromuscular O
junction O
( O
NMJ O
) O
in O
fast O
- O
twitch O
muscle O
, O
and O
this O
expression O
depends O
on O
trophic O
factors O
supplied O
by O
motor O
neurons O
signaling O
via O
a O
cAMP B
- O
dependent O
pathway O
in O
muscle O
. O

To O
further O
elucidate O
the O
molecular O
basis O
of O
ColQ O
- O
1a O
' O
s O
synaptic O
expression O
, O
here O
we O
investigated O
the O
expression O
and O
localization O
of O
cAMP B
- O
responsive O
element O
binding O
protein O
( O
CREB O
) O
at O
the O
synaptic O
and O
extra O
- O
synaptic O
regions O
of O
fast O
- O
and O
slow O
- O
twitch O
muscles O
from O
adult O
rats O
. O

The O
total O
amount O
of O
active O
, O
phosphorylated O
CREB O
( O
P O
- O
CREB O
) O
present O
in O
slow O
- O
twitch O
soleus O
muscle O
was O
higher O
than O
that O
in O
fast O
- O
twitch O
tibialis O
muscle O
, O
but O
P O
- O
CREB O
was O
predominantly O
expressed O
in O
the O
fast O
- O
twitch O
muscle O
at O
NMJs O
. O

In O
contrast O
, O
P O
- O
CREB O
was O
detected O
in O
both O
synaptic O
and O
extra O
- O
synaptic O
regions O
of O
slow O
- O
twitch O
muscle O
. O

These O
results O
reveal O
, O
for O
the O
first O
time O
, O
the O
differential O
distribution O
of O
P O
- O
CREB O
in O
fast O
- O
and O
slow O
- O
twitch O
muscles O
, O
which O
might O
support O
the O
crucial O
role O
of O
cAMP B
- O
dependent O
signaling O
in O
controlling O
the O
synapse O
- O
specific O
expression O
of O
ColQ O
- O
1a O
in O
fast O
- O
twitch O
muscles O
. O

The O
determination O
of O
exogenous O
formaldehyde B
in O
blood O
of O
rats O
during O
and O
after O
inhalation O
exposure O
. O

Formaldehyde B
( O
FA O
) O
is O
suspected O
of O
being O
associated O
with O
the O
development O
of O
leukemia O
. O

An O
inhalation O
experiment O
with O
FA O
was O
performed O
in O
rats O
to O
study O
whether O
FA O
can O
enter O
the O
blood O
and O
could O
thus O
cause O
systemic O
toxicity O
in O
remote O
tissues O
such O
as O
the O
bone O
marrow O
. O

Therefore O
, O
a O
sophisticated O
analytical O
method O
was O
developed O
to O
detect O
blood O
concentrations O
of O
FA O
during O
and O
after O
single O
6 O
- O
h O
exposure O
by O
inhalation O
. O

In O
order O
to O
differentiate O
between O
exogenous O
and O
endogenous O
FA O
the O
rats O
were O
exposed O
to O
stable O
isotope O
( O
( B
13 I
) I
C I
) O
labeled O
FA O
by O
inhalation O
. O

During O
and O
after O
exposure O
of O
the O
rats O
to O
( B
13 I
) I
C I
- I
FA I
their O
blood O
was O
analyzed O
to O
determine O
the O
ratio O
between O
labeled O
and O
natural O
FA O
in O
blood O
and O
the O
total O
blood O
concentration O
of O
FA O
. O

With O
respect O
to O
sensitivity O
, O
with O
the O
applied O
method O
exogenous O
( B
13 I
) I
C I
- I
FA I
could O
have O
been O
detected O
in O
blood O
at O
a O
concentration O
approximately O
1 O
. O
5 O
% O
of O
the O
endogenous O
FA O
blood O
concentration O
. O

Exogenous O
( B
13 I
) I
C I
- I
FA I
was O
not O
detectable O
in O
the O
blood O
of O
rats O
either O
during O
or O
up O
to O
30 O
min O
after O
the O
exposure O
. O

It O
was O
concluded O
that O
the O
inhalation O
of O
( B
13 I
) I
C I
- I
FA I
at O
10 O
ppm O
for O
6h O
did O
not O
result O
in O
an O
increase O
of O
the O
total O
FA O
concentration O
in O
blood O
. O

Analysis O
of O
microRNA O
and O
gene O
expression O
profiling O
in O
triazole B
fungicide O
- O
treated O
HepG2 O
cell O
line O
. O

MicroRNA O
( O
miRNA O
) O
plays O
an O
important O
role O
in O
various O
diseases O
and O
in O
cellular O
and O
molecular O
responses O
to O
toxicants O
. O

In O
the O
present O
study O
, O
we O
investigated O
differential O
expression O
of O
miRNAs O
in O
response O
to O
three O
triazole B
fungicides O
( O
myclobutanil B
, O
propiconazole B
, O
and O
triadimefon B
) O
. O

The O
human O
hepatoma O
cell O
line O
( O
HepG2 O
) O
was O
treated O
with O
the O
above O
triazoles B
for O
3 O
h O
or O
48 O
h O
. O

miRNA O
- O
based O
microarray O
experiments O
were O
carried O
out O
using O
the O
Agilent O
human O
miRNA O
v13 O
array O
. O

At O
early O
exposure O
( O
3h O
) O
, O
six O
miRNAs O
were O
differentially O
expressed O
and O
at O
late O
exposure O
( O
48 O
h O
) O
, O
three O
miRNAs O
were O
significantly O
expressed O
. O

Overall O
, O
this O
study O
provides O
an O
array O
of O
potential O
biomarkers O
for O
the O
above O
triazole B
fungicides O
. O

Furthermore O
, O
these O
miRNAs O
induced O
by O
triazoles B
could O
be O
the O
foundation O
for O
the O
development O
of O
a O
miRNA O
- O
based O
toxic O
biomarker O
library O
that O
can O
predict O
environmental O
toxicity O
. O

Hydroxysafflor B
yellow I
a I
inhibits O
lipopolysaccharide O
- O
induced O
inflammatory O
signal O
transduction O
in O
human O
alveolar O
epithelial O
A549 O
cells O
. O

Hydroxysafflor B
yellow I
A I
( O
HSYA B
) O
is O
an O
active O
ingredient O
obtained O
from O
the O
flower O
of O
Carthamus O
tinctorius O
L O
. O

The O
present O
study O
investigated O
the O
effects O
of O
HSYA B
on O
lipopolysaccharide O
( O
LPS O
) O
- O
induced O
inflammatory O
signal O
transduction O
in O
human O
alveolar O
epithelial O
A549 O
cells O
. O

A549 O
cells O
stimulated O
with O
LPS O
were O
incubated O
with O
three O
doses O
of O
HSYA B
( O
1 O
, O
4 O
and O
16 O
mu O
mol O
/ O
L O
) O
. O

HSYA O
suppressed O
the O
expression O
of O
TLR O
- O
4 O
, O
Myd88 O
, O
ICAM O
- O
1 O
, O
TNF O
alpha O
, O
IL O
- O
1 O
beta O
and O
IL O
- O
6 O
at O
the O
mRNA O
and O
protein O
level O
, O
and O
inhibited O
the O
adhesion O
of O
leukocytes O
to O
A549 O
cells O
. O

HSYA B
treatment O
also O
decreased O
NF O
- O
kappa O
B O
p65 O
nuclear O
translocation O
and O
inhibited O
the O
phosphorylation O
of O
p38 O
mitogen O
- O
activated O
protein O
kinase O
( O
p38 O
MAPK O
) O
. O

These O
findings O
suggest O
that O
HSYA B
effectively O
inhibits O
LPS O
- O
induced O
inflammatory O
signal O
transduction O
in O
A549 O
cells O
. O

CD36 O
homolog O
divergence O
is O
responsible O
for O
the O
selectivity O
of O
carotenoid O
species O
migration O
to O
the O
silk O
gland O
of O
the O
silkworm O
Bombyx O
mori O
. O

Dietary O
carotenoids O
are O
absorbed O
in O
the O
intestine O
and O
delivered O
to O
various O
tissues O
by O
circulating O
lipoproteins O
; O
however O
, O
the O
mechanism O
underlying O
selective O
delivery O
of O
different O
carotenoid O
species O
to O
individual O
tissues O
remains O
elusive O
. O

The O
products O
of O
the O
Yellow O
cocoon O
( O
C O
) O
gene O
and O
the O
Flesh O
( O
F O
) O
gene O
of O
the O
silkworm O
Bombyx O
mori O
determine O
the O
selectivity O
for O
transport O
of O
lutein B
and O
beta B
- I
carotene I
, O
respectively O
, O
to O
the O
silk O
gland O
. O

We O
previously O
showed O
that O
the O
C O
gene O
encodes O
Cameo2 O
, O
a O
CD36 O
family O
member O
, O
which O
is O
thought O
to O
function O
as O
a O
transmembrane O
lipoprotein O
receptor O
. O

Here O
, O
we O
elucidated O
the O
molecular O
identity O
of O
the O
F O
gene O
product O
by O
positional O
cloning O
, O
as O
SCRB15 O
, O
a O
paralog O
of O
Cameo2 O
with O
26 O
% O
amino B
acid I
identity O
. O

In O
the O
F O
mutant O
, O
SCRB15 O
mRNA O
structure O
was O
severely O
disrupted O
, O
due O
to O
a O
1 O
. O
4 O
kb O
genomic O
insertion O
in O
a O
coding O
exon O
. O

Transgenic O
expression O
of O
SCRB15 O
in O
the O
middle O
silk O
gland O
using O
the O
binary O
GAL4 O
- O
UAS O
expression O
system O
enhanced O
selective O
beta B
- I
carotene I
uptake O
by O
the O
middle O
silk O
gland O
, O
while O
transgenic O
expression O
of O
Cameo2 O
enhanced O
selective O
lutein B
uptake O
under O
the O
same O
GAL4 O
driver O
. O

Our O
findings O
indicate O
that O
divergence O
of O
genes O
in O
the O
CD36 O
family O
determines O
the O
selectivity O
of O
carotenoid O
species O
uptake O
by O
silk O
gland O
tissue O
and O
that O
CD36 O
- O
homologous O
proteins O
can O
discriminate O
among O
carotenoid O
species O
. O

Emergence O
of O
superconductivity O
from O
the O
dynamically O
heterogeneous O
insulating O
state O
in O
La B
( I
2 I
- I
x I
) I
Sr I
( I
x I
) I
CuO4 I
. O

A O
central O
issue O
for O
copper B
oxides I
is O
the O
nature O
of O
the O
insulating O
ground O
state O
at O
low O
carrier O
densities O
and O
the O
emergence O
of O
high O
- O
temperature O
superconductivity O
from O
that O
state O
with O
doping O
. O

Even O
though O
this O
superconductor O
- O
insulator O
transition O
( O
SIT O
) O
is O
a O
zero O
- O
temperature O
transition O
, O
measurements O
are O
not O
usually O
carried O
out O
at O
low O
temperatures O
. O

Here O
we O
use O
magnetoresistance O
to O
probe O
both O
the O
insulating O
state O
at O
very O
low O
temperatures O
and O
the O
presence O
of O
superconducting O
fluctuations O
in O
La B
( I
2 I
- I
x I
) I
Sr I
( I
x I
) I
CuO I
( I
4 I
) I
films O
, O
for O
doping O
levels O
that O
range O
from O
the O
insulator O
to O
the O
superconductor O
( O
x O
= O
0 O
. O
03 O
- O
0 O
. O
08 O
) O
. O

We O
observe O
that O
the O
charge O
glass O
behaviour O
, O
characteristic O
of O
the O
insulating O
state O
, O
is O
suppressed O
with O
doping O
, O
but O
it O
coexists O
with O
superconducting O
fluctuations O
that O
emerge O
already O
on O
the O
insulating O
side O
of O
the O
SIT O
. O

The O
unexpected O
quenching O
of O
the O
superconducting O
fluctuations O
by O
the O
competing O
charge O
order O
at O
low O
temperatures O
provides O
a O
new O
perspective O
on O
the O
mechanism O
for O
the O
SIT O
. O

M1 O
. O
3 O
- O
- O
a O
small O
scaffold O
for O
DNA O
origami O
. O

The O
DNA O
origami O
method O
produces O
programmable O
nanoscale O
objects O
that O
form O
when O
one O
long O
scaffold O
strand O
hybridizes O
to O
numerous O
oligonucleotide O
staple O
strands O
. O

One O
scaffold O
strand O
is O
dominating O
the O
field O
: O
M13mp18 O
, O
a O
bacteriophage O
- O
derived O
vector O
7249 O
nucleotides B
in O
length O
. O

The O
full O
- O
length O
M13 O
is O
typically O
folded O
by O
using O
over O
200 O
staple O
oligonucleotides O
. O

Here O
we O
report O
the O
convenient O
preparation O
of O
a O
704 O
nt O
fragment O
dubbed O
" O
M1 O
. O
3 O
" O
as O
a O
linear O
or O
cyclic O
scaffold O
and O
the O
assembly O
of O
small O
origami O
structures O
with O
just O
15 O
- O
24 O
staple O
strands O
. O

A O
typical O
M1 O
. O
3 O
origami O
is O
large O
enough O
to O
be O
visualized O
by O
TEM O
, O
but O
small O
enough O
to O
show O
a O
cooperativity O
in O
its O
assembly O
and O
thermal O
denaturation O
that O
is O
reminiscent O
of O
oligonucleotide O
duplexes O
. O

Due O
to O
its O
medium O
size O
, O
M1 O
. O
3 O
origami O
with O
globally O
modified O
staples O
is O
affordable O
. O

As O
a O
proof O
of O
principle O
, O
two O
origami O
structures O
with O
globally O
5 O
' O
- O
capped O
staples O
were O
prepared O
and O
were O
shown O
to O
give O
higher O
UV O
- O
melting O
points O
than O
the O
corresponding O
assembly O
with O
unmodified O
DNA O
. O

M1 O
. O
3 O
has O
the O
size O
of O
a O
gene O
, O
not O
a O
genome O
, O
and O
may O
function O
as O
a O
model O
for O
gene O
- O
based O
nanostructures O
. O

Small O
origami O
with O
M1 O
. O
3 O
as O
a O
scaffold O
may O
serve O
as O
a O
workbench O
for O
chemical O
, O
physical O
, O
and O
biological O
experiments O
. O

RBCK1 O
, O
an O
E3 O
ubiquitin O
ligase O
, O
interacts O
with O
and O
ubiquinates O
the O
human O
pregnane B
X O
receptor O
. O

The O
pregnane O
X O
receptor O
( O
PXR O
, O
NR1I2 O
) O
plays O
a O
pivotal O
role O
in O
the O
disposition O
and O
detoxification O
of O
numerous O
foreign O
and O
endogenous O
chemicals O
by O
increasing O
transcription O
of O
numerous O
target O
genes O
, O
including O
phase O
I O
and O
II O
drug O
- O
metabolizing O
enzymes O
and O
transporters O
. O

In O
the O
present O
study O
, O
yeast O
two O
- O
hybrid O
screening O
identified O
an O
E3 O
ubiquitin O
ligase O
, O
RBCK1 O
( O
Ring O
- O
B O
- O
box O
- O
coiled O
- O
coil O
protein O
interacting O
with O
protein O
kinase O
C O
- O
1 O
) O
, O
as O
a O
human O
pregnane B
X O
receptor O
( O
hPXR O
) O
- O
interacting O
protein O
. O

Coimmunoprecipitatio O
studies O
confirmed O
the O
interaction O
between O
RBCK1 O
and O
hPXR O
when O
both O
were O
ectopically O
expressed O
in O
AD O
- O
293 O
cells O
. O

Domain O
mapping O
studies O
showed O
that O
the O
interaction O
between O
RBCK1 O
and O
hPXR O
involves O
all O
RBCK1 O
domains O
. O

We O
further O
demonstrate O
that O
RBCK1 O
ubiquitinates O
hPXR O
, O
and O
this O
may O
target O
hPXR O
for O
degradation O
by O
the O
ubiquitin O
- O
proteasome O
pathway O
. O

Simultaneous O
ectopic O
overexpression O
of O
RBCK1 O
and O
PXR O
decreased O
PXR O
levels O
in O
AD O
- O
293 O
cells O
, O
and O
this O
decrease O
was O
inhibited O
by O
the O
proteasomal O
inhibitor O
MG B
- I
132 I
( O
carbobenzoxy B
- I
Leu I
- I
Leu I
- I
leucinal I
) O
. O

Furthermore O
, O
overexpression O
of O
RBCK1 O
decreased O
endogenous O
levels O
of O
PXR O
in O
HepG2 O
cells O
. O

Of O
importance O
, O
ectopic O
overexpression O
and O
silencing O
of O
endogenous O
RBCK1 O
in O
primary O
human O
hepatocytes O
resulted O
in O
a O
decrease O
and O
increase O
, O
respectively O
, O
in O
endogenous O
PXR O
protein O
levels O
and O
in O
the O
induction O
of O
PXR O
target O
genes O
by O
rifampicin B
. O

These O
results O
suggest O
that O
RBCK1 O
is O
important O
for O
the O
ubiquitination O
of O
PXR O
and O
may O
play O
a O
role O
in O
its O
proteasomal O
degradation O
. O

The O
effect O
of O
C B
- O
vacancy O
on O
hydrogen B
storage O
and O
characterization O
of O
H2 B
modes O
on O
Ti B
functionalized O
C60 B
fullerene B
a O
first O
principles O
study O
. O

Density O
functional O
theory O
calculations O
were O
performed O
to O
examine O
the O
effect O
of O
a O
C B
vacancy O
on O
the O
physisorption O
of O
H B
( I
2 I
) I
onto O
Ti B
- O
functionalized O
C B
( I
60 I
) I
fullerene B
when O
H B
( I
2 I
) I
is O
oriented O
along O
the O
x O
- O
, O
y O
- O
, O
and O
z O
- O
axes O
of O
the O
fullerene B
. O

The O
effect O
of O
the O
C B
vacancy O
on O
the O
physisorption O
modes O
of O
H B
( I
2 I
) I
was O
investigated O
as O
a O
function O
of O
H B
( I
2 I
) I
binding O
energy O
within O
the O
energy O
window O
( O
- O
0 O
. O
2 O
to O
- O
0 O
. O
6 O
eV O
) O
targeted O
by O
the O
Department O
of O
Energy O
( O
DOE O
) O
, O
and O
as O
functions O
of O
a O
variety O
of O
other O
physicochemical O
properties O
. O

The O
results O
indicate O
that O
the O
preferential O
orientations O
of O
H B
( I
2 I
) I
in O
the O
defect O
- O
free O
( O
i O
. O
e O
. O
, O
no O
C B
vacancy O
) O
C B
( I
60 I
) I
TiH I
( I
2 I
) I
complex O
are O
along O
the O
x O
- O
and O
y O
- O
axes O
of O
C B
( I
60 I
) I
( O
with O
adsorption O
energies O
of O
- O
0 O
. O
23 O
and O
- O
0 O
. O
21 O
eV O
, O
respectively O
) O
, O
making O
these O
orientations O
the O
most O
suitable O
ones O
for O
hydrogen B
storage O
, O
in O
contrast O
to O
the O
results O
obtained O
for O
defect O
- O
containing O
fullerenes B
. O

The O
defect O
- O
containing O
( O
i O
. O
e O
. O
, O
containing O
a O
C B
vacancy O
) O
C B
( I
59 I
) I
TiH I
( I
2 I
) I
complex O
do O
not O
exhibit O
adsorption O
energies O
within O
the O
targeted O
energy O
range O
. O

Charge O
transfer O
occurs O
from O
Ti B
3d O
to O
C B
2p O
of O
the O
fullerene B
. O

The O
binding O
of O
H B
( I
2 I
) I
is O
dominated O
by O
the O
pairwise O
support O
- O
metal O
interaction O
energy O
E O
( O
i O
) O
( O
Cn B
. O
. O
. O
Ti B
) O
, O
and O
the O
role O
of O
the O
fullerene B
is O
not O
restricted O
to O
supporting O
the O
metal O
. O

The O
C B
vacancy O
enhances O
the O
adsorption O
energy O
of O
Ti B
, O
in O
contrast O
to O
that O
of O
H B
( I
2 I
) I
. O

A O
significant O
reduction O
in O
the O
energy O
gap O
of O
the O
pristine O
C B
( I
60 I
) I
fullerene B
is O
observed O
when O
TiH B
( I
2 I
) I
is O
adsorbed O
by O
it O
. O

While O
the O
C B
( I
n I
) I
fullerene B
readily O
participates O
in O
nucleophilic O
processes O
, O
the O
adjacent O
TiH B
( I
2 I
) I
fragment O
is O
available O
for O
electrophilic O
processes O
. O

Functional O
characterization O
of O
three O
mouse O
formyl B
peptide O
receptors O
. O

The O
evolutionary O
relationship O
and O
functional O
correlation O
between O
human O
formyl B
peptide O
receptors O
( O
FPRs O
) O
and O
their O
mouse O
counterparts O
remain O
incompletely O
understood O
. O

We O
examined O
three O
members O
of O
the O
mouse O
formyl B
peptide O
receptor O
subfamily O
( O
mFprs O
) O
and O
found O
that O
they O
differ O
in O
agonist O
preference O
and O
cellular O
distributions O
. O

When O
stably O
expressed O
in O
transfected O
rat O
basophilic O
leukemia O
( O
RBL O
- O
2H3 O
) O
cells O
, O
mFpr1 O
was O
readily O
activated O
by O
N B
- I
formylated I
peptides O
derived O
from O
Listeria O
monocytogenes O
( O
fMIVTLF O
) O
, O
Staphylococcus O
aureus O
( O
fMIFL O
) O
, O
and O
mitochondria O
( O
fMMYALF O
) O
. O

In O
contrast O
, O
the O
Escherichia O
coli O
- O
derived O
fMLF O
was O
1000 O
- O
fold O
less O
potent O
. O

The O
aforementioned O
peptides O
were O
much O
less O
efficacious O
at O
mFpr2 O
, O
which O
responded O
better O
to O
the O
synthetic O
hexapeptide O
WKYMVm O
, O
the O
synthetic O
agonists O
Quin B
- O
C1 O
( O
a O
substituted O
quinazolinone B
) O
, O
and O
compound O
43 O
( O
a O
nitrosylated B
pyrazolone I
derivative O
) O
. O

Saturation O
binding O
assays O
showed O
that O
mFpr1 O
and O
mFpr2 O
were O
expressed O
at O
similar O
levels O
on O
the O
cell O
surface O
, O
although O
their O
affinity O
for O
N B
- I
formyl I
- I
Met I
- I
Leu I
- I
Phe I
- I
Ile I
- I
Ile I
- I
Lys I
- I
fluorescein I
isothiocyanate I
varied O
by O
more O
than O
1000 O
- O
fold O
[ O
dissociation O
constant O
( O
K O
( O
d O
) O
) O
values O
of O
2 O
. O
8 O
nM O
for O
mFpr1 O
and O
4 O
. O
8 O
mu O
M O
for O
mFpr2 O
] O
) O
. O

Contrary O
to O
these O
receptors O
, O
mFpr O
- O
rs1 O
responded O
poorly O
to O
all O
the O
previously O
mentioned O
peptides O
that O
were O
tested O
. O

Fluorescent O
microscopy O
revealed O
an O
intracellular O
distribution O
pattern O
of O
mFpr O
- O
rs1 O
. O

On O
the O
basis O
of O
these O
results O
, O
we O
conclude O
that O
mFpr1 O
is O
an O
ortholog O
of O
human O
FPR1 O
with O
certain O
pharmacologic O
properties O
of O
human O
FPR2 O
/ O
ALX O
, O
whereas O
mFpr2 O
has O
much O
lower O
affinity O
for O
formyl B
peptides O
. O

The O
intracellular O
distribution O
of O
mFpr O
- O
rs1 O
suggests O
an O
evolutionary O
correlation O
with O
human O
FPR3 O
. O

The O
role O
of O
voltage O
- O
gated O
potassium B
channels O
Kv2 O
. O
1 O
and O
Kv2 O
. O
2 O
in O
the O
regulation O
of O
insulin O
and O
somatostatin O
release O
from O
pancreatic O
islets O
. O

The O
voltage O
- O
gated O
potassium B
channels O
Kv2 O
. O
1 O
and O
Kv2 O
. O
2 O
are O
highly O
expressed O
in O
pancreatic O
islets O
, O
yet O
their O
contribution O
to O
islet O
hormone O
secretion O
is O
not O
fully O
understood O
. O

Here O
we O
investigate O
the O
role O
of O
Kv2 O
channels O
in O
pancreatic O
islets O
using O
a O
combination O
of O
genetic O
and O
pharmacologic O
approaches O
. O

Pancreatic O
beta O
- O
cells O
from O
Kv2 O
. O
1 O
( O
- O
/ O
- O
) O
mice O
possess O
reduced O
Kv O
current O
and O
display O
greater O
glucose B
- O
stimulated O
insulin O
secretion O
( O
GSIS O
) O
relative O
to O
WT O
beta O
- O
cells O
. O

Inhibition O
of O
Kv2 O
. O
x O
channels O
with O
selective O
peptidyl O
[ O
guangxitoxin O
- O
1E O
( O
GxTX O
- O
1E O
) O
] O
or O
small O
molecule O
( O
RY796 O
) O
inhibitors O
enhances O
GSIS O
in O
isolated O
wild O
- O
type O
( O
WT O
) O
mouse O
and O
human O
islets O
, O
but O
not O
in O
islets O
from O
Kv2 O
. O
1 O
( O
- O
/ O
- O
) O
mice O
. O

However O
, O
in O
WT O
mice O
neither O
inhibitor O
improved O
glucose B
tolerance O
in O
vivo O
. O

GxTX O
- O
1E O
and O
RY796 B
enhanced O
somatostatin B
release O
in O
isolated O
human O
and O
mouse O
islets O
and O
in O
situ O
perfused O
pancreata O
from O
WT O
and O
Kv2 O
. O
1 O
( O
- O
/ O
- O
) O
mice O
. O

Kv2 O
. O
2 O
silencing O
in O
mouse O
islets O
by O
adenovirus O
- O
small O
hairpin O
RNA O
( O
shRNA O
) O
specifically O
enhanced O
islet O
somatostatin B
, O
but O
not O
insulin O
, O
secretion O
. O

In O
mice O
lacking O
somatostatin B
receptor O
5 O
, O
GxTX O
- O
1E O
stimulated O
insulin O
secretion O
and O
improved O
glucose B
tolerance O
. O

Collectively O
, O
these O
data O
show O
that O
Kv2 O
. O
1 O
regulates O
insulin O
secretion O
in O
beta O
- O
cells O
and O
Kv2 O
. O
2 O
modulates O
somatostatin B
release O
in O
delta O
- O
cells O
. O

Development O
of O
selective O
Kv2 O
. O
1 O
inhibitors O
without O
cross O
inhibition O
of O
Kv2 O
. O
2 O
may O
provide O
new O
avenues O
to O
promote O
GSIS O
for O
the O
treatment O
of O
type O
2 O
diabetes O
. O

Effects O
of O
a O
bioassay O
- O
derived O
ivermectin B
lowest O
observed O
effect O
concentration O
on O
life O
- O
cycle O
traits O
of O
the O
nematode O
Caenorhabditis O
elegans O
. O

The O
pharmaceutical O
ivermectin B
is O
used O
to O
treat O
parasitic O
infections O
, O
such O
as O
those O
caused O
by O
nematodes O
. O

While O
several O
studies O
have O
demonstrated O
the O
severe O
effects O
of O
ivermectin B
on O
non O
- O
target O
organisms O
, O
little O
is O
known O
about O
the O
drug O
' O
s O
impact O
on O
free O
- O
living O
nematodes O
. O

In O
the O
present O
work O
, O
a O
full O
life O
- O
cycle O
experiment O
was O
conducted O
to O
estimate O
how O
an O
ivermectin B
lowest O
observed O
effect O
concentration O
derived O
from O
a O
Caenorhabditis O
elegans O
bioassay O
( O
endpoint O
reproduction O
) O
might O
translate O
into O
effects O
at O
the O
population O
level O
of O
this O
free O
- O
living O
nematode O
. O

The O
results O
showed O
that O
fecundity O
decreased O
to O
levels O
similar O
to O
those O
determined O
in O
the O
bioassay O
after O
a O
time O
of O
corresponding O
duration O
( O
18 O
. O
6 O
% O
inhibition O
compared O
to O
the O
control O
) O
, O
but O
the O
impact O
then O
rather O
weakened O
until O
the O
end O
of O
the O
experiment O
, O
at O
which O
point O
the O
net O
reproductive O
rate O
( O
R O
( O
0 O
) O
) O
was O
still O
, O
but O
not O
significantly O
, O
reduced O
by O
12 O
. O
4 O
% O
. O

Moreover O
, O
the O
average O
lifespan O
, O
length O
of O
the O
reproductive O
period O
, O
maximum O
daily O
reproduction O
rate O
, O
and O
intrinsic O
rate O
of O
increase O
( O
r O
( O
m O
) O
) O
were O
significantly O
reduced O
by O
30 O
. O
0 O
, O
25 O
. O
9 O
, O
11 O
. O
2 O
, O
and O
3 O
. O
5 O
% O
, O
respectively O
. O

The O
experiment O
revealed O
that O
a O
4 O
- O
day O
bioassay O
is O
protective O
enough O
for O
C O
. O
elegans O
with O
respect O
to O
ivermectin B
' O
s O
effects O
on O
fecundity O
. O

However O
, O
the O
pronounced O
effects O
of O
a O
low O
drug O
concentration O
on O
survival O
, O
a O
highly O
elastic O
trait O
, O
may O
better O
account O
for O
the O
observed O
population O
- O
level O
response O
, O
i O
. O
e O
. O
, O
a O
decrease O
of O
r O
( O
m O
) O
, O
than O
the O
effects O
on O
fecundity O
. O

These O
results O
emphasize O
that O
full O
life O
- O
cycle O
experiments O
are O
valuable O
for O
assessment O
of O
pollutants O
, O
because O
the O
effects O
on O
several O
life O
- O
cycle O
traits O
can O
be O
simultaneously O
measured O
and O
integrated O
into O
an O
ecologically O
relevant O
parameter O
, O
the O
population O
growth O
rate O
, O
that O
reflects O
a O
population O
' O
s O
response O
to O
a O
specific O
pollutant O
. O

Interspecific O
effects O
of O
4A O
- O
DNT O
( O
4 B
- I
amino I
- I
2 I
, I
6 I
- I
dinitrotoluene I
) O
and O
RDX O
( O
1 B
, I
3 I
, I
5 I
- I
trinitro I
- I
1 I
, I
3 I
, I
5 I
- I
triazine I
) O
in O
Japanese O
quail O
, O
Northern O
bobwhite O
, O
and O
Zebra O
finch O
. O

The O
purpose O
of O
this O
study O
was O
to O
assess O
the O
toxicological O
effects O
of O
two O
munition O
compounds O
, O
4 B
- I
amino I
- I
2 I
, I
6 I
- I
dinitrotoluene I
( O
4A O
- O
DNT O
) O
and O
1 B
, I
3 I
, I
5 I
- I
trinitro I
- I
1 I
, I
3 I
, I
5 I
- I
triazine I
( O
RDX O
) O
, O
on O
three O
different O
bird O
species O
: O
two O
common O
toxicological O
model O
species O
- O
the O
Northern O
Bobwhite O
( O
Colinus O
virginianus O
) O
and O
the O
Japanese O
Quail O
( O
Coturnix O
japonica O
) O
, O
and O
a O
representative O
passerine O
- O
the O
Zebra O
Finch O
( O
Taeniopygia O
guttata O

) O
. O

Bobwhite O
were O
exposed O
to O
4A B
- I
DNT I
at O
0 O
, O
8 O
, O
15 O
, O
30 O
, O
60 O
, O
or O
150 O
mg O
/ O
kg O
body O
weight O
( O
bw O
) O
d O
by O
oral O
gavage O
for O
seven O
days O
; O
because O
the O
high O
dose O
of O
4A B
- I
DNT I
was O
lethal O
to O
bobwhite O
, O
the O
maximum O
dose O
was O
changed O
to O
100 O
mg O
/ O
kg O
bw O
d O
for O
Japanese O
quail O
and O
finches O
to O
ensure O
tissue O
could O
be O
used O
for O
future O
toxicogenomic O
work O
. O

RDX O
was O
similarly O
administered O
at O
0 O
, O
0 O
. O
5 O
, O
1 O
. O
5 O
, O
3 O
, O
6 O
, O
or O
12 O
mg O
/ O
kg O
bw O
d O
. O

Blood O
was O
drawn O
prior O
to O
euthanasia O
for O
blood O
cellularity O
and O
chemistry O
analyses O
. O

Finches O
were O
clearly O
least O
affected O
by O
4A B
- I
DNT I
as O
evidenced O
by O
a O
lack O
of O
observable O
effects O
. O

Bobwhite O
appeared O
to O
be O
the O
most O
sensitive O
species O
to O
4A B
- I
DNT I
as O
observed O
through O
changes O
in O
blood O
cellularity O
and O
plasma O
chemistry O
effects O
. O

Bobwhite O
appeared O
to O
be O
more O
sensitive O
to O
RDX O
than O
Japanese O
Quail O
due O
to O
increased O
effects O
on O
measures O
of O
plasma O
chemistries O
. O

Finches O
exhibited O
the O
greatest O
sensitivity O
to O
RDX O
through O
increased O
mortality O
and O
seizure O
activity O
. O

This O
study O
suggests O
that O
sensitivity O
among O
species O
is O
chemical O
- O
specific O
and O
provides O
data O
that O
could O
be O
used O
to O
refine O
current O
avian O
sensitivity O
models O
used O
in O
ecological O
risk O
assessments O
. O

Ilexpublesnins B
C I
- I
M I
, O
eleven O
new O
triterpene B
saponins I
from O
the O
roots O
of O
Ilex O
pubescens O
. O

Eleven O
new O
triterpene B
saponins I
, O
ilexpublesnins B
C I
- I
M I
( O
1 O
- O
11 O
) O
, O
along O
with O
ten O
known O
analogues O
were O
isolated O
from O
the O
roots O
of O
Ilex O
pubescens O
. O

Their O
structures O
were O
elucidated O
on O
the O
basis O
of O
extensive O
spectroscopic O
analysis O
, O
including O
1D O
and O
2D O
NMR O
experiments O
. O

Compounds O
1 O
, O
2 O
, O
10 O
, O
and O
11 O
contain O
a O
24 B
- I
aldehyde I
, O
which O
is O
rare O
for O
triterpene B
saponins I
from O
Ilex O
. O

These O
compounds O
were O
evaluated O
in O
vitro O
for O
their O
cytotoxic O
effects O
on O
human O
cancer O
cell O
lines O
HepG2 O
, O
HLE O
, O
BEL7402 O
, O
BEL7403 O
, O
BEL7405 O
, O
MCF O
- O
7 O
, O
and O
HeLa O
. O

Among O
them O
, O
only O
compounds O
6 O
and O
19 O
showed O
cytotoxicity O
against O
the O
MCF O
- O
7 O
cell O
line O
[ O
inhibition O
( O
% O
) O
: O
33 O
. O
14 O
and O
34 O
. O
03 O
, O
respectively O
] O
. O

Two O
- O
stage O
metal O
- O
catalyst O
- O
free O
growth O
of O
high O
- O
quality O
polycrystalline O
graphene B
films O
on O
silicon B
nitride I
substrates O
. O

By O
using O
two O
- O
stage O
, O
metal O
- O
catalyst O
- O
free O
chemical O
vapor O
deposition O
( O
CVD O
) O
, O
it O
is O
demonstrated O
that O
high O
- O
quality O
polycrystalline O
graphene B
films O
can O
directly O
grow O
on O
silicon B
nitride I
substrates O
. O

The O
carrier O
mobility O
can O
reach O
about O
1500 O
cm O
( O
2 O
) O
V O
( O
- O
1 O
) O
s O
( O
- O
1 O
) O
, O
which O
is O
about O
three O
times O
the O
value O
of O
those O
grown O
on O
SiO B
( I
2 I
) I
/ O
Si B
substrates O
, O
and O
also O
is O
better O
than O
some O
examples O
of O
metal O
- O
catalyzed O
graphene B
, O
reflecting O
the O
good O
quality O
of O
the O
graphene B
lattice O
. O

Relationship O
of O
land O
use O
and O
elevated O
ionic O
strength O
in O
Appalachian O
watersheds O
. O

Coal B
mining O
activities O
have O
been O
implicated O
as O
sources O
that O
increase O
stream O
specific O
conductance O
in O
Central O
Appalachia O
. O

The O
present O
study O
characterized O
potential O
sources O
of O
elevated O
ionic O
strength O
for O
small O
subwatersheds O
within O
the O
Coal O
, O
Upper O
Kanawha O
, O
Gauley O
, O
and O
New O
Rivers O
in O
West O
Virginia O
. O

From O
a O
large O
monitoring O
data O
set O
developed O
by O
the O
West O
Virginia O
Department O
of O
Environmental O
Protection O
, O
162 O
< O
20 O
- O
km O
( O
2 O
) O
- O
watersheds O
were O
identified O
that O
had O
detailed O
land O
cover O
information O
in O
southwestern O
West O
Virginia O
with O
at O
least O
one O
water O
chemistry O
sample O
. O

Scatter O
plots O
of O
specific O
conductance O
were O
generated O
for O
nine O
land O
cover O
classifications O
: O
open O
water O
, O
agriculture O
, O
forest O
, O
residential O
, O
barren O
, O
total O
mining O
, O
valley O
fill O
, O
abandoned O
mine O
lands O
, O
and O
mining O
excluding O
valley O
fill O
and O
abandoned O
mine O
lands O
. O

Conductivity O
was O
negatively O
correlated O
with O
the O
percentage O
of O
forest O
area O
and O
positively O
associated O
with O
other O
land O
uses O
. O

In O
a O
multiple O
regression O
, O
the O
percentage O
of O
area O
in O
valley O
fill O
was O
the O
strongest O
contributor O
to O
increased O
ionic O
strength O
, O
followed O
by O
percentage O
of O
area O
in O
urban O
( O
residential O
/ O
buildings O
) O
land O
use O
and O
other O
mining O
land O
use O
. O

Based O
on O
the O
10th O
quantile O
regression O
, O
300 O
micro O
S O
/ O
cm O
was O
exceeded O
at O
3 O
. O
3 O
% O
of O
area O
in O
valley O
fill O
. O

In O
most O
catchments O
, O
HCO B
3 I
( I
- I
) I
and O
SO B
4 I
( I
2 I
- I
) I
concentrations O
were O
greater O
than O
Cl B
( I
- I
) I
concentration O
. O

These O
findings O
confirm O
coal B
mining O
activities O
as O
the O
primary O
source O
of O
high O
conductivity O
waters O
. O

Such O
activities O
might O
be O
redressed O
with O
the O
goal O
of O
protecting O
sources O
of O
dilute O
freshwater O
in O
the O
region O
. O

Next O
generation O
sequencing O
in O
predicting O
gene O
function O
in O
podophyllotoxin O
biosynthesis O
. O

Podophyllum O
species O
are O
sources O
of O
( B
- I
) I
- I
podophyllotoxin I
, O
an O
aryltetralin B
lignan I
used O
for O
semi O
- O
synthesis O
of O
various O
powerful O
and O
extensively O
employed O
cancer O
- O
treating O
drugs O
. O

Its O
biosynthetic O
pathway O
, O
however O
, O
remains O
largely O
unknown O
, O
with O
the O
last O
unequivocally O
demonstrated O
intermediate O
being O
( B
- I
) I
- I
matairesinol I
. O

Herein O
, O
massively O
parallel O
sequencing O
of O
Podophyllum O
hexandrum O
and O
Podophyllum O
peltatum O
transcriptomes O
and O
subsequent O
bioinformatics O
analyses O
of O
the O
corresponding O
assemblies O
were O
carried O
out O
. O

Validation O
of O
the O
assembly O
process O
was O
first O
achieved O
through O
confirmation O
of O
assembled O
sequences O
with O
those O
of O
various O
genes O
previously O
established O
as O
involved O
in O
podophyllotoxin O
biosynthesis O
as O
well O
as O
other O
candidate O
biosynthetic O
pathway O
genes O
. O

This O
contribution O
describes O
characterization O
of O
two O
of O
the O
latter O
, O
namely O
the O
cytochrome O
P450s O
, O
CYP719A23 O
from O
P O
. O
hexandrum O
and O
CYP719A24 O
from O
P O
. O
peltatum O
. O

Both O
enzymes O
were O
capable O
of O
converting O
( B
- I
) I
- I
matairesinol I
into O
( B
- I
) I
- I
pluviatolide I
by O
catalyzing O
methylenedioxy B
bridge O
formation O
and O
did O
not O
act O
on O
other O
possible O
substrates O
tested O
. O

Interestingly O
, O
the O
enzymes O
described O
herein O
were O
highly O
similar O
to O
methylenedioxy B
bridge O
- O
forming O
enzymes O
from O
alkaloid O
biosynthesis O
, O
whereas O
candidates O
more O
similar O
to O
lignan O
biosynthetic O
enzymes O
were O
catalytically O
inactive O
with O
the O
substrates O
employed O
. O

This O
overall O
strategy O
has O
thus O
enabled O
facile O
further O
identification O
of O
enzymes O
putatively O
involved O
in O
( B
- I
) I
- I
podophyllotoxin I
biosynthesis O
and O
underscores O
the O
deductive O
power O
of O
next O
generation O
sequencing O
and O
bioinformatics O
to O
probe O
and O
deduce O
medicinal O
plant O
biosynthetic O
pathways O
. O

Phosphorylation O
of O
dopamine B
transporter O
serine B
7 O
modulates O
cocaine B
analog O
binding O
. O

As O
an O
approach O
to O
elucidating O
dopamine B
transporter O
( O
DAT O
) O
phosphorylation O
characteristics O
, O
we O
examined O
in O
vitro O
phosphorylation O
of O
a O
recombinant O
rat O
DAT O
N B
- O
terminal O
peptide O
( O
NDAT O
) O
using O
purified O
protein O
kinases O
. O

We O
found O
that O
NDAT O
becomes O
phosphorylated O
at O
single O
distinct O
sites O
by O
protein O
kinase O
A O
( O
Ser B
- O
7 O
) O
and O
calcium B
- O
calmodulin O
- O
dependent O
protein O
kinase O
II O
( O
Ser B
- O
13 O
) O
and O
at O
multiple O
sites O
( O
Ser B
- O
4 O
, O
Ser B
- O
7 O
, O
and O
Ser B
- O
13 O
) O
by O
protein O
kinase O
C O
( O
PKC O
) O
, O
implicating O
these O
residues O
as O
potential O
sites O
of O
DAT O
phosphorylation O
by O
these O
kinases O
. O

Mapping O
of O
rat O
striatal O
DAT O
phosphopeptides O
by O
two O
- O
dimensional O
thin O
layer O
chromatography O
revealed O
basal O
and O
PKC O
- O
stimulated O
phosphorylation O
of O
the O
same O
peptide O
fragments O
and O
comigration O
of O
PKC O
- O
stimulated O
phosphopeptide O
fragments O
with O
NDAT O
Ser B
- O
7 O
phosphopeptide O
markers O
. O

We O
further O
confirmed O
by O
site O
- O
directed O
mutagenesis O
and O
mass O
spectrometry O
that O
Ser B
- O
7 O
is O
a O
site O
for O
PKC O
- O
stimulated O
phosphorylation O
in O
heterologously O
expressed O
rat O
and O
human O
DATs O
. O

Mutation O
of O
Ser B
- O
7 O
and O
nearby O
residues O
strongly O
reduced O
the O
affinity O
of O
rat O
DAT O
for O
the O
cocaine B
analog O
( B
- I
) I
- I
2 I
beta I
- I
carbomethoxy I
- I
3 I
beta I
- I
( I
4 I
- I
fluorophenyl I
) I
tropane I
( O
CFT B
) O
, O
whereas O
in O
rat O
striatal O
tissue O
, O
conditions O
that O
promote O
DAT O
phosphorylation O
caused O
increased O
CFT B
affinity O
. O

Ser B
- O
7 O
mutation O
also O
affected O
zinc B
modulation O
of O
CFT O
binding O
, O
with O
Ala B
and O
Asp B
substitutions O
inducing O
opposing O
effects O
. O

These O
results O
identify O
Ser B
- O
7 O
as O
a O
major O
site O
for O
basal O
and O
PKC O
- O
stimulated O
phosphorylation O
of O
native O
and O
expressed O
DAT O
and O
suggest O
that O
Ser B
- O
7 O
phosphorylation O
modulates O
transporter O
conformational O
equilibria O
, O
shifting O
the O
transporter O
between O
high O
and O
low O
affinity O
cocaine B
binding O
states O
. O

A O
method O
for O
assessing O
causation O
of O
field O
exposure O
- O
response O
relationships O
. O

Because O
associations O
between O
agents O
and O
environmental O
effects O
are O
not O
necessarily O
causal O
, O
it O
is O
necessary O
to O
assess O
causation O
before O
using O
such O
relationships O
in O
environmental O
management O
. O

The O
authors O
adapted O
epidemiological O
methods O
to O
assess O
general O
causal O
hypotheses O
. O

General O
causation O
establishes O
that O
an O
agent O
is O
capable O
of O
causing O
an O
effect O
. O

The O
method O
uses O
all O
relevant O
and O
good O
- O
quality O
evidence O
in O
a O
weight O
- O
of O
- O
evidence O
system O
. O

The O
system O
is O
credible O
due O
to O
its O
explicit O
a O
priori O
criteria O
. O

The O
evidence O
is O
organized O
in O
terms O
of O
six O
characteristics O
of O
causation O
: O
co O
- O
occurrence O
, O
preceding O
causation O
, O
interaction O
, O
alteration O
, O
sufficiency O
, O
and O
time O
order O
. O

The O
causal O
assessment O
proceeds O
through O
six O
steps O
that O
generate O
, O
organize O
, O
and O
score O
evidence O
to O
determine O
whether O
causation O
is O
adequately O
supported O
by O
the O
body O
of O
evidence O
. O

Application O
of O
multiple O
geochemical O
markers O
to O
investigate O
organic O
pollution O
in O
a O
dynamic O
coastal O
zone O
. O

Multiple O
geochemical O
markers O
, O
including O
aliphatic B
hydrocarbons I
( O
n B
- I
alkanes I
) O
, O
linear B
alkylbenzenes I
( O
LABs O
) O
, O
and O
polycyclic B
aromatic I
hydrocarbons I
( O
PAHs B
) O
, O
were O
employed O
to O
relate O
sediment O
organic O
chemical O
pollution O
in O
the O
coastal O
zone O
off O
South O
China O
to O
socioeconomic O
development O
there O
. O

Concentrations O
of O
Sigma O
n B
- O
C I
( O
15 O
- O
35 O
) O
( O
n B
- I
alkanes I
with O
15 O
- O
35 O
carbon B
atoms O
) O
, O
Sigma O
LAB O
( O
sum O
of O
C B
( O
10 O
) O
to O
C B
( O
13 O
) O
LABs O
) O
, O
and O
Sigma O
( O
26 O
) O
PAH B
( O
sum O
of O
26 O
PAH B
compounds O
) O
ranged O
from O
110 O
to O
3 O
, O
160 O
, O
11 O
to O
160 O
, O
and O
26 O
to O
600 O
ng O
/ O
g O
, O
with O
medians O
of O
730 O
, O
40 O
, O
and O
230 O
ng O
/ O
g O
, O
respectively O
. O

Natural O
hydrocarbons B
were O
mainly O
derived O
from O
terrestrial O
higher O
plant O
waxes O
, O
and O
in O
minor O
amounts O
from O
aquatic O
plankton O
and O
bacteria O
. O

Compositions O
of O
LABs O
indicated O
that O
considerable O
amounts O
of O
poorly O
treated O
wastewater O
had O
been O
directly O
discharged O
or O
transported O
to O
the O
eastern O
and O
western O
coastal O
areas O
of O
Guangdong O
Province O
. O

In O
addition O
, O
anthropogenic O
hydrocarbons B
were O
derived O
largely O
from O
vehicular O
emissions O
and O
combustion O
of O
domestic O
coal B
and O
biomass O
and O
to O
a O
lesser O
extent O
from O
oil O
spills O
. O

Eastern O
and O
western O
coastal O
sediments O
contained O
higher O
levels O
of O
LABs O
but O
lower O
levels O
of O
PAHs B
than O
those O
of O
the O
Pearl O
River O
Estuary O
, O
a O
coastal O
area O
of O
the O
Pearl O
River O
Delta O
. O

This O
spatial O
pattern O
of O
organic O
pollution O
was O
consistent O
with O
chemical O
use O
patterns O
. O

The O
eastern O
and O
western O
regions O
of O
Guangdong O
Province O
are O
economically O
less O
developed O
than O
the O
Pearl O
River O
Delta O
region O
, O
where O
more O
domestic O
wastewater O
treatment O
plants O
have O
been O
built O
. O

However O
, O
greater O
amounts O
of O
energy O
are O
consumed O
in O
the O
latter O
region O
to O
produce O
more O
combustion O
- O
derived O
PAH O
contamination O
. O

Comparison O
of O
gel O
- O
based O
phosphoproteomic O
approaches O
to O
analyse O
scarce O
oviductal O
epithelial O
cell O
samples O
. O

The O
reversible O
change O
of O
the O
phosphorylation O
state O
of O
proteins O
regulates O
key O
cellular O
processes O
. O

In O
the O
present O
study O
, O
three O
different O
gel O
- O
based O
approaches O
were O
compared O
with O
regard O
to O
their O
applicability O
to O
quantitatively O
analyse O
the O
phosphoproteome O
of O
scarce O
biological O
material O
obtained O
ex O
vivo O
. O

Our O
results O
show O
that O
the O
phosphoproteome O
characterisation O
of O
oviductal O
epithelial O
cells O
isolated O
from O
the O
female O
reproductive O
tract O
requires O
affinity O
enrichment O
and O
pre O
- O
electrophoretic O
labelling O
using O
fluorescence O
dyes O
. O

Using O
this O
approach O
, O
30 O
mu O
g O
of O
enriched O
phosphoproteins O
proved O
to O
be O
sufficient O
for O
the O
phosphoproteome O
characterisation O
. O

In O
contrast O
, O
sequential O
fluorescence O
staining O
of O
2D O
- O
separated O
total O
cell O
lysates O
as O
well O
as O
sequential O
staining O
in O
conjunction O
with O
a O
pre O
- O
enrichment O
step O
led O
to O
detection O
discrepancies O
and O
excluded O
further O
analysis O
steps O
. O

Information O
gained O
from O
this O
study O
provides O
a O
successful O
approach O
for O
the O
phosphoproteome O
analysis O
of O
scarce O
samples O
. O

In O
addition O
, O
the O
cellular O
processes O
taking O
place O
in O
the O
female O
reproductive O
tract O
can O
be O
monitored O
ex O
vivo O
. O

Large O
area O
resist O
- O
free O
soft O
lithographic O
patterning O
of O
graphene B
. O

Large O
area O
low O
- O
cost O
patterning O
is O
a O
challenging O
problem O
in O
graphene B
research O
. O

A O
resist O
- O
free O
, O
single O
- O
step O
, O
large O
area O
and O
cost O
effective O
soft O
lithographic O
patterning O
strategy O
is O
presented O
for O
graphene B
. O

The O
technique O
is O
applicable O
on O
any O
arbitrary O
substrate O
that O
needs O
to O
be O
covered O
with O
a O
graphene B
film O
and O
provides O
a O
viable O
route O
to O
large O
- O
area O
patterning O
of O
graphene B
for O
device O
applications O
. O

Do O
Subtoxic O
levels O
of O
chlorate B
influence O
the O
desiccation O
tolerance O
of O
Egeria O
densa O
? O

Among O
the O
different O
factors O
hypothesized O
to O
be O
responsible O
for O
the O
virtual O
disappearance O
of O
Egeria O
densa O
, O
once O
a O
dominant O
aquatic O
macrophyte O
in O
a O
southern O
Chile O
wetland O
ecosystem O
, O
are O
the O
negative O
effects O
of O
certain O
chemical O
compounds O
( O
mainly O
chlorate B
) O
and O
harsh O
environmental O
conditions O
( O
desiccation O
caused O
by O
prolonged O
atmospheric O
exposure O
) O
. O

The O
authors O
performed O
an O
integrated O
experiment O
in O
which O
E O
. O
densa O
plants O
were O
first O
exposed O
for O
four O
weeks O
inside O
a O
mesocosm O
system O
to O
levels O
of O
chlorate B
that O
existed O
in O
the O
wetland O
at O
the O
time O
of O
the O
plant O
' O
s O
demise O
and O
then O
exposed O
to O
desiccation O
conditions O
that O
also O
resembled O
those O
that O
the O
system O
had O
experienced O
. O

Hence O
, O
the O
authors O
tested O
the O
hypothesis O
that O
E O
. O
densa O
plants O
exposed O
to O
sublethal O
levels O
of O
chlorate B
are O
more O
susceptible O
to O
the O
deleterious O
effect O
of O
desiccation O
compared O
with O
plants O
that O
had O
not O
been O
exposed O
to O
chlorate B
. O

This O
hypothesis O
was O
tested O
by O
means O
of O
quantifying O
physiologically O
related O
parameters O
in O
plants O
right O
after O
the O
four O
weeks O
under O
water O
and O
then O
after O
the O
desiccation O
period O
of O
6 O
h O
. O

Their O
results O
rejected O
this O
hypothesis O
, O
because O
all O
plants O
, O
regardless O
of O
their O
history O
, O
are O
equally O
affected O
by O
desiccation O
. O

Solid O
- O
state O
NMR O
structure O
determination O
of O
whole O
anchoring O
threads O
from O
the O
blue O
mussel O
Mytilus O
edulis O
. O

The O
molecular O
structure O
of O
the O
blue O
mussel O
Mytilus O
edulis O
whole O
anchoring O
threads O
was O
studied O
by O
two O
- O
dimensional O
( B
13 I
) I
C I
solid O
- O
state O
NMR O
on O
fully O
labeled O
fibers O
. O

This O
unique O
material O
proves O
to O
be O
well O
ordered O
at O
a O
molecular O
level O
despite O
its O
heterogeneous O
composition O
as O
evidenced O
by O
the O
narrow O
measured O
linewidths O
below O
1 O
. O
5 O
ppm O
. O

The O
spectra O
are O
dominated O
by O
residues O
in O
collagen O
environments O
, O
as O
determined O
from O
chemical O
shift O
analysis O
, O
and O
a O
complete O
two O
- O
dimensional O
assignment O
( O
including O
minor O
amino B
acids I
) O
was O
possible O
. O

The O
best O
agreement O
between O
predicted O
and O
experimental O
backbone O
chemical O
shifts O
was O
obtained O
for O
collagen O
helices O
with O
torsion O
angles O
( O
- O
75 O
degrees O
, O
+ O
150 O
degrees O
) O
. O

The O
abundant O
glycine B
and O
alanine B
residues O
can O
be O
resolved O
in O
up O
to O
five O
different O
structural O
environments O
. O

Alanine B
peaks O
could O
be O
assigned O
to O
collagen O
triple O
- O
helices O
, O
beta O
- O
sheets O
( O
parallel O
and O
antiparallel O
) O
, O
beta O
- O
turns O
, O
and O
unordered O
structures O
. O

The O
use O
of O
ATR O
- O
FTIR O
microscopy O
confirmed O
the O
presence O
of O
these O
structural O
environments O
and O
enabled O
their O
location O
in O
the O
core O
of O
the O
thread O
( O
collagen O
helices O
and O
antiparallel O
beta O
- O
sheets O
) O
or O
its O
cuticle O
( O
unordered O
structures O
) O
. O

The O
approach O
should O
enable O
characterization O
at O
the O
molecular O
level O
of O
a O
wide O
range O
of O
byssus O
macroscopic O
properties O
. O

A O
question O
of O
time O
: O
the O
land O
snail O
Murella O
muralis O
( O
Gastropoda O
: O
Pulmonata O
) O
reveals O
constraints O
on O
past O
ecological O
speciation O
. O

The O
lively O
debate O
about O
speciation O
currently O
focuses O
on O
the O
relative O
importance O
of O
factors O
driving O
population O
differentiation O
. O

While O
many O
studies O
are O
increasingly O
producing O
results O
on O
the O
importance O
of O
selection O
, O
little O
is O
known O
about O
the O
interaction O
between O
drift O
and O
selection O
. O

Moreover O
, O
there O
is O
still O
little O
knowledge O
on O
the O
spatial O
- O
temporal O
scales O
at O
which O
speciation O
occurs O
, O
that O
is O
, O
arrangement O
of O
habitat O
patches O
, O
abruptness O
of O
habitat O
transitions O
, O
climate O
and O
habitat O
changes O
interacting O
with O
selective O
forces O
. O

To O
investigate O
these O
questions O
, O
we O
quantified O
variation O
on O
a O
fine O
geographical O
scale O
analysing O
morphological O
( O
shell O
) O
and O
genetic O
data O
sets O
coupled O
with O
environmental O
data O
in O
the O
land O
snail O
Murella O
muralis O
, O
endemic O
to O
the O
Mediterranean O
island O
of O
Sicily O
. O

Analysis O
of O
a O
fragment O
of O
the O
mitochondrial O
DNA O
cytochrome O
oxidase O
I O
gene O
( O
COI O
) O
and O
eight O
nuclear O
microsatellite O
loci O
showed O
that O
genetic O
variation O
is O
highly O
structured O
at O
a O
very O
fine O
spatial O
scale O
by O
local O
palaeogeographical O
events O
and O
historical O
population O
dynamics O
. O

Molecular O
clock O
estimates O
, O
calibrated O
here O
specifically O
for O
Tyrrhenian O
land O
snails O
, O
provided O
a O
framework O
of O
palaeogeographical O
events O
responsible O
for O
the O
observed O
geographical O
variations O
and O
migration O
routes O
. O

Finally O
, O
we O
showed O
for O
the O
first O
time O
well O
- O
documented O
lines O
of O
evidence O
of O
selection O
in O
the O
past O
, O
which O
explains O
divergence O
of O
land O
snail O
shell O
shapes O
. O

We O
suggest O
that O
time O
and O
palaeogeographical O
history O
acted O
as O
constraints O
in O
the O
progress O
along O
the O
ecological O
speciation O
continuum O
. O

Our O
study O
shows O
that O
testing O
for O
correlation O
among O
palaeogeography O
, O
morphology O
and O
genetic O
data O
on O
a O
fine O
geographical O
scale O
provides O
information O
fundamental O
for O
a O
detailed O
understanding O
of O
ecological O
speciation O
processes O
. O

The O
structure O
and O
properties O
of O
septin O
3 O
: O
a O
possible O
missing O
link O
in O
septin O
filament O
formation O
. O

The O
human O
genome O
codes O
for O
13 O
members O
of O
a O
family O
of O
filament O
- O
forming O
GTP B
- O
binding O
proteins O
known O
as O
septins O
. O

These O
have O
been O
divided O
into O
four O
different O
subgroups O
on O
the O
basis O
of O
sequence O
similarity O
. O

The O
differences O
between O
the O
subgroups O
are O
believed O
to O
control O
their O
correct O
assembly O
into O
heterofilaments O
which O
have O
specific O
roles O
in O
membrane O
remodelling O
events O
. O

Many O
different O
combinations O
of O
the O
13 O
proteins O
are O
theoretically O
possible O
and O
it O
is O
therefore O
important O
to O
understand O
the O
structural O
basis O
of O
specific O
filament O
assembly O
. O

However O
, O
three O
- O
dimensional O
structures O
are O
currently O
available O
for O
only O
three O
of O
the O
four O
subgroups O
. O

In O
the O
present O
study O
we O
describe O
the O
crystal O
structure O
of O
a O
construct O
of O
human O
SEPT3 O
which O
belongs O
to O
the O
outstanding O
subgroup O
. O

This O
construct O
( O
SEPT3 O
- O
GC O
) O
, O
which O
includes O
the O
GTP B
- O
binding O
and O
C B
- O
terminal O
domains O
, O
purifies O
as O
a O
nucleotide B
- O
free O
monomer O
, O
allowing O
for O
its O
characterization O
in O
terms O
of O
GTP B
- O
binding O
and O
hydrolysis O
. O

In O
the O
crystal O
structure O
, O
SEPT3 O
- O
GC O
forms O
foreshortened O
filaments O
which O
employ O
the O
same O
NC O
and O
G O
interfaces O
observed O
in O
the O
heterotrimeric O
complex O
of O
human O
septins O
2 O
, O
6 O
and O
7 O
, O
reinforcing O
the O
notion O
of O
' O
promiscuous O
' O
interactions O
described O
previously O
. O

In O
the O
present O
study O
we O
describe O
these O
two O
interfaces O
and O
relate O
the O
structure O
to O
its O
tendency O
to O
form O
monomers O
and O
its O
efficiency O
in O
the O
hydrolysis O
of O
GTP B
. O

The O
relevance O
of O
these O
results O
is O
emphasized O
by O
the O
fact O
that O
septins O
from O
the O
SEPT3 O
subgroup O
may O
be O
important O
determinants O
of O
polymerization O
by O
occupying O
the O
terminal O
position O
in O
octameric O
units O
which O
themselves O
form O
the O
building O
blocks O
of O
at O
least O
some O
heterofilaments O
. O

Receptors O
, O
endocytosis O
, O
and O
trafficking O
: O
the O
biological O
basis O
of O
targeted O
delivery O
of O
antisense O
and O
siRNA O
oligonucleotides O
. O

The O
problem O
of O
targeted O
delivery O
of O
antisense O
and O
siRNA O
oligonucleotides O
can O
be O
resolved O
into O
two O
distinct O
aspects O
. O

The O
first O
concerns O
devising O
ligand O
- O
oligonucleotide O
or O
ligand O
- O
carrier O
moieties O
that O
bind O
with O
high O
selectivity O
to O
receptors O
on O
the O
cell O
type O
of O
interest O
and O
that O
are O
efficiently O
internalized O
by O
endocytosis O
. O

The O
second O
concerns O
releasing O
oligonucleotides O
from O
pharmacologically O
inert O
endomembrane O
compartments O
so O
that O
they O
can O
access O
RNA O
in O
the O
cytosol O
or O
nucleus O
. O

In O
this O
review O
, O
we O
will O
address O
both O
of O
these O
aspects O
. O

Thus O
, O
we O
present O
information O
on O
three O
important O
receptor O
families O
, O
the O
integrins O
, O
the O
receptor O
tyrosine B
kinases O
, O
and O
the O
G O
protein O
- O
coupled O
receptors O
in O
terms O
of O
their O
suitability O
for O
targeted O
delivery O
of O
oligonucleotides O
. O

This O
includes O
discussion O
of O
receptor O
abundance O
, O
internalization O
and O
trafficking O
pathways O
, O
and O
the O
availability O
of O
suitable O
high O
affinity O
ligands O
. O

We O
also O
consider O
the O
process O
of O
oligonucleotide O
uptake O
and O
intracellular O
trafficking O
and O
discuss O
approaches O
to O
modulating O
these O
processes O
in O
a O
pharmacologically O
productive O
manner O
. O

Hopefully O
, O
the O
basic O
information O
presented O
in O
this O
review O
will O
be O
of O
value O
to O
investigators O
involved O
in O
designing O
delivery O
approaches O
for O
oligonucleotides O
. O

A O
new O
ganoderic B
acid I
from O
Ganoderma O
lucidum O
mycelia O
and O
its O
stability O
. O

A O
new O
ganoderic B
acid I
( O
GA O
) O
, O
3 B
alpha I
, I
22 I
beta I
- I
diacetoxy I
- I
7 I
alpha I
- I
hydroxyl I
- I
5 I
alpha I
- I
lanost I
- I
8 I
, I
24E I
- I
dien I
- I
26 I
- I
oic I
acid I
( O
1 O
) O
, O
together O
with O
four O
known O
compounds O
GA O
- O
Mk B
( O
2 O
) O
, O
- O
Mc B
( O
3 O
) O
, O
- O
S B
( O
4 O
) O
and O
- O
Mf B
( O
5 O
) O
, O
was O
isolated O
and O
characterized O
from O
Ganoderma O
lucidum O
mycelia O
. O

The O
structure O
of O
compound O
1 O
was O
elucidated O
on O
the O
basis O
of O
interpretation O
of O
extensive O
spectroscopic O
data O
( O
HRMS O
, O
IR O
, O
UV O
, O
1D O
and O
2D O
NMR O
) O
. O

Due O
to O
its O
apparent O
degradation O
during O
preparation O
procedures O
, O
the O
stability O
of O
compound O
1 O
was O
assessed O
in O
several O
solvents O
in O
a O
short O
- O
term O
study O
that O
demonstrated O
the O
optimal O
stability O
in O
aproptic O
environment O
. O

A O
possible O
mechanism O
of O
acid O
- O
catalyzed O
degradation O
of O
compound O
1 O
in O
methanol B
was O
proposed O
, O
consisting O
of O
a O
fast O
protonation O
, O
followed O
by O
a O
committed O
step O
of O
hydroxyl B
group O
removal O
. O

In O
addition O
, O
all O
isolated O
compounds O
were O
tested O
in O
vitro O
for O
their O
cytotoxic O
activities O
against O
95D O
and O
HeLa O
tumor O
cell O
lines O
, O
with O
IC O
( O
50 O
) O
values O
ranging O
from14 O
. O
7 O
to O
38 O
. O
5 O
mu O
M O
. O

The O
results O
may O
improve O
the O
understanding O
of O
chemical O
stability O
of O
GAs O
and O
provide O
valuable O
information O
on O
their O
separation O
, O
analysis O
and O
application O
. O

Ipsilateral O
feeding O
- O
specific O
circuits O
between O
the O
nucleus O
accumbens O
shell O
and O
the O
lateral O
hypothalamus O
: O
regulation O
by O
glutamate B
and O
GABA B
receptor O
subtypes O
. O

The O
nucleus O
accumbens O
shell O
( O
AcbSh O
) O
and O
the O
lateral O
hypothalamus O
( O
LH O
) O
are O
both O
involved O
in O
the O
control O
of O
food O
intake O
. O

Activation O
of O
GABA B
( O
A O
) O
receptors O
or O
blockade O
of O
AMPA B
and O
kainate B
receptors O
within O
the O
AcbSh O
induces O
feeding O
, O
as O
does O
blockade O
of O
GABA B
( O
A O
) O
receptors O
or O
activation O
of O
NMDA B
receptors O
in O
the O
LH O
. O

Further O
, O
evidence O
suggests O
that O
feeding O
induced O
via O
the O
AcbSh O
can O
be O
suppressed O
by O
LH O
inhibition O
. O

However O
, O
it O
is O
unclear O
if O
this O
suppression O
is O
specific O
to O
feeding O
. O

Adult O
male O
Sprague O
- O
Dawley O
rats O
with O
3 O
intracranial O
guide O
cannulas O
, O
one O
unilaterally O
into O
the O
AcbSh O
and O
two O
bilaterally O
into O
the O
LH O
, O
were O
used O
to O
explore O
this O
issue O
. O

DNQX B
( O
1 O
. O
25 O
mu O
g O
) O
or O
muscimol B
( O
100 O
ng O
) O
infused O
into O
the O
AcbSh O
unilaterally O
elicited O
feeding O
, O
and O
this O
elicited O
intake O
was O
suppressed O
by O
bilateral O
LH O
injection O
of O
d B
- I
AP5 I
( O
2 O
mu O
g O
) O
or O
muscimol B
( O
25 O
ng O
) O
. O

The O
effectiveness O
of O
d B
- I
AP5 I
or O
muscimol B
infusion O
into O
either O
the O
LH O
site O
ipsilateral O
or O
contralateral O
to O
the O
AcbSh O
injection O
was O
compared O
. O

Ipsilateral O
LH O
injection O
of O
d B
- I
AP5 I
or O
muscimol B
was O
significantly O
more O
effective O
than O
contralateral O
injection O
in O
suppressing O
food O
intake O
initiated O
by O
AcbSh O
injection O
of O
DNQX B
or O
muscimol B
. O

These O
results O
add O
to O
the O
prior O
evidence O
that O
inhibition O
of O
the O
LH O
through O
pharmacological O
modulation O
of O
NMDA B
or O
GABA B
( O
A O
) O
receptors O
specifically O
suppresses O
feeding O
initiated O
by O
AcbSh O
inhibition O
, O
and O
that O
these O
two O
regions O
communicate O
via O
an O
ipsilateral O
circuit O
to O
specifically O
regulate O
feeding O
. O

The O
glycogen O
synthase O
kinase O
- O
3 O
beta O
/ O
nuclear O
factor O
- O
kappa O
B O
pathway O
is O
involved O
in O
cinobufagin B
- O
induced O
apoptosis O
in O
cultured O
osteosarcoma O
cells O
. O

Cinobufagin B
, O
a O
major O
component O
of O
cinobufacini O
( O
huachansu O
) O
, O
is O
an O
important O
cardenolidal B
steroid I
. O

Several O
studies O
have O
suggested O
that O
cinobufagin B
has O
potent O
anti O
- O
cancer O
effects O
. O

The O
present O
study O
examines O
the O
apoptosis O
- O
inducing O
activity O
and O
the O
underlying O
mechanism O
of O
action O
of O
cinobufagin B
in O
osteosarcoma O
( O
OS O
) O
cells O
. O

Our O
results O
showed O
that O
cinobufagin B
potently O
inhibited O
the O
proliferation O
of O
U2OS O
, O
MG63 O
and O
SaOS O
- O
2 O
cells O
. O

Significant O
increases O
in O
G2 O
/ O
M O
cell O
- O
cycle O
arrest O
and O
apoptosis O
in O
OS O
cells O
were O
also O
observed O
. O

The O
expression O
levels O
of O
several O
apoptotic O
proteins O
were O
assessed O
after O
cinobufagin B
treatment O
in O
U2OS O
cells O
. O

Among O
them O
, O
xIAP O
, O
cIAP O
- O
1 O
, O
survivin O
and O
Bcl O
- O
2 O
levels O
decreased O
remarkably O
, O
while O
the O
levels O
of O
Bax O
and O
cleaved O
- O
PARP O
increased O
. O

Furthermore O
, O
we O
validated O
the O
inhibition O
of O
GSK O
- O
3 O
beta O
/ O
NF O
- O
kappa O
B O
signaling O
following O
cinobufagin B
treatment O
. O

Western O
blots O
showed O
a O
decrease O
in O
nuclear O
p65 O
protein O
expression O
after O
exposure O
to O
different O
concentrations O
of O
cinobufagin B
, O
while O
the O
phosphorylation O
of O
GSK O
- O
3 O
beta O
was O
simultaneously O
increased O
. O

Transduction O
with O
constitutively O
active O
forms O
of O
GSK O
- O
3 O
beta O
could O
protect O
against O
the O
downregulation O
of O
p65 O
and O
upregulation O
of O
cleaved O
- O
PARP O
that O
are O
induced O
by O
cinobufagin B
treatment O
. O

However O
, O
combined O
treatment O
with O
cinobufagin B
and O
SB216367 B
resulted O
in O
a O
significant O
reduction O
in O
p65 O
and O
an O
increase O
in O
cleaved O
- O
PARP O
in O
U2OS O
cells O
. O

Altogether O
, O
these O
results O
show O
that O
cinobufagin B
is O
a O
promising O
agent O
for O
the O
treatment O
of O
OS O
. O

These O
studies O
are O
the O
first O
to O
reveal O
the O
involvement O
of O
the O
GSK O
- O
3 O
beta O
/ O
NF O
- O
kappa O
B O
pathway O
in O
cinobufagin B
- O
induced O
apoptosis O
. O

Pathophysiological O
roles O
of O
aldo O
- O
keto O
reductases O
( O
AKR1C1 O
and O
AKR1C3 O
) O
in O
development O
of O
cisplatin B
resistance O
in O
human O
colon O
cancers O
. O

Cisplatin B
( O
cis B
- I
diamminedichloroplat I
, O
CDDP B
) O
is O
widely O
used O
for O
treatment O
of O
patients O
with O
solid O
tumors O
formed O
in O
various O
organs O
including O
the O
lung O
, O
prostate O
and O
cervix O
, O
but O
is O
much O
less O
sensitive O
in O
colon O
and O
breast O
cancers O
. O

One O
major O
factor O
implicated O
in O
the O
ineffectiveness O
has O
been O
suggested O
to O
be O
acquisition O
of O
the O
CDDP O
resistance O
. O

Here O
, O
we O
established O
the O
CDDP B
- O
resistant O
phenotypes O
of O
human O
colon O
HCT15 O
cells O
by O
continuously O
exposing O
them O
to O
incremental O
concentrations O
of O
the O
drug O
, O
and O
monitored O
expressions O
of O
aldo O
- O
keto O
reductases O
( O
AKRs O
) O
1A1 O
, O
1B1 O
, O
1B10 O
, O
1C1 O
, O
1C2 O
and O
1C3 O
. O

Among O
the O
six O
AKRs O
, O
AKR1C1 O
and O
AKR1C3 O
are O
highly O
induced O
with O
the O
CDDP B
resistance O
. O

The O
resistance O
lowered O
the O
sensitivity O
toward O
cellular O
damages O
evoked O
by O
oxidative O
stress O
- O
derived O
aldehydes B
, O
4 B
- I
hydroxy I
- I
2 I
- I
nonenal I
and O
4 B
- I
oxo I
- I
2 I
- I
nonenal I
that O
are O
detoxified O
by O
AKR1C1 O
and O
AKR1C3 O
. O

Overexpression O
of O
AKR1C1 O
or O
AKR1C3 O
in O
the O
parental O
HCT15 O
cells O
mitigated O
the O
cytotoxicity O
of O
the O
aldehydes B
and O
CDDP O
. O

Knockdown O
of O
both O
AKR1C1 O
and O
AKR1C3 O
in O
the O
resistant O
cells O
or O
treatment O
of O
the O
cells O
with O
specific O
inhibitors O
of O
the O
AKRs O
increased O
the O
sensitivity O
to O
CDDP O
toxicity O
. O

Thus O
, O
the O
two O
AKRs O
participate O
in O
the O
mechanism O
underlying O
the O
CDDP O
resistance O
probably O
via O
detoxification O
of O
the O
aldehydes B
resulting O
from O
enhanced O
oxidative O
stress O
. O

The O
resistant O
cells O
also O
showed O
an O
enhancement O
in O
proteolytic O
activity O
of O
proteasome O
accompanied O
by O
overexpression O
of O
its O
catalytic O
subunits O
( O
PSM O
beta O
9 O
and O
PSM O
beta O
10 O
) O
. O

Pretreatment O
of O
the O
resistant O
cells O
with O
a O
potent O
proteasome O
inhibitor O
Z B
- I
Leu I
- I
Leu I
- I
Leu I
- I
al I
augmented O
the O
CDDP O
sensitization O
elicited O
by O
the O
AKR O
inhibitors O
. O

Additionally O
, O
the O
treatment O
of O
the O
cells O
with O
Z B
- I
Leu I
- I
Leu I
- I
Leu I
- I
al I
and O
the O
AKR O
inhibitors O
induced O
the O
expressions O
of O
the O
two O
AKRs O
and O
proteasome O
subunits O
. O

Collectively O
, O
these O
results O
suggest O
the O
involvement O
of O
up O
- O
regulated O
AKR1C1 O
, O
AKR1C3 O
and O
proteasome O
in O
CDDP B
resistance O
of O
colon O
cancers O
and O
support O
a O
chemotherapeutic O
role O
for O
their O
inhibitors O
. O

Local O
structure O
and O
dynamics O
of O
benzene B
confined O
in O
the O
IRMOF O
- O
1 O
nanocavity O
as O
studied O
by O
molecular O
dynamics O
simulation O
. O

The O
local O
structure O
and O
dynamic O
behaviour O
of O
a O
benzene B
molecular O
assembly O
confined O
within O
the O
nano O
- O
cavities O
of O
a O
zinc B
- O
based O
metal O
- O
organic O
framework O
, O
[ B
Zn I
( I
4 I
) I
O I
( I
CO I
( I
2 I
) I
C I
( I
6 I
) I
H I
( I
4 I
) I
CO I
( I
2 I
) I
) I
( I
3 I
) I
] I
( I
n I
) I
( O
IRMOF O
- O
1 O
) O
, O
were O
investigated O
by O
means O
of O
molecular O
dynamics O
( O
MD O
) O
simulations O
. O

The O
local O
structure O
of O
the O
confined O
benzene B
molecules O
was O
evaluated O
using O
radial O
distribution O
functions O
. O

The O
sites O
for O
adsorption O
of O
benzene B
in O
IRMOF O
- O
1 O
were O
well O
defined O
by O
the O
simulation O
. O

The O
diffusion O
coefficients O
at O
ambient O
temperature O
suggested O
that O
the O
mobility O
of O
the O
confined O
benzene B
was O
high O
, O
comparable O
to O
the O
bulk O
fluid O
. O

Decreasing O
the O
temperature O
gave O
rise O
to O
the O
aggregation O
of O
benzene B
in O
the O
IRMOF O
- O
1 O
frameworks O
. O

Molecular O
aggregation O
was O
attributed O
to O
the O
localization O
of O
benzene B
in O
the O
large O
and O
the O
small O
cavities O
of O
IRMOF O
- O
1 O
, O
respectively O
. O

Both O
the O
translational O
diffusion O
coefficient O
and O
the O
trajectory O
of O
benzene B
provided O
evidence O
that O
the O
localization O
of O
benzene B
in O
the O
large O
and O
the O
small O
cavities O
takes O
place O
at O
ca O
. O

200 O
K O
. O

Furthermore O
, O
at O
high O
benzene B
loading O
, O
the O
migration O
of O
benzene B
in O
the O
small O
cavities O
was O
prevented O
( O
frozen O
) O
below O
135 O
K O
. O

Thus O
, O
the O
translational O
degree O
of O
freedom O
of O
the O
benzene B
molecules O
changed O
drastically O
, O
depending O
on O
the O
temperature O
. O

Computer O
simulation O
study O
of O
nanoparticle O
interaction O
with O
a O
lipid O
membrane O
under O
mechanical O
stress O
. O

Pore O
formation O
of O
lipid O
bilayers O
under O
mechanical O
stress O
is O
critical O
to O
biological O
processes O
. O

A O
series O
of O
coarse O
grained O
molecular O
dynamics O
simulations O
of O
lipid O
bilayers O
with O
carbon B
nanoparticles O
different O
in O
size O
have O
been O
performed O
. O

Surface O
tension O
was O
applied O
to O
study O
the O
disruption O
of O
lipid O
bilayers O
by O
nanoparticles O
and O
the O
formation O
of O
pores O
inside O
the O
bilayers O
. O

The O
presence O
of O
small O
nanoparticles O
enhances O
the O
probability O
of O
water O
penetration O
thus O
decreasing O
the O
membrane O
rupture O
tension O
, O
while O
big O
nanoparticles O
have O
the O
opposite O
effect O
. O

Nanoparticle O
volume O
affects O
bilayer O
strength O
indirectly O
, O
and O
particle O
surface O
density O
can O
complicate O
the O
interaction O
. O

The O
structural O
, O
dynamic O
, O
elastic O
properties O
and O
lateral O
densities O
of O
lipid O
bilayers O
with O
nanoparticles O
under O
mechanical O
stress O
were O
analyzed O
. O

The O
results O
demonstrate O
the O
ability O
of O
nanoparticles O
to O
adjust O
the O
structural O
and O
dynamic O
properties O
of O
a O
lipid O
membrane O
, O
and O
to O
efficiently O
regulate O
the O
pore O
formation O
behavior O
and O
hydrophobicity O
of O
membranes O
. O

Development O
of O
automated O
paper O
- O
based O
devices O
for O
sequential O
multistep O
sandwich O
enzyme O
- O
linked O
immunosorbent O
assays O
using O
inkjet O
printing O
. O

To O
the O
best O
of O
our O
knowledge O
, O
this O
is O
the O
first O
report O
on O
paper O
- O
based O
devices O
for O
automating O
the O
sequential O
multistep O
procedures O
of O
a O
sandwich O
- O
type O
enzyme O
- O
linked O
immunosorbent O
assay O
( O
ELISA O
) O
that O
require O
only O
a O
single O
- O
step O
application O
of O
the O
sample O
solution O
. O

The O
device O
was O
based O
on O
a O
piece O
of O
nitrocellulose O
( O
NC O
) O
membrane O
with O
specially O
designed O
channels O
, O
where O
all O
the O
reagents O
are O
applied O
at O
different O
locations O
in O
order O
to O
control O
the O
fluid O
travel O
to O
the O
detection O
region O
. O

The O
inkjet O
printing O
method O
, O
a O
simple O
and O
low O
- O
cost O
process O
, O
was O
used O
to O
create O
the O
flow O
channel O
and O
device O
barrier O
patterns O
. O

The O
fabricated O
barrier O
was O
found O
to O
be O
an O
efficient O
boundary O
for O
the O
liquid O
along O
the O
printed O
design O
in O
the O
NC O
membrane O
, O
enabling O
direct O
control O
of O
the O
reagent O
flow O
time O
. O

ELISA O
results O
were O
obtained O
with O
a O
single O
- O
step O
sample O
application O
. O

The O
developed O
devices O
( O
so O
- O
called O
automated O
paper O
- O
based O
devices O
) O
provided O
a O
simple O
procedure O
for O
the O
sandwich O
ELISA O
, O
while O
reducing O
assay O
time O
and O
reagent O
consumption O
. O

Colorimetric O
results O
were O
measured O
using O
digital O
camera O
imaging O
with O
software O
processing O
. O

The O
capability O
of O
the O
method O
developed O
herein O
was O
successfully O
used O
to O
determine O
the O
levels O
of O
human O
chorionic O
gonadotropin O
( O
hCG O
) O
by O
ELISA O
. O

A O
VUV O
photoionization O
study O
of O
the O
multichannel O
reaction O
of O
phenyl B
radicals O
with O
1 B
, I
3 I
- I
butadiene I
under O
combustion O
relevant O
conditions O
. O

We O
studied O
the O
reaction O
of O
phenyl B
radicals O
( O
C B
( I
6 I
) I
H I
( I
5 I
) I
) O
with O
1 B
, I
3 I
- I
butadiene I
( O
H B
( I
2 I
) I
CCHCHCH I
( I
2 I
) I
) O
exploiting O
a O
high O
temperature O
chemical O
reactor O
under O
combustion O
- O
like O
conditions O
( O
300 O
Torr O
, O
873 O
K O
) O
. O

The O
reaction O
products O
were O
probed O
in O
a O
supersonic O
beam O
by O
utilizing O
VUV O
radiation O
from O
the O
Advanced O
Light O
Source O
and O
by O
recording O
the O
experimental O
PIE O
curves O
at O
mass O
- O
to O
- O
charge O
ratios O
of O
m O
/ O
z O
= O
130 O
( O
C B
( I
10 I
) I
H I
( I
10 I
) I
( I
+ I
) I
) O
, O
116 O
( O
C B
( I
9 I
) I
H I
( I
8 I
) I
( I
+ I
) I
) O
, O
and O
104 O
( O
C B
( I
8 I
) I
H I
( I
8 I
) I
( I
+ I
) I
) O
. O

Our O
data O
suggest O
that O
the O
atomic O
hydrogen B
( O
H B
) O
, O
methyl B
( O
CH B
( I
3 I
) I
) O
, O
and O
vinyl B
( O
C B
( I
2 I
) I
H I
( I
3 I
) I
) O
losses O
are O
open O
with O
estimated O
branching O
ratios O
of O
about O
86 O
+ O
/ O
- O
4 O
% O
, O
8 O
+ O
/ O
- O
2 O
% O
, O
and O
6 O
+ O
/ O
- O
2 O
% O
, O
respectively O
. O

The O
isomer O
distributions O
were O
probed O
further O
by O
fitting O
the O
experimentally O
recorded O
PIE O
curves O
with O
a O
linear O
combination O
of O
the O
PIE O
curves O
of O
individual O
C B
( I
10 I
) I
H I
( I
10 I
) I
, O
C B
( I
9 I
) I
H I
( I
8 I
) I
, O
and O
C B
( I
8 I
) I
H I
( I
8 I
) I
isomers O
. O

These O
fits O
indicate O
the O
formation O
of O
three O
C B
( I
10 I
) I
H I
( I
10 I
) I
isomers O
( O
trans B
- I
1 I
, I
3 I
- I
butadienylbenzene I
, O
1 B
, I
4 I
- I
dihydronaphthalene I
, O
1 B
- I
methylindene I
) O
, O
three O
C B
( I
9 I
) I
H I
( I
8 I
) I
isomers O
( O
indene B
, O
phenylallene B
, O
1 B
- I
phenyl I
- I
1 I
- I
methylacetylene I
) O
, O
and O
a O
C B
( I
8 I
) I
H I
( I
8 I
) I
isomer O
( O
styrene B
) O
. O

A O
comparison O
with O
results O
from O
recent O
crossed O
molecular O
beam O
studies O
of O
the O
1 B
, I
3 I
- I
butadiene I
- O
phenyl B
radical O
reaction O
and O
electronic O
structure O
calculations O
suggests O
that O
trans B
- I
1 I
, I
3 I
- I
butadienylbenzene I
( O
130 O
amu O
) O
, O
1 B
, I
4 I
- I
dihydronaphthalene I
( O
130 O
amu O
) O
, O
and O
styrene B
( O
104 O
amu O
) O
are O
reaction O
products O
formed O
as O
a O
consequence O
of O
a O
bimolecular O
reaction O
between O
the O
phenyl B
radical O
and O
1 B
, I
3 I
- I
butadiene I
. O

1 B
- I
Methylindene I
( O
130 O
amu O
) O
, O
indene B
( O
116 O
amu O
) O
, O
phenylallene B
( O
116 O
amu O
) O
, O
and O
1 B
- I
phenyl I
- I
1 I
- I
methylacetylene I
( O
116 O
amu O
) O
are O
synthesized O
upon O
reaction O
of O
the O
phenyl B
radical O
with O
three O
C B
( I
4 I
) I
H I
( I
6 I
) I
isomers O
: O
1 B
, I
2 I
- I
butadiene I
( O
H B
( I
2 I
) I
CCCH I
( I
CH I
( I
3 I
) I
) O
) O
, O
1 B
- I
butyne I
( O
HCCC B
( I
2 I
) I
H I
( I
5 I
) I
) O
, O
and O
2 B
- I
butyne I
( O
CH B
( I
3 I
) I
CCCH I
( O

3 I
) I
) O
; O
these O
C B
( I
4 I
) I
H I
( I
6 I
) I
isomers O
can O
be O
formed O
from O
1 B
, I
3 I
- I
butadiene I
via O
hydrogen B
atom O
assisted O
isomerization O
reactions O
or O
via O
thermal O
rearrangements O
of O
1 B
, I
3 I
- I
butadiene I
involving O
hydrogen B
shifts O
in O
the O
high O
temperature O
chemical O
reactor O
. O

EphB4 O
enhances O
the O
process O
of O
endochondral O
ossification O
and O
inhibits O
remodeling O
during O
bone O
fracture O
repair O
. O

Previous O
reports O
have O
identified O
a O
role O
for O
the O
tyrosine B
kinase O
receptor O
EphB4 O
and O
its O
ligand O
, O
ephrinB2 O
, O
as O
potential O
mediators O
of O
both O
bone O
formation O
by O
osteoblasts O
and O
bone O
resorption O
by O
osteoclasts O
. O

In O
the O
present O
study O
, O
we O
examined O
the O
role O
of O
EphB4 O
during O
bone O
repair O
after O
traumatic O
injury O
. O

We O
performed O
femoral O
fractures O
with O
internal O
fixation O
in O
transgenic O
mice O
that O
overexpress O
EphB4 O
under O
the O
collagen O
type O
1 O
promoter O
( O
Col1 O
- O
EphB4 O
) O
and O
investigated O
the O
bone O
repair O
process O
up O
to O
12 O
weeks O
postfracture O
. O

The O
data O
indicated O
that O
Col1 O
- O
EphB4 O
mice O
exhibited O
stiffer O
and O
stronger O
bones O
after O
fracture O
compared O
with O
wild O
- O
type O
mice O
. O

The O
fractured O
bones O
of O
Col1 O
- O
EphB4 O
transgenic O
mice O
displayed O
significantly O
greater O
tissue O
and O
bone O
volume O
2 O
weeks O
postfracture O
compared O
with O
that O
of O
wild O
- O
type O
mice O
. O

These O
findings O
correlated O
with O
increased O
chondrogenesis O
and O
mineral O
formation O
within O
the O
callus O
site O
at O
2 O
weeks O
postfracture O
, O
as O
demonstrated O
by O
increased O
safranin B
O I
and O
von O
Kossa O
staining O
, O
respectively O
. O

Interestingly O
, O
Col1 O
- O
EphB4 O
mice O
were O
found O
to O
possess O
significantly O
greater O
numbers O
of O
clonogenic O
mesenchymal O
stromal O
progenitor O
cells O
( O
CFU O
- O
F O
) O
, O
with O
an O
increased O
capacity O
to O
form O
mineralized O
nodules O
in O
vitro O
under O
osteogenic O
conditions O
, O
when O
compared O
with O
those O
of O
the O
wild O
- O
type O
control O
mice O
. O

Furthermore O
, O
Col1 O
- O
EphB4 O
mice O
had O
significantly O
lower O
numbers O
of O
TRAP O
- O
positive O
multinucleated O
osteoclasts O
within O
the O
callus O
site O
. O

Taken O
together O
, O
these O
observations O
suggest O
that O
EphB4 O
promotes O
endochondral O
ossification O
while O
inhibiting O
osteoclast O
development O
during O
callus O
formation O
and O
may O
represent O
a O
novel O
drug O
target O
for O
the O
repair O
of O
fractured O
bones O
. O

Compartmentalization O
and O
antiviral O
effect O
of O
efavirenz B
metabolites O
in O
blood O
plasma O
, O
seminal O
plasma O
, O
and O
cerebrospinal O
fluid O
. O

Efavirenz B
( O
EFV B
) O
is O
one O
of O
the O
most O
commonly O
prescribed O
antiretrovirals O
for O
use O
in O
the O
treatment O
of O
human O
immunodeficiency O
virus O
( O
HIV O
) O
infection O
. O

EFV B
is O
extensively O
metabolized O
by O
cytochrome O
P450 O
to O
a O
number O
of O
oxygenated O
products O
; O
however O
, O
the O
pharmacologic O
activity O
and O
distribution O
of O
these O
metabolites O
in O
anatomic O
compartments O
have O
yet O
to O
be O
explored O
. O

The O
systemic O
distribution O
of O
EFV B
oxidative O
metabolites O
was O
examined O
in O
blood O
plasma O
, O
seminal O
plasma O
, O
and O
cerebrospinal O
fluid O
from O
subjects O
on O
an O
EFV B
- O
based O
regimen O
. O

The O
8 B
- I
hydroxy I
EFV I
metabolite O
was O
detected O
in O
blood O
plasma O
, O
seminal O
plasma O
, O
and O
cerebrospinal O
fluid O
, O
with O
median O
concentrations O
of O
314 O
. O
5 O
ng O
/ O
ml O
, O
358 O
. O
5 O
ng O
/ O
ml O
, O
and O
3 O
. O
37 O
ng O
/ O
ml O
, O
respectively O
. O

In O
contrast O
, O
7 B
- I
hydroxy I
and O
8 B
, I
14 I
- I
hydroxy I
EFV I
were O
only O
detected O
in O
blood O
plasma O
and O
seminal O
plasma O
with O
median O
concentrations O
of O
8 O
. O
84 O
ng O
/ O
ml O
and O
10 O
. O
23 O
ng O
/ O
ml O
, O
and O
5 O
. O
63 O
ng O
/ O
ml O
and O
5 O
. O
43 O
ng O
/ O
ml O
, O
respectively O
. O

Interestingly O
, O
protein O
- O
free O
concentrations O
of O
metabolites O
were O
only O
detectable O
in O
seminal O
plasma O
, O
where O
a O
novel O
dihdyroxylated O
metabolite O
of O
EFV B
was O
also O
detected O
. O

This O
accumulation O
of O
protein O
- O
free O
EFV O
metabolites O
was O
demonstrated O
to O
be O
the O
result O
of O
differential O
protein O
binding O
in O
seminal O
plasma O
compared O
with O
that O
of O
blood O
plasma O
. O

In O
addition O
, O
the O
oxidative O
metabolites O
of O
EFV B
did O
not O
present O
with O
any O
significant O
pharmacologic O
activity O
toward O
HIV O
- O
1 O
as O
measured O
using O
an O
HIV O
green O
fluorescent O
protein O
single O
- O
round O
infectivity O
assay O
. O

This O
study O
is O
the O
first O
to O
report O
the O
physiologic O
distribution O
of O
metabolites O
of O
an O
antiretroviral O
into O
biologic O
compartments O
that O
the O
virus O
is O
known O
to O
distribute O
and O
to O
examine O
their O
anti O
- O
HIV O
activity O
. O

These O
data O
suggest O
that O
the O
male O
genital O
tract O
may O
be O
a O
novel O
compartment O
that O
should O
be O
considered O
in O
the O
evaluation O
of O
drug O
metabolite O
exposure O
. O

Molecular O
interaction O
studies O
of O
HIV O
- O
1 O
matrix O
protein O
p17 O
and O
heparin O
: O
identification O
of O
the O
heparin O
- O
binding O
motif O
of O
p17 O
as O
a O
target O
for O
the O
development O
of O
multitarget O
antagonists O
. O

Once O
released O
by O
HIV O
( O
+ O
) O
cells O
, O
p17 O
binds O
heparan O
sulfate O
proteoglycans O
( O
HSPGs O
) O
and O
CXCR1 O
on O
leukocytes O
causing O
their O
dysfunction O
. O

By O
exploiting O
an O
approach O
integrating O
computational O
modeling O
, O
site O
- O
directed O
mutagenesis O
of O
p17 O
, O
chemical O
desulfation O
of O
heparin O
, O
and O
surface O
plasmon O
resonance O
, O
we O
characterized O
the O
interaction O
of O
p17 O
with O
heparin O
, O
a O
HSPG O
structural O
analog O
, O
and O
CXCR1 O
. O

p17 O
binds O
to O
heparin O
with O
an O
affinity O
( O
K O
( O
d O
) O
= O
190 O
nm O
) O
that O
is O
similar O
to O
those O
of O
other O
heparin O
- O
binding O
viral O
proteins O
. O

Two O
stretches O
of O
basic O
amino B
acids I
( O
basic O
motifs O
) O
are O
present O
in O
p17 O
N B
and O
C B
termini O
. O

Neutralization O
( O
Arg B
- O
- O
> O
Ala B
substitution O
) O
of O
the O
N B
- O
terminal O
, O
but O
not O
of O
the O
C B
- O
terminal O
basic O
motif O
, O
causes O
the O
loss O
of O
p17 O
heparin O
- O
binding O
capacity O
. O

The O
N B
- O
terminal O
heparin O
- O
binding O
motif O
of O
p17 O
partially O
overlaps O
the O
CXCR1 O
- O
binding O
domain O
. O

Accordingly O
, O
its O
neutralization O
prevents O
also O
p17 O
binding O
to O
the O
chemochine O
receptor O
. O

Competition O
experiments O
demonstrated O
that O
free O
heparin O
and O
heparan O
sulfate B
( O
HS O
) O
, O
but O
not O
selectively O
2 B
- I
O I
- O
, O
6 I
- I
O I
- O
, O
and O
N B
- I
O I
desulfated O
heparins O
, O
prevent O
p17 O
binding O
to O
substrate O
- O
immobilized O
heparin O
, O
indicating O
that O
the O
sulfate B
groups O
of O
the O
glycosaminoglycan O
mediate O
p17 O
interaction O
. O

Evaluation O
of O
the O
p17 O
antagonist O
activity O
of O
a O
panel O
of O
biotechnological O
heparins O
derived O
by O
chemical O
sulfation O
of O
the O
Escherichia O
coli O
K5 O
polysaccharide O
revealed O
that O
the O
highly O
N B
, O
O B
- O
sulfated O
derivative O
prevents O
the O
binding O
of O
p17 O
to O
both O
heparin O
and O
CXCR1 O
, O
thus O
inhibiting O
p17 O
- O
driven O
chemotactic O
migration O
of O
human O
monocytes O
with O
an O
efficiency O
that O
is O
higher O
than O
those O
of O
heparin O
and O
HS O
. O

Here O
, O
we O
characterized O
at O
a O
molecular O
level O
the O
interaction O
of O
p17 O
with O
its O
cellular O
receptors O
, O
laying O
the O
basis O
for O
the O
development O
of O
heparin O
- O
mimicking O
p17 O
antagonists O
. O

Insight O
into O
tissue O
unbound O
concentration O
: O
utility O
in O
drug O
discovery O
and O
development O
. O

In O
a O
preclinical O
setting O
, O
plasma O
or O
whole O
tissue O
drug O
concentrations O
are O
often O
correlated O
with O
pharmacodynamics O
, O
although O
according O
to O
the O
free O
drug O
hypothesis O
, O
unbound O
drug O
concentration O
should O
be O
more O
pharmacologically O
relevant O
. O

Alternatively O
, O
blood O
concentrations O
may O
be O
a O
good O
surrogate O
for O
tissue O
concentration O
for O
passively O
permeable O
compounds O
. O

However O
, O
for O
a O
large O
number O
of O
compounds O
that O
are O
substrates O
for O
uptake O
and O
/ O
or O
efflux O
transporters O
expressed O
at O
the O
tissue O
level O
, O
significant O
discrepancies O
are O
expected O
between O
unbound O
concentrations O
in O
blood O
and O
those O
in O
tissues O
. O

Consequently O
, O
attempts O
have O
been O
made O
to O
measure O
tissue O
unbound O
drug O
concentrations O
using O
tissue O
homogenates O
, O
slices O
and O
microdialysis O
. O

Mathematical O
expressions O
for O
calculating O
the O
rate O
and O
extent O
of O
drug O
distribution O
into O
tissues O
have O
also O
been O
established O
. O

For O
example O
, O
a O
ratio O
of O
unbound O
concentration O
in O
the O
tissue O
to O
that O
in O
plasma O
( O
K O
( O
p O
, O
uu O
) O
) O
is O
the O
best O
indicator O
of O
the O
extent O
of O
tissue O
distribution O
. O

Despite O
these O
technical O
advances O
, O
however O
, O
very O
few O
examples O
demonstrate O
a O
focus O
on O
tissue O
unbound O
drug O
concentrations O
in O
a O
preclinical O
setting O
. O

This O
review O
will O
illustrate O
various O
techniques O
to O
estimate O
tissue O
unbound O
drug O
concentrations O
, O
relevant O
parameters O
to O
calculate O
the O
rate O
and O
extent O
of O
tissue O
distribution O
and O
different O
factors O
affecting O
tissue O
unbound O
concentration O
. O

The O
review O
will O
also O
highlight O
various O
examples O
from O
the O
literature O
where O
tissue O
unbound O
drug O
concentrations O
have O
demonstrated O
a O
superior O
correlation O
with O
efficacy O
. O

The O
impact O
of O
tissue O
unbound O
drug O
concentrations O
on O
the O
projection O
of O
human O
efficacious O
dose O
is O
also O
discussed O
. O

Positive O
allosteric O
modulator O
of O
alpha O
7 O
nicotinic O
- O
acetylcholine B
receptors O
, O
PNU B
- I
120596 I
augments O
the O
effects O
of O
donepezil B
on O
learning O
and O
memory O
in O
aged O
rodents O
and O
non O
- O
human O
primates O
. O

The O
development O
of O
novel O
therapeutic O
agents O
for O
disorders O
of O
cognition O
such O
as O
Alzheimer O
' O
s O
disease O
( O
AD O
) O
is O
of O
paramount O
importance O
given O
the O
ever O
- O
increasing O
elderly O
population O
, O
however O
; O
there O
is O
also O
considerable O
interest O
in O
any O
strategy O
that O
might O
enhance O
the O
clinical O
efficacy O
of O
currently O
available O
treatments O
. O

The O
purpose O
of O
this O
study O
was O
to O
evaluate O
an O
adjunctive O
treatment O
strategy O
to O
memory O
enhancement O
, O
namely O
combining O
the O
commonly O
prescribed O
acetylcholinesterase O
inhibitor O
( O
AChEI O
) O
donepezil B
, O
with O
a O
positive O
allosteric O
modulator O
( O
PAM O
) O
of O
alpha O
7 O
nicotinic O
- O
acetylcholine B
receptors O
( O
alpha O
7 O
- O
nAChRs O
) O
, O
PNU B
- I
120596 I
. O

The O
treatment O
strategy O
was O
evaluated O
in O
a O
( O
non O
- O
spatial O
) O
spontaneous O
novel O
object O
recognition O
( O
NOR O
) O
task O
in O
young O
rats O
; O
a O
water O
maze O
spatial O
learning O
and O
recall O
procedure O
in O
aged O
, O
cognitively O
- O
impaired O
rats O
, O
and O
a O
delayed O
match O
to O
sample O
( O
working O
/ O
short O
term O
memory O
) O
task O
in O
aged O
rhesus O
monkeys O
. O

In O
all O
three O
experiments O
a O
similar O
drug O
response O
was O
observed O
, O
namely O
that O
donepezil B
administered O
alone O
improved O
task O
performance O
in O
a O
dose O
- O
dependent O
manner O
; O
that O
PNU B
- I
120596 I
administered O
alone O
was O
without O
significant O
effect O
, O
but O
that O
the O
combination O
of O
PNU B
- I
120596 I
with O
a O
subthreshold O
dose O
of O
donepezil B
was O
effective O
. O

The O
positive O
effect O
of O
the O
drug O
combination O
appeared O
to O
be O
alpha O
7 O
- O
nAChR O
mediated O
given O
that O
it O
was O
blocked O
in O
the O
NOR O
task O
by O
the O
selective O
alpha O
7 O
- O
nAChR O
antagonist O
methyllycaconitine B
( O
MLA B
) O
. O

Collectively O
, O
these O
data O
indicate O
that O
PNU B
- I
120596 I
increases O
the O
effective O
dose O
range O
of O
donepezil B
in O
learning O
/ O
memory O
- O
related O
tasks O
in O
young O
and O
age O
- O
impaired O
animal O
models O
. O

The O
results O
suggest O
that O
alpha O
7 O
- O
nAChR O
- O
selective O
PAMs O
like O
PNU B
- I
120596 I
have O
potential O
as O
adjunctive O
treatments O
with O
acetylcholinesterase O
inhibitors O
( O
e O
. O
g O
. O
, O
donepezil B
) O
for O
age O
- O
related O
illnesses O
such O
as O
AD O
as O
well O
memory O
disorders O
not O
necessarily O
associated O
with O
advanced O
age O
. O

1H B
NMR O
spectra O
of O
ethane B
- I
1 I
, I
2 I
- I
diol I
and O
other O
vicinal B
diols I
in O
benzene B
: O
GIAO O
/ O
DFT O
shift O
calculations O
. O

The O
proton O
NMR O
spectra O
of O
several O
1 B
, I
2 I
- I
diols I
in O
benzene B
have O
been O
analysed O
so O
as O
to O
associate O
each O
magnetically O
nonequivalent O
proton O
with O
its O
chemical O
shift O
. O

The O
shifts O
and O
coupling O
constants O
of O
the O
OH B
and O
methylene B
protons O
of O
ethane B
- I
1 I
, I
2 I
- I
diol I
have O
been O
determined O
in O
a O
wide O
range O
of O
solvents O
. O

The O
conformer O
distribution O
and O
the O
proton O
NMR O
shifts O
of O
these O
1 B
, I
2 I
- I
diols I
in O
benzene B
have O
been O
computed O
on O
the O
basis O
of O
density O
functional O
theory O
. O

The O
solvent O
is O
included O
using O
the O
integral O
- O
equation O
- O
formalism O
polarizable O
continuum O
model O
implemented O
in O
Gaussian O
09 O
. O

Relative O
Gibbs O
energies O
for O
all O
stable O
conformers O
are O
calculated O
at O
the O
Perdew O
, O
Burke O
and O
Enzerhof O
( O
PBE O
) O
0 O
/ O
6 O
- O
311 O
+ O
G O
( O
d O
, O
p O
) O
level O
, O
and O
shifts O
are O
calculated O
using O
the O
gauge O
- O
including O
atomic O
orbital O
method O
with O
the O
PBE0 O
/ O
6 O
- O
311 O
+ O
G O
( O
d O
, O
p O
) O
geometry O
but O
using O
the O
cc O
- O
pVTZ O
basis O
set O
. O

Previous O
calculations O
on O
ethane B
- I
1 I
, I
2 I
- I
diol I
and O
propane B
- I
1 I
, I
2 I
- I
diol I
have O
been O
corrected O
and O
extended O
. O

New O
calculations O
on O
tert B
- I
butylethane I
- I
1 I
, I
2 I
- I
diol I
, O
phenylethane B
- I
1 I
, I
2 I
- I
diol I
, O
butane B
- I
2 I
, I
3 I
- I
diols I
( O
dl O
and O
meso O
) O
and O
cyclohexane B
- I
1 I
, I
2 I
- I
diols I
( O
cis O
and O
trans O
) O
are O
presented O
. O

Overall O
, O
the O
computed O
NMR O
shifts O
are O
in O
good O
agreement O
with O
experimental O
values O
for O
the O
OH B
protons O
but O
remain O
systematically O
high O
for O
CH B
protons O
. O

Some O
results O
based O
on O
the O
Gaussian O
03 O
solvation O
model O
are O
included O
for O
comparison O
. O

Discovery O
of O
Schaeffer B
' I
s I
acid I
analogues O
as O
lead O
structures O
of O
mycobacterium O
tuberculosis O
type O
II O
dehydroquinase O
using O
a O
rational O
drug O
design O
approach O
. O

Rational O
ligand O
design O
: O
Schaeffer B
' I
s I
acid I
analogues O
were O
identified O
as O
novel O
inhibitors O
of O
M O
. O
tuberculosis O
type O
II O
dehydroquinase O
, O
a O
key O
enzyme O
of O
the O
shikimate O
pathway O
. O

Their O
likely O
binding O
mode O
was O
predicted O
using O
a O
combination O
of O
ensemble O
docking O
and O
flexible O
active O
site O
residues O
. O

Potentially O
, O
this O
scaffold O
could O
provide O
a O
good O
starting O
point O
for O
the O
design O
of O
antitubercular O
agents O
. O

Stem O
cell O
- O
mediated O
gene O
delivering O
for O
the O
treatment O
of O
cerebral O
ischemia O
: O
progress O
and O
prospectives O
. O

Ischemic O
stroke O
is O
one O
of O
the O
leading O
causes O
of O
death O
and O
disability O
worldwide O
. O

There O
is O
no O
effective O
treatment O
for O
ischemic O
stroke O
apart O
from O
thrombolytic O
therapy O
, O
which O
has O
a O
narrow O
therapeutic O
time O
window O
. O

Gene O
therapy O
has O
proven O
to O
be O
effective O
in O
experimental O
stroke O
, O
but O
it O
suffers O
from O
disadvantages O
that O
limit O
its O
clinical O
application O
, O
such O
as O
difficulty O
in O
intracranial O
delivering O
of O
therapeutic O
genes O
, O
low O
efficacy O
in O
transfecting O
host O
cells O
and O
long O
- O
term O
expression O
of O
exogenous O
genes O
. O

Delivering O
therapeutic O
genes O
to O
the O
ischemic O
brain O
via O
stem O
cells O
is O
an O
alternative O
strategy O
of O
combined O
gene O
and O
stem O
cell O
therapy O
. O

There O
are O
advantages O
for O
stem O
cell O
- O
mediated O
gene O
delivery O
as O
opposed O
to O
direct O
gene O
transfer O
. O

In O
recent O
years O
, O
studies O
used O
stem O
cells O
that O
over O
- O
express O
different O
neurotrophic O
factors O
, O
such O
as O
BDNF O
, O
GDNT O
, O
or O
NT3 O
, O
and O
found O
that O
the O
delivery O
of O
these O
genetically O
- O
modified O
stem O
cells O
to O
animal O
models O
of O
ischemic O
stroke O
is O
safe O
and O
effective O
, O
thus O
suggesting O
that O
stem O
cell O
- O
based O
gene O
therapy O
may O
be O
a O
promising O
treatment O
for O
stroke O
. O

This O
review O
summarizes O
the O
advantages O
and O
recent O
progress O
of O
stem O
cell O
- O
based O
gene O
therapy O
for O
ischemic O
stroke O
. O

We O
also O
discuss O
the O
relevant O
strategy O
for O
optimizing O
stem O
cell O
- O
based O
gene O
therapy O
and O
discuss O
the O
potential O
strategies O
for O
its O
future O
application O
. O

Structure O
Based O
Lead O
Optimization O
Approach O
in O
Discovery O
of O
Selective O
DPP4 O
Inhibitors O
. O

Diabetes O
mellitus O
is O
a O
chronic O
progressive O
metabolic O
disorder O
that O
has O
profound O
consequences O
for O
individuals O
, O
families O
, O
and O
society O
. O

To O
date O
, O
main O
available O
oral O
antidiabetic O
medications O
target O
either O
insulin O
resistance O
( O
metformin B
, O
glitazones B
) O
, O
or O
insulin O
deficiency O
( O
sulfonylureas B
, O
glinides B
) O
, O
but O
leading O
to O
shortfalls O
in O
medication O
. O

Advancement O
in O
modern O
oral O
hypoglycemic O
agents O
may O
be O
encouraged O
with O
or O
in O
place O
of O
traditional O
therapies O
. O

The O
lower O
risk O
for O
hypoglycemic O
events O
as O
compared O
with O
other O
insulinotropic O
or O
insulin O
- O
sensitizing O
agents O
make O
DPP O
- O
4 O
inhibitors O
very O
promising O
candidates O
for O
a O
more O
physiological O
treatment O
of O
type O
- O
2 O
diabetes O
. O

Only O
some O
DPP O
- O
4 O
inhibitors O
are O
currently O
used O
for O
the O
treatment O
of O
type O
2 O
diabetes O
( O
T2DM O
) O
and O
various O
inhibitors O
currently O
undergoing O
animal O
and O
human O
testing O
. O

A O
number O
of O
catalytically O
active O
DPPs O
distinct O
from O
DPP O
- O
4 O
( O
DPP O
II O
, O
FAP O
, O
DPP O
- O
8 O
, O
and O
DPP O
- O
9 O
) O
have O
been O
described O
that O
is O
associated O
with O
side O
- O
effect O
and O
toxicity O
. O

To O
discover O
potent O
and O
selective O
and O
safer O
drugs O
in O
a O
shorter O
time O
frame O
and O
with O
reduced O
cost O
it O
requires O
using O
an O
innovative O
approach O
for O
designing O
novel O
inhibitors O
. O

This O
review O
article O
focuses O
on O
the O
status O
of O
advanced O
lead O
candidates O
of O
DPP O
group O
and O
their O
binding O
affinity O
with O
the O
active O
site O
residue O
of O
target O
structure O
which O
help O
in O
discovery O
of O
potent O
and O
selective O
DPP O
- O
4 O
inhibitors O
by O
lead O
optimization O
approach O
. O

Metabolomics O
and O
mass O
isotopomer O
analysis O
as O
a O
strategy O
for O
pathway O
discovery O
: O
pyrrolyl B
and O
cyclopentenyl B
derivatives O
of O
the O
pro O
- O
drug O
of O
abuse O
, O
levulinate B
. O

We O
recently O
reported O
that O
levulinate B
( O
4 B
- I
ketopentanoate I
) O
is O
converted O
in O
the O
liver O
to O
4 B
- I
hydroxypentanoate I
, O
a O
drug O
of O
abuse O
, O
and O
that O
the O
formation O
of O
4 B
- I
hydroxypentanoate I
is O
stimulated O
by O
ethanol B
oxidation O
. O

We O
also O
identified O
3 O
parallel O
beta O
- O
oxidation O
pathways O
by O
which O
levulinate B
and O
4 B
- I
hydroxypentanoate I
are O
catabolized O
to O
propionyl B
- I
CoA I
and O
acetyl B
- I
CoA I
. O

We O
now O
report O
that O
levulinate B
forms O
three O
seven B
- I
carbon I
cyclical I
CoA I
esters I
by O
processes O
starting O
with O
the O
elongation O
of O
levulinyl B
- I
CoA I
by O
acetyl B
- I
CoA I
to O
3 B
, I
6 I
- I
diketoheptanoyl I
- I
CoA I
. O

The O
latter O
gamma B
- I
diketo I
CoA I
ester I
undergoes O
two O
parallel O
cyclization O
processes O
. O

One O
process O
yields O
a O
mixture O
of O
tautomers O
, O
i O
. O
e O
. O
, O
cyclopentenyl B
- I
and I
cyclopentadienyl I
- I
acyl I
- I
CoAs I
. O

The O
second O
cyclization O
process O
yields O
a O
methyl B
- I
pyrrolyl I
- I
acetyl I
- I
CoA I
containing O
a O
nitrogen B
atom O
derived O
from O
the O
epsilon B
- I
nitrogen I
of O
lysine B
but O
without O
carbons B
from O
lysine B
. O

The O
cyclic B
CoA I
esters I
were O
identified O
in O
rat O
livers O
perfused O
with O
levulinate B
and O
in O
livers O
and O
brains O
from O
rats O
gavaged O
with O
calcium B
levulinate I
+ I
/ I
- I
ethanol I
. O

Lastly O
, O
3 B
, I
6 I
- I
diketoheptanoyl I
- I
CoA I
, O
like O
2 B
, I
5 I
- I
diketohexane I
, O
pyrrolates B
free O
lysine B
and O
, O
presumably O
, O
lysine B
residues O
from O
proteins O
. O

This O
may O
represent O
a O
new O
pathway O
for O
protein O
pyrrolation O
. O

The O
cyclic B
CoA I
esters I
and O
related O
pyrrolation O
processes O
may O
play O
a O
role O
in O
the O
toxic O
effects O
of O
4 B
- I
hydroxypentanoate I
. O

The O
evolution O
of O
north O
- O
east O
Atlantic O
gadfly O
petrels O
using O
statistical O
phylogeography O
. O

Macaronesia O
( O
north O
- O
east O
Atlantic O
archipelagos O
) O
has O
been O
host O
to O
complex O
patterns O
of O
colonization O
and O
differentiation O
in O
many O
groups O
of O
organisms O
including O
seabirds O
such O
as O
gadfly O
petrels O
( O
genus O
Pterodroma O
) O
. O

Considering O
the O
subspecies O
of O
widely O
distributed O
soft O
- O
plumaged O
petrel O
for O
many O
years O
, O
the O
taxonomic O
status O
of O
the O
three O
gadfly O
petrel O
taxa O
breeding O
in O
Macaronesia O
is O
not O
yet O
settled O
, O
some O
authors O
advocating O
the O
presence O
of O
three O
, O
two O
or O
one O
species O
. O

These O
birds O
have O
already O
been O
the O
subject O
of O
genetic O
studies O
with O
only O
one O
mtDNA O
gene O
and O
relatively O
modest O
sample O
sizes O
. O

In O
this O
study O
, O
using O
a O
total O
of O
five O
genes O
( O
two O
mitochondrial O
genes O
and O
three O
nuclear O
introns O
) O
, O
we O
investigated O
the O
population O
and O
phylogeographical O
histories O
of O
petrel O
populations O
breeding O
on O
Madeira O
and O
Cape O
Verde O
archipelagos O
. O

Despite O
confirming O
complete O
lineage O
sorting O
with O
mtDNA O
, O
analyses O
with O
nucDNA O
failed O
to O
reveal O
any O
population O
structuring O
and O
Isolation O
with O
Migration O
analysis O
revealed O
the O
absence O
of O
gene O
flow O
during O
the O
differentiation O
process O
of O
these O
populations O
. O

It O
appears O
that O
the O
three O
populations O
diverged O
in O
the O
late O
Pleistocene O
in O
the O
last O
150 O
000 O
years O
, O
that O
is O
10 O
times O
more O
recently O
than O
previous O
estimates O
based O
solely O
on O
one O
mtDNA O
gene O
. O

Finally O
, O
our O
results O
suggest O
that O
the O
Madeira O
petrel O
population O
is O
ancestral O
rather O
than O
that O
from O
Cape O
Verde O
. O

This O
study O
strongly O
advocates O
the O
use O
of O
nuclear O
loci O
in O
addition O
to O
mtDNA O
in O
demographical O
and O
phylogeographical O
history O
studies O
. O

WDDD O
: O
Worm O
Developmental O
Dynamics O
Database O
. O

During O
animal O
development O
, O
cells O
undergo O
dynamic O
changes O
in O
position O
and O
gene O
expression O
. O

A O
collection O
of O
quantitative O
information O
about O
morphological O
dynamics O
under O
a O
wide O
variety O
of O
gene O
perturbations O
would O
provide O
a O
rich O
resource O
for O
understanding O
the O
molecular O
mechanisms O
of O
development O
. O

Here O
, O
we O
created O
a O
database O
, O
the O
Worm O
Developmental O
Dynamics O
Database O
( O
http O
: O
/ O
/ O
so O
. O
qbic O
. O
riken O
. O
jp O
/ O
wddd O
/ O
) O
, O
which O
stores O
a O
collection O
of O
quantitative O
information O
about O
cell O
division O
dynamics O
in O
early O
Caenorhabditis O
elegans O
embryos O
with O
single O
genes O
silenced O
by O
RNA O
- O
mediated O
interference O
. O

The O
information O
contains O
the O
three O
- O
dimensional O
coordinate O
values O
of O
the O
outlines O
of O
nuclear O
regions O
and O
the O
dynamics O
of O
the O
outlines O
over O
time O
. O

The O
database O
provides O
free O
access O
to O
50 O
sets O
of O
quantitative O
data O
for O
wild O
- O
type O
embryos O
and O
136 O
sets O
of O
quantitative O
data O
for O
RNA O
- O
mediated O
interference O
embryos O
corresponding O
to O
72 O
of O
the O
97 O
essential O
embryonic O
genes O
on O
chromosome O
III O
. O

The O
database O
also O
provides O
sets O
of O
four O
- O
dimensional O
differential O
interference O
contrast O
microscopy O
images O
on O
which O
the O
quantitative O
data O
were O
based O
. O

The O
database O
will O
provide O
a O
novel O
opportunity O
for O
the O
development O
of O
computational O
methods O
to O
obtain O
fresh O
insights O
into O
the O
mechanisms O
of O
development O
. O

The O
quantitative O
information O
and O
microscopy O
images O
can O
be O
synchronously O
viewed O
through O
a O
web O
browser O
, O
which O
is O
designed O
for O
easy O
access O
by O
experimental O
biologists O
. O

Atomically O
flat O
, O
large O
- O
sized O
, O
two O
- O
dimensional O
organic O
nanocrystals O
. O

Large O
- O
sized O
, O
2D O
single O
crystals O
of O
perylene B
are O
grown O
by O
both O
solution O
- O
cast O
and O
physical O
vapor O
transport O
methods O
. O

The O
crystals O
have O
a O
atomically O
flat O
parallelogram O
morphology O
and O
the O
aspect O
ratios O
of O
the O
lateral O
extension O
compared O
to O
the O
thickness O
are O
up O
to O
10 O
( O
3 O
) O
. O

The O
atomically O
flat O
feature O
leads O
to O
good O
interface O
contact O
, O
making O
a O
single O
- O
crystal O
field O
- O
effect O
transistor O
with O
higher O
mobility O
. O

The O
mobility O
of O
atomically O
flat O
crystals O
can O
be O
10 O
( O
3 O
) O
- O
10 O
( O
4 O
) O
times O
higher O
than O
rough O
crystals O
. O

3D O
- O
QSAR O
- O
assisted O
drug O
design O
: O
identification O
of O
a O
potent O
quinazoline B
- O
based O
Aurora O
kinase O
inhibitor O
. O

We O
describe O
the O
3D O
- O
QSAR O
- O
assisted O
design O
of O
an O
Aurora O
kinase O
A O
inhibitor O
with O
improved O
physicochemical O
properties O
, O
in O
vitro O
activity O
, O
and O
in O
vivo O
pharmacokinetic O
profiles O
over O
those O
of O
the O
initial O
lead O
. O

Three O
different O
3D O
- O
QSAR O
models O
were O
built O
and O
validated O
by O
using O
a O
set O
of O
66 O
pyrazole B
( O
Model O
I O
) O
and O
furanopyrimidine B
( O
Model O
II O
) O
compounds O
with O
IC O
( O
50 O
) O
values O
toward O
Aurora O
kinase O
A O
ranging O
from O
33 O
nM O
to O
10 O
. O
5 O
mu O
M O
. O

The O
best O
3D O
- O
QSAR O
model O
, O
Model O
III O
, O
constructed O
with O
24 O
training O
set O
compounds O
from O
both O
series O
, O
showed O
robustness O
( O
r O
( O
2 O
) O
( O
CV O
) O
= O
0 O
. O
54 O
and O
0 O
. O
52 O
for O
CoMFA O
and O
CoMSIA O
, O
respectively O
) O
and O
superior O
predictive O
capacity O
for O
42 O
test O
set O
compounds O
( O
R O
( O
2 O
) O
( O
pred O
) O
= O
0 O
. O
52 O
and O
0 O
. O
67 O
, O
CoMFA O
and O
CoMSIA O
) O
. O

Superimposition O
of O
CoMFA O
and O
CoMSIA O
Model O
III O
over O
the O
crystal O
structure O
of O
Aurora O
kinase O
A O
suggests O
the O
potential O
to O
improve O
the O
activity O
of O
the O
ligands O
by O
decreasing O
the O
steric O
clash O
with O
Val147 B
and O
Leu139 B
and O
by O
increasing O
hydrophobic O
contact O
with O
Leu139 B
and O
Gly216 B
residues O
in O
the O
solvent O
- O
exposed O
region O
of O
the O
enzyme O
. O

Based O
on O
these O
suggestions O
, O
the O
rational O
redesign O
of O
furanopyrimidine B
24 O
( O
clog O
P O
= O
7 O
. O
41 O
; O
Aurora O
A O
IC O
( O
50 O
) O
= O
43 O
nM O
; O
HCT O
- O
116 O
IC O
( O
50 O
) O
= O
400 O
nM O
) O
led O
to O
the O
identification O
of O
quinazoline B
67 O
( O
clog O
P O
= O
5 O
. O
28 O
; O
Aurora O
A O
IC O
( O
50 O
) O
= O
25 O
nM O
; O
HCT O
- O
116 O
IC O
( O
50 O
) O
= O
23 O
nM O
) O
. O

Rat O
in O
vivo O
pharmacokinetic O
studies O
showed O
that O
67 O
has O
better O
systemic O
exposure O
after O
i O
. O
v O
. O
administration O
than O
24 O
, O
and O
holds O
potential O
for O
further O
development O
. O

Assessing O
the O
potential O
effectiveness O
of O
food O
and O
beverage O
taxes O
and O
subsidies O
for O
improving O
public O
health O
: O
a O
systematic O
review O
of O
prices O
, O
demand O
and O
body O
weight O
outcomes O
. O

Taxes O
and O
subsidies O
are O
increasingly O
being O
considered O
as O
potential O
policy O
instruments O
to O
incentivize O
consumers O
to O
improve O
their O
food O
and O
beverage O
consumption O
patterns O
and O
related O
health O
outcomes O
. O

This O
study O
provided O
a O
systematic O
review O
of O
recent O
U O
. O
S O
. O
studies O
on O
the O
price O
elasticity O
of O
demand O
for O
sugar B
- O
sweetened O
beverages O
( O
SSBs O
) O
, O
fast O
food O
, O
and O
fruits O
and O
vegetables O
, O
as O
well O
as O
the O
direct O
associations O
of O
prices O
/ O
taxes O
with O
body O
weight O
outcomes O
. O

Based O
on O
the O
recent O
literature O
, O
the O
price O
elasticity O
of O
demand O
for O
SSBs O
, O
fast O
food O
, O
fruits O
and O
vegetables O
was O
estimated O
to O
be O
- O
1 O
. O
21 O
, O
- O
0 O
. O
52 O
, O
- O
0 O
. O
49 O
and O
- O
0 O
. O
48 O
, O
respectively O
. O

The O
studies O
that O
linked O
soda O
taxes O
to O
weight O
outcomes O
showed O
minimal O
impacts O
on O
weight O
; O
however O
, O
they O
were O
based O
on O
existing O
state O
- O
level O
sales O
taxes O
that O
were O
relatively O
low O
. O

Higher O
fast O
- O
food O
prices O
were O
associated O
with O
lower O
weight O
outcomes O
particularly O
among O
adolescents O
, O
suggesting O
that O
raising O
prices O
would O
potentially O
impact O
weight O
outcomes O
. O

Lower O
fruit O
and O
vegetable O
prices O
were O
generally O
found O
to O
be O
associated O
with O
lower O
body O
weight O
outcomes O
among O
both O
low O
- O
income O
children O
and O
adults O
, O
suggesting O
that O
subsidies O
that O
would O
reduce O
the O
cost O
of O
fruits O
and O
vegetables O
for O
lower O
- O
socioeconomic O
populations O
may O
be O
effective O
in O
reducing O
obesity O
. O

Pricing O
instruments O
should O
continue O
to O
be O
considered O
and O
evaluated O
as O
potential O
policy O
instruments O
to O
address O
public O
health O
risks O
. O

Cannabinoid O
agonists O
increase O
the O
interaction O
between O
beta O
- O
Arrestin O
2 O
and O
ERK1 O
/ O
2 O
and O
upregulate O
beta O
- O
Arrestin O
2 O
and O
5 B
- I
HT I
( O
2A O
) O
receptors O
. O

We O
have O
recently O
reported O
that O
selective O
cannabinoid O
2 O
( O
CB O
( O
2 O
) O
) O
receptor O
agonists O
upregulate O
5 B
- I
HT I
( O
2A O
) O
receptors O
by O
enhancing O
ERK1 O
/ O
2 O
signaling O
in O
prefrontal O
cortex O
( O
PFCx O
) O
. O

Increased O
activity O
of O
cortical O
5 B
- I
HT I
( O
2A O
) O
receptors O
has O
been O
associated O
with O
several O
neuropsychiatric O
disorders O
such O
as O
anxiety O
and O
schizophrenia O
. O

Here O
we O
examine O
the O
mechanisms O
involved O
in O
this O
enhanced O
ERK1 O
/ O
2 O
activation O
in O
rat O
PFCx O
and O
in O
a O
neuronal O
cell O
model O
. O

Sprague O
- O
Dawley O
rats O
treated O
with O
a O
non O
- O
selective O
cannabinoid O
agonist O
( O
CP55940 B
, O
50 O
mu O
g O
/ O
kg O
, O
7 O
days O
, O
i O
. O
p O
. O
) O
showed O
enhanced O
co O
- O
immunoprecipitation O
of O
beta O
- O
Arrestin O
2 O
and O
ERK1 O
/ O
2 O
, O
enhanced O
pERK O
protein O
levels O
, O
and O
enhanced O
expression O
of O
beta O
- O
Arrestin O
2 O
mRNA O
and O
protein O
levels O
in O
PFCx O
. O

In O
a O
neuronal O
cell O
line O
, O
we O
found O
that O
selective O
CB O
( O
2 O
) O
receptor O
agonists O
upregulate O
beta O
- O
Arrestin O
2 O
, O
an O
effect O
that O
was O
prevented O
by O
selective O
CB O
( O
2 O
) O
receptor O
antagonist O
JTE B
- I
907 I
and O
CB O
( O
2 O
) O
shRNA O
lentiviral O
particles O
. O

Additionally O
, O
inhibition O
of O
clathrin O
- O
mediated O
endocytosis O
, O
ERK1 O
/ O
2 O
, O
and O
the O
AP O
- O
1 O
transcription O
factor O
also O
prevented O
the O
cannabinoid O
receptor O
- O
induced O
upregulation O
of O
beta O
- O
Arrestin O
2 O
. O

Our O
results O
suggest O
that O
sustained O
activation O
of O
CB O
( O
2 O
) O
receptors O
would O
enhance O
beta O
- O
Arrestin O
2 O
expression O
possibly O
contributing O
to O
its O
increased O
interaction O
with O
ERK1 O
/ O
2 O
, O
thereby O
driving O
the O
upregulation O
of O
5 B
- I
HT I
( O
2A O
) O
receptors O
. O

The O
CB O
( O
2 O
) O
receptor O
- O
mediated O
upregulation O
of O
beta O
- O
Arrestin O
2 O
would O
be O
mediated O
, O
at O
least O
in O
part O
, O
by O
an O
ERK1 O
/ O
2 O
- O
dependent O
activation O
of O
AP O
- O
1 O
. O

These O
data O
could O
provide O
the O
rationale O
for O
some O
of O
the O
adverse O
effects O
associated O
with O
repeated O
cannabinoid O
exposure O
and O
shed O
light O
on O
some O
CB O
( O
2 O
) O
receptor O
agonists O
that O
could O
represent O
an O
alternative O
therapeutic O
because O
of O
their O
minimal O
effect O
on O
serotonergic O
neurotransmission O
. O

Beneficial O
effects O
of O
polyphenols B
on O
cardiovascular O
disease O
. O

In O
recent O
years O
, O
numerous O
studies O
have O
demonstrated O
the O
health O
benefits O
of O
polyphenols B
, O
and O
special O
attention O
has O
been O
paid O
to O
their O
beneficial O
effects O
against O
cardiovascular O
disease O
, O
the O
leading O
cause O
of O
death O
in O
the O
world O
today O
. O

Polyphenols B
present O
vasodilator O
effects O
and O
are O
able O
to O
improve O
lipid O
profiles O
and O
attenuate O
the O
oxidation O
of O
low O
density O
lipoproteins O
. O

In O
addition O
, O
they O
present O
clear O
anti O
- O
inflammatory O
effects O
and O
can O
modulate O
apoptotic O
processes O
in O
the O
vascular O
endothelium O
. O

It O
has O
been O
suggested O
that O
most O
of O
these O
effects O
are O
a O
consequence O
of O
the O
antioxidant O
properties O
of O
polyphenols B
, O
but O
this O
idea O
is O
not O
completely O
accepted O
, O
and O
many O
other O
mechanisms O
have O
been O
proposed O
recently O
to O
explain O
the O
health O
effects O
of O
these O
compounds O
. O

In O
fact O
, O
different O
signaling O
pathways O
have O
been O
linked O
to O
polyphenols B
. O

This O
review O
brings O
together O
some O
recent O
studies O
which O
establish O
the O
beneficial O
properties O
of O
polyphenols B
for O
cardiovascular O
disease O
and O
analyzes O
the O
mechanisms O
involved O
in O
these O
properties O
. O

Deficits O
in O
male O
sexual O
behavior O
in O
adulthood O
after O
social O
instability O
stress O
in O
adolescence O
in O
rats O
. O

There O
is O
increasing O
evidence O
that O
exposure O
to O
stressors O
in O
adolescence O
has O
long O
- O
lasting O
effects O
on O
emotional O
and O
cognitive O
behavior O
, O
but O
little O
is O
known O
as O
to O
whether O
reproductive O
functions O
are O
affected O
. O

We O
investigated O
appetitive O
and O
consummatory O
aspects O
of O
sexual O
behavior O
in O
male O
rats O
that O
were O
exposed O
to O
chronic O
social O
instability O
stress O
( O
SS O
, O
n O
= O
24 O
) O
for O
16 O
days O
in O
mid O
- O
adolescence O
compared O
to O
control O
rats O
( O
CTL O
, O
n O
= O
24 O
) O
. O

Over O
five O
sexual O
behavior O
test O
sessions O
with O
a O
receptive O
female O
, O
SS O
rats O
made O
fewer O
ejaculations O
( O
p O
= O
0 O
. O
02 O
) O
and O
had O
longer O
latencies O
to O
ejaculation O
( O
p O
= O
0 O
. O
03 O
) O
. O

When O
only O
data O
from O
rats O
that O
ejaculated O
in O
the O
fifth O
session O
were O
analyzed O
, O
SS O
rats O
( O
n O
= O
18 O
) O
had O
reduced O
copulatory O
efficiency O
( O
more O
mounts O
and O
intromissions O
before O
ejaculation O
) O
compared O
to O
CTL O
rats O
( O
n O
= O
19 O
) O
( O
p O
= O
0 O
. O
004 O
) O
, O
and O
CTL O
rats O
were O
twice O
as O
likely O
as O
SS O
rats O
to O
make O
more O
than O
one O
ejaculation O
in O
the O
fifth O
session O
( O
p O
= O
0 O
. O
05 O
) O
. O

Further O
, O
more O
CTL O
( O
14 O
/ O
24 O
) O
than O
SS O
( O
5 O
/ O
25 O
) O
rats O
ejaculated O
in O
four O
or O
more O
sessions O
( O
p O
= O
0 O
. O
05 O
) O
. O

SS O
rats O
had O
lower O
plasma O
testosterone B
concentrations O
than O
CTL O
rats O
( O
p O
= O
0 O
. O
05 O
) O
, O
but O
did O
not O
differ O
in O
androgen B
receptor O
, O
estrogen B
receptor O
alpha O
, O
or O
Fos O
immunoreactive O
cell O
counts O
in O
the O
medial O
preoptic O
area O
. O

The O
groups O
did O
not O
differ O
in O
a O
partner O
preference O
test O
administered O
between O
the O
fourth O
and O
fifth O
sexual O
behavior O
session O
. O

The O
results O
suggest O
that O
developmental O
history O
contributes O
to O
individual O
differences O
in O
reproductive O
behavior O
, O
and O
that O
stress O
exposures O
in O
adolescence O
may O
be O
a O
factor O
in O
sexual O
sluggishness O
. O

Angiotensin O
AT2 O
receptor O
activates O
the O
cyclic B
- I
AMP I
signaling O
pathway O
in O
eel O
. O

A O
unique O
angiotensin O
type O
2 O
receptor O
( O
AT2 O
) O
that O
induces O
a O
cAMP B
signaling O
pathway O
was O
cloned O
and O
characterized O
for O
the O
first O
time O
in O
fish O
, O
Anguilla O
japonica O
. O

Phylogeny O
and O
synteny O
results O
showed O
that O
the O
AT2s O
among O
fishes O
and O
tetrapods O
share O
the O
same O
origin O
despite O
a O
sub O
- O
cluster O
formation O
among O
eel O
, O
salmon O
, O
and O
zebrafish O
. O

The O
eel O
AT2 O
was O
expressed O
abundantly O
in O
the O
spleen O
and O
localized O
at O
straight O
arterioles O
and O
ellipsoid O
regions O
prior O
to O
the O
sinusoid O
, O
suggesting O
a O
role O
in O
the O
regulation O
of O
microcirculation O
and O
/ O
or O
immune O
response O
. O

Various O
angiotensin O
( O
Ang O
) O
peptides O
, O
including O
Ang O
II O
, O
Ang O
III O
, O
and O
Ang O
IV O
, O
were O
detected O
in O
the O
spleen O
by O
a O
radioimmunoassay O
coupled O
with O
HPLC O
separation O
, O
and O
these O
endogenous O
peptides O
stimulated O
a O
cAMP B
signaling O
, O
which O
has O
no O
crosstalk O
with O
cGMP B
pathway O
. O

The O
common O
and O
contrasting O
features O
of O
AT2 O
between O
fishes O
and O
mammals O
imply O
some O
ancestral O
characters O
of O
AT2 O
, O
which O
are O
important O
information O
for O
receptor O
binding O
and O
evolutionary O
studies O
. O

Intraindividual O
and O
interindividual O
variabilities O
in O
endogenous O
cortisol B
6 O
beta O
- O
hydroxylation O
clearance O
as O
an O
index O
for O
in O
vivo O
CYP3A O
phenotyping O
in O
humans O
. O

This O
study O
was O
designed O
to O
evaluate O
the O
in O
vivo O
activity O
of O
cytochrome O
P450 O
3A O
( O
CYP3A O
) O
in O
49 O
healthy O
Japanese O
subjects O
aged O
22 O
- O
58 O
years O
using O
endogenous O
cortisol B
6 O
beta O
- O
hydroxylation O
clearance O
[ O
CLm O
( O
6 O
beta O
) O
] O
, O
a O
novel O
biomarker O
for O
CYP3A O
phenotyping O
. O

CLm O
( O
6 O
beta O
) O
in O
the O
49 O
healthy O
subjects O
was O
2 O
. O
40 O
+ O
/ O
- O
0 O
. O
79 O
ml O
/ O
min O
with O
an O
approximately O
4 O
- O
fold O
interindividual O
variability O
of O
CYP3A O
activity O
. O

The O
mean O
clearance O
in O
the O
24 O
women O
was O
2 O
. O
50 O
+ O
/ O
- O
0 O
. O
89 O
ml O
/ O
min O
; O
the O
value O
in O
the O
women O
was O
higher O
than O
in O
the O
25 O
men O
( O
2 O
. O
30 O
+ O
/ O
- O
0 O
. O
69 O
ml O
/ O
min O
) O
by O
approximately O
9 O
% O
. O

We O
also O
measured O
the O
change O
of O
CLm O
( O
6 O
beta O
) O
in O
14 O
healthy O
subjects O
in O
the O
morning O
at O
10 O
: O
00 O
- O
12 O
: O
00 O
every O
2 O
or O
3 O
days O
over O
a O
period O
of O
36 O
- O
53 O
days O
and O
observed O
a O
1 O
. O
5 O
- O
fold O
to O
3 O
. O
4 O
- O
fold O
day O
- O
to O
- O
day O
intraindividual O
variability O
in O
the O
CYP3A O
activity O
. O

The O
mean O
value O
for O
CLm O
( O
6 O
beta O
) O
in O
each O
subject O
for O
36 O
- O
53 O
days O
was O
2 O
. O
54 O
+ O
/ O
- O
0 O
. O
76 O
ml O
/ O
min O
( O
n O
= O
14 O
) O
. O

We O
also O
evaluated O
the O
CLm O
( O
6 O
beta O
) O
every O
2 O
hours O
from O
8 O
: O
00 O
- O
20 O
: O
00 O
in O
26 O
healthy O
subjects O
. O

The O
within O
- O
day O
intraindividual O
clearance O
variability O
was O
1 O
. O
1 O
- O
fold O
to O
2 O
. O
5 O
- O
fold O
( O
2 O
. O
45 O
+ O
/ O
- O
0 O
. O
91 O
ml O
/ O
min O
, O
n O
= O
26 O
) O
. O

No O
characteristic O
diurnal O
rhythms O
were O
observed O
in O
the O
in O
vivo O
activity O
of O
CYP3A O
. O

Chemotherapy O
of O
leishmaniasis O
part O
X O
: O
synthesis O
and O
bioevaluation O
of O
novel O
terpenyl B
heterocycles O
. O

Some O
novel O
alpha B
and I
beta I
ionone I
based O
chalcones B
and O
their O
dihydropyrazolidines B
/ O
pyrazolidines B
have O
been O
synthesized O
and O
evaluated O
for O
their O
in O
vitro O
and O
in O
vivo O
antileishmanial O
activities O
against O
Leishmania O
donovani O
. O

Amongest O
all O
, O
one O
compound O
( O
4d O
) O
exhibited O
significant O
in O
vitro O
activity O
against O
intracellular O
amastigotes O
of O
Leishmania O
donovani O
with O
IC O
( O
50 O
) O
values O
of O
7 O
. O
49 O
mu O
M O
and O
was O
found O
promising O
as O
compared O
to O
reference O
drug O
, O
miltefosine B
. O

On O
the O
basis O
of O
good O
Selectivity O
Index O
( O
S O
. O
I O
. O
) O
, O
the O
compound O
was O
further O
tested O
for O
its O
in O
vivo O
response O
against O
Leishmania O
donovani O
/ O
hamster O
model O
and O
has O
shown O
significant O
inhibition O
of O
parasite O
multiplication O
( O
81 O
% O
) O
. O

The O
present O
study O
has O
helped O
us O
in O
identifying O
a O
new O
lead O
that O
could O
be O
exploited O
as O
a O
potential O
antileishmanial O
agent O
. O

Design O
, O
synthesis O
and O
inhibitory O
activities O
of O
naringenin B
derivatives O
on O
human O
colon O
cancer O
cells O
. O

Based O
on O
the O
previous O
result O
, O
several O
naringenin B
derivatives O
modified O
at O
position O
7 O
with O
bulky O
substituents O
were O
designed O
and O
synthesized O
, O
and O
their O
inhibitory O
effects O
on O
HCT116 O
human O
colon O
cancer O
cells O
were O
tested O
using O
a O
clonogenic O
assay O
. O

The O
half O
maximal O
inhibitory O
concentrations O
( O
IC O
( O
50 O
) O
) O
of O
five O
naringenin B
derivatives O
ranged O
between O
1 O
. O
20 O
mu O
M O
and O
20 O
. O
01 O
mu O
M O
which O
are O
much O
better O
than O
naringenin B
used O
as O
a O
control O
. O

In O
addition O
, O
new O
structural O
modification O
at O
C O
- O
4 O
of O
flavanone B
results O
in O
improving O
both O
the O
anti O
- O
cancer O
effect O
and O
anti O
- O
oxidative O
effect O
. O

In O
vitro O
cyclin O
dependent O
kinase O
2 O
( O
CDK2 O
) O
binding O
assay O
was O
carried O
out O
based O
on O
the O
previous O
results O
. O

To O
elucidate O
the O
possible O
interaction O
between O
naringenin B
derivatives O
and O
CDK2 O
, O
in O
silico O
docking O
study O
was O
performed O
. O

This O
result O
demonstrates O
the O
rationale O
for O
the O
different O
inhibitory O
activities O
of O
the O
naringenin B
derivatives O
. O

These O
findings O
could O
be O
used O
for O
designing O
cancer O
therapeutic O
or O
preventive O
flavanone B
- O
derived O
agents O
. O

Triazoyl B
- I
phenyl I
linker O
system O
enhancing O
the O
aqueous O
solubility O
of O
a O
molecular O
probe O
and O
its O
efficiency O
in O
affinity O
labeling O
of O
a O
target O
protein O
for O
jasmonate B
glucoside I
. O

In O
methods O
employing O
molecular O
probes O
to O
explore O
the O
targets O
of O
bioactive O
small O
molecules O
, O
long O
or O
rigid O
linker O
moieties O
are O
thought O
to O
be O
critical O
factors O
for O
efficient O
tagging O
of O
target O
protein O
. O

We O
previously O
reported O
the O
synthesis O
of O
a O
jasmonate B
glucoside I
probe O
with O
a O
highly O
rigid O
linker O
consisting O
of O
a O
triazoyl B
- I
phenyl I
( O
TAzP B
) O
moiety O
, O
and O
this O
probe O
demonstrated O
effective O
target O
tagging O
. O

Here O
we O
compare O
the O
TAzP O
probe O
with O
other O
rigid O
or O
flexible O
probes O
with O
respect O
to O
target O
tagging O
efficiency O
, O
hydrophobic O
parameters O
, O
aqueous O
solubility O
, O
and O
dihedral O
angles O
around O
the O
biaryl B
linkage O
by O
a O
combination O
of O
empirical O
and O
calculation O
methods O
. O

The O
rigid O
biaryl O
linkage O
of O
the O
TAzP O
probe O
has O
a O
skewed O
conformation O
that O
influences O
its O
aqueous O
solubility O
. O

Such O
features O
that O
include O
rigidness O
and O
good O
aqueous O
solubility O
resulted O
in O
highly O
efficient O
target O
tagging O
. O

These O
findings O
provide O
a O
promising O
guideline O
toward O
designing O
of O
better O
linkers O
for O
improving O
molecular O
probe O
performance O
. O

Discovery O
of O
a O
selective O
M O
4 O
positive O
allosteric O
modulator O
based O
on O
the O
3 B
- I
amino I
- I
thieno I
[ I
2 I
, I
3 I
- I
b I
] I
pyridine I
- I
2 I
- I
carboxamide I
scaffold O
: O
development O
of O
ML253 B
, O
a O
potent O
and O
brain O
penetrant O
compound O
that O
is O
active O
in O
a O
preclinical O
model O
of O
schizophrenia O
. O

Herein O
we O
report O
a O
next O
generation O
muscarinic O
receptor O
4 O
( O
M O
( O
4 O
) O
) O
positive O
allosteric O
modulator O
( O
PAM O
) O
, O
ML253 B
which O
exhibits O
nanomolar O
activity O
at O
both O
the O
human O
( O
EC O
( O
50 O
) O
= O
56 O
nM O
) O
and O
rat O
( O
EC O
( O
50 O
) O
= O
176 O
nM O
) O
receptors O
and O
excellent O
efficacy O
by O
the O
left O
- O
ward O
shift O
of O
the O
ACh O
concentration O
response O
curve O
( O
fold O
shift O
, O
human O
= O
106 O
; O
rat O
= O
50 O
) O
. O

In O
addition O
, O
ML253 B
is O
selective O
against O
the O
four O
other O
muscarinic O
subtypes O
, O
displays O
excellent O
CNS O
exposure O
and O
is O
active O
in O
an O
amphetamine B
- O
induced O
hyperlocomotion O
assay O
. O

Protein O
tyrosine B
phosphatase O
1B O
inhibitory O
effect O
by O
dammarane B
- O
type O
triterpenes B
from O
hydrolyzate O
of O
total O
Gynostemma O
pentaphyllum O
saponins B
. O

Protein O
tyrosine B
phosphatase O
1B O
( O
PTP1B O
) O
is O
an O
important O
factor O
in O
non O
- O
insulin O
- O
dependent O
diabetes O
mellitus O
( O
type O
- O
2 O
diabetes O
) O
, O
and O
a O
promising O
target O
for O
treatment O
of O
diabetes O
and O
obesity O
. O

Therefore O
, O
the O
aim O
of O
this O
study O
is O
to O
investigate O
the O
inhibitory O
activities O
of O
constituents O
( O
three O
new O
together O
with O
twelve O
known O
triterpenes B
compounds O
) O
isolated O
from O
the O
hydrolyzate O
of O
total O
saponins B
from O
Gynostemma O
pentaphyllum O
. O

Their O
structures O
were O
accomplished O
mainly O
base O
on O
the O
spectroscopic O
methods O
, O
and O
then O
were O
further O
confirmed O
by O
X O
- O
ray O
crystal O
diffraction O
. O

All O
the O
compounds O
were O
evaluated O
for O
inhibitory O
activity O
against O
PTP1B O
. O

Current O
data O
suggested O
that O
the O
compounds O
1 O
, O
3 O
, O
12 O
, O
13 O
and O
14 O
were O
considered O
to O
be O
potential O
as O
antidiabetic O
agents O
, O
in O
which O
they O
could O
significantly O
inhibit O
the O
PTP1B O
enzyme O
activity O
in O
a O
dose O
- O
dependent O
manner O
. O

Constant O
light O
disrupts O
the O
circadian O
rhythm O
of O
steroidogenic O
proteins O
in O
the O
rat O
adrenal O
gland O
. O

The O
circadian O
rhythm O
of O
corticosterone B
( O
CORT B
) O
secretion O
from O
the O
adrenal O
cortex O
is O
regulated O
by O
the O
suprachiasmatic O
nucleus O
( O
SCN O
) O
, O
which O
is O
entrained O
to O
the O
light O
- O
dark O
cycle O
. O

Since O
the O
circadian O
CORT B
rhythm O
is O
associated O
with O
circadian O
expression O
of O
the O
steroidogenic O
acute O
regulatory O
( O
StAR O
) O
protein O
, O
we O
investigated O
the O
24h O
pattern O
of O
hormonal O
secretion O
( O
ACTH O
and O
CORT B
) O
, O
steroidogenic O
gene O
expression O
( O
StAR O
, O
SF O
- O
1 O
, O
DAX1 O
and O
Nurr77 O
) O
and O
the O
expression O
of O
genes O
involved O
in O
ACTH O
signalling O
( O
MC2R O
and O
MRAP O
) O
in O
rats O
entrained O
to O
a O
normal O
light O
- O
dark O
cycle O
. O

We O
found O
that O
circadian O
changes O
in O
ACTH O
and O
CORT B
were O
associated O
with O
the O
circadian O
expression O
of O
all O
gene O
targets O
; O
with O
SF O
- O
1 O
, O
Nurr77 O
and O
MRAP O
peaking O
in O
the O
evening O
, O
and O
DAX1 O
and O
MC2R O
peaking O
in O
the O
morning O
. O

Since O
disruption O
of O
normal O
SCN O
activity O
by O
exposure O
to O
constant O
light O
abolishes O
the O
circadian O
rhythm O
of O
CORT B
in O
the O
rat O
, O
we O
also O
investigated O
whether O
the O
AM O
- O
PM O
variation O
of O
our O
target O
genes O
was O
also O
disrupted O
in O
rats O
exposed O
to O
constant O
light O
conditions O
for O
5weeks O
. O

We O
found O
that O
the O
disruption O
of O
the O
AM O
- O
PM O
variation O
of O
ACTH O
and O
CORT B
secretion O
in O
rats O
exposed O
to O
constant O
light O
was O
accompanied O
by O
a O
loss O
of O
AM O
- O
PM O
variation O
in O
StAR O
, O
SF O
- O
1 O
and O
DAX1 O
, O
and O
a O
reversed O
AM O
- O
PM O
variation O
in O
Nurr77 O
, O
MC2R O
and O
MRAP O
. O

Our O
data O
suggest O
that O
circadian O
expression O
of O
StAR O
is O
regulated O
by O
the O
circadian O
expression O
of O
nuclear O
receptors O
and O
proteins O
involved O
in O
both O
ACTH O
signalling O
and O
StAR O
transcription O
. O

We O
propose O
that O
ACTH O
regulates O
the O
secretion O
of O
CORT B
via O
the O
circadian O
control O
of O
steroidogenic O
gene O
pathways O
that O
become O
dysregulated O
under O
the O
influence O
of O
constant O
light O
. O

Synthesis O
and O
anti O
- O
tumor O
evaluation O
of O
novel O
25 B
- I
hydroxyprotopanaxadi I
analogs O
incorporating O
natural O
amino B
acids I
. O

In O
the O
current O
study O
, O
derivatives O
of O
25 B
- I
hydroxyprotopanaxadi I
( O
25 B
- I
OH I
- I
PPD I
) O
were O
prepared O
and O
their O
in O
vitro O
anti O
- O
tumor O
activities O
were O
tested O
on O
six O
different O
human O
tumor O
cell O
lines O
by O
standard O
MTT B
assay O
. O

The O
results O
showed O
that O
combining O
an O
ester B
group O
combined O
with O
the O
presence O
of O
an O
amino B
acid I
moiety O
led O
to O
a O
10 O
- O
fold O
improved O
anti O
- O
tumor O
activity O
. O

Compound O
1c O
exhibited O
the O
best O
anti O
- O
tumor O
activity O
in O
the O
in O
vitro O
assays O
. O

Compounds O
2c O
, O
3c O
, O
4c O
, O
5c O
, O
6c O
and O
8b O
showed O
better O
anti O
- O
tumor O
activities O
compared O
to O
the O
parent O
compound O
25 B
- I
OH I
- I
PPD I
. O

The O
current O
results O
may O
provide O
useful O
data O
for O
researching O
and O
developing O
new O
anti O
- O
cancer O
agents O
. O

Pulmonary O
delivery O
of O
an O
aerosolized O
recombinant O
human O
butyrylcholinesteras O
pretreatment O
protects O
against O
aerosolized O
paraoxon B
in O
macaques O
. O

Butyrylcholinesteras O
( O
BChE O
) O
is O
the O
leading O
pretreatment O
candidate O
against O
exposure O
to O
organophosphates B
( O
OPs B
) O
, O
which O
pose O
an O
ever O
increasing O
public O
and O
military O
health O
. O

Since O
respiratory O
failure O
is O
the O
primary O
cause O
of O
death O
following O
acute O
OP O
poisoning O
, O
an O
inhaled O
BChE O
therapeutic O
could O
prove O
highly O
efficacious O
in O
preventing O
acute O
toxicity O
as O
well O
as O
the O
associated O
delayed O
neuropathy O
. O

To O
address O
this O
, O
studies O
have O
been O
performed O
in O
mice O
and O
macaques O
using O
Chinese O
Hamster O
Ovary O
cells O
( O
CHO O
) O
- O
derived O
recombinant O
( O
r O
) O
BChE O
delivered O
by O
the O
pulmonary O
route O
, O
to O
examine O
whether O
the O
deposition O
of O
both O
macaque O
( O
Ma O
) O
and O
human O
( O
Hu O
) O
rBChE O
administered O
as O
aerosols O
( O
aer O
) O
favored O
the O
creation O
and O
retention O
of O
an O
efficient O
protective O
" O
pulmonary O
bioshield O
" O
that O
could O
scavenge O
incoming O
( O
inhaled O
) O
OPs O
in O
situ O
thereby O
preventing O
entry O
into O
the O
circulation O
and O
inhibition O
of O
plasma O
BChE O
and O
AChE O
on O
red O
blood O
cells O
( O

RBC O
- O
AChE O
) O
and O
in O
cholinergic O
synapses O
. O

In O
contrast O
to O
parenteral O
delivery O
of O
rBChE O
, O
which O
currently O
requires O
posttranslational O
modification O
for O
good O
plasma O
stability O
, O
an O
unmodified O
aer O
- O
rBChE O
pretreatment O
given O
1 O
- O
40h O
prior O
to O
> O
1 O
LD50 O
of O
aer O
- O
paraoxon B
( O
Px O
) O
was O
able O
to O
prevent O
inhibition O
of O
circulating O
cholinesterase O
in O
a O
dose O
- O
dependent O
manner O
. O

These O
studies O
are O
the O
first O
to O
show O
protection O
by O
rBChE O
against O
a O
pesticide O
such O
as O
paraoxon B
when O
delivered O
directly O
into O
the O
lung O
and O
bode O
well O
for O
the O
use O
of O
a O
non O
- O
invasive O
and O
consumer O
friendly O
method O
of O
rHuBChE O
delivery O
as O
a O
human O
treatment O
to O
counteract O
OP O
toxicity O
. O

Aspidin B
PB I
, O
a O
phloroglucinol B
derivative O
, O
induces O
apoptosis O
in O
human O
hepatocarcinoma O
HepG2 O
cells O
by O
modulating O
PI3K O
/ O
Akt O
/ O
GSK3 O
beta O
pathway O
. O

Aspidin B
PB I
, O
a O
phloroglucinol B
derivative O
isolated O
from O
Dryopteris O
fragrans O
( O
L O
. O
) O
Schott O
, O
has O
been O
previously O
reported O
to O
exert O
high O
biological O
activities O
. O

In O
the O
present O
study O
, O
we O
analyzed O
the O
apoptotic O
mechanisms O
of O
aspidin B
PB I
on O
human O
hepatoma O
cell O
line O
, O
HepG2 O
. O

Initially O
, O
aspidin B
PB I
was O
shown O
to O
inhibit O
the O
growth O
of O
HepG2 O
cells O
in O
a O
time O
and O
dose O
- O
dependent O
manner O
. O

After O
treatment O
with O
aspidin B
PB I
for O
72 O
h O
, O
48 O
h O
and O
24 O
h O
using O
MTT B
assay O
, O
the O
IC O
( O
50 O
) O
values O
were O
10 O
. O
59 O
mu O
M O
, O
20 O
. O
86 O
mu O
M O
and O
46 O
. O
59 O
mu O
M O
, O
respectively O
. O

Aspidin B
PB I
was O
capable O
to O
induce O
apoptosis O
, O
as O
measured O
by O
mitochondrial O
membrane O
potential O
( O
Delta O
Psi O
m O
) O
, O
acridine B
orange I
( O
AO B
) O
staining O
and O
propidium B
iodide I
( O
PI O
) O
/ O
annexin O
V O
- O
FITC B
double O
staining O
. O

To O
further O
explore O
the O
signaling O
pathway O
of O
aspidin B
PB B
- O
mediated O
apoptosis O
, O
we O
examined O
PI3K O
/ O
Akt O
related O
proteins O
. O

Western O
blot O
analysis O
revealed O
that O
aspidin B
PB I
inhibited O
PI3K O
expression O
, O
phosphorylation O
of O
Ser473 B
Akt O
and O
Ser9 B
GSK3 O
beta O
followed O
by O
up O
- O
regulation O
of O
nonsteroidal O
anti O
- O
inflammatory O
drugs O
activated O
gene O
- O
1 O
( O
NAG O
- O
1 O
) O
expression O
. O

Similarly O
, O
the O
effects O
of O
aspidin B
PB I
on O
PI3K O
, O
Akt O
, O
GSK3 O
beta O
, O
NAG O
- O
1 O
expression O
were O
abolished O
by O
treatment O
with O
the O
PI3K O
inhibitor O
, O
wortmannin B
. O

Taken O
together O
, O
our O
data O
suggested O
that O
the O
PI3K O
/ O
Akt O
/ O
GSK3 O
beta O
signal O
pathway O
may O
represent O
one O
of O
the O
major O
mechanisms O
of O
the O
effects O
of O
aspidin B
PB I
on O
human O
hepatocarcinoma O
cells O
. O

Adaptation O
of O
bifidobacteria O
to O
the O
gastrointestinal O
tract O
and O
functional O
consequences O
. O

Members O
of O
the O
genus O
Bifidobacterium O
are O
considered O
to O
be O
important O
constituents O
of O
the O
microbiota O
of O
animals O
, O
from O
insects O
to O
mammals O
. O

They O
are O
gut O
commensals O
extensively O
used O
by O
the O
food O
industry O
as O
probiotic O
microorganisms O
, O
since O
some O
strains O
have O
been O
shown O
to O
have O
specific O
beneficial O
effects O
. O

However O
, O
the O
molecular O
processes O
underlying O
their O
functional O
capacities O
to O
promote O
a O
healthy O
status O
in O
the O
host O
, O
as O
well O
as O
those O
involved O
in O
survival O
, O
colonization O
and O
persistence O
of O
bifidobacteria O
in O
the O
gut O
, O
are O
far O
from O
being O
completely O
understood O
. O

This O
review O
summarizes O
the O
current O
knowledge O
on O
the O
mechanisms O
used O
by O
bifidobacteria O
to O
cope O
with O
gastrointestinal O
factors O
and O
to O
adapt O
to O
them O
, O
and O
discusses O
the O
advantages O
of O
the O
adaptive O
traits O
acquired O
by O
these O
microorganisms O
as O
a O
consequence O
of O
their O
interactions O
with O
the O
gastrointestinal O
tract O
environment O
, O
as O
well O
as O
the O
impact O
of O
such O
adaptations O
in O
the O
functional O
characteristics O
of O
bifidobacteria O
. O

Inhibition O
of O
CIP2A O
determines O
erlotinib B
- O
induced O
apoptosis O
in O
hepatocellular O
carcinoma O
. O

Erlotinib B
is O
a O
small O
- O
molecular O
inhibitor O
of O
epidermal O
growth O
factor O
receptor O
( O
EGFR O
) O
. O

Here O
, O
we O
identify O
that O
cancerous O
inhibitor O
of O
protein O
phosphatase O
2A O
( O
CIP2A O
) O
is O
a O
major O
determinant O
mediating O
erlotinib B
- O
induced O
apoptosis O
in O
hepatocellular O
carcinoma O
( O
HCC O
) O
. O

Erlotinib B
showed O
differential O
effects O
on O
apoptosis O
in O
4 O
human O
HCC O
cell O
lines O
. O

Erlotinib B
induced O
significant O
apoptosis O
in O
Hep3B O
and O
PLC5 O
cell O
lines O
; O
however O
, O
Huh O
- O
7 O
and O
HA59T O
cell O
lines O
showed O
resistance O
to O
erlotinib B
- O
induced O
apoptosis O
at O
all O
tested O
doses O
. O

Down O
- O
regulation O
of O
CIP2A O
, O
a O
cellular O
inhibitor O
of O
protein O
phosphatase O
2A O
( O
PP2A O
) O
, O
mediated O
the O
apoptotic O
effect O
of O
erlotinib B
in O
HCC O
. O

Erlotinib B
inhibited O
CIP2A O
in O
a O
dose O
- O
and O
time O
- O
dependent O
manner O
in O
all O
sensitive O
HCC O
cells O
whereas O
no O
alterations O
in O
CIP2A O
were O
found O
in O
resistant O
cells O
. O

Overexpression O
of O
CIP2A O
upregulated O
phospho B
- O
Akt O
and O
protected O
Hep3B O
cells O
from O
erlotinib B
- O
induced O
apoptosis O
. O

In O
addition O
, O
silencing O
CIP2A O
by O
siRNA O
restored O
the O
effects O
of O
erlotinib B
in O
Huh O
- O
7 O
cells O
. O

Moreover O
, O
adding O
okadaic B
acid I
, O
a O
PP2A O
inhibitor O
, O
abolished O
the O
effects O
of O
erlotinib B
on O
apoptosis O
in O
Hep3B O
cells O
; O
and O
forskolin B
, O
a O
PP2A O
agonist O
enhanced O
the O
effect O
of O
erlotinib B
in O
resistant O
HA59T O
cells O
. O

Combining O
Akt O
inhibitor O
MK B
- I
2206 I
with O
erlotinib B
restored O
the O
sensitivity O
of O
HA59T O
cells O
to O
erlotinib B
. O

Furthermore O
, O
in O
vivo O
xenograft O
data O
showed O
that O
erlotinib B
inhibited O
the O
growth O
of O
PLC5 O
tumor O
but O
had O
no O
effect O
on O
Huh O
- O
7 O
tumor O
. O

Erlotinib B
downregulated O
CIP2A O
and O
upregulated O
PP2A O
activity O
in O
PLC5 O
tumors O
, O
but O
not O
in O
Huh O
- O
7 O
tumors O
. O

In O
conclusion O
, O
inhibition O
of O
CIP2A O
determines O
the O
effects O
of O
erlotinib B
on O
apoptosis O
in O
HCC O
. O

CIP2A O
may O
be O
useful O
as O
a O
therapeutic O
biomarker O
for O
predicting O
clinical O
response O
to O
erlotinib B
in O
HCC O
treatment O
. O

Boldine O
protects O
endothelial O
function O
in O
hyperglycemia O
- O
induced O
oxidative O
stress O
through O
an O
antioxidant O
mechanism O
. O

Increased O
oxidative O
stress O
is O
involved O
in O
the O
pathogenesis O
and O
progression O
of O
diabetes O
. O

Antioxidants O
are O
therapeutically O
beneficial O
for O
oxidative O
stress O
- O
associated O
diseases O
. O

Boldine B
( O
[ B
s I
] I
- I
2 I
, I
9 I
- I
dihydroxy I
- I
1 I
, I
10 I
- I
dimethoxyaporphine I
) O
is O
a O
major O
alkaloid O
present O
in O
the O
leaves O
and O
bark O
of O
the O
boldo O
tree O
( O
Peumus O
boldus O
Molina O
) O
, O
with O
known O
an O
antioxidant O
activity O
. O

This O
study O
examined O
the O
protective O
effects O
of O
boldine B
against O
high O
glucose B
- O
induced O
oxidative O
stress O
in O
rat O
aortic O
endothelial O
cells O
( O
RAEC O
) O
and O
its O
mechanisms O
of O
vasoprotection O
related O
to O
diabetic O
endothelial O
dysfunction O
. O

In O
RAEC O
exposed O
to O
high O
glucose B
( O
30 O
mM O
) O
for O
48 O
h O
, O
pre O
- O
treatment O
with O
boldine B
reduced O
the O
elevated O
ROS O
and O
nitrotyrosine B
formation O
, O
and O
preserved O
nitric B
oxide I
( O
NO B
) O
production O
. O

Pre O
- O
incubation O
with O
beta B
- I
NAPDH I
reduced O
the O
acetylcholine B
- O
induced O
endothelium O
- O
dependent O
relaxation O
; O
this O
attenuation O
was O
reversed O
by O
boldine B
. O

Compared O
with O
control O
, O
endothelium O
- O
dependent O
relaxation O
in O
the O
aortas O
of O
streptozotocin B
( O
STZ B
) O
- O
treated O
diabetic O
rats O
was O
significantly O
improved O
by O
both O
acute O
( O
1 O
mu O
M O
, O
30 O
min O
) O
and O
chronic O
( O
20mg O
/ O
kg O
/ O
daily O
, O
i O
. O
p O
. O
, O
7 O
days O
) O
treatment O
with O
boldine B
. O

Intracellular O
superoxide B
and O
peroxynitrite B
formation O
measured O
by O
DHE B
fluorescence O
or O
chemiluminescence O
assay O
were O
higher O
in O
sections O
of O
aortic O
rings O
from O
diabetic O
rats O
compared O
with O
control O
. O

Chronic O
boldine B
treatment O
normalized O
ROS O
over O
- O
production O
in O
the O
diabetic O
group O
and O
this O
correlated O
with O
reduction O
of O
NAD B
( I
P I
) I
H I
oxidase O
subunits O
, O
NOX2 O
and O
p47 O
( O
phox O
) O
. O

The O
present O
study O
shows O
that O
boldine B
reversed O
the O
increased O
ROS O
formation O
in O
high O
glucose B
- O
treated O
endothelial O
cells O
and O
restored O
endothelial O
function O
in O
STZ B
- O
induced O
diabetes O
by O
inhibiting O
oxidative O
stress O
and O
thus O
increasing O
NO B
bioavailability O
. O

Relationship O
between O
DNA O
damage O
in O
sperm O
after O
ex O
vivo O
exposure O
and O
abnormal O
embryo O
development O
in O
the O
progeny O
of O
the O
three O
- O
spined O
stickleback O
. O

Many O
xenobiotics O
released O
in O
the O
aquatic O
environment O
exhibit O
a O
genotoxic O
potential O
toward O
organisms O
. O

Long O
term O
exposure O
to O
such O
compounds O
is O
expected O
to O
lead O
to O
multigenerational O
reproductive O
defects O
, O
further O
influencing O
the O
recruitment O
rate O
and O
hence O
, O
the O
population O
dynamics O
. O

Paternal O
exposure O
to O
genotoxicants O
was O
previously O
shown O
to O
increase O
abnormal O
development O
in O
the O
progeny O
of O
mammalian O
or O
aquatic O
species O
. O

The O
aim O
of O
this O
study O
was O
to O
evaluate O
the O
relationship O
between O
DNA O
damage O
in O
sperm O
of O
the O
fish O
three O
- O
spined O
stickleback O
and O
progeny O
developmental O
defects O
. O

Spermatozoa O
were O
exposed O
ex O
vivo O
to O
an O
alkylating O
agent O
( O
methyl B
methanesulfonate I
) O
before O
in O
vitro O
fertilization O
and O
DNA O
damage O
was O
assessed O
by O
the O
alkaline O
comet O
assay O
. O

A O
significant O
relationship O
between O
abnormal O
development O
and O
sperm O
DNA O
damage O
was O
underlined O
. O

This O
study O
illustrates O
the O
interest O
to O
use O
germ O
cell O
DNA O
damage O
after O
ex O
vivo O
exposure O
to O
evaluate O
the O
impact O
of O
genotoxic O
compounds O
on O
progeny O
fitness O
in O
aquatic O
organisms O
. O

Integrated O
pharmacokinetic O
- O
driven O
approach O
to O
screen O
candidate O
anticancer O
drugs O
for O
brain O
tumor O
chemotherapy O
. O

The O
goal O
of O
the O
study O
was O
to O
develop O
an O
effective O
screening O
strategy O
to O
select O
new O
agents O
for O
brain O
tumor O
chemotherapy O
from O
a O
series O
of O
low O
molecular O
weight O
anticancer O
agents O
[ O
ON123x B
] O
by O
the O
combined O
use O
of O
in O
silico O
, O
in O
vitro O
cytotoxicity O
, O
and O
in O
vitro O
ADME O
profiling O
studies O
. O

The O
results O
of O
these O
studies O
were O
cast O
into O
a O
pipeline O
of O
tier O
1 O
and O
tier O
2 O
procedures O
that O
resulted O
in O
the O
identification O
of O
ON123300 B
as O
the O
lead O
compound O
. O

Of O
the O
154 O
ON123xx O
compounds O
, O
13 O
met O
tier O
1 O
screening O
criteria O
based O
on O
physicochemical O
properties O
[ O
i O
. O
e O
. O
, O
MW O
< O
450 O
Da O
, O
predicted O
log O
P O
between O
2 O
and O
3 O
. O
5 O
] O
and O
in O
vitro O
glioma O
cell O
cytotoxicity O
[ O
i O
. O
e O
. O
, O
IC50 O
< O
10 O
mu O
M O
] O
and O
were O
further O
tested O
in O
tier O
2 O
assays O
. O

The O
tier O
2 O
profiling O
studies O
consisted O
of O
metabolic O
stability O
, O
MDCK O
- O
MDR1 O
cell O
permeability O
and O
plasma O
and O
brain O
protein O
binding O
that O
were O
combined O
to O
globally O
assess O
whether O
favorable O
pharmacokinetic O
properties O
and O
brain O
penetration O
could O
be O
achieved O
in O
vivo O
. O

In O
vivo O
cassette O
dosing O
studies O
were O
conducted O
in O
mice O
for O
12 O
compounds O
that O
permitted O
examination O
of O
in O
vitro O
/ O
in O
vivo O
relationships O
that O
confirmed O
the O
suitability O
of O
the O
in O
vitro O
assays O
. O

A O
parameter O
derived O
from O
the O
in O
vitro O
assays O
accurately O
predicted O
the O
extent O
of O
drug O
accumulation O
in O
the O
brain O
based O
on O
the O
area O
under O
the O
drug O
concentration O
- O
time O
curve O
in O
brain O
measured O
in O
the O
cassette O
dosing O
study O
( O
r O
( O
2 O
) O
= O
0 O
. O
920 O
) O
. O

Overall O
, O
the O
current O
studies O
demonstrated O
the O
value O
of O
an O
integrated O
pharmacokinetic O
- O
driven O
approach O
to O
identify O
potentially O
efficacious O
agents O
for O
brain O
tumor O
chemotherapy O
. O

Two O
new O
C B
- I
benzylated I
dihydrochalcone I
derivatives O
from O
the O
leaves O
of O
Melodorum O
siamensis O
. O

Two O
new O
C B
- I
benzylated I
dihydrochalcone I
derivatives O
, O
4 B
, I
2 I
' I
, I
4 I
' I
- I
trihydroxy I
- I
6 I
' I
- I
methoxy I
- I
3 I
' I
( I
2 I
' I
' I
- I
hydroxybenzyl I
) I
dihydrochalcone I
( O
1 O
) O
and O
2 B
' I
, I
4 I
' I
- I
dihydroxy I
- I
4 I
, I
6 I
' I
- I
dimethoxy I
- I
3 I
' I
( I
2 I
' I
' I
- I
hydroxybenzyl I
) I
dihydrochalcone I
( O
2 O
) O
, O
along O
with O
six O
known O
flavonoid B
derivatives O
( O
3 O
- O
8 O
) O
, O
a O

known O
dihydrochalcone B
dimer O
( O
9 O
) O
, O
three O
known O
aromatic B
esters I
( O
10 O
- O
12 O
) O
, O
and O
one O
known O
aromatic B
amide I
( O
13 O
) O
, O
were O
isolated O
from O
the O
leaves O
of O
Melodorum O
siamensis O
. O

The O
structures O
of O
the O
compounds O
were O
elucidated O
by O
spectroscopic O
analysis O
, O
mainly O
1D O
and O
2D O
NMR O
techniques O
( O
1H B
, O
13C B
, O
COSY O
, O
HMQC O
, O
and O
HMBC O
) O
, O
as O
well O
as O
by O
comparison O
with O
literature O
data O
. O

The O
isolated O
compounds O
with O
a O
sufficient O
amount O
for O
biological O
assays O
were O
evaluated O
for O
their O
antimalarial O
, O
antimycobactirial O
, O
and O
cytotoxic O
activities O
. O

Compounds O
1 O
, O
2 O
, O
and O
13 O
exhibited O
strong O
cytotoxicity O
against O
human O
tumor O
cell O
lines O
KB O
and O
NCI O
- O
H187 O
, O
with O
IC50 O
values O
in O
the O
range O
of O
0 O
. O
66 O
- O
7 O
. O
16 O
micro O
g O
/ O
mL O
. O

Avoidance O
of O
contaminated O
sediments O
by O
an O
amphipod O
( O
Melita O
plumulosa O
) O
, O
A O
harpacticoid O
copepod O
( O
Nitocra O
spinipes O
) O
, O
and O
a O
snail O
( O
Phallomedusa O
solida O
) O
. O

The O
distribution O
of O
contaminants O
is O
seldom O
homogeneous O
in O
aquatic O
systems O
. O

In O
the O
present O
study O
, O
the O
avoidance O
response O
of O
Melita O
plumulosa O
, O
Nitocra O
spinipes O
, O
and O
Phallomedusa O
solida O
when O
exposed O
to O
contaminated O
sediments O
was O
investigated O
. O

Test O
vessels O
were O
designed O
to O
allow O
the O
congruent O
placement O
of O
two O
sediments O
and O
assessment O
of O
the O
movement O
of O
organisms O
between O
the O
sediments O
. O

When O
exposed O
to O
reference O
sediment O
, O
each O
species O
dispersed O
evenly O
between O
test O
chambers O
regardless O
of O
differences O
in O
sediment O
particle O
size O
. O

In O
the O
presence O
of O
contaminated O
sediment O
, O
the O
magnitude O
and O
rate O
of O
avoidance O
varied O
. O

Avoidance O
assays O
showed O
that O
test O
species O
avoided O
contaminated O
sediment O
as O
early O
as O
6 O
, O
6 O
, O
and O
24 O
h O
following O
exposure O
for O
N O
. O
spinipes O
, O
P O
. O
solida O
, O
and O
M O
. O
plumulosa O
, O
respectively O
. O

The O
48 O
- O
h O
avoidance O
response O
of O
M O
. O
plumulosa O
for O
nine O
contaminated O
sediments O
of O
varying O
toxicity O
showed O
that O
avoidance O
was O
generally O
greater O
for O
sediments O
which O
elicited O
greater O
10 O
- O
d O
lethality O
to O
this O
species O
. O

The O
study O
demonstrated O
that O
each O
of O
these O
species O
has O
the O
ability O
to O
respond O
to O
chemical O
cues O
in O
the O
environment O
to O
inhabit O
sediment O
that O
provides O
the O
best O
opportunity O
for O
survival O
. O

The O
avoidance O
response O
for O
each O
species O
indicates O
the O
potential O
for O
developing O
rapid O
screening O
methods O
to O
assess O
sediment O
quality O
. O

Evidence O
suggests O
that O
avoidance O
was O
related O
to O
sediment O
toxicity O
and O
that O
static O
10 O
- O
d O
toxicity O
methods O
are O
likely O
to O
overestimate O
toxicity O
for O
species O
, O
which O
would O
avoid O
contamination O
in O
heterogeneous O
field O
settings O
. O

Facile O
and O
clean O
release O
of O
vertical O
Si B
nanowires O
by O
wet O
chemical O
etching O
based O
on O
alkali B
hydroxides I
. O

A O
simple O
method O
to O
release O
Si B
nanowires O
( O
SiNWs O
) O
from O
a O
substrate O
, O
with O
their O
original O
length O
almost O
intact O
, O
is O
demonstrated O
. O

By O
exploiting O
the O
unique O
chemistry O
involved O
for O
the O
fabrication O
of O
vertical O
arrays O
of O
SiNWs O
in O
metal O
- O
assisted O
chemical O
etching O
( O
MaCE O
) O
based O
either O
on O
HF B
/ O
AgNO3 B
or O
HF B
/ O
H2O2 B
chemistries O
, O
wet O
etching O
with O
alkali B
hydroxides I
such O
as O
NaOH B
or O
KOH B
preferentially O
attacks O
the O
bottom O
part O
of O
the O
vertical O
SiNWs O
. O

A O
protective O
layer O
of O
Si B
oxide B
is O
found O
to O
exist O
on O
the O
outer O
wall O
of O
the O
SiNWs O
and O
to O
play O
the O
key O
role O
of O
etch O
mask O
during O
the O
release O
- O
etching O
by O
alkali O
hydroxides B
. O

The O
clean O
release O
of O
SiNWs O
also O
enables O
the O
repeated O
use O
of O
the O
Si B
substrate O
for O
the O
fabrication O
of O
vertical O
SiNW O
arrays O
by O
MaCE O
. O

The O
released O
SiNWs O
are O
further O
used O
for O
the O
fabrication O
of O
field O
- O
effect O
transistors O
on O
a O
flexible O
plastic O
substrate O
. O

The O
method O
developed O
here O
, O
when O
combined O
with O
a O
suitable O
assembling O
technique O
, O
can O
be O
very O
useful O
in O
implementing O
flexible O
electronics O
, O
or O
in O
the O
fabrication O
of O
SiNW O
composites O
with O
other O
functional O
materials O
. O

Enantioseparation O
of O
four O
organophosphonate B
derivatives O
on O
N B
- I
( I
3 I
, I
5 I
- I
dinitrobenzoyl I
) I
- I
L I
- I
leucine I
- I
n I
- I
propylamide I
stationary O
phase O
by O
molecular O
modeling O
. O

Four O
groups O
of O
organophosphonate B
derivatives O
enantiomers O
were O
separated O
on O
N B
- I
( I
3 I
, I
5 I
- I
dinitrobenzoyl I
) I
- I
S I
- I
leucine I
chiral O
stationary O
phase O
. O

The O
three O
- O
dimensional O
structures O
of O
the O
complexes O
between O
the O
single O
enantiotopic O
chiral O
compounds O
and O
chiral O
stationary O
phase O
have O
been O
studied O
using O
molecular O
model O
and O
molecular O
dynamics O
simulation O
. O

Detailed O
results O
regarding O
the O
conformation O
, O
auto O
- O
docking O
, O
and O
thermodynamic O
estimation O
are O
presented O
. O

The O
elution O
order O
of O
the O
enantiomer O
could O
be O
determined O
from O
the O
energy O
. O

The O
predicted O
chiral O
discrimination O
was O
obtained O
by O
computational O
results O
. O

Lattice O
deformation O
and O
domain O
distortion O
in O
the O
self O
- O
assembly O
of O
block O
copolymer O
thin O
films O
on O
chemical O
patterns O
. O

The O
self O
- O
assembly O
of O
cylinder O
- O
forming O
block O
copolymer O
( O
BCP O
) O
microdomains O
confined O
within O
chemical O
stripe O
patterns O
of O
widths O
incommensurate O
with O
the O
natural O
period O
of O
the O
copolymers O
, O
L0 O
, O
is O
studied O
. O

It O
is O
shown O
that O
this O
incommensurability O
causes O
changes O
in O
both O
the O
shapes O
of O
the O
microdomains O
and O
their O
spatial O
period O
. O

Specifically O
, O
a O
transition O
from O
n O
to O
n O
+ O
1 O
rows O
of O
microdomains O
is O
observed O
when O
the O
stripe O
width O
is O
about O
n O
+ O
/ O
- O
1 O
/ O
2 O
L0 O
. O

When O
the O
stripe O
' O
s O
width O
is O
comparable O
to O
L0 O
, O
ellipticity O
of O
microdomains O
can O
be O
induced O
with O
an O
aspect O
ratio O
up O
to O
2 O
. O
2 O
. O

Free O
energy O
models O
are O
applied O
to O
describe O
the O
energetic O
origin O
of O
such O
behavior O
. O

Although O
our O
observations O
qualitatively O
resemble O
results O
in O
sphere O
- O
forming O
BCPs O
confined O
in O
topographical O
trenches O
, O
the O
quantitative O
difference O
is O
noteworthy O
and O
technologically O
important O
for O
the O
design O
of O
nanostructures O
with O
programmable O
shapes O
. O

Enantioanalysis O
of O
pipecolic B
acid I
with O
stochastic O
and O
potentiometric O
microsensors O
. O

Stochastic O
and O
potentiometric O
microsensors O
based O
on O
porphyrins B
and O
polymeric O
surfactants O
such O
as O
polysodium B
N I
- I
undecanoyl I
- I
L I
- I
leucylvanilate I
and O
polysodium B
N I
- I
undecanoyl I
- I
L I
- I
vanilate I
were O
developed O
for O
enantioselective O
assay O
of O
pipecolic B
acid I
. O

The O
matrices O
used O
for O
the O
design O
of O
the O
stochastic O
sensors O
were O
diamond B
paste O
and O
graphite B
paste O
, O
while O
the O
matrix O
used O
for O
the O
design O
of O
potentiometric O
sensors O
was O
carbon B
paste O
. O

The O
response O
characteristics O
of O
the O
microsensors O
were O
determined O
for O
the O
enantiomers O
of O
pipecolic B
acid I
. O

The O
response O
characteristics O
, O
selectivity O
, O
and O
enantioselectivity O
studies O
proved O
that O
the O
proposed O
microsensors O
can O
be O
used O
for O
clinical O
enantioanalysis O
of O
pipecolic B
acid I
in O
biological O
fluids O
, O
e O
. O
g O
. O
, O
urine O
and O
whole O
blood O
. O

Brewster O
angle O
microscopy O
of O
Langmuir O
films O
of O
athabasca O
bitumens O
, O
n O
- O
C5 O
asphaltenes O
, O
and O
SAGD O
bitumen O
during O
pressure O
- O
area O
hysteresis O
. O

Bitumen B
films O
formed O
on O
water O
surfaces O
have O
negative O
consequences O
, O
both O
environmental O
and O
economic O
. O

CanmetENERGY O
has O
placed O
considerable O
research O
emphasis O
on O
understanding O
the O
structures O
of O
the O
bitumen B
films O
on O
water O
as O
a O
necessary O
step O
before O
optimization O
of O
bitumen B
extraction O
. O

The O
detailed O
structures O
of O
the O
adsorbed O
molecules O
and O
, O
especially O
, O
the O
role O
of O
asphaltene O
molecules O
at O
the O
interfaces O
are O
still O
under O
scrutiny O
and O
debate O
. O

In O
the O
present O
study O
, O
we O
compared O
bitumen B
and O
asphaltene O
films O
as O
they O
were O
compressed O
and O
expanded O
under O
various O
surface O
pressures O
in O
order O
to O
achieve O
a O
clearer O
understanding O
of O
bitumen B
film O
structures O
. O

We O
used O
a O
customized O
NIMA O
Langmuir O
trough O
interfaced O
to O
a O
Brewster O
angle O
microscope O
( O
BAM O
) O
and O
CCD O
camera O
( O
Nanofilm O
_ O
ep3BAM O
, O
Accurion O
, O
previously O
Nanofilm O
Gmbh O
) O
to O
study O
images O
of O
bitumen B
films O
at O
the O
air O
/ O
water O
interface O
. O

The O
bitumen B
film O
appeared O
uniform O
with O
high O
reflectivity O
at O
a O
surface O
pressure O
of O
18 O
mN O
. O
m O
( O
- O
1 O
) O
and O
exhibited O
a O
coarse O
pebblelike O
interface O
with O
reduced O
reflectivity O
in O
the O
liquid O
condensed O
( O
LC O
) O
phase O
at O
higher O
pressures O
( O
18 O
- O
35 O
mN O
. O
m O
( O
- O
1 O
) O
) O
. O

During O
the O
first O
cycle O
of O
compression O
asphaltene O
films O
showed O
well O
- O
defined O
phase O
transitions O
and O
a O
uniformly O
smooth O
interface O
in O
the O
LC O
phase O
between O
9 O
and O
35 O
mN O
. O
m O
( O
- O
1 O
) O
. O

However O
, O
folding O
or O
buckling O
occurred O
at O
surface O
pressures O
from O
35 O
to O
44 O
mN O
. O
m O
( O
- O
1 O
) O
. O

On O
expansion O
, O
asphaltene O
films O
appeared O
to O
break O
into O
islands O
. O

The O
hysteresis O
of O
the O
pressure O
- O
area O
isotherm O
was O
much O
larger O
for O
asphaltenes O
than O
for O
bitumen O
. O

In O
both O
compression O
and O
expansion O
cycles O
, O
BAM O
images O
for O
bitumen O
films O
appeared O
to O
be O
more O
reproducible O
than O
those O
of O
the O
asphaltene O
films O
at O
the O
same O
surface O
pressures O
. O

Films O
for O
low O
- O
degrees O
API O
SAGD O
bitumen B
were O
almost O
identical O
to O
those O
for O
surface O
- O
mined O
bitumen B
. O

Films O
formed O
from O
partially O
deasphalted O
surface O
- O
mined O
bitumens O
showed O
higher O
compressibility O
and O
lower O
rigidity O
than O
the O
original O
bitumen O
. O

The O
BAM O
images O
illustrated O
significant O
differences O
between O
the O
partially O
deasphalted O
and O
original O
bitumen B
films O
. O

Other O
components O
in O
bitumen B
also O
played O
important O
roles O
in O
determining O
the O
interfacial O
properties O
of O
bitumen B
films O
. O

Novel O
2 B
- I
aminooctahydrocyclop I
- I
3a I
- I
carboxamides I
as O
potent O
CCR2 O
antagonists O
. O

Novel O
CCR2 O
antagonists O
with O
a O
novel O
2 B
- I
aminooctahydrocyclop I
- I
3a I
- I
carboxamide I
scaffold O
were O
designed O
. O

SAR O
studies O
led O
to O
a O
series O
of O
potent O
compounds O
. O

For O
example O
, O
compound O
51 O
had O
a O
good O
PK O
profile O
in O
both O
dog O
and O
monkey O
, O
and O
exhibited O
excellent O
efficacy O
when O
dosed O
orally O
in O
an O
inflammation O
model O
in O
hCCR2 O
KI O
mice O
. O

In O
addition O
, O
an O
asymmetric O
synthesis O
to O
the O
core O
structures O
was O
developed O
. O

Assessing O
the O
chemical O
accuracy O
of O
protein O
structures O
via O
peptide O
acidity O
. O

Although O
the O
protein O
native O
state O
is O
a O
Boltzmann O
conformational O
ensemble O
, O
practical O
applications O
often O
require O
a O
representative O
model O
from O
the O
most O
populated O
region O
of O
that O
distribution O
. O

The O
acidity O
of O
the O
backbone O
amides B
, O
as O
reflected O
in O
hydrogen B
exchange O
rates O
, O
is O
exquisitely O
sensitive O
to O
the O
surrounding O
charge O
and O
dielectric O
volume O
distribution O
. O

For O
each O
of O
four O
proteins O
, O
three O
independently O
determined O
X O
- O
ray O
structures O
of O
differing O
crystallographic O
resolution O
were O
used O
to O
predict O
exchange O
for O
the O
static O
solvent O
- O
exposed O
amide B
hydrogens I
. O

The O
average O
correlation O
coefficients O
range O
from O
0 O
. O
74 O
for O
ubiquitin O
to O
0 O
. O
93 O
for O
Pyrococcus O
furiosus O
rubredoxin O
, O
reflecting O
the O
larger O
range O
of O
experimental O
exchange O
rates O
exhibited O
by O
the O
latter O
protein O
. O

The O
exchange O
prediction O
errors O
modestly O
correlate O
with O
the O
crystallographic O
resolution O
. O

MODELLER O
9v6 O
- O
derived O
homology O
models O
at O
~ O
60 O
% O
sequence O
identity O
( O
36 O
% O
identity O
for O
chymotrypsin O
inhibitor O
CI2 O
) O
yielded O
correlation O
coefficients O
that O
are O
~ O
0 O
. O
1 O
smaller O
than O
for O
the O
cognate O
X O
- O
ray O
structures O
. O

The O
most O
recently O
deposited O
NOE O
- O
based O
ubiquitin O
structure O
and O
the O
original O
NMR O
structure O
of O
CI2 O
fail O
to O
provide O
statistically O
significant O
predictions O
of O
hydrogen B
exchange O
. O

However O
, O
the O
more O
recent O
RECOORD O
refinement O
study O
of O
CI2 O
yielded O
predictions O
comparable O
to O
the O
X O
- O
ray O
and O
homology O
model O
- O
based O
analyses O
. O

Incidence O
and O
predictors O
of O
right O
paraesophageal O
lymph O
node O
metastasis O
of O
N0 O
papillary O
thyroid O
carcinoma O
located O
in O
the O
right O
lobe O
. O

Papillary O
thyroid O
carcinoma O
( O
PTC O
) O
frequently O
metastasizes O
to O
the O
regional O
lymph O
nodes O
and O
, O
thus O
, O
guidelines O
edited O
by O
Japan O
Association O
of O
Endocrine O
Surgeons O
/ O
Japanese O
Society O
of O
Thyroid O
Surgery O
routinely O
recommend O
central O
node O
dissection O
even O
for O
patients O
with O
no O
clinically O
detectable O
node O
metastasis O
( O
N0 O
) O
. O

However O
, O
in O
the O
central O
compartment O
, O
metastasis O
to O
the O
right O
paraesophageal O
node O
has O
not O
been O
intensively O
investigated O
. O

We O
investigated O
the O
incidence O
and O
predictors O
of O
right O
paraesophageal O
node O
metastasis O
based O
on O
pre O
- O
and O
intraoperative O
findings O
in O
922 O
patients O
with O
N0 O
PTC O
in O
the O
right O
lobe O
. O

Fourteen O
percent O
of O
patients O
were O
microscopically O
positive O
for O
right O
paraesophageal O
node O
metastasis O
, O
and O
the O
incidence O
was O
smaller O
than O
that O
for O
pre O
- O
and O
right O
paratracheal O
node O
metastasis O
( O
46 O
% O
) O
. O

On O
multivariate O
analysis O
, O
a O
tumor O
size O
> O
= O
2 O
cm O
and O
significant O
extrathyroid O
extension O
were O
independent O
predictors O
of O
metastasis O
. O

Microscopically O
pre O
- O
and O
right O
paratracheal O
node O
- O
positive O
PTC O
more O
often O
( O
p O
< O
0 O
. O
0001 O
) O
metastasized O
to O
the O
right O
paraesophageal O
node O
. O

Taken O
together O
, O
in O
N0 O
PTC O
in O
the O
right O
lobe O
, O
right O
paraesophageal O
node O
dissection O
should O
be O
considered O
in O
tumors O
2 O
cm O
or O
larger O
and O
/ O
or O
with O
significant O
extrathyroid O
extension O
, O
or O
when O
pre O
- O
and O
right O
paratracheal O
node O
metastasis O
is O
suspected O
based O
on O
the O
intraoperative O
findings O
. O

Effects O
of O
ozone B
and O
fine O
particulate O
matter O
( O
PM O
( O
2 O
. O
5 O
) O
) O
on O
rat O
system O
inflammation O
and O
cardiac O
function O
. O

In O
order O
to O
understand O
the O
toxic O
mechanisms O
of O
cardiovascular O
system O
injuries O
induced O
by O
ambient O
PM O
( O
2 O
. O
5 O
) O
and O
/ O
or O
ozone B
, O
a O
subacute O
toxicological O
animal O
experiment O
was O
designed O
with O
exposure O
twice O
a O
week O
for O
3 O
continuous O
weeks O
. O

Wistar O
rats O
were O
randomly O
categorized O
into O
8 O
groups O
( O
n O
= O
6 O
) O
: O
1 O
control O
group O
, O
3 O
groups O
exposed O
to O
fine O
particulate O
matters O
( O
PM O
( O
2 O
. O
5 O
) O
) O
alone O
at O
3 O
doses O
( O
0 O
. O
2 O
, O
0 O
. O
8 O
, O
or O
3 O
. O
2 O
mg O
/ O
rat O
) O
, O
1 O
group O
to O
ozone B
( O
0 O
. O
81 O
ppm O
) O
alone O
and O
3 O
groups O
to O
ozone B
plus O
PM O
( O
2 O
. O
5 O
) O
at O
3 O
doses O
( O
0 O
. O
2 O
, O
0 O
. O
8 O
, O
or O
3 O
. O
2 O
mg O
/ O
rat O
) O
. O

Heart O
rate O
( O
HR O
) O
and O
electrocardiogram O
( O
ECG O
) O
was O
monitored O
at O
approximately O
24 O
- O
h O
both O
after O
the O
3rd O
exposure O
and O
the O
last O
( O
6th O
) O
exposure O
, O
and O
systolic O
blood O
pressure O
( O
SBP O
) O
was O
monitored O
at O
approximately O
24 O
- O
h O
after O
the O
6th O
exposure O
. O

Biomarkers O
of O
systemic O
inflammation O
and O
injuries O
( O
CRP O
, O
IL O
- O
6 O
, O
LDH O
, O
CK O
) O
, O
heart O
oxidative O
stress O
( O
MDA B
, O
SOD O
) O
and O
endothelial O
function O
( O
ET O
- O
1 O
, O
VEGF O
) O
were O
analyzed O
after O
the O
6th O
exposure O
. O

Additionally O
, O
myocardial O
ultrastructural O
alterations O
were O
observed O
under O
transmission O
electron O
microscopy O
( O
TEM O
) O
for O
histopathological O
analyses O
. O

Results O
showed O
that O
PM B
( I
2 I
. I
5 I
) I
alone O
exposure O
could O
trigger O
the O
significant O
increase O
of O
CRP O
, O
MDA B
, O
CK O
, O
ET O
- O
1 O
and O
SBP O
and O
decrease O
of O
heart O
rate O
variability O
( O
HRV O
) O
, O
a O
marker O
of O
cardiac O
autonomic O
nervous O
system O
( O
ANS O
) O
function O
. O

Ozone B
alone O
exposure O
in O
rats O
did O
not O
show O
significant O
alterations O
in O
any O
indicators O
. O

Ozone B
plus O
PM O
( O
2 O
. O
5 O
) O
exposure O
, O
however O
, O
induced O
CRP O
, O
IL O
- O
6 O
, O
CK O
, O
LDH O
and O
MDA B
increase O
, O
SOD O
and O
HRV O
decrease O
significantly O
in O
a O
dose O
- O
response O
way O
. O

Meanwhile O
, O
abnormal O
ECG O
types O
were O
monitored O
in O
rats O
exposed O
to O
PM O
( O
2 O
. O
5 O
) O
with O
and O
without O
ozone B
and O
obvious O
myocardial O
ultrastructural O
changes O
were O
observed O
by O
TEM O
. O

In O
conclusion O
, O
PM O
( O
2 O
. O
5 O
) O
alone O
exposure O
could O
cause O
inflammation O
, O
endothelial O
function O
and O
ANS O
injuries O
, O
and O
ozone B
potentiated O
these O
effects O
induced O
by O
PM O
( O
2 O
. O
5 O
) O
. O

Dynamics O
of O
silver B
nanoparticle O
formation O
and O
agglomeration O
inside O
the O
cavitation O
bubble O
after O
pulsed O
laser O
ablation O
in O
liquid O
. O

The O
formation O
of O
nanoparticles O
within O
the O
laser O
- O
induced O
cavitation O
bubble O
is O
studied O
in O
situ O
using O
small O
angle O
X O
- O
ray O
scattering O
with O
high O
spatiotemporal O
resolution O
. O

Directly O
after O
laser O
ablation O
, O
two O
different O
particle O
fractions O
consisting O
of O
compact O
primary O
particles O
of O
8 O
- O
10 O
nm O
size O
and O
agglomerates O
of O
40 O
- O
60 O
nm O
size O
are O
formed O
. O

The O
abundance O
of O
these O
species O
is O
strongly O
influenced O
by O
the O
dynamics O
of O
the O
oscillating O
cavitation O
bubble O
. O

Primary O
particle O
mass O
is O
most O
abundant O
during O
maximal O
expansion O
of O
the O
first O
bubble O
and O
reappears O
a O
little O
weaker O
in O
the O
rebound O
. O

In O
contrast O
to O
this O
, O
the O
mass O
abundance O
of O
agglomerates O
is O
relatively O
low O
in O
the O
first O
bubble O
but O
strongly O
increases O
during O
first O
bubble O
collapse O
and O
following O
rebound O
. O

Although O
most O
of O
the O
ablated O
material O
is O
trapped O
inside O
the O
bubble O
and O
follows O
its O
oscillation O
, O
a O
minor O
fraction O
of O
both O
species O
could O
be O
detected O
outside O
the O
cavitation O
bubble O
even O
before O
its O
final O
collapse O
. O

Limits O
of O
metastability O
in O
amorphous O
ices O
: O
2H B
- O
NMR O
relaxation O
. O

The O
high O
- O
frequency O
reorientation O
dynamics O
of O
O B
- I
( I
2 I
) I
H I
bonds O
is O
investigated O
in O
various O
amorphous O
ices O
including O
eHDA O
( O
expanded O
high O
density O
amorphous O
ice O
) O
, O
LDA O
- O
II O
( O
low O
density O
amorphous O
ice O
II O
) O
and O
HGW O
( O
hyperquenched O
glassy O
water O
) O
using O
( B
2 I
) I
H I
- O
NMR O
spin O
- O
lattice O
relaxation O
as O
a O
local O
probe O
. O

Both O
low O
density O
forms O
, O
HGW B
and O
LDA B
- O
II O
, O
show O
similar O
spin O
- O
lattice O
relaxation O
but O
differ O
in O
the O
thermal O
stability O
with O
respect O
to O
the O
transition O
into O
crystalline O
cubic O
ice O
I O
( O
c O
) O
. O

HGW B
already O
transforms O
slightly O
above O
135 O
K O
whereas O
LDA B
- I
II I
crystallizes O
at O
150 O
K O
. O

eHDA O
is O
distinguishable O
from O
other O
high O
density O
amorphous O
ices O
in O
its O
thermal O
stability O
and O
spin O
- O
lattice O
relaxation O
. O

Its O
relaxation O
times O
are O
much O
larger O
compared O
to O
those O
of O
VHDA O
( O
very O
high O
density O
amorphous O
ice O
) O
and O
uHDA O
( O
unrelaxed O
high O
density O
amorphous O
ice O
) O
. O

eHDA B
does O
not O
show O
annealing O
effects O
, O
transforms O
sharply O
into O
LDA O
- O
II O
above O
123 O
K O
and O
provides O
higher O
thermal O
stability O
as O
compared O
to O
other O
high O
density O
forms O
. O

Nanoporous O
silicon B
networks O
as O
anodes O
for O
lithium B
ion O
batteries O
. O

Nanoporous O
silicon B
( O
Si B
) O
networks O
with O
controllable O
porosity O
and O
thickness O
are O
fabricated O
by O
a O
simple O
and O
scalable O
electrochemical O
process O
, O
and O
then O
released O
from O
Si B
wafers O
and O
transferred O
to O
flexible O
and O
conductive O
substrates O
. O

These O
nanoporous O
Si B
networks O
serve O
as O
high O
performance O
Li B
- O
ion O
battery O
electrodes O
, O
with O
an O
initial O
discharge O
capacity O
of O
2570 O
mA O
h O
g O
( O
- O
1 O
) O
, O
above O
1000 O
mA O
h O
g O
( O
- O
1 O
) O
after O
200 O
cycles O
without O
any O
electrolyte O
additives O
. O

Recent O
progress O
in O
the O
development O
and O
use O
of O
organic O
ionic O
plastic O
crystal O
electrolytes O
. O

Significant O
progress O
has O
been O
made O
recently O
in O
the O
development O
of O
Organic O
Ionic O
Plastic O
Crystals O
( O
OIPCs O
) O
, O
a O
unique O
family O
of O
solid O
state O
electrolytes O
with O
applications O
in O
electrochemical O
devices O
such O
as O
lithium B
batteries O
and O
dye O
- O
sensitised O
solar O
cells O
. O

The O
negligible O
volatility O
of O
OIPCs B
renders O
them O
more O
suitable O
than O
molecular O
species O
for O
long O
- O
term O
device O
use O
, O
while O
the O
high O
thermal O
and O
electrochemical O
stability O
of O
many O
OIPCs B
fulfils O
an O
essential O
requirement O
for O
solid O
state O
electrolytes O
for O
many O
device O
applications O
. O

However O
, O
the O
complex O
mechanisms O
of O
conduction O
through O
these O
materials O
, O
both O
in O
their O
pure O
state O
and O
in O
the O
presence O
of O
a O
small O
amount O
of O
a O
second O
component O
( O
such O
as O
lithium B
salts O
to O
enable O
their O
use O
in O
lithium B
batteries O
) O
are O
still O
not O
fully O
understood O
. O

At O
the O
same O
time O
, O
the O
range O
of O
anions O
and O
cations O
utilised O
in O
the O
synthesis O
of O
plastic O
crystal O
phases O
continues O
to O
increase O
. O

This O
perspective O
concentrates O
on O
recent O
research O
into O
both O
fundamental O
and O
device O
- O
oriented O
aspects O
of O
these O
materials O
. O

Important O
fundamental O
understanding O
of O
the O
physical O
properties O
and O
transport O
mechanisms O
of O
different O
OIPCs B
has O
been O
achieved O
through O
use O
of O
techniques O
including O
variable O
temperature O
solid O
- O
state O
NMR O
and O
crystallographic O
analysis O
, O
as O
well O
as O
detailed O
molecular O
dynamics O
simulations O
. O

In O
parallel O
, O
the O
applicability O
of O
these O
materials O
as O
electrolytes O
for O
dye O
- O
sensitised O
solar O
cells O
and O
lithium B
batteries O
is O
being O
more O
widely O
demonstrated O
. O

The O
possibility O
of O
using O
OIPCs O
as O
solid O
state O
electrolytes O
for O
fuel O
cells O
is O
also O
discussed O
. O

Deep O
brain O
stimulation O
of O
the O
subthalamic O
nucleus O
, O
but O
not O
dopaminergic O
medication O
, O
improves O
proactive O
inhibitory O
control O
of O
movement O
initiation O
in O
Parkinson O
' O
s O
disease O
. O

Slowness O
in O
movement O
initiation O
is O
a O
cardinal O
feature O
of O
Parkinson O
' O
s O
disease O
( O
PD O
) O
that O
is O
still O
poorly O
understood O
and O
unsuccessfully O
alleviated O
by O
standard O
therapies O
. O

Here O
, O
we O
raise O
this O
major O
clinical O
issue O
within O
the O
framework O
of O
a O
novel O
theoretical O
model O
that O
allows O
a O
better O
understanding O
of O
the O
basic O
mechanisms O
involved O
in O
movement O
initiation O
. O

This O
model O
assumes O
that O
movement O
triggering O
is O
inhibited O
by O
default O
to O
prevent O
automatic O
responses O
to O
unpredictable O
events O
. O

We O
investigated O
to O
which O
extent O
the O
top O
- O
down O
control O
necessary O
to O
release O
this O
locking O
state O
before O
initiating O
actions O
is O
impaired O
in O
PD O
and O
restored O
by O
standard O
therapies O
. O

We O
used O
a O
cue O
- O
target O
reaction O
time O
task O
to O
test O
both O
the O
ability O
to O
initiate O
fast O
responses O
to O
targets O
and O
the O
ability O
to O
refrain O
from O
reacting O
to O
cues O
. O

Fourteen O
patients O
with O
dopaminergic O
( O
DA O
) O
medication O
and O
11 O
with O
subthalamic O
nucleus O
( O
STN O
) O
stimulation O
were O
tested O
on O
and O
off O
treatment O
, O
and O
compared O
with O
14 O
healthy O
controls O
. O

We O
found O
evidence O
that O
patients O
withdrawn O
from O
treatment O
have O
trouble O
voluntarily O
releasing O
proactive O
inhibitory O
control O
; O
while O
DA O
medication O
broadly O
reduces O
movement O
initiation O
latency O
, O
it O
does O
not O
reinstate O
a O
normal O
pattern O
of O
movement O
initiation O
; O
and O
stimulation O
of O
the O
STN O
specifically O
re O
- O
establishes O
the O
efficiency O
of O
the O
top O
- O
down O
control O
of O
proactive O
inhibition O
. O

These O
results O
suggest O
that O
movement O
initiation O
disorders O
that O
resist O
DA O
medication O
are O
due O
to O
executive O
, O
not O
motor O
, O
dysfunctions O
. O

This O
conclusion O
is O
discussed O
with O
regard O
to O
the O
role O
the O
STN O
may O
play O
as O
an O
interface O
between O
non O
- O
DA O
executive O
and O
DA O
motor O
systems O
in O
cortico O
- O
basal O
ganglia O
loops O
. O

High O
physical O
fitness O
in O
young O
adulthood O
reduces O
the O
risk O
of O
fractures O
later O
in O
life O
in O
men O
: O
A O
nationwide O
cohort O
study O
. O

A O
few O
studies O
have O
indicated O
that O
self O
- O
reported O
physical O
activity O
is O
associated O
with O
the O
risk O
of O
fractures O
in O
middle O
- O
aged O
and O
elderly O
men O
. O

We O
investigated O
whether O
objectively O
measured O
physical O
fitness O
in O
young O
adulthood O
was O
associated O
with O
the O
risk O
of O
low O
- O
energy O
fractures O
later O
in O
life O
in O
men O
. O

Aerobic O
capacity O
and O
isometric O
muscle O
strength O
were O
measured O
in O
435 O
, O
445 O
Swedish O
men O
who O
were O
conscripted O
for O
military O
service O
from O
1969 O
to O
1978 O
. O

Incident O
fractures O
were O
searched O
in O
national O
registers O
. O

During O
a O
median O
follow O
- O
up O
period O
of O
35 O
years O
( O
range O
, O
11 O
- O
41 O
years O
) O
, O
8030 O
subjects O
sustained O
at O
least O
one O
fracture O
, O
increasing O
the O
risk O
of O
death O
1 O
. O
8 O
times O
( O
95 O
% O
CI O
, O
1 O
. O
6 O
- O
2 O
. O
0 O
) O
during O
follow O
up O
. O

When O
comparing O
men O
in O
the O
lowest O
and O
highest O
decile O
of O
physical O
fitness O
, O
the O
risk O
of O
a O
fracture O
was O
1 O
. O
8 O
times O
higher O
( O
95 O
% O
CI O
, O
1 O
. O
6 O
- O
2 O
. O
1 O
) O
and O
that O
of O
hip O
fracture O
was O
2 O
. O
7 O
times O
higher O
( O
95 O
% O
CI O
, O
1 O
. O
6 O
- O
4 O
. O
7 O
) O
. O

The O
risk O
of O
fracture O
was O
also O
1 O
. O
4 O
to O
1 O
. O
5 O
times O
higher O
when O
comparing O
the O
extreme O
deciles O
of O
muscle O
strength O
( O
p O
< O
0 O
. O
001 O
for O
all O
) O
. O

In O
a O
subcohort O
of O
1009 O
twin O
pairs O
, O
up O
to O
22 O
% O
of O
the O
variation O
in O
physical O
fitness O
and O
27 O
% O
to O
39 O
% O
of O
the O
variation O
in O
muscle O
strength O
was O
attributable O
to O
environmental O
factors O
unique O
to O
one O
twin O
; O
eg O
, O
physical O
activity O
. O

In O
conclusion O
, O
low O
aerobic O
capacity O
and O
muscle O
strength O
in O
young O
adulthood O
are O
associated O
with O
an O
increased O
risk O
of O
low O
- O
energy O
fractures O
later O
in O
life O
. O

( O
c O
) O
2013 O
American O
Society O
for O
Bone O
and O
Mineral O
Research O
. O

Ion O
pair O
dynamics O
: O
solvolyses O
of O
chiral O
1 B
, I
3 I
- I
diarylallyl I
carboxylates I
as O
a O
case O
study O
. O

Chiral O
ion O
pairs O
play O
a O
key O
role O
in O
modern O
enantioselective O
synthesis O
, O
though O
little O
is O
known O
about O
their O
properties O
. O

We O
have O
now O
used O
the O
special O
features O
of O
unsymmetrically O
substituted O
allyl B
derivatives O
to O
obtain O
unprecedented O
insight O
into O
ion O
pair O
dynamics O
. O

By O
employing O
chiral O
high O
- O
performance O
liquid O
chromatography O
, O
it O
was O
possible O
to O
follow O
the O
time O
- O
dependent O
concentrations O
of O
all O
four O
isomeric O
esters B
( O
two O
regioisomeric O
pairs O
of O
enantiomers O
) O
and O
all O
four O
isomeric O
alcohols B
generated O
during O
the O
hydrolysis O
of O
enantiopure O
1 B
- I
( I
4 I
- I
chlorophenyl I
) I
- I
3 I
- I
phenylallyl I
and O
3 B
- I
( I
4 I
- I
chlorophenyl I
) I
- I
1 I
- I
phenylallyl I
4 I
- I
nitrobenzoates I
. O

Combination O
of O
these O
results O
with O
the O
directly O
measured O
rate O
constant O
for O
the O
reaction O
of O
the O
laser O
- O
flash O
photolytically O
generated O
1 B
- I
( I
4 I
- I
chlorophenyl I
) I
- I
3 I
- I
phenylallyl I
cation O
with O
water O
provided O
a O
complete O
mechanistic O
scheme O
for O
allyl B
carboxylate I
solvolysis O
. O

It O
is O
demonstrated O
that O
solvolysis O
and O
internal O
return O
can O
be O
explained O
by O
the O
same O
intermediates O
. O

The O
correlation O
equation O
log O
k O
= O
s O
( O
N O
) O
( O
N O
+ O
E O
) O
was O
used O
to O
elucidate O
the O
variable O
importance O
of O
external O
and O
internal O
return O
in O
the O
solvolysis O
reactions O
. O

This O
information O
will O
be O
crucial O
for O
the O
interpretation O
of O
the O
ultrafast O
dynamics O
of O
ion O
pairs O
generated O
by O
femtosecond O
laser O
pulses O
. O

Effects O
of O
ultrasound O
frequency O
and O
acoustic O
amplitude O
on O
the O
size O
of O
sonochemically O
active O
bubbles O
- O
Theoretical O
study O
. O

Numerical O
simulation O
of O
chemical O
reactions O
inside O
an O
isolated O
spherical O
bubble O
of O
oxygen B
has O
been O
performed O
for O
various O
ambient O
bubble O
radii O
at O
different O
frequencies O
and O
acoustic O
amplitudes O
to O
study O
the O
effects O
of O
these O
two O
parameters O
on O
the O
range O
of O
ambient O
radius O
for O
an O
active O
bubble O
in O
sonochemical O
reactions O
. O

The O
employed O
model O
combines O
the O
dynamic O
of O
bubble O
collapse O
with O
the O
chemical O
kinetics O
of O
single O
cavitation O
bubble O
. O

Results O
from O
this O
model O
were O
compared O
with O
some O
experimental O
results O
presented O
in O
the O
literature O
and O
good O
apparent O
trends O
between O
them O
were O
observed O
. O

The O
numerical O
calculations O
of O
this O
study O
showed O
that O
there O
always O
exists O
an O
optimal O
ambient O
bubble O
radius O
at O
which O
the O
production O
of O
oxidizing O
species O
at O
the O
end O
of O
the O
bubble O
collapse O
attained O
their O
upper O
limit O
. O

It O
was O
shown O
that O
the O
range O
of O
ambient O
radius O
for O
an O
active O
bubble O
increased O
with O
increasing O
acoustic O
amplitude O
and O
decreased O
with O
increasing O
ultrasound O
frequency O
. O

The O
optimal O
ambient O
radius O
decreased O
with O
increasing O
frequency O
. O

Analysis O
of O
curves O
showing O
optimal O
ambient O
radius O
versus O
acoustic O
amplitude O
for O
different O
ultrasonic O
frequencies O
indicated O
that O
for O
200 O
and O
300kHz O
, O
the O
optimal O
ambient O
radius O
increased O
linearly O
with O
increasing O
acoustic O
amplitude O
up O
to O
3atm O
. O

However O
, O
slight O
minima O
of O
optimal O
radius O
were O
observed O
for O
the O
curves O
obtained O
at O
500 O
and O
1000kHz O
. O

Decolourization O
of O
direct O
blue B
15 I
by O
Fenton O
/ O
ultrasonic O
process O
using O
a O
zero O
- O
valent O
iron B
aggregate O
catalyst O
. O

Decolourization O
of O
direct O
azo B
dye O
, O
direct B
blue I
15 I
( O
DB15 B
) O
, O
by O
an O
advanced O
Fenton O
process O
coupled O
with O
ultrasonic O
irradiation O
( O
Fenton O
/ O
US O
) O
was O
investigated O
. O

Zero O
- O
valent O
iron B
( O
ZVI O
) O
aggregates O
were O
used O
as O
the O
catalyst O
. O

A O
positive O
synergistic O
effect O
occurred O
when O
Fenton O
' O
s O
reagent O
was O
combined O
with O
ultrasonic O
irradiation O
. O

Experimental O
results O
showed O
that O
the O
optimum O
conditions O
for O
decolourization O
were O
pH O
3 O
. O
0 O
, O
Fe B
( I
0 I
) I
1g O
/ O
L O
, O
H B
( I
2 I
) I
O I
( I
2 I
) I
5 O
. O
15 O
x O
10 O
( O
- O
3 O
) O
mol O
/ O
L O
with O
ultrasound O
density O
of O
120W O
/ O
L O
at O
60kHz O
. O

These O
conditions O
yielded O
99 O
% O
decolouration O
of O
4 O
. O
7 O
x O
10 O
( O
- O
5 O
) O
M O
DB15 B
( O
4130 O
ADMI O
) O
solution O
within O
10min O
. O

DB15 O
decolouration O
follows O
the O
first O
- O
order O
decolouration O
kinetics O
. O

Although O
the O
solutions O
containing O
H B
( I
2 I
) I
CO I
( I
3 I
) I
, O
Cl B
( I
- I
) I
, O
ClO B
( I
4 I
) I
( I
- I
) I
, O
NO B
( I
3 I
) I
( I
- I
) I
and O
SO B
( I
4 I
) I
( I
2 I
- I
) I
ions O
did O
not O
have O
a O
significant O
effect O
on O
the O
decolouration O
, O
the O
H B
( I
2 I
) I
PO I
( I
4 I
) I
( I
- I
) I
ion O
did O
decrease O
the O
decolouration O
rate O
. O

High O
ultrasonic O
input O
power O
accelerated O
the O
reaction O
and O
increased O
decolourization O
efficiency O
. O

The O
cost O
effectiveness O
of O
this O
process O
at O
high O
ultrasound O
density O
could O
be O
controlled O
despite O
the O
high O
electricity O
costs O
incurred O
by O
the O
process O
. O

ZVI O
aggregates O
were O
reusable O
; O
however O
, O
an O
increase O
in O
the O
number O
of O
times O
ZVI O
was O
recycled O
decreased O
the O
decolourization O
rate O
. O

This O
study O
demonstrates O
that O
a O
Fenton O
/ O
US O
process O
can O
effectively O
decolour O
the O
direct O
azo B
dye O
DB15 B
in O
wastewater O
. O

Effects O
of O
bidentate O
coordination O
on O
the O
molecular O
properties O
rapta O
- O
C O
based O
complex O
using O
theoretical O
approach O
. O

In O
this O
work O
several O
quantum O
properties O
including O
the O
NEDA O
and O
QTAIM O
are O
computed O
on O
three O
models O
of O
rapta O
- O
C O
complexes O
using O
DFT O
with O
hybrid O
functional O
and O
basis O
set O
with O
ECP O
and O
without O
ECP O
. O

Several O
interesting O
correlations O
within O
the O
observed O
properties O
and O
also O
with O
the O
reported O
experimental O
behaviors O
of O
these O
complexes O
including O
their O
biological O
activities O
are O
presented O
. O

The O
study O
shows O
that O
the O
stability O
of O
the O
two O
complexes O
with O
bidentate O
ligands O
is O
associated O
with O
their O
high O
hydrogen B
bonding O
stability O
and O
existence O
of O
stronger O
non O
- O
covalent O
metal O
- O
ligand O
bonds O
. O

The O
energy O
decomposition O
analysis O
indicated O
that O
inter O
- O
atomic O
interactions O
in O
the O
three O
forms O
of O
rapta O
- O
C O
complexes O
and O
their O
stability O
are O
governed O
by O
the O
charge O
transfer O
term O
with O
significant O
contributions O
from O
polarization O
and O
electrostatic O
terms O
. O

The O
higher O
stability O
of O
complex O
1 O
and O
2 O
over O
3 O
comes O
from O
the O
lower O
exchange O
repulsion O
and O
higher O
polarization O
contributions O
to O
their O
stability O
which O
agrees O
perfectly O
with O
the O
experimental O
observation O
. O

Our O
results O
provide O
insight O
into O
the O
nature O
of O
intramolecular O
forces O
that O
influence O
the O
structural O
stability O
of O
the O
three O
complexes O
. O

Genome O
- O
wide O
mapping O
of O
human O
DNA O
- O
replication O
origins O
: O
levels O
of O
transcription O
at O
ORC1 O
sites O
regulate O
origin O
selection O
and O
replication O
timing O
. O

We O
report O
the O
genome O
- O
wide O
mapping O
of O
ORC1 O
binding O
sites O
in O
mammals O
, O
by O
chromatin O
immunoprecipitation O
and O
parallel O
sequencing O
( O
ChIP O
- O
seq O
) O
. O

ORC1 O
binding O
sites O
in O
HeLa O
cells O
were O
validated O
as O
active O
DNA O
replication O
origins O
( O
ORIs O
) O
using O
Repli O
- O
seq O
, O
a O
method O
that O
allows O
identification O
of O
ORI O
- O
containing O
regions O
by O
parallel O
sequencing O
of O
temporally O
ordered O
replicating O
DNA O
. O

ORC1 O
sites O
were O
universally O
associated O
with O
transcription O
start O
sites O
( O
TSSs O
) O
of O
coding O
or O
noncoding O
RNAs O
( O
ncRNAs O
) O
. O

Transcription O
levels O
at O
the O
ORC1 O
sites O
directly O
correlated O
with O
replication O
timing O
, O
suggesting O
the O
existence O
of O
two O
classes O
of O
ORIs O
: O
those O
associated O
with O
moderate O
/ O
high O
transcription O
levels O
( O
> O
= O
1 O
RNA O
copy O
/ O
cell O
) O
, O
firing O
in O
early O
S O
and O
mapping O
to O
the O
TSSs O
of O
coding O
RNAs O
; O
and O
those O
associated O
with O
low O
transcription O
levels O
( O
< O
1 O
RNA O
copy O
/ O
cell O
) O
, O
firing O
throughout O
the O
entire O
S O
and O
mapping O
to O
TSSs O
of O
ncRNAs O
. O

These O
findings O
are O
compatible O
with O
a O
scenario O
whereby O
TSS O
expression O
levels O
influence O
the O
efficiency O
of O
ORC1 O
recruitment O
at O
G O
( O
1 O
) O
and O
the O
probability O
of O
firing O
during O
S O
. O

Highlights O
on O
contemporary O
recognition O
and O
sensing O
of O
fluoride B
anion O
in O
solution O
and O
in O
the O
solid O
state O
. O

The O
fluoride B
anion O
has O
recently O
gained O
well O
deserved O
attention O
among O
the O
scientific O
community O
for O
its O
importance O
in O
many O
fields O
of O
human O
activities O
, O
but O
also O
for O
concerns O
on O
its O
effect O
on O
health O
and O
the O
environment O
. O

Although O
surprisingly O
overlooked O
in O
systematic O
studies O
in O
the O
past O
, O
fluoride B
has O
nowadays O
become O
a O
topical O
target O
in O
the O
field O
of O
anion O
recognition O
. O

A O
multitude O
of O
scientific O
reports O
are O
published O
every O
year O
where O
the O
establishment O
of O
efficient O
and O
specific O
interaction O
with O
fluoride B
is O
sought O
in O
polar O
and O
aqueous O
media O
. O

Here O
, O
the O
emphasis O
is O
directed O
to O
a O
detailed O
description O
of O
the O
most O
interesting O
contemporary O
studies O
in O
the O
field O
, O
with O
a O
particular O
focus O
given O
to O
those O
published O
in O
the O
last O
few O
years O
. O

Phosphorylation O
of O
ribosomal O
protein O
S3 O
and O
antiapoptotic O
TRAF2 O
protein O
mediates O
radioresistance O
in O
non O
- O
small O
cell O
lung O
cancer O
cells O
. O

Radioresistance O
is O
considered O
as O
a O
main O
factor O
restricting O
efficacy O
of O
radiotherapy O
. O

However O
, O
the O
exact O
molecular O
mechanism O
of O
radioresistance O
has O
not O
been O
explained O
yet O
. O

In O
this O
study O
, O
to O
elucidate O
radioresistance O
mechanism O
in O
lung O
cancer O
, O
we O
compared O
radiation O
responses O
in O
two O
types O
of O
non O
- O
small O
cell O
lung O
cancer O
( O
NSCLC O
) O
cells O
with O
different O
radiosensitivity O
and O
identified O
key O
molecules O
conferring O
radioresistance O
. O

In O
radioresistant O
NSCLC O
cells O
, O
ionizing O
radiation O
( O
IR O
) O
led O
to O
casein O
kinase O
2 O
alpha O
( O
CK2 O
alpha O
) O
- O
and O
PKC O
- O
mediated O
phosphorylation O
of O
rpS3 O
and O
TRAF2 O
, O
respectively O
, O
which O
induced O
dissociation O
of O
rpS3 O
- O
TRAF2 O
complex O
and O
NF O
- O
kappa O
B O
activation O
, O
resulting O
in O
significant O
up O
- O
regulation O
of O
prosurvival O
genes O
( O
cIAP1 O
, O
cIAP2 O
, O
and O
survivin O
) O
. O

Also O
, O
dissociated O
phospho B
- O
rpS3 O
translocated O
into O
nucleus O
and O
bound O
with O
NF O
- O
kappa O
B O
complex O
( O
p65 O
and O
p50 O
) O
, O
contributing O
to O
p65 O
DNA O
binding O
property O
and O
specificity O
. O

However O
, O
in O
radiosensitive O
NSCLC O
cells O
, O
IR O
- O
mediated O
rpS3 O
phosphorylation O
was O
not O
detected O
due O
to O
the O
absence O
of O
CK2 O
alpha O
overexpression O
. O

Consequently O
, O
IR O
- O
induced O
rpS3 O
- O
TRAF2 O
complex O
dissociation O
, O
NF O
- O
kappa O
B O
activation O
, O
and O
prosurvival O
gene O
expression O
were O
not O
presented O
. O

Taken O
together O
, O
our O
findings O
revealed O
a O
novel O
radioresistance O
mechanism O
through O
functional O
orchestration O
of O
rpS3 O
, O
TRAF2 O
, O
and O
NF O
- O
kappa O
B O
in O
NSCLC O
cells O
. O

Moreover O
, O
we O
provided O
the O
first O
evidence O
for O
the O
function O
of O
rpS3 O
as O
a O
new O
TRAF2 O
- O
binding O
protein O
and O
demonstrated O
that O
phosphorylation O
of O
both O
rpS3 O
and O
TRAF2 O
is O
a O
key O
control O
point O
of O
radioresistance O
in O
NSCLC O
cells O
. O

These O
results O
suggest O
that O
regulation O
of O
rpS3 O
and O
TRAF2 O
in O
combination O
with O
radiotherapy O
could O
have O
high O
pharmacological O
therapeutic O
potency O
for O
radioresistance O
of O
NSCLC O
. O

Theoretical O
studies O
on O
muti B
- I
hydroxyimides I
as O
highly O
efficient O
catalysts O
for O
aerobic O
oxidation O
. O

N B
, I
N I
- I
dihydroxypyromelliti I
( O
NDHPI B
) O
and O
N B
, I
N I
' I
, I
N I
' I
' I
- I
trihydroxyisocyanuri I
acid I
( O
THICA B
) O
have O
been O
recently O
demonstrated O
to O
act O
as O
better O
carbon B
- O
radical O
- O
producing O
catalysts O
than O
the O
popular O
N B
- I
hydroxyphthalimide I
( O
NHPI B
) O
. O

To O
gain O
a O
mature O
understanding O
of O
these O
particular O
catalysts O
, O
herein O
their O
geometrical O
, O
electronic O
, O
and O
thermochemical O
properties O
, O
as O
well O
as O
their O
catalytic O
activities O
, O
have O
been O
systemically O
investigated O
by O
a O
theoretical O
analysis O
. O

It O
appears O
that O
THICA B
, O
unlike O
NDHPI B
and O
NHPI B
, O
is O
unsuitable O
for O
solvent O
- O
free O
catalysis O
or O
catalysis O
in O
aprotic O
solvents O
due O
to O
its O
favorable O
coexistent O
planar O
conformer O
. O

Besides O
, O
the O
more O
remarkable O
catalytic O
efficiencies O
of O
NDHPI B
and O
THICA B
compared O
to O
NHPI B
can O
be O
ascribed O
to O
the O
lower O
barriers O
and O
the O
endothermicity O
in O
the O
H B
- O
abstraction O
processes O
by O
their O
radicals O
, O
especially O
by O
their O
multi O
- O
radicals O
which O
show O
stronger O
electron O
- O
withdrawing O
effects O
. O

Furthermore O
, O
the O
generation O
of O
THICA B
radicals O
would O
be O
much O
feasible O
at O
high O
temperature O
without O
co O
- O
catalysts O
. O

This O
study O
provides O
a O
new O
perspective O
towards O
the O
rational O
design O
of O
reactive O
hydroxyimide B
organocatalysts O
for O
industrial O
applications O
. O

A O
novel O
adipose O
- O
specific O
gene O
deletion O
model O
demonstrates O
potential O
pitfalls O
of O
existing O
methods O
. O

Adipose O
- O
specific O
gene O
deletion O
in O
mice O
is O
crucial O
in O
determining O
gene O
function O
in O
adipocyte O
homeostasis O
and O
the O
development O
of O
obesity O
. O

We O
noted O
100 O
% O
mortality O
when O
the O
Hdac3 O
gene O
was O
conditionally O
deleted O
using O
Fabp4 O
- O
Cre O
mice O
, O
the O
most O
commonly O
used O
model O
of O
adipose O
- O
targeted O
Cre O
recombinase O
. O

However O
, O
this O
surprising O
result O
was O
not O
reproduced O
using O
other O
models O
of O
adipose O
targeting O
of O
Cre O
, O
including O
a O
novel O
Retn O
- O
Cre O
mouse O
. O

These O
findings O
underscore O
the O
need O
for O
caution O
when O
interpreting O
data O
obtained O
using O
Fabp4 O
- O
Cre O
mice O
and O
should O
encourage O
the O
use O
of O
additional O
or O
alternative O
adipose O
- O
targeting O
Cre O
mouse O
models O
before O
drawing O
conclusions O
about O
in O
vivo O
adipocyte O
- O
specific O
functions O
. O

High O
- O
dose O
resveratrol B
supplementation O
in O
obese O
men O
: O
an O
investigator O
- O
initiated O
, O
randomized O
, O
placebo O
- O
controlled O
clinical O
trial O
of O
substrate O
metabolism O
, O
insulin O
sensitivity O
, O
and O
body O
composition O
. O

Obesity O
, O
diabetes O
, O
hypertension O
, O
and O
hyperlipidemia O
constitute O
risk O
factors O
for O
morbidity O
and O
premature O
mortality O
. O

Based O
on O
animal O
and O
in O
vitro O
studies O
, O
resveratrol B
reverts O
these O
risk O
factors O
via O
stimulation O
of O
silent O
mating O
type O
information O
regulation O
2 O
homolog O
1 O
( O
SIRT1 O
) O
, O
but O
data O
in O
human O
subjects O
are O
scarce O
. O

The O
objective O
of O
this O
study O
was O
to O
examine O
the O
metabolic O
effects O
of O
high O
- O
dose O
resveratrol B
in O
obese O
human O
subjects O
. O

In O
a O
randomized O
, O
placebo O
- O
controlled O
, O
double O
- O
blinded O
, O
and O
parallel O
- O
group O
design O
, O
24 O
obese O
but O
otherwise O
healthy O
men O
were O
randomly O
assigned O
to O
4 O
weeks O
of O
resveratrol B
or O
placebo O
treatment O
. O

Extensive O
metabolic O
examinations O
including O
assessment O
of O
glucose B
turnover O
and O
insulin O
sensitivity O
( O
hyperinsulinemic O
euglycemic O
clamp O
) O
were O
performed O
before O
and O
after O
the O
treatment O
. O

Insulin O
sensitivity O
, O
the O
primary O
outcome O
measure O
, O
deteriorated O
insignificantly O
in O
both O
groups O
. O

Endogenous O
glucose B
production O
and O
the O
turnover O
and O
oxidation O
rates O
of O
glucose B
remained O
unchanged O
. O

Resveratrol B
supplementation O
also O
had O
no O
effect O
on O
blood O
pressure O
; O
resting O
energy O
expenditure O
; O
oxidation O
rates O
of O
lipid O
; O
ectopic O
or O
visceral O
fat O
content O
; O
or O
inflammatory O
and O
metabolic O
biomarkers O
. O

The O
lack O
of O
effect O
disagrees O
with O
persuasive O
data O
obtained O
from O
rodent O
models O
and O
raises O
doubt O
about O
the O
justification O
of O
resveratrol B
as O
a O
human O
nutritional O
supplement O
in O
metabolic O
disorders O
. O

Islet O
alpha O
- O
, O
beta O
- O
, O
and O
delta O
- O
cell O
development O
is O
controlled O
by O
the O
Ldb1 O
coregulator O
, O
acting O
primarily O
with O
the O
islet O
- O
1 O
transcription O
factor O
. O

Ldb1 O
and O
Ldb2 O
are O
coregulators O
that O
mediate O
Lin11 O
- O
Isl1 O
- O
Mec3 O
( O
LIM O
) O
- O
homeodomain O
( O
HD O
) O
and O
LIM O
- O
only O
transcription O
factor O
- O
driven O
gene O
regulation O
. O

Although O
both O
Ldb1 O
and O
Ldb2 O
mRNA O
were O
produced O
in O
the O
developing O
and O
adult O
pancreas O
, O
immunohistochemical O
analysis O
illustrated O
a O
broad O
Ldb1 O
protein O
expression O
pattern O
during O
early O
pancreatogenesis O
, O
which O
subsequently O
became O
enriched O
in O
islet O
and O
ductal O
cells O
perinatally O
. O

The O
islet O
- O
enriched O
pattern O
of O
Ldb1 O
was O
similar O
to O
pan O
- O
endocrine O
cell O
- O
expressed O
Islet O
- O
1 O
( O
Isl1 O
) O
, O
which O
was O
demonstrated O
in O
this O
study O
to O
be O
the O
primary O
LIM O
- O
HD O
transcription O
factor O
in O
developing O
and O
adult O
islet O
cells O
. O

Endocrine O
cell O
- O
specific O
removal O
of O
Ldb1 O
during O
mouse O
development O
resulted O
in O
a O
severe O
reduction O
of O
hormone O
+ O
cell O
numbers O
( O
i O
. O
e O
. O
, O
alpha O
, O
beta O
, O
and O
delta O
) O
and O
overt O
postnatal O
hyperglycemia O
, O
reminiscent O
of O
the O
phenotype O
described O
for O
the O
Isl1 O
conditional O
mutant O
. O

In O
contrast O
, O
neither O
endocrine O
cell O
development O
nor O
function O
was O
affected O
in O
the O
pancreas O
of O
Ldb2 O
( O
- O
/ O
- O
) O
mice O
. O

Gene O
expression O
and O
chromatin O
immunoprecipitation O
( O
ChIP O
) O
analyses O
demonstrated O
that O
many O
important O
Isl1 O
- O
activated O
genes O
were O
coregulated O
by O
Ldb1 O
, O
including O
MafA O
, O
Arx O
, O
insulin O
, O
and O
Glp1r O
. O

However O
, O
some O
genes O
( O
i O
. O
e O
. O
, O
Hb9 O
and O
Glut2 O
) O
only O
appeared O
to O
be O
impacted O
by O
Ldb1 O
during O
development O
. O

These O
findings O
establish O
Ldb1 O
as O
a O
critical O
transcriptional O
coregulator O
during O
islet O
alpha O
- O
, O
beta O
- O
, O
and O
delta O
- O
cell O
development O
through O
Isl1 O
- O
dependent O
and O
potentially O
Isl1 O
- O
independent O
control O
. O

Hyperglycemia O
slows O
embryonic O
growth O
and O
suppresses O
cell O
cycle O
via O
cyclin O
D1 O
and O
p21 O
. O

In O
pregnant O
women O
, O
the O
diabetic O
condition O
results O
in O
a O
three O
- O
to O
fivefold O
increased O
risk O
for O
fetal O
cardiac O
malformations O
as O
a O
result O
of O
elevated O
glucose B
concentrations O
and O
the O
resultant O
osmotic O
stress O
in O
the O
developing O
embryo O
and O
fetus O
. O

Heart O
development O
before O
septation O
in O
the O
chick O
embryo O
was O
studied O
under O
two O
hyperglycemic O
conditions O
. O

Pulsed O
hyperglycemia O
induced O
by O
daily O
administration O
of O
glucose B
during O
3 O
days O
of O
development O
caused O
daily O
spikes O
in O
plasma O
glucose B
concentration O
. O

In O
a O
second O
model O
, O
sustained O
hyperglycemia O
was O
induced O
with O
a O
single O
injection O
of O
glucose B
into O
the O
yolk O
on O
day O
0 O
. O

The O
sustained O
model O
raised O
the O
average O
plasma O
glucose B
concentration O
from O
70 O
mg O
/ O
dL O
to O
180 O
mg O
/ O
dL O
and O
led O
to O
decreased O
gene O
expression O
of O
glucose B
transporter O
GLUT1 O
. O

Both O
models O
of O
hyperglycemia O
reduced O
embryo O
size O
, O
increased O
mortality O
, O
and O
delayed O
development O
. O

Within O
the O
heart O
outflow O
tract O
, O
reduced O
proliferation O
of O
myocardial O
and O
endocardial O
cells O
resulted O
from O
the O
sustained O
hyperglycemia O
and O
hyperosmolarity O
. O

The O
cell O
cycle O
inhibitor O
p21 O
was O
significantly O
increased O
, O
whereas O
cyclin O
D1 O
, O
a O
cell O
cycle O
promoter O
, O
decreased O
in O
sustained O
hyperglycemia O
compared O
with O
controls O
. O

The O
evidence O
suggests O
that O
hyperglycemia O
- O
induced O
developmental O
delays O
are O
associated O
with O
slowed O
cell O
cycle O
progression O
, O
leading O
to O
reduced O
cellular O
proliferation O
. O

The O
suppression O
of O
critical O
developmental O
steps O
may O
underlie O
the O
cardiac O
defects O
observed O
during O
late O
gestation O
under O
hyperglycemic O
conditions O
. O

H2DB O
: O
a O
heritability O
database O
across O
multiple O
species O
by O
annotating O
trait O
- O
associated O
genomic O
loci O
. O

H2DB O
( O
http O
: O
/ O
/ O
tga O
. O
nig O
. O
ac O
. O
jp O
/ O
h2db O
/ O
) O
, O
an O
annotation O
database O
of O
genetic O
heritability O
estimates O
for O
humans O
and O
other O
species O
, O
has O
been O
developed O
as O
a O
knowledge O
database O
to O
connect O
trait O
- O
associated O
genomic O
loci O
. O

Heritability O
estimates O
have O
been O
investigated O
for O
individual O
species O
, O
particularly O
in O
human O
twin O
studies O
and O
plant O
/ O
animal O
breeding O
studies O
. O

However O
, O
there O
appears O
to O
be O
no O
comprehensive O
heritability O
database O
for O
both O
humans O
and O
other O
species O
. O

Here O
, O
we O
introduce O
an O
annotation O
database O
for O
genetic O
heritabilities O
of O
various O
species O
that O
was O
annotated O
by O
manually O
curating O
online O
public O
resources O
in O
PUBMED O
abstracts O
and O
journal O
contents O
. O

The O
proposed O
heritability O
database O
contains O
attribute O
information O
for O
trait O
descriptions O
, O
experimental O
conditions O
, O
trait O
- O
associated O
genomic O
loci O
and O
broad O
- O
and O
narrow O
- O
sense O
heritability O
specifications O
. O

Annotated O
trait O
- O
associated O
genomic O
loci O
, O
for O
which O
most O
are O
single O
- O
nucleotide O
polymorphisms O
derived O
from O
genome O
- O
wide O
association O
studies O
, O
may O
be O
valuable O
resources O
for O
experimental O
scientists O
. O

In O
addition O
, O
we O
assigned O
phenotype O
ontologies O
to O
the O
annotated O
traits O
for O
the O
purposes O
of O
discussing O
heritability O
distributions O
based O
on O
phenotypic O
classifications O
. O

PTMcode O
: O
a O
database O
of O
known O
and O
predicted O
functional O
associations O
between O
post O
- O
translational O
modifications O
in O
proteins O
. O

Post O
- O
translational O
modifications O
( O
PTMs O
) O
are O
involved O
in O
the O
regulation O
and O
structural O
stabilization O
of O
eukaryotic O
proteins O
. O

The O
combination O
of O
individual O
PTM O
states O
is O
a O
key O
to O
modulate O
cellular O
functions O
as O
became O
evident O
in O
a O
few O
well O
- O
studied O
proteins O
. O

This O
combinatorial O
setting O
, O
dubbed O
the O
PTM O
code O
, O
has O
been O
proposed O
to O
be O
extended O
to O
whole O
proteomes O
in O
eukaryotes O
. O

Although O
we O
are O
still O
far O
from O
deciphering O
such O
a O
complex O
language O
, O
thousands O
of O
protein O
PTM O
sites O
are O
being O
mapped O
by O
high O
- O
throughput O
technologies O
, O
thus O
providing O
sufficient O
data O
for O
comparative O
analysis O
. O

PTMcode O
( O
http O
: O
/ O
/ O
ptmcode O
. O
embl O
. O
de O
) O
aims O
to O
compile O
known O
and O
predicted O
PTM O
associations O
to O
provide O
a O
framework O
that O
would O
enable O
hypothesis O
- O
driven O
experimental O
or O
computational O
analysis O
of O
various O
scales O
. O

In O
its O
first O
release O
, O
PTMcode O
provides O
PTM O
functional O
associations O
of O
13 O
different O
PTM O
types O
within O
proteins O
in O
8 O
eukaryotes O
. O

They O
are O
based O
on O
five O
evidence O
channels O
: O
a O
literature O
survey O
, O
residue O
co O
- O
evolution O
, O
structural O
proximity O
, O
PTMs O
at O
the O
same O
residue O
and O
location O
within O
PTM O
highly O
enriched O
protein O
regions O
( O
hotspots O
) O
. O

PTMcode O
is O
presented O
as O
a O
protein O
- O
based O
searchable O
database O
with O
an O
interactive O
web O
interface O
providing O
the O
context O
of O
the O
co O
- O
regulation O
of O
nearly O
75 O
000 O
residues O
in O
> O
10 O
000 O
proteins O
. O

The O
chemopreventive O
effect O
of O
beta B
- I
cryptoxanthin I
from O
mandarin O
on O
human O
stomach O
cells O
( O
BGC O
- O
823 O
) O
. O

beta B
- I
Cryptoxanthin I
, O
a O
provitaminic O
carotenoid O
, O
present O
in O
many O
fruits O
and O
vegetables O
, O
has O
been O
associated O
with O
decreased O
risk O
of O
chronic O
diseases O
, O
including O
cancer O
. O

The O
influence O
of O
beta B
- I
cryptoxanthin I
derived O
from O
mandarin O
on O
the O
proliferation O
of O
the O
stomach O
tumor O
cell O
line O
BGC O
- O
823 O
was O
tested O
using O
MTT B
and O
cell O
count O
assay O
at O
72 O
h O
and O
dose O
- O
response O
( O
from O
0 O
. O
01 O
to O
20 O
mu O
M O
) O
. O

beta B
- I
Cryptoxanthin I
suppressed O
the O
cell O
migration O
by O
the O
scratch O
assay O
. O

Furthermore O
, O
beta B
- I
cryptoxanthin I
induced O
an O
accumulation O
of O
cells O
in O
the O
G1 O
/ O
G0 O
phase O
of O
the O
cell O
cycle O
( O
as O
detected O
by O
flow O
cytometry O
) O
, O
which O
was O
in O
accordance O
with O
an O
increased O
expression O
of O
p21 O
and O
down O
regulations O
of O
cyclin O
D1 O
and O
cyclin O
E O
, O
detected O
by O
Western O
blot O
analysis O
, O
and O
beta B
- I
cryptoxanthin I
increased O
the O
mRNA O
levels O
of O
retinoic B
acid I
receptor O
beta O
( O
RAR O
beta O
) O
with O
the O
treatment O
at O
10 O
mu O
M O
for O
24 O
h O
. O

Collectively O
, O
the O
above O
findings O
suggest O
that O
beta B
- I
cryptoxanthin I
could O
be O
therapeutic O
in O
the O
treatment O
of O
stomach O
cancer O
cell O
in O
vitro O
. O

Edible O
and O
non O
- O
edible O
olive O
oils O
discrimination O
by O
the O
application O
of O
a O
sensory O
olfactory O
system O
based O
on O
tin B
dioxide I
sensors O
. O

An O
array O
of O
semiconductor O
sensors O
has O
been O
developed O
to O
discriminate O
virgin O
olive O
oil O
samples O
based O
on O
their O
organoleptic O
characteristics O
. O

The O
multisensor O
, O
developed O
at O
laboratory O
, O
is O
composed O
by O
14 O
sensing O
elements O
of O
tin B
dioxide I
thin O
layers O
( O
doped O
with O
Cr B
and O
In B
, O
and O
undoped O
) O
deposited O
by O
the O
reactive O
sputtering O
technique O
. O

The O
sensors O
are O
stable O
and O
show O
good O
repeatability O
. O

Off O
- O
flavors O
and O
extra O
- O
virgin O
olive O
oil O
samples O
, O
taken O
at O
the O
outlet O
of O
the O
vertical O
centrifuge O
of O
a O
small O
experimental O
olive O
oil O
mill O
and O
sensory O
evaluated O
, O
have O
been O
used O
. O

A O
good O
discrimination O
of O
edible O
( O
extra O
- O
virgin O
and O
virgin O
) O
from O
non O
- O
edible O
( O
lampante O
) O
olive O
oils O
has O
been O
obtained O
through O
the O
statistical O
method O
of O
principal O
component O
analysis O
( O
PCA O
) O
. O

Phenolic O
profiles O
and O
antioxidant O
activity O
of O
litchi O
pulp O
of O
different O
cultivars O
cultivated O
in O
Southern O
China O
. O

The O
phenolic O
profiles O
and O
antioxidant O
activity O
of O
litchi O
pulp O
of O
13 O
varieties O
were O
investigated O
. O

The O
free O
, O
bound O
and O
total O
phenolic O
contents O
were O
66 O
. O
17 O
- O
226 O
. O
03 O
, O
11 O
. O
18 O
- O
40 O
. O
54 O
, O
and O
101 O
. O
51 O
- O
259 O
. O
18 O
mg O
of O
gallic B
acid I
equivalents O
/ O
100 O
g O
, O
respectively O
. O

The O
free O
, O
bound O
and O
total O
flavonoid B
contents O
were O
16 O
. O
68 O
- O
110 O
. O
33 O
, O
10 O
. O
48 O
- O
22 O
. O
75 O
, O
and O
39 O
. O
43 O
- O
129 O
. O
86 O
mg O
of O
catechin B
equivalents O
/ O
100 O
g O
, O
respectively O
. O

Free O
phenolics B
and O
flavonoids B
contributed O
averagely O
80 O
. O
1 O
% O
and O
75 O
% O
to O
their O
total O
contents O
, O
respectively O
. O

Six O
individual O
phenolics B
( O
gallic B
acid I
, O
chlorogenic B
acid I
, O
( B
+ I
) I
- I
catechin I
, O
caffeic B
acid I
, O
( B
- I
) I
- I
epicatechin I
, O
and O
rutin B
) O
were O
detected O
in O
litchi O
pulp O
by O
HPLC O
. O

The O
contents O
of O
each O
compound O
in O
free O
and O
bound O
fractions O
were O
determined O
. O

Significant O
varietal O
discrepancy O
in O
antioxidant O
activity O
was O
also O
found O
by O
FRAP O
and O
DPPH B
scavenging O
capacity O
methods O
. O

Antioxidant O
activity O
was O
significantly O
correlated O
with O
phenolic B
and O
flavonoid B
contents O
. O

Thus O
, O
phenolics B
and O
flavonoids B
exist O
mainly O
in O
the O
free O
form O
in O
litchi O
pulp O
. O

There O
were O
significant O
varietal O
differences O
in O
phytochemical O
contents O
and O
antioxidant O
activity O
of O
litchi O
pulp O
. O

Immunomodulatory O
effect O
of O
Ganoderma O
atrum O
polysaccharide O
on O
CT26 O
tumor O
- O
bearing O
mice O
. O

Ganoderma O
atrum O
has O
attracted O
great O
attention O
for O
its O
antitumor O
activity O
. O

However O
, O
the O
mechanism O
remains O
unclear O
. O

A O
G O
. O
atrum O
polysaccharide O
( O
PSG O
- O
1 O
) O
showed O
pronounced O
antitumor O
activity O
in O
this O
study O
. O

PSG O
- O
1 O
did O
not O
kill O
CT26 O
cells O
directly O
, O
but O
inhibited O
the O
proliferation O
of O
CT26 O
cells O
via O
the O
activation O
of O
peritoneal O
macrophages O
( O
M O
Phi O
) O
. O

In O
vivo O
, O
PSG O
- O
1 O
significantly O
suppressed O
the O
tumor O
growth O
in O
CT26 O
tumor O
- O
bearing O
mice O
. O

The O
treatment O
caused O
a O
significant O
increase O
in O
the O
immune O
organ O
index O
and O
the O
phagocytosis O
of O
macrophages O
. O

The O
production O
of O
TNF O
- O
alpha O
, O
IL O
- O
1 O
beta O
and O
nitric B
oxide I
also O
increased O
. O

Furthermore O
, O
we O
found O
that O
PSG O
- O
1 O
acted O
on O
Toll O
- O
like O
receptor O
( O
TLR O
) O
4 O
, O
signaled O
through O
p38 O
MAPK O
pathway O
, O
then O
activated O
NF O
- O
kappa O
B O
and O
stimulated O
TNF O
- O
alpha O
production O
. O

We O
further O
found O
that O
PSG O
- O
1 O
increased O
the O
expression O
of O
TLR4 O
and O
NF O
- O
kappa O
B O
, O
the O
degradation O
of O
I O
kappa O
B O
alpha O
and O
the O
phosphorylation O
of O
p38 O
MAPK O
. O

In O
summary O
, O
we O
have O
demonstrated O
that O
PSG O
- O
1 O
could O
activate O
macrophages O
via O
TLR4 O
- O
dependent O
signaling O
pathways O
, O
improve O
immunity O
and O
inhibit O
tumor O
growth O
. O

Identification O
of O
hydroxychavicol B
and O
its O
dimers O
, O
the O
lipase O
inhibitors O
contained O
in O
the O
Indonesian O
spice O
, O
Eugenia O
polyantha O
. O

Inhibition O
of O
pancreatic O
lipase O
is O
effective O
for O
a O
prevention O
of O
obesity O
. O

Eugenia O
polyantha O
is O
a O
tropical O
tree O
whose O
leaves O
are O
known O
as O
a O
spice O
and O
also O
as O
an O
ingredient O
for O
Jamu O
, O
the O
traditional O
medicine O
of O
Indonesia O
. O

We O
found O
inhibitory O
activity O
against O
pancreatic O
lipase O
in O
the O
extract O
of O
E O
. O
polyantha O
leaves O
. O

Purification O
of O
the O
active O
principals O
resulted O
in O
isolation O
of O
hydroxychavicol B
, O
and O
two O
structurally O
new O
dimers O
. O

All O
of O
the O
isolated O
compounds O
showed O
inhibitory O
activity O
against O
the O
porcine O
pancreatic O
lipase O
and O
high O
content O
of O
hydroxychavicol B
( O
1 O
. O
83 O
wt O
. O
% O
) O
indicated O
this O
compound O
to O
be O
responsible O
for O
the O
majority O
of O
inhibitory O
activity O
of O
E O
. O
polyantha O
extract O
. O

Furthermore O
, O
hydroxychavicol B
is O
reported O
to O
possess O
anti O
- O
carcinogenic O
, O
anti O
- O
oxidant O
, O
anti O
- O
microbial O
and O
anti O
- O
inflammatory O
activity O
which O
is O
related O
to O
traditional O
usage O
of O
this O
plant O
. O

These O
results O
offer O
this O
plant O
as O
an O
attractive O
material O
for O
treating O
various O
health O
problems O
including O
obesity O
. O

Contents O
of O
dietary O
fibre O
components O
and O
their O
relation O
to O
associated O
bioactive O
components O
in O
whole O
grain O
wheat O
samples O
from O
the O
HEALTHGRAIN O
diversity O
screen O
. O

A O
large O
and O
diverse O
material O
collection O
of O
whole O
grain O
wheat O
samples O
( O
n O
= O
129 O
) O
was O
analysed O
for O
total O
dietary O
fibre O
( O
TDF O
) O
content O
and O
composition O
, O
including O
fructan O
( O
11 O
. O
5 O
- O
15 O
. O
5 O
% O
) O
. O

Correlations O
between O
the O
dietary O
fibre O
components O
, O
associated O
bioactive O
components O
( O
e O
. O
g O
. O
tocols B
, O
sterols B
, O
phenolic B
acids I
and O
folates B
) O
and O
agronomic O
properties O
previously O
determined O
on O
the O
same O
samples O
were O
found O
with O
multivariate O
analysis O
( O
PCA O
) O
. O

Samples O
from O
the O
same O
countries O
had O
similar O
characteristics O
. O

The O
first O
PC O
described O
variation O
in O
components O
concentrated O
in O
the O
starchy O
endosperm O
( O
e O
. O
g O
. O
starch O
, O
beta O
- O
glucan O
and O
fructan O
) O
and O
the O
dietary O
fibre O
components O
concentrated O
in O
the O
bran O
( O
e O
. O
g O
. O
TDF O
, O
arabinoxylan O
and O
cellulose O
) O
. O

The O
second O
PC O
described O
the O
variation O
in O
kernel O
weight O
and O
other O
bran O
components O
such O
as O
alkylresorcinols B
, O
tocols B
and O
sterols B
. O

Interestingly O
, O
there O
was O
no O
correlation O
among O
these O
different O
groups O
of O
bran O
components O
, O
which O
reflected O
their O
concentration O
in O
different O
bran O
tissues O
. O

The O
results O
are O
of O
importance O
for O
plant O
breeders O
who O
wish O
to O
develop O
varieties O
with O
health O
- O
promoting O
effects O
. O

Muscle O
composition O
slightly O
affects O
in O
vitro O
digestion O
of O
aged O
and O
cooked O
meat O
: O
identification O
of O
associated O
proteomic O
markers O
. O

Meat O
is O
an O
appropriate O
source O
of O
proteins O
and O
minerals O
for O
human O
nutrition O
. O

Technological O
treatments O
modify O
the O
physical O
- O
chemical O
properties O
of O
proteins O
, O
making O
them O
liable O
to O
decrease O
the O
nutritional O
potential O
of O
meat O
. O

To O
counteract O
this O
damage O
, O
antioxidants O
and O
chaperone O
proteins O
in O
muscle O
cells O
can O
prevent O
oxidation O
, O
restore O
the O
function O
of O
denatured O
proteins O
, O
and O
thus O
prevent O
aggregation O
. O

This O
study O
aimed O
to O
explore O
the O
impact O
of O
indoor O
vs O
outdoor O
- O
reared O
meat O
protein O
composition O
on O
digestion O
and O
to O
associate O
protein O
markers O
to O
in O
vitro O
digestion O
parameters O
. O

Indoor O
- O
reared O
meat O
tended O
to O
show O
less O
oxidation O
and O
denaturation O
than O
outdoor O
- O
reared O
meat O
and O
was O
characterised O
by O
an O
overexpression O
of O
contractile O
and O
chaperone O
proteins O
. O

Outdoor O
- O
reared O
meat O
showed O
amplification O
of O
antioxidant O
and O
detoxification O
metabolism O
defending O
against O
oxidised O
compounds O
. O

Impacts O
on O
digestion O
remained O
minor O
. O

Several O
protein O
markers O
of O
in O
vitro O
digestion O
parameters O
were O
found O
for O
aged O
and O
cooked O
meat O
, O
linked O
to O
the O
detoxification O
process O
and O
to O
muscle O
contraction O
. O

Determination O
of O
herb O
authenticity O
by O
low O
- O
field O
NMR O
. O

The O
safe O
use O
of O
herbal O
medicines O
requires O
prior O
authentication O
of O
the O
raw O
materials O
used O
to O
make O
them O
. O

This O
is O
an O
important O
step O
, O
since O
the O
ingestion O
of O
herbal O
preparations O
or O
extracts O
can O
cause O
serious O
health O
problems O
. O

Among O
the O
different O
analytical O
techniques O
, O
nuclear O
magnetic O
resonance O
( O
NMR O
) O
spectroscopy O
has O
the O
advantage O
of O
being O
non O
- O
invasive O
and O
therefore O
suitable O
for O
the O
characterization O
of O
natural O
products O
such O
as O
medicinal O
plants O
. O

This O
work O
presents O
a O
characterisation O
study O
of O
the O
samples O
of O
the O
popular O
plant O
Maytenus O
ilicifolia O
, O
obtained O
from O
different O
commercial O
producers O
. O

This O
plant O
is O
used O
for O
the O
treatment O
of O
gastrointestinal O
disorders O
, O
as O
it O
possesses O
antitumorigenic O
, O
analgesic O
, O
anti O
- O
inflammatory O
and O
antioxidant O
properties O
. O

The O
differences O
in O
the O
chemical O
structure O
and O
molecular O
organisation O
detected O
by O
thermogravimetric O
analysis O
( O
TGA O
) O
, O
infrared O
spectroscopy O
( O
FTIR O
) O
and O
nuclear O
magnetic O
resonance O
spectroscopy O
( O
NMR O
) O
were O
also O
investigated O
by O
proton O
nuclear O
magnetic O
resonance O
relaxometry O
, O
in O
particular O
by O
fast O
field O
cycling O
( O
FFC O
) O
relaxometry O
, O
and O
relaxometry O
in O
the O
rotating O
frame O
. O

All O
results O
confirmed O
the O
similarity O
between O
the O
control O
sample O
and O
only O
one O
of O
the O
plant O
investigated O
. O

The O
differences O
detected O
between O
the O
samples O
could O
be O
related O
to O
their O
non O
- O
authenticity O
, O
due O
to O
the O
non O
recognise O
the O
plant O
due O
to O
the O
leaves O
similarity O
among O
plants O
from O
the O
same O
family O
and O
/ O
or O
contamination O
, O
due O
to O
addition O
of O
similar O
other O
plants O
parts O
to O
the O
commercial O
ones O
, O
as O
they O
are O
mixed O
together O
this O
difficulties O
the O
acceptation O
of O
the O
plant O
. O

Monitoring O
of O
Escherichia O
coli O
O157 O
: O
H7 O
in O
food O
samples O
using O
lectin O
based O
surface O
plasmon O
resonance O
biosensor O
. O

A O
novel O
surface O
plasmon O
resonance O
( O
SPR O
) O
biosensor O
using O
lectin O
as O
bioreceptor O
was O
developed O
for O
the O
rapid O
detection O
of O
Escherichia O
coli O
( O
E O
. O
coli O
) O
O157 O
: O
H7 O
. O

The O
selective O
interaction O
of O
lectins O
with O
carbohydrate B
components O
from O
bacterial O
cells O
surface O
was O
used O
as O
the O
recognition O
principle O
for O
the O
detection O
. O

Five O
types O
of O
lectins O
from O
Triticum O
vulgaris O
, O
Canavailia O
ensiformis O
, O
Ulex O
europaeus O
, O
Arachis O
hypogaea O
, O
and O
Maackia O
amurensis O
, O
were O
employed O
to O
evaluate O
the O
selectivity O
of O
the O
approach O
for O
binding O
E O
. O
coli O
O157 O
: O
H7 O
effectively O
. O

A O
detection O
limit O
of O
3 O
x O
10 O
( O
3 O
) O
cfu O
mL O
( O
- O
1 O
) O
was O
obtained O
for O
determination O
of O
E O
. O
coli O
O157 O
: O
H7 O
when O
used O
the O
lectin O
from O
T O
. O
vulgaris O
as O
the O
binding O
molecule O
. O

Furthermore O
, O
the O
proposed O
biosensor O
was O
used O
to O
detect O
E O
. O
coli O
O157 O
: O
H7 O
in O
real O
food O
samples O
. O

Results O
showed O
that O
the O
lectin O
based O
SPR O
biosensor O
was O
sensitive O
, O
reliable O
and O
effective O
for O
detection O
of O
E O
. O
coli O
O157 O
: O
H7 O
, O
which O
hold O
a O
great O
promise O
in O
food O
safety O
analysis O
. O

Development O
and O
validation O
of O
an O
HPLC O
method O
for O
the O
determination O
of O
six O
penicillin B
and O
three O
amphenicol B
antibiotics O
in O
gilthead O
seabream O
( O
Sparus O
Aurata O
) O
tissue O
according O
to O
the O
European O
Union O
Decision O
2002 O
/ O
657 O
/ O
EC O
. O

A O
confirmatory O
high O
performance O
liquid O
chromatography O
method O
for O
the O
determination O
of O
six O
penicillin B
antibiotics O
and O
three O
amphenicol B
antibiotics O
in O
gilthead O
seabream O
( O
Sparus O
Aurata O
) O
tissue O
was O
developed O
. O

Ampicillin B
( O
AMP B
) O
, O
penicillin B
G I
( O
PG O
) O
, O
penicillin B
V I
( O
PV O
) O
, O
oxacillin B
( O
OXA B
) O
, O
cloxacillin B
( O
CLO B
) O
, O
dicloxacillin B
( O
DICLO B
) O
, O
thiamphenicol B
( O
TAP B
) O
, O
florfenicol B
( O
FFC B
) O
and O
chloramphenicol B
( O
CAP B
) O
were O
separated O
on O
an O
Inertsil O
, O
C O
( O
8 O
) O
( O
250 O
x O
4 O
mm O
, O
5 O
mu O
m O
) O
column O
by O
gradient O
elution O
with O
a O
mobile O
phase O
consisting O
of O

ammonium B
acetate I
0 O
. O
05 O
M O
and O
acetonitrile B
at O
25 O
degrees O
C O
. O

Diode O
array O
detection O
with O
monitoring O
at O
225 O
nm O
( O
for O
the O
determination O
of O
AMP B
, O
PG O
, O
PV O
, O
TAP B
and O
FFC O
) O
, O
240 O
nm O
( O
for O
OXA B
, O
CLO B
and O
DICLO B
) O
and O
278 O
nm O
( O
for O
CAP B
) O
was O
applied O
. O

Examined O
antibiotics O
were O
isolated O
from O
gilthead O
seabream O
tissue O
by O
liquid O
- O
liquid O
extraction O
and O
further O
clean O
- O
up O
was O
performed O
by O
solid O
phase O
extraction O
using O
Oasis O
HLB O
( O
200 O
mg O
/ O
6 O
mL O
) O
cartridges O
. O

The O
developed O
method O
was O
fully O
validated O
in O
terms O
of O
selectivity O
, O
linearity O
, O
accuracy O
, O
precision O
, O
stability O
and O
sensitivity O
according O
to O
the O
European O
Union O
Decision O
2002 O
/ O
657 O
/ O
EC O
. O

Metabolite O
profiling O
of O
ginsenoside B
Re I
in O
rat O
urine O
and O
faeces O
after O
oral O
administration O
. O

Following O
oral O
administration O
of O
ginsenoside B
Re I
, O
the O
compound O
and O
its O
metabolites O
were O
identified O
and O
quantified O
in O
rat O
urine O
and O
faeces O
by O
liquid O
chromatography O
coupled O
with O
triple O
quadrupole O
mass O
spectrometry O
( O
LC O
- O
MS O
/ O
MS O
) O
. O

Ginsenoside B
Re I
( O
200 O
mg O
/ O
kg O
) O
was O
orally O
administered O
to O
rats O
by O
gastric O
intubation O
, O
and O
urine O
and O
faeces O
samples O
were O
then O
collected O
during O
the O
next O
24 O
h O
using O
metabolic O
cages O
. O

Samples O
were O
prepared O
by O
solid O
phase O
extraction O
and O
analysed O
by O
LC O
- O
MS O
/ O
MS O
. O

The O
precursor O
- O
product O
ion O
pairs O
used O
for O
LC O
- O
MS O
/ O
MS O
analysis O
were O
: O
m O
/ O
z O
945 O
- O
- O
> O
475 O
for O
ginsenoside B
Re I
, O
799 O
- O
- O
> O
637 O
for O
ginsenoside B
Rg1 I
, O
783 O
- O
- O
> O
475 O
for O
ginsenoside B
Rg2 I
, O
637 O
- O
- O
> O
475 O
for O
ginsenosides B
Rh1 I
and I
F1 I
, O
475 O
- O
- O
> O
391 O
for O
protopanaxatriol B
, O
and O
779 O
- O
- O
> O
641 O
for O
digoxin B
( O
internal O
standard O
) O
. O

The O
major O
ginsenosides B
excreted O
in O
urine O
were O
ginsenosides B
Re I
and I
Rg1 I
, O
and O
only O
minimal O
amounts O
of O
ginsenosides B
Rg2 I
and I
Rh1 I
were O
found O
. O

Greater O
amounts O
of O
ginsenoside B
metabolites O
were O
detected O
in O
the O
faeces O
samples O
; O
biotransformation O
to O
ginsenoside B
Rg1 I
was O
predominant O
but O
further O
deglycosylated O
metabolites O
including O
ginsenoside B
F1 I
and O
protopanaxatriol B
were O
additionally O
detected O
. O

The O
total O
recovery O
of O
ginsenosides B
over O
24 O
h O
was O
approximately O
46 O
% O
. O

Characterization O
and O
identification O
of O
the O
chemical O
constituents O
from O
tartary O
buckwheat O
( O
Fagopyrum O
tataricum O
Gaertn O
) O
by O
high O
performance O
liquid O
chromatography O
/ O
photodiode O
array O
detector O
/ O
linear O
ion O
trap O
FTICR O
hybrid O
mass O
spectrometry O
. O

In O
recent O
years O
tartary O
buckwheat O
has O
become O
popular O
healthful O
food O
due O
to O
its O
antioxidant O
, O
antidiabetic O
and O
antitumor O
activities O
. O

However O
, O
its O
chemical O
constituents O
have O
not O
yet O
been O
fully O
characterized O
and O
identified O
. O

In O
this O
paper O
, O
a O
novel O
high O
performance O
liquid O
chromatography O
coupled O
with O
photodiode O
array O
detector O
and O
linear O
ion O
trap O
FTICR O
hybrid O
mass O
spectrometry O
( O
HPLC O
- O
PDA O
/ O
LTQ O
- O
FTICRMS O
) O
method O
was O
established O
to O
characterize O
and O
identify O
a O
total O
of O
36 O
compounds O
by O
a O
single O
run O
. O

The O
retention O
time O
, O
maximum O
UV O
absorption O
wavelength O
, O
accurate O
mass O
weight O
and O
characteristic O
fragment O
ions O
were O
collected O
on O
line O
. O

To O
confirm O
the O
structures O
, O
11 O
compounds O
were O
isolated O
and O
identified O
by O
MS O
and O
NMR O
experiments O
. O

1 B
, I
3 I
, I
6 I
, I
6 I
' I
- I
tetra I
- I
feruloyl I
sucrose I
named O
taroside B
was O
a O
new O
phenlypropanoid B
glycoside I
, O
together O
with O
3 B
, I
6 I
- I
di I
- I
p I
- I
coumaroyl I
- I
1 I
, I
6 I
' I
- I
di I
- I
feruloyl I
sucrose I
, O
1 B
, I
6 I
, I
6 I
' I
- I
tri I
- I
feruloyl I
- I
3 I
- I
p I
- I
coumaroyl I
sucrose I
, O
N B
- I
trans I
- I
feruloyltyramine I
and O
quercetin B
- I
3 I
- I
O I
- I
[ I
beta I
- I
D I
- I
xyloxyl I
- I

( I
1 I
- I
- I
> I
2 I
) I
- I
alpha I
- I
L I
- I
rhamnoside I
] O
were O
isolated O
for O
the O
first O
time O
from O
the O
Fagopyrum O
species O
. O

The O
research O
enriched O
the O
chemical O
information O
of O
tartary O
buckwheat O
. O

Identification O
and O
thermal O
stability O
of O
purple O
- O
fleshed O
sweet O
potato O
anthocyanins B
in O
aqueous O
solutions O
with O
various O
pH O
values O
and O
fruit O
juices O
. O

Thirteen O
anthocyanins B
were O
identified O
in O
the O
purple O
- O
fleshed O
sweet O
potato O
cultivar O
Jihei O
No O
. O
1 O
. O

The O
main O
anthocyanins B
were O
3 B
- I
sophoroside I
- I
5 I
- I
glucoside I
derivatives O
from O
cyanidin B
and O
peonidin B
, O
acylated O
with O
p B
- I
hydroxybenzoic I
acid I
, O
ferulic B
acid I
, O
or O
caffeic B
acid I
. O

A O
unique O
anthocyanin B
, O
delphinidin B
- I
3 I
, I
5 I
- I
diglucoside I
was O
also O
found O
. O

The O
thermal O
stability O
of O
purple O
- O
fleshed O
sweet O
potato O
anthocyanins B
( O
PSPAs O
) O
followed O
a O
first O
- O
order O
kinetics O
model O
. O

Aqueous O
solutions O
with O
various O
pH O
( O
2 O
, O
3 O
, O
4 O
, O
5 O
, O
and O
6 O
) O
and O
fruit O
juices O
( O
apple O
, O
pear O
, O
grapefruit O
, O
orange O
, O
tangerine O
, O
kiwifruit O
, O
and O
lemon O
) O
were O
coloured O
with O
PSPAs O
. O

The O
enrichment O
and O
degradation O
kinetics O
of O
anthocyanins B
in O
these O
matrices O
were O
investigated O
at O
80 O
, O
90 O
, O
and O
100 O
degrees O
C O
. O

A O
higher O
stability O
of O
anthocyanins B
was O
obtained O
in O
aqueous O
solutions O
with O
pH O
3 O
and O
4 O
and O
in O
apple O
and O
pear O
juices O
. O

Moreover O
, O
the O
activation O
energies O
for O
PSPA B
degradation O
in O
aqueous O
solutions O
with O
various O
pH O
and O
fruit O
juices O
ranged O
from O
66 O
. O
56 O
kJ O
/ O
mol O
to O
111 O
. O
57 O
kJ O
/ O
mol O
and O
46 O
. O
76 O
kJ O
/ O
mol O
to O
75 O
. O
68 O
kJ O
/ O
mol O
, O
respectively O
. O

Rapid O
analysis O
of O
sugars B
in O
honey O
by O
processing O
Raman O
spectrum O
using O
chemometric O
methods O
and O
artificial O
neural O
networks O
. O

The O
aim O
of O
this O
study O
was O
to O
quantify O
glucose B
, O
fructose B
, O
sucrose B
and O
maltose B
contents O
of O
honey O
samples O
using O
Raman O
spectroscopy O
as O
a O
rapid O
method O
. O

By O
performing O
a O
single O
measurement O
, O
quantifications O
of O
sugar B
contents O
have O
been O
said O
to O
be O
unaffordable O
according O
to O
the O
molecular O
similarities O
between O
sugar B
molecules O
in O
honey O
matrix O
. O

This O
bottleneck O
was O
overcome O
by O
coupling O
Raman O
spectroscopy O
with O
chemometric O
methods O
( O
principal O
component O
analysis O
( O
PCA O
) O
and O
partial O
least O
squares O
( O
PLS O
) O
) O
and O
an O
artificial O
neural O
network O
( O
ANN O
) O
. O

Model O
solutions O
of O
four O
sugars B
were O
processed O
with O
PCA O
and O
significant O
separation O
was O
observed O
. O

This O
operation O
, O
done O
with O
the O
spectral O
features O
by O
using O
PLS O
and O
ANN O
methods O
, O
led O
to O
the O
discriminant O
analysis O
of O
sugar B
contents O
. O

Models O
/ O
trained O
networks O
were O
created O
using O
a O
calibration O
data O
set O
and O
evaluated O
using O
a O
validation O
data O
set O
. O

The O
correlation O
coefficient O
values O
between O
actual O
and O
predicted O
values O
of O
glucose B
, O
fructose B
, O
sucrose B
and O
maltose B
were O
determined O
as O
0 O
. O
964 O
, O
0 O
. O
965 O
, O
0 O
. O
968 O
and O
0 O
. O
949 O
for O
PLS O
and O
0 O
. O
965 O
, O
0 O
. O
965 O
, O
0 O
. O
978 O
and O
0 O
. O
956 O
for O
ANN O
, O
respectively O
. O

The O
requirement O
of O
rapid O
analysis O
of O
sugar B
contents O
of O
commercial O
honeys O
has O
been O
met O
by O
the O
data O
processed O
within O
this O
article O
. O

Structural O
analysis O
of O
linear O
mixed O
- O
linkage O
glucooligosaccharide O
by O
tandem O
mass O
spectrometry O
. O

Dextrans O
and O
glucooligosaccharide O
( O
GLOS O
) O
are O
produced O
by O
lactic B
acid I
bacteria O
( O
LAB O
) O
during O
sourdough O
fermentation O
. O

The O
dextrans O
can O
act O
as O
hydrocolloids B
in O
sourdough O
bread O
, O
while O
the O
GLOS O
may O
have O
antistaling O
and O
prebiotic O
properties O
, O
depending O
on O
their O
structure O
. O

Development O
of O
high O
- O
throughput O
methods O
for O
screening O
the O
structural O
properties O
of O
dextrans O
and O
GLOS O
produced O
by O
different O
LAB O
in O
varying O
fermentation O
conditions O
is O
therefore O
of O
interest O
. O

In O
this O
study O
we O
explored O
the O
possibility O
of O
using O
electrospray O
ionisation O
tandem O
mass O
spectroscopy O
( O
ESI O
- O
MS O
/ O
MS O
) O
to O
unequivocally O
determine O
the O
structures O
of O
underivatised O
GLOS O
. O

The O
emphasis O
was O
on O
linear O
mixed O
linked O
model O
GLOS O
, O
especially O
those O
containing O
( O
1 O
- O
- O
> O
3 O
) O
linkages O
that O
are O
common O
in O
dextrans O
. O

After O
evaluation O
of O
the O
model O
GLOS O
, O
the O
ESI O
- O
MS O
/ O
MS O
method O
was O
used O
to O
determine O
the O
linkage O
positions O
of O
two O
mixed O
- O
linked O
tetrasaccharides B
obtained O
by O
hydrolysis O
of O
Weissella O
confusa O
and O
Leuconostoc O
citreum O
dextrans O
. O

In O
positive O
mode O
, O
only O
the O
reducing O
end O
linkage O
could O
be O
determined O
because O
isomeric O
fragment O
ions O
, O
present O
in O
subsequent O
MS O
( O
n O
) O
cycles O
, O
hindered O
assignment O
of O
the O
remaining O
linkages O
. O

By O
contrast O
, O
it O
was O
possible O
to O
unambiguously O
assign O
all O
the O
linkages O
in O
each O
GLOS O
using O
the O
negative O
mode O
spectra O
. O

The O
present O
study O
thus O
shows O
that O
negative O
mode O
is O
the O
preferred O
method O
for O
ESI O
- O
MS O
/ O
MS O
structural O
analysis O
of O
underivatised O
GLOS O
. O

In O
combination O
with O
liquid O
chromatography O
this O
method O
will O
enable O
rapid O
profiling O
of O
the O
structural O
variation O
of O
dextrans O
and O
prebiotic O
GLOS O
. O

Accumulation O
of O
heavy O
metals O
in O
edible O
parts O
of O
vegetables O
irrigated O
with O
waste O
water O
and O
their O
daily O
intake O
to O
adults O
and O
children O
, O
District O
Mardan O
, O
Pakistan O
. O

Green O
vegetable O
crops O
irrigated O
with O
wastewater O
are O
highly O
contaminated O
with O
heavy O
metals O
and O
are O
the O
main O
source O
of O
human O
exposure O
to O
the O
contaminants O
. O

In O
this O
study O
accumulation O
of O
eight O
heavy O
metals O
( O
Cu B
, O
Ni B
, O
Zn B
, O
Cr B
, O
Fe B
, O
Mn B
, O
Co B
and O
Pb B
) O
in O
green O
vegetables O
like O
Allium O
cepa O
, O
Allium O
sativum O
, O
Solanum O
lycopersicum O
and O
Solanum O
melongena O
, O
irrigated O
with O
wastewater O
in O
Mardan O
are O
studied O
using O
Atomic O
Absorption O
spectrophotometer O
. O

The O
studied O
metals O
in O
vegetable O
grown O
on O
wastewater O
irrigated O
soil O
were O
significantly O
higher O
than O
those O
of O
tube O
well O
water O
irrigated O
soil O
and O
WHO O
/ O
FAO O
permissible O
limits O
( O
P O
< O
0 O
. O
05 O
) O
. O

The O
most O
heavily O
contaminated O
vegetable O
was O
wastewater O
irrigated O
A O
. O
cepa O
, O
where O
the O
accumulation O
of O
Mn B
( O
28 O
. O
05 O
mg O
kg O
( O
- O
1 O
) O
) O
in O
the O
edible O
parts O
was O
50 O
- O
fold O
greater O
than O
A O
. O
cepa O
irrigated O
with O
tube O
well O
water O
irrigated O
soil O
. O

It O
may O
be O
concluded O
that O
both O
adults O
and O
children O
consuming O
these O
vegetables O
grown O
in O
wastewater O
irrigated O
soil O
ingest O
significant O
amount O
of O
these O
metals O
and O
thus O
can O
cause O
serious O
health O
problems O
. O

Principal O
component O
analysis O
of O
proteolytic O
profiles O
as O
markers O
of O
authenticity O
of O
PDO O
cheeses O
. O

The O
casein O
fraction O
of O
13 O
Portuguese O
PDO O
cheeses O
were O
analysed O
using O
Urea B
- O
PAGE O
and O
reverse O
phase O
- O
high O
performance O
liquid O
chromatography O
( O
RP O
- O
HPLC O
) O
and O
then O
subjected O
to O
chemometric O
evaluation O
. O

The O
chemometric O
techniques O
of O
cluster O
analysis O
( O
CA O
) O
and O
principal O
component O
analysis O
( O
PCA O
) O
were O
used O
for O
the O
classification O
studies O
. O

Peptide O
mapping O
using O
Urea B
- O
PAGE O
followed O
by O
CA O
revealed O
two O
major O
clusters O
according O
to O
the O
similarity O
of O
the O
proteolytic O
profile O
of O
the O
cheeses O
. O

PCA O
results O
were O
in O
accordance O
with O
the O
grouping O
performed O
using O
CA O
. O

CA O
of O
RP O
- O
HPLC O
results O
of O
the O
matured O
cheeses O
revealed O
the O
presence O
of O
one O
major O
cluster O
comprising O
samples O
manufactured O
with O
only O
ovine O
milk O
or O
milk O
admixtures O
. O

When O
the O
results O
of O
CA O
technique O
were O
compared O
with O
the O
two O
PCA O
approaches O
performed O
, O
it O
was O
found O
that O
the O
grouping O
of O
the O
samples O
was O
similar O
. O

Both O
approaches O
, O
revealed O
the O
potential O
of O
proteolytic O
profiles O
( O
which O
is O
an O
essential O
aspect O
of O
cheese O
maturation O
) O
as O
markers O
of O
authenticity O
of O
PDO O
cheeses O
in O
terms O
of O
ripening O
time O
and O
milk O
admixtures O
not O
mentioned O
on O
the O
label O
. O

Isotopic O
analysis O
of O
eggs O
: O
evaluating O
sample O
collection O
and O
preparation O
. O

Egg O
traceability O
/ O
authenticity O
is O
a O
worldwide O
concern O
. O

Stable O
isotope O
techniques O
have O
been O
suggested O
as O
a O
tool O
to O
address O
this O
issue O
. O

To O
further O
validate O
the O
use O
of O
these O
techniques O
, O
a O
research O
project O
was O
undertaken O
to O
evaluate O
what O
effect O
sample O
collection O
and O
preparation O
have O
on O
the O
measured O
isotopic O
composition O
of O
egg O
components O
. O

The O
timing O
of O
egg O
collection O
, O
the O
timing O
of O
egg O
preparation O
after O
collection O
, O
and O
the O
use O
of O
pasteurisation O
were O
investigated O
. O

The O
C B
, O
N B
, O
O B
, O
and O
S B
isotopic O
compositions O
of O
egg O
components O
from O
7 O
different O
production O
systems O
were O
measured O
. O

Two O
sets O
of O
eggs O
were O
collected O
( O
4 O
months O
apart O
) O
. O

It O
was O
found O
that O
the O
' O
isotopic O
fingerprint O
' O
of O
a O
particular O
production O
system O
was O
maintained O
over O
time O
, O
and O
that O
it O
may O
be O
possible O
to O
trace O
liquid O
egg O
products O
based O
on O
isotopic O
data O
from O
fresh O
eggs O
. O

The O
findings O
from O
this O
study O
support O
the O
integration O
of O
stable O
isotope O
techniques O
in O
egg O
traceability O
/ O
authenticity O
systems O
. O

The O
application O
of O
Near O
- O
Infrared O
Reflectance O
Spectroscopy O
( O
NIRS O
) O
to O
detect O
melamine B
adulteration O
of O
soya O
bean O
meal O
. O

Soya O
bean O
products O
are O
used O
widely O
in O
the O
animal O
feed O
industry O
as O
a O
protein O
based O
feed O
ingredient O
and O
have O
been O
found O
to O
be O
adulterated O
with O
melamine B
. O

This O
was O
highlighted O
in O
the O
Chinese O
scandal O
of O
2008 O
. O

Dehulled O
soya O
( O
GM O
and O
non O
- O
GM O
) O
, O
soya O
hulls O
and O
toasted O
soya O
were O
contaminated O
with O
melamine B
and O
spectra O
were O
generated O
using O
Near O
Infrared O
Reflectance O
Spectroscopy O
( O
NIRS O
) O
. O

By O
applying O
chemometrics O
to O
the O
spectral O
data O
, O
excellent O
calibration O
models O
and O
prediction O
statistics O
were O
obtained O
. O

The O
coefficients O
of O
determination O
( O
R O
( O
2 O
) O
) O
were O
found O
to O
be O
0 O
. O
89 O
- O
0 O
. O
99 O
depending O
on O
the O
mathematical O
algorithm O
used O
, O
the O
data O
pre O
- O
processing O
applied O
and O
the O
sample O
type O
used O
. O

The O
corresponding O
values O
for O
the O
root O
mean O
square O
error O
of O
calibration O
and O
prediction O
were O
found O
to O
be O
0 O
. O
081 O
- O
0 O
. O
276 O
% O
and O
0 O
. O
134 O
- O
0 O
. O
368 O
% O
, O
respectively O
, O
again O
depending O
on O
the O
chemometric O
treatment O
applied O
to O
the O
data O
and O
sample O
type O
. O

In O
addition O
, O
adopting O
a O
qualitative O
approach O
with O
the O
spectral O
data O
and O
applying O
PCA O
, O
it O
was O
possible O
to O
discriminate O
between O
the O
four O
samples O
types O
and O
also O
, O
by O
generation O
of O
Cooman O
' O
s O
plots O
, O
possible O
to O
distinguish O
between O
adulterated O
and O
non O
- O
adulterated O
samples O
. O

Detection O
of O
pyrrolizidine B
alkaloids I
in O
commercial O
honey O
using O
liquid O
chromatography O
- O
ion O
trap O
mass O
spectrometry O
. O

Pyrrolizidine B
alkaloids I
( O
PAs B
) O
are O
known O
secondary O
plant O
metabolites O
which O
can O
cause O
hepatotoxicity O
in O
both O
humans O
and O
livestock O
. O

PAs O
can O
be O
consumed O
through O
the O
use O
of O
plants O
for O
food O
, O
medicinal O
purposes O
and O
as O
contaminants O
of O
agricultural O
crops O
and O
food O
. O

PA O
contaminated O
grain O
has O
posed O
the O
largest O
health O
risk O
, O
although O
any O
PA O
contamination O
in O
our O
food O
chain O
should O
be O
recognised O
as O
a O
potential O
health O
threat O
. O

For O
this O
purpose O
, O
retail O
honeys O
were O
tested O
by O
LC O
- O
MS O
/ O
MS O
. O

The O
method O
allows O
for O
specific O
identification O
of O
toxic O
retronecine B
and O
otonecine B
- O
type O
PAs O
by O
comparison O
to O
reference O
compounds O
via O
a O
spectral O
library O
. O

In O
total O
, O
50 O
honey O
samples O
were O
matched O
to O
the O
reference O
spectra O
within O
a O
set O
of O
tolerance O
parameters O
. O

Accurate O
data O
analysis O
and O
quick O
detection O
of O
positive O
samples O
was O
possible O
. O

Positive O
samples O
contained O
an O
average O
PA O
concentration O
of O
1260 O
mu O
g O
kg O
( O
- O
1 O
) O
of O
honey O
. O

Good O
linear O
calibrations O
were O
obtained O
( O
R O
( O
2 O
) O
> O
0 O
. O
991 O
) O
. O

LOD O
and O
LOQ O
ranged O
from O
0 O
. O
0134 O
to O
0 O
. O
0305 O
and O
0 O
. O
0446 O
to O
0 O
. O
1018 O
mu O
g O
mL O
( O
- O
1 O
) O
, O
respectively O
. O

Endocrine O
disruptor O
activity O
in O
bottled O
mineral O
and O
flavoured O
water O
. O

A O
panel O
of O
reporter O
gene O
assays O
( O
RGAs O
) O
coupled O
with O
a O
single O
solid O
phase O
extraction O
( O
SPE O
) O
step O
was O
developed O
and O
used O
to O
screen O
bottled O
mineral O
water O
for O
the O
presence O
of O
four O
classes O
of O
endocrine O
disruptors O
( O
EDs O
) O
, O
oestrogens B
, O
androgens B
, O
progestagens B
and O
glucocorticoids O
. O

Fourteen O
brands O
of O
bottled O
mineral O
water O
in O
triplicate O
( O
42 O
samples O
) O
were O
analysed O
. O

Overall O
, O
hormonal O
activity O
was O
found O
in O
78 O
% O
of O
the O
samples O
. O

Oestrogenic O
, O
androgenic O
, O
progestagenic O
and O
glucocorticoid O
activity O
was O
found O
in O
38 O
% O
, O
38 O
% O
, O
36 O
% O
and O
55 O
% O
of O
the O
samples O
, O
respectively O
at O
an O
average O
concentration O
of O
10 O
ng O
/ O
l O
17 B
beta I
- I
estradiol I
equivalent O
( O
EEQ O
) O
, O
26 O
ng O
/ O
l O
testosterone B
equivalent O
( O
TEQ O
) O
, O
123 O
ng O
/ O
l O
progesterone B
equivalent O
( O
PEQ O
) O
and O
13 O
. O
5 O
ng O
/ O
l O
hydrocortisone B
equivalent O
( O
HEQ O
) O
. O

The O
level O
of O
oestrogenic O
, O
androgenic O
and O
progestagenic O
activity O
observed O
is O
not O
considered O
a O
matter O
of O
concern O
for O
the O
consumers O
' O
health O
. O

It O
is O
unknown O
whether O
the O
glucocorticoid O
levels O
observed O
are O
safe O
. O

The O
ED O
source O
, O
long O
term O
exposure O
and O
mixture O
effects O
remain O
to O
be O
investigated O
. O

Comparison O
of O
consumer O
perception O
and O
acceptability O
for O
steaks O
cooked O
to O
different O
endpoints O
: O
validation O
of O
photographic O
approach O
. O

Photographs O
have O
been O
used O
to O
enhance O
consumer O
reporting O
of O
preference O
of O
meat O
doneness O
, O
however O
, O
the O
use O
of O
photographs O
has O
not O
been O
validated O
for O
this O
purpose O
. O

This O
study O
used O
standard O
cooking O
methods O
to O
produce O
steaks O
of O
five O
different O
degrees O
of O
doneness O
( O
rare O
medium O
, O
medium O
well O
, O
well O
done O
and O
very O
well O
done O
) O
to O
study O
the O
consumer O
' O
s O
perception O
of O
doneness O
, O
from O
both O
the O
external O
and O
internal O
surface O
of O
the O
cooked O
steak O
and O
also O
from O
corresponding O
photographs O
of O
each O
sample O
. O

Consumers O
evaluated O
each O
surface O
of O
the O
cooked O
steaks O
in O
relation O
to O
doneness O
for O
acceptability O
, O
' O
just O
about O
right O
' O
and O
perception O
of O
doneness O
. O

Data O
were O
analysed O
using O
a O
split O
plot O
ANOVA O
and O
least O
significant O
test O
. O

Perception O
scores O
( O
for O
both O
external O
and O
internal O
surfaces O
) O
between O
different O
presentation O
methods O
( O
steak O
samples O
and O
corresponding O
photos O
) O
, O
were O
not O
significantly O
different O
( O
p O
> O
0 O
. O
05 O
) O
. O

The O
result O
indicates O
that O
photographs O
can O
be O
used O
as O
a O
valid O
approach O
for O
assessing O
preference O
for O
meat O
doneness O
. O

Chrysin B
suppresses O
renal O
carcinogenesis O
via O
amelioration O
of O
hyperproliferation O
, O
oxidative O
stress O
and O
inflammation O
: O
plausible O
role O
of O
NF O
- O
kappa O
B O
. O

Flavonoid B
family O
is O
a O
rich O
source O
of O
polyphenolic B
compounds O
and O
hence O
possess O
strong O
antioxidant O
and O
anti O
inflammatory O
properties O
. O

The O
aim O
of O
this O
study O
was O
to O
determine O
the O
efficacy O
of O
chrysin B
; O
a O
bio O
- O
active O
flavonoid B
as O
an O
anticancer O
agent O
. O

Renal O
cancer O
was O
initiated O
by O
single O
intraperitoneal O
( O
i O
. O
p O
. O
) O
injection O
of O
N B
- I
nitrosodiethylamine I
( O
DEN B
200 O
mg O
/ O
kg O
BW O
body O
weight O
) O
and O
promoted O
by O
twice O
weekly O
administration O
of O
ferric B
nitrilotriacetate I
( O
Fe B
- I
NTA I
) O
9 O
mg O
Fe B
/ O
kg O
BW O
for O
16 O
wk O
. O

In O
the O
present O
study O
, O
we O
report O
the O
chemopreventive O
effects O
of O
chrysin B
against O
( O
Fe B
- I
NTA I
) O
induced O
renal O
oxidative O
stress O
, O
inflammation O
, O
hyperproliferative O
response O
, O
and O
two O
- O
stage O
renal O
carcinogenesis O
. O

To O
ascertain O
the O
molecular O
mechanism O
implicated O
in O
the O
antitumor O
promoting O
activity O
of O
chrysin B
, O
its O
effect O
was O
investigated O
on O
markers O
of O
tumor O
promotion O
and O
inflammation O
: O
ornithine B
decarboxylase O
( O
ODC O
) O
activity O
, O
proliferating O
cell O
nuclear O
antigen O
( O
PCNA O
) O
, O
inducible O
nitric B
oxide I
synthase O
( O
iNOS O
) O
and O
cyclo O
- O
oxygenase O
- O
2 O
( O
COX O
- O
2 O
) O
expression O
, O
and O
on O
levels O
of O
proinflammatory O
cytokines O
interleukin O
- O
6 O
( O
IL O
- O
6 O
) O
, O
tumor O
necrosis O
factor O
- O
alpha O
( O

TNF O
- O
alpha O
) O
, O
and O
prostaglandin B
E I
( I
2 I
) I
( O
PGE B
( I
2 I
) I
) O
. O

Pretreatment O
of O
animals O
with O
chrysin B
at O
both O
doses O
( O
20 O
and O
40 O
mg O
/ O
kg O
body O
weight O
) O
markedly O
inhibited O
all O
. O

Further O
, O
Fe B
- I
NTA I
enhances O
renal O
lipid O
peroxidation O
, O
with O
concomitant O
reduction O
in O
reduced B
glutathione I
content O
( O
GSH B
) O
, O
antioxidant O
enzymes O
, O
and O
phase O
II O
metabolizing O
enzymes O
. O

It O
induces O
serum O
toxicity O
markers O
, O
viz O
. O
, O
blood O
urea B
nitrogen B
( O
BUN O
) O
, O
creatinine B
and O
lactate B
dehydrogenase O
( O
LDH O
) O
. O

Prophylactic O
treatment O
of O
animals O
with O
chrysin B
before O
the O
administration O
of O
Fe B
- O
NTA B
was O
effective O
in O
modulating O
oxidative O
and O
renal O
injury O
markers O
and O
resulted O
in O
the O
diminution O
of O
Fe B
- O
NTA B
mediated O
injury O
. O

These O
results O
suggest O
chrysin B
as O
an O
effective O
chemopreventive O
agent O
having O
the O
capability O
to O
obstruct O
DEN B
initiated O
and O
Fe B
- I
NTA I
promoted O
renal O
cancer O
in O
the O
rat O
model O
. O

Effect O
of O
blood O
- O
retinal O
barrier O
development O
on O
formation O
of O
selenite B
nuclear O
cataract O
in O
rat O
. O

Selenite B
cataract O
, O
as O
an O
experimental O
animal O
model O
of O
nuclear O
cataract O
to O
mimic O
human O
senile O
cataract O
, O
is O
produced O
only O
when O
overdose O
selenite B
is O
injected O
to O
neonatal O
rats O
before O
eyelid O
opening O
. O

To O
clarify O
the O
cause O
of O
age O
differences O
on O
selenite B
cataract O
formation O
in O
rats O
, O
mRNA O
expression O
of O
GPx1 O
, O
MsrA O
and O
MsrB1 O
, O
as O
well O
as O
GPx O
activity O
in O
Wistar O
rat O
lens O
at O
different O
ages O
were O
assayed O
, O
level O
of O
lipid O
peroxidation O
, O
extent O
of O
lens O
damage O
induced O
by O
sodium B
selenite I
and O
barricade O
function O
of O
blood O
- O
retinal O
barrier O
( O
BRB O
) O
were O
investigated O
. O

The O
results O
showed O
that O
mRNA O
expressions O
and O
activity O
of O
antioxidant O
enzymes O
in O
neonatal O
rat O
lens O
before O
eyelid O
opening O
were O
the O
highest O
and O
then O
decreased O
with O
age O
, O
and O
revealed O
by O
transmission O
electron O
microscopy O
( O
TEM O
) O
using O
lanthanum B
hydroxide I
as O
tracer O
that O
higher O
selenite B
content O
entering O
eyes O
injured O
lens O
and O
resulted O
in O
cataract O
formation O
for O
immature O
BRB O
before O
eyelid O
opening O
, O
moreover O
, O
a O
little O
selenite B
content O
entering O
eyes O
was O
not O
enough O
to O
induce O
cataract O
formation O
after O
eyelid O
opening O
because O
of O
mature O
BRB O
. O

The O
cucurbitacins B
E I
, I
D I
and I
I I
: O
investigation O
of O
their O
cytotoxicity O
toward O
human O
chondrosarcoma O
SW O
1353 O
cell O
line O
and O
their O
biotransformation O
in O
man O
liver O
. O

Cucurbitacins B
are O
a O
class O
of O
natural O
compounds O
known O
for O
their O
numerous O
potential O
pharmacological O
effects O
. O

The O
purpose O
of O
this O
work O
was O
to O
compare O
the O
cytotoxicity O
of O
three O
cucurbitacins B
I I
, I
D I
, I
E I
on O
the O
chondrosarcoma O
SW O
1353 O
cancer O
cell O
line O
and O
to O
investigate O
their O
biotransformation O
in O
man O
. O

Cucurbitacins B
I I
and I
D I
showed O
a O
very O
strong O
cytotoxicity O
, O
which O
was O
higher O
than O
that O
of O
cytochalasin B
D I
, O
used O
as O
a O
drug O
reference O
. O

Almost O
100 O
% O
of O
the O
cells O
were O
apoptotic O
as O
observed O
by O
DNA O
fragmentation O
( O
TUNEL O
assay O
) O
after O
12 O
h O
with O
cucurbitacins B
I I
and I
D I
( O
1 O
mu O
M O
) O
and O
cucurbitacin B
E I
( O
10 O
mu O
M O
) O
. O

In O
terms O
of O
IC O
( O
50 O
) O
values O
, O
cucurbitacins B
I I
and I
E I
presented O
a O
higher O
toxicity O
compared O
to O
that O
of O
cucurbitacin B
D I
( O
MTT B
assay O
) O
. O

Cucurbitacin B
E I
was O
readily O
hydrolyzed O
by O
human O
hepatic O
microsomes O
, O
leading O
to O
cucurbitacin B
I I
( O
K O
( O
m O
) O
22 O
mu O
M O
, O
V O
( O
max O
) O
571 O
nmol O
/ O
mg O
proteins O
/ O
min O
) O
. O

On O
the O
other O
hand O
, O
the O
three O
cucurbitacins B
were O
hydroxylated O
at O
a O
very O
low O
extent O
, O
but O
they O
were O
sulfated O
and O
glucuronidated O
. O

In O
terms O
of O
V O
( O
max O
) O
/ O
K O
( O
m O
) O
, O
the O
cucurbitacin B
E I
was O
the O
best O
substrate O
of O
UDP B
- O
glucuronosyltransfer O
. O

This O
study O
shows O
that O
cucurbitacins B
I I
, I
D I
and I
E I
present O
a O
potent O
cytotoxic O
activity O
toward O
the O
chondrosarcoma O
SW O
1353 O
cell O
line O
and O
are O
metabolized O
as O
sulfate B
and O
glucuronide O
conjugates O
. O

alpha O
C O
helix O
displacement O
as O
a O
general O
approach O
for O
allosteric O
modulation O
of O
protein O
kinases O
. O

Owing O
to O
their O
crucial O
role O
in O
the O
modulation O
of O
cell O
pathways O
, O
protein O
kinases O
are O
important O
targets O
for O
several O
human O
diseases O
, O
including O
but O
not O
limited O
to O
cancer O
. O

The O
classic O
approach O
of O
targeting O
the O
ATP B
active O
site O
has O
recently O
come O
up O
against O
selectivity O
issues O
, O
which O
can O
be O
considerably O
reduced O
by O
following O
an O
allosteric O
modulation O
approach O
. O

Being O
closely O
related O
to O
protein O
kinase O
inactivation O
, O
allosteric O
targeting O
via O
displacement O
of O
the O
conserved O
structural O
alpha O
C O
helix O
enables O
a O
direct O
and O
specific O
modulation O
mechanism O
. O

A O
structure O
- O
based O
survey O
of O
the O
allosteric O
regulation O
of O
alpha O
C O
helix O
conformation O
in O
various O
kinase O
families O
is O
provided O
, O
highlighting O
key O
allosteric O
pockets O
and O
modulation O
mechanisms O
that O
appear O
to O
be O
more O
broadly O
conserved O
than O
was O
previously O
thought O
. O

Increased O
protein O
kinase O
A O
type O
I O
alpha O
regulatory O
subunit O
expression O
in O
parathyroid O
gland O
adenomas O
of O
patients O
with O
primary O
hyperparathyroidism O
. O

Protein O
kinase O
A O
( O
PKA O
) O
regulatory O
subunit O
type O
I O
alpha O
( O
RI O
alpha O
) O
is O
a O
major O
regulatory O
subunit O
that O
functions O
as O
an O
inhibitor O
of O
PKA O
kinase O
activity O
. O

We O
have O
previously O
demonstrated O
that O
elevated O
RI O
alpha O
expression O
is O
associated O
with O
diffuse O
- O
to O
- O
nodular O
transformation O
of O
hyperplasia O
in O
parathyroid O
glands O
of O
renal O
hyperparathyroidism O
. O

The O
aim O
of O
the O
current O
study O
was O
to O
determine O
whether O
or O
not O
RI O
alpha O
expression O
is O
increased O
in O
adenomas O
of O
primary O
hyperparathyroidism O
( O
PHPT O
) O
, O
because O
monoclonal O
proliferation O
has O
been O
demonstrated O
in O
both O
adenomas O
and O
nodular O
hyperplasia O
. O

Surgical O
specimens O
comprising O
22 O
adenomas O
and O
11 O
normal O
glands O
, O
obtained O
from O
22 O
patients O
with O
PHPT O
, O
were O
analyzed O
. O

Western O
blot O
and O
immunohistochemical O
analyses O
were O
employed O
to O
evaluate O
RI O
alpha O
expression O
. O

PKA O
activities O
were O
determined O
in O
several O
adenomas O
highly O
expressing O
RI O
alpha O
. O

RI O
alpha O
expression O
was O
also O
separately O
evaluated O
in O
chief O
and O
oxyphilic O
cells O
using O
the O
" O
Allred O
score O
" O
system O
. O

Expression O
of O
proliferating O
cell O
nuclear O
antigen O
( O
PCNA O
) O
, O
a O
proliferation O
marker O
, O
was O
also O
immunohistochemicall O
examined O
. O

Western O
blot O
analysis O
revealed O
that O
5 O
out O
of O
8 O
adenomas O
highly O
expressed O
RI O
alpha O
, O
compared O
with O
normal O
glands O
. O

PKA O
activity O
in O
adenomas O
was O
significantly O
less O
than O
in O
normal O
glands O
. O

Immunohistochemical O
analysis O
further O
demonstrated O
high O
expression O
of O
RI O
alpha O
in O
20 O
out O
of O
22 O
adenomas O
. O

In O
adenomas O
, O
the O
greater O
RI O
alpha O
expression O
and O
more O
PCNA O
positive O
cells O
were O
observed O
in O
both O
chief O
and O
oxyphilic O
cells O
. O

The O
present O
study O
suggested O
that O
high O
RI O
alpha O
expression O
could O
contribute O
to O
monoclonal O
proliferation O
of O
parathyroid O
cells O
by O
impairing O
the O
cAMP B
/ O
PKA O
signaling O
pathway O
. O

Selenium B
( O
Se B
) O
seed O
priming O
induced O
growth O
and O
biochemical O
changes O
in O
wheat O
under O
water O
deficit O
conditions O
. O

Insufficient O
stand O
establishment O
at O
early O
growth O
stages O
in O
wheat O
( O
Triticum O
aestivum O
L O
. O
) O
due O
to O
drought O
stress O
is O
a O
major O
problem O
that O
limits O
overall O
efficiency O
and O
yield O
of O
crop O
. O

Priming O
of O
seed O
is O
an O
effective O
method O
for O
raising O
seed O
performance O
and O
improving O
tolerance O
of O
crops O
to O
abiotic O
stresses O
especially O
drought O
. O

The O
seeds O
of O
two O
local O
wheat O
cultivars O
( O
Kohistan O
- O
97 O
and O
Pasban O
- O
90 O
) O
were O
soaked O
in O
distilled O
water O
or O
sodium B
selenate I
solutions O
of O
25 O
, O
50 O
, O
75 O
, O
and O
100 O
mu O
M O
for O
1 O
/ O
2 O
or O
1 O
h O
at O
25 O
degrees O
C O
and O
later O
re O
- O
dried O
to O
their O
original O
moisture O
levels O
before O
sowing O
. O

One O
- O
hour O
priming O
significantly O
increased O
root O
length O
stress O
tolerance O
index O
, O
dry O
matter O
stress O
tolerance O
index O
, O
and O
total O
biomass O
of O
seedlings O
; O
however O
, O
no O
significant O
effect O
of O
changing O
duration O
of O
Se B
seed O
priming O
was O
observed O
on O
plant O
height O
stress O
tolerance O
index O
and O
shoot O
/ O
root O
ratio O
. O

Among O
cultivars O
, O
Kohistan O
- O
97 O
was O
found O
to O
be O
more O
responsive O
to O
Se B
seed O
treatment O
as O
1 O
h O
priming O
at O
100 O
mu O
M O
significantly O
increased O
its O
total O
biomass O
by O
43 O
% O
as O
compared O
to O
control O
treatment O
. O

Although O
biomass O
of O
seedlings O
was O
not O
affected O
with O
Se B
seed O
priming O
under O
normal O
conditions O
, O
but O
it O
increased O
significantly O
with O
increase O
in O
rates O
of O
Se B
under O
drought O
stress O
conditions O
. O

One O
- O
hour O
priming O
at O
75 O
mu O
M O
increased O
the O
total O
sugar B
content O
and O
total O
free O
amino B
acids I
in O
both O
wheat O
cultivars O
. O

A O
more O
significant O
decrease O
in O
soluble O
proteins O
of O
seedlings O
was O
observed O
by O
1 O
h O
priming O
than O
1 O
/ O
2 O
h O
priming O
under O
drought O
stress O
conditions O
. O

Bisphenol B
A I
inhibits O
voltage O
- O
activated O
Ca B
( I
2 I
+ I
) I
channels O
in O
vitro O
: O
mechanisms O
and O
structural O
requirements O
. O

Bisphenol B
A I
( O
BPA B
) O
, O
a O
high O
volume O
production O
chemical O
compound O
attracts O
growing O
attention O
as O
a O
health O
- O
relevant O
xenobiotic O
in O
humans O
. O

It O
can O
directly O
bind O
to O
hormone O
receptors O
, O
enzymes O
, O
and O
ion O
channels O
to O
become O
biologically O
active O
. O

In O
this O
study O
we O
show O
that O
BPA B
acts O
as O
a O
potent O
blocker O
of O
voltage O
- O
activated O
Ca B
( I
2 I
+ I
) I
channels O
. O

We O
determined O
the O
mechanisms O
of O
block O
and O
the O
structural O
elements O
of O
BPA B
essential O
for O
its O
action O
. O

Macroscopic O
Ba B
( I
2 I
+ I
) I
/ O
Ca B
( I
2 I
+ I
) I
currents O
through O
native O
L O
- O
, O
N O
- O
, O
P O
/ O
Q O
- O
, O
T O
- O
type O
Ca B
( I
2 I
+ I
) I
channels O
in O
rat O
endocrine O
GH O
( O
3 O
) O
cells O
, O
mouse O
dorsal O
root O
ganglion O
neurons O
or O
cardiac O
myocytes O
, O
and O
recombinant O
human O
R O
- O
type O
Ca B
( I
2 I
+ I
) I
channels O
expressed O
in O
human O
embryonic O
kidney O
( O
HEK O
) O
293 O
cells O
were O
rapidly O
and O
reversibly O
inhibited O
by O
BPA B
with O
similar O
potency O
( O
EC O
( O
50 O
) O
values O
: O
26 O
- O
35 O
mu O
M O
) O
. O

Pharmacological O
and O
biophysical O
analysis O
of O
R O
- O
type O
Ca B
( I
2 I
+ I
) I
channels O
revealed O
that O
BPA B
interacts O
with O
the O
extracellular O
part O
of O
the O
channel O
protein O
. O

Its O
action O
does O
not O
require O
intracellular O
signaling O
pathways O
, O
is O
neither O
voltage O
- O
nor O
use O
- O
dependent O
, O
and O
does O
not O
affect O
channel O
gating O
. O

This O
indicates O
that O
BPA B
interacts O
with O
the O
channel O
in O
its O
resting O
state O
by O
directly O
binding O
to O
an O
external O
site O
outside O
the O
pore O
- O
forming O
region O
. O

Structure O
- O
effect O
analyses O
of O
various O
phenolic B
and O
bisphenolic B
compounds O
revealed O
that O
1 O
) O
a O
double O
- O
alkylated O
( O
R I
- I
C I
( I
CH I
( I
3 I
) I
) I
( I
2 I
) I
- I
R I
, O
R B
- I
C I
( I
CH I
( I
3 I
) I
) I
( I
CH I
( I
2 I
) I
CH I
( I
3 I
) I
) I
- I
R I
) O
, O
or O
double O
- O
trifluoromethylated O
sp O
( O
3 O
) O
- O
hybridized O
carbon B
atom O
between O
the O
two O
aromatic O
rings O
and O
2 O
) O
the O
two O
aromatic O
moieties O
in O
angulated O
orientation O
are O
optimal O
for O
BPA B
' O
s O
effectiveness O
. O

Since O
BPA B
highly O
pollutes O
the O
environment O
and O
is O
incorporated O
into O
the O
human O
organism O
, O
our O
data O
may O
provide O
a O
basis O
for O
future O
studies O
relevant O
for O
human O
health O
and O
development O
. O

Electronic O
size O
effects O
in O
three O
- O
dimensional O
nanostructures O
. O

We O
show O
that O
bismuth B
nanostructures O
form O
three O
- O
dimensional O
patterns O
governed O
by O
two O
- O
dimensional O
electronic O
effects O
. O

Scanning O
tunneling O
microscopy O
reveals O
that O
both O
the O
vertical O
and O
the O
lateral O
dimensions O
of O
the O
structures O
strongly O
favor O
certain O
values O
and O
that O
the O
preferred O
widths O
are O
substantially O
different O
for O
each O
preferred O
height O
. O

First O
- O
principles O
calculations O
demonstrate O
that O
this O
vertical O
- O
lateral O
correlation O
is O
governed O
by O
the O
Fermi O
surface O
topology O
and O
that O
this O
is O
itself O
sensitively O
dependent O
on O
the O
dimensions O
of O
the O
structure O
. O

Physicochemical O
analysis O
from O
real O
- O
time O
imaging O
of O
liposome O
tubulation O
reveals O
the O
characteristics O
of O
individual O
F O
- O
BAR O
domain O
proteins O
. O

The O
Fer O
- O
CIP4 O
homology O
- O
BAR O
( O
F O
- O
BAR O
) O
domain O
, O
which O
was O
identified O
as O
a O
biological O
membrane O
- O
deforming O
module O
, O
has O
been O
reported O
to O
transform O
lipid O
bilayer O
membranes O
into O
tubules O
. O

However O
, O
details O
of O
the O
tubulation O
process O
, O
the O
mechanism O
, O
and O
the O
properties O
of O
the O
generated O
tubules O
remain O
unknown O
. O

Here O
, O
we O
successfully O
monitored O
the O
entire O
process O
of O
tubulation O
and O
the O
behavior O
of O
elongated O
tubules O
caused O
by O
four O
different O
F O
- O
BAR O
domain O
family O
proteins O
( O
FBP17 O
, O
CIP4 O
, O
PSTPIP1 O
, O
and O
Pacsin2 O
) O
using O
direct O
real O
- O
time O
imaging O
of O
giant O
unilamellar O
liposomes O
with O
dark O
- O
field O
optical O
microscopy O
. O

FBP17 O
and O
CIP4 O
develop O
many O
protrusions O
simultaneously O
over O
the O
entire O
surface O
of O
individual O
liposomes O
, O
whereas O
PSTPIP1 O
and O
Pacsin2 O
develop O
only O
a O
few O
protrusions O
from O
a O
narrow O
restricted O
part O
of O
the O
surface O
of O
individual O
liposomes O
. O

Tubules O
formed O
by O
FBP17 O
or O
CIP4 O
have O
higher O
bending O
rigidities O
than O
those O
formed O
by O
PSTPIP1 O
or O
Pacsin2 O
. O

The O
results O
provide O
striking O
evidence O
that O
these O
four O
F O
- O
BAR O
domain O
family O
proteins O
should O
be O
classified O
into O
two O
groups O
: O
one O
group O
of O
FBP17 O
and O
CIP4 O
and O
another O
group O
of O
PSTPIP1 O
and O
Pacsin2 O
. O

This O
classification O
is O
consistent O
with O
the O
phylogenetic O
proximity O
among O
these O
proteins O
and O
suggests O
that O
the O
nature O
of O
the O
respective O
tubulation O
is O
associated O
with O
biological O
function O
. O

These O
findings O
aid O
in O
the O
quantitative O
assessment O
with O
respect O
to O
manipulating O
the O
morphology O
of O
lipid O
bilayers O
using O
membrane O
- O
deforming O
proteins O
. O

Polymethoxyflavones B
as O
agents O
that O
prevent O
formation O
of O
cataract O
: O
nobiletin B
congeners O
show O
potent O
growth O
inhibitory O
effects O
in O
human O
lens O
epithelial O
cells O
. O

Posterior O
capsular O
opacification O
( O
PCO O
) O
is O
the O
most O
frequent O
complication O
and O
the O
primary O
reason O
for O
visual O
decrease O
after O
extracapsular O
cataract O
surgery O
. O

The O
proliferation O
and O
migration O
of O
leftover O
lens O
epithelial O
cells O
( O
LECs O
) O
after O
surgery O
may O
contribute O
to O
the O
development O
of O
PCO O
. O

To O
prevent O
PCO O
, O
a O
rational O
approach O
would O
be O
to O
inhibit O
both O
the O
proliferation O
and O
the O
migration O
of O
LECs O
using O
nontoxic O
xenobiotics O
. O

Nobiletin B
, O
one O
of O
the O
most O
abundant O
polymethoxyflavones B
( O
PMFs B
) O
in O
citrus O
peel O
, O
and O
its O
synthetic O
congeners O
displayed O
a O
potent O
inhibition O
of O
LEC O
proliferation O
. O

Structural O
features O
which O
enhance O
anti O
- O
proliferative O
activity O
have O
also O
been O
discussed O
. O

Structural O
studies O
on O
matrices O
of O
deacylated O
gellan O
with O
polydextrose B
. O

The O
effect O
of O
varying O
concentrations O
of O
co O
- O
solute O
( O
polydextrose B
) O
on O
thermomechanical O
and O
physicochemical O
properties O
of O
deacylated O
gellan O
matrices O
is O
presented O
. O

Modulated O
differential O
scanning O
calorimetry O
, O
micro O
differential O
scanning O
calorimetry O
, O
small O
deformation O
dynamic O
oscillation O
in O
shear O
, O
Fourier O
transform O
infrared O
spectroscopy O
, O
wide O
angle O
X O
- O
ray O
diffraction O
and O
environmental O
scanning O
electron O
microscopy O
have O
been O
used O
to O
investigate O
the O
structural O
transformations O
in O
aqueous O
, O
low O
- O
solid O
and O
condensed O
systems O
. O

There O
was O
a O
rise O
in O
values O
of O
storage O
modulus O
as O
the O
level O
of O
co O
- O
solute O
was O
increased O
, O
followed O
by O
a O
significant O
decline O
at O
intermediate O
concentrations O
, O
with O
high O
modulus O
values O
being O
regained O
as O
more O
of O
the O
co O
- O
solute O
was O
incorporated O
. O

These O
results O
confirm O
the O
hypothesis O
of O
a O
structural O
transformation O
from O
a O
highly O
enthalpic O
aggregated O
assembly O
in O
the O
aqueous O
/ O
low O
- O
solid O
environment O
to O
a O
lightly O
cross O
linked O
polysaccharide O
network O
in O
the O
high O
solids O
regime O
. O

Time O
- O
temperature O
superposition O
( O
TTS O
) O
phenomena O
observed O
for O
amorphous O
synthetic O
polymers O
have O
been O
utilised O
to O
generate O
master O
curves O
of O
viscoelasticity O
, O
which O
afforded O
rationalisation O
of O
results O
on O
the O
basis O
of O
the O
free O
volume O
theory O
. O

Determination O
of O
lead O
in O
milk O
and O
yoghurt O
samples O
by O
solid O
phase O
extraction O
using O
a O
novel O
aminothioazole B
- O
polymeric O
resin O
. O

A O
preconcentration O
method O
was O
developed O
by O
using O
a O
new O
aminothioazole B
- O
containing O
sulfonamide B
resin O
in O
solid O
phase O
extraction O
for O
the O
determination O
of O
lead O
and O
nickel B
in O
milk O
and O
yoghurt O
samples O
. O

The O
optimisation O
of O
experimental O
conditions O
was O
performed O
. O

The O
optimum O
parameters O
for O
Pb B
and O
Ni B
were O
found O
to O
be O
3 O
. O
5 O
, O
30 O
min O
and O
2 O
. O
5 O
mL O
for O
pH O
, O
contact O
time O
, O
eluate O
volume O
, O
respectively O
. O

After O
preconcentration O
step O
, O
atomic O
absorption O
spectrometry O
was O
used O
for O
the O
determinations O
. O

The O
enhancement O
of O
350 O
- O
and O
50 O
- O
fold O
in O
the O
sensitivity O
of O
Pb B
and O
Ni B
were O
achieved O
by O
combination O
of O
the O
slotted O
tube O
atom O
trap O
- O
atomic O
absorption O
spectrometry O
with O
the O
optimised O
preconcentration O
method O
, O
respectively O
. O

Limits O
of O
detection O
were O
found O
to O
be O
0 O
. O
15 O
ng O
mL O
- O
( O
1 O
) O
for O
Pb B
and O
0 O
. O
75 O
ng O
mL O
- O
( O
1 O
) O
for O
Ni B
. O

The O
lead O
concentrations O
in O
the O
studied O
samples O
were O
found O
to O
be O
in O
the O
range O
of O
15 O
- O
61 O
ng O
Pb B
mL O
- O
( O
1 O
) O
for O
milk O
and O
21 O
- O
42 O
ng O
Pb B
g O
- O
( O
1 O
) O
for O
yoghurt O
samples O
. O

Sitosterol B
as O
an O
antioxidant O
in O
frying O
oils O
. O

The O
antioxidative O
effect O
of O
sitosterol B
at O
1 O
, O
2 O
and O
5 O
% O
levels O
, O
in O
triolein B
, O
refined O
canola O
, O
high O
oleic O
sunflower O
and O
flaxseed O
oils O
, O
continuously O
heated O
for O
a O
period O
of O
up O
to O
72 O
h O
at O
frying O
temperature O
of O
180 O
degrees O
C O
, O
was O
studied O
. O

High O
Pressure O
Size O
Exclusion O
Chromatography O
( O
HPSEC O
) O
was O
used O
to O
monitor O
changes O
in O
peak O
areas O
of O
triacylglycerol B
( O
TG O
) O
polymer O
, O
monomer O
and O
ester B
hydrolysis O
products O
. O

The O
presence O
of O
enhanced O
levels O
of O
sitosterol B
was O
found O
to O
significantly O
decrease O
TG O
polymer O
formation O
in O
triolein B
and O
the O
vegetable O
oil O
samples O
after O
heating O
at O
180 O
degrees O
C O
for O
a O
period O
of O
72 O
h O
. O

A O
corresponding O
increase O
in O
the O
level O
of O
intact O
TG O
monomer O
and O
the O
extent O
of O
TG O
ester B
hydrolysis O
was O
observed O
in O
all O
samples O
with O
enhanced O
levels O
of O
sitosterol B
. O

Conversion O
of O
sterol B
to O
steradiene B
, O
by O
the O
1 O
, O
2 O
elimination O
of O
water O
, O
may O
be O
responsible O
for O
the O
antioxidative O
effect O
of O
sitosterol B
at O
frying O
temperatures O
. O

Identification O
of O
high O
beta O
- O
glucan O
oat O
lines O
and O
localization O
and O
chemical O
characterization O
of O
their O
seed O
kernel O
beta O
- O
glucans O
. O

Oat O
, O
( O
Avena O
sativa O
) O
is O
an O
excellent O
source O
of O
mixed O
linkage O
beta O
- O
glucans O
( O
( O
1 O
- O
- O
> O
3 O
) O
( O
1 O
- O
- O
> O
4 O
) O
- O
beta O
- O
D O
- O
glucan O
) O
, O
a O
dietary O
fibre O
with O
cholesterol B
lowering O
properties O
. O

Using O
a O
mutagenized O
oat O
- O
population O
we O
screened O
1700 O
different O
lines O
and O
identified O
ten O
lines O
that O
displayed O
beta O
- O
glucan O
levels O
above O
6 O
. O
7 O
% O
and O
10 O
below O
3 O
. O
6 O
% O
. O
The O
extreme O
values O
were O
1 O
. O
8 O
% O
and O
7 O
. O
5 O
% O
. O

We O
chose O
six O
lines O
with O
an O
increased O
- O
and O
four O
lines O
with O
a O
reduced O
beta O
- O
glucan O
content O
for O
further O
study O
. O

By O
longitudinal O
- O
and O
cross O
- O
sections O
of O
seeds O
it O
was O
shown O
that O
localization O
of O
beta O
- O
glucan O
varied O
between O
the O
different O
lines O
. O

In O
addition O
, O
beta O
- O
glucan O
quality O
parameters O
like O
molecular O
weight O
and O
solubility O
were O
also O
determined O
. O

Although O
the O
selection O
was O
designed O
for O
quantitative O
differences O
, O
qualitative O
differences O
between O
the O
beta O
- O
glucans O
from O
the O
different O
lines O
were O
found O
. O

The O
high O
and O
low O
beta O
- O
glucan O
lines O
will O
now O
be O
used O
as O
a O
model O
system O
to O
study O
molecular O
regulation O
of O
beta O
- O
glucan O
biosynthesis O
as O
well O
as O
possible O
links O
between O
fibre O
quality O
and O
biological O
activity O
. O

Geographical O
provenance O
of O
palm O
oil O
by O
fatty B
acid I
and O
volatile O
compound O
fingerprinting O
techniques O
. O

Analytical O
methods O
are O
required O
in O
addition O
to O
administrative O
controls O
to O
verify O
the O
geographical O
origin O
of O
vegetable O
oils O
such O
as O
palm O
oil O
in O
an O
objective O
manner O
. O

In O
this O
study O
the O
application O
of O
fatty B
acid I
and O
volatile O
organic O
compound O
fingerprinting O
in O
combination O
with O
chemometrics O
have O
been O
applied O
to O
verify O
the O
geographical O
origin O
of O
crude O
palm O
oil O
( O
continental O
scale O
) O
. O

For O
this O
purpose O
94 O
crude O
palm O
oil O
samples O
were O
collected O
from O
South O
East O
Asia O
( O
55 O
) O
, O
South O
America O
( O
11 O
) O
and O
Africa O
( O
28 O
) O
. O

Partial O
least O
squares O
discriminant O
analysis O
( O
PLS O
- O
DA O
) O
was O
used O
to O
develop O
a O
hierarchical O
classification O
model O
by O
combining O
two O
consecutive O
binary O
PLS O
- O
DA O
models O
. O

First O
, O
a O
PLS O
- O
DA O
model O
was O
built O
to O
distinguish O
South O
East O
Asian O
from O
non O
- O
South O
East O
Asian O
palm O
oil O
samples O
. O

Then O
a O
second O
model O
was O
developed O
, O
only O
for O
the O
non O
- O
Asian O
samples O
, O
to O
discriminate O
African O
from O
South O
American O
crude O
palm O
oil O
. O

Models O
were O
externally O
validated O
by O
using O
them O
to O
predict O
the O
identity O
of O
new O
authentic O
samples O
. O

The O
fatty B
acid I
fingerprinting O
model O
revealed O
three O
misclassified O
samples O
. O

The O
volatile O
compound O
fingerprinting O
models O
showed O
an O
88 O
% O
, O
100 O
% O
and O
100 O
% O
accuracy O
for O
the O
South O
East O
Asian O
, O
African O
and O
American O
class O
, O
respectively O
. O

The O
verification O
of O
the O
geographical O
origin O
of O
crude O
palm O
oil O
is O
feasible O
by O
fatty B
acid I
and O
volatile O
compound O
fingerprinting O
. O

Further O
research O
is O
required O
to O
further O
validate O
the O
approach O
and O
to O
increase O
its O
spatial O
specificity O
to O
country O
/ O
province O
scale O
. O

Fluorescent O
ligands O
for O
adenosine B
receptors O
. O

Interest O
is O
increasing O
in O
developing O
fluorescent O
ligands O
for O
characterization O
of O
adenosine B
receptors O
( O
ARs O
) O
, O
which O
hold O
a O
promise O
of O
usefulness O
in O
the O
drug O
discovery O
process O
. O

The O
size O
of O
a O
strategically O
labeled O
AR O
ligand O
can O
be O
greatly O
increased O
after O
the O
attachment O
of O
a O
fluorophore O
. O

The O
choice O
of O
dye O
moiety O
( O
e O
. O
g O
. O
Alexa B
Fluor I
488 I
) O
, O
attachment O
point O
and O
linker O
length O
can O
alter O
the O
selectivity O
and O
potency O
of O
the O
parent O
molecule O
. O

Fluorescent O
derivatives O
of O
adenosine B
agonists O
and O
antagonists O
( O
e O
. O
g O
. O
XAC O
and O
other O
heterocyclic O
antagonist O
scaffolds O
) O
have O
been O
synthesized O
and O
characterized O
pharmacologically O
. O

Some O
are O
useful O
AR O
probes O
for O
flow O
cytometry O
, O
fluorescence O
correlation O
spectroscopy O
, O
fluorescence O
microscopy O
, O
fluorescence O
polarization O
, O
fluorescence O
resonance O
energy O
transfer O
, O
and O
scanning O
confocal O
microscopy O
. O

Thus O
, O
the O
approach O
of O
fluorescent O
labeled O
GPCR O
ligands O
, O
including O
those O
for O
ARs O
, O
is O
a O
growing O
dynamic O
research O
field O
. O

Investigating O
the O
binding O
interactions O
of O
galantamine B
with O
beta O
- O
amyloid O
peptide O
. O

The O
anti O
- O
Alzheimer O
' O
s O
agent O
galantamine B
is O
known O
to O
possess O
anti O
- O
amyloid O
properties O
. O

However O
the O
exact O
mechanisms O
are O
not O
clear O
. O

We O
studied O
the O
binding O
interactions O
of O
galantamine B
with O
amyloid O
peptide O
dimer O
( O
A O
beta O
( O
1 O
- O
40 O
) O
) O
through O
molecular O
docking O
and O
molecular O
dynamics O
simulations O
. O

Galantamine B
' O
s O
binding O
site O
within O
the O
amyloid O
peptide O
dimer O
was O
identified O
by O
docking O
experiments O
and O
the O
most O
stable O
complex O
was O
analyzed O
by O
molecular O
dynamics O
simulation O
. O

These O
studies O
show O
that O
galantamine B
was O
interacting O
with O
the O
central O
region O
of O
the O
amyloid O
dimer O
( O
Lys16 B
- O
Ala21 B
) O
and O
the O
C B
- O
terminal O
region O
( O
Ile31 B
- O
Val36 B
) O
with O
minimum O
structural O
drift O
of O
C O
alpha O
atom O
in O
those O
regions O
. O

Strikingly O
, O
a O
significant O
drift O
was O
observed O
at O
the O
turn O
region O
from O
Asp23 B
- O
Gly29 B
( O
C O
alpha O
atom O
RMSD O
= O
9 O
. O
2 O
A O
and O
11 O
. O
6 O
A O
at O
50 O
fs O
and O
100 O
fs O
respectively O
) O
. O

Furthermore O
, O
galantamine B
' O
s O
binding O
mode O
disrupts O
the O
key O
pi O
- O
pi O
stacking O
interaction O
between O
aromatic O
rings O
of O
Phe19 B
( O
chain O
A O
) O
and O
Phe19 B
( O
chain O
B O
) O
and O
intermolecular O
hydrogen B
bonds O
seen O
in O
unbound O
peptide O
dimer O
. O

Noticeably O
, O
the O
azepine B
tertiary B
nitrogen I
of O
galantamine B
was O
in O
close O
proximity O
to O
backbone O
CO B
of O
Leu34 B
( O
distance O
< O
3 O
. O
5 O
A O
) O
to O
stabilize O
the O
dimer O
conformation O
. O

In O
summary O
, O
the O
results O
indicate O
that O
galantamine B
binding O
to O
amyloid O
peptide O
dimer O
leads O
to O
a O
significant O
conformational O
change O
at O
the O
turn O
region O
( O
Asp23 B
- O
Gly29 B
) O
that O
disrupts O
interactions O
between O
individual O
beta O
- O
strands O
and O
promotes O
a O
nontoxic O
conformation O
of O
A O
beta O
( O
1 O
- O
40 O
) O
to O
prevent O
the O
formation O
of O
neurotoxic O
oligomers O
. O

Detection O
of O
designer O
steroid B
methylstenbolone B
in O
" O
nutritional O
supplement O
" O
using O
gas O
chromatography O
and O
tandem O
mass O
spectrometry O
: O
elucidation O
of O
its O
urinary O
metabolites O
. O

The O
use O
of O
" O
nutritional O
supplements O
" O
containing O
unapproved O
substances O
has O
become O
a O
regular O
practice O
in O
amateur O
and O
professional O
athletes O
. O

This O
represents O
a O
dangerous O
habit O
for O
their O
health O
once O
no O
data O
about O
toxicological O
or O
pharmacological O
effects O
of O
these O
supplements O
are O
available O
. O

Most O
of O
them O
are O
freely O
commercialized O
online O
and O
any O
person O
can O
buy O
them O
without O
medical O
surveillance O
. O

Usually O
, O
the O
steroids B
intentionally O
added O
to O
the O
" O
nutritional O
supplements O
" O
are O
testosterone B
analogues O
with O
some O
structural O
modifications O
. O

In O
this O
study O
, O
the O
analyzed O
product O
was O
bought O
online O
and O
a O
new O
anabolic O
steroid O
known O
as O
methylstenbolone B
( O
2 B
, I
17 I
alpha I
- I
dimethyl I
- I
17 I
beta I
- I
hydroxy I
- I
5 I
alpha I
- I
androst I
- I
1 I
- I
en I
- I
3 I
- I
one I
) O
was O
detected O
, O
as O
described O
on O
label O
. O

Generally O
, O
anabolic O
steroids O
are O
extensively O
metabolized O
, O
thus O
in O
- O
depth O
knowledge O
of O
their O
metabolism O
is O
mandatory O
for O
doping O
control O
purposes O
. O

For O
this O
reason O
, O
a O
human O
excretion O
study O
was O
carried O
out O
with O
four O
volunteers O
after O
a O
single O
oral O
dose O
to O
determine O
the O
urinary O
metabolites O
of O
the O
steroid B
. O

Urine O
samples O
were O
submitted O
to O
enzymatic O
hydrolysis O
of O
glucuconjugated O
metabolites O
followed O
by O
liquid O
- O
liquid O
extraction O
and O
analysis O
of O
the O
trimethylsilyl B
derivatives O
by O
gas O
chromatography O
coupled O
to O
tandem O
mass O
spectrometry O
. O

Mass O
spectrometric O
data O
allowed O
the O
proposal O
of O
two O
plausible O
metabolites O
: O
2 B
, I
17 I
alpha I
- I
dimethyl I
- I
16 I
xi I
, I
17 I
beta I
- I
dihydroxy I
- I
5 I
alpha I
- I
androst I
- I
1 I
- I
en I
- I
3 I
- I
one I
( O
S1 O
) O
, O
2 B
, I
17 I
alpha I
- I
dimethyl I
- I
3 I
alpha I
, I
16 I
xi I
, I
17 I
beta I
- I
trihydroxy I
- I
5 I
alpha I
- I
androst I
- I
1 I
- I
ene I
( O
S2 O
) O
. O

Their O
electron O
impact O
mass O
spectra O
are O
compatible O
with O
16 B
- I
hydroxylated I
steroids I
O B
- I
TMS I
derivatives O
presenting O
diagnostic O
ions O
such O
as O
m O
/ O
z O
231 O
and O
m O
/ O
z O
218 O
. O

These O
metabolites O
were O
detectable O
after O
one O
week O
post O
administration O
while O
unchanged O
methylstenbolone B
was O
only O
detectable O
in O
a O
brief O
period O
of O
45 O
h O
. O

Tigecycline B
prevents O
LPS O
- O
induced O
release O
of O
pro O
- O
inflammatory O
and O
apoptotic O
mediators O
in O
neuronal O
cells O
. O

Pro O
- O
inflammatory O
and O
pro O
- O
apoptotic O
mediators O
have O
been O
involved O
in O
the O
pathogenesis O
of O
neurodegenerative O
diseases O
. O

Tigecycline B
( O
Tig B
) O
, O
a O
glycylcycline B
antibiotic O
and O
an O
analog O
of O
Minocycline B
, O
is O
shown O
to O
exert O
anti O
- O
inflammatory O
effects O
that O
are O
distinct O
from O
its O
anti O
- O
microbial O
activity O
. O

Its O
neuroprotective O
mechanism O
is O
unknown O
. O

In O
this O
study O
, O
we O
investigated O
the O
direct O
protective O
mechanisms O
of O
tigecycline B
against O
lipopolysaccharide O
( O
LPS O
) O
- O
induced O
Rat O
pheochromocytoma O
( O
PC12 O
) O
cells O
. O

The O
results O
showed O
that O
tigecycline B
significantly O
attenuated O
the O
expression O
and O
the O
release O
of O
nuclear O
factor O
- O
kappa O
beta O
( O
NF O
- O
kappa O
B O
) O
, O
tumor O
necrosis O
factor O
- O
alpha O
( O
TNF O
- O
alpha O
) O
and O
interleukin O
- O
1beta O
( O
IL O
- O
1 O
beta O
) O
, O
as O
well O
as O
nitric B
oxide I
( O
NO B
) O
levels O
in O
LPS O
- O
induced O
PC12 O
cells O
. O

In O
addition O
, O
tigecycline B
dose O
- O
dependently O
decreased O
cytochrome O
c O
release O
and O
caspase O
- O
3 O
activity O
. O

This O
later O
finding O
corroborated O
the O
results O
of O
decreased O
pro O
- O
apoptotic O
Bad O
, O
and O
increased O
anti O
- O
apoptotic O
Bcl O
- O
2 O
protein O
expression O
thus O
, O
confirming O
a O
neuroprotective O
effect O
of O
the O
drug O
in O
differentiated O
PC12 O
cells O
induced O
with O
LPS O
. O

The O
findings O
of O
our O
study O
suggest O
new O
targets O
for O
tigecycline B
and O
support O
the O
potential O
for O
tigecycline B
to O
be O
investigated O
as O
a O
therapeutic O
agent O
for O
neurodegenerative O
disorders O
. O

Bradykinetic O
alcohol B
dehydrogenases O
make O
yeast O
fitter O
for O
growth O
in O
the O
presence O
of O
allyl B
alcohol I
. O

Previous O
studies O
showed O
that O
fitter O
yeast O
( O
Saccharomyces O
cerevisiae O
) O
that O
can O
grow O
by O
fermenting O
glucose B
in O
the O
presence O
of O
allyl B
alcohol I
, O
which O
is O
oxidized O
by O
alcohol B
dehydrogenase O
I O
( O
ADH1 O
) O
to O
toxic O
acrolein B
, O
had O
mutations O
in O
the O
ADH1 O
gene O
that O
led O
to O
decreased O
ADH O
activity O
. O

These O
yeast O
may O
grow O
more O
slowly O
due O
to O
slower O
reduction O
of O
acetaldehyde B
and O
a O
higher O
NADH B
/ O
NAD B
( I
+ I
) I
ratio O
, O
which O
should O
decrease O
the O
oxidation O
of O
allyl B
alcohol I
. O

We O
determined O
steady O
- O
state O
kinetic O
constants O
for O
three O
yeast O
ADHs O
with O
new O
site O
- O
directed O
substitutions O
and O
examined O
the O
correlation O
between O
catalytic O
efficiency O
and O
growth O
on O
selective O
media O
of O
yeast O
expressing O
six O
different O
ADHs O
. O

The O
H15R O
substitution O
( O
a O
test O
for O
electrostatic O
effects O
) O
is O
on O
the O
surface O
of O
ADH O
and O
has O
small O
effects O
on O
the O
kinetics O
. O

The O
H44R O
substitution O
( O
affecting O
interactions O
with O
the O
coenzyme O
pyrophosphate B
) O
was O
previously O
shown O
to O
decrease O
affinity O
for O
coenzymes O
2 O
- O
4 O
- O
fold O
and O
turnover O
numbers O
( O
V O
/ O
Et O
) O
by O
4 O
- O
6 O
- O
fold O
. O

The O
W82R O
substitution O
is O
distant O
from O
the O
active O
site O
, O
but O
decreases O
turnover O
numbers O
by O
5 O
- O
6 O
- O
fold O
, O
perhaps O
by O
effects O
on O
protein O
dynamics O
. O

The O
E67Q O
substitution O
near O
the O
catalytic O
zinc B
was O
shown O
previously O
to O
increase O
the O
Michaelis O
constant O
for O
acetaldehyde B
and O
to O
decrease O
turnover O
for O
ethanol B
oxidation O
. O

The O
W54R O
substitution O
, O
in O
the O
substrate O
binding O
site O
, O
increases O
kinetic O
constants O
( O
Ks O
, O
by O
> O
10 O
- O
fold O
) O
while O
decreasing O
turnover O
numbers O
by O
2 O
- O
7 O
- O
fold O
. O

Growth O
of O
yeast O
expressing O
the O
different O
ADHs O
on O
YPD O
plates O
( O
yeast O
extract O
, O
peptone O
and O
dextrose B
) O
plus O
antimycin B
to O
require O
fermentation O
, O
was O
positively O
correlated O
with O
the O
log O
of O
catalytic O
efficiency O
for O
the O
sequential O
bi O
reaction O
( O
V1 O
/ O
KiaKb O
= O
KeqV2 O
/ O
KpKiq O
, O
varying O
over O
4 O
orders O
of O
magnitude O
, O
adjusted O
for O
different O
levels O
of O
ADH O
expression O
) O
in O
the O
order O
: O
WT O
= O
~ O
H15R O
> O
H44R O
> O
W82R O
> O
E67Q O
> O
W54R O
. O

Growth O
on O
YPD O
plus O
10mM O
allyl B
alcohol I
was O
inversely O
correlated O
with O
catalytic O
efficiency O
. O

The O
fitter O
yeast O
are O
" O
bradytrophs O
" O
( O
slow O
growing O
) O
because O
the O
ADHs O
have O
decreased O
catalytic O
efficiency O
. O

Oligochitosan O
polyplexes O
as O
carriers O
for O
retinal B
gene O
delivery O
. O

Non O
- O
viral O
gene O
therapy O
represents O
a O
promising O
approach O
for O
the O
treatment O
of O
retinal O
diseases O
. O

However O
, O
the O
lack O
of O
an O
efficient O
carrier O
hampers O
the O
implementation O
of O
this O
therapy O
. O

In O
this O
study O
, O
we O
evaluated O
low O
molecular O
weight O
ultrapure O
oligochitosans O
for O
the O
delivery O
of O
the O
pCMS O
- O
EGFP O
plasmid O
into O
the O
rat O
retina O
cells O
after O
subretinal O
and O
intravitreal O
administrations O
. O

Polyplexes B
were O
technologically O
characterized O
. O

Resulting O
polyplexes O
based O
on O
ultrapure O
oligochitosans O
were O
slightly O
spherical O
, O
protected O
the O
plasmid O
against O
enzymatic O
digestion O
, O
and O
their O
charge O
and O
size O
values O
ranged O
from O
8 O
to O
14 O
millivolts O
and O
from O
150 O
to O
69 O
nm O
respectively O
depending O
on O
the O
N O
/ O
P O
ratio O
. O

In O
HEK O
- O
293 O
cultured O
cells O
, O
transfection O
efficiency O
significantly O
increased O
from O
12 O
% O
to O
30 O
% O
when O
pH O
decreased O
from O
7 O
. O
4 O
to O
7 O
. O
1 O
( O
data O
normalized O
to O
Lipofectamine O
( O
TM O
) O
2000 O
) O
. O

However O
, O
no O
significant O
transfection O
was O
detected O
in O
ARPE O
- O
19 O
cultured O
cells O
. O

Subretinal O
administrations O
transfected O
mainly O
the O
pigmented O
cells O
of O
the O
retinal O
pigment O
epithelium O
and O
the O
light O
sensitive O
photoreceptor O
cells O
, O
whereas O
intravitreal O
injections O
transfected O
cells O
in O
the O
ganglion O
cell O
layer O
, O
blood O
vessels O
in O
the O
inner O
layers O
of O
the O
retina O
and O
photoreceptors O
. O

These O
results O
support O
the O
potential O
use O
of O
oligochitosans O
for O
delivering O
genetic O
material O
into O
retinal O
cells O
in O
vivo O
. O

Effect O
of O
volume O
ratio O
of O
ultrafiltrate O
to O
sample O
solution O
on O
the O
analysis O
of O
free O
drug O
and O
measurement O
of O
free O
carbamazepine B
in O
clinical O
drug O
monitoring O
. O

Traditional O
ultrafiltration O
( O
UF O
) O
usually O
has O
a O
large O
volume O
ratio O
of O
ultrafiltrate O
to O
sample O
solution O
, O
and O
this O
ratio O
cannot O
be O
well O
controlled O
. O

It O
can O
break O
the O
balance O
of O
protein O
- O
binding O
equilibrium O
and O
exert O
an O
influence O
on O
the O
analysis O
of O
free O
drug O
. O

In O
the O
present O
study O
, O
we O
evaluated O
the O
influence O
of O
volume O
ratio O
of O
ultrafiltrate O
to O
sample O
solution O
on O
the O
analysis O
of O
free O
drug O
in O
human O
plasma O
. O

We O
used O
carbamazepine B
as O
a O
model O
drug O
and O
studied O
the O
effect O
of O
different O
centrifugation O
times O
on O
ultrafitrate O
volume O
and O
the O
related O
effects O
on O
unbound O
carbamazepine B
measurement O
. O

Moreover O
, O
we O
compared O
the O
hollow O
fiber O
centrifugal O
ultrafiltration O
( O
HFCF O
- O
UF O
) O
with O
traditional O
UF O
. O

Our O
results O
showed O
that O
the O
ultrafiltrate O
volume O
was O
changed O
from O
40 O
to O
400 O
mu O
L O
with O
the O
increase O
of O
centrifugation O
time O
for O
the O
traditional O
UF O
, O
and O
the O
related O
changes O
in O
unbound O
concentration O
were O
significant O
. O

The O
rate O
of O
protein O
binding O
( O
BP O
) O
was O
changed O
from O
40 O
% O
to O
70 O
% O
. O

In O
contrast O
, O
a O
tiny O
and O
invariant O
ultrafiltrate O
yield O
( O
40 O
mu O
L O
) O
was O
obtained O
using O
the O
HFCF O
- O
UF O
method O
, O
and O
the O
BP O
rate O
was O
around O
72 O
% O
. O

In O
addition O
, O
with O
the O
HFCF O
- O
UF O
method O
, O
the O
volume O
ratio O
of O
ultrafiltrate O
to O
sample O
solution O
could O
be O
also O
well O
controlled O
by O
the O
inner O
diameters O
of O
both O
the O
glass O
tube O
and O
hollow O
fiber O
. O

The O
HFCF O
- O
UF O
method O
was O
a O
more O
accurate O
plasma O
pretreatment O
procedure O
, O
by O
which O
the O
in O
vivo O
balance O
of O
protein O
- O
binding O
equilibrium O
was O
hardly O
broken O
. O

Therefore O
, O
this O
method O
was O
successfully O
employed O
to O
quantify O
the O
free O
fraction O
of O
carbamazepine B
in O
clinical O
samples O
. O

Determination O
of O
aflatoxins B
, O
deoxynivalenol B
, O
ochratoxin B
A I
and O
zearalenone B
in O
wheat O
and O
oat O
based O
bran O
supplements O
sold O
in O
the O
Spanish O
market O
. O

The O
aflatoxins B
( O
AFs B
) O
, O
deoxynivalenol B
( O
DON B
) O
, O
ochratoxin B
A I
( O
OTA B
) O
and O
zearalenone B
( O
ZEA B
) O
are O
mycotoxins O
produced O
by O
fungal O
species O
which O
can O
contaminate O
, O
alone O
or O
simultaneously O
, O
cereal O
- O
based O
raw O
materials O
. O

Usually O
, O
the O
higher O
mycotoxins O
concentrations O
in O
cereals O
are O
found O
in O
the O
external O
layers O
of O
the O
grain O
( O
bran O
) O
. O

Nowadays O
bran O
is O
increasingly O
consumed O
for O
its O
high O
fibre O
concentration O
. O

The O
objectives O
of O
this O
study O
were O
determining O
the O
concentration O
of O
these O
mycotoxins O
in O
bran O
samples O
intended O
for O
direct O
human O
consumption O
and O
to O
study O
the O
influence O
of O
some O
characteristics O
of O
the O
samples O
that O
may O
affect O
the O
mycotoxins O
content O
, O
there O
are O
not O
studies O
about O
fibre O
for O
direct O
human O
consumption O
. O

67 O
bran O
samples O
from O
shops O
and O
supermarkets O
from O
two O
different O
Spanish O
cities O
were O
analyzed O
, O
being O
37 O
samples O
of O
wheat O
bran O
and O
the O
remaining O
of O
oat O
bran O
. O

The O
results O
showed O
a O
major O
presence O
of O
DON B
in O
the O
analyzed O
samples O
, O
with O
levels O
above O
the O
EU O
legislation O
in O
some O
samples O
. O

Presence O
of O
DON B
was O
more O
frequent O
in O
wheat O
samples O
, O
compared O
to O
oats O
ones O
( O
p O
< O
0 O
. O
05 O
) O
. O

Extruded O
or O
toasted O
samples O
, O
subjected O
to O
a O
heat O
treatment O
during O
processing O
, O
presented O
a O
significantly O
lower O
concentration O
of O
OTA O
, O
and O
differences O
between O
the O
organically O
and O
conventionally O
produced O
samples O
were O
also O
detected O
in O
OTA O
, O
which O
showed O
higher O
levels O
in O
the O
organic O
samples O
. O

Co O
- O
occurrence O
was O
frequently O
found O
between O
the O
Fusarium O
mycotoxins O
( O
ZEA B
and O
DON B
) O
. O

Due O
to O
the O
high O
levels O
of O
DON B
in O
the O
analyzed O
samples O
, O
a O
calculation O
of O
DON B
intake O
has O
been O
made O
and O
it O
has O
been O
demonstrated O
that O
bran O
can O
account O
for O
an O
important O
percentage O
of O
DON B
exposure O
in O
the O
total O
diet O
. O

Phyllanthus O
urinaria O
suppresses O
human O
osteosarcoma O
cell O
invasion O
and O
migration O
by O
transcriptionally O
inhibiting O
u O
- O
PA O
via O
ERK O
and O
Akt O
signaling O
pathways O
. O

Phyllanthus O
urinaria O
is O
widely O
used O
as O
anti O
- O
inflammatory O
, O
antiviral O
, O
antibacterial O
, O
and O
anti O
- O
hepatotoxic O
medicines O
in O
almost O
every O
tropical O
country O
. O

However O
, O
scientific O
evidence O
supporting O
its O
use O
in O
cancer O
metastasis O
is O
limited O
, O
particularly O
osteosarcoma O
. O

We O
investigated O
the O
effect O
of O
P O
. O
urinaria O
extract O
( O
PUE O
) O
on O
cell O
viability O
, O
invasion O
, O
and O
migration O
in O
the O
human O
osteosarcoma O
Saos O
- O
2 O
cell O
line O
, O
and O
looked O
at O
the O
impact O
of O
PUE O
on O
several O
relevant O
proteases O
and O
signaling O
pathways O
. O

This O
study O
demonstrates O
that O
PUE O
, O
at O
a O
range O
of O
concentrations O
( O
from O
0 O
to O
100 O
mu O
g O
/ O
ml O
) O
, O
concentration O
- O
dependently O
inhibited O
the O
migration O
/ O
invasion O
capacities O
of O
Saos O
- O
2 O
without O
cytotoxic O
effects O
. O

Zymographic O
and O
western O
blot O
analyses O
revealed O
that O
PUE O
inhibited O
the O
urokinase O
- O
type O
plasminogen O
activator O
( O
u O
- O
PA O
) O
and O
matrix O
metalloproteinase O
- O
2 O
( O
MMP O
- O
2 O
) O
enzyme O
activity O
, O
as O
well O
as O
protein O
expression O
. O

Western O
blot O
analysis O
also O
showed O
that O
PUE O
inhibits O
phosphorylation O
of O
ERK1 O
/ O
2 O
and O
Akt O
. O

Testing O
of O
mRNA O
level O
, O
quantitative O
real O
- O
time O
PCR O
, O
and O
promoter O
assays O
evaluated O
the O
inhibitory O
effects O
of O
PUE O
on O
u O
- O
PA O
expression O
in O
Saos O
- O
2 O
cells O
. O

The O
chromatin O
immunoprecipitation O
( O
ChIP O
) O
assay O
was O
reactive O
to O
the O
transcription O
protein O
SP O
- O
1 O
, O
which O
was O
inhibited O
by O
PUE O
. O

In O
conclusion O
, O
PUE O
suppresses O
human O
osteosarcoma O
Saos O
- O
2 O
cell O
invasion O
and O
migration O
by O
transcriptionally O
inhibiting O
u O
- O
PA O
via O
ERK O
and O
Akt O
signaling O
pathways O
. O

Therefore O
, O
PUE O
produces O
anti O
- O
metastatic O
activity O
in O
Saos O
- O
2 O
cells O
. O

Chronic O
exposure O
to O
paclobutrazol B
causes O
hepatic O
steatosis O
in O
male O
rockfish O
Sebastiscus O
marmoratus O
and O
the O
mechanism O
involved O
. O

Paclobutrazol B
( O
PBZ B
) O
is O
a O
triazole B
- O
containing O
fungicide O
which O
is O
widely O
used O
in O
agriculture O
. O

Acute O
toxicity O
can O
follow O
its O
extensive O
use O
but O
it O
is O
generally O
weaker O
than O
traditional O
pesticides O
such O
as O
organochlorine B
and O
organophosphorus B
. O

However O
, O
its O
adverse O
effects O
on O
aquatic O
organisms O
need O
to O
be O
investigated O
. O

This O
study O
was O
conducted O
to O
investigate O
the O
effect O
of O
PBZ B
exposure O
on O
the O
hepatic O
lipid O
metabolism O
of O
Sebastiscus O
marmoratus O
. O

After O
PBZ B
exposure O
for O
50 O
days O
, O
hepatic O
lipid O
droplets O
were O
enlarged O
and O
the O
hepatic O
total O
lipid O
, O
triglyceride B
, O
total O
cholesterol B
and O
free O
fatty B
acid I
content O
had O
increased O
in O
a O
dose O
dependent O
manner O
compared O
to O
the O
control O
. O

The O
mRNA O
expression O
of O
lipid O
metabolism O
associated O
genes O
such O
as O
peroxisome O
proliferator O
- O
activated O
receptors O
( O
PPARs O
) O
, O
androgen B
receptor O
, O
acetyl B
- I
CoA I
carboxylase O
1 O
, O
fatty B
acid I
synthesis O
, O
fatty B
acid I
bing O
protein O
4 O
, O
liver O
X O
receptor O
alpha O
( O
LXR O
alpha O
) O
and O
stearoyl B
- I
CoA I
desaturase O
were O
up O
- O
regulated O
by O
PBZ B
exposure O
. O

These O
results O
indicated O
that O
triazole B
- O
containing O
fungicides O
might O
affect O
the O
metabolism O
and O
health O
of O
fish O
via O
the O
multi O
- O
signal O
pathways O
of O
nuclear O
receptors O
such O
as O
PPARs O
and O
LXR O
. O

Hierarchical O
assembly O
of O
ultrathin O
hexagonal O
SnS2 B
nanosheets O
onto O
electrospun O
TiO2 B
nanofibers O
: O
enhanced O
photocatalytic O
activity O
based O
on O
photoinduced O
interfacial O
charge O
transfer O
. O

Well O
- O
designed O
hierarchical O
nanostructures O
with O
one O
dimensional O
( O
1D O
) O
TiO B
( I
2 I
) I
nanofibers O
( O
120 O
- O
350 O
nm O
in O
diameter O
and O
several O
micrometers O
in O
length O
) O
and O
ultrathin O
hexagonal O
SnS B
( I
2 I
) I
nanosheets O
( O
40 O
- O
70 O
nm O
in O
lateral O
size O
and O
4 O
- O
8 O
nm O
in O
thickness O
) O
were O
successfully O
synthesized O
by O
combining O
the O
electrospinning O
technique O
( O
for O
TiO B
( I
2 I
) I
nanofibers O
) O
and O
a O
hydrothermal O
growth O
method O
( O
for O
SnS B
( I
2 I
) I
nanosheets O
) O
. O

The O
single O
- O
crystalline O
SnS B
( I
2 I
) I
nanosheets O
with O
a O
2D O
layered O
structure O
were O
uniformly O
grown O
onto O
the O
electrospun O
TiO B
( I
2 I
) I
nanofibers O
consisted O
of O
either O
anatase O
( O
A O
) O
phase O
or O
anatase O
- O
rutile O
( O
AR O
) O
mixed O
phase O
TiO B
( I
2 I
) I
nanoparticles O
. O

The O
definite O
heterojunction O
interface O
between O
SnS B
( I
2 I
) I
nanosheets O
and O
TiO B
( I
2 I
) I
( O
A O
or O
R O
) O
nanoparticles O
were O
investigated O
by O
high O
resolution O
transmission O
electron O
microscopy O
( O
HRTEM O
) O
and O
X O
- O
ray O
photoelectron O
spectroscopy O
( O
XPS O
) O
. O

Moreover O
, O
the O
as O
- O
prepared O
SnS B
( I
2 I
) I
/ O
TiO B
( I
2 I
) I
hierarchical O
nanostructures O
as O
nanoheterojunction O
photocatalysts O
exhibited O
excellent O
UV O
and O
visible O
light O
photocatalytic O
activities O
for O
the O
degradation O
of O
organic O
dyes O
( O
rhodamine B
B I
and O
methyl B
orange I
) O
and O
phenols B
( O
4 B
- I
nitrophenol I
) O
, O
remarkably O
superior O
to O
the O
TiO B
( I
2 I
) I
nanofibers O
and O
the O
SnS B
( I
2 I
) I
nanosheets O
, O
mainly O
owing O
to O
the O
photoinduced O
interfacial O
charge O
transfer O
based O
on O
the O

photosynergistic O
effect O
of O
the O
SnS B
( I
2 I
) I
/ O
TiO B
( I
2 I
) I
heterojunction O
. O

Significantly O
, O
the O
SnS B
( I
2 I
) I
/ O
TiO B
( I
2 I
) I
( O
AR O
) O
hierarchical O
nanostructures O
as O
the O
tricomponent O
heterojunction O
system O
possessed O
stronger O
photocatalytic O
activity O
than O
the O
bicomponent O
heterojunction O
system O
of O
SnS B
( I
2 I
) I
/ O
TiO B
( I
2 I
) I
( O
A O
) O
hierarchical O
nanostructures O
or O
TiO B
( I
2 I
) I
( O
AR O
) O
nanofibers O
, O
which O
was O
discussed O
in O
terms O
of O
the O
three O
- O
way O
photosynergistic O
effect O
between O
SnS B
( I
2 I
) I
, O
TiO B
( I
2 I

) O
( O
A O
) O
and O
TiO B
( I
2 I
) I
( O
R O
) O
component O
in O
the O
SnS B
( I
2 I
) I
/ O
TiO B
( I
2 I
) I
( O
AR O
) O
heterojunction O
resulting O
in O
the O
high O
separation O
efficiency O
of O
photoinduced O
electron O
- O
hole O
pairs O
, O
as O
evidenced O
by O
photoluminescence O
( O
PL O
) O
and O
surface O
photovoltage O
spectra O
( O
SPS O
) O
. O

Chronic O
arsenic B
exposure O
in O
nanomolar O
concentrations O
compromises O
wound O
response O
and O
intercellular O
signaling O
in O
airway O
epithelial O
cells O
. O

Paracrine O
ATP B
signaling O
in O
the O
lung O
epithelium O
participates O
in O
a O
variety O
of O
innate O
immune O
functions O
, O
including O
mucociliary O
clearance O
, O
bactericide O
production O
, O
and O
as O
an O
initiating O
signal O
in O
wound O
repair O
. O

We O
evaluated O
the O
effects O
of O
chronic O
low O
- O
dose O
arsenic B
relevant O
to O
U O
. O
S O
. O
drinking O
water O
standards O
( O
i O
. O
e O
. O
, O
10 O
ppb O
[ O
130nM O
] O
) O
on O
airway O
epithelial O
cells O
. O

Immortalized O
human O
bronchial O
epithelial O
cells O
( O
16HBE14o O
- O
) O
were O
exposed O
to O
0 O
, O
130 O
, O
or O
330nM O
arsenic B
( O
as O
Na B
- I
arsenite I
) O
for O
4 O
- O
5 O
weeks O
and O
examined O
for O
wound O
repair O
efficiency O
and O
ATP B
- O
mediated O
Ca B
( I
2 I
+ I
) I
signaling O
. O

We O
found O
that O
chronic O
arsenic B
exposure O
at O
these O
low O
doses O
slows O
wound O
repair O
and O
reduces O
ATP B
- O
mediated O
Ca B
( I
2 I
+ I
) I
signaling O
. O

We O
further O
show O
that O
arsenic B
compromises O
ATP B
- O
mediated O
Ca B
( I
2 I
+ I
) I
signaling O
by O
altering O
both O
Ca B
( I
2 I
+ I
) I
release O
from O
intracellular O
stores O
( O
via O
metabotropic O
P2Y O
receptors O
) O
and O
Ca B
( I
2 I
+ I
) I
influx O
mechanisms O
( O
via O
ionotropic O
P2X O
receptors O
) O
. O

To O
better O
model O
the O
effects O
of O
arsenic B
on O
ATP B
- O
mediated O
Ca B
( I
2 I
+ I
) I
signaling O
under O
conditions O
of O
natural O
exposure O
, O
we O
cultured O
tracheal O
epithelial O
cells O
obtained O
from O
mice O
exposed O
to O
control O
or O
50 O
ppb O
Na B
- I
arsenite I
supplemented O
drinking O
water O
for O
4 O
weeks O
. O

Tracheal O
epithelial O
cells O
from O
arsenic B
- O
exposed O
mice O
displayed O
reduced O
ATP B
- O
mediated O
Ca B
( I
2 I
+ I
) I
signaling O
dynamics O
similar O
to O
our O
in O
vitro O
chronic O
exposure O
. O

Our O
findings O
demonstrate O
that O
chronic O
arsenic B
exposure O
at O
levels O
that O
are O
commonly O
found O
in O
drinking O
water O
( O
i O
. O
e O
. O
, O
10 O
- O
50 O
ppb O
) O
alters O
cellular O
mechanisms O
critical O
to O
airway O
innate O
immunity O
. O

Identification O
of O
ginkgolic B
acid I
( O
15 B
: I
1 I
) O
metabolites O
in O
rats O
following O
oral O
administration O
by O
high O
- O
performance O
liquid O
chromatography O
coupled O
to O
tandem O
mass O
spectrometry O
. O

1 O
. O
In O
this O
article O
, O
metabolites O
of O
ginkgolic B
acid I
( O
GA O
) O
( O
15 O
: O
1 O
) O
in O
rats O
plasma O
, O
bile O
, O
urine O
and O
faeces O
after O
oral O
administration O
have O
been O
investigated O
for O
the O
first O
time O
by O
high O
- O
performance O
liquid O
chromatography O
coupled O
to O
tandem O
mass O
spectrometry O
( O
HPLC O
- O
MS O
/ O
MS O
) O
with O
the O
aid O
of O
on O
- O
line O
hydrogen B
/ O
deuterium B
( O
H B
/ O
D B
) O
exchange O
technique O
and O
beta O
- O
glucuronidase O
hydrolysis O
experiments O
. O

2 O
. O
After O
oral O
administration O
of O
GA O
( O
15 O
: O
1 O
, O
M0 O
) O
to O
rats O
at O
a O
dose O
of O
10 O
mg O
/ O
kg O
, O
it O
was O
found O
that O
metabolites O
M1 O
- O
M5 O
together O
with O
parent O
compound O
( O
M0 O
) O
existed O
in O
rat O
plasma O
; O
parent O
compound O
( O
M0 O
) O
and O
metabolites O
M2 O
- O
M5 O
were O
observed O
in O
rat O
bile O
, O
and O
parent O
compound O
( O
M0 O
) O
with O
metabolites O
M1 O
and O
M2 O
were O
discovered O
in O
rat O
faeces O
, O
and O
there O
was O
no O
parent O
compound O
and O
metabolite O
detectable O
in O
rat O
urine O
. O

3 O
. O
Two O
oxidative O
metabolites O
of O
GA O
( O
15 O
: O
1 O
, O
M0 O
) O
were O
identified O
as O
2 B
- I
hydroxy I
- I
6 I
- I
( I
pentadec I
- I
8 I
- I
enyl I
- I
10 I
- I
hydroxy I
) I
benzoic I
acid I
( O
M1 O
) O
and O
2 B
- I
hydroxy I
- I
6 I
- I
( I
pentadec I
- I
8 I
- I
enyl I
- I
11 I
- I
hydroxy I
- I
13 I
- I
carbonyl I
) I
benzoic I
acid I
( O
M2 O
) O
, O
respectively O
. O

Metabolites O
M3 O
, O
M4 O
and O
M5 O
were O
identified O
as O
the O
mono B
- I
glucuronic I
acid I
conjugates O
of O
parent O
compound O
( O
M0 O
) O
, O
M1 O
and O
M2 O
, O
respectively O
. O

4 O
. O
The O
results O
indicated O
that O
M1 O
and O
M2 O
with O
parent O
compound O
( O
M0 O
) O
were O
mainly O
eliminated O
in O
faeces O
and O
three O
glucuronide O
metabolites O
( O
M3 O
, O
M4 O
and O
M5 O
) O
excreted O
in O
bile O
as O
the O
predominant O
forms O
after O
oral O
administration O
of O
GA O
( O
15 O
: O
1 O
) O
to O
rats O
. O

Shear O
modulus O
property O
characterization O
of O
nanorods O
. O

We O
demonstrate O
an O
innovative O
technique O
for O
the O
direct O
measurement O
on O
the O
shear O
modulus O
of O
an O
individual O
nanorod O
. O

This O
measurement O
is O
based O
on O
atomic O
force O
microscopy O
( O
AFM O
) O
and O
microfabrication O
techniques O
. O

A O
nanorod O
is O
first O
aligned O
along O
the O
edge O
of O
a O
small O
trench O
in O
a O
silicon B
substrate O
, O
and O
then O
one O
end O
of O
the O
nanorod O
is O
fixed O
on O
the O
substrate O
. O

When O
an O
AFM O
tip O
scans O
over O
the O
nanorod O
in O
contact O
mode O
, O
the O
nanorod O
will O
be O
twisted O
by O
the O
comprehensive O
action O
from O
the O
force O
of O
the O
AFM O
tip O
, O
confinement O
from O
the O
trench O
edge O
and O
the O
fixing O
end O
. O

The O
shear O
deformation O
and O
the O
corresponding O
force O
that O
caused O
the O
deformation O
can O
be O
retrieved O
from O
topography O
and O
lateral O
force O
image O
, O
respectively O
. O

By O
small O
- O
angle O
approximation O
, O
the O
shear O
modulus O
of O
the O
ZnO B
NR O
, O
which O
has O
a O
radius O
of O
166 O
nm O
and O
a O
length O
of O
4 O
mu O
m O
, O
is O
measured O
to O
be O
8 O
. O
1 O
+ O
/ O
- O
1 O
. O
9 O
GPa O
. O

This O
method O
can O
be O
applied O
directly O
to O
characterize O
the O
shear O
modulus O
of O
any O
nanowire O
/ O
nanorod O
that O
possesses O
a O
polygon O
cross O
section O
. O

From O
an O
atypical O
wake O
- O
promoting O
agent O
to O
potent O
histamine B
- O
3 O
receptor O
inverse O
agonists O
. O

Utilizing O
atypical O
wake O
- O
promoting O
agent O
modafinil B
( O
inactive O
in O
both O
rH O
( O
3 O
) O
and O
hH O
( O
3 O
) O
binding O
assays O
) O
as O
a O
launching O
pad O
, O
a O
series O
of O
sulfinyl B
- O
and O
sulfone I
- O
derived O
H O
( O
3 O
) O
receptor O
inverse O
agonists O
were O
developed O
. O

Brain O
- O
permeable O
compound O
27 O
, O
a O
potent O
member O
of O
the O
series O
displayed O
excellent O
selectivity O
against O
related O
family O
members O
( O
H O
( O
1 O
) O
, O
H O
( O
2 O
) O
, O
and O
H O
( O
4 O
) O
receptors O
) O
. O

YopK O
controls O
both O
rate O
and O
fidelity O
of O
Yop O
translocation O
. O

Yersinia O
pestis O
, O
the O
causative O
agent O
of O
plague O
, O
utilizes O
a O
type O
III O
secretion O
system O
( O
T3SS O
) O
to O
intoxicate O
host O
cells O
. O

The O
injection O
of O
T3SS O
substrates O
must O
be O
carefully O
controlled O
, O
and O
dysregulation O
leads O
to O
altered O
infection O
kinetics O
and O
early O
clearance O
of O
Y O
. O
pestis O
. O

While O
the O
sequence O
of O
events O
leading O
up O
to O
cell O
contact O
and O
initiation O
of O
translocation O
has O
received O
much O
attention O
, O
the O
regulatory O
events O
that O
take O
place O
after O
effector O
translocation O
is O
less O
understood O
. O

Here O
we O
show O
that O
the O
regulator O
YopK O
is O
required O
to O
maintain O
fidelity O
of O
substrate O
specificity O
, O
in O
addition O
to O
controlling O
translocation O
rate O
. O

YopK O
was O
found O
to O
interact O
with O
YopD O
within O
targeted O
cells O
during O
Y O
. O
pestis O
infection O
, O
suggesting O
that O
YopK O
' O
s O
regulatory O
mechanism O
involves O
a O
direct O
interaction O
with O
the O
translocation O
pore O
. O

In O
addition O
, O
we O
identified O
a O
single O
amino B
acid I
in O
YopK O
that O
is O
essential O
for O
translocation O
rate O
regulation O
but O
is O
dispensable O
for O
maintaining O
fidelity O
of O
translocation O
. O

Furthermore O
, O
we O
found O
that O
expression O
of O
YopK O
within O
host O
cells O
was O
sufficient O
to O
downregulate O
translocation O
rate O
, O
but O
it O
did O
not O
affect O
translocation O
fidelity O
. O

Together O
, O
our O
data O
support O
a O
model O
in O
which O
YopK O
is O
a O
bifunctional O
protein O
whose O
activities O
are O
genetically O
and O
spatially O
distinct O
such O
that O
fidelity O
control O
occurs O
within O
bacteria O
and O
rate O
control O
occurs O
within O
host O
cells O
. O

Highly O
efficient O
preparation O
of O
multiscaled O
quantum O
dot O
barcodes O
for O
multiplexed O
hepatitis O
B O
detection O
. O

Both O
disease O
diagnosis O
and O
therapeutic O
treatments O
require O
real O
- O
time O
information O
from O
assays O
capable O
of O
identifying O
multiple O
targets O
. O

Among O
various O
multiplexed O
biochips O
, O
multiplexed O
suspension O
assays O
of O
quantum O
dot O
( O
QD O
) O
- O
encoded O
microspheres O
are O
highly O
advantageous O
. O

This O
arises O
from O
the O
excellent O
fluorescent O
properties O
of O
the O
QDs O
incorporated O
into O
these O
microspheres O
, O
thus O
allowing O
them O
to O
serve O
as O
" O
QD O
barcodes O
" O
. O

QD O
barcodes O
can O
be O
prepared O
through O
various O
approaches O
. O

However O
, O
the O
formulation O
of O
improved O
synthetic O
techniques O
that O
may O
allow O
more O
efficient O
preparation O
of O
QD O
barcodes O
with O
better O
encoding O
accuracy O
still O
remains O
a O
challenge O
. O

In O
this O
report O
, O
we O
describe O
a O
combined O
membrane O
emulsification O
- O
solvent O
evaporation O
( O
MESE O
) O
approach O
for O
the O
efficient O
preparation O
of O
QD O
barcodes O
. O

By O
combining O
the O
advantages O
of O
the O
MESE O
approach O
in O
controlling O
the O
barcode O
sizes O
with O
accurate O
encoding O
, O
a O
three O
- O
dimensional O
barcode O
library O
that O
integrates O
the O
signals O
of O
the O
forward O
scattering O
, O
fluorescence O
1 O
, O
and O
fluorescence O
4 O
channels O
was O
established O
via O
flow O
cytometry O
. O

The O
five O
indexes O
of O
hepatitis O
B O
viruses O
were O
chosen O
as O
diagnostic O
targets O
to O
examine O
the O
feasibility O
of O
the O
QD O
barcodes O
in O
high O
- O
throughput O
diagnosis O
. O

On O
the O
basis O
of O
showing O
that O
singleplex O
detection O
is O
feasible O
, O
we O
demonstrate O
the O
ability O
of O
these O
QD O
barcodes O
to O
simultaneously O
and O
selectively O
detect O
a O
multitude O
of O
diverse O
biomolecular O
targets O
. O

Identification O
of O
a O
novel O
benzimidazole B
derivative O
as O
a O
highly O
potent O
NPY O
Y5 O
receptor O
antagonist O
with O
an O
anti O
- O
obesity O
profile O
. O

Optimization O
of O
HTS O
hit O
1 O
for O
NPY O
Y5 O
receptor O
binding O
affinity O
, O
CYP450 O
inhibition O
, O
solubility O
and O
metabolic O
stability O
led O
to O
the O
identification O
of O
some O
orally O
available O
oxygen B
- O
linker O
derivatives O
for O
in O
vivo O
study O
. O

Among O
them O
, O
derivative O
4i O
inhibited O
food O
intake O
induced O
by O
the O
NPY O
Y5 O
selective O
agonist O
, O
and O
chronic O
oral O
administration O
of O
4i O
in O
DIO O
mice O
caused O
a O
dose O
- O
dependent O
reduction O
of O
body O
weight O
gain O
. O

Testosterone B
positively O
associated O
with O
both O
male O
mating O
effort O
and O
paternal O
behavior O
in O
savanna O
baboons O
( O
Papio O
cynocephalus O
) O
. O

Testosterone B
( O
T O
) O
is O
often O
positively O
associated O
with O
male O
sexual O
behavior O
and O
negatively O
associated O
with O
paternal O
care O
. O

These O
associations O
have O
primarily O
been O
demonstrated O
in O
species O
where O
investment O
in O
paternal O
care O
begins O
well O
after O
mating O
activity O
is O
complete O
, O
when O
offspring O
are O
hatched O
or O
born O
. O

Different O
patterns O
may O
emerge O
in O
studies O
of O
species O
where O
investment O
in O
mating O
and O
paternal O
care O
overlap O
temporally O
, O
for O
instance O
in O
non O
- O
seasonal O
breeders O
in O
which O
males O
mate O
with O
multiple O
females O
sequentially O
and O
may O
simultaneously O
have O
multiple O
offspring O
of O
different O
ages O
. O

In O
a O
9 O
- O
year O
data O
set O
on O
levels O
of O
T O
in O
male O
baboons O
, O
fecal O
concentrations O
of O
T O
( O
fT O
) O
were O
positively O
associated O
with O
both O
mate O
guarding O
( O
" O
consortship O
" O
) O
- O
a O
measure O
of O
current O
reproductive O
activity O
- O
and O
with O
the O
number O
of O
immature O
offspring O
a O
male O
had O
in O
his O
social O
group O
- O
a O
measure O
of O
past O
reproductive O
activity O
and O
an O
indicator O
of O
likely O
paternal O
behavior O
. O

To O
further O
examine O
the O
relationship O
between O
T O
and O
potential O
paternal O
behavior O
, O
we O
next O
drew O
on O
an O
intensive O
8 O
- O
month O
study O
of O
male O
behavior O
, O
and O
found O
that O
fathers O
were O
more O
likely O
to O
be O
in O
close O
proximity O
to O
their O
offspring O
than O
expected O
by O
chance O
. O

Because O
male O
baboons O
are O
known O
to O
provide O
paternal O
care O
, O
and O
because O
time O
in O
proximity O
to O
offspring O
would O
facilitate O
such O
care O
, O
this O
suggests O
that O
T O
concentrations O
in O
wild O
male O
baboons O
may O
be O
associated O
with O
both O
current O
reproductive O
activity O
and O
with O
current O
paternal O
behavior O
. O

These O
results O
are O
consistent O
with O
the O
predicted O
positive O
association O
between O
T O
and O
mating O
effort O
but O
not O
with O
a O
negative O
association O
between O
T O
and O
paternal O
care O
; O
in O
male O
baboons O
, O
high O
levels O
of O
T O
occur O
in O
males O
that O
are O
differentially O
associating O
with O
their O
offspring O
. O

Silexan O
, O
an O
essential O
oil O
from O
flowers O
of O
Lavandula O
angustifolia O
, O
is O
not O
recognized O
as O
benzodiazepine B
- O
like O
in O
rats O
trained O
to O
discriminate O
a O
diazepam B
cue O
. O

Recently O
, O
an O
essential O
oil O
of O
selected O
quality O
produced O
from O
the O
flowering O
tops O
of O
Lavandula O
angustifolia O
Mill O
. O
by O
steam O
distillation O
( O
Silexan O
) O
has O
been O
approved O
in O
Germany O
for O
the O
treatment O
of O
restlessness O
in O
case O
of O
anxious O
mood O
. O

Based O
on O
the O
observed O
clinical O
effects O
, O
it O
has O
been O
speculated O
that O
lavender O
oil O
may O
exert O
benzodiazepine B
- O
like O
action O
including O
the O
known O
dependence O
and O
abuse O
potential O
of O
this O
class O
of O
drugs O
. O

Although O
no O
evidence O
for O
such O
an O
activity O
was O
generated O
during O
the O
long O
- O
standing O
medicinal O
use O
of O
lavender O
oil O
, O
further O
preclinical O
investigations O
were O
now O
conducted O
to O
evaluate O
this O
potential O
side O
effect O
in O
more O
detail O
. O

Twelve O
adult O
, O
male O
, O
Sprague O
- O
Dawley O
rats O
were O
trained O
to O
discriminate O
the O
benzodiazepine B
drug O
diazepam B
( O
2 O
mg O
/ O
kg O
i O
. O
p O
. O
) O
from O
saline O
using O
a O
two O
- O
lever O
operant O
procedure O
. O

After O
approximately O
40 O
training O
sessions O
the O
majority O
of O
rats O
learned O
the O
discrimination O
and O
pre O
- O
treatment O
with O
ascending O
doses O
of O
diazepam B
( O
0 O
. O
3 O
- O
2 O
mg O
/ O
kg O
i O
. O
p O
. O
) O
produced O
a O
dose O
related O
generalization O
to O
the O
diazepam B
cue O
. O

In O
these O
same O
animals O
Silexan O
was O
administered O
to O
see O
if O
animals O
recognized O
the O
drug O
as O
" O
diazepam B
- O
like O
" O
i O
. O
e O
. O
generalized O
to O
diazepam B
or O
" O
saline O
- O
like O
" O
. O

Silexan O
tested O
at O
doses O
3 O
- O
30 O
mg O
/ O
kg O
i O
. O
p O
. O
produced O
almost O
exclusively O
( O
> O
90 O
% O
) O
saline O
- O
like O
responding O
. O

Also O
there O
was O
no O
effect O
of O
Silexan O
on O
response O
rate O
, O
i O
. O
e O
. O
rate O
of O
lever O
pressing O
, O
at O
any O
dose O
suggesting O
that O
the O
test O
article O
is O
well O
tolerated O
and O
does O
not O
exert O
a O
sedating O
effect O
. O

In O
sum O
, O
Silexan O
has O
no O
diazepam B
- O
like O
interoceptive O
property O
in O
adult O
, O
male O
rats O
. O

This O
suggests O
that O
Silexan O
does O
not O
share O
the O
potential O
of O
benzodiazepines B
to O
induce O
the O
development O
of O
tolerance O
, O
dependence O
and O
addiction O
. O

Combination O
of O
phenylpropanoids B
with O
5 B
- I
fluorouracil I
as O
anti O
- O
cancer O
agents O
against O
human O
cervical O
cancer O
( O
HeLa O
) O
cell O
line O
. O

Combination O
therapy O
is O
the O
most O
effective O
treatment O
strategy O
in O
cancer O
to O
overcome O
drug O
toxicity O
and O
drug O
induced O
resistance O
. O

The O
effect O
of O
eight O
phenylpropanoids B
in O
combination O
with O
5 B
- I
fluorouracil I
against O
the O
cervical O
cancer O
cells O
( O
HeLa O
) O
is O
reported O
here O
. O

The O
cytotoxic O
activity O
of O
these O
phenylpropanoids B
against O
HeLa O
cells O
is O
in O
the O
order O
of O
eugenol B
> O
ferulic B
> O
cinnamic B
> O
caffeic B
> O
chlorogenic B
> O
p B
- I
coumaric I
> O
3 B
, I
4 I
- I
dimethoxycinnamic I
> O
2 B
, I
4 I
, I
5 I
- I
trimethoxycinnamic I
acids I
. O

Eugenol B
, O
ferulic B
and I
caffeic I
acids I
interacted O
synergistically O
with O
the O
drug O
, O
in O
bringing O
about O
a O
reduction O
in O
the O
amount O
of O
the O
latter O
. O

Flow O
cytometry O
results O
indicated O
that O
the O
combination O
of O
eugenol B
and O
5 B
- I
fluorouracil I
increased O
the O
number O
of O
cells O
in O
the O
S O
and O
G2 O
/ O
M O
phases O
when O
compared O
to O
treatment O
with O
the O
individual O
compounds O
alone O
. O

This O
indicates O
that O
they O
possess O
different O
cell O
cycle O
targets O
and O
induce O
apoptosis O
in O
the O
cancer O
cells O
. O

In O
vitro O
hemolytic O
activity O
of O
phenylpropanoids B
on O
human O
erythrocytes O
showed O
that O
the O
compounds O
possessed O
minimum O
amount O
of O
hemolytic O
activity O
, O
indicating O
that O
they O
can O
be O
used O
as O
drugs O
without O
causing O
adverse O
toxicity O
. O

3D O
- O
quantitative O
structure O
activity O
relationship O
studies O
indicate O
the O
importance O
of O
electrostatic O
region O
near O
the O
substitutions O
present O
in O
the O
benzene B
ring O
and O
near O
the O
double O
bond O
of O
the O
compounds O
for O
anticancer O
and O
hemolytic O
activities O
, O
respectively O
. O

The O
models O
derived O
had O
good O
statistical O
predictive O
capability O
. O

Understanding O
the O
interactions O
between O
metabolites O
isolated O
from O
Achyrocline O
satureioides O
in O
relation O
to O
its O
antibacterial O
activity O
. O

As O
part O
of O
our O
ongoing O
research O
on O
the O
antibacterial O
activity O
of O
Achyrocline O
satureioides O
, O
this O
study O
seeks O
to O
better O
understand O
the O
interactions O
between O
the O
metabolites O
isolated O
from O
this O
plant O
. O

For O
this O
purpose O
, O
the O
combined O
effect O
of O
23 B
- I
methyl I
- I
6 I
- I
O I
- I
desmethylauricepyron I
( O
1 O
) O
, O
quercetin B
( O
2 O
) O
and O
3 B
- I
O I
- I
methylquercetin I
( O
3 O
) O
, O
obtained O
through O
bioguided O
fractionation O
from O
A O
. O
satureioides O
ethanol B
extract O
, O
was O
evaluated O
against O
Staphylococcus O
aureus O
and O
Escherichia O
coli O
. O

In O
first O
place O
, O
the O
antibacterial O
effect O
of O
the O
combination O
of O
flavonols B
2 O
and O
3 O
was O
assessed O
, O
as O
these O
showed O
individual O
effectiveness O
lower O
than O
or O
equal O
to O
that O
of O
the O
fraction O
from O
which O
they O
were O
obtained O
. O

When O
the O
flavonols B
were O
applied O
together O
at O
concentrations O
below O
their O
minimum O
inhibitory O
concentration O
( O
MIC O
) O
values O
, O
a O
synergistic O
effect O
( O
FICI O
< O
0 O
. O
30 O
) O
against O
S O
. O
aureus O
was O
observed O
. O

In O
addition O
, O
compounds O
2 O
and O
3 O
in O
combination O
reduced O
1000 O
times O
the O
MIC O
of O
compound O
1 O
, O
showing O
a O
clear O
synergistic O
interaction O
( O
FICI O
< O
0 O
. O
15 O
) O
in O
treatments O
against O
the O
Gram O
( O
+ O
) O
bacterium O
. O

The O
most O
active O
combination O
against O
E O
. O
coli O
showed O
an O
additive O
interaction O
( O
FICI O
< O
0 O
. O
62 O
) O
between O
the O
three O
assayed O
compounds O
1 O
- O
3 O
. O

These O
results O
indicated O
the O
existence O
of O
concerted O
action O
between O
these O
metabolites O
, O
evidence O
of O
the O
importance O
of O
the O
synergistic O
interactions O
between O
the O
components O
of O
plant O
- O
derived O
extracts O
for O
the O
control O
of O
pathogenic O
bacteria O
. O

pH O
- O
responsive O
composite O
microspheres O
based O
on O
magnetic O
mesoporous O
silica B
nanoparticle O
for O
drug O
delivery O
. O

pH O
- O
responsive O
composite O
microspheres O
, O
consisting O
of O
a O
core O
of O
Fe3O4 B
nanoparticle O
, O
a O
sandwiched O
layer O
of O
mesoporous O
silica B
and O
a O
shell O
of O
crosslinked O
poly B
( I
methacrylic I
acid I
) I
( O
PMAA B
) O
, O
were O
successfully O
synthesized O
via O
distillation O
precipitation O
polymerization O
. O

The O
pKa O
of O
the O
composite O
microsphere O
increased O
with O
the O
increase O
in O
the O
crosslinking O
density O
. O

Doxorubicin B
hydrochloride I
( O
DOX B
) O
was O
applied O
as O
a O
model O
drug O
, O
and O
the O
behavior O
of O
drug O
storage O
/ O
release O
was O
investigated O
. O

The O
cumulative O
release O
of O
DOX B
- O
loaded O
composite O
microsphere O
in O
vitro O
showed O
that O
the O
drug O
release O
rate O
was O
much O
faster O
below O
its O
pKa O
than O
that O
of O
above O
its O
pKa O
. O

Because O
pH O
of O
most O
tumor O
tissues O
was O
lower O
than O
that O
of O
normal O
tissues O
, O
the O
pH O
- O
responsive O
composite O
microspheres O
are O
promising O
drug O
delivery O
system O
especially O
for O
cancer O
therapy O
. O

Expression O
of O
antagonists O
of O
WNT O
and O
BMP O
signaling O
after O
non O
- O
rigid O
fixation O
of O
osteotomies O
. O

Delayed O
fracture O
healing O
and O
non O
- O
unions O
represent O
rare O
but O
severe O
complications O
in O
orthopedic O
surgery O
. O

Further O
knowledge O
on O
the O
mechanisms O
of O
the O
bone O
repair O
process O
and O
of O
the O
development O
of O
a O
pseudoarthrosis O
is O
essential O
to O
predict O
and O
prevent O
impaired O
healing O
of O
fractures O
. O

The O
present O
study O
aimed O
at O
elucidating O
differences O
in O
gene O
expression O
during O
the O
repair O
of O
rigidly O
and O
non O
- O
rigidly O
fixed O
osteotomies O
. O

For O
this O
purpose O
, O
the O
MouseFix O
( O
TM O
) O
and O
the O
FlexiPlate O
( O
TM O
) O
systems O
( O
AO O
Development O
Institute O
, O
Davos O
, O
CH O
) O
, O
allowing O
the O
creation O
of O
well O
defined O
osteotomies O
in O
mouse O
femora O
, O
were O
employed O
. O

A O
time O
course O
following O
the O
healing O
process O
of O
the O
osteotomy O
was O
performed O
and O
bones O
and O
periimplant O
tissues O
were O
analyzed O
by O
high O
- O
resolution O
X O
- O
ray O
, O
MicroCT O
and O
by O
histology O
. O

For O
the O
assessment O
of O
gene O
expression O
, O
Low O
Density O
Arrays O
( O
LDA O
) O
were O
done O
. O

In O
animals O
with O
rigid O
fixation O
, O
X O
- O
ray O
and O
MicroCT O
revealed O
healing O
of O
the O
osteotomy O
within O
3 O
weeks O
. O

Using O
the O
FlexiPlate O
( O
TM O
) O
system O
, O
the O
osteotomy O
was O
still O
visible O
by O
X O
- O
ray O
after O
3 O
weeks O
and O
a O
stabilizing O
cartilaginous O
callus O
was O
formed O
. O

After O
4 O
. O
5 O
weeks O
, O
the O
callus O
was O
remodeled O
and O
the O
osteotomy O
was O
, O
on O
a O
histological O
level O
, O
healed O
. O

Gene O
expression O
studies O
revealed O
levels O
of O
transcripts O
encoding O
proteins O
associated O
with O
inflammatory O
processes O
not O
to O
be O
altered O
in O
tissues O
from O
bones O
with O
rigid O
and O
non O
- O
rigid O
fixation O
, O
respectively O
. O

Levels O
of O
transcripts O
encoding O
proteins O
of O
the O
extracellular O
matrix O
and O
essential O
for O
bone O
cell O
functions O
were O
not O
increased O
in O
the O
rigidly O
fixed O
group O
when O
compared O
to O
controls O
without O
osteotomy O
. O

In O
the O
FlexiPlate O
( O
TM O
) O
group O
, O
levels O
of O
transcripts O
encoding O
the O
same O
set O
of O
genes O
were O
significantly O
increased O
3 O
weeks O
after O
surgery O
. O

Expression O
of O
transcripts O
encoding O
BMPs O
and O
BMP O
antagonists O
was O
increased O
after O
3 O
weeks O
in O
repair O
tissues O
from O
bones O
fixed O
with O
FlexiPlate O
( O
TM O
) O
, O
as O
were O
inhibitors O
of O
the O
WNT O
signaling O
pathways O
. O

Little O
changes O
only O
were O
detected O
in O
transcript O
levels O
of O
tissues O
from O
rigidly O
fixed O
bones O
. O

The O
data O
of O
the O
present O
study O
suggest O
that O
rigid O
fixation O
enables O
accelerated O
healing O
of O
an O
experimental O
osteotomy O
as O
compared O
to O
non O
- O
rigid O
fixation O
. O

The O
changes O
in O
the O
healing O
process O
after O
non O
- O
rigid O
fixation O
are O
accompanied O
by O
an O
increase O
in O
the O
levels O
of O
transcripts O
encoding O
inhibitors O
of O
osteogenic O
pathways O
and O
, O
probably O
as O
a O
consequence O
, O
by O
temporal O
changes O
in O
bone O
matrix O
synthesis O
. O

Microstructured O
, O
functional O
PVA B
hydrogels O
through O
bioconjugation O
with O
oligopeptides O
under O
physiological O
conditions O
. O

In O
this O
work O
, O
bioconjugation O
techniques O
are O
developed O
to O
achieve O
peptide O
functionalization O
of O
poly B
( I
vinyl I
alcohol I
) I
, O
PVA B
, O
as O
both O
a O
polymer O
in O
solution O
and O
within O
microstructured O
physical O
hydrogels O
, O
in O
both O
cases O
under O
physiological O
conditions O
. O

PVA B
is O
unique O
in O
that O
it O
is O
one O
of O
very O
few O
polymers O
with O
excellent O
biocompatibility O
and O
safety O
and O
has O
FDA O
approval O
for O
clinical O
uses O
in O
humans O
. O

However O
, O
decades O
of O
development O
have O
documented O
only O
scant O
opportunities O
in O
bioconjugation O
with O
PVA B
. O

As O
such O
, O
materials O
derived O
thereof O
fail O
to O
answer O
the O
call O
for O
functional O
biomaterials O
for O
advanced O
cell O
culture O
and O
tissue O
engineering O
applications O
. O

To O
address O
these O
limitations O
, O
PVA B
is O
synthesized O
with O
terminal O
thiol B
groups O
and O
conjugated O
with O
thiolated O
peptides O
using O
PVA B
in O
solution O
. O

Further O
, O
microstructured O
, O
surface O
- O
adhered O
PVA B
physical O
hydrogels O
are O
assembled O
, O
the O
available O
conjugation O
sites O
within O
the O
hydrogels O
are O
quantified O
, O
and O
quantitative O
kinetic O
data O
are O
collected O
on O
peptide O
conjugation O
to O
the O
hydrogels O
. O

The O
success O
of O
bioconjugation O
in O
the O
gel O
phase O
is O
quantified O
through O
the O
use O
of O
a O
cell O
- O
adhesive O
peptide O
and O
visualization O
of O
cell O
adhesion O
on O
PVA B
hydrogels O
as O
cell O
culture O
substrates O
. O

Taken O
together O
, O
the O
presented O
data O
establish O
a O
novel O
paradigm O
in O
bioconjugation O
and O
functionalization O
of O
PVA B
physical O
hydrogels O
. O

Coupled O
with O
an O
excellent O
safety O
profile O
of O
PVA B
, O
these O
results O
deliver O
a O
superior O
biomaterial O
for O
diverse O
biomedical O
applications O
. O

Novel O
Three O
- O
Dimensional O
Nanoporous O
Alumina B
as O
a O
Template O
for O
Hierarchical O
TiO2 B
Nanotube O
Arrays O
. O

Hierarchical O
micro O
- O
/ O
nano O
- O
structures O
made O
easy O
. O

By O
using O
extremely O
rough O
, O
chemically O
etched O
microstructured O
aluminium B
foils O
, O
anodization O
in O
phosphoric B
acid I
under O
very O
harsh O
conditions O
, O
e O
. O
g O
. O
, O
10 O
wt O
% O
phosphoric B
acid I
and O
room O
temperature O
, O
can O
be O
repeatedly O
accomplished O
without O
suffering O
from O
breakdown O
. O

As O
a O
result O
, O
an O
alumina B
membrane O
with O
a O
three O
- O
dimensionally O
distributed O
nanopore O
structure O
is O
formed O
, O
which O
can O
be O
used O
as O
a O
general O
template O
to O
fabricate O
hierarchical O
micro O
- O
/ O
nano O
- O
structures O
. O

Application O
of O
hybrid O
approach O
based O
on O
empirical O
and O
physiological O
concept O
for O
predicting O
pharmacokinetics O
in O
humans O
- O
- O
usefulness O
of O
exponent O
on O
prospective O
evaluation O
of O
predictability O
. O

We O
developed O
a O
hybrid O
method O
for O
predicting O
plasma O
concentration O
- O
time O
curves O
in O
humans O
by O
integrating O
species O
differences O
in O
in O
vitro O
intrinsic O
clearance O
( O
CL O
( O
int O
) O
) O
into O
the O
Dedrick O
approach O
based O
on O
the O
allometry O
concept O
. O

With O
prediction O
of O
clearance O
( O
CL O
) O
by O
allometric O
scaling O
, O
taking O
in O
vitro O
CL O
( O
int O
) O
into O
consideration O
improved O
the O
accuracy O
and O
reduced O
the O
average O
fold O
error O
from O
2 O
. O
72 O
to O
1 O
. O
99 O
. O

With O
the O
hybrid O
approach O
of O
applying O
the O
same O
concept O
to O
the O
Dedrick O
approach O
, O
the O
predictability O
of O
plasma O
concentration O
profiles O
was O
compared O
with O
the O
results O
of O
the O
conventional O
Dedrick O
approach O
and O
the O
physiologically O
based O
pharmacokinetic O
model O
using O
15 O
compounds O
with O
widely O
ranging O
physicochemical O
and O
pharmacokinetic O
profiles O
. O

The O
hybrid O
approach O
showed O
the O
highest O
predictability O
among O
the O
examined O
methods O
. O

For O
CL O
and O
the O
apparent O
volume O
of O
distribution O
at O
the O
steady O
state O
( O
V O
( O
ss O
) O
) O
, O
the O
relationship O
between O
the O
exponent O
of O
allometric O
equation O
and O
fold O
error O
was O
also O
evaluated O
with O
the O
hybrid O
approach O
. O

The O
relationship O
appeared O
to O
be O
a O
horseshoe O
curve O
. O

Six O
compounds O
with O
exponents O
ranging O
from O
0 O
. O
7 O
to O
1 O
. O
1 O
for O
both O
CL O
and O
V O
( O
ss O
) O
[ O
antipyrine B
, O
caffeine B
, O
epiroprim B
, O
propafenone B
, O
theophylline B
, O
and O
verapamil B
] O
displayed O
higher O
predictability O
. O

Three O
compounds O
with O
an O
exponent O
ranging O
from O
0 O
. O
7 O
to O
1 O
. O
1 O
for O
CL O
showed O
better O
predictability O
for O
CL O
, O
and O
the O
other O
four O
compounds O
appeared O
to O
display O
similar O
relationship O
between O
the O
exponent O
and O
predictability O
for O
V O
( O
ss O
) O
. O

These O
findings O
indicated O
that O
the O
exponent O
becomes O
a O
preliminary O
index O
to O
speculate O
on O
predictability O
. O

Combination O
of O
the O
hybrid O
approach O
and O
exponent O
allows O
us O
to O
prospectively O
draw O
human O
plasma O
concentration O
- O
time O
curves O
, O
with O
the O
implication O
of O
possible O
prediction O
accuracy O
prior O
to O
clinical O
studies O
. O

The O
potential O
of O
Sutherlandia O
frutescens O
for O
herb O
- O
drug O
interaction O
. O

In O
Africa O
, O
Sutherlandia O
frutescens O
is O
a O
popular O
medicinal O
herb O
widely O
consumed O
by O
people O
living O
with O
human O
immunodeficiency O
virus O
/ O
AIDS O
. O

Concomitant O
use O
with O
antiretroviral O
drugs O
has O
generated O
concerns O
of O
herb O
- O
drug O
interaction O
( O
HDI O
) O
. O

This O
study O
investigated O
the O
inhibitory O
effects O
of O
the O
crude O
extracts O
of O
S O
. O
frutescens O
on O
the O
major O
cytochrome O
P450 O
isozymes O
with O
the O
use O
of O
pooled O
human O
liver O
microsomes O
. O

Its O
effect O
on O
the O
metabolic O
clearance O
of O
midazolam B
using O
cryopreserved O
hepatocytes O
was O
also O
monitored O
. O

The O
potential O
of O
S O
. O
frutescens O
to O
inhibit O
human O
ATP B
- O
binding O
cassette O
transporters O
( O
P O
- O
gp O
and O
BCRP O
) O
and O
the O
human O
organic O
anion O
transporting O
polypeptide O
( O
OATP1B1 O
and O
OATP1B3 O
) O
activity O
was O
assessed O
using O
cell O
lines O
overexpressing O
the O
transporter O
proteins O
. O

S O
. O
frutescens O
showed O
inhibitory O
potency O
for O
CYP1A2 O
( O
IC O
( O
50 O
) O
= O
41 O
. O
0 O
micro O
g O
/ O
ml O
) O
, O
CYP2A6 O
( O
IC O
( O
50 O
) O
= O
160 O
micro O
g O
/ O
ml O
) O
, O
CYP2B6 O
( O
IC O
( O
50 O
) O
= O
20 O
. O
0 O
micro O
g O
/ O
ml O
) O
, O
CYP2C8 O
( O
IC O
( O
50 O
) O
= O
22 O
. O
4 O
micro O
g O
/ O
ml O
) O
, O
CYP2C9 O
( O
IC O
( O
50 O
) O
= O
23 O
. O
0 O
micro O
g O
/ O
ml O
) O
, O
CYP2C19 O
( O

IC O
( O
50 O
) O
= O
35 O
. O
9 O
micro O
g O
/ O
ml O
) O
, O
and O
CYP3A4 O
/ O
5 O
( O
IC O
( O
50 O
) O
= O
17 O
. O
5 O
micro O
g O
/ O
ml O
[ O
with O
midazolam1 B
' O
- O
hydroxylation O
] O
; O
IC O
( O
50 O
) O
= O
28 O
. O
3 O
micro O
g O
/ O
ml O
[ O
with O
testosterone B
6 O
beta O
- O
hydroxylation O
] O
) O
. O

Time O
- O
dependent O
( O
irreversible O
) O
inhibition O
by O
S O
. O
frutescens O
was O
observed O
for O
CYP3A4 O
/ O
5 O
( O
K O
( O
I O
) O
= O
296 O
micro O
g O
/ O
ml O
, O
k O
( O
inact O
) O
= O
0 O
. O
063 O
min O
( O
- O
1 O
) O
) O
under O
the O
conditions O
of O
this O
study O
. O

S O
. O
frutescens O
also O
delays O
the O
production O
of O
midazolam B
metabolites O
in O
the O
hepatocytes O
, O
decreasing O
its O
clearance O
by O
40 O
% O
. O

Furthermore O
, O
S O
. O
frutescens O
inhibited O
P O
- O
gp O
( O
IC O
( O
50 O
) O
= O
324 O
. O
8 O
micro O
g O
/ O
ml O
) O
, O
OATP1B1 O
( O
IC O
( O
50 O
) O
= O
10 O
. O
4 O
micro O
g O
/ O
ml O
) O
, O
and O
OATP1B3 O
( O
IC O
( O
50 O
) O
= O
6 O
. O
6 O
micro O
g O
/ O
ml O
) O
. O

The O
result O
indicates O
the O
potential O
for O
HDI O
between O
S O
. O
frutescens O
and O
the O
substrates O
of O
the O
affected O
enzymes O
, O
if O
sufficient O
in O
vivo O
concentration O
of O
the O
extract O
is O
attained O
. O

Burial O
of O
the O
polymorphic O
residue O
129 O
in O
amyloid O
fibrils O
of O
prion O
stop O
mutants O
. O

Misfolding O
of O
the O
natively O
alpha O
- O
helical O
prion O
protein O
into O
a O
beta O
- O
sheet O
rich O
isoform O
is O
related O
to O
various O
human O
diseases O
such O
as O
Creutzfeldt O
- O
Jakob O
disease O
and O
Gerstmann O
- O
Str O
a O
ussler O
- O
Scheinker O
syndrome O
. O

In O
humans O
, O
the O
disease O
phenotype O
is O
modified O
by O
a O
methionine B
/ O
valine B
polymorphism O
at O
codon O
129 O
of O
the O
prion O
protein O
gene O
. O

Using O
a O
combination O
of O
hydrogen B
/ O
deuterium B
exchange O
coupled O
to O
NMR O
spectroscopy O
, O
hydroxyl B
radical O
probing O
detected O
by O
mass O
spectrometry O
, O
and O
site O
- O
directed O
mutagenesis O
, O
we O
demonstrate O
that O
stop O
mutants O
of O
the O
human O
prion O
protein O
have O
a O
conserved O
amyloid O
core O
. O

The O
129 O
residue O
is O
deeply O
buried O
in O
the O
amyloid O
core O
structure O
, O
and O
its O
mutation O
strongly O
impacts O
aggregation O
. O

Taken O
together O
the O
data O
support O
a O
critical O
role O
of O
the O
polymorphic O
residue O
129 O
of O
the O
human O
prion O
protein O
in O
aggregation O
and O
disease O
. O

Bioresorbable O
surface O
- O
adhered O
enzymatic O
microreactors O
based O
on O
physical O
hydrogels O
of O
poly B
( I
vinyl I
alcohol I
) I
. O

Hydrogel O
biomaterials O
based O
on O
poly B
( I
vinyl I
alcohol I
) I
, O
PVA B
, O
have O
an O
extensive O
history O
of O
biomedical O
applications O
, O
yet O
in O
their O
current O
form O
suffer O
from O
significant O
shortcomings O
, O
such O
as O
a O
lack O
of O
mechanism O
of O
biodegradation O
and O
poor O
opportunities O
in O
controlled O
drug O
release O
. O

We O
investigate O
physical O
hydrogels O
of O
PVA B
as O
surface O
- O
adhered O
materials O
and O
present O
biodegradable O
matrices O
equipped O
with O
innovative O
tools O
in O
substrate O
- O
mediated O
drug O
release O
. O

Toward O
the O
final O
goal O
, O
PVA B
chains O
with O
narrow O
polydispersities O
( O
1 O
. O
1 O
- O
1 O
. O
2 O
) O
and O
molecular O
weights O
of O
5 O
, O
10 O
, O
and O
28 O
kDa O
are O
synthesized O
via O
controlled O
radical O
polymerization O
( O
RAFT O
) O
. O

These O
molecular O
weights O
are O
shown O
to O
be O
suitably O
high O
to O
afford O
robust O
hydrogel O
matrices O
and O
at O
the O
same O
time O
suitably O
low O
to O
allow O
gradual O
erosion O
of O
the O
hydrogels O
with O
kinetics O
of O
degradation O
controlled O
via O
polymer O
macromolecular O
characteristics O
. O

For O
opportunities O
in O
controlled O
drug O
release O
, O
hydrogels O
are O
equipped O
with O
enzymatic O
cargo O
to O
achieve O
an O
in O
situ O
conversion O
of O
externally O
added O
prodrug O
into O
a O
final O
product O
, O
thus O
giving O
rise O
to O
surface O
- O
adhered O
enzymatic O
microreactors O
. O

Hydrogel O
- O
mediated O
enzymatic O
activity O
was O
investigated O
as O
a O
function O
of O
polymer O
molecular O
weight O
and O
concentration O
of O
solution O
taken O
for O
assembly O
of O
hydrogels O
. O

Taken O
together O
, O
we O
present O
, O
to O
the O
best O
of O
our O
knowledge O
, O
the O
first O
example O
of O
bioresorbable O
physical O
hydrogel O
based O
on O
PVA B
with O
engineered O
opportunities O
in O
substrate O
- O
mediated O
enzymatic O
activity O
and O
envisioned O
utility O
in O
surface O
- O
mediated O
drug O
delivery O
and O
tissue O
engineering O
. O

Catechol B
- O
initiated O
polyethers B
: O
multifunctional O
hydrophilic O
ligands O
for O
PEGylation O
and O
functionalization O
of O
metal B
oxide I
nanoparticles O
. O

Bifunctional O
CA B
- I
PEG I
( O
catechol B
- I
poly I
( I
ethylene I
glycol I
) I
) O
and O
multifunctional O
CA B
- I
PEG I
- I
PGA I
/ O
PEVGE B
( O
poly B
( I
glycidyl I
amine I
) I
/ O
poly B
( I
ethylene I
glycol I
vinyl I
glycidyl I
ether I
) I
) O
ligands O
for O
the O
functionalization O
and O
solubilization O
of O
nanoparticles O
are O
introduced O
. O

Tunable O
polymers O
with O
polydispersities O
< O
1 O
. O
25 O
and O
molecular O
weights O
in O
the O
range O
500 O
- O
7700 O
g O
mol O
( O
- O
1 O
) O
containing O
a O
catechol B
moiety O
for O
conjugation O
to O
metal B
oxide I
nanoparticles O
were O
prepared O
. O

The O
functional O
PEG B
ligands O
were O
synthesized O
starting O
from O
the O
acetonide B
- O
protected O
catechol B
initiator O
2 B
, I
2 I
- I
dimethyl I
- I
1 I
, I
3 I
- I
benzodioxole I
- I
5 I
- I
propanol I
( O
CA B
- I
OH I
) O
for O
oxyanionic O
polymerization O
. O

CA B
- I
OH I
was O
used O
both O
for O
homopolymerization O
of O
ethylene B
oxide I
( O
EO O
) O
as O
well O
as O
copolymerization O
with O
functional O
epoxides B
N B
, I
N I
- I
diallyl I
glycidyl I
amine I
( O
DAGA B
) O
, O
releasing O
primary B
amino I
groups O
and O
ethylene B
glycol I
vinyl I
glycidyl I
ether I
( O
EVGE B
) O
, O
exhibiting O
a O
double O
bond O
for O
click O
- O
type O
reactions O
, O
to O
generate O
CA B
- I
PEG I
and O
CA B
- I
PEG I
- I
PGA I
/ O
PEVGE B
. O

We O
demonstrate O
the O
potential O
of O
the O
functional O
ligands O
by O
binding O
to O
MnO B
nanoparticles O
, O
rendering O
the O
PEGylated O
nanoparticles O
highly O
stable O
in O
aqueous O
environment O
. O

Furthermore O
, O
addressability O
of O
the O
functional O
groups O
has O
been O
proven O
, O
for O
example O
, O
by O
coupling O
with O
fluoresceine B
isothiocyanate I
( O
FITC B
) O
, O
to O
allow O
for O
optical O
monitoring O
of O
the O
nanoparticle O
fate O
in O
biological O
systems O
. O

New O
chemotherapeutic O
strategies O
against O
malaria O
, O
leishmaniasis O
and O
trypanosomiases O
. O

Due O
to O
the O
persistent O
lack O
of O
suitable O
vaccines O
, O
chemotherapy O
remains O
the O
only O
option O
for O
the O
treatment O
of O
patients O
infected O
by O
protozoan O
parasites O
. O

However O
, O
most O
available O
antiparasitic O
drugs O
have O
serious O
disadvantages O
, O
ranging O
from O
high O
cost O
and O
poor O
compliance O
to O
high O
toxicity O
and O
rapid O
induction O
of O
resistance O
. O

In O
recent O
decades O
basic O
research O
laboratories O
identified O
a O
considerable O
number O
of O
promising O
new O
molecules O
, O
but O
their O
development O
has O
not O
been O
pursued O
in O
depth O
by O
pharmaceutical O
firms O
because O
of O
poor O
prospects O
of O
economic O
return O
. O

The O
establishment O
of O
adequately O
funded O
public O
- O
private O
partnerships O
is O
currently O
reversing O
the O
trend O
. O

This O
review O
deals O
with O
new O
drugs O
against O
Plasmodium O
, O
Leishmania O
and O
Trypanosoma O
parasites O
, O
focusing O
on O
the O
molecules O
that O
are O
in O
the O
most O
advanced O
stage O
of O
development O
. O

The O
purpose O
of O
this O
article O
is O
to O
provide O
the O
reader O
with O
a O
panoramic O
view O
of O
the O
updated O
literature O
on O
the O
challenges O
and O
strategies O
of O
contemporary O
antiprotozoal O
drug O
research O
, O
paying O
the O
due O
attention O
to O
the O
already O
published O
reviews O
. O

New O
molecular O
and O
cellular O
targets O
for O
chemoprevention O
and O
treatment O
of O
skin O
tumors O
by O
plant O
polyphenols B
: O
a O
critical O
review O
. O

As O
the O
incidence O
of O
skin O
tumors O
has O
been O
steadily O
growing O
, O
there O
is O
an O
urgent O
need O
for O
the O
preventive O
measures O
as O
well O
as O
the O
improved O
therapeutic O
approaches O
. O

In O
the O
last O
two O
decades O
, O
natural O
plant O
derived O
polyphenols B
( O
PPs O
, O
resveratrol B
, O
silibinin B
, O
green O
tea O
polyphenols B
, O
flavonoids B
, O
anthocyanins B
, O
etc O
. O
) O
have O
been O
drawing O
particular O
interest O
as O
emerging O
active O
substances O
in O
dermatological O
/ O
cosmeceutical O
compositions O
for O
the O
prevention O
, O
slowing O
, O
or O
reversion O
of O
skin O
tumorigenesis O
( O
chemoprevention O
) O
. O

When O
chronically O
applied O
to O
the O
skin O
, O
they O
supposedly O
would O
not O
damage O
normal O
skin O
cells O
or O
negatively O
affect O
their O
functions O
while O
they O
would O
suppress O
tumorigenic O
cell O
transformation O
, O
inhibit O
tumor O
cell O
proliferation O
, O
and O
activate O
tumor O
cell O
apoptosis O
. O

PPs O
are O
also O
reported O
to O
synergize O
with O
conventional O
anti O
- O
cancer O
therapies O
. O

The O
major O
aim O
of O
this O
critical O
review O
is O
to O
provide O
recent O
updates O
on O
the O
molecular O
and O
cellular O
targets O
for O
the O
prevention O
and O
therapy O
of O
skin O
tumors O
with O
a O
special O
focus O
on O
the O
crossroad O
between O
inflammation O
and O
carcinogenesis O
as O
the O
most O
promising O
approach O
to O
chemoprevention O
. O

Novel O
therapeutic O
targets O
as O
different O
as O
epidermal O
stem O
cells O
, O
cellular O
senescence O
, O
epigenetic O
enzymes O
involved O
in O
carcinogenesis O
, O
epidermal O
growth O
factor O
and O
aryl B
hydrocarbon I
receptors O
, O
and O
metabolic O
CYP1 O
subfamily O
enzymes O
are O
highlighted O
. O

The O
mechanisms O
of O
PPs O
interaction O
with O
these O
molecular O
and O
cellular O
targets O
are O
reviewed O
. O

The O
feasibility O
of O
PPs O
to O
prevent O
/ O
cure O
specific O
cutaneous O
toxicity O
connected O
to O
anti O
- O
EGFR O
therapy O
and O
to O
reduce O
multidrug O
resistance O
of O
skin O
tumors O
is O
also O
discussed O
. O

Colchicine B
semisynthetics O
: O
chemotherapeutics O
for O
cancer O
? O

Nitrogen B
- O
containing O
bioactive O
alkaloids O
of O
plant O
origin O
play O
a O
significant O
role O
in O
human O
health O
and O
medicine O
. O

Several O
semisynthetic O
antimitotic O
alkaloids O
are O
successful O
in O
anticancer O
drug O
development O
. O

Gloriosa O
superba O
biosynthesizes O
substantial O
quantities O
of O
colchicine B
, O
a O
bioactive O
molecule O
for O
gout O
treatment O
. O

Colchicine B
also O
has O
antimitotic O
activity O
, O
preventing O
growth O
of O
cancer O
cells O
by O
interacting O
with O
microtubules O
, O
which O
could O
lead O
to O
the O
design O
of O
better O
cancer O
therapeutics O
. O

Further O
, O
several O
colchicine B
semisynthetics O
are O
less O
toxic O
than O
colchicine B
. O

Research O
is O
being O
conducted O
on O
effective O
, O
less O
toxic O
colchicine B
semisynthetic O
formulations O
with O
potential O
drug O
delivery O
strategies O
directly O
targeting O
multiple O
solid O
cancers O
. O

This O
article O
reviews O
the O
dynamic O
state O
of O
anticancer O
drug O
development O
from O
colchicine B
semisynthetics O
and O
natural O
colchicine B
production O
and O
briefly O
discusses O
colchicine B
biosynthesis O
. O

Antimicrobial O
plant O
metabolites O
: O
structural O
diversity O
and O
mechanism O
of O
action O
. O

Microbial O
infectious O
diseases O
continue O
to O
be O
one O
of O
the O
leading O
causes O
of O
morbidity O
and O
mortality O
. O

It O
has O
been O
estimated O
that O
microbial O
species O
comprise O
about O
60 O
% O
of O
the O
Earth O
' O
s O
biomass O
. O

This O
, O
together O
with O
the O
fact O
that O
their O
genetic O
, O
metabolic O
and O
physiological O
diversity O
is O
extraordinary O
, O
makes O
them O
a O
major O
threat O
to O
the O
health O
and O
development O
of O
populations O
across O
the O
world O
. O

Widespread O
antibiotic O
resistance O
, O
the O
emergence O
of O
new O
pathogens O
in O
addition O
to O
the O
resurgence O
of O
old O
ones O
, O
and O
the O
lack O
of O
effective O
new O
therapeutics O
exacerbate O
the O
problems O
. O

Thus O
, O
the O
need O
to O
discover O
and O
develop O
new O
antimicrobial O
agents O
is O
critical O
to O
improve O
mankind O
' O
s O
future O
health O
. O

Plant O
secondary O
metabolites O
( O
PSMs O
) O
offer O
particular O
promise O
in O
this O
sense O
. O

Plant O
Kingdom O
could O
be O
considered O
a O
rich O
source O
of O
the O
most O
diverse O
structures O
( O
e O
. O
g O
. O
there O
are O
more O
than O
12 O
, O
000 O
known O
alkaloids O
, O
more O
than O
8 O
, O
000 O
phenolic B
compounds O
and O
over O
25 O
, O
000 O
different O
terpenoids B
) O
, O
many O
of O
which O
were O
proven O
to O
possess O
strong O
antimicrobial O
properties O
( O
e O
. O
g O
. O
thymol B
, O
eurabienol B
, O
etc O
. O
) O
. O

In O
many O
instances O
, O
PSMs O
can O
be O
easily O
isolated O
from O
the O
plant O
matrix O
, O
either O
in O
pure O
state O
or O
in O
the O
form O
of O
mixtures O
of O
chemically O
related O
compounds O
. O

What O
is O
also O
important O
is O
that O
the O
development O
of O
bacterial O
resistance O
toward O
natural O
plant O
products O
( O
that O
are O
generally O
regarded O
as O
eco O
- O
friendly O
) O
has O
been O
thus O
far O
documented O
in O
a O
very O
limited O
number O
of O
cases O
( O
e O
. O
g O
. O
for O
reserpine B
) O
. O

Having O
all O
of O
the O
mentioned O
advantages O
of O
PSMs O
as O
potential O
antimicrobials O
in O
mind O
, O
a O
major O
question O
arises O
: O
why O
is O
it O
that O
there O
are O
still O
no O
commercially O
available O
or O
commonly O
used O
antibiotics O
of O
plant O
origin O
? O

This O
review O
tries O
to O
give O
a O
critical O
answer O
to O
this O
question O
by O
considering O
potential O
mechanisms O
of O
antimicrobial O
action O
of O
PSMs O
( O
inhibition O
of O
cell O
wall O
or O
protein O
synthesis O
, O
inducing O
leakage O
from O
the O
cells O
by O
tampering O
with O
the O
function O
of O
the O
membranes O
, O
interfering O
with O
intermediary O
metabolisms O
or O
DNA O
/ O
RNA O
synthesis O
/ O
function O
) O
, O
as O
well O
as O
their O
physical O
and O
chemical O
properties O
( O
e O
. O
g O
. O
hydrophilicity O
/ O
lipophilicity O
, O
chemical O
stability O
) O
. O

To O
address O
the O
possible O
synergistic O
/ O
antagonistic O
effects O
between O
PSMs O
and O
with O
standard O
antibiotics O
, O
special O
attention O
has O
been O
given O
to O
the O
antimicrobial O
activity O
of O
PSM O
- O
mixtures O
( O
e O
. O
g O
. O
essential O
oils O
, O
plant O
extracts O
) O
. O

Moreover O
, O
possible O
ways O
of O
overcoming O
some O
of O
PSMs O
molecular O
limitations O
in O
respect O
to O
their O
usage O
as O
potential O
antibiotics O
were O
also O
discussed O
( O
e O
. O
g O
. O
derivatization O
that O
would O
enable O
fine O
tuning O
of O
certain O
molecular O
characteristics O
) O
. O

From O
traditional O
European O
medicine O
to O
discovery O
of O
new O
drug O
candidates O
for O
the O
treatment O
of O
dementia O
and O
Alzheimer O
' O
s O
disease O
: O
acetylcholinesterase O
inhibitors O
. O

The O
leading O
Alzheimer O
' O
s O
disease O
( O
AD O
) O
therapeutics O
to O
date O
involves O
inhibitors O
of O
acetylcholinesterase O
( O
AChE O
) O
, O
which O
should O
, O
in O
principle O
, O
elevate O
cholinergic O
signaling O
and O
limit O
inflammation O
. O

In O
spite O
of O
the O
effectiveness O
in O
20 O
% O
- O
30 O
% O
of O
AD O
patients O
, O
more O
attention O
has O
been O
paid O
to O
find O
new O
anti O
- O
AChE O
agents O
from O
medicinal O
plants O
. O

Galanthamine B
, O
contained O
in O
the O
bulbs O
and O
flowers O
of O
Galanthus O
and O
related O
genera O
like O
Narcissus O
, O
represents O
a O
good O
example O
. O

The O
aim O
of O
this O
study O
is O
to O
review O
the O
role O
of O
possible O
AChE O
inhibitors O
( O
AChEI O
) O
present O
in O
plants O
traditionally O
used O
in O
European O
medicine O
for O
improving O
memory O
. O

Starting O
from O
Galanthamine B
, O
properties O
of O
Melissa O
species O
, O
Salvia O
officinalis O
, O
Arnica O
chamissonis O
and O
Ruta O
graveolens O
are O
discussed O
to O
point O
to O
the O
role O
of O
these O
plants O
as O
potential O
sources O
for O
the O
development O
of O
therapeutic O
agents O
for O
AD O
. O

Preclinical O
profile O
of O
bacopasides B
from O
Bacopa O
monnieri O
( O
BM O
) O
as O
an O
emerging O
class O
of O
therapeutics O
for O
management O
of O
chronic O
pains O
. O

Chronic O
pains O
management O
costs O
billions O
of O
dollars O
in O
medical O
exchequer O
to O
the O
world O
population O
. O

Additionally O
, O
77 O
% O
of O
people O
with O
chronic O
pains O
also O
have O
a O
degree O
of O
medically O
treatable O
depression O
. O

Opioids O
have O
a O
narrower O
safety O
index O
due O
to O
their O
side O
effects O
associated O
with O
its O
tolerance O
, O
hyperalgesia O
and O
subsequent O
dependence O
. O

Likewise O
, O
non O
steroidal O
anti O
- O
inflammatory O
drugs O
and O
anticonvulsants O
, O
also O
have O
limited O
safety O
and O
tolerability O
profile O
in O
the O
management O
of O
chronic O
pains O
. O

Bacopa O
monnieri O
, O
a O
renowned O
ayurvedic O
medicine O
has O
a O
strong O
antidepressant O
effect O
and O
significant O
antinociceptive O
effect O
, O
which O
is O
comparable O
to O
the O
effect O
of O
morphine B
via O
adenosinergic O
, O
opioidergic O
, O
and O
adrenergic O
mechanisms O
. O

BM O
has O
been O
also O
reported O
to O
be O
effective O
in O
neuropathic O
pains O
. O

Additionally O
, O
it O
has O
a O
strong O
anti O
- O
inflammatory O
effect O
mediated O
via O
COX O
- O
2 O
inhibitory O
mechanism O
. O

Apart O
from O
its O
effect O
of O
augmenting O
morphine B
analgesia O
, O
BM O
also O
inhibits O
opioid O
- O
withdrawal O
induced O
hyperalgesia O
, O
and O
acquisition O
and O
expression O
of O
morphine B
tolerance O
. O

BM O
is O
reported O
to O
have O
a O
strong O
protective O
effect O
against O
toxic O
effects O
of O
opiates O
on O
major O
organs O
like O
brain O
, O
kidneys O
and O
heart O
. O

BM O
is O
well O
documented O
to O
be O
safe O
and O
well O
tolerated O
herbal O
therapy O
in O
multiple O
clinical O
trials O
including O
various O
age O
groups O
. O

This O
minireview O
evaluated O
the O
preclinical O
data O
that O
highlights O
potential O
of O
BM O
as O
a O
future O
candidate O
for O
clinical O
management O
of O
chronic O
pains O
. O

Cantharidin B
as O
an O
antitumor O
agent O
: O
a O
retrospective O
review O
. O

This O
review O
summarizes O
the O
progress O
that O
has O
been O
made O
recently O
in O
the O
medicinal O
chemistry O
of O
cantharidin B
, O
a O
potent O
antitumor O
agent O
from O
traditional O
Chinese O
medicine O
. O

Thousands O
of O
analogs O
have O
been O
synthesized O
on O
the O
basis O
of O
cantharidin B
, O
a O
part O
of O
which O
shows O
excellent O
properties O
, O
in O
particular O
, O
norcantharidin B
and O
norcantharimide B
. O

Despite O
the O
enormous O
efforts O
made O
, O
the O
intriguing O
bioactivities O
, O
mechanism O
, O
indications O
, O
and O
their O
interplay O
are O
still O
ill O
- O
defined O
. O

This O
review O
provides O
our O
up O
- O
to O
- O
date O
understanding O
in O
connection O
with O
the O
therapeutic O
use O
, O
mechanism O
, O
structure O
- O
activity O
relationship O
( O
SAR O
) O
and O
interesting O
properties O
of O
cantharidin B
analogs O
. O

Considerable O
development O
in O
the O
design O
of O
cantharidin B
analogs O
, O
in O
combination O
with O
mechanistic O
studies O
, O
has O
laid O
a O
foundation O
for O
transforming O
novel O
antitumor O
drugs O
into O
the O
clinic O
. O

Metabolomics O
analysis O
for O
biomarker O
discovery O
: O
advances O
and O
challenges O
. O

Over O
the O
last O
decades O
there O
has O
been O
a O
change O
in O
biomedical O
research O
with O
the O
search O
for O
single O
genes O
, O
transcripts O
, O
proteins O
, O
or O
metabolites O
being O
substituted O
by O
the O
coverage O
of O
the O
entire O
genome O
, O
transcriptome O
, O
proteome O
, O
and O
metabolome O
with O
the O
" O
omics O
" O
approaches O
. O

The O
emergence O
of O
metabolomics O
, O
defined O
as O
the O
comprehensive O
analysis O
of O
all O
metabolites O
in O
a O
system O
, O
is O
still O
recent O
compared O
to O
other O
" O
omics O
" O
fields O
, O
but O
its O
particular O
features O
and O
the O
improvement O
of O
both O
analytical O
techniques O
and O
pattern O
recognition O
methods O
has O
contributed O
greatly O
to O
its O
increasingly O
use O
. O

The O
feasibility O
of O
metabolomics O
for O
biomarker O
discovery O
is O
supported O
by O
the O
assumption O
that O
metabolites O
are O
important O
players O
in O
biological O
systems O
and O
that O
diseases O
cause O
disruption O
of O
biochemical O
pathways O
, O
which O
are O
not O
new O
concepts O
. O

In O
fact O
, O
metabolomics O
, O
meaning O
the O
parallel O
assessment O
of O
multiple O
metabolites O
, O
has O
been O
shown O
to O
have O
benefits O
in O
various O
clinical O
areas O
. O

Compared O
to O
classical O
diagnostic O
approaches O
and O
conventional O
clinical O
biomarkers O
, O
metabolomics O
offers O
potential O
advantages O
in O
sensitivity O
and O
specificity O
. O

Despite O
its O
potential O
, O
metabolomics O
still O
retains O
several O
intrinsic O
limitations O
which O
have O
a O
great O
impact O
on O
its O
widespread O
implementation O
- O
these O
limitations O
in O
biological O
and O
experimental O
measurements O
. O

This O
review O
will O
provide O
an O
insight O
to O
the O
characteristics O
, O
strengths O
, O
limitations O
, O
and O
recent O
advances O
in O
metabolomics O
, O
always O
keeping O
in O
mind O
its O
potential O
application O
in O
clinical O
/ O
health O
areas O
as O
a O
biomarker O
discovery O
tool O
. O

Confined O
synthesis O
and O
integration O
of O
functional O
materials O
in O
sub O
- O
nanoliter O
volumes O
. O

We O
present O
a O
novel O
microchip O
- O
based O
approach O
to O
combine O
the O
synthesis O
, O
characterization O
, O
and O
utilization O
of O
different O
functional O
materials O
on O
a O
single O
platform O
. O

A O
two O
- O
layer O
microfluidic O
device O
comprising O
10 O
parallel O
actuated O
reaction O
chambers O
with O
volumes O
of O
a O
few O
hundred O
picoliters O
is O
used O
to O
localize O
and O
confine O
the O
synthesis O
, O
while O
the O
surfaces O
of O
the O
reaction O
chambers O
comprise O
an O
electrode O
array O
for O
direct O
integration O
and O
further O
characterization O
of O
the O
created O
crystalline O
assemblies O
without O
the O
need O
for O
further O
manipulation O
or O
positioning O
devices O
. O

First O
we O
visualized O
and O
evaluated O
the O
dynamics O
of O
our O
method O
by O
monitoring O
the O
formation O
of O
a O
fluorescent O
metal O
- O
organic O
complex O
( O
Zn B
( O
bix O
) O
) O
. O

Next O
, O
we O
induced O
the O
site O
- O
specific O
growth O
of O
two O
types O
of O
organic O
conductive O
crystals O
, O
AuTTF O
and O
AgTCNQ B
, O
directly O
onto O
the O
electrode O
arrays O
in O
one O
- O
and O
two O
- O
step O
reactions O
, O
respectively O
. O

The O
performance O
of O
the O
created O
AgTCNQ B
crystals O
as O
memory O
elements O
was O
thoroughly O
examined O
. O

Moreover O
, O
we O
proved O
for O
first O
time O
that O
AuTTF O
composites O
can O
be O
used O
as O
label O
- O
free O
sensing O
elements O
. O

Pharmacological O
characterization O
of O
1 B
- I
nitrosocyclohexyl I
acetate I
, O
a O
long O
- O
acting O
nitroxyl B
donor O
that O
shows O
vasorelaxant O
and O
antiaggregatory O
effects O
. O

Nitroxyl B
( O
HNO B
) O
donors O
have O
potential O
benefit O
in O
the O
treatment O
of O
heart O
failure O
and O
other O
cardiovascular O
diseases O
. O

1 B
- I
Nitrosocyclohexyl I
acetate I
( O
NCA B
) O
, O
a O
new O
HNO B
donor O
, O
in O
contrast O
to O
the O
classic O
HNO B
donors O
Angeli B
' I
s I
salt I
and O
isopropylamine B
NONOate I
, O
predominantly O
releases O
HNO B
and O
has O
a O
longer O
half O
- O
life O
. O

This O
study O
investigated O
the O
vasodilatative O
properties O
of O
NCA B
in O
isolated O
aortic O
rings O
and O
human O
platelets O
and O
its O
mechanism O
of O
action O
. O

NCA O
was O
applied O
on O
aortic O
rings O
isolated O
from O
wild O
- O
type O
mice O
and O
apolipoprotein O
E O
- O
deficient O
mice O
and O
in O
endothelial O
- O
denuded O
aortae O
. O

The O
mechanism O
of O
action O
of O
HNO B
was O
examined O
by O
applying O
NCA O
in O
the O
absence O
and O
presence O
of O
the O
HNO B
scavenger O
glutathione B
( O
GSH B
) O
and O
inhibitors O
of O
soluble O
guanylyl B
cyclase O
( O
sGC O
) O
, O
adenylyl O
cyclase O
( O
AC O
) O
, O
calcitonin O
gene O
- O
related O
peptide O
receptor O
( O
CGRP O
) O
, O
and O
K B
( I
+ I
) I
channels O
. O

NCA B
induced O
a O
concentration O
- O
dependent O
relaxation O
( O
EC O
( O
50 O
) O
, O
4 O
. O
4 O
micro O
M O
) O
. O

This O
response O
did O
not O
differ O
between O
all O
groups O
, O
indicating O
an O
endothelium O
- O
independent O
relaxation O
effect O
. O

The O
concentration O
- O
response O
was O
markedly O
decreased O
in O
the O
presence O
of O
excess O
GSH B
; O
the O
nitric B
oxide I
scavenger O
2 B
- I
( I
4 I
- I
carboxyphenyl I
) I
- I
4 I
, I
4 I
, I
5 I
, I
5 I
- I
tetramethylimidazoli I
- I
1 I
- I
oxyl I
- I
3 I
- I
oxide I
had O
no O
effect O
. O

Inhibitors O
of O
sGC O
, O
CGRP O
, O
and O
voltage O
- O
dependent O
K B
( I
+ I
) I
channels O
each O
significantly O
impaired O
the O
vasodilator O
response O
to O
NCA O
. O

In O
contrast O
, O
inhibitors O
of O
AC O
, O
ATP B
- O
sensitive O
K B
( I
+ I
) I
channels O
, O
or O
high O
- O
conductance O
Ca B
( I
2 I
+ I
) I
- O
activated O
K B
( I
+ I
) I
channels O
did O
not O
change O
the O
effects O
of O
NCA O
. O

NCA O
significantly O
reduced O
contractile O
response O
and O
platelet O
aggregation O
mediated O
by O
the O
thromboxane B
A I
( I
2 I
) I
mimetic O
9 B
, I
11 I
- I
dideoxy I
- I
11 I
alpha I
, I
9 I
alpha I
- I
epoxymethanoprostagl I
F I
( I
2 I
) I
( O
alpha O
) O
in O
a O
cGMP B
- O
dependent O
manner O
. O

In O
summary O
, O
NCA O
shows O
vasoprotective O
effects O
and O
may O
have O
a O
promising O
profile O
as O
a O
therapeutic O
agent O
in O
vascular O
dysfunction O
, O
warranting O
further O
evaluation O
. O

Liver O
X O
Receptors O
and O
female O
reproduction O
: O
when O
cholesterol B
meets O
fertility O
! O

The O
role O
of O
cholesterol B
in O
female O
reproductive O
physiology O
has O
been O
suspected O
for O
a O
long O
time O
, O
while O
the O
molecular O
bases O
were O
unknown O
. O

Cholesterol B
is O
the O
precursor O
of O
ovarian O
steroid B
biosynthesis O
and O
is O
also O
essential O
for O
fertility O
. O

In O
the O
uterus O
, O
cholesterol B
is O
essential O
to O
achieve O
correct O
contractions O
at O
term O
, O
but O
an O
excessive O
uterine O
cholesterol B
concentration O
has O
been O
associated O
with O
contractility O
defects O
. O

Liver O
X O
Receptor O
( O
LXR O
) O
alpha O
and O
LXR O
beta O
are O
nuclear O
receptors O
activated O
by O
oxysterols B
, O
oxidized O
derivatives O
of O
cholesterol B
. O

Since O
their O
discovery O
, O
the O
role O
of O
LXR O
in O
the O
control O
of O
cholesterol B
homeostasis O
has O
been O
widely O
described O
. O

Beyond O
their O
cholesterol B
- O
lowering O
role O
, O
more O
recent O
data O
have O
linked O
these O
nuclear O
receptors O
to O
various O
physiological O
processes O
. O

In O
particular O
, O
they O
control O
ovarian O
endocrine O
and O
exocrine O
functions O
, O
as O
well O
as O
uterine O
contractility O
. O

Their O
contribution O
to O
female O
reproductive O
cancers O
will O
also O
be O
discussed O
. O

This O
review O
will O
try O
to O
enlighten O
on O
the O
LXR O
as O
a O
molecular O
link O
between O
dietary O
cholesterol B
and O
reproductive O
diseases O
in O
women O
. O

In O
the O
future O
, O
a O
better O
comprehension O
of O
the O
various O
physiological O
processes O
regulated O
by O
the O
LXR O
will O
help O
to O
develop O
new O
ligands O
to O
prevent O
or O
to O
cure O
these O
pathologies O
in O
women O
. O

Studies O
on O
the O
bioactivity O
of O
aqueous O
extract O
of O
pu O
- O
erh O
tea O
and O
its O
fractions O
: O
in O
vitro O
antioxidant O
activity O
and O
alpha O
- O
glycosidase O
inhibitory O
property O
, O
and O
their O
effect O
on O
postprandial O
hyperglycemia O
in O
diabetic O
mice O
. O

Despite O
abundant O
research O
that O
has O
been O
carried O
out O
on O
the O
potential O
health O
benefits O
of O
pu O
- O
erh O
tea O
, O
no O
consensus O
till O
now O
, O
has O
been O
reached O
on O
which O
constituent O
is O
mainly O
responsible O
for O
its O
bioactivity O
. O

In O
this O
work O
, O
the O
aqueous O
extract O
( O
AE O
) O
and O
its O
fraction O
enriched O
with O
active O
constituents O
were O
prepared O
from O
pu O
- O
erh O
tea O
, O
and O
their O
bioactivities O
were O
investigated O
. O

It O
was O
found O
that O
tea O
polyphenols B
( O
TP O
) O
, O
tea O
polysaccharides O
( O
TPS O
) O
, O
caffeine B
( O
Caf B
) O
, O
protein O
( O
Pro O
) O
, O
amino B
acids I
( O
AA O
) O
were O
accumulated O
in O
several O
fractions O
after O
solvent O
extraction O
despite O
not O
being O
separated O
completely O
. O

Meanwhile O
, O
95 O
% O
ethanol B
precipitate O
( O
EP O
) O
and O
ethyl B
acetate I
fraction O
( O
EF O
) O
possessed O
remarkable O
antioxidant O
activity O
and O
potent O
inhibitory O
effects O
against O
alpha O
- O
glycosidase O
in O
vitro O
. O

Furthermore O
, O
all O
the O
extracts O
( O
50 O
mg O
/ O
kg O
BW O
) O
showed O
a O
significant O
( O
p O
< O
0 O
. O
05 O
) O
effect O
on O
postprandial O
hyperglycemia O
in O
diabetic O
mice O
as O
compared O
with O
a O
model O
group O
, O
and O
the O
suppression O
of O
EP O
was O
not O
significantly O
( O
p O
> O
0 O
. O
05 O
) O
different O
from O
that O
of O
acarbose B
at O
the O
same O
dosage O
( O
50 O
mg O
/ O
kg O
BW O
) O
, O
which O
indicate O
that O
these O
fractions O
could O
be O
developed O
as O
potential O
anti O
- O
diabetic O
agents O
. O

beta O
- O
catenin O
regulates O
GnRH B
- O
induced O
FSH O
beta O
gene O
expression O
. O

The O
regulation O
of O
gonadotropin O
synthesis O
by O
GnRH B
plays O
an O
essential O
role O
in O
the O
neuroendocrine O
control O
of O
reproduction O
. O

The O
known O
signaling O
mechanisms O
involved O
in O
gonadotropin O
synthesis O
have O
been O
expanding O
. O

For O
example O
, O
involvement O
of O
beta O
- O
catenin O
in O
LH O
beta O
induction O
by O
GnRH B
has O
been O
discovered O
. O

We O
examined O
the O
role O
of O
beta O
- O
catenin O
in O
FSH O
beta O
gene O
expression O
in O
L O
beta O
T2 O
gonadotrope O
cells O
. O

GnRH B
caused O
a O
sustained O
increase O
in O
nuclear O
beta O
- O
catenin O
levels O
, O
which O
was O
significantly O
reduced O
by O
c O
- O
Jun O
N B
- O
terminal O
kinase O
( O
JNK O
) O
inhibition O
. O

Small O
interfering O
RNA O
- O
mediated O
knockdown O
of O
beta O
- O
catenin O
mRNA O
demonstrated O
that O
induction O
of O
FSH O
beta O
mRNA O
by O
GnRH B
depended O
on O
beta O
- O
catenin O
and O
that O
regulation O
of O
FSH O
beta O
by O
beta O
- O
catenin O
occurred O
independently O
of O
the O
JNK O
- O
c O
- O
jun O
pathway O
. O

beta O
- O
Catenin O
depletion O
had O
no O
impact O
on O
FSH O
beta O
mRNA O
stability O
. O

In O
L O
beta O
T2 O
cells O
transfected O
with O
FSH O
beta O
promoter O
luciferase O
fusion O
constructs O
, O
GnRH B
responsiveness O
was O
conferred O
by O
the O
proximal O
promoter O
( O
- O
944 O
/ O
- O
1 O
) O
and O
was O
markedly O
decreased O
by O
beta O
- O
catenin O
knockdown O
. O

However O
, O
none O
of O
the O
T O
- O
cell O
factor O
/ O
lymphoid O
enhancer O
factor O
binding O
sites O
in O
that O
region O
were O
required O
for O
promoter O
activation O
by O
GnRH B
. O

Chromatin O
immunoprecipitation O
further O
corroborated O
the O
absence O
of O
direct O
interaction O
between O
beta O
- O
catenin O
and O
the O
1 O
. O
8 O
- O
kb O
FSH O
beta O
promoter O
. O

To O
elucidate O
the O
mechanism O
for O
the O
beta O
- O
catenin O
effect O
, O
we O
analyzed O
approximately O
1 O
billion O
reads O
of O
next O
- O
generation O
RNA O
sequencing O
beta O
- O
catenin O
knockdown O
assays O
and O
selected O
the O
nuclear O
cofactor O
breast O
cancer O
metastasis O
- O
suppressor O
1 O
- O
like O
( O
Brms1L O
) O
as O
one O
candidate O
for O
further O
study O
. O

Subsequent O
experiments O
confirmed O
that O
Brms1L O
mRNA O
expression O
was O
decreased O
by O
beta O
- O
catenin O
knockdown O
as O
well O
as O
by O
JNK O
inhibition O
. O

Furthermore O
, O
knockdown O
of O
Brms1L O
significantly O
attenuated O
GnRH B
- O
induced O
FSH O
beta O
expression O
. O

Thus O
, O
our O
findings O
indicate O
that O
the O
expression O
of O
Brms1L O
depends O
on O
beta O
- O
catenin O
activity O
and O
contributes O
to O
FSH O
beta O
induction O
by O
GnRH B
. O

GATA2 O
- O
induced O
silencing O
and O
LIM O
- O
homeodomain O
protein O
- O
induced O
activation O
are O
mediated O
by O
a O
bi O
- O
functional O
response O
element O
in O
the O
rat O
GnRH B
receptor O
gene O
. O

GATA2 O
transcription O
factor O
and O
LIM O
homeodomain O
proteins O
Islet1 O
( O
ISL1 O
) O
and O
LIM O
homeobox O
3 O
( O
LHX3 O
) O
are O
suspected O
to O
be O
involved O
in O
gonadotrope O
cell O
fate O
and O
maintenance O
. O

The O
GnRH B
receptor O
gene O
( O
Gnrhr O
) O
, O
crucial O
for O
gonadotrope O
function O
, O
is O
expressed O
in O
the O
pituitary O
gland O
from O
embryonic O
day O
13 O
. O
5 O
onward O
, O
well O
before O
LH O
and O
FSH O
beta O
- O
subunits O
. O

This O
expression O
pattern O
together O
with O
the O
presence O
of O
WGATAR O
and O
TAAT O
motifs O
in O
Gnrhr O
promoter O
sequences O
suggests O
the O
involvement O
of O
early O
transcription O
factors O
in O
promoter O
activation O
. O

In O
this O
study O
, O
using O
a O
well O
- O
characterized O
transgenic O
mouse O
model O
, O
GATA2 O
was O
found O
colocalized O
with O
Gnrhr O
promoter O
activity O
in O
the O
pituitary O
. O

Transient O
transfection O
of O
Gnrhr O
promoter O
luciferase O
fusion O
constructs O
together O
with O
either O
GATA2 O
expression O
vectors O
or O
small O
interfering O
RNA O
in O
gonadotrope O
cell O
lines O
indicated O
that O
GATA2 O
, O
which O
typically O
acts O
as O
a O
trans O
- O
activator O
, O
unexpectedly O
repressed O
Gnrhr O
promoter O
activity O
. O

Using O
DNA O
chromatography O
affinity O
and O
EMSA O
, O
we O
demonstrated O
that O
GATA2 O
operates O
via O
a O
response O
element O
containing O
a O
peculiar O
palindromic O
GATA O
motif O
that O
overlaps O
a O
critical O
TAAT O
motif O
involved O
in O
LHX3 O
/ O
ISL1 O
trans O
- O
activation O
. O

Indeed O
, O
despite O
the O
inhibitory O
action O
of O
GATA2 O
, O
this O
element O
displayed O
a O
clear O
- O
cut O
enhancer O
activity O
in O
gonadotrope O
cells O
. O

Chromatin O
immunoprecipitation O
assays O
indicated O
that O
GATA2 O
, O
LHX3 O
, O
and O
ISL1 O
interact O
with O
a O
Gnrhr O
promoter O
fragment O
encompassing O
this O
element O
. O

The O
trans O
- O
repressive O
action O
of O
GATA2 O
on O
Gnrhr O
promoter O
activity O
is O
likely O
balanced O
or O
even O
hindered O
by O
trans O
- O
activating O
effects O
of O
LIM O
homeodomain O
proteins O
via O
this O
novel O
bifunctional O
LIM O
/ O
GATA O
response O
element O
. O

Such O
a O
hierarchical O
interplay O
may O
contribute O
to O
finely O
adjust O
Gnrhr O
gene O
expression O
in O
gonadotrope O
cell O
lineage O
during O
pituitary O
development O
as O
well O
as O
in O
the O
adult O
animal O
. O

Halting O
metastasis O
through O
CXCR4 O
inhibition O
. O

Metastasis O
occurs O
when O
cancer O
cells O
leave O
the O
primary O
tumor O
site O
and O
migrate O
to O
distant O
parts O
of O
the O
body O
. O

The O
CXCR4 O
- O
SDF O
- O
1 O
pathway O
facilitates O
this O
migration O
, O
and O
its O
expression O
has O
become O
the O
hallmark O
of O
several O
metastatic O
cancers O
. O

Targeted O
approaches O
are O
currently O
being O
developed O
to O
inhibit O
this O
pathway O
, O
and O
several O
candidates O
are O
now O
in O
clinical O
trials O
. O

Continued O
exploration O
of O
CXCR4 O
inhibitors O
will O
generate O
compounds O
that O
have O
improved O
activity O
over O
current O
candidates O
. O

l B
- I
DOPA I
modifies O
the O
antidepressant O
- O
like O
effects O
of O
reboxetine B
and O
fluoxetine B
in O
rats O
. O

Nowadays O
the O
most O
widely O
used O
antidepressants O
are O
selective O
serotonin B
reuptake O
inhibitors O
( O
SSRI O
) O
or O
noradrenaline B
reuptake O
inhibitors O
( O
NRI O
) O
, O
however O
, O
these O
take O
four O
to O
eight O
weeks O
to O
exert O
their O
effects O
and O
each O
drug O
is O
efficacious O
only O
in O
60 O
- O
70 O
% O
of O
patients O
. O

In O
an O
attempt O
to O
improve O
the O
efficacy O
of O
antidepressants O
, O
new O
drugs O
that O
also O
modify O
dopamine B
levels O
are O
being O
developed O
. O

The O
aim O
of O
this O
study O
was O
to O
investigate O
the O
impact O
of O
l B
- I
DOPA I
administration O
on O
the O
effect O
elicited O
by O
antidepressants O
on O
serotonergic O
and O
noradrenergic O
neurotransmission O
. O

To O
this O
end O
, O
single O
- O
unit O
extracellular O
recordings O
of O
the O
noradrenergic O
nucleus O
, O
locus O
coeruleus O
( O
LC O
) O
, O
and O
the O
serotonergic O
nucleus O
, O
dorsal O
raphe O
( O
DRN O
) O
combined O
with O
behavioural O
approaches O
were O
performed O
. O

l B
- I
DOPA I
did O
not O
modify O
the O
basal O
neuronal O
activity O
in O
either O
the O
LC O
or O
the O
DRN O
or O
induce O
any O
change O
in O
the O
modified O
forced O
swimming O
test O
. O

However O
, O
l B
- I
DOPA I
enhanced O
the O
neuronal O
response O
to O
reboxetine B
in O
the O
LC O
and O
increased O
its O
antidepressant O
- O
like O
effects O
but O
counteracted O
the O
effect O
of O
fluoxetine B
on O
neurons O
in O
the O
LC O
and O
decreased O
its O
antidepressant O
- O
like O
effect O
. O

The O
sensitivity O
of O
neurons O
in O
the O
DRN O
to O
reboxetine B
and O
fluoxetine B
was O
not O
altered O
by O
the O
administration O
of O
l B
- I
DOPA I
. O

Taken O
together O
, O
these O
results O
indicate O
that O
l B
- I
DOPA I
modifies O
the O
effect O
of O
SSRI O
and O
NRI O
antidepressants O
in O
opposing O
ways O
. O

Prospects O
for O
treatment O
of O
latent O
HIV O
. O

Recent O
advances O
in O
antiretroviral O
therapy O
( O
ART O
) O
have O
drastically O
improved O
the O
quality O
of O
life O
for O
people O
with O
HIV O
infection O
. O

However O
, O
owing O
to O
the O
persistence O
of O
latent O
HIV O
in O
the O
presence O
of O
therapy O
, O
patients O
must O
remain O
on O
therapy O
indefinitely O
. O

Currently O
, O
the O
solution O
to O
the O
HIV O
pandemic O
rests O
on O
the O
prevention O
of O
new O
infections O
and O
many O
decades O
of O
ART O
for O
the O
steadily O
expanding O
number O
of O
people O
infected O
worldwide O
. O

ART O
is O
costly O
, O
requires O
ongoing O
medical O
care O
, O
and O
can O
have O
side O
effects O
, O
thereby O
preventing O
its O
universal O
availability O
. O

Therefore O
, O
to O
escape O
the O
ironic O
burdens O
of O
therapy O
, O
efforts O
have O
begun O
to O
develop O
treatments O
for O
latent O
HIV O
infection O
. O

Current O
approaches O
propose O
either O
complete O
eradication O
of O
infection O
or O
induction O
of O
a O
state O
of O
stringent O
control O
over O
viral O
replication O
without O
ART O
. O

This O
review O
will O
discuss O
these O
strategies O
in O
detail O
and O
their O
potential O
for O
clinical O
development O
. O

Emerging O
target O
- O
based O
paradigms O
to O
prevent O
and O
treat O
migraine O
. O

Migraine O
is O
a O
primary O
brain O
disorder O
resulting O
from O
altered O
modulation O
of O
normal O
sensory O
stimuli O
and O
trigeminal O
nerve O
dysfunction O
. O

The O
second O
edition O
of O
the O
International O
Classification O
of O
Headache O
Disorders O
( O
ICHD O
- O
2 O
) O
defines O
seven O
subtypes O
of O
migraine O
. O

Migraine O
treatment O
can O
be O
acute O
or O
preventive O
. O

New O
targeted O
therapies O
include O
5 O
- I
HT O
( O
1F O
) O
receptor O
agonists O
, O
calcitonin O
gene O
- O
related O
peptide O
( O
CGRP O
) O
antagonists O
, O
nitric B
oxide I
synthetase O
inhibitors O
, O
and O
ion O
channel O
antagonists O
. O

A O
recent O
development O
is O
the O
creation O
of O
antibodies O
to O
CGRP O
and O
its O
receptor O
for O
migraine O
prevention O
. O

Evolving O
approaches O
of O
hematopoietic O
stem O
cell O
- O
based O
therapies O
to O
induce O
tolerance O
to O
organ O
transplants O
: O
the O
long O
road O
to O
tolerance O
. O

The O
immunoregulatory O
properties O
of O
hematopoietic O
stem O
cells O
( O
HSCs O
) O
have O
been O
recognized O
for O
more O
than O
60 O
years O
, O
beginning O
in O
1945 O
, O
when O
Owen O
reported O
that O
genetically O
disparate O
freemartin O
cattle O
sharing O
a O
common O
placenta O
were O
red O
blood O
cell O
chimeras O
. O

In O
1953 O
, O
Billingham O
, O
Brent O
, O
and O
Medawar O
demonstrated O
that O
murine O
neonatal O
chimeras O
prepared O
by O
infusion O
of O
donor O
- O
derived O
hematopoietic O
cells O
exhibited O
donor O
- O
specific O
tolerance O
to O
skin O
allografts O
. O

Various O
approaches O
using O
HSCs O
in O
organ O
transplantation O
have O
gradually O
brought O
closer O
to O
reality O
the O
dream O
of O
inducing O
donor O
- O
specific O
tolerance O
in O
organ O
transplant O
recipients O
. O

Several O
hurdles O
needed O
to O
be O
overcome O
, O
especially O
the O
risk O
of O
graft O
- O
versus O
- O
host O
disease O
( O
GVHD O
) O
, O
the O
toxicity O
of O
ablative O
conditioning O
, O
and O
the O
need O
for O
close O
donor O
- O
recipient O
matching O
. O

For O
wide O
acceptance O
, O
HSC O
therapy O
must O
be O
safe O
and O
reproducible O
in O
mismatched O
donor O
- O
recipient O
combinations O
. O

Discoveries O
in O
other O
disciplines O
have O
often O
unexpectedly O
and O
synergistically O
contributed O
to O
progress O
in O
this O
area O
. O

This O
review O
presents O
a O
historic O
perspective O
of O
the O
quest O
for O
tolerance O
in O
organ O
transplantation O
, O
highlighting O
current O
clinical O
approaches O
. O

Impairment O
of O
novel O
object O
recognition O
in O
adulthood O
after O
neonatal O
exposure O
to O
diazinon B
. O

Diazinon B
is O
an O
organophosphate B
pesticide O
that O
is O
still O
heavily O
used O
in O
agriculture O
, O
home O
gardening O
, O
and O
indoor O
pest O
control O
in O
Japan O
. O

The O
present O
study O
investigated O
the O
effect O
of O
neonatal O
exposure O
to O
diazinon B
on O
hippocampus O
- O
dependent O
novel O
object O
recognition O
test O
performance O
and O
the O
expression O
of O
the O
N B
- I
methyl I
- I
D I
- I
aspartate I
( O
NMDA B
) O
receptor O
and O
its O
signal O
transduction O
pathway O
- O
related O
genes O
in O
the O
hippocampi O
of O
young O
adult O
and O
adult O
mice O
. O

Male O
offspring O
of O
C3H O
/ O
HeN O
mice O
were O
subcutaneously O
treated O
with O
0 O
, O
0 O
. O
5 O
, O
or O
5 O
mg O
/ O
kg O
of O
diazinon B
for O
4 O
consecutive O
days O
beginning O
on O
postnatal O
day O
( O
PND O
) O
8 O
. O

Beginning O
on O
PND O
46 O
or O
PND O
81 O
, O
a O
novel O
object O
recognition O
test O
was O
performed O
on O
4 O
consecutive O
days O
. O

The O
hippocampi O
were O
collected O
on O
PND O
50 O
or O
PND O
85 O
after O
the O
completion O
of O
the O
novel O
object O
recognition O
test O
, O
and O
the O
expression O
levels O
of O
neurotrophins O
and O
the O
NMDA B
receptor O
and O
its O
signal O
transduction O
pathway O
- O
related O
genes O
were O
examined O
using O
real O
- O
time O
RT O
- O
PCR O
. O

Diazinon B
- O
injected O
mice O
exhibited O
a O
poor O
ability O
to O
discriminate O
between O
novel O
and O
familiar O
objects O
during O
both O
the O
PND O
49 O
and O
the O
PND O
84 O
tests O
. O

The O
NMDA B
receptor O
subunits O
NR1 O
and O
NR2B O
and O
the O
related O
protein O
kinase O
calcium B
/ O
calmodulin O
- O
dependent O
protein O
kinase O
( O
CaMK O
) O
- O
IV O
and O
the O
transcription O
factor O
cyclic B
AMP I
responsive O
element O
binding O
protein O
( O
CREB O
) O
- O
1 O
mRNA O
levels O
were O
reduced O
in O
the O
PND O
50 O
mice O
. O

However O
, O
no O
significant O
changes O
in O
the O
expressions O
of O
the O
NMDA B
subunits O
and O
their O
signal O
transduction O
molecules O
were O
observed O
in O
the O
hippocampi O
of O
the O
PND O
85 O
mice O
. O

The O
expression O
level O
of O
nerve O
growth O
factor O
mRNA O
was O
significantly O
reduced O
in O
the O
PND O
50 O
or O
85 O
mice O
. O

These O
results O
indicate O
that O
neonatal O
diazinon B
exposure O
impaired O
the O
hippocampus O
- O
dependent O
novel O
object O
recognition O
ability O
, O
accompanied O
by O
a O
modulation O
in O
the O
expressions O
of O
the O
NMDA B
receptor O
and O
neurotrophin O
in O
young O
adult O
and O
adult O
mice O
. O

The O
role O
of O
native O
salinity O
regime O
on O
grass O
shrimp O
( O
Palaemonetes O
pugio O
) O
sensitivity O
to O
cadmium B
. O

In O
euryhaline O
crustaceans O
, O
sensitivity O
to O
toxic O
trace O
metals O
may O
be O
linked O
to O
osmoregulation O
and O
salinity O
conditions O
. O

This O
study O
investigated O
if O
grass O
shrimp O
( O
Palaemonetes O
pugio O
) O
populations O
from O
different O
salinity O
regimes O
differed O
in O
sensitivity O
to O
cadmium B
( O
Cd B
) O
. O

Grass O
shrimp O
were O
collected O
in O
May O
2011 O
from O
two O
marsh O
sites O
with O
average O
salinities O
of O
~ O
3 O
. O
0 O
ppt O
and O
24 O
. O
0 O
ppt O
. O

Groups O
were O
acclimated O
for O
3 O
- O
32 O
weeks O
in O
either O
their O
respective O
native O
salinity O
( O
3 O
. O
0 O
ppt O
- O
- O
> O
3 O
. O
0 O
ppt O
and O
24 O
. O
0 O
ppt O
- O
- O
> O
24 O
. O
0 O
ppt O
) O
, O
or O
the O
average O
of O
the O
salinities O
of O
the O
two O
collection O
sites O
( O
3 O
. O
0 O
ppt O
- O
- O
> O
13 O
. O
5 O
ppt O
and O
24 O
. O
0 O
ppt O
- O
- O
> O
13 O
. O
5 O
ppt O
) O
. O

After O
acclimation O
, O
groups O
were O
exposed O
to O
equivalent O
free O
- O
ion O
Cd B
concentration O
( O
4 O
. O
8 O
+ O
/ O
- O
0 O
. O
3 O
mg O
/ O
L O
, O
Cd B
( I
2 I
+ I
) I
) O
in O
their O
respective O
acclimated O
salinity O
to O
compare O
survival O
among O
salinity O
treatments O
. O

Results O
of O
Kaplan O
- O
Meier O
survival O
analysis O
indicated O
that O
3 O
. O
0 O
ppt O
- O
- O
> O
3 O
. O
0 O
ppt O
shrimp O
were O
more O
sensitive O
to O
Cd B
( I
2 I
+ I
) I
than O
any O
other O
group O
( O
p O
< O
0 O
. O
0001 O
) O
. O

Additionally O
, O
3 O
. O
0 O
ppt O
- O
- O
> O
13 O
. O
5 O
ppt O
shrimp O
were O
less O
sensitive O
to O
Cd B
( I
2 I
+ I
) I
than O
were O
24 O
. O
0 O
ppt O
- O
- O
> O
13 O
. O
5 O
ppt O
shrimp O
( O
p O
= O
0 O
. O
0013 O
) O
. O

These O
results O
suggest O
that O
sensitivity O
of O
grass O
shrimp O
to O
Cd B
is O
dependent O
upon O
the O
salinity O
during O
exposure O
, O
and O
the O
salinity O
regime O
from O
which O
the O
tested O
population O
originated O
. O

The O
implication O
is O
that O
toxicity O
studies O
and O
risk O
assessments O
using O
euryhaline O
crustaceans O
should O
consider O
the O
salinity O
of O
test O
population O
collection O
sites O
when O
interpreting O
and O
comparing O
results O
. O

Enhancement O
of O
hepatic O
4 O
- O
hydroxylation O
of O
25 B
- I
hydroxyvitamin I
D3 I
through O
CYP3A4 O
induction O
in O
vitro O
and O
in O
vivo O
: O
Implications O
for O
drug O
- O
induced O
osteomalacia O
. O

Long O
- O
term O
therapy O
with O
certain O
drugs O
, O
especially O
cytochrome O
P450 O
( O
P450 O
; O
CYP O
) O
- O
inducing O
agents O
, O
confers O
an O
increased O
risk O
of O
osteomalacia O
that O
is O
attributed O
to O
vitamin B
D I
deficiency O
. O

Human O
CYP24A1 O
, O
CYP3A4 O
, O
and O
CYP27B1 O
catalyze O
the O
inactivation O
and O
activation O
of O
vitamin B
D I
and O
have O
been O
implicated O
in O
the O
adverse O
drug O
response O
. O

In O
this O
study O
, O
the O
inducibility O
of O
these O
enzymes O
and O
monohydroxylation O
of O
25 B
- I
hydroxyvitamin I
D3 I
( O
25OHD3 B
) O
were O
evaluated O
after O
exposure O
to O
P450 O
- O
inducing O
drugs O
. O

With O
human O
hepatocytes O
, O
treatment O
with O
phenobarbital B
, O
hyperforin B
, O
carbamazepine B
, O
and O
rifampin B
significantly O
increased O
the O
levels O
of O
CYP3A4 O
, O
but O
not O
CYP24A1 O
or O
CYP27B1 O
mRNA O
. O

In O
addition O
, O
rifampin B
pretreatment O
resulted O
in O
an O
8 O
- O
fold O
increase O
in O
formation O
of O
the O
major O
metabolite O
of O
25OHD3 B
, O
4 B
beta I
, I
25 I
( I
OH I
) I
2 I
D3 I
. O

This O
inductive O
effect O
was O
blocked O
by O
the O
addition O
of O
6 B
' I
, I
7 I
' I
- I
dihydroxybergamottin I
, O
a O
selective O
CYP3A4 O
inhibitor O
. O

With O
human O
renal O
proximal O
tubular O
HK O
- O
2 O
cells O
, O
treatment O
with O
the O
same O
inducers O
did O
not O
alter O
CYP3A4 O
, O
CYP24A1 O
, O
or O
CYP27B1 O
expression O
. O

24R B
, I
25 I
( I
OH I
) I
2 I
D3 I
was O
the O
predominant O
monohydroxy B
metabolite O
produced O
from O
25OHD3 B
, O
but O
its O
formation O
was O
unaffected O
by O
the O
inducers O
. O

With O
healthy O
volunteers O
, O
the O
mean O
plasma O
concentration O
of O
4 B
beta I
, I
25 I
( I
OH I
) I
2 I
D3 I
was O
increased O
60 O
% O
( O
p O
< O
0 O
. O
01 O
) O
after O
short O
- O
term O
rifampin B
administration O
. O

This O
was O
accompanied O
by O
a O
statistically O
significant O
reduction O
in O
plasma O
1 B
alpha I
, I
25 I
( I
OH I
) I
2 I
D3 I
( O
- O
10 O
% O
; O
p O
= O
0 O
. O
03 O
) O
, O
and O
a O
nonsignificant O
change O
in O
24R B
, I
25 I
( I
OH I
) I
2 I
D3 I
( O
- O
8 O
% O
; O
p O
= O
0 O
. O
09 O
) O
levels O
. O

Further O
analysis O
revealed O
a O
negative O
correlation O
between O
the O
increase O
in O
4 B
beta I
, I
25 I
( I
OH I
) I
2 I
D3 I
and O
decrease O
in O
1 B
alpha I
, I
25 I
( I
OH I
) I
2 I
D3 I
levels O
. O

Examination O
of O
the O
plasma O
monohydroxy B
metabolite O
/ O
25OHD3 B
ratios O
indicated O
selective O
induction O
of O
the O
CYP3A4 O
- O
dependent O
4 O
beta O
- O
hydroxylation O
pathway O
of O
25OHD3 B
elimination O
. O

These O
results O
suggest O
that O
induction O
of O
hepatic O
CYP3A4 O
may O
be O
important O
in O
the O
etiology O
of O
drug O
- O
induced O
osteomalacia O
. O

( O
c O
) O
2013 O
American O
Society O
for O
Bone O
and O
Mineral O
Research O
. O

Nonallelic O
homologous O
recombination O
between O
retrotransposable O
elements O
is O
a O
driver O
of O
de O
novo O
unbalanced O
translocations O
. O

Large O
- O
scale O
analysis O
of O
balanced O
chromosomal O
translocation O
breakpoints O
has O
shown O
nonhomologous O
end O
joining O
and O
microhomology O
- O
mediated O
repair O
to O
be O
the O
main O
drivers O
of O
interchromosomal O
structural O
aberrations O
. O

Breakpoint O
sequences O
of O
de O
novo O
unbalanced O
translocations O
have O
not O
yet O
been O
investigated O
systematically O
. O

We O
analyzed O
12 O
de O
novo O
unbalanced O
translocations O
and O
mapped O
the O
breakpoints O
in O
nine O
. O

Surprisingly O
, O
in O
contrast O
to O
balanced O
translocations O
, O
we O
identify O
nonallelic O
homologous O
recombination O
( O
NAHR O
) O
between O
( O
retro O
) O
transposable O
elements O
and O
especially O
long O
interspersed O
elements O
( O
LINEs O
) O
as O
the O
main O
mutational O
mechanism O
. O

This O
finding O
shows O
yet O
another O
involvement O
of O
( O
retro O
) O
transposons O
in O
genomic O
rearrangements O
and O
exposes O
a O
profoundly O
different O
mutational O
mechanism O
compared O
with O
balanced O
chromosomal O
translocations O
. O

Furthermore O
, O
we O
show O
the O
existence O
of O
compound O
maternal O
/ O
paternal O
derivative O
chromosomes O
, O
reinforcing O
the O
hypothesis O
that O
human O
cleavage O
stage O
embryogenesis O
is O
a O
cradle O
of O
chromosomal O
rearrangements O
. O

Bioengineered O
chimeric O
spider O
silk O
- O
uranium B
binding O
proteins O
. O

Heavy O
metals O
constitute O
a O
source O
of O
environmental O
pollution O
. O

Here O
, O
novel O
functional O
hybrid O
biomaterials O
for O
specific O
interactions O
with O
heavy O
metals O
are O
designed O
by O
bioengineering O
consensus O
sequence O
repeats O
from O
spider O
silk O
of O
Nephila O
clavipes O
with O
repeats O
of O
a O
uranium B
peptide O
recognition O
motif O
from O
a O
mutated O
33 O
- O
residue O
of O
calmodulin O
protein O
from O
Paramecium O
tetraurelia O
. O

The O
self O
- O
assembly O
features O
of O
the O
silk O
to O
control O
nanoscale O
organic O
/ O
inorganic O
material O
interfaces O
provides O
new O
biomaterials O
for O
uranium B
recovery O
. O

With O
subsequent O
enzymatic O
digestion O
of O
the O
silk O
to O
concentrate O
the O
sequestered O
metals O
, O
options O
can O
be O
envisaged O
to O
use O
these O
new O
chimeric O
protein O
systems O
in O
environmental O
engineering O
, O
including O
to O
remediate O
environments O
contaminated O
by O
uranium B
. O

Interparticle O
dispersion O
, O
membrane O
curvature O
, O
and O
penetration O
induced O
by O
single O
- O
walled O
carbon B
nanotubes O
wrapped O
with O
lipids O
and O
PEGylated O
lipids O
. O

Single O
- O
walled O
carbon B
nanotubes O
( O
SWNTs O
) O
wrapped O
with O
different O
types O
of O
lipids O
and O
polyethylene B
glycol I
( O
PEG B
) O
- O
grafted O
lipids O
were O
simulated O
with O
lipid O
bilayers O
. O

Simulations O
were O
carried O
out O
with O
the O
previously O
parametrized O
coarse O
- O
grained O
( O
CG O
) O
SWNT O
and O
PEG B
force O
fields O
that O
had O
captured O
the O
experimentally O
observed O
conformations O
of O
self O
- O
assembled O
SWNT O
- O
lipid O
complexes O
and O
phase O
behavior O
of O
PEG B
- O
grafted O
lipids O
. O

Simulations O
of O
multiple O
copies O
of O
the O
SWNT O
in O
water O
show O
that O
all O
pure O
SWNTs O
aggregate O
, O
lipid O
- O
wrapped O
SWNTs O
partially O
aggregate O
, O
but O
those O
wrapped O
with O
lipids O
grafted O
to O
PEG B
( O
M O
( O
w O
) O
= O
550 O
) O
completely O
disperse O
, O
indicating O
the O
effect O
of O
short O
PEG B
chains O
on O
interparticle O
aggregation O
, O
in O
agreement O
with O
experiment O
. O

Starting O
with O
initial O
SWNT O
orientation O
parallel O
to O
the O
bilayer O
surface O
, O
SWNTs O
wrapped O
with O
lysophospholipids B
and O
PEG B
( O
M O
( O
w O
) O
= O
550 O
) O
- O
grafted O
lipids O
insert O
into O
the O
hydrophobic O
region O
of O
the O
bilayer O
, O
while O
SWNTs O
wrapped O
with O
phospholipids O
and O
longer O
PEG B
( O
M O
( O
w O
) O
= O
2000 O
) O
- O
grafted O
lipids O
do O
not O
. O

These O
indicate O
that O
SWNTs O
insert O
because O
of O
the O
hydrophobic O
interaction O
with O
the O
bilayer O
tails O
, O
but O
the O
tight O
wrapping O
of O
charged O
lipid O
headgroups O
and O
long O
hydrophilic O
PEG B
chains O
can O
weaken O
the O
hydrophobic O
interaction O
and O
inhibit O
SWNT O
insertion O
. O

The O
inserted O
SWNTs O
contact O
the O
entire O
tails O
of O
neighboring O
lipids O
in O
one O
leaflet O
of O
the O
bilayer O
, O
which O
disorders O
the O
lipid O
bilayer O
and O
induces O
positive O
curvature O
. O

Our O
findings O
indicate O
that O
interparticle O
aggregation O
, O
SWNT O
penetration O
, O
and O
membrane O
curvature O
can O
be O
modulated O
by O
the O
SWNT O
- O
lipid O
structure O
and O
the O
PEG B
length O
. O

Radiosynthesis O
and O
evaluation O
of O
[ B
( I
1 I
) I
( I
1 I
) I
C I
- I
carbonyl I
] I
- I
labeled I
carbamates I
as O
fatty B
acid I
amide I
hydrolase O
radiotracers O
for O
positron O
emission O
tomography O
. O

Fatty B
acid I
amide I
hydrolase O
( O
FAAH O
) O
plays O
a O
key O
role O
in O
regulating O
the O
tone O
of O
the O
endocannabinoid O
system O
. O

Radiotracers O
are O
required O
to O
image O
and O
quantify O
FAAH O
activity O
in O
vivo O
. O

We O
have O
synthesized O
a O
series O
of O
potent O
FAAH O
inhibitors O
encompassing O
two O
classes O
of O
N B
- I
alkyl I
- I
O I
- I
arylcarbamates I
and O
radiolabeled O
eight O
of O
them O
with O
carbon B
- O
11 O
. O

The O
[ O
( B
1 I
) I
( I
1 I
) I
C I
- I
carbonyl I
] O
- O
radiotracers O
were O
evaluated O
in O
vitro O
and O
ex O
vivo O
in O
rats O
as O
potential O
FAAH O
imaging O
agents O
for O
positron O
emission O
tomography O
( O
PET O
) O
. O

Both O
sets O
of O
[ B
( I
1 I
) I
( I
1 I
) I
C I
] I
O I
- I
arylcarbamates I
showed O
good O
to O
excellent O
brain O
penetration O
and O
an O
appropriate O
regional O
distribution O
. O

Pretreatments O
with O
a O
FAAH O
inhibitor O
demonstrated O
that O
80 O
- O
95 O
% O
of O
brain O
uptake O
of O
radioactivity O
constituted O
binding O
of O
the O
radiotracers O
to O
FAAH O
. O

Brain O
extraction O
measurements O
showed O
that O
binding O
to O
FAAH O
was O
irreversible O
and O
kinetically O
different O
for O
the O
two O
classes O
of O
carbamates B
. O

These O
promising O
results O
are O
discussed O
in O
terms O
of O
the O
requirements O
of O
a O
suitable O
radiotracer O
for O
the O
in O
vivo O
imaging O
of O
FAAH O
using O
PET O
. O

Foams O
stabilized O
by O
multilamellar O
polyglycerol B
ester I
self O
- O
assemblies O
. O

The O
importance O
of O
surfactant O
self O
- O
assemblies O
in O
foam O
stabilization O
is O
well O
- O
known O
. O

The O
aim O
of O
the O
current O
study O
was O
to O
investigate O
the O
self O
- O
assemblies O
of O
the O
nonionic O
surfactant O
polyglycerol B
ester I
( O
PGE B
) O
in O
bulk O
solutions O
, O
at O
the O
interface O
and O
within O
foams O
, O
using O
a O
combined O
approach O
of O
small O
- O
angle O
neutron O
scattering O
, O
neutron O
reflectivity O
, O
and O
electron O
microscopy O
. O

PGE B
bulk O
solutions O
contain O
vesicles O
as O
well O
as O
open O
lamellar O
structures O
. O

Upon O
heating O
of O
the O
solutions O
the O
lamellar O
spacing O
increases O
, O
with O
significant O
differences O
in O
the O
presence O
of O
NaCl B
or O
CaCl B
( I
2 I
) I
as O
compared O
to O
the O
standard O
solution O
. O

The O
adsorption O
of O
the O
multilamellar O
structures O
present O
in O
the O
bulk O
solutions O
lead O
to O
a O
multilayered O
film O
at O
the O
air O
- O
water O
interface O
. O

The O
ordering O
within O
this O
film O
was O
increased O
as O
a O
result O
of O
a O
20 O
% O
area O
compression O
mimicking O
a O
coalescence O
event O
. O

Finally O
, O
PGE B
foams O
were O
shown O
to O
be O
stabilized O
not O
only O
by O
strong O
interfacial O
films O
but O
also O
by O
agglomerated O
self O
- O
assemblies O
within O
the O
interstitial O
areas O
of O
the O
foams O
. O

Analysis O
of O
15N B
- I
1H I
NMR O
relaxation O
in O
proteins O
by O
a O
combined O
experimental O
and O
molecular O
dynamics O
simulation O
approach O
: O
picosecond O
- O
nanosecond O
dynamics O
of O
the O
Rho O
GTPase O
binding O
domain O
of O
plexin O
- O
B1 O
in O
the O
dimeric O
state O
indicates O
allosteric O
pathways O
. O

We O
investigate O
picosecond O
- O
nanosecond O
dynamics O
of O
the O
Rho O
- O
GTPase O
Binding O
Domain O
( O
RBD O
) O
of O
plexin O
- O
B1 O
, O
which O
plays O
a O
key O
role O
in O
plexin O
- O
mediated O
cell O
signaling O
. O

Backbone O
15N B
relaxation O
data O
of O
the O
dimeric O
RBD O
are O
analyzed O
with O
the O
model O
- O
free O
( O
MF O
) O
method O
, O
and O
with O
the O
slowly O
relaxing O
local O
structure O
/ O
molecular O
dynamics O
( O
SRLS O
- O
MD O
) O
approach O
. O

Independent O
analysis O
of O
the O
MD O
trajectories O
, O
based O
on O
the O
MF O
paradigm O
, O
is O
also O
carried O
out O
. O

MF O
is O
a O
widely O
popular O
and O
simple O
method O
, O
SRLS O
is O
a O
general O
approach O
, O
and O
SRLS O
- O
MD O
is O
an O
integrated O
approach O
we O
developed O
recently O
. O

Corresponding O
parameters O
from O
the O
RBD O
dimer O
, O
a O
previously O
studied O
RBD O
monomer O
mutant O
, O
and O
the O
previously O
studied O
complex O
of O
the O
latter O
with O
the O
GTPase O
Rac1 O
, O
are O
compared O
. O

The O
L2 O
, O
L3 O
, O
and O
L4 O
loops O
of O
the O
plexin O
- O
B1 O
RBD O
are O
involved O
in O
interactions O
with O
other O
plexin O
domains O
, O
GTPase O
binding O
, O
and O
RBD O
dimerization O
, O
respectively O
. O

Peptide O
groups O
in O
the O
loops O
of O
both O
the O
monomeric O
and O
dimeric O
RBD O
are O
found O
to O
experience O
weak O
and O
moderately O
asymmetric O
local O
ordering O
centered O
approximately O
at O
the O
C O
( O
i O
- O
1 O
) O
( O
alpha O
) O
- O
C O
( O
i O
) O
( O
alpha O
) O
axes O
, O
and O
nanosecond O
backbone O
motion O
. O

Peptide O
groups O
in O
the O
alpha O
- O
helices O
and O
the O
beta O
- O
strands O
of O
the O
dimer O
( O
the O
beta O
- O
strands O
of O
the O
monomer O
) O
experience O
strong O
and O
highly O
asymmetric O
local O
ordering O
centered O
approximately O
at O
the O
C O
( O
i O
- O
1 O
) O
( O
alpha O
) O
- O
C O
( O
i O
) O
( O
alpha O
) O
axes O
( O
N B
- I
H I
bonds O
) O
. O

N B
- I
H I
fluctuations O
occur O
on O
the O
picosecond O
time O
scale O
. O

An O
allosteric O
pathway O
for O
GTPase O
binding O
, O
providing O
new O
insights O
into O
plexin O
function O
, O
is O
delineated O
. O

Surface O
- O
scribed O
transparency O
- O
based O
microplates O
. O

Transparency O
sheets O
, O
which O
are O
normally O
associated O
with O
use O
on O
overhead O
projectors O
, O
offer O
lowered O
costs O
and O
high O
amenability O
for O
optical O
diagnostics O
in O
microplate O
instrumentation O
. O

An O
alternative O
microplate O
design O
in O
which O
circles O
are O
scribed O
on O
the O
surface O
of O
the O
transparency O
to O
create O
the O
boundaries O
to O
hold O
the O
drop O
in O
place O
is O
investigated O
here O
. O

The O
3D O
profile O
of O
the O
scribed O
regions O
obtained O
optically O
showed O
strong O
likelihood O
of O
affecting O
three O
- O
phase O
contact O
line O
interactions O
. O

During O
dispensation O
, O
the O
contact O
angle O
( O
= O
~ O
95 O
degrees O
) O
was O
larger O
than O
the O
drop O
advancing O
state O
( O
= O
~ O
80 O
degrees O
) O
due O
to O
a O
period O
of O
nonadhesion O
, O
where O
the O
contact O
angle O
later O
reduced O
to O
the O
drop O
advancing O
state O
followed O
by O
increase O
in O
the O
liquid O
area O
coverage O
on O
the O
substrate O
. O

It O
was O
established O
that O
50 O
mu O
L O
was O
needed O
to O
fill O
the O
well O
fully O
, O
and O
the O
maximum O
volume O
retainable O
before O
breaching O
was O
190 O
mu O
L O
. O

While O
the O
tilt O
angle O
needed O
for O
displacement O
reduced O
significantly O
from O
50 O
to O
95 O
mu O
L O
, O
this O
was O
markedly O
better O
than O
nonscribed O
surfaces O
, O
where O
tilt O
angles O
always O
had O
to O
be O
kept O
to O
within O
30 O
degrees O
. O

It O
was O
found O
that O
there O
was O
greater O
ability O
to O
fill O
the O
well O
with O
smaller O
volumes O
with O
dispensation O
at O
the O
center O
. O

This O
was O
attributed O
to O
the O
growing O
contact O
line O
not O
meeting O
the O
scribed O
edge O
in O
parallel O
if O
liquid O
was O
dispensed O
closer O
to O
it O
, O
wherein O
pinning O
reduction O
in O
some O
directions O
permitted O
liquid O
travel O
along O
the O
scribed O
edge O
to O
undergo O
contact O
angle O
hysteresis O
. O

Fluorescence O
measurements O
conducted O
showed O
no O
performance O
compromise O
when O
using O
scribed O
transparency O
microplates O
over O
standard O
microplates O
. O

Amplified O
fluorescent O
sensing O
of O
DNA O
using O
graphene B
oxide I
and O
a O
conjugated O
cationic O
polymer O
. O

We O
explore O
the O
interactions O
between O
a O
fluorescein B
( O
FAM B
) O
- O
labeled O
single O
- O
stranded O
DNA O
( O
P O
) O
, O
graphene B
oxide I
( O
GO O
) O
, O
and O
a O
cationic O
conjugated O
polymer O
, O
poly B
[ I
( I
9 I
, I
9 I
- I
bis I
( I
6 I
' I
- I
N I
, I
N I
, I
N I
- I
trimethylammonium I
) I
hexyl I
) I
- I
fluorenylene I
phenylene I
dibromide I
] I
( O
PFP B
) O
. O

It O
is O
found O
that O
the O
fluorescence O
change O
of O
P O
- O
GO O
- O
PFP B
system O
is O
dependent O
on O
the O
addition O
order O
of O
P O
and O
PFP B
. O

When O
adding O
PFP O
into O
P O
/ O
GO O
complex O
, O
the O
fluorescence O
resonance O
energy O
transfer O
( O
FRET O
) O
from O
PFP O
to O
P O
is O
inefficient O
. O

If O
P O
is O
added O
to O
PFP O
/ O
GO O
complex O
, O
efficient O
FRET O
is O
obtained O
. O

This O
may O
be O
attributed O
to O
the O
equal O
binding O
ability O
for O
P O
and O
PFP B
to O
GO O
. O

The O
results O
of O
time O
- O
resolved O
fluorescence O
and O
fluorescence O
anisotropy O
support O
the O
different O
fluorescent O
response O
under O
different O
addition O
order O
of O
P O
and O
PFP B
to O
GO O
. O

Based O
on O
the O
above O
phenomenon O
, O
we O
demonstrate O
a O
method O
to O
reduce O
the O
high O
background O
signal O
of O
a O
traditional O
PFP O
- O
based O
DNA O
sensor O
by O
introducing O
GO O
. O

In O
comparison O
to O
the O
use O
of O
single O
PFP B
, O
the O
combination O
of O
PFP B
with O
GO O
- O
based O
method O
shows O
enhanced O
sensitivity O
with O
a O
detection O
limit O
as O
low O
as O
40 O
pM O
for O
target O
DNA O
detection O
. O

Alpha O
- O
heteroatom O
derivatized O
analogues O
of O
3 B
- I
( I
acetylhydroxyamino I
) I
propyl I
phosphonic I
acid I
( O
FR900098 B
) O
as O
antimalarials O
. O

To O
explore O
the O
hitherto O
successful O
derivatization O
of O
the O
alpha B
- I
carbon I
of O
fosmidomycin B
, O
a O
series O
of O
new O
alpha O
- O
substituted O
analogues O
was O
prepared O
. O

This O
was O
done O
by O
introduction O
of O
a O
heteroatom O
( O
N B
or O
O B
) O
in O
alpha O
- O
position O
to O
the O
phosphonate B
and O
using O
the O
resultant O
OH B
and O
NH B
2 I
groups O
as O
a O
handle O
for O
appending O
a O
variety O
of O
substituents O
by O
means O
of O
several O
functional O
groups O
such O
as O
ether B
, O
amide B
, O
urea B
, O
and O
1 B
, I
4 I
- I
triazole I
. O

The O
synthesized O
molecules O
, O
as O
a O
racemic O
mixture O
, O
were O
assayed O
for O
their O
EcDXR O
inhibitory O
potency O
. O

Both O
the O
alpha B
- I
azido I
- O
analogue O
and O
the O
alpha O
- O
hydroxylated O
analogue O
proved O
most O
promising O
, O
and O
docking O
experiments O
were O
performed O
. O

Although O
several O
compounds O
showed O
high O
potency O
when O
assayed O
against O
Plasmodium O
falciparum O
K1 O
in O
human O
erythrocytes O
, O
a O
clear O
correlation O
between O
the O
enzyme O
inhibition O
constants O
and O
P O
. O
falciparum O
inhibition O
concentrations O
could O
not O
be O
found O
. O

Super O
- O
resolution O
mapping O
of O
reactive O
sites O
on O
titania B
- O
based O
nanoparticles O
with O
water O
- O
soluble O
fluorogenic O
probes O
. O

Interfacial O
charge O
transfer O
at O
the O
heterogeneous O
surface O
of O
semiconductor O
nanoparticles O
is O
a O
fundamental O
process O
that O
is O
relevant O
to O
many O
important O
applications O
, O
such O
as O
photocatalysis O
, O
solar O
cells O
, O
and O
sensors O
. O

In O
this O
study O
, O
we O
developed O
new O
water O
- O
soluble O
fluorogenic O
probes O
for O
interfacial O
electron O
transfer O
reactions O
on O
semiconductor O
nanoparticles O
. O

The O
synthesized O
boron B
- I
dipyrromethene I
- O
based O
fluorescence O
dyes O
have O
one O
or O
two O
sulfonate B
groups O
, O
which O
confer O
solubility O
in O
aqueous O
media O
, O
and O
a O
dinitrophenyl B
group O
as O
a O
redox O
reaction O
site O
. O

These O
probes O
produce O
the O
corresponding O
fluorescent O
products O
via O
multiple O
interfacial O
electron O
transfer O
processes O
, O
allowing O
us O
to O
investigate O
the O
photoinduced O
redox O
reactions O
over O
individual O
pristine O
and O
Au B
- O
nanoparticle O
- O
deposited O
TiO B
( I
2 I
) I
nanoparticles O
at O
the O
single O
- O
particle O
, O
single O
- O
molecule O
levels O
. O

The O
minimum O
probe O
concentration O
to O
detect O
single O
- O
product O
molecules O
on O
a O
single O
TiO B
( I
2 I
) I
nanoparticle O
was O
found O
to O
be O
in O
the O
nanomolar O
range O
( O
< O
10 O
nM O
) O
in O
acidic O
solution O
. O

Furthermore O
, O
super O
- O
resolution O
mapping O
of O
the O
reaction O
sites O
revealed O
that O
visible O
- O
light O
- O
induced O
reduction O
reactions O
preferentially O
occurred O
on O
the O
TiO B
( I
2 I
) I
surface O
within O
a O
distance O
of O
a O
few O
tens O
of O
nanometers O
around O
the O
deposited O
Au B
nanoparticles O
. O

This O
result O
was O
qualitatively O
interpreted O
on O
the O
basis O
of O
plasmon O
- O
induced O
electron O
and O
/ O
or O
energy O
transfer O
mechanisms O
. O

Overall O
, O
this O
study O
provides O
a O
great O
deal O
of O
valuable O
information O
related O
to O
solar O
- O
energy O
- O
conversion O
processes O
that O
is O
impossible O
or O
difficult O
to O
obtain O
from O
ensemble O
- O
averaged O
experiments O
. O

Self O
- O
assembled O
pH O
- O
sensitive O
cholesteryl B
pullulan O
nanogel O
as O
a O
protein O
delivery O
vehicle O
. O

A O
self O
- O
assembled O
nanogel O
, O
derived O
from O
an O
acid O
- O
labile O
cholesteryl B
- O
modified O
pullulan O
( O
acL O
- O
CHP O
) O
, O
was O
prepared O
by O
grafting O
vinyl B
ether I
- O
cholesterol B
substituents O
onto O
a O
100 O
kD O
pullulan O
main O
chain O
polymer O
backbone O
. O

Stable O
nanogels O
are O
formed O
by O
acL B
- I
CHP I
self O
- O
assemblies O
at O
neutral O
pH O
. O

The O
hydrodynamic O
radius O
of O
the O
nanogels O
, O
observed O
to O
be O
26 O
. O
5 O
+ O
/ O
- O
5 O
. O
1 O
nm O
at O
pH O
7 O
. O
0 O
, O
increased O
by O
~ O
135 O
% O
upon O
acidification O
of O
the O
solution O
to O
pH O
4 O
. O
0 O
. O

SEC O
analysis O
of O
the O
acL O
- O
CHP B
nanogel O
at O
pH O
4 O
. O
0 O
showed O
that O
the O
grafts O
were O
nearly O
80 O
% O
degraded O
after O
24 O
h O
, O
whereas O
little O
or O
no O
degradation O
was O
observed O
over O
the O
same O
time O
period O
for O
a O
pH O
stable O
analog O
( O
acS B
- I
CHP I
) O
at O
pH O
4 O
. O
0 O
or O
the O
acL O
- O
CHP B
at O
pH O
7 O
. O
0 O
. O

Complexation O
of O
BSA O
with O
the O
acL O
- O
CHP O
nanogel O
was O
observed O
at O
pH O
7 O
. O
0 O
with O
subsequent O
release O
of O
the O
protein O
upon O
acidification O
. O

These O
findings O
suggest O
that O
stimuli O
- O
responsive O
, O
self O
- O
assembled O
nanogels O
can O
release O
protein O
cargo O
in O
a O
manner O
that O
is O
controlled O
by O
the O
degradation O
rate O
of O
the O
cholesterol B
- O
pullulan O
grafting O
moiety O
. O

An O
ultrastrong O
nanofibrillar O
biomaterial O
: O
the O
strength O
of O
single O
cellulose O
nanofibrils O
revealed O
via O
sonication O
- O
induced O
fragmentation O
. O

We O
report O
the O
mechanical O
strength O
of O
native O
cellulose O
nanofibrils O
. O

Native O
cellulose O
nanofibrils O
, O
purified O
from O
wood O
and O
sea O
tunicate O
, O
were O
fully O
dispersed O
in O
water O
via O
a O
topochemical O
modification O
of O
cellulose O
nanofibrils O
using O
2 B
, I
2 I
, I
6 I
, I
6 I
- I
tetramethylpiperidin I
- I
1 I
- I
oxyl I
( O
TEMPO B
) O
as O
a O
catalyst O
. O

The O
strength O
of O
individual O
nanofibrils O
was O
estimated O
based O
on O
a O
model O
for O
the O
sonication O
- O
induced O
fragmentation O
of O
filamentous O
nanostructures O
. O

The O
resulting O
strength O
parameters O
were O
then O
analyzed O
based O
on O
fracture O
statistics O
. O

The O
mean O
strength O
of O
the O
wood O
cellulose O
nanofibrils O
ranged O
from O
1 O
. O
6 O
to O
3 O
GPa O
, O
depending O
on O
the O
method O
used O
to O
measure O
the O
nanofibril O
width O
. O

The O
highly O
crystalline O
, O
thick O
tunicate O
cellulose O
nanofibrils O
exhibited O
higher O
mean O
strength O
of O
3 O
- O
6 O
GPa O
. O

The O
strength O
values O
estimated O
for O
the O
cellulose O
nanofibrils O
in O
the O
present O
study O
are O
comparable O
with O
those O
of O
commercially O
available O
multiwalled O
carbon B
nanotubes O
. O

Synergistic O
activity O
and O
mechanism O
of O
action O
of O
ceftazidime B
and O
apigenin B
combination O
against O
ceftazidime B
- O
resistant O
Enterobacter O
cloacae O
. O

The O
purpose O
of O
this O
investigation O
was O
to O
examine O
the O
antibacterial O
and O
synergistic O
effect O
of O
naturally O
occurring O
flavonoids B
, O
apigenin B
, O
quercetin B
, O
naringenin B
and O
ceftazidime B
when O
use O
singly O
and O
in O
combination O
against O
ceftazidime B
- O
resistant O
Enterobacter O
cloacae O
strains O
by O
minimum O
inhibitory O
concentration O
( O
MIC O
) O
, O
checkerboard O
and O
viable O
count O
methods O
. O

The O
mode O
of O
actions O
were O
also O
studied O
by O
electronmicoscopy O
, O
enzyme O
assay O
, O
outer O
and O
inner O
membrane O
permeabilisation O
. O

The O
results O
showed O
that O
these O
strains O
were O
positive O
in O
the O
ESBL O
- O
ampC O
genes O
combination O
by O
multiplex O
PCR O
. O

These O
findings O
were O
confirmed O
by O
MICs O
that O
these O
strains O
were O
resistant O
to O
ceftazidime B
, O
cefepime B
and O
flomoxef B
at O
> O
1024 O
, O
16 O
- O
24 O
, O
> O
256 O
mu O
g O
/ O
ml O
respectively O
, O
while O
susceptible O
to O
imipenem B
at O
1 O
- O
2 O
mu O
g O
/ O
ml O
. O

The O
synergistic O
activity O
was O
observed O
at O
ceftazidime B
plus O
either O
apigenin B
or O
naringenin B
combinations O
with O
FIC O
indixes O
between O
< O
0 O
. O
01 O
and O
< O
0 O
. O
27 O
against O
these O
strains O
, O
whereas O
ceftazidime B
plus O
clavulanic B
acid I
or O
quercetin B
did O
not O
exhibit O
synergy O
. O

The O
modulation O
of O
ceftazidime B
- O
resistance O
by O
apigenin B
or O
narigenin B
significantly O
enhanced O
the O
activities O
of O
ceftazidime B
. O

The O
5 B
, I
7 I
- I
OH I
group O
of O
A O
ring O
and O
one O
4 B
' I
- I
OH I
group O
of O
the O
B O
ring O
in O
apigenin B
and O
naringenin B
are O
important O
for O
synergistic O
activity O
. O

Viable O
counts O
showed O
that O
the O
killing O
of O
ceftazidime B
- O
resistant O
E O
. O
cloacae O
DMST O
21394 O
( O
CREC O
) O
cells O
by O
3 O
mu O
g O
/ O
ml O
ceftazidime B
was O
potentiated O
by O
3 O
mu O
g O
/ O
ml O
apigenin B
to O
low O
levels O
( O
10 O
( O
3 O
) O
cfu O
/ O
ml O
) O
over O
6h O
. O

Electronmicroscopy O
clearly O
showed O
that O
ceftazidime B
3 O
mu O
g O
/ O
ml O
in O
combination O
with O
3 O
mu O
g O
/ O
ml O
of O
apigenin B
also O
caused O
marked O
morphological O
damage O
of O
cell O
wall O
, O
cell O
shape O
and O
plasma O
membrane O
of O
this O
strain O
. O

Enzymes O
assays O
indicated O
that O
apigenin B
showed O
marked O
inhibitory O
activity O
against O
penicillinase O
type O
IV O
from O
E O
. O
cloacae O
. O

The O
results O
for O
outer O
membrane O
( O
OM O
) O
permeabilization O
in O
both O
nitrocefin B
( O
NCF B
) O
assay O
and O
crystal B
violet I
uptake O
showed O
that O
the O
combination O
of O
ceftazidime B
plus O
apigenin B
significantly O
altered O
OM O
permeabilisation O
of O
CREC O
compared O
to O
control O
or O
single O
treatment O
of O
these O
agents O
. O

Both O
o B
- I
nitrophenyl I
- I
beta I
- I
D I
- I
galactoside I
( O
ONPG B
) O
uptake O
and O
release O
of O
UV O
- O
absorbing O
material O
concentrations O
results O
exhibited O
that O
ceftazidime B
and O
apigenin B
combination O
damaged O
CREC O
cytoplasmic O
membrane O
( O
CM O
) O
and O
caused O
subsequent O
leakage O
of O
intracellular O
constituents O
. O

From O
the O
results O
, O
it O
can O
be O
concluded O
that O
apigenin B
and O
naringenin B
have O
the O
synergistic O
effect O
with O
ceftazidime B
to O
reverse O
bacterial O
resistance O
to O
this O
cephalosporin B
against O
CREC O
. O

This O
activity O
may O
be O
involved O
three O
mechanisms O
of O
action O
by O
apigenin B
. O

The O
first O
is O
on O
the O
peptidoglycan O
synthesis O
inhibition O
. O

The O
second O
mechanism O
is O
inhibition O
the O
activity O
of O
certain O
beta O
- O
lactamase O
enzymes O
. O

The O
third O
mode O
of O
action O
is O
alteration O
of O
OM O
and O
CM O
permeabilization O
. O

Apigenin B
and O
naringenin B
have O
a O
sufficient O
margin O
of O
safety O
for O
therapeutic O
use O
. O

For O
this O
reason O
, O
apigenin B
and O
naringenin B
offer O
for O
the O
development O
of O
a O
valuable O
adjunct O
to O
ceftazidime B
against O
CREC O
, O
which O
currently O
almost O
cephalosporins O
resistance O
. O

Fragment O
- O
based O
discovery O
of O
novel O
and O
selective O
mPGES O
- O
1 O
inhibitors O
Part O
1 O
: O
identification O
of O
sulfonamido B
- I
1 I
, I
2 I
, I
3 I
- I
triazole I
- I
4 I
, I
5 I
- I
dicarboxylic I
acid I
. O

Microsomal O
prostaglandin B
E I
synthase O
- O
1 O
( O
mPGES O
- O
1 O
) O
is O
an O
inducible O
prostaglandin B
E I
synthase O
that O
catalyzes O
the O
conversion O
of O
prostaglandin B
PGH B
( I
2 I
) I
to O
PGE B
( I
2 I
) I
and O
represents O
a O
novel O
target O
for O
therapeutic O
treatment O
of O
inflammatory O
disorders O
. O

It O
is O
essential O
to O
identify O
mPGES O
- O
1 O
inhibitor O
with O
novel O
scaffold O
as O
new O
hit O
or O
lead O
compound O
for O
the O
purpose O
of O
the O
next O
- O
generation O
anti O
- O
inflammatory O
drugs O
. O

Herein O
we O
report O
the O
discovery O
of O
sulfonamido B
- I
1 I
, I
2 I
, I
3 I
- I
triazole I
- I
4 I
, I
5 I
- I
dicarboxylic I
derivatives O
as O
a O
novel O
class O
of O
mPGES O
- O
1 O
inhibitors O
identified O
through O
fragment O
- O
based O
virtual O
screening O
and O
in O
vitro O
assays O
on O
the O
inhibitory O
activity O
of O
the O
actual O
compounds O
. O

1 B
- I
[ I
2 I
- I
( I
N I
- I
Phenylbenzenesulfona I
) I
ethyl I
] I
- I
1H I
- I
1 I
, I
2 I
, I
3 I
- I
triazole I
- I
4 I
, I
5 I
- I
dicarboxylic I
acid I
( O
6f O
) O
inhibits O
human O
mPGES O
- O
1 O
( O
IC O
( O
50 O
) O
of O
1 O
. O
1 O
mu O
M O
) O
with O
high O
selectivity O
( O
ca O
. O
1000 O
- O
fold O
) O
over O
both O
COX O
- O
1 O
and O
COX O
- O
2 O
in O
a O
cell O
- O
free O
assay O
. O

In O
addition O
, O
the O
activity O
of O
compound O
6f O
was O
again O
tested O
at O
10 O
mu O
M O
concentration O
in O
presence O
of O
0 O
. O
1 O
% O
Triton B
X I
- I
100 I
and O
found O
to O
be O
reduced O
to O
1 O
/ O
4 O
of O
its O
original O
activity O
without O
this O
detergent O
. O

Compared O
to O
the O
complete O
loss O
of O
activity O
of O
nuisance O
inhibitor O
with O
the O
detergent O
, O
therefore O
, O
compound O
6f O
would O
be O
regarded O
as O
a O
partial O
nuisance O
inhibitor O
of O
mPGES O
- O
1 O
with O
a O
novel O
scaffold O
for O
the O
optimal O
design O
of O
more O
potent O
mPGES O
- O
1 O
inhibitors O
. O

The O
discovery O
of O
potent O
and O
selective O
4 B
- I
aminothienopyridines I
as O
B O
- O
Raf O
kinase O
inhibitors O
. O

A O
series O
of O
novel O
, O
potent O
4 B
- I
aminothienopyridine I
B O
- O
Raf O
kinase O
inhibitors O
was O
designed O
and O
synthesized O
using O
knowledge O
- O
based O
design O
. O

Compounds O
5f O
, O
and O
6k O
exhibited O
not O
only O
excellent O
potency O
in O
both O
enzyme O
assay O
( O
IC O
( O
50 O
) O
= O
5 O
. O
1 O
, O
16 O
. O
6 O
nM O
) O
and O
cellular O
assay O
( O
IC O
( O
50 O
) O
= O
0 O
. O
2 O
, O
0 O
. O
2 O
mu O
M O
) O
, O
but O
also O
had O
an O
outstanding O
selectivity O
profile O
against O
other O
kinases O
. O

Mutational O
consequences O
of O
dNTP B
pool O
imbalances O
in O
E O
. O
coli O
. O

The O
accuracy O
of O
DNA O
synthesis O
depends O
on O
the O
accuracy O
of O
the O
polymerase O
as O
well O
as O
the O
quality O
and O
concentration O
( O
s O
) O
of O
the O
available O
5 B
' I
- I
deoxynucleoside I
- I
triphosphate I
DNA O
precursors O
( O
dNTPs B
) O
. O

The O
relationships O
between O
dNTPs B
and O
error O
rates O
have O
been O
studied O
in O
vitro O
, O
but O
only O
limited O
insights O
exist O
into O
these O
correlations O
during O
in O
vivo O
replication O
. O

We O
have O
investigated O
this O
issue O
in O
the O
bacterium O
Escherichia O
coli O
by O
analyzing O
the O
mutational O
properties O
of O
dcd O
and O
ndk O
strains O
. O

These O
strains O
, O
defective O
in O
dCTP B
deaminase O
and O
nucleoside B
diphosphate I
kinase O
, O
respectively O
, O
are O
characterized O
by O
both O
disturbances O
of O
dNTP B
pools O
and O
a O
mutator O
phenotype O
. O
ndk O
strains O
have O
been O
studied O
before O
, O
but O
were O
included O
in O
this O
study O
, O
as O
controversies O
exist O
regarding O
the O
source O
of O
its O
mutator O
phenotype O
. O

We O
show O
that O
dcd O
strains O
suffer O
from O
increased O
intracellular O
levels O
of O
dCTP B
( O
4 O
- O
fold O
) O
and O
reduced O
levels O
of O
dGTP B
( O
2 O
- O
fold O
) O
, O
while O
displaying O
, O
as O
measured O
using O
a O
set O
of O
lacZ O
reversion O
markers O
in O
a O
mismatch O
- O
repair O
defective O
( O
mutL O
) O
background O
, O
a O
strong O
mutator O
effect O
for O
G O
. O
C O
- O
- O
> O
T O
. O
A O
and O
A O
. O
T O
- O
- O
> O
T O
. O
A O
transversions O
( O
27 O
- O
and O
42 O
- O
fold O
enhancement O
, O
respectively O
) O
. O

In O
contrast O
, O
ndk O
strains O
possess O
a O
lowered O
dATP B
level O
( O
4 O
- O
fold O
) O
and O
modestly O
enhanced O
dCTP B
level O
( O
2 O
- O
fold O
) O
, O
while O
its O
mutator O
effect O
is O
specific O
for O
just O
the O
A O
. O
T O
- O
- O
> O
T O
. O
A O
transversions O
. O

The O
two O
strains O
also O
display O
differential O
mutability O
for O
rifampicin B
- O
resistant O
mutants O
. O

Overall O
, O
our O
analysis O
reveals O
for O
both O
strains O
a O
satisfactory O
correlation O
between O
dNTP B
pool O
alterations O
and O
the O
replication O
error O
rates O
, O
and O
also O
suggests O
that O
a O
minimal O
explanation O
for O
the O
ndk O
mutator O
does O
not O
require O
assumptions O
beyond O
the O
predicted O
effect O
of O
the O
dNTP B
pools O
. O

Parametrisation O
of O
the O
free O
energy O
of O
ATP B
binding O
to O
wild O
- O
type O
and O
mutant O
Kir6 O
. O
2 O
potassium B
channels O
. O

ATP B
- O
sensitive O
K B
( I
+ I
) I
( O
K B
( O
ATP B
) O
) O
channels O
, O
comprised O
of O
pore O
- O
forming O
Kir6 O
. O
x O
and O
regulatory O
SURx O
subunits O
, O
play O
important O
roles O
in O
many O
cellular O
functions O
; O
because O
of O
their O
sensitivity O
to O
inhibition O
by O
intracellular O
ATP B
, O
K B
( O
ATP B
) O
channels O
provide O
a O
link O
between O
cell O
metabolism O
and O
membrane O
electrical O
activity O
. O

We O
constructed O
structural O
homology O
models O
of O
Kir6 O
. O
2 O
and O
a O
series O
of O
Kir6 O
. O
2 O
channels O
carrying O
mutations O
within O
the O
putative O
ATP B
- O
binding O
site O
. O

Computational O
docking O
was O
carried O
out O
to O
determine O
the O
conformation O
of O
ATP B
in O
its O
binding O
site O
. O

The O
Linear O
Interaction O
Energy O
( O
LIE O
) O
method O
was O
used O
to O
estimate O
the O
free O
- O
energy O
of O
ATP B
binding O
to O
wild O
- O
type O
and O
mutant O
Kir6 O
. O
2 O
channels O
. O

Comparisons O
of O
the O
theoretical O
binding O
free O
energies O
for O
ATP B
with O
those O
determined O
from O
mutational O
experiments O
enabled O
the O
identification O
of O
the O
most O
probable O
conformation O
of O
ATP B
bound O
to O
the O
Kir6 O
. O
2 O
channel O
. O

A O
set O
of O
LIE O
parameters O
was O
defined O
that O
may O
enable O
prediction O
of O
the O
effects O
of O
additional O
Kir6 O
. O
2 O
mutations O
within O
the O
ATP B
binding O
site O
on O
the O
affinity O
for O
ATP B
. O

Achyrofuran B
is O
an O
antibacterial O
agent O
capable O
of O
killing O
methicillin B
- O
resistant O
vancomycin B
- O
intermediate O
Staphylococcus O
aureus O
in O
the O
nanomolar O
range O
. O

Currently O
, O
there O
is O
a O
pressing O
need O
for O
novel O
antibacterial O
agents O
against O
drug O
- O
resistant O
bacteria O
, O
especially O
those O
which O
have O
been O
common O
in O
our O
communities O
and O
hospitals O
, O
such O
as O
methicillin B
- O
resistant O
Staphylococcus O
aureus O
( O
MRSA O
) O
. O

The O
South O
American O
plant O
Achyrocline O
satureioides O
( O
" O
Marcela O
" O
) O
has O
been O
widely O
used O
in O
traditional O
medicine O
for O
a O
number O
of O
diseases O
, O
including O
infections O
. O

Several O
crude O
extracts O
from O
this O
plant O
have O
shown O
good O
antimicrobial O
activities O
in O
vitro O
. O

In O
the O
search O
for O
the O
active O
principle O
( O
s O
) O
that O
confers O
these O
antimicrobial O
activities O
, O
we O
have O
processed O
the O
dichloromethane B
extract O
from O
the O
aerial O
parts O
of O
the O
plant O
. O

One O
of O
the O
isolated O
compounds O
showed O
extraordinary O
antibacterial O
activities O
against O
a O
set O
of O
clinically O
relevant O
Gram O
- O
positive O
strains O
that O
widely O
differ O
in O
their O
antibiogram O
profiles O
. O

This O
compound O
was O
identified O
as O
achyrofuran B
on O
the O
basis O
of O
its O
spectroscopic O
and O
physical O
data O
. O

We O
determined O
the O
MIC O
to O
be O
around O
0 O
. O
1 O
mu O
M O
( O
0 O
. O
07 O
mu O
g O
/ O
ml O
) O
for O
the O
reference O
methicillin B
- O
resistant O
and O
vancomycin B
- O
intermediate O
S O
. O
aureus O
strain O
NRS402 O
. O

Moreover O
, O
nanomolar O
concentrations O
of O
achyrofuran B
killed O
10 O
( O
6 O
) O
bacteria O
within O
12 O
h O
. O

Based O
on O
the O
presence O
of O
the O
2 B
, I
2 I
' I
- I
biphenol I
core O
, O
we O
further O
studied O
whether O
achyrofuran B
killed O
bacteria O
through O
a O
mechanism O
of O
action O
similar O
to O
that O
reported O
for O
the O
naturally O
occurring O
antibiotic O
MC21 B
- I
A I
. O

Indeed O
, O
we O
found O
that O
achyrofuran B
was O
not O
bacteriolytic O
by O
itself O
although O
it O
greatly O
compromised O
membrane O
impermeability O
as O
determined O
by O
increased O
SYTOX B
Green I
uptake O
. O

Anti O
- O
tumor O
and O
anti O
- O
metastatic O
actions O
of O
wogonin B
isolated O
from O
Scutellaria O
baicalensis O
roots O
through O
anti O
- O
lymphangiogenesis O
. O

Tumor O
growth O
and O
metastasis O
are O
associated O
with O
angiogenesis O
and O
lymphangiogenesis O
through O
the O
production O
of O
vascular O
endothelial O
growth O
factor O
( O
VEGF O
) O
or O
VEGF O
- O
C O
in O
tumors O
, O
and O
the O
phosphorylation O
of O
VEGF O
receptor O
( O
VEGFR O
) O
- O
2 O
or O
VEGFR O
- O
3 O
in O
vascular O
endothelial O
cells O
or O
lymphatic O
endothelial O
cells O
( O
LECs O
) O
. O

Tumor O
- O
associated O
macrophages O
( O
TAMs O
) O
play O
an O
important O
role O
in O
tumor O
lymphangiogenesis O
, O
and O
consequently O
stimulate O
metastasis O
through O
the O
lymphatic O
system O
to O
lymph O
nodes O
. O

We O
examined O
the O
effects O
of O
wogonin B
isolated O
from O
Scutellaria O
baicalensis O
roots O
on O
tumor O
growth O
and O
metastasis O
using O
a O
highly O
metastatic O
model O
in O
osteosarcoma O
LM8 O
- O
bearing O
mice O
. O

Wogonin B
( O
25 O
and O
50 O
mg O
/ O
kg O
, O
twice O
daily O
) O
reduced O
tumor O
growth O
and O
metastasis O
to O
the O
lung O
, O
liver O
and O
kidney O
, O
angiogenesis O
( O
CD31 O
- O
positive O
cells O
) O
, O
lymphangiogenesis O
( O
LYVE O
- O
1 O
- O
positive O
cells O
) O
, O
and O
TAM O
( O
F4 O
/ O
80 O
- O
positive O
cell O
) O
numbers O
in O
the O
tumors O
of O
LM8 O
- O
bearing O
mice O
. O

Wogonin B
( O
10 O
- O
100 O
mu O
M O
) O
also O
inhibited O
increases O
in O
IL O
- O
1 O
beta O
production O
and O
cyclooxygenase O
( O
COX O
) O
- O
2 O
expression O
induced O
by O
lipopolysaccharide O
in O
THP O
- O
1 O
macrophages O
. O

Wogonin B
had O
no O
effect O
on O
VEGF O
- O
C O
production O
in O
LM8 O
cells O
, O
or O
VEGFR O
- O
3 O
expression O
in O
human O
lymphatic O
endothelial O
cells O
( O
HLECs O
) O
, O
however O
, O
it O
inhibited O
VEGF O
- O
C O
- O
induced O
VEGFR O
- O
3 O
phosphorylation O
in O
HLECs O
. O

The O
anti O
- O
tumor O
and O
anti O
- O
metastatic O
actions O
of O
wogonin B
may O
be O
associated O
with O
the O
inhibition O
of O
VEGF O
- O
C O
- O
induced O
lymphangiogenesis O
through O
a O
reduction O
in O
VEGF O
- O
C O
- O
induced O
VEGFR O
- O
3 O
phosphorylation O
by O
the O
inhibition O
of O
COX O
- O
2 O
expression O
and O
IL O
- O
1 O
beta O
production O
in O
TAMs O
. O

Ginkgo O
biloba O
leaves O
extract O
( O
EGb O
761 O
) O
attenuates O
lipopolysaccharide O
- O
induced O
acute O
lung O
injury O
via O
inhibition O
of O
oxidative O
stress O
and O
NF O
- O
kappa O
B O
- O
dependent O
matrix O
metalloproteinase O
- O
9 O
pathway O
. O

Acute O
lung O
injury O
( O
ALI O
) O
presents O
high O
mortality O
and O
morbidity O
clinically O
and O
by O
far O
no O
effective O
preventive O
strategy O
has O
been O
established O
. O

Extract O
of O
Ginkgo O
biloba O
leaves O
, O
EGb O
761 O
, O
is O
a O
complex O
mixture O
that O
possesses O
several O
clinical O
beneficial O
effects O
such O
as O
anti O
- O
oxidation O
, O
anti O
- O
inflammation O
, O
anti O
- O
tumor O
, O
and O
cardioprotective O
property O
. O

With O
EGb O
761 O
pretreatment O
, O
both O
lipopolysaccharide O
( O
LPS O
) O
- O
induced O
protein O
leakage O
and O
neutrophil O
infiltration O
, O
and O
LPS O
- O
induced O
inflammatory O
responses O
including O
increased O
myeloperoxidase O
( O
MPO O
) O
activity O
, O
lipid O
peroxidation O
, O
and O
metalloproteinase O
( O
MMP O
) O
- O
9 O
activity O
, O
were O
inhibited O
; O
LPS O
- O
suppressed O
activation O
of O
antioxidative O
enzymes O
( O
AOE O
) O
were O
reversed O
; O
and O
not O
only O
the O
phosphorylation O
of O
NF O
- O
kappa O
B O
but O
also O
the O
degradation O
of O
its O
inhibitor O
, O

I O
kappa O
B O
, O
were O
suppressed O
. O

These O
results O
suggested O
that O
the O
protection O
mechanism O
of O
EGb O
761 O
is O
by O
inhibition O
of O
NF O
kappa O
B O
activation O
, O
possibly O
via O
the O
up O
- O
regulation O
of O
antioxidative O
enzymes O
. O

More O
studies O
are O
needed O
to O
further O
evaluate O
whether O
EGb O
761 O
is O
a O
suitable O
candidate O
as O
an O
effective O
dietary O
strategy O
to O
reduce O
the O
incidence O
of O
endotoxin O
- O
induced O
ALI O
. O

The O
discovery O
, O
engineering O
and O
characterisation O
of O
a O
highly O
potent O
anti O
- O
human O
IL O
- O
13 O
fab O
fragment O
designed O
for O
administration O
by O
inhalation O
. O

We O
describe O
the O
discovery O
, O
engineering O
and O
characterisation O
of O
a O
highly O
potent O
anti O
- O
human O
interleukin O
( O
IL O
) O
- O
13 O
Fab O
fragment O
designed O
for O
administration O
by O
inhalation O
. O

The O
lead O
candidate O
molecule O
was O
generated O
via O
a O
novel O
antibody O
discovery O
process O
, O
and O
the O
selected O
IgG O
variable O
region O
genes O
were O
successfully O
humanised O
and O
reformatted O
as O
a O
human O
IgG O
gamma O
1 O
Fab O
fragment O
. O

Evaluation O
of O
the O
biophysical O
properties O
of O
a O
selection O
of O
humanised O
Fab O
fragments O
in O
a O
number O
of O
assays O
allowed O
us O
to O
select O
the O
molecule O
with O
the O
optimal O
stability O
profile O
. O

The O
resulting O
lead O
candidate O
, O
CA652 O
. O
g2 O
Fab O
, O
was O
shown O
to O
have O
comparable O
activity O
to O
the O
parental O
IgG O
molecule O
in O
a O
range O
of O
in O
vitro O
assays O
and O
was O
highly O
stable O
. O

Following O
nebulisation O
using O
a O
mesh O
nebuliser O
, O
CA652 O
. O
g2 O
Fab O
retained O
full O
binding O
affinity O
, O
functional O
neutralisation O
potency O
and O
structural O
integrity O
. O

Epitope O
mapping O
using O
solution O
nuclear O
magnetic O
resonance O
confirmed O
that O
the O
antibody O
bound O
to O
the O
region O
of O
human O
IL O
- O
13 O
implicated O
in O
the O
interaction O
with O
IL O
- O
13R O
alpha O
1 O
and O
IL O
- O
13R O
alpha O
2 O
. O

The O
work O
described O
here O
resulted O
in O
the O
discovery O
and O
design O
of O
CA652 O
. O
g2 O
human O
gamma O
1 O
Fab O
, O
a O
highly O
stable O
and O
potent O
anti O
- O
IL O
- O
13 O
molecule O
suitable O
for O
delivery O
via O
inhalation O
. O

beta B
- I
phenylethyl I
isothiocyanate I
reverses O
platinum B
resistance O
by O
a O
GSH B
- O
dependent O
mechanism O
in O
cancer O
cells O
with O
epithelial O
- O
mesenchymal O
transition O
phenotype O
. O

Platinum B
( O
Pt B
) O
- O
based O
chemotherapy O
is O
an O
important O
regimen O
in O
the O
clinical O
treatment O
of O
cancer O
, O
but O
development O
of O
drug O
resistance O
presents O
a O
major O
challenge O
. O

One O
key O
mechanism O
involved O
in O
resistance O
to O
Pt O
drugs O
is O
the O
decrease O
of O
intracellular O
Pt O
due O
to O
the O
drug O
efflux O
through O
the O
glutathione B
( O
GSH B
) O
- O
mediated O
export O
, O
and O
this O
is O
particularly O
significant O
in O
cancer O
cells O
with O
stem O
- O
cell O
like O
properties O
. O

In O
the O
present O
study O
, O
we O
showed O
that O
two O
Pt B
- O
resistant O
human O
cancer O
cell O
lines O
exhibited O
stem O
- O
cell O
like O
EMT O
properties O
, O
had O
high O
cellular O
GSH B
and O
accumulated O
significantly O
less O
cellular O
Pt B
compared O
to O
their O
parental O
cells O
, O
and O
failed O
to O
undergo O
apoptosis O
when O
exposed O
to O
Pt B
at O
the O
drug O
concentrations O
toxic O
to O
the O
parental O
cells O
. O

Importantly O
, O
we O
found O
that O
the O
natural O
compound O
beta B
- I
phenylethyl I
isothiocyanate I
( O
PEITC B
) O
was O
able O
to O
effectively O
abolish O
this O
drug O
resistant O
mechanism O
by O
effective O
depletion O
of O
cellular O
GSH B
, O
leading O
to O
a O
significant O
increase O
in O
cellular O
Pt O
as O
well O
as O
DNA O
- O
bound O
Pt O
. O

A O
combination O
of O
PEITC B
and O
Pt O
showed O
a O
striking O
synergistic O
anticancer O
activity O
both O
in O
vitro O
and O
in O
vivo O
, O
as O
evidenced O
by O
an O
increase O
in O
drug O
- O
induced O
apoptosis O
, O
a O
loss O
of O
colony O
formation O
capacity O
, O
and O
significant O
suppression O
of O
tumor O
growth O
in O
mice O
. O

Taken O
together O
, O
our O
study O
shows O
a O
promising O
therapeutic O
strategy O
to O
overcome O
drug O
resistance O
to O
platinum B
- O
based O
chemotherapy O
and O
may O
potentially O
have O
broad O
implications O
in O
clinical O
treatment O
of O
cancer O
. O

Analysis O
by O
substituted O
cysteine B
scanning O
mutagenesis O
of O
the O
fourth O
transmembrane O
domain O
of O
the O
CXCR4 O
receptor O
in O
its O
inactive O
and O
active O
state O
. O

The O
chemokine O
SDF O
- O
1 O
( O
CXCL12 O
) O
selectively O
binds O
to O
CXCR4 O
, O
a O
member O
of O
the O
G O
protein O
- O
coupled O
receptor O
( O
GPCR O
) O
superfamily O
. O

In O
this O
study O
, O
we O
used O
the O
substituted O
- O
cysteine B
accessibility O
method O
( O
SCAM O
) O
to O
identify O
specific O
residues O
of O
the O
fourth O
transmembrane O
domain O
( O
TM4 O
) O
that O
contribute O
to O
the O
formation O
of O
the O
binding O
pocket O
of O
CXCR4 O
in O
its O
inactive O
and O
active O
state O
. O

We O
successively O
substituted O
each O
residue O
from O
E179 O
( O
( O
4 O
. O
68 O
) O
) O
to O
K154 O
( O
( O
4 O
. O
43 O
) O
) O
with O
cysteine B
and O
expressed O
the O
mutants O
in O
COS O
- O
7 O
cells O
. O

Mutant O
receptors O
were O
then O
alkylated O
with O
methanethiosulfonate B
- I
ethylammonium I
( O
MTSEA B
) O
, O
and O
binding O
inhibition O
was O
monitored O
using O
the O
CXCR4 O
antagonist O
FC131 B
[ O
cyclo B
( I
- I
D I
- I
Tyr I
( I
1 I
) I
- I
Arg I
( I
2 I
) I
- I
Arg I
( I
3 I
) I
- I
Nal I
( I
4 I
) I
- I
Gly I
( I
5 I
) I
- I
) I
] O
, O
which O
displays O
anti O
- O
HIV O
activity O
. O

MTSEA B
treatment O
resulted O
in O
a O
significant O
reduction O
of O
FC131 B
binding O
to O
D171C O
( O
( O
4 O
. O
60 O
) O
) O
and O
P170C O
( O
( O
4 O
. O
59 O
) O
) O
. O

To O
assess O
TM4 O
accessibility O
in O
an O
active O
state O
of O
CXCR4 O
, O
TM4 O
cysteine B
mutants O
were O
transposed O
within O
the O
constitutively O
active O
mutant O
N119S O
( O
( O
3 O
. O
35 O
) O
) O
. O

MTSEA B
treatment O
of O
TM4 O
mutants O
N119S O
- O
S178C O
( O
( O
4 O
. O
67 O
) O
) O
, O
N119S O
- O
V177C O
( O
( O
4 O
. O
66 O
) O
) O
and O
N119S O
- O
I173C O
( O
( O
4 O
. O
62 O
) O
) O
resulted O
in O
a O
significant O
reduction O
in O
FC131 O
binding O
. O

Protection O
assays O
using O
FC131 B
prior O
to O
MTSEA O
treatment O
significantly O
reduced O
the O
alkylation O
of O
all O
MTSEA O
- O
sensitive O
mutants O
. O

The O
accessibility O
of O
the O
D171C O
( O
( O
4 O
. O
60 O
) O
) O
and O
P170C O
( O
( O
4 O
. O
59 O
) O
) O
residues O
suggests O
that O
they O
are O
oriented O
towards O
a O
water O
- O
accessible O
area O
of O
the O
binding O
pocket O
of O
CXCR4 O
. O

S178C O
( O
( O
4 O
. O
67 O
) O
) O
, O
V177C O
( O
( O
4 O
. O
66 O
) O
) O
and O
I173C O
( O
( O
4 O
. O
62 O
) O
) O
showed O
binding O
inhibition O
only O
in O
an O
N119S O
( O
( O
3 O
. O
35 O
) O
) O
background O
. O

Taken O
together O
our O
results O
suggest O
that O
TM4 O
and O
ECL2 O
undergo O
conformational O
changes O
during O
CXCR4 O
activation O
and O
also O
demonstrate O
how O
TM4 O
is O
an O
important O
feature O
for O
the O
binding O
of O
anti O
- O
HIV O
compounds O
. O

Discovery O
of O
alkenylboronic B
acids I
as O
neuroprotective O
agents O
affecting O
multiple O
biological O
targets O
involved O
in O
Alzheimer O
' O
s O
disease O
. O

Alkenylboronic B
acids I
have O
shown O
important O
biological O
activities O
that O
contribute O
to O
neuroprotection O
. O

We O
have O
determined O
their O
influence O
on O
the O
beta O
- O
amyloid O
( O
beta O
A O
) O
aggregation O
process O
, O
beta O
- O
secretase O
and O
acethylcholinesteras B
activities O
on O
cell O
- O
free O
systems O
, O
on O
the O
redox O
and O
lipid O
peroxidation O
status O
, O
and O
on O
the O
vulnerability O
to O
apoptotic O
death O
in O
an O
APPswe O
neuroblastoma O
cell O
line O
, O
before O
and O
after O
hydrogen B
peroxide I
treatment O
. O

We O
have O
discovered O
that O
2 B
- I
arylvinylboronic I
acids I
and O
some O
of O
their O
esters O
possess O
a O
set O
of O
properties O
which O
makes O
them O
highly O
useful O
as O
neuroprotective O
agents O
affecting O
multiple O
biological O
targets O
involved O
in O
AD O
. O

These O
properties O
are O
not O
paralleled O
by O
the O
related O
2 B
- I
arylboronic I
acids I
. O

Studies O
on O
percutaneous O
penetration O
of O
chemicals O
- O
Impact O
of O
storage O
conditions O
for O
excised O
human O
skin O
. O

According O
to O
international O
guidelines O
skin O
penetration O
experiments O
can O
be O
carried O
out O
using O
freshly O
excised O
or O
frozen O
stored O
skin O
. O

However O
, O
this O
recommendation O
refers O
to O
data O
obtained O
in O
experiments O
with O
human O
cadaver O
skin O
. O

In O
our O
study O
, O
the O
percutaneous O
penetration O
of O
the O
occupationally O
relevant O
chemicals O
anisole B
, O
cyclohexanone B
and O
1 B
, I
4 I
- I
dioxane I
was O
investigated O
for O
freshly O
excised O
as O
well O
as O
for O
4 O
and O
30 O
days O
at O
- O
20 O
degrees O
C O
stored O
human O
skin O
using O
the O
diffusion O
cell O
technique O
. O

As O
indicator O
for O
the O
impairment O
of O
skin O
barrier O
by O
freezing O
cholesterol B
dissolution O
was O
determined O
in O
the O
solvents O
in O
exposure O
chambers O
of O
diffusion O
cells O
. O

Considering O
the O
percutaneously O
penetrated O
amounts O
, O
the O
following O
ranking O
was O
determined O
: O
1 B
, I
4 I
- I
dioxane I
> O
anisole B
> O
cyclohexanone B
( O
decline O
to O
a O
factor O
of O
5 O
. O
9 O
) O
. O

The O
differences O
of O
fluxes O
between O
freshly O
excised O
and O
frozen O
stored O
skin O
( O
4 O
and O
30 O
days O
) O
were O
not O
significant O
( O
p O
> O
0 O
. O
05 O
) O
. O

Cholesterol B
dissolved O
from O
the O
skin O
indicates O
no O
significant O
differences O
between O
freshly O
excised O
and O
frozen O
stored O
skin O
. O

This O
study O
shows O
that O
freezing O
of O
human O
skin O
for O
up O
to O
30 O
days O
does O
not O
alter O
the O
skin O
barrier O
function O
and O
the O
permeability O
of O
chemicals O
. O

Off O
- O
target O
effects O
of O
thrombolytic O
drugs O
: O
apolipoprotein O
A O
- O
I O
proteolysis O
by O
alteplase O
and O
tenecteplase O
. O

The O
administration O
of O
thrombolytic O
drugs O
is O
of O
proven O
benefit O
in O
a O
variety O
of O
clinical O
conditions O
requiring O
acute O
revascularization O
, O
including O
acute O
myocardial O
infarction O
( O
AMI O
) O
, O
ischemic O
stroke O
, O
pulmonary O
embolism O
, O
and O
venous O
thrombosis O
. O

Generated O
plasmin O
can O
degrade O
non O
- O
target O
proteins O
, O
including O
apolipoprotein O
A O
- O
I O
( O
apoA O
- O
I O
) O
, O
the O
major O
protein O
constituent O
of O
high O
- O
density O
lipoproteins O
( O
HDL O
) O
. O

Aim O
of O
the O
present O
study O
was O
to O
compare O
the O
extent O
of O
apoA O
- O
I O
proteolytic O
degradation O
in O
AMI O
patients O
treated O
with O
two O
thrombolytic O
drugs O
, O
alteplase O
and O
the O
genetically O
engineered O
t O
- O
PA O
variant O
tenecteplase O
. O

ApoA O
- O
I O
degradation O
was O
evaluated O
in O
sera O
from O
38 O
AMI O
patients O
treated O
with O
alteplase O
or O
tenecteplase O
. O

In O
vitro O
, O
apoA O
- O
I O
degradation O
was O
tested O
by O
incubating O
control O
sera O
or O
purified O
HDL O
with O
alteplase O
or O
tenecteplase O
at O
different O
concentrations O
( O
5 O
- O
100 O
mu O
g O
/ O
ml O
) O
. O

Treatment O
with O
alteplase O
and O
tenecteplase O
results O
in O
apoA O
- O
I O
proteolysis O
; O
the O
extent O
of O
apoA O
- O
I O
degradation O
was O
more O
pronounced O
in O
alteplase O
- O
treated O
patients O
than O
in O
tenecteplase O
- O
treated O
patients O
. O

In O
vitro O
, O
the O
extent O
of O
apoA O
- O
I O
proteolysis O
was O
higher O
in O
alteplase O
- O
treated O
sera O
than O
in O
tenecteplase O
- O
treated O
sera O
, O
in O
the O
whole O
drug O
concentration O
range O
. O

No O
direct O
effect O
of O
the O
two O
thrombolytic O
agents O
on O
apoA O
- O
I O
degradation O
was O
observed O
. O

In O
addition O
to O
apoA O
- O
I O
, O
apoA O
- O
IV O
was O
also O
degraded O
by O
the O
two O
thrombolytic O
agents O
and O
again O
proteolytic O
degradation O
was O
higher O
with O
alteplase O
than O
tenecteplase O
. O

In O
conclusion O
, O
this O
study O
indicates O
that O
both O
alteplase O
and O
tenecteplase O
cause O
plasmin O
- O
mediated O
proteolysis O
of O
apoA O
- O
I O
, O
with O
alteplase O
resulting O
in O
a O
greater O
apoA O
- O
I O
degradation O
than O
tenecteplase O
, O
potentially O
causing O
a O
transient O
impairment O
of O
HDL O
atheroprotective O
functions O
. O

Structural O
determinants O
of O
substrate O
specificity O
in O
aldehyde B
dehydrogenases O
. O

Within O
the O
aldehyde B
dehydrogenase O
( O
ALDH O
) O
superfamily O
, O
proteins O
belonging O
to O
the O
ALDH9 O
, O
ALDH10 O
, O
ALDH25 O
, O
ALDH26 O
and O
ALDH27 O
families O
display O
activity O
as O
omega B
- I
aminoaldehyde I
dehydrogenases O
( O
AMADHs O
) O
. O

These O
enzymes O
participate O
in O
polyamine B
, O
choline B
and O
arginine B
catabolism O
, O
as O
well O
as O
in O
synthesis O
of O
several O
osmoprotectants O
and O
carnitine B
. O

Active O
site O
aromatic O
and O
acidic O
residues O
are O
involved O
in O
binding O
the O
omega B
- I
aminoaldehydes I
in O
plant O
ALDH10 O
enzymes O
. O

In O
order O
to O
ascertain O
the O
degree O
of O
conservation O
of O
these O
residues O
among O
AMADHs O
and O
to O
evaluate O
their O
possible O
relevance O
in O
determining O
the O
aminoaldehyde B
specificity O
, O
we O
compared O
the O
known O
amino B
acid I
sequences O
of O
every O
ALDH O
family O
that O
have O
at O
least O
one O
member O
with O
known O
crystal O
structure O
, O
as O
well O
as O
the O
electrostatic O
potential O
surface O
of O
the O
aldehyde B
binding O
sites O
of O
these O
structures O
. O

Our O
analyses O
showed O
that O
four O
or O
three O
aromatic O
residues O
form O
a O
similar O
" O
aromatic O
box O
" O
in O
the O
active O
site O
of O
the O
AMADH O
enzymes O
, O
being O
the O
equivalents O
to O
Phe170 B
and O
Trp177 B
( O
human O
ALDH2 O
numbering O
) O
strictly O
conserved O
in O
all O
of O
them O
, O
which O
supports O
their O
relevance O
in O
binding O
the O
aminoaldehyde B
by O
cation O
- O
pi O
interactions O
. O

In O
addition O
, O
all O
AMADHs O
exhibit O
a O
negative O
electrostatic O
potential O
surface O
in O
the O
aldehyde B
- O
entrance O
tunnel O
, O
due O
to O
side O
- O
chain O
carboxyl B
and O
hydroxyl B
groups O
or O
main O
- O
chain O
carbonyl B
groups O
. O

In O
contrast O
, O
ALDHs O
that O
have O
non O
- O
polar O
or O
negatively O
charged O
substrates O
exhibit O
neutral O
or O
positive O
electrostatic O
potential O
surfaces O
, O
respectively O
. O

Finally O
, O
our O
comparative O
sequence O
analyses O
revealed O
that O
the O
residues O
equivalent O
to O
Asp121 B
and O
Phe170 B
are O
highly O
conserved O
in O
many O
ALDH O
families O
irrespective O
of O
their O
substrate O
specificity O
- O
suggesting O
that O
they O
perform O
a O
role O
in O
catalysis O
additional O
or O
different O
to O
binding O
of O
the O
substrate O
- O
and O
that O
the O
positions O
Met124 B
, O
Cys301 B
, O
and O
Cys303 B
are O
hot O
spots O
changed O
during O
evolution O
to O
confer O
aldehyde B
specificity O
to O
several O
ALDH O
families O
. O

Micelles O
of O
zinc B
protoporphyrin I
conjugated O
to O
N B
- I
( I
2 I
- I
hydroxypropyl I
) I
methacrylamide I
( O
HPMA B
) O
copolymer O
for O
imaging O
and O
light O
- O
induced O
antitumor O
effects O
in O
vivo O
. O

We O
synthesized O
N B
- I
( I
2 I
- I
hydroxypropyl I
) I
methacrylamide I
polymer O
conjugated O
with O
zinc B
protoporphyrin I
( O
HPMA B
- I
ZnPP I
) O
and O
evaluated O
its O
application O
for O
tumor O
detection O
by O
imaging O
and O
treatment O
by O
light O
exposure O
using O
in O
mouse O
sarcoma O
model O
. O

To O
characterize O
HPMA B
- O
ZnPP B
micelle O
, O
we O
measured O
its O
micellar O
size O
, O
surface O
charge O
, O
stability O
, O
photochemical O
, O
biochemical O
properties O
and O
tissue O
distribution O
. O

In O
vivo O
anti O
- O
tumor O
effect O
and O
fluorescence O
imaging O
were O
carried O
out O
to O
validate O
the O
tumor O
selective O
accumulation O
and O
therapeutic O
effect O
by O
inducing O
singlet O
oxygen B
by O
light O
exposure O
. O

HPMA B
- O
ZnPP B
was O
highly O
water O
soluble O
and O
formed O
micelles O
spontaneously O
having O
hydrophobic O
clustered O
head O
group O
of O
ZnPP B
, O
in O
aqueous O
solution O
, O
with O
a O
hydrodynamic O
diameter O
of O
82 O
. O
8 O
+ O
/ O
- O
41 O
. O
8 O
nm O
and O
zeta O
- O
potential O
of O
+ O
1 O
. O
12 O
mV O
. O

HPMA B
- O
ZnPP B
had O
a O
long O
plasma O
half O
- O
life O
and O
effectively O
and O
selectively O
accumulated O
in O
tumors O
. O

Although O
HPMA B
- O
ZnPP B
alone O
had O
no O
toxicity O
in O
S O
- O
180 O
tumor O
- O
bearing O
mice O
, O
light O
- O
irradiation O
significantly O
suppressed O
tumor O
growth O
in O
vivo O
, O
similar O
to O
the O
cytotoxicity O
to O
HeLa O
cells O
in O
vitro O
upon O
endoscopic O
light O
- O
irradiation O
. O

HPMA B
- O
ZnPP I
can O
visualize O
tumors O
by O
fluorescence O
after O
i O
. O
v O
. O
injection O
, O
which O
suggests O
that O
this O
micelle O
may O
be O
useful O
for O
both O
tumor O
imaging O
and O
therapy O
. O

Here O
we O
describe O
preparation O
of O
a O
new O
fluorescence O
nanoprobe O
that O
is O
useful O
for O
simultaneous O
tumor O
imaging O
and O
treatment O
, O
and O
application O
to O
fluorescence O
endoscopy O
is O
now O
at O
visible O
distance O
. O

In O
vivo O
biocompatibility O
, O
sustained O
- O
release O
and O
stability O
of O
triptorelin B
formulations O
based O
on O
a O
liquid O
, O
degradable O
polymer O
. O

Hexylsubstituted B
poly I
( I
lactic I
acid I
) I
( O
hexPLA B
) O
is O
a O
viscous O
polymer O
, O
which O
degrades O
in O
the O
presence O
of O
water O
similar O
to O
the O
structure O
related O
poly B
( I
lactic I
acid I
) I
. O

With O
hydrophilic O
active O
compounds O
, O
like O
Triptorelin B
acetate I
, O
the O
lipophilic O
polymer O
was O
formulated O
in O
form O
of O
parenterally O
injectable O
suspensions O
. O

This O
first O
in O
vivo O
study O
toward O
the O
biocompatibility O
of O
hexPLA B
implants O
in O
rats O
over O
3 O
months O
in O
comparison O
to O
in O
situ O
forming O
poly B
( I
lactic I
- I
co I
- I
glycolic I
acid I
) I
( O
PLGA B
) O
formulations O
is O
presented O
here O
. O

The O
hexPLA B
implants O
showed O
only O
a O
mild O
acute O
inflammation O
at O
the O
injection O
site O
after O
application O
, O
which O
continuously O
regressed O
. O

In O
contrast O
to O
the O
PLGA B
formulations O
, O
hexPLA B
did O
not O
provoke O
an O
encapsulation O
of O
the O
implant O
with O
extracellular O
matrix O
. O

Prior O
to O
the O
formulation O
application O
, O
the O
stability O
of O
Triptorelin B
inside O
the O
hexPLA O
matrix O
was O
assessed O
under O
different O
storage O
conditions O
and O
in O
the O
presence O
of O
buffer O
to O
simulate O
a O
peptide O
degrading O
environment O
. O

At O
5 O
degrees O
C O
Triptorelin B
showed O
a O
stability O
of O
98 O
% O
inside O
the O
polymer O
for O
at O
least O
6 O
months O
. O

The O
stability O
was O
still O
78 O
% O
at O
an O
elevated O
temperature O
of O
40 O
degrees O
C O
. O

HexPLA B
protected O
the O
incorporated O
peptide O
from O
the O
surrounding O
aqueous O
environment O
, O
which O
resulted O
in O
20 O
% O
less O
degradation O
inside O
the O
polymer O
compared O
to O
the O
solution O
. O

This O
protection O
effect O
supports O
the O
use O
of O
Triptorelin B
- O
hexPLA B
formulations O
for O
parenteral O
sustained O
- O
release O
formulations O
. O

In O
a O
second O
in O
vivo O
evaluation O
in O
Wistar O
Hannover O
rats O
, O
formulations O
containing O
5 O
% O
and O
10 O
% O
Triptorelin B
in O
the O
polymeric O
matrix O
released O
the O
active O
compound O
continuously O
for O
6 O
months O
. O

The O
formulations O
showed O
a O
higher O
release O
during O
the O
initial O
7 O
days O
, O
which O
is O
necessary O
for O
the O
clinical O
use O
to O
down O
- O
regulate O
all O
GnRH O
- O
receptors O
. O

Afterwards O
, O
a O
zero O
order O
drug O
release O
was O
observed O
over O
the O
first O
3 O
months O
. O

After O
3 O
months O
, O
the O
plasma O
levels O
decreased O
slowly O
but O
remained O
at O
effective O
concentrations O
for O
the O
total O
of O
6 O
months O
. O

Furthermore O
, O
a O
qualitative O
in O
vitro O
- O
in O
vivo O
correlation O
was O
observed O
, O
possibly O
facilitating O
future O
optimization O
of O
the O
Triptorelin B
- O
hexPLA B
sustained O
- O
release O
formulations O
. O

Nanogel O
vaccines O
targeting O
dendritic O
cells O
: O
contributions O
of O
the O
surface O
decoration O
and O
vaccine O
cargo O
on O
cell O
targeting O
and O
activation O
. O

Dendritic O
cells O
( O
DCs O
) O
play O
crucial O
roles O
in O
initiating O
and O
promoting O
immune O
defences O
, O
providing O
a O
pivotal O
target O
for O
vaccines O
. O

Although O
nanoparticle O
/ O
nanogel O
- O
based O
delivery O
vehicles O
are O
showing O
potential O
for O
delivering O
vaccines O
to O
the O
immune O
system O
, O
there O
is O
little O
information O
on O
their O
characteristics O
of O
interaction O
with O
DCs O
. O

While O
particle O
uptake O
by O
DCs O
has O
been O
shown O
, O
the O
mechanism O
of O
cell O
targeting O
has O
not O
been O
studied O
. O

Moreover O
, O
it O
is O
still O
unclear O
how O
particle O
surface O
decoration O
influences O
the O
handling O
of O
such O
vaccines O
by O
DCs O
. O

Accordingly O
, O
chitosan O
nanogels O
carrying O
a O
model O
antigen O
, O
ovalbumin O
( O
ova O
) O
, O
were O
analysed O
for O
interaction O
with O
and O
processing O
by O
DCs O
. O

Nanogel O
surfaces O
decorated O
with O
alginate O
( O
alg O
) O
or O
mannosylated O
alginate O
( O
alg O
- O
man O
) O
, O
were O
used O
for O
targeting O
particular O
DC O
receptors O
. O

DC O
uptake O
of O
particles O
was O
observed O
, O
being O
dependent O
on O
endosomal O
- O
based O
processes O
. O

Inhibiting O
PI3 O
- O
kinase O
or O
lipid O
raft O
activities O
impaired O
the O
uptake O
, O
which O
was O
only O
reduced O
, O
indicating O
the O
involvement O
of O
more O
than O
one O
endocytic O
pathway O
; O
notably O
, O
this O
was O
observed O
with O
both O
nanogel O
- O
delivered O
or O
free O
ova O
. O

Importantly O
, O
surface O
decoration O
of O
particles O
was O
less O
influential O
on O
particle O
uptake O
, O
contrasting O
with O
the O
ova O
cargo O
which O
played O
the O
major O
role O
. O

Such O
influence O
of O
the O
vaccine O
cargo O
has O
to O
date O
been O
largely O
ignored O
. O

When O
receptors O
interacting O
directly O
with O
ova O
were O
blocked O
, O
this O
altered O
the O
uptake O
of O
alg O
- O
nanogels O
and O
alg O
- O
man O
- O
nanogels O
carrying O
ova O
. O

The O
nanogels O
did O
have O
an O
influential O
role O
, O
in O
that O
modulation O
of O
DC O
functional O
activity O
owed O
more O
to O
the O
nanogel O
structure O
. O

Using O
an O
in O
vitro O
restimulation O
assay O
with O
ova O
- O
specific O
lymphocytes O
, O
nanogel O
- O
delivered O
and O
free O
ova O
were O
similarly O
effective O
at O
inducing O
specific O
antibody O
. O

Nanogel O
- O
delivered O
ova O
with O
mannose B
surface O
decoration O
was O
superior O
to O
free O
ova O
for O
inducing O
interferon O
- O
gamma O
production O
by O
T O
- O
lymphocytes O
. O

Together O
, O
the O
data O
demonstrates O
that O
particle O
- O
based O
vaccine O
delivery O
should O
consider O
the O
influences O
of O
both O
the O
surface O
decoration O
and O
the O
vaccine O
cargo O
; O
each O
can O
influence O
different O
aspects O
of O
the O
interaction O
with O
DCs O
. O

Such O
combined O
influences O
are O
likely O
to O
impinge O
on O
the O
characteristics O
of O
the O
immune O
response O
induced O
. O

Treating O
epilepsy O
in O
Italy O
between O
XIX O
and O
XX O
century O
. O

Epilepsy O
is O
a O
neurological O
disorder O
which O
has O
been O
recognized O
since O
antiquity O
. O

This O
paper O
evaluates O
the O
prophylactic O
and O
therapeutic O
remedies O
used O
by O
folk O
medicine O
to O
cure O
epilepsy O
in O
Italy O
. O

The O
data O
has O
been O
collected O
by O
reviewing O
written O
sources O
of O
physicians O
, O
ethnographers O
, O
folklorists O
between O
the O
late O
nineteenth O
and O
mid O
twentieth O
century O
. O

This O
approach O
leads O
to O
unearthing O
of O
78 O
heterogeneous O
healing O
methods O
that O
have O
been O
divided O
into O
16 O
( O
20 O
% O
) O
magical O
, O
20 O
( O
26 O
% O
) O
religious O
and O
42 O
( O
54 O
% O
) O
natural O
remedies O
. O

The O
latter O
has O
been O
subdivided O
into O
18 O
( O
43 O
% O
) O
animal O
remedies O
, O
17 O
( O
40 O
% O
) O
plant O
remedies O
and O
7 O
( O
17 O
% O
) O
other O
remedies O
. O

Religious O
and O
magical O
remedies O
were O
used O
with O
the O
conviction O
that O
they O
would O
be O
able O
to O
provide O
recovery O
from O
epilepsy O
and O
to O
ward O
off O
evil O
spirits O
which O
had O
taken O
possession O
of O
the O
sick O
. O

Interestingly O
, O
the O
herbal O
remedies O
highlighted O
12 O
( O
70 O
% O
) O
plants O
that O
play O
or O
might O
play O
an O
important O
role O
with O
respect O
to O
the O
mechanisms O
that O
generate O
the O
epileptic O
seizures O
. O

This O
leads O
us O
to O
reconsider O
the O
historical O
significance O
of O
folk O
medicine O
, O
too O
often O
it O
is O
underestimated O
owing O
to O
its O
use O
of O
ineffective O
remedies O
, O
born O
of O
incompetence O
and O
superstition O
. O

Food O
reward O
- O
sensitive O
interaction O
of O
ghrelin O
and O
opioid O
receptor O
pathways O
in O
mesolimbic O
dopamine B
system O
. O

Ghrelin O
is O
a O
stomach O
- O
derived O
orexigenic O
peptide O
. O

The O
goal O
of O
the O
study O
was O
to O
investigate O
the O
roles O
of O
mu O
and O
kappa O
opioid O
receptors O
in O
systemic O
ghrelin O
- O
mediated O
regulation O
of O
the O
mesolimbic O
dopamine B
system O
. O

To O
evaluate O
the O
interaction O
of O
systemic O
ghrelin O
with O
values O
of O
food O
reward O
, O
rats O
were O
exposed O
to O
food O
removal O
, O
regular O
food O
or O
palatable O
food O
after O
systemic O
ghrelin O
administration O
. O

Extracellular O
dopamine B
levels O
were O
quantified O
in O
the O
nucleus O
accumbens O
( O
NAc O
) O
and O
receptor O
- O
specific O
compounds O
were O
infused O
into O
the O
ventral O
tegmental O
area O
( O
VTA O
) O
using O
dual O
- O
probe O
microdialysis O
. O

Consumption O
of O
regular O
or O
palatable O
food O
without O
systemic O
ghrelin O
administration O
induced O
an O
increase O
in O
dopamine B
levels O
in O
the O
NAc O
via O
activation O
of O
mu O
opioid O
receptors O
in O
the O
VTA O
. O

Systemic O
ghrelin O
administration O
( O
3 O
nmol O
, O
i O
. O
v O
. O
) O
followed O
by O
no O
food O
induced O
a O
decrease O
in O
dopamine B
levels O
via O
activation O
of O
kappa O
opioid O
receptors O
in O
the O
VTA O
. O

Systemic O
ghrelin O
administration O
followed O
by O
consumption O
of O
regular O
food O
induced O
an O
increase O
in O
dopamine B
levels O
via O
preferential O
activation O
of O
mu O
opioid O
receptors O
, O
whereas O
systemic O
ghrelin O
administration O
followed O
by O
consumption O
of O
palatable O
food O
suppressed O
the O
increase O
in O
dopamine B
levels O
via O
preferential O
activation O
of O
kappa O
opioid O
receptors O
. O

Thus O
, O
natural O
food O
reward O
and O
systemic O
ghrelin O
activate O
mu O
and O
kappa O
opioid O
receptor O
pathways O
in O
the O
VTA O
, O
respectively O
, O
resulting O
in O
opposite O
influences O
on O
dopamine B
release O
in O
the O
NAc O
. O

Furthermore O
, O
systemic O
ghrelin O
induces O
switching O
of O
the O
dominant O
opioid O
receptor O
pathway O
for O
highly O
rewarding O
food O
from O
mu O
to O
kappa O
, O
resulting O
in O
suppression O
of O
the O
mesolimbic O
dopamine B
system O
. O

These O
novel O
findings O
might O
provide O
insights O
into O
the O
neural O
pathways O
involved O
in O
eating O
disorders O
. O

Characterisation O
of O
an O
mGlu8 O
receptor O
- O
selective O
agonist O
and O
antagonist O
in O
the O
lateral O
and O
medial O
perforant O
path O
inputs O
to O
the O
dentate O
gyrus O
. O

Since O
its O
characterisation O
in O
2001 O
, O
the O
mGlu8 O
- O
selective O
agonist O
DCPG B
has O
been O
widely O
used O
to O
explore O
the O
potential O
functional O
role O
of O
this O
group O
III O
mGlu O
receptor O
within O
the O
central O
nervous O
system O
. O

This O
research O
has O
implicated O
mGlu8 O
receptors O
in O
a O
number O
of O
disease O
states O
and O
conditions O
such O
as O
epilepsy O
and O
anxiety O
, O
suggesting O
that O
mGlu8 O
- O
selective O
ligands O
may O
hold O
important O
therapeutic O
potential O
. O

However O
, O
there O
is O
evidence O
that O
DCPG B
exerts O
off O
- O
target O
effects O
at O
higher O
concentrations O
, O
limiting O
its O
use O
as O
an O
mGlu8 O
- O
selective O
agonist O
. O

Here O
, O
we O
have O
used O
field O
recordings O
in O
rat O
hippocampal O
slices O
to O
investigate O
the O
effects O
of O
DCPG B
in O
the O
lateral O
perforant O
path O
( O
LPP O
) O
, O
a O
pathway O
known O
to O
express O
high O
levels O
of O
mGlu8 O
. O

We O
show O
that O
DCPG B
does O
inhibit O
excitatory O
transmission O
in O
this O
pathway O
, O
but O
produces O
a O
biphasic O
concentration O
- O
response O
curve O
suggesting O
activation O
of O
two O
distinct O
receptor O
types O
. O

The O
putative O
mGlu8 O
- O
selective O
antagonist O
MDCPG B
antagonises O
the O
high O
, O
but O
not O
the O
low O
, O
potency O
component O
of O
this O
concentration O
- O
response O
curve O
. O

In O
addition O
, O
higher O
concentrations O
of O
DCPG B
also O
depress O
excitatory O
transmission O
in O
the O
medial O
perforant O
path O
( O
MPP O
) O
, O
a O
pathway O
expressing O
very O
low O
levels O
of O
mGlu8 O
receptors O
. O

Experiments O
in O
slices O
from O
mice O
lacking O
mGlu8 O
receptors O
indicate O
that O
concentrations O
of O
DCPG B
> O
1 O
mu O
M O
produce O
large O
non O
- O
selective O
effects O
in O
both O
the O
LPP O
and O
MPP O
. O

Further O
experiments O
in O
slices O
from O
mGlu2 O
, O
4 O
and O
7 O
knock O
- O
out O
mice O
, O
as O
well O
as O
in O
an O
mGlu2 O
- O
deficient O
substrain O
of O
Wistar O
rat O
, O
reveal O
that O
these O
non O
- O
selective O
effects O
are O
mediated O
primarily O
by O
mGlu2 O
receptors O
. O

Taken O
together O
, O
our O
results O
confirm O
the O
mGlu8 O
- O
selectivity O
of O
DCPG B
at O
submicromolar O
concentrations O
, O
but O
suggest O
that O
care O
must O
be O
taken O
when O
employing O
higher O
concentrations O
of O
the O
agonist O
, O
which O
may O
additionally O
activate O
mGlu2 O
receptors O
, O
especially O
at O
synapses O
where O
their O
expression O
is O
high O
. O

MDCPG B
may O
be O
a O
useful O
tool O
in O
determining O
whether O
observable O
DCPG B
effects O
are O
attributable O
to O
mGlu8 O
, O
versus O
mGlu2 O
, O
receptor O
activation O
. O

Organochlorines B
and O
metals O
induce O
changes O
in O
the O
mitochondria O
- O
rich O
cells O
of O
fish O
gills O
: O
an O
integrative O
field O
study O
involving O
chemical O
, O
biochemical O
and O
morphological O
analyses O
. O

Through O
integrating O
chemical O
, O
biochemical O
and O
morphological O
analyses O
, O
this O
study O
investigated O
the O
effects O
of O
multiple O
pollutants O
on O
the O
gill O
mitochondria O
- O
rich O
cells O
( O
MRCs O
) O
in O
two O
fish O
species O
, O
Astyanax O
fasciatus O
and O
Pimelodus O
maculatus O
, O
collected O
from O
five O
sites O
( O
FU10 O
, O
FU20 O
, O
FU30 O
, O
FU40 O
and O
FU50 O
) O
in O
the O
Furnas O
Hydroelectric O
Power O
Station O
reservoir O
. O

Water O
analyses O
revealed O
aluminum B
, O
iron B
and O
zinc B
as O
well O
as O
organochlorine B
( O
aldrin B
/ O
dieldrin B
, O
endosulfan B
, O
heptachlor B
/ O
heptachlor B
epoxide I
and O
metolachlor B
) O
contamination O
at O
all O
of O
the O
sites O
, O
with O
the O
exception O
of O
FU10 O
. O

Copper B
, O
chrome B
, O
iron B
and O
zinc B
were O
detected O
in O
the O
gills O
of O
both O
species O
, O
and O
aldrin B
/ O
dieldrin B
, O
endosulfan B
and O
heptachlor B
/ O
heptachlor B
epoxide I
were O
detected O
in O
the O
gills O
of O
fish O
from O
all O
of O
the O
sites O
, O
with O
the O
exception O
of O
FU10 O
. O

Fish O
collected O
at O
FU20 O
, O
FU30 O
and O
FU50 O
exhibited O
numerous O
alterations O
in O
the O
surface O
architecture O
of O
their O
pavement O
cells O
and O
MRCs O
. O

The O
surface O
MRC O
density O
and O
MRC O
fractional O
area O
were O
lower O
in O
fish O
from O
FU20 O
, O
FU30 O
, O
FU40 O
and O
FU50 O
than O
in O
those O
from O
the O
reference O
site O
( O
FU10 O
) O
in O
the O
winter O
, O
and O
some O
variability O
between O
the O
sites O
was O
observed O
in O
the O
summer O
. O

The O
organochlorine B
contamination O
at O
FU20 O
and O
FU50 O
was O
associated O
with O
variable O
changes O
in O
the O
MRCs O
and O
inhibition O
of O
Na B
( I
+ I
) I
/ O
K B
( I
+ I
) I
- O
ATPase O
( O
NKA O
) O
activity O
, O
especially O
in O
P O
. O
maculatus O
. O

At O
FU30 O
, O
the O
alterations O
in O
the O
MRCs O
were O
associated O
with O
the O
contaminants O
present O
, O
especially O
metals O
. O

A O
multivariate O
analysis O
demonstrated O
a O
positive O
association O
between O
the O
biological O
responses O
of O
both O
species O
and O
environmental O
contamination O
, O
indicating O
that O
under O
realistic O
conditions O
, O
a O
mixture O
of O
organochlorines B
and O
metals O
affected O
the O
MRCs O
by O
inhibiting O
NKA O
activity O
and O
inducing O
morphological O
changes O
, O
which O
may O
cause O
an O
ionic O
imbalance O
. O

Identification O
and O
discrimination O
of O
snake O
venoms O
from O
Egyptian O
elapids O
. O

The O
avidity O
to O
the O
corresponding O
antigens O
is O
often O
higher O
than O
to O
the O
cross O
- O
reactive O
antigens O
. O

This O
was O
demonstrated O
with O
the O
highly O
cross O
- O
reactive O
elapid O
Egyptian O
snake O
venoms O
Naja O
haje O
( O
Nh O
) O
, O
Naja O
nigricollis O
( O
Nn O
) O
and O
Walterinnesia O
aegyptia O
( O
Wa O
) O
, O
and O
used O
for O
the O
differentiation O
among O
the O
three O
species O
in O
a O
simple O
ELISA O
- O
based O
assay O
. O

A O
three O
- O
step O
immuno O
- O
affinity O
protocol O
was O
followed O
and O
the O
titer O
and O
avidity O
of O
the O
different O
antibody O
( O
Ab O
) O
preparations O
were O
assessed O
and O
evaluated O
. O

The O
advantages O
offered O
by O
the O
avidity O
power O
of O
the O
venom O
specific O
antibodies O
( O
VS O
- O
Abs O
) O
obtained O
after O
one O
step O
purification O
, O
outweigh O
the O
specificity O
of O
the O
species O
- O
specific O
antibodies O
( O
SS O
- O
Abs O
) O
obtained O
after O
further O
purification O
. O

The O
efficiency O
of O
the O
VS O
- O
Abs O
as O
special O
immunodiagnostics O
was O
validated O
using O
16 O
venom O
samples O
collected O
from O
individual O
snakes O
of O
different O
size O
and O
age O
at O
different O
time O
intervals O
. O

The O
avidities O
of O
the O
VS O
- O
Abs O
to O
the O
homologous O
venoms O
were O
2 O
. O
53 O
+ O
/ O
- O
0 O
. O
4 O
, O
2 O
. O
66 O
+ O
/ O
- O
0 O
. O
31 O
and O
2 O
. O
8 O
+ O
/ O
- O
0 O
. O
06 O
for O
Nh O
, O
Nn O
and O
Wa O
venoms O
respectively O
; O
whereas O
the O
avidity O
of O
the O
same O
Abs O
to O
the O
heterologous O
venoms O
could O
hardly O
exceed O
1 O
. O

Venom O
concentrations O
in O
the O
range O
between O
10 O
- O
1250 O
ng O
/ O
well O
were O
detected O
with O
almost O
the O
same O
efficiency O
, O
an O
extra O
advantage O
that O
could O
be O
added O
to O
the O
assay O
to O
assure O
equal O
sensitivity O
allover O
the O
mentioned O
venom O
concentration O
range O
. O

Effects O
of O
the O
natural O
endocrine O
disruptor O
equol B
on O
the O
pituitary O
function O
in O
adult O
male O
rats O
. O

Equol B
( O
EQ O
) O
, O
a O
potent O
biologically O
active O
metabolite O
of O
the O
soy O
isoflavone B
daidzein B
, O
interacts O
with O
estrogen B
receptors O
( O
ERs O
) O
, O
however O
, O
as O
suggested O
recently O
, O
EQ O
may O
also O
exert O
anti O
- O
androgenic O
actions O
in O
androgen B
regulated O
tissues O
like O
prostate O
and O
seminal O
vesicles O
in O
adult O
male O
rats O
. O

However O
, O
data O
regarding O
a O
putative O
anti O
- O
androgenic O
activity O
of O
EQ O
on O
pituitary O
function O
in O
male O
individuals O
are O
still O
lacking O
. O

Therefore O
, O
we O
investigated O
the O
effects O
of O
EQ O
on O
androgen B
- O
and O
estrogen B
- O
regulated O
gene O
expressions O
in O
the O
pituitary O
and O
circulating O
luteinizing O
hormone O
( O
LH O
) O
and O
prolactin O
( O
PRL O
) O
levels O
in O
adult O
male O
rats O
. O

3 O
- O
Month O
- O
old O
male O
Sprague O
- O
Dawley O
rats O
( O
n O
= O
12 O
per O
group O
) O
were O
treated O
by O
gavage O
for O
5 O
days O
with O
either O
EQ O
( O
100 O
and O
250 O
mg O
/ O
kg O
BW O
/ O
day O
) O
or O
vehicle O
olive O
oil O
( O
1 O
ml O
/ O
rat O
/ O
day O
) O
. O

As O
reference O
compound O
, O
the O
pure O
anti O
- O
androgenic O
drug O
flutamide B
( O
FLUT B
) O
was O
employed O
at O
a O
dose O
of O
100 O
mg O
/ O
kg O
BW O
/ O
day O
. O

At O
day O
5 O
, O
animals O
were O
sacrificed O
. O

Levels O
of O
pituitary O
hormones O
and O
gene O
expression O
were O
measured O
by O
radioimmunoassays O
and O
quantitative O
TaqMan O
( O
( O
R O
) O
) O
real O
- O
time O
reverse O
transcription O
polymerase O
chain O
reaction O
, O
respectively O
. O

The O
present O
findings O
revealed O
that O
the O
pituitary O
mechanisms O
involved O
in O
the O
effects O
of O
EQ O
and O
FLUT B
were O
different O
due O
to O
the O
opposite O
changes O
in O
the O
mRNA O
expression O
levels O
of O
estrogen B
receptor O
subtype O
alpha O
( O
ER O
alpha O
) O
- O
, O
truncated O
estrogen B
receptor O
product O
- O
1 O
( O
TERP B
- O
1 O
) O
- O
and O
- O
2 O
( O
TERP B
- O
2 O
) O
- O
, O
gonadotropin B
releasing O
hormone O
receptor O
( O
GnRH B
receptor O
) O
- O
, O
beta O
- O
subunit O
of O
LH O
( O
LH O
beta O
) O
- O
, O
and O
gonadotropin O
alpha O
subunit O
( O
alpha O
- O
subunit O
) O
genes O
. O

EQ O
displayed O
typical O
ER O
- O
agonistic O
actions O
as O
shown O
by O
the O
significant O
increases O
in O
ER O
alpha O
- O
, O
TERP O
- O
1 O
/ O
- O
2 O
mRNA O
expressions O
and O
serum O
PRL O
levels O
along O
with O
the O
significant O
reduction O
in O
serum O
LH O
levels O
, O
whereas O
FLUT B
exerted O
opposite O
effects O
on O
gonadotropin O
secretion O
and O
expression O
. O

Taken O
together O
, O
our O
findings O
are O
the O
first O
in O
vivo O
data O
that O
upon O
sub O
- O
acute O
oral O
exposure O
of O
EQ O
show O
an O
estrogenic O
effect O
on O
reproductive O
endocrine O
activity O
of O
the O
pituitary O
in O
adult O
male O
rats O
. O

However O
, O
EQ O
did O
not O
exert O
anti O
- O
androgenic O
effects O
on O
male O
rat O
pituitary O
function O
as O
observed O
at O
the O
levels O
of O
mRNA O
expression O
of O
androgen B
- O
and O
estrogen B
- O
regulated O
genes O
and O
circulating O
pituitary O
hormones O
. O

Retinoic B
acid I
biosynthesis O
catalyzed O
by O
retinal B
dehydrogenases O
relies O
on O
a O
rate O
- O
limiting O
conformational O
transition O
associated O
with O
substrate O
recognition O
. O

Retinoic B
acid I
( O
RA O
) O
, O
a O
metabolite O
of O
vitamin B
A I
, O
exerts O
pleiotropic O
effects O
throughout O
life O
in O
vertebrate O
organisms O
. O

Thus O
, O
RA O
action O
must O
be O
tightly O
regulated O
through O
the O
coordinated O
action O
of O
biosynthetic O
and O
degrading O
enzymes O
. O

The O
last O
step O
of O
retinoic B
acid I
biosynthesis O
is O
irreversibly O
catalyzed O
by O
the O
NAD B
- O
dependent O
retinal B
dehydrogenases O
( O
RALDH O
) O
, O
which O
are O
members O
of O
the O
aldehyde B
dehydrogenase O
( O
ALDH O
) O
superfamily O
. O

Low O
intracellular O
retinal B
concentrations O
imply O
efficient O
substrate O
molecular O
recognition O
to O
ensure O
high O
affinity O
and O
specificity O
of O
RALDHs O
for O
retinal B
. O

This O
study O
addresses O
the O
molecular O
basis O
of O
retinal B
recognition O
in O
human O
ALDH1A1 O
( O
or O
RALDH1 O
) O
and O
rat O
ALDH1A2 O
( O
or O
RALDH2 O
) O
, O
through O
the O
comparison O
of O
the O
catalytic O
behavior O
of O
retinal B
analogs O
and O
use O
of O
the O
fluorescence O
properties O
of O
retinol B
. O

We O
show O
that O
, O
in O
contrast O
to O
long O
chain O
unsaturated O
substrates O
, O
the O
rate O
- O
limiting O
step O
of O
retinal B
oxidation O
by O
RALDHs O
is O
associated O
with O
acylation O
. O

Use O
of O
the O
fluorescence O
resonance O
energy O
transfer O
upon O
retinol B
interaction O
with O
RALDHs O
provides O
evidence O
that O
retinal B
recognition O
occurs O
in O
two O
steps O
: O
binding O
into O
the O
substrate O
access O
channel O
, O
and O
a O
slower O
structural O
reorganization O
with O
a O
rate O
constant O
of O
the O
same O
magnitude O
as O
the O
kcat O
for O
retinal B
oxidation O
: O
0 O
. O
18 O
vs O
. O
0 O
. O
07 O
and O
0 O
. O
25 O
vs O
. O
0 O
. O
1 O
s O
( O
- O
1 O
) O
for O
ALDH1A1 O
and O
ALDH1A2 O
, O
respectively O
. O

This O
suggests O
that O
the O
conformational O
transition O
of O
the O
RALDH O
- O
retinal B
complex O
significantly O
contributes O
to O
the O
rate O
- O
limiting O
step O
that O
controls O
the O
kinetics O
of O
retinal B
oxidation O
, O
as O
a O
prerequisite O
for O
the O
formation O
of O
a O
catalytically O
competent O
Michaelis O
complex O
. O

This O
conclusion O
is O
consistent O
with O
the O
general O
notion O
that O
structural O
flexibility O
within O
the O
active O
site O
of O
ALDH O
enzymes O
has O
been O
shown O
to O
be O
an O
integral O
component O
of O
catalysis O
. O

Inhibition O
of O
human O
alcohol B
and O
aldehyde B
dehydrogenases O
by O
cimetidine B
and O
assessment O
of O
its O
effects O
on O
ethanol B
metabolism O
. O

Previous O
studies O
have O
reported O
that O
cimetidine B
, O
an O
H2 O
- O
receptor O
antagonist O
used O
to O
treat O
gastric O
and O
duodenal O
ulcers O
, O
can O
inhibit O
alcohol B
dehydrogenases O
( O
ADHs O
) O
and O
ethanol B
metabolism O
. O

Human O
alcohol B
dehydrogenases O
and O
aldehyde B
dehydrogenases O
( O
ALDHs O
) O
, O
the O
principal O
enzymes O
responsible O
for O
metabolism O
of O
ethanol B
, O
are O
complex O
enzyme O
families O
that O
exhibit O
functional O
polymorphisms O
among O
ethnic O
groups O
and O
distinct O
tissue O
distributions O
. O

We O
investigated O
the O
inhibition O
by O
cimetidine B
of O
alcohol B
oxidation O
by O
recombinant O
human O
ADH1A O
, O
ADH1B1 O
, O
ADH1B2 O
, O
ADH1B3 O
, O
ADH1C1 O
, O
ADH1C2 O
, O
ADH2 O
, O
and O
ADH4 O
, O
and O
aldehyde B
oxidation O
by O
ALDH1A1 O
and O
ALDH2 O
at O
pH O
7 O
. O
5 O
and O
a O
cytosolic O
NAD B
( I
+ I
) I
concentration O
. O

Cimetidine B
acted O
as O
competitive O
or O
noncompetitive O
inhibitors O
for O
the O
ADH O
and O
ALDH O
isozymes O
/ O
allozymes O
with O
near O
mM O
inhibition O
constants O
. O

The O
metabolic O
interactions O
between O
cimetidine B
and O
ethanol B
/ O
acetaldehyde B
were O
assessed O
by O
computer O
simulation O
using O
the O
inhibition O
equations O
and O
the O
determined O
kinetic O
constants O
. O

At O
therapeutic O
drug O
levels O
( O
0 O
. O
015 O
mM O
) O
and O
physiologically O
relevant O
concentrations O
of O
ethanol B
( O
10 O
mM O
) O
and O
acetaldehyde B
( O
10 O
mu O
M O
) O
in O
target O
tissues O
, O
cimetidine B
could O
weakly O
inhibit O
( O
< O
5 O
% O
) O
the O
activities O
of O
ADH1B2 O
and O
ADH1B3 O
in O
liver O
, O
ADH2 O
in O
liver O
and O
small O
intestine O
, O
ADH4 O
in O
stomach O
, O
and O
ALDH1A1 O
in O
the O
three O
tissues O
, O
but O
not O
significantly O
affect O
ADH1A O
, O
ADH1B1 O
, O
ADH1C1 O
/ O
2 O
, O
or O
ALDH2 O
. O

At O
higher O
drug O
levels O
, O
which O
may O
accumulate O
in O
cells O
( O
0 O
. O
2 O
mM O
) O
, O
the O
activities O
of O
the O
weakly O
- O
inhibited O
enzymes O
may O
be O
decreased O
more O
significantly O
. O

The O
quantitative O
effects O
of O
cimetidine B
on O
metabolism O
of O
ethanol B
and O
other O
physiological O
substrates O
of O
ADHs O
need O
further O
investigation O
. O

Anti O
- O
inflammatory O
properties O
of O
fruit O
juices O
enriched O
with O
pine O
bark O
extract O
in O
an O
in O
vitro O
model O
of O
inflamed O
human O
intestinal O
epithelium O
: O
the O
effect O
of O
gastrointestinal O
digestion O
. O

Enrichment O
of O
fruit O
juices O
with O
pine O
bark O
extract O
( O
PBE O
) O
could O
be O
a O
strategy O
to O
compensate O
for O
phenolic O
losses O
during O
the O
gastrointestinal O
digestion O
. O

A O
coculture O
system O
with O
Caco O
- O
2 O
cells O
and O
RAW O
264 O
. O
7 O
macrophages O
was O
established O
as O
an O
in O
vitro O
model O
of O
inflamed O
human O
intestinal O
epithelium O
for O
evaluating O
the O
anti O
- O
inflammatory O
capacity O
of O
fruit O
juices O
enriched O
with O
PBE O
( O
0 O
. O
5 O
g O
L O
( O
- O
1 O
) O
) O
before O
and O
after O
in O
vitro O
digestion O
. O

The O
digestion O
of O
both O
PBE O
- O
enriched O
pineapple O
and O
red O
fruit O
juice O
led O
to O
significant O
changes O
in O
most O
of O
the O
analysed O
phenolic B
compounds O
. O

The O
in O
vitro O
inflammatory O
state O
showed O
cell O
barrier O
dysfunction O
and O
overproduction O
of O
IL O
- O
8 O
, O
nitric B
oxide I
( O
NO B
) O
and O
reactive O
oxygen B
species O
( O
ROS O
) O
. O

In O
the O
inflamed O
cells O
, O
incubation O
with O
nondigested O
samples O
reduced O
( O
P O
< O
0 O
. O
05 O
) O
the O
production O
of O
IL O
- O
8 O
and O
NO B
compared O
with O
digested O
samples O
. O

ROS O
production O
increased O
in O
the O
inflamed O
cells O
exposed O
to O
digested O
commercial O
red O
fruit O
juice O
( O
86 O
. O
8 O
+ O
/ O
- O
1 O
. O
3 O
% O
) O
compared O
with O
fresh O
juice O
( O
77 O
. O
4 O
+ O
/ O
- O
0 O
. O
8 O
% O
) O
and O
increased O
in O
the O
inflamed O
cells O
exposed O
to O
digested O
enriched O
red O
fruit O
juice O
( O
82 O
. O
6 O
+ O
/ O
- O
1 O
. O
6 O
% O
) O
compared O
with O
the O
fresh O
enriched O
juice O
( O
55 O
. O
8 O
+ O
/ O
- O
6 O
% O
) O
. O

The O
anti O
- O
inflammatory O
properties O
of O
PBE O
- O
enriched O
fruit O
juices O
decreased O
after O
digestion O
; O
further O
research O
on O
the O
bioavailability O
of O
the O
assayed O
compounds O
is O
needed O
to O
properly O
assess O
their O
usefulness O
for O
the O
treatment O
of O
gut O
inflammation O
. O

New O
mycotoxins O
from O
marine O
- O
derived O
fungus O
Aspergillus O
sp O
. O

SCSGAF0093 O
. O

Nine O
mycotoxins O
including O
six O
aspergillic B
acid I
group O
toxins O
, O
aluminiumneoaspergil B
( O
1 O
) O
, O
zirconiumneoaspergil B
( O
2 O
) O
, O
aspergilliamide B
( O
3 O
) O
, O
ferrineoaspergillin B
( O
5 O
) O
, O
flavacol B
( O
6 O
) O
, O
neoaspergillic B
acid I
( O
7 O
) O
, O
and O
three O
ochratoxins B
, O
ochratoxin B
A I
n I
- I
butyl I
ester I
( O
4 O
) O
, O
ochratoxin B
A I
( O
8 O
) O
, O
ochratoxin B
A I
methyl I
ester I
( O
9 O
) O
, O
were O
isolated O
from O

the O
fermentation O
broth O
of O
marine O
gorgonian O
derived O
fungus O
Aspergillus O
sp O
. O

SCSGAF0093 O
. O

Four O
of O
them O
( O
1 O
- O
4 O
) O
were O
new O
mycotoxins O
, O
and O
their O
structures O
were O
elucidated O
on O
the O
basis O
of O
spectroscopic O
analysis O
and O
chemical O
evidence O
. O

The O
bio O
- O
toxicity O
of O
compounds O
1 O
- O
9 O
were O
determined O
by O
brine O
shrimp O
lethality O
bioassay O
with O
median O
lethal O
concentration O
( O
LC O
( O
50 O
) O
) O
values O
of O
2 O
. O
59 O
- O
205 O
. O
67 O
mu O
M O
. O

This O
was O
the O
first O
report O
about O
zirconium B
complex O
obtained O
from O
nature O
and O
ochratoxins B
isolated O
from O
marine O
environment O
. O

The O
selective O
SYK O
inhibitor O
P505 O
- O
15 O
( O
PRT062607 B
) O
inhibits O
B O
cell O
signaling O
and O
function O
in O
vitro O
and O
in O
vivo O
and O
augments O
the O
activity O
of O
fludarabine B
in O
chronic O
lymphocytic O
leukemia O
. O

B O
- O
cell O
receptor O
( O
BCR O
) O
associated O
kinases O
including O
spleen O
tyrosine B
kinase O
( O
SYK O
) O
contribute O
to O
the O
pathogenesis O
of O
B O
- O
cell O
malignancies O
. O

SYK O
is O
persistently O
phosphorylated O
in O
a O
subset O
of O
non O
- O
Hodgkin O
lymphoma O
( O
NHL O
) O
and O
chronic O
lymphocytic O
leukemia O
( O
CLL O
) O
, O
and O
SYK O
inhibition O
results O
in O
abrogation O
of O
downstream O
kinase O
activity O
and O
apoptosis O
. O

P505 O
- O
15 O
( O
also O
known O
as O
PRT062607 B
) O
is O
a O
novel O
, O
highly O
selective O
, O
and O
orally O
bioavailable O
small O
molecule O
SYK O
inhibitor O
( O
SYK O
IC O
( O
50 O
) O
= O
1 O
nM O
) O
with O
anti O
- O
SYK O
activity O
that O
is O
at O
least O
80 O
- O
fold O
greater O
than O
its O
affinity O
for O
other O
kinases O
. O

We O
evaluated O
the O
preclinical O
characteristics O
of O
P505 O
- O
15 O
in O
models O
of O
NHL O
and O
CLL O
. O

P505 O
- O
15 O
successfully O
inhibited O
SYK O
- O
mediated O
B O
- O
cell O
receptor O
signaling O
and O
decreased O
cell O
viability O
in O
NHL O
and O
CLL O
. O

Oral O
dosing O
in O
mice O
prevented O
BCR O
- O
mediated O
splenomegaly O
and O
significantly O
inhibited O
NHL O
tumor O
growth O
in O
a O
xenograft O
model O
. O

In O
addition O
, O
combination O
treatment O
of O
primary O
CLL O
cells O
with O
P505 O
- O
15 O
plus O
fludarabine B
produced O
synergistic O
enhancement O
of O
activity O
at O
nanomolar O
concentrations O
. O

Our O
findings O
support O
the O
ongoing O
development O
of O
P505 O
- O
15 O
as O
a O
therapeutic O
agent O
for O
B O
- O
cell O
malignancies O
. O

A O
dose O
finding O
study O
in O
healthy O
volunteers O
has O
been O
completed O
. O

Ticlopidine B
, O
a O
cholestatic O
liver O
injury O
- O
inducible O
drug O
, O
causes O
dysfunction O
of O
bile O
formation O
via O
diminished O
biliary O
secretion O
of O
phospholipids O
: O
involvement O
of O
biliary O
- O
excreted O
glutathione B
- O
conjugated O
ticlopidine B
metabolites O
. O

The O
antiplatelet O
drug O
, O
ticlopidine B
( O
TIC B
) O
, O
reportedly O
causes O
cholestatic O
liver O
injuries O
. O

The O
present O
study O
analyzed O
the O
effect O
of O
TIC B
on O
bile O
formation O
, O
revealing O
that O
the O
biliary O
secretion O
of O
phospholipids O
was O
significantly O
decreased O
in O
TIC B
- O
administered O
Sprague O
Dawley O
( O
SD O
) O
rats O
. O

However O
, O
the O
effect O
of O
TIC O
on O
biliary O
phospholipids O
was O
not O
observed O
in O
SD O
rats O
pretreated O
with O
diethylaminoethyl B
diphenylpropylacetat I
that O
inhibits O
cytochrome O
P450s O
( O
P450 O
) O
, O
or O
in O
Eisai O
hyperbilirubinemic O
rats O
( O
EHBR O
) O
lacking O
functional O
multidrug O
resistance O
- O
associated O
protein O
2 O
( O
MRP2 O
/ O
ABCC2 O
) O
. O

These O
results O
suggest O
that O
glutathione B
- O
conjugated O
TIC B
metabolites O
( O
TIC O
- O
SGs O
) O
, O
which O
were O
formed O
in O
the O
liver O
after O
P450s O
- O
mediated O
metabolism O
and O
were O
excreted O
extensively O
into O
bile O
by O
MRP2 O
, O
mediated O
the O
observed O
alterations O
of O
the O
bile O
composition O
. O

Administration O
of O
TIC O
caused O
significant O
liver O
injuries O
in O
SD O
rats O
, O
with O
decreased O
biliary O
phospholipids O
, O
but O
not O
in O
EHBR O
, O
consistent O
with O
the O
in O
vitro O
observation O
that O
phospholipid O
- O
bile B
acid I
- O
mixed O
micelles O
moderated O
the O
cytotoxic O
effects O
of O
bile B
acids I
. O

Further O
analyses O
revealed O
that O
TIC O
- O
SGs O
did O
not O
directly O
inhibit O
multidrug O
resistance O
3 O
P O
- O
glycoprotein O
( O
MDR3 O
/ O
ABCB4 O
) O
- O
mediated O
phosphatidylcholine B
efflux O
in O
vitro O
. O

Because O
the O
diminished O
biliary O
secretion O
of O
phospholipids O
with O
TIC O
administration O
was O
restored O
by O
taurocholate B
infusion O
in O
SD O
rats O
, O
the O
decreased O
biliary O
concentration O
of O
bile B
acids I
, O
due O
to O
the O
stimulation O
of O
bile B
acid I
- O
independent O
bile O
flow O
driven O
by O
TIC O
- O
SGs O
, O
might O
have O
indirectly O
attenuated O
phospholipid O
secretion O
. O

In O
conclusion O
, O
extensive O
biliary O
excretion O
of O
TIC O
- O
SGs O
decreased O
the O
biliary O
secretion O
of O
phospholipids O
, O
which O
might O
have O
increased O
the O
risk O
of O
TIC O
- O
induced O
cholestatic O
liver O
injury O
. O

Apomorphine B
is O
a O
bimodal O
modulator O
of O
TRPA1 O
channels O
. O

Apomorphine B
is O
a O
non O
- O
narcotic O
derivative O
of O
morphine B
, O
which O
acts O
as O
a O
dopamine B
agonist O
and O
is O
clinically O
used O
to O
treat O
" O
off O
- O
states O
" O
in O
patients O
suffering O
from O
Parkinson O
' O
s O
disease O
. O

Adverse O
effects O
of O
apomorphine B
treatment O
include O
severe O
emesis O
and O
nausea O
, O
and O
ulceration O
and O
pain O
at O
the O
injection O
site O
. O

We O
wanted O
to O
test O
whether O
sensory O
transient O
receptor O
potential O
( O
TRP O
) O
channels O
are O
a O
molecular O
target O
for O
apomorphine B
. O

Here O
, O
we O
show O
that O
rTRPV1 O
, O
rTRPV2 O
, O
rTRPV3 O
, O
and O
mTRPV4 O
, O
as O
well O
as O
hTRPM8 O
, O
and O
rTRPM3 O
, O
which O
are O
expressed O
in O
dorsal O
root O
ganglion O
neurons O
, O
are O
insensitive O
toward O
apomorphine B
treatment O
. O

This O
also O
applied O
to O
the O
cellular O
redox O
sensor O
hTRPM2 O
. O

On O
the O
contrary O
, O
human O
TRPA1 O
could O
be O
concentration O
- O
dependently O
modulated O
by O
apomorphine B
. O

Whereas O
the O
addition O
of O
apomorphine B
in O
the O
low O
micromolar O
range O
produced O
an O
irreversible O
activation O
of O
the O
channel O
, O
application O
of O
higher O
concentrations O
caused O
a O
reversible O
voltage O
- O
dependent O
inhibition O
of O
heterologously O
expressed O
TRPA1 O
channels O
, O
resulting O
from O
a O
reduction O
of O
single O
- O
channel O
open O
times O
. O

In O
addition O
, O
we O
provide O
evidence O
that O
apomorphine B
also O
acts O
on O
endogenous O
TRPA1 O
in O
cultured O
dorsal O
root O
ganglion O
neurons O
from O
rats O
and O
in O
the O
enterochromaffin O
model O
cell O
line O
QGP O
- O
1 O
, O
from O
which O
serotonin B
is O
released O
upon O
activation O
of O
TRPA1 O
. O

Our O
study O
shows O
that O
human O
TRPA1 O
is O
a O
target O
for O
apomorphine B
, O
suggesting O
that O
an O
activation O
of O
TRPA1 O
might O
contribute O
to O
adverse O
side O
effects O
such O
as O
nausea O
and O
painful O
injections O
, O
which O
can O
occur O
during O
treatment O
with O
apomorphine B
. O

Human O
stearoyl B
- I
CoA I
desaturase O
1 O
( O
SCD O
- O
1 O
) O
gene O
expression O
is O
negatively O
regulated O
by O
thyroid B
hormone I
without O
direct O
binding O
of O
thyroid B
hormone I
receptor O
to O
the O
gene O
promoter O
. O

Stearoyl B
- I
CoA I
desaturase O
- O
1 O
( O
SCD O
- O
1 O
) O
plays O
a O
pivotal O
role O
in O
an O
increase O
of O
triglyceride B
by O
an O
excess O
of O
dietary O
carbohydrate B
intake O
. O

Dietary O
carbohydrates B
increase O
SCD O
- O
1 O
gene O
expression O
in O
liver O
by O
sterol B
response O
element O
binding O
protein O
( O
SREBP O
) O
- O
1c O
- O
dependent O
and O
SREBP O
- O
1c O
- O
independent O
pathways O
. O

Previous O
report O
demonstrated O
that O
thyroid O
hormone O
( O
TH O
) O
negatively O
regulates O
mouse O
SCD O
- O
1 O
gene O
promoter O
before O
SREBP O
- O
1c O
was O
revealed O
. O

We O
reported O
that O
TH O
negatively O
regulates O
SREBP O
- O
1c O
recently O
. O

Therefore O
, O
in O
the O
current O
study O
, O
we O
examined O
whether O
and O
how O
TH O
regulates O
human O
SCD O
- O
1 O
gene O
expression O
and O
evaluated O
SREBP O
- O
1c O
effect O
on O
the O
negative O
regulation O
. O

Luciferase O
assays O
revealed O
that O
TH O
suppresses O
both O
mouse O
and O
human O
SCD O
- O
1 O
gene O
promoter O
activity O
. O

In O
SREBP O
- O
1 O
knockdown O
HepG2 O
cells O
, O
TH O
still O
suppresses O
SCD O
- O
1 O
gene O
promoter O
activity O
, O
and O
it O
also O
exerted O
the O
negative O
regulation O
under O
cotransfection O
of O
a O
small O
amount O
of O
SREBP O
- O
1c O
. O

These O
data O
indicated O
that O
SREBP O
- O
1c O
does O
not O
play O
the O
decisive O
role O
for O
the O
negative O
regulation O
by O
TH O
. O

The O
responsible O
region O
for O
the O
negative O
regulation O
in O
human O
SCD O
- O
1 O
gene O
promoter O
turned O
out O
to O
be O
between O
- O
124 O
and O
- O
92 O
bp O
, O
referred O
to O
as O
site O
A O
. O

Chromatin O
immunoprecipitation O
assays O
demonstrated O
that O
TH O
receptor O
- O
beta O
is O
recruited O
to O
the O
region O
upon O
T O
( O
3 O
) O
administration O
, O
although O
TR O
- O
beta O
does O
not O
bind O
directly O
to O
site O
A O
. O

In O
conclusion O
, O
TH O
negatively O
regulates O
human O
SCD O
- O
1 O
gene O
expression O
in O
without O
direct O
binding O
of O
the O
TH O
receptor O
to O
the O
SCD O
- O
1 O
gene O
promoter O
. O

An O
in O
vitro O
network O
of O
intermolecular O
interactions O
between O
viral O
RNA O
segments O
of O
an O
avian O
H5N2 O
influenza O
A O
virus O
: O
comparison O
with O
a O
human O
H3N2 O
virus O
. O

The O
genome O
of O
influenza O
A O
viruses O
( O
IAV O
) O
is O
split O
into O
eight O
viral O
RNAs O
( O
vRNAs O
) O
that O
are O
encapsidated O
as O
viral O
ribonucleoproteins O
. O

The O
existence O
of O
a O
segment O
- O
specific O
packaging O
mechanism O
is O
well O
established O
, O
but O
the O
molecular O
basis O
of O
this O
mechanism O
remains O
to O
be O
deciphered O
. O

Selective O
packaging O
could O
be O
mediated O
by O
direct O
interaction O
between O
the O
vRNA O
packaging O
regions O
, O
but O
such O
interactions O
have O
never O
been O
demonstrated O
in O
virions O
. O

Recently O
, O
we O
showed O
that O
the O
eight O
vRNAs O
of O
a O
human O
H3N2 O
IAV O
form O
a O
single O
interaction O
network O
in O
vitro O
that O
involves O
regions O
of O
the O
vRNAs O
known O
to O
contain O
packaging O
signals O
in O
the O
case O
of O
H1N1 O
IAV O
strains O
. O

Here O
, O
we O
show O
that O
the O
eight O
vRNAs O
of O
an O
avian O
H5N2 O
IAV O
also O
form O
a O
single O
network O
of O
interactions O
in O
vitro O
, O
but O
, O
interestingly O
, O
the O
interactions O
and O
the O
regions O
of O
the O
vRNAs O
they O
involve O
differ O
from O
those O
described O
for O
the O
human O
H3N2 O
virus O
. O

We O
identified O
the O
vRNA O
sequences O
involved O
in O
five O
of O
these O
interactions O
at O
the O
nucleotide B
level O
, O
and O
in O
two O
cases O
, O
we O
validated O
the O
existence O
of O
the O
interaction O
using O
compensatory O
mutations O
in O
the O
interacting O
sequences O
. O

Electron O
tomography O
also O
revealed O
significant O
differences O
in O
the O
interactions O
taking O
place O
between O
viral O
ribonucleoproteins O
in O
H5N2 O
and O
H3N2 O
virions O
, O
despite O
their O
canonical O
' O
7 O
+ O
1 O
' O
arrangement O
. O

Chromatin O
- O
dependent O
and O
- O
independent O
regulation O
of O
DNA O
replication O
origin O
activation O
in O
budding O
yeast O
. O

To O
elucidate O
the O
role O
of O
the O
chromatin O
environment O
in O
the O
regulation O
of O
replication O
origin O
activation O
, O
autonomously O
replicating O
sequences O
were O
inserted O
into O
identical O
locations O
in O
the O
budding O
yeast O
genome O
and O
their O
activation O
times O
in O
S O
phase O
determined O
. O

Chromatin O
- O
dependent O
origins O
adopt O
to O
the O
firing O
time O
of O
the O
surrounding O
locus O
. O

In O
contrast O
, O
the O
origins O
containing O
two O
binding O
sites O
for O
Forkhead O
transcription O
factors O
are O
activated O
early O
in O
the O
S O
phase O
regardless O
of O
their O
location O
in O
the O
genome O
. O

Our O
results O
also O
show O
that O
genuinely O
late O
- O
replicating O
parts O
of O
the O
genome O
can O
be O
converted O
into O
early O
- O
replicating O
loci O
by O
insertion O
of O
a O
chromatin O
- O
independent O
early O
replication O
origin O
, O
ARS607 O
, O
whereas O
insertion O
of O
two O
Forkhead O
- O
binding O
sites O
is O
not O
sufficient O
for O
conversion O
. O

HLA O
- O
DO O
acts O
as O
a O
substrate O
mimic O
to O
inhibit O
HLA O
- O
DM O
by O
a O
competitive O
mechanism O
. O

Mammalian O
class O
II O
major O
histocompatibility O
( O
MHCII O
) O
proteins O
bind O
peptide O
antigens O
in O
endosomal O
compartments O
of O
antigen O
- O
presenting O
cells O
. O

The O
nonclassical O
MHCII O
protein O
HLA O
- O
DM O
chaperones O
peptide O
- O
free O
MHCII O
, O
protecting O
it O
against O
inactivation O
, O
and O
catalyzes O
peptide O
exchange O
on O
loaded O
MHCII O
. O

Another O
nonclassical O
MHCII O
protein O
, O
HLA O
- O
DO O
, O
binds O
HLA O
- O
DM O
and O
influences O
the O
repertoire O
of O
peptides O
presented O
by O
MHCII O
proteins O
. O

However O
, O
the O
mechanism O
by O
which O
HLA O
- O
DO O
functions O
is O
unclear O
. O

Here O
we O
have O
used O
X O
- O
ray O
crystallography O
, O
enzyme O
kinetics O
and O
mutagenesis O
approaches O
to O
investigate O
human O
HLA O
- O
DO O
structure O
and O
function O
. O

In O
complex O
with O
HLA O
- O
DM O
, O
HLA O
- O
DO O
adopts O
a O
classical O
MHCII O
structure O
, O
with O
alterations O
near O
the O
alpha O
subunit O
' O
s O
3 O
1 O
0 O
helix O
. O

HLA O
- O
DO O
binds O
to O
HLA O
- O
DM O
at O
the O
same O
sites O
implicated O
in O
MHCII O
interaction O
, O
and O
kinetic O
analysis O
showed O
that O
HLA O
- O
DO O
acts O
as O
a O
competitive O
inhibitor O
. O

These O
results O
show O
that O
HLA O
- O
DO O
inhibits O
HLA O
- O
DM O
function O
by O
acting O
as O
a O
substrate O
mimic O
, O
and O
the O
findings O
also O
limit O
the O
possible O
functional O
roles O
for O
HLA O
- O
DO O
in O
antigen O
presentation O
. O

DAXX O
- O
dependent O
supply O
of O
soluble O
( O
H3 O
. O
3 O
- O
H4 O
) O
dimers O
to O
PML O
bodies O
pending O
deposition O
into O
chromatin O
. O

Replication O
- O
independent O
chromatin O
deposition O
of O
histone O
variant O
H3 O
. O
3 O
is O
mediated O
by O
several O
chaperones O
. O

We O
report O
a O
multistep O
targeting O
of O
newly O
synthesized O
epitope O
- O
tagged O
H3 O
. O
3 O
to O
chromatin O
via O
PML O
bodies O
. O

H3 O
. O
3 O
is O
recruited O
to O
PML O
bodies O
in O
a O
DAXX O
- O
dependent O
manner O
, O
a O
process O
facilitated O
by O
ASF1A O
. O

DAXX O
is O
required O
for O
enrichment O
of O
ATRX O
, O
but O
not O
ASF1A O
or O
HIRA O
, O
with O
PML O
. O

Nonetheless O
, O
the O
chaperones O
colocalize O
with O
H3 O
. O
3 O
at O
PML O
bodies O
and O
are O
found O
in O
one O
or O
more O
complexes O
with O
PML O
. O

Both O
DAXX O
and O
PML O
are O
necessary O
to O
prevent O
accumulation O
of O
a O
soluble O
, O
nonincorporated O
pool O
of O
H3 O
. O
3 O
. O

H3 O
. O
3 O
targeting O
to O
PML O
is O
enhanced O
with O
an O
( O
H3 O
. O
3 O
- O
H4 O
) O
2 O
tetramerization O
mutant O
of O
H3 O
. O
3 O
, O
suggesting O
H3 O
. O
3 O
recruitment O
to O
PML O
as O
an O
( O
H3 O
. O
3 O
- O
H4 O
) O
dimer O
rather O
than O
as O
a O
tetramer O
. O

Our O
data O
support O
a O
model O
of O
DAXX O
- O
mediated O
recruitment O
of O
( O
H3 O
. O
3 O
- O
H4 O
) O
dimers O
to O
PML O
bodies O
, O
which O
may O
function O
as O
triage O
centers O
for O
H3 O
. O
3 O
deposition O
into O
chromatin O
by O
distinct O
chaperones O
. O

Cell O
- O
based O
screening O
identifies O
paroxetine B
as O
an O
inhibitor O
of O
diabetic O
endothelial O
dysfunction O
. O

We O
have O
conducted O
a O
phenotypic O
screening O
in O
endothelial O
cells O
exposed O
to O
elevated O
extracellular O
glucose B
( O
an O
in O
vitro O
model O
of O
hyperglycemia O
) O
to O
identify O
compounds O
that O
prevent O
hyperglycemia O
- O
induced O
reactive O
oxygen B
species O
( O
ROS O
) O
formation O
without O
adversely O
affecting O
cell O
viability O
. O

From O
a O
focused O
library O
of O
> O
6 O
, O
000 O
clinically O
used O
drug O
- O
like O
and O
pharmacologically O
active O
compounds O
, O
several O
classes O
of O
active O
compounds O
emerged O
, O
with O
a O
confirmed O
hit O
rate O
of O
< O
0 O
. O
5 O
% O
. O

Follow O
- O
up O
studies O
focused O
on O
paroxetine B
, O
a O
clinically O
used O
antidepressant O
compound O
that O
has O
not O
been O
previously O
implicated O
in O
the O
context O
of O
hyperglycemia O
or O
diabetes O
. O

Paroxetine B
reduced O
hyperglycemia O
- O
induced O
mitochondrial O
ROS O
formation O
, O
mitochondrial O
protein O
oxidation O
, O
and O
mitochondrial O
and O
nuclear O
DNA O
damage O
, O
without O
interfering O
with O
mitochondrial O
electron O
transport O
or O
cellular O
bioenergetics O
. O

The O
ability O
of O
paroxetine B
to O
improve O
hyperglycemic O
endothelial O
cell O
injury O
was O
unique O
among O
serotonin B
reuptake O
blockers O
and O
can O
be O
attributed O
to O
its O
antioxidant O
effect O
, O
which O
primarily O
resides O
within O
its O
sesamol B
moiety O
. O

Paroxetine B
maintained O
the O
ability O
of O
vascular O
rings O
to O
respond O
to O
the O
endothelium O
- O
dependent O
relaxant O
acetylcholine B
, O
both O
during O
in O
vitro O
hyperglycemia O
and O
ex O
vivo O
, O
in O
a O
rat O
model O
of O
streptozotocin B
- O
induced O
diabetes O
. O

Thus O
, O
the O
current O
work O
identifies O
a O
novel O
pharmacological O
action O
of O
paroxetine B
as O
a O
protector O
of O
endothelial O
cells O
against O
hyperglycemic O
injury O
and O
raises O
the O
potential O
of O
repurposing O
of O
this O
drug O
for O
the O
experimental O
therapy O
of O
diabetic O
cardiovascular O
complications O
. O

Gamma O
- O
radiolysis O
- O
assisted O
cobalt B
oxide I
nanoparticle O
formation O
. O

The O
formation O
of O
Co B
( I
3 I
) I
O I
( I
4 I
) I
nano O
- O
scale O
colloid O
particles O
by O
gamma O
irradiation O
of O
CoSO B
( I
4 I
) I
solutions O
was O
investigated O
. O

Solutions O
of O
0 O
. O
2 O
- O
0 O
. O
3 O
mM O
CoSO B
( I
4 I
) I
at O
pH O
6 O
. O
0 O
and O
10 O
. O
6 O
( O
air O
- O
saturated O
and O
Ar O
- O
purged O
) O
were O
irradiated O
at O
an O
absorbed O
dose O
rate O
of O
5 O
. O
5 O
kGy O
h O
( O
- O
1 O
) O
. O

The O
resulting O
concentrations O
of O
H B
( I
2 I
) I
, O
H B
( I
2 I
) I
O I
( I
2 I
) I
, O
Co B
( I
II I
) I
and O
Co B
( I
III I
) I
species O
in O
solution O
and O
the O
chemical O
composition O
and O
sizes O
of O
particles O
that O
were O
formed O
were O
measured O
as O
a O
function O
of O
irradiation O
time O
. O

Particle O
formation O
was O
observed O
only O
for O
initially O
air O
- O
saturated O
CoSO B
( I
4 I
) I
solutions O
at O
pH O
10 O
. O
6 O
. O

Analysis O
of O
the O
particle O
formation O
as O
a O
function O
of O
irradiation O
time O
shows O
that O
the O
particles O
evolve O
from O
Co B
( I
OH I
) I
( I
2 I
) I
to O
CoOOH B
and O
then O
to O
Co B
( I
3 I
) I
O I
( I
4 I
) I
. O

The O
radiolytic O
oxidation O
of O
Co B
( I
II I
) I
to O
Co B
( I
III I
) I
was O
completed O
in O
100 O
min O
and O
the O
chemical O
composition O
of O
the O
final O
particles O
was O
identified O
as O
Co B
( I
3 I
) I
O I
( I
4 I
) I
by O
XPS O
, O
Raman O
and O
UV O
- O
Vis O
spectroscopy O
. O

Transmission O
electron O
microscopy O
( O
TEM O
) O
images O
show O
the O
final O
particles O
are O
approximately O
uniform O
in O
size O
, O
ranging O
from O
8 O
to O
20 O
nm O
. O

A O
mechanism O
is O
proposed O
to O
explain O
the O
particle O
formation O
. O

A O
key O
factor O
is O
the O
low O
solubility O
of O
Co B
( I
OH I
) I
( I
2 I
) I
in O
air O
- O
saturated O
solutions O
at O
high O
pH O
. O

This O
mechanism O
for O
particle O
formation O
is O
compared O
with O
the O
mechanism O
previously O
reported O
for O
the O
radiolytic O
formation O
of O
gamma B
- I
FeOOH I
nanoparticles O
. O

Plasma O
electrochemistry O
: O
voltammetry O
in O
a O
flame O
plasma O
electrolyte O
. O

In O
this O
paper O
we O
present O
detailed O
dynamic O
electrochemical O
measurements O
in O
a O
flame O
plasma O
electrolyte O
in O
the O
presence O
of O
tungsten B
oxide I
salts O
. O

Defined O
reproducible O
redox O
processes O
are O
measured O
using O
conventional O
cyclic O
voltammetry O
in O
an O
operational O
potential O
window O
between O
1 O
and O
- O
9 O
V O
. O

This O
wide O
potential O
window O
is O
possible O
due O
to O
the O
absence O
of O
solvent O
and O
its O
associated O
limits O
due O
to O
solvent O
electrolysis O
at O
high O
over O
potentials O
. O

The O
measurements O
were O
enabled O
through O
the O
development O
of O
a O
new O
reference O
electrode O
, O
composed O
of O
yttria B
stabilised O
zirconia B
( O
YSZ B
) O
which O
maintains O
a O
stable O
potential O
at O
1100 O
K O
. O

In O
this O
paper O
we O
focus O
on O
developing O
a O
phenomenological O
understanding O
of O
electron O
transfer O
at O
the O
solid O
- O
gas O
interface O
, O
using O
cyclic O
voltammetry O
. O

The O
effect O
of O
working O
electrode O
surface O
area O
and O
material O
, O
as O
well O
as O
potential O
scan O
rate O
on O
the O
voltammetric O
redox O
features O
is O
presented O
. O

We O
discuss O
the O
physical O
origin O
of O
the O
observed O
Faradaic O
current O
peaks O
measured O
in O
a O
flame O
plasma O
electrolyte O
, O
and O
propose O
a O
simple O
model O
to O
describe O
the O
redox O
processes O
occurring O
. O

We O
conclude O
that O
redox O
processes O
at O
the O
solid O
- O
gas O
interface O
are O
actually O
similar O
to O
the O
analogous O
processes O
at O
the O
solid O
- O
liquid O
interface O
described O
by O
conventional O
electrochemical O
theory O
; O
the O
departures O
are O
mainly O
due O
to O
the O
mass O
transport O
processes O
that O
dominate O
in O
the O
gas O
phase O
. O

We O
associate O
migration O
effects O
with O
the O
total O
absence O
of O
any O
oxidation O
processes O
. O

Parenteral O
nutrition O
- O
associated O
hyperglycemia O
in O
non O
- O
critically O
ill O
inpatients O
increases O
the O
risk O
of O
in O
- O
hospital O
mortality O
( O
multicenter O
study O
) O
. O

OBJECTIVE O
Hyperglycemia O
may O
increase O
mortality O
in O
patients O
who O
receive O
total O
parenteral O
nutrition O
( O
TPN O
) O
. O

However O
, O
this O
has O
not O
been O
well O
studied O
in O
noncritically O
ill O
patients O
( O
i O
. O
e O
. O
, O
patients O
in O
the O
nonintensive O
care O
unit O
setting O
) O
. O

The O
aim O
of O
this O
study O
was O
to O
determine O
whether O
mean O
blood O
glucose B
level O
during O
TPN O
infusion O
is O
associated O
with O
increased O
mortality O
in O
noncritically O
ill O
hospitalized O
patients O
. O

RESEARCH O
DESIGN O
AND O
METHODS O
This O
prospective O
multicenter O
study O
involved O
19 O
Spanish O
hospitals O
. O

Noncritically O
ill O
patients O
who O
were O
prescribed O
TPN O
were O
included O
prospectively O
, O
and O
data O
were O
collected O
on O
demographic O
, O
clinical O
, O
and O
laboratory O
variables O
as O
well O
as O
on O
in O
- O
hospital O
mortality O
. O

RESULTS O
The O
study O
included O
605 O
patients O
( O
mean O
age O
63 O
. O
2 O
+ O
/ O
- O
15 O
. O
7 O
years O
) O
. O

The O
daily O
mean O
TPN O
values O
were O
1 O
. O
630 O
+ O
/ O
- O
323 O
kcal O
, O
3 O
. O
2 O
+ O
/ O
- O
0 O
. O
7 O
g O
carbohydrates B
/ O
kg O
, O
1 O
. O
26 O
+ O
/ O
- O
0 O
. O
3 O
g O
amino B
acids I
/ O
kg O
, O
and O
0 O
. O
9 O
+ O
/ O
- O
0 O
. O
2 O
g O
lipids O
/ O
kg O
. O

Multiple O
logistic O
regression O
analysis O
showed O
that O
the O
patients O
who O
had O
mean O
blood O
glucose B
levels O
> O
180 O
mg O
/ O
dL O
during O
the O
TPN O
infusion O
had O
a O
risk O
of O
mortality O
that O
was O
5 O
. O
6 O
times O
greater O
than O
those O
with O
mean O
blood O
glucose B
levels O
< O
140 O
mg O
/ O
dL O
( O
95 O
% O
CI O
1 O
. O
47 O
- O
21 O
. O
4 O
mg O
/ O
dL O
) O
after O
adjusting O
for O
age O
, O
sex O
, O
nutritional O
state O
, O
presence O
of O
diabetes O
or O
hyperglycemia O
before O
starting O
TPN O
, O
diagnosis O
, O
prior O
comorbidity O
, O
carbohydrates B
infused O
, O
use O
of O
steroid O
therapy O
, O
SD O
of O
blood O
glucose B
level O
, O

insulin O
units O
supplied O
, O
infectious O
complications O
, O
albumin O
, O
C O
- O
reactive O
protein O
, O
and O
HbA1c O
levels O
. O

CONCLUSIONS O
Hyperglycemia O
( O
mean O
blood O
glucose B
level O
> O
180 O
mg O
/ O
dL O
) O
in O
noncritically O
ill O
patients O
who O
receive O
TPN O
is O
associated O
with O
a O
higher O
risk O
of O
in O
- O
hospital O
mortality O
. O

Effect O
of O
nuclear O
vibrations O
, O
temperature O
, O
co O
- O
adsorbed O
water O
, O
and O
dye O
orientation O
on O
light O
absorption O
, O
charge O
injection O
and O
recombination O
conditions O
in O
organic O
dyes O
on O
TiO2 B
. O

We O
study O
the O
effect O
of O
nuclear O
motions O
at O
different O
temperatures O
, O
including O
the O
effect O
of O
a O
dye O
molecule O
' O
s O
orientation O
with O
respect O
to O
the O
oxide B
surface O
, O
on O
factors O
determining O
the O
performance O
of O
dye O
sensitized O
solar O
cells O
: O
light O
absorption O
, O
electron O
injection O
, O
and O
back O
- O
donation O
. O

We O
perform O
ab O
initio O
molecular O
dynamics O
simulations O
of O
aminophenyl B
acid I
dyes O
NK1 O
and O
NK7 O
, O
differing O
by O
the O
electron O
donating O
group O
, O
in O
a O
vacuum O
and O
adsorbed O
in O
mono O
- O
and O
bi O
- O
dentate O
modes O
on O
a O
dry O
and O
a O
water O
- O
covered O
anatase O
( O
101 O
) O
surface O
of O
TiO B
( I
2 I
) I
, O
at O
300 O
and O
350 O
K O
. O

Nuclear O
vibrations O
and O
an O
increase O
of O
temperature O
cause O
a O
red O
shift O
in O
the O
absorption O
spectra O
of O
free O
dyes O
. O

This O
effect O
is O
preserved O
in O
dyes O
on O
dry O
TiO B
( I
2 I
) I
but O
largely O
disappears O
in O
the O
presence O
of O
water O
. O

Averaged O
over O
nuclear O
vibrations O
, O
the O
driving O
force O
to O
injection O
, O
Delta O
G O
, O
differs O
from O
the O
static O
estimate O
. O

It O
depends O
on O
the O
adsorption O
mode O
and O
the O
presence O
of O
H B
( I
2 I
) I
O I
but O
is O
almost O
the O
same O
for O
300 O
and O
350 O
K O
. O

Recombination O
to O
the O
dye O
cation O
is O
expected O
to O
be O
much O
enhanced O
by O
the O
approach O
of O
the O
dye O
oxidation O
equivalent O
hole O
to O
the O
surface O
during O
dye O
wagging O
around O
TiO B
( I
2 I
) I
. O

This O
effect O
is O
somewhat O
mitigated O
by O
the O
co O
- O
adsorbed O
water O
. O

The O
dynamics O
of O
Delta O
G O
( O
t O
) O
are O
explained O
by O
uncorrelated O
evolution O
of O
the O
energies O
of O
the O
dye O
excited O
state O
and O
the O
conduction O
band O
minimum O
of O
the O
oxide B
due O
to O
their O
respective O
vibrations O
, O
and O
are O
almost O
independent O
of O
dye O
orientation O
. O

It O
may O
therefore O
be O
possible O
to O
independently O
control O
the O
conditions O
of O
recombination O
and O
of O
injection O
. O

Loss O
of O
LARGE2 O
disrupts O
functional O
glycosylation O
of O
alpha O
- O
dystroglycan O
in O
prostate O
cancer O
. O

Dystroglycan O
( O
DG O
) O
is O
a O
cell O
surface O
receptor O
for O
extracellular O
matrix O
proteins O
and O
is O
involved O
in O
cell O
polarity O
, O
matrix O
organization O
, O
and O
mechanical O
stability O
of O
tissues O
. O

Previous O
studies O
documented O
loss O
of O
DG O
protein O
expression O
and O
glycosylation O
in O
a O
variety O
of O
cancer O
types O
, O
but O
the O
underlying O
mechanisms O
and O
the O
functional O
consequences O
with O
respect O
to O
cancer O
progression O
remain O
unclear O
. O

Here O
, O
we O
show O
that O
the O
level O
of O
expression O
of O
the O
beta O
DG O
subunit O
as O
well O
as O
the O
glycosylation O
status O
of O
the O
alpha O
DG O
subunit O
inversely O
correlate O
with O
the O
Gleason O
scores O
of O
prostate O
cancers O
; O
furthermore O
, O
we O
show O
that O
the O
functional O
glycosylation O
of O
alpha O
DG O
is O
substantially O
reduced O
in O
prostate O
cancer O
metastases O
. O

Additionally O
, O
we O
demonstrate O
that O
LARGE2 O
( O
GYLTL1B O
) O
, O
a O
gene O
not O
previously O
implicated O
in O
cancer O
, O
regulates O
functional O
alpha O
DG O
glycosylation O
in O
prostate O
cancer O
cell O
lines O
; O
knockdown O
of O
LARGE2 O
resulted O
in O
hypoglycosylation O
of O
alpha O
DG O
and O
loss O
of O
its O
ability O
to O
bind O
laminin O
- O
111 O
while O
overexpression O
restored O
ligand O
binding O
and O
diminished O
growth O
and O
migration O
of O
an O
aggressive O
prostate O
cancer O
cell O
line O
. O

Finally O
, O
our O
analysis O
of O
LARGE2 O
expression O
in O
human O
cancer O
specimens O
reveals O
that O
LARGE2 O
is O
significantly O
down O
- O
regulated O
in O
the O
context O
of O
prostate O
cancer O
, O
and O
that O
its O
reduction O
correlates O
with O
disease O
progression O
. O

Our O
results O
describe O
a O
novel O
molecular O
mechanism O
to O
account O
for O
the O
commonly O
observed O
hypoglycosylation O
of O
alpha O
DG O
in O
prostate O
cancer O
. O

Prolyl B
4 O
- O
hydroxlase O
activity O
is O
essential O
for O
development O
and O
cuticle O
formation O
in O
the O
human O
infective O
parasitic O
nematode O
Brugia O
malayi O
. O

Collagen O
prolyl B
4 O
- O
hydroxylases O
( O
C O
- O
P4H O
) O
are O
required O
for O
formation O
of O
extracellular O
matrices O
in O
higher O
eukaryotes O
. O

These O
enzymes O
convert O
proline B
residues O
within O
the O
repeat O
regions O
of O
collagen O
polypeptides O
to O
4 B
- I
hydroxyproline I
, O
a O
modification O
essential O
for O
the O
stability O
of O
the O
final O
triple O
helix O
. O

C O
- O
P4H O
are O
most O
often O
oligomeric O
complexes O
, O
with O
enzymatic O
activity O
contributed O
by O
the O
alpha O
subunits O
, O
and O
the O
beta O
subunits O
formed O
by O
protein O
disulfide B
isomerase O
( O
PDI O
) O
. O

Here O
, O
we O
characterize O
this O
enzyme O
class O
in O
the O
important O
human O
parasitic O
nematode O
Brugia O
malayi O
. O

All O
potential O
C O
- O
P4H O
subunits O
were O
identified O
by O
detailed O
bioinformatic O
analysis O
of O
sequence O
databases O
, O
function O
was O
investigated O
both O
by O
RNAi O
in O
the O
parasite O
and O
heterologous O
expression O
in O
Caenorhabditis O
elegans O
, O
whereas O
biochemical O
activity O
and O
complex O
formation O
were O
examined O
via O
co O
- O
expression O
in O
insect O
cells O
. O

Simultaneous O
RNAi O
of O
two O
B O
. O
malayi O
C O
- O
P4H O
alpha O
subunit O
- O
like O
genes O
resulted O
in O
a O
striking O
, O
highly O
penetrant O
body O
morphology O
phenotype O
in O
parasite O
larvae O
. O

This O
was O
replicated O
by O
single O
RNAi O
of O
a O
B O
. O
malayi O
C O
- O
P4H O
beta O
subunit O
- O
like O
PDI O
. O

Surprisingly O
, O
however O
, O
the O
B O
. O
malayi O
proteins O
were O
not O
capable O
of O
rescuing O
a O
C O
. O
elegans O
alpha O
subunit O
mutant O
, O
whereas O
the O
human O
enzymes O
could O
. O

In O
contrast O
, O
the O
B O
. O
malayi O
PDI O
did O
functionally O
complement O
the O
lethal O
phenotype O
of O
a O
C O
. O
elegans O
beta O
subunit O
mutant O
. O

Comparison O
of O
recombinant O
and O
parasite O
derived O
material O
indicates O
that O
enzymatic O
activity O
may O
be O
dependent O
on O
a O
non O
- O
reducible O
covalent O
link O
, O
present O
only O
in O
the O
parasite O
. O

We O
therefore O
demonstrate O
that O
C O
- O
P4H O
activity O
is O
essential O
for O
development O
of O
B O
. O
malayi O
and O
uncover O
a O
novel O
parasite O
- O
specific O
feature O
of O
these O
collagen O
biosynthetic O
enzymes O
that O
may O
be O
exploited O
in O
future O
parasite O
control O
. O

Alteration O
of O
the O
expression O
of O
pesticide O
- O
metabolizing O
enzymes O
in O
pregnant O
mice O
: O
potential O
role O
in O
the O
increased O
vulnerability O
of O
the O
developing O
brain O
. O

Studies O
on O
therapeutic O
drug O
disposition O
in O
humans O
have O
shown O
significant O
alterations O
as O
the O
result O
of O
pregnancy O
. O

However O
, O
it O
is O
not O
known O
whether O
pesticide O
metabolic O
capacity O
changes O
throughout O
pregnancy O
, O
which O
could O
affect O
exposure O
of O
the O
developing O
brain O
. O

We O
sought O
to O
determine O
the O
effect O
of O
pregnancy O
on O
the O
expression O
of O
hepatic O
enzymes O
involved O
in O
the O
metabolism O
of O
pesticides O
. O

Livers O
were O
collected O
from O
virgin O
and O
pregnant O
C57BL O
/ O
6 O
mice O
at O
gestational O
days O
( O
GD O
) O
7 O
, O
GD11 O
, O
GD14 O
, O
GD17 O
, O
and O
postpartum O
days O
( O
PD O
) O
1 O
, O
PD15 O
, O
and O
PD30 O
. O

Relative O
mRNA O
expression O
of O
several O
enzymes O
involved O
in O
the O
metabolism O
of O
pesticides O
, O
including O
hepatic O
cytochromes O
( O
Cyp O
) O
P450s O
, O
carboxylesterases O
( O
Ces O
) O
, O
and O
paraoxonase O
1 O
( O
Pon1 O
) O
, O
were O
assessed O
in O
mice O
during O
gestation O
and O
the O
postpartum O
period O
. O

Compared O
with O
virgin O
mice O
, O
alterations O
in O
the O
expression O
occurred O
at O
multiple O
time O
points O
, O
with O
the O
largest O
changes O
observed O
on O
GD14 O
. O

At O
this O
time O
point O
, O
the O
expression O
of O
most O
of O
the O
Cyps O
involved O
in O
pesticide O
metabolism O
in O
the O
liver O
( O
Cyp1a2 O
, O
Cyp2d22 O
, O
Cyp2c37 O
, O
Cyp2c50 O
, O
Cyp2c54 O
, O
and O
Cyp3a11 O
) O
were O
downregulated O
by O
30 O
% O
or O
more O
. O

Expression O
of O
various O
Ces O
isoforms O
and O
Pon1 O
were O
also O
decreased O
along O
with O
Pon1 O
activity O
. O

These O
data O
demonstrate O
significant O
alterations O
in O
the O
expression O
of O
key O
enzymes O
that O
detoxify O
pesticides O
during O
pregnancy O
, O
which O
could O
alter O
exposure O
of O
developing O
animals O
to O
these O
chemicals O
. O

Altered O
UDP B
- O
glucuronosyltransfer O
and O
sulfotransferase O
expression O
and O
function O
during O
progressive O
stages O
of O
human O
nonalcoholic O
fatty O
liver O
disease O
. O

The O
UDP B
- O
glucuronosyltransfer O
( O
UGTs O
) O
and O
sulfotransferases O
( O
SULTs O
) O
represent O
major O
phase O
II O
drug O
- O
metabolizing O
enzymes O
that O
are O
also O
responsible O
for O
maintaining O
cellular O
homeostasis O
by O
metabolism O
of O
several O
endogenous O
molecules O
. O

Perturbations O
in O
the O
expression O
or O
function O
of O
these O
enzymes O
can O
lead O
to O
metabolic O
disorders O
and O
improper O
management O
of O
xenobiotics O
and O
endobiotics O
. O

Nonalcoholic O
fatty O
liver O
disease O
( O
NAFLD O
) O
represents O
a O
spectrum O
of O
liver O
damage O
ranging O
from O
steatosis O
to O
nonalcoholic O
steatohepatitis O
( O
NASH O
) O
and O
cirrhosis O
. O

Because O
the O
liver O
plays O
a O
central O
role O
in O
the O
metabolism O
of O
xenobiotics O
, O
the O
purpose O
of O
the O
current O
study O
was O
to O
determine O
the O
effect O
of O
human O
NAFLD O
progression O
on O
the O
expression O
and O
function O
of O
UGTs O
and O
SULTs O
in O
normal O
, O
steatosis O
, O
NASH O
( O
fatty O
) O
, O
and O
NASH O
( O
not O
fatty O
/ O
cirrhosis O
) O
samples O
. O

We O
identified O
upregulation O
of O
UGT1A9 O
, O
2B10 O
, O
and O
3A1 O
and O
SULT1C4 O
mRNA O
in O
both O
stages O
of O
NASH O
, O
whereas O
UGT2A3 O
, O
2B15 O
, O
and O
2B28 O
and O
SULT1A1 O
, O
2B1 O
, O
and O
4A1 O
as O
well O
as O
3 B
' I
- I
phosphoadenosine I
- I
5 I
' I
- I
phosphosulfate I
synthase O
1 O
were O
increased O
in O
NASH O
( O
not O
fatty O
/ O
cirrhosis O
) O
only O
. O

UGT1A9 O
and O
1A6 O
and O
SULT1A1 O
and O
2A1 O
protein O
levels O
were O
decreased O
in O
NASH O
; O
however O
, O
SULT1C4 O
was O
increased O
. O

Measurement O
of O
the O
glucuronidation O
and O
sulfonation O
of O
acetaminophen B
( O
APAP B
) O
revealed O
no O
alterations O
in O
glucuronidation O
; O
however O
, O
SULT O
activity O
was O
increased O
in O
steatosis O
compared O
with O
normal O
samples O
, O
but O
then O
decreased O
in O
NASH O
compared O
with O
steatosis O
. O

In O
conclusion O
, O
the O
expression O
of O
specific O
UGT O
and O
SULT O
isoforms O
appears O
to O
be O
differentially O
regulated O
, O
whereas O
sulfonation O
of O
APAP B
is O
disrupted O
during O
progression O
of O
NAFLD O
. O

SERS O
performance O
of O
gold O
nanotubes O
obtained O
by O
sputtering O
onto O
polycarbonate B
track O
- O
etched O
membranes O
. O

Surface O
- O
enhanced O
Raman O
scattering O
( O
SERS O
) O
is O
a O
powerful O
and O
versatile O
tool O
for O
studying O
molecules O
on O
metallic O
surfaces O
with O
great O
impact O
on O
areas O
such O
as O
electrochemistry O
, O
catalysis O
and O
related O
subjects O
. O

The O
search O
for O
new O
SERS O
- O
active O
substrates O
with O
high O
performance O
, O
namely O
high O
enhancement O
factors O
and O
reproducibility O
, O
is O
currently O
the O
main O
focus O
of O
several O
research O
groups O
. O

Here O
is O
shown O
an O
alternative O
easy O
and O
inexpensive O
synthetic O
approach O
to O
a O
SERS O
- O
substrate O
comprised O
of O
gold O
nanotubes O
obtained O
by O
the O
sputtering O
onto O
polycarbonate B
track O
- O
etched O
membranes O
used O
as O
template O
. O

Its O
SERS O
performance O
was O
evaluated O
by O
mapping O
( O
10 O
x O
10 O
) O
mu O
m O
( O
2 O
) O
areas O
and O
resulted O
in O
average O
enhancement O
factors O
that O
span O
from O
2 O
. O
3 O
x O
10 O
( O
3 O
) O
to O
1 O
. O
2 O
x O
10 O
( O
5 O
) O
with O
a O
maximum O
enhancement O
factor O
of O
2 O
. O
5 O
x O
10 O
( O
5 O
) O
. O

The O
enhancement O
depended O
strongly O
on O
the O
template O
pore O
diameter O
, O
with O
the O
best O
performance O
obtained O
when O
membranes O
with O
pore O
diameters O
of O
400 O
nm O
were O
used O
as O
template O
. O

Further O
analysis O
showed O
that O
the O
larger O
enhancements O
came O
from O
coalesced O
gold O
nanotubes O
and O
detection O
of O
the O
dye O
rhodamine B
6G I
at O
concentrations O
as O
low O
as O
0 O
. O
1 O
nM O
was O
possible O
. O

These O
results O
put O
this O
substrate O
as O
a O
valuable O
and O
easy O
- O
to O
- O
fabricate O
tool O
for O
studying O
and O
detecting O
molecules O
on O
surfaces O
. O

The O
proposed O
methodology O
could O
be O
easily O
adapted O
to O
other O
metals O
, O
such O
as O
silver B
and O
copper B
. O

Advanced O
gecko O
- O
foot O
- O
mimetic O
dry O
adhesives O
based O
on O
carbon B
nanotubes O
. O

Geckos O
can O
run O
freely O
on O
vertical O
walls O
and O
even O
ceilings O
. O

Recent O
studies O
have O
discovered O
that O
gecko O
' O
s O
extraordinary O
climbing O
ability O
comes O
from O
a O
remarkable O
design O
of O
nature O
with O
nanoscale O
beta O
- O
keratin O
elastic O
hairs O
on O
their O
feet O
and O
toes O
, O
which O
collectively O
generate O
sufficiently O
strong O
van O
der O
Waals O
force O
to O
hold O
the O
animal O
onto O
an O
opposing O
surface O
while O
at O
the O
same O
time O
disengaging O
at O
will O
. O

Vertically O
aligned O
carbon B
nanotube O
( O
VA O
- O
CNT O
) O
arrays O
, O
resembling O
gecko O
' O
s O
adhesive O
foot O
hairs O
with O
additional O
superior O
mechanical O
, O
chemical O
and O
electrical O
properties O
, O
have O
been O
demonstrated O
to O
be O
a O
promising O
candidate O
for O
advanced O
fibrillar O
dry O
adhesives O
. O

The O
VA O
- O
CNT O
arrays O
with O
tailor O
- O
made O
hierarchical O
structures O
can O
be O
patterned O
and O
/ O
or O
transferred O
onto O
various O
flexible O
substrates O
, O
including O
responsive O
polymers O
. O

This O
, O
together O
with O
recent O
advances O
in O
nanofabrication O
techniques O
, O
could O
offer O
' O
smart O
' O
dry O
adhesives O
for O
various O
potential O
applications O
, O
even O
where O
traditional O
adhesives O
cannot O
be O
used O
. O

A O
detailed O
understanding O
of O
the O
underlying O
mechanisms O
governing O
the O
material O
properties O
and O
adhesion O
performances O
is O
critical O
to O
the O
design O
and O
fabrication O
of O
gecko O
inspired O
CNT O
dry O
adhesives O
of O
practical O
significance O
. O

In O
this O
feature O
article O
, O
we O
present O
an O
overview O
of O
recent O
progress O
in O
both O
fundamental O
and O
applied O
frontiers O
for O
the O
development O
of O
CNT O
- O
based O
adhesives O
by O
summarizing O
important O
studies O
in O
this O
exciting O
field O
, O
including O
our O
own O
work O
. O

Factors O
limiting O
device O
efficiency O
in O
organic O
photovoltaics O
. O

The O
power O
conversion O
efficiency O
of O
the O
most O
efficient O
organic O
photovoltaic O
( O
OPV O
) O
cells O
has O
recently O
increased O
to O
over O
10 O
% O
. O

To O
enable O
further O
increases O
, O
the O
factors O
limiting O
the O
device O
efficiency O
in O
OPV O
must O
be O
identified O
. O

In O
this O
review O
, O
the O
operational O
mechanism O
of O
OPV O
cells O
is O
explained O
and O
the O
detailed O
balance O
limit O
to O
photovoltaic O
energy O
conversion O
, O
as O
developed O
by O
Shockley O
and O
Queisser O
, O
is O
outlined O
. O

The O
various O
approaches O
that O
have O
been O
developed O
to O
estimate O
the O
maximum O
practically O
achievable O
efficiency O
in O
OPV O
are O
then O
discussed O
, O
based O
on O
empirical O
knowledge O
of O
organic O
semiconductor O
materials O
. O

Subsequently O
, O
approaches O
made O
to O
adapt O
the O
detailed O
balance O
theory O
to O
incorporate O
some O
of O
the O
fundamentally O
different O
processes O
in O
organic O
solar O
cells O
that O
originate O
from O
using O
a O
combination O
of O
two O
complementary O
, O
donor O
and O
acceptor O
, O
organic O
semiconductors O
using O
thermodynamic O
and O
kinetic O
approaches O
are O
described O
. O

The O
more O
empirical O
formulations O
to O
the O
efficiency O
limits O
provide O
estimates O
of O
10 O
- O
12 O
% O
, O
but O
the O
more O
fundamental O
descriptions O
suggest O
limits O
of O
20 O
- O
24 O
% O
to O
be O
reachable O
in O
single O
junctions O
, O
similar O
to O
the O
highest O
efficiencies O
obtained O
for O
crystalline O
silicon B
p O
- O
n O
junction O
solar O
cells O
. O

Closing O
this O
gap O
sets O
the O
stage O
for O
future O
materials O
research O
and O
development O
of O
OPV O
. O

Exploring O
the O
polyamine B
regulatory O
site O
of O
the O
NMDA B
receptor O
: O
a O
parallel O
synthesis O
approach O
. O

The O
elongated O
structures O
of O
polyamine B
inverse O
agonists O
such O
as O
1 B
, I
12 I
- I
diaminododecane I
( O
N12N O
) O
and O
5 B
- I
( I
4 I
- I
aminobutyl I
) I
- I
2 I
- I
thiopheneoctanamine I
( O
N4T8N O
) O
lend O
themselves O
to O
a O
combinatorial O
chemistry O
approach O
to O
explore O
a O
potential O
polyamine B
pharmacophore O
at O
the O
NMDA B
receptor O
. O

Herein O
we O
describe O
more O
than O
100 O
new O
analogues O
of O
N4T8N O
obtained O
by O
breaking O
up O
the O
long O
octanamine B
arm O
into O
a O
dipeptide B
chain O
of O
equivalent O
length O
. O

Solid O
- O
phase O
parallel O
synthesis O
based O
on O
cross O
- O
linked O
polystyrene B
and O
a O
Wang O
anchor O
allowed O
the O
low O
- O
scale O
preparation O
of O
four O
small O
libraries O
based O
on O
the O
combination O
of O
two O
amino B
acid I
residues O
( O
out O
of O
Gly B
, O
Leu B
, O
Phe B
, O
Lys B
, O
phenylglycine B
, O
Tyr B
, O
Trp B
, O
His B
, O
and O
Arg B
) O
. O

The O
obtained O
compounds O
were O
tested O
as O
modulators O
of O
[ B
( I
3 I
) I
H I
] I
MK I
- I
801 I
binding O
to O
rat O
brain O
membranes O
and O
of O
NMDA B
- O
induced O
currents O
in O
cultured O
rat O
hippocampal O
neurons O
. O

Compounds O
with O
two O
aromatic O
residues O
acted O
as O
binding O
inhibitors O
( O
inverse O
agonists O
) O
. O

Compounds O
with O
two O
Lys B
residues O
acted O
as O
binding O
stimulators O
( O
agonists O
) O
and O
had O
stimulatory O
and O
inhibitory O
effects O
on O
NMDA B
- O
induced O
currents O
, O
depending O
on O
the O
holding O
potential O
. O

High O
sensitivity O
of O
binding O
inhibition O
to O
spermine B
was O
conferred O
by O
a O
Tyr B
residue O
, O
whereas O
a O
His B
residue O
favored O
high O
potency O
at O
acidic O
pH O
. O

Design O
strategies O
and O
applications O
of O
tissue O
bioadhesives O
. O

In O
the O
past O
two O
decades O
tissue O
adhesives O
and O
sealants O
have O
revolutionized O
bleeding O
control O
and O
wound O
healing O
. O

This O
paper O
focuses O
on O
existing O
tissue O
adhesive O
design O
, O
their O
structure O
, O
functioning O
mechanism O
, O
and O
their O
pros O
and O
cons O
in O
wound O
management O
. O

It O
also O
includes O
the O
latest O
advances O
in O
the O
development O
of O
new O
tissue O
adhesives O
as O
well O
as O
the O
emerging O
applications O
in O
regenerative O
medicine O
. O

We O
expect O
that O
this O
paper O
will O
provide O
insightful O
discussion O
on O
tissue O
bioadhesive O
design O
and O
lead O
to O
innovations O
for O
the O
development O
of O
the O
next O
generation O
of O
tissue O
bioadhesives O
and O
their O
related O
biomedical O
applications O
. O

Microbial O
transformation O
of O
asiatic B
acid I
. O

Asiatic B
acid I
( O
1 O
) O
, O
a O
major O
pentacyclic B
triterpene I
of O
Centella O
asiatica O
, O
was O
subjected O
to O
transformation O
by O
Penicillium O
lilacinum O
ACCC O
31890 O
, O
Fusarium O
equiseti O
CGMCC O
3 O
. O
3658 O
, O
and O
Streptomyces O
griseus O
CGMCC O
4 O
. O
18 O
strains O
. O

Incubation O
of O
asiatic B
acid I
with O
P O
. O
lilacinum O
ACCC O
31890 O
and O
F O
. O
equiseti O
CGMCC O
3 O
. O
3658 O
gave O
an O
identical O
product O
: O
2 B
alpha I
, I
3 I
beta I
, I
15 I
alpha I
, I
23 I
- I
tetrahydroxyurs I
- I
12 I
- I
en I
- I
28 I
- I
oic I
acid I
( O
2 O
) O
. O

Biotransformation O
of O
asiatic B
acid I
by O
S O
. O
griseus O
CGMCC O
4 O
. O
18 O
resulted O
in O
three O
derivatives O
: O
2 B
alpha I
, I
3 I
beta I
, I
21 I
beta I
, I
23 I
- I
tetrahydroxyurs I
- I
12 I
- I
en I
- I
28 I
- I
oic I
acid I
( O
3 O
) O
, O
2 B
alpha I
, I
3 I
beta I
, I
23 I
- I
trihydroxyurs I
- I
12 I
- I
en I
- I
28 I
, I
30 I
- I
dioic I
acid I
( O
4 O
) O
, O
and O
2 B
alpha I
, I
3 I
beta I
, I
23 I
, I
30 I
- I
tetrahydroxyurs I
- I
12 I
- I
en I
- I
28 I
- I
oic I
acid I
( O
5 O
) O
. O

The O
structures O
of O
those O
derivatives O
were O
deduced O
from O
their O
spectral O
data O
. O

Products O
( O
2 O
) O
, O
( O
3 O
) O
, O
and O
( O
4 O
) O
were O
new O
compounds O
. O

In O
addition O
, O
the O
in O
vitro O
cytotoxicities O
of O
those O
derivatives O
along O
with O
1 O
were O
evaluated O
with O
several O
human O
cancer O
cell O
lines O
. O

Predicting O
dislocations O
and O
grain O
boundaries O
in O
two O
- O
dimensional O
metal B
- I
disulfides I
from O
the O
first O
principles O
. O

Guided O
by O
the O
principles O
of O
dislocation O
theory O
, O
we O
use O
the O
first O
- O
principles O
calculations O
to O
determine O
the O
structure O
and O
properties O
of O
dislocations O
and O
grain O
boundaries O
( O
GB O
) O
in O
single O
- O
layer O
transition B
metal I
disulfides I
MS B
( I
2 I
) I
( O
M O
= O
Mo B
or O
W B
) O
. O

In O
sharp O
contrast O
to O
other O
two O
- O
dimensional O
materials O
( O
truly O
planar O
graphene B
and O
h O
- O
BN O
) O
, O
here O
the O
edge O
dislocations O
extend O
in O
third O
dimension O
, O
forming O
concave O
dreidel O
- O
shaped O
polyhedra O
. O

They O
include O
different O
number O
of O
homoelemental O
bonds O
and O
, O
by O
reacting O
with O
vacancies O
, O
interstitials O
, O
and O
atom O
substitutions O
, O
yield O
families O
of O
the O
derivative O
cores O
for O
each O
Burgers O
vector O
. O

The O
overall O
structures O
of O
GB O
are O
controlled O
by O
both O
local O
- O
chemical O
and O
far O
- O
field O
mechanical O
energies O
and O
display O
different O
combinations O
of O
dislocation O
cores O
. O

Further O
, O
we O
find O
two O
distinct O
electronic O
behaviors O
of O
GB O
. O

Typically O
, O
their O
localized O
deep O
- O
level O
states O
act O
as O
sinks O
for O
carriers O
but O
at O
large O
60 O
degrees O
- O
tilt O
the O
GB O
become O
metallic O
. O

The O
analysis O
shows O
how O
the O
versatile O
GB O
in O
MS O
( O
2 O
) O
( O
if O
carefully O
engineered O
) O
should O
enable O
new O
developments O
for O
electronic O
and O
opto O
- O
electronic O
applications O
. O

Terpenoids B
from O
Incarvillea O
arguta O
. O

One O
new O
monoterpenoid B
, O
( B
+ I
) I
- I
argutoid I
A I
( O
1 O
) O
, O
three O
new O
iridoids B
, O
( B
- I
) I
- I
incarvoid I
A I
( O
2 O
) O
, O
( B
+ I
) I
- I
incarvoid I
B I
( O
3 O
) O
, O
and O
incarvoid B
C I
( O
4 O
) O
, O
and O
five O
known O
compounds O
were O
isolated O
from O
Incarvillea O
arguta O
. O

Their O
structures O
were O
characterized O
by O
means O
of O
spectroscopic O
methods O
. O

Amino B
acid I
- O
based O
zwitterionic O
poly B
( I
serine I
methacrylate I
) I
as O
an O
antifouling O
material O
. O

A O
serine B
- O
based O
zwitterionic O
poly B
( I
serine I
methacrylate I
) I
( O
pSerMA B
) O
was O
developed O
in O
this O
work O
to O
be O
used O
as O
a O
potential O
antifouling O
material O
. O

A O
surface O
- O
initiated O
photoiniferter O
- O
mediated O
polymerization O
( O
SI O
- O
PIMP O
) O
method O
was O
used O
to O
graft O
polymer O
brushes O
on O
gold O
surfaces O
. O

The O
pSerMA B
- O
grafted O
samples O
with O
different O
polymer O
film O
thicknesses O
were O
readily O
prepared O
by O
varying O
the O
UV O
- O
irradiation O
time O
. O

With O
the O
optimal O
film O
thickness O
, O
the O
adsorptions O
from O
bovine O
serum O
albumin O
, O
human O
serum O
, O
and O
human O
plasma O
onto O
the O
pSerMA B
- O
grafted O
surfaces O
, O
as O
evaluated O
by O
a O
surface O
plasmon O
resonance O
( O
SPR O
) O
biosensor O
, O
were O
1 O
. O
8 O
, O
9 O
. O
2 O
, O
and O
12 O
. O
9 O
ng O
/ O
cm O
( O
2 O
) O
, O
respectively O
, O
comparable O
to O
the O
traditional O
antifouling O
material O
such O
as O
poly B
( I
ethylene I
glycol I
) I
. O

The O
pSerMA B
- O
grafted O
surfaces O
also O
strongly O
resisted O
adhesion O
from O
bovine O
aortic O
endothelial O
cells O
. O

This O
is O
the O
first O
work O
to O
develop O
an O
amino B
acid I
- O
based O
zwitterionic O
polymer O
as O
an O
antifouling O
material O
, O
demonstrating O
that O
pSerMA B
is O
a O
promising O
alternative O
to O
the O
traditional O
ethylene B
glycol I
- O
based O
antifouling O
materials O
. O

Discriminating O
the O
endogenous O
and O
exogenous O
urinary O
estrogens B
in O
human O
by O
isotopic O
ratio O
mass O
spectrometry O
and O
its O
potential O
clinical O
value O
. O

Estrogens B
were O
prohibited O
in O
the O
food O
producing O
animals O
by O
European O
Union O
( O
96 O
/ O
22 O
/ O
EC O
directive O
) O
and O
added O
to O
the O
Report O
on O
Carcinogens O
in O
United O
States O
since O
2002 O
. O

Due O
to O
very O
low O
concentration O
in O
serum O
or O
urine O
( O
~ O
pg O
/ O
mL O
) O
, O
the O
method O
of O
control O
its O
abuse O
had O
not O
been O
fully O
developed O
. O

The O
endogenous O
estrogens B
were O
separated O
from O
urines O
of O
18 O
adult O
men O
and O
women O
. O

The O
exogenous O
estrogens B
were O
chemical O
reference O
standards O
and O
over O
the O
counter O
preparations O
. O

Two O
patients O
of O
dysfunctional O
uterine O
bleeding O
( O
DUB O
) O
administered O
exogenous O
estradiol B
and O
the O
urines O
were O
collected O
for O
72 O
h O
. O

The O
urinary O
estrogens B
were O
separated O
by O
high O
- O
performance O
liquid O
chromatography O
( O
HPLC O
) O
and O
confirmed O
. O

The O
exogenous O
and O
exogenous O
estrogens B
were O
analyzed O
by O
gas O
chromatography O
combustion O
isotope O
ratio O
mass O
spectrometry O
( O
GC O
- O
C O
- O
IRMS O
) O
to O
determine O
the O
( B
13 I
) I
C I
/ O
( B
12 I
) I
C I
ratio O
( O
delta O
( B
13 I
) I
C I
/ O
1000 O
) O
. O

The O
delta O
( B
13 I
) I
C I
/ O
1000 O
values O
of O
reference O
standard O
of O
E1 O
, O
E2 O
, O
and O
E3 O
were O
- O
29 O
. O
36 O
+ O
/ O
- O
0 O
. O
72 O
, O
- O
27 O
. O
98 O
+ O
/ O
- O
0 O
. O
35 O
, O
- O
27 O
. O
62 O
+ O
/ O
- O
0 O
. O
51 O
, O
respectively O
. O

The O
delta O
( B
13 I
) I
C I
/ O
1000 O
values O
of O
the O
endogenous O
E1 O
, O
E2 O
, O
and O
E3 O
were O
- O
21 O
. O
62 O
+ O
/ O
- O
1 O
. O
07 O
, O
- O
22 O
. O
14 O
+ O
/ O
- O
0 O
. O
98 O
, O
and O
- O
21 O
. O
88 O
+ O
/ O
- O
1 O
. O
16 O
, O
with O
P O
< O
0 O
. O
01 O
( O
t O
- O
test O
) O
. O

Two O
DUB O
patients O
' O
urinary O
estradiol B
delta O
( B
13 I
) I
C I
/ O
1000 O
values O
was O
depleted O
to O
- O
28 O
. O
02 O
+ O
/ O
- O
0 O
. O
33 O
after O
the O
administration O
. O

The O
progesterone B
, O
17 B
alpha I
- I
hydroxyprogesterone I
, O
pregnanediol B
, O
as O
well O
as O
desogestrel B
and O
ethinylestradiol B
from O
contraceptives O
were O
also O
determined O
. O

Stable O
carbon B
isotope O
analysis O
can O
distinguish O
the O
endogenous O
and O
exogenous O
urinary O
estrogen B
in O
human O
. O

Identification O
and O
characterization O
of O
MIP O
- O
1 O
alpha O
/ O
CCL3 O
isoform O
2 O
from O
bovine O
serum O
as O
a O
potent O
monocyte O
/ O
dendritic O
cell O
chemoattractant O
. O

Bovine O
serum O
is O
a O
rich O
source O
of O
cytokines O
and O
growth O
factors O
supporting O
in O
vitro O
cell O
culture O
. O

Here O
, O
a O
novel O
bovine O
monocyte O
chemotactic O
factor O
( O
boMCF O
- O
1 O
) O
was O
isolated O
from O
commercial O
bovine O
serum O
by O
a O
four O
step O
purification O
procedure O
including O
adsorption O
to O
silicic B
acid I
, O
heparin O
affinity O
and O
cation O
- O
exchange O
chromatography O
and O
reversed O
phase O
HPLC O
. O

Homogeneous O
boMCF O
- O
1 O
was O
characterized O
as O
a O
7717Da O
protein O
by O
mass O
spectrometry O
and O
identified O
by O
Edman O
degradation O
as O
the O
predicted O
product O
of O
bovine O
macrophage O
inflammatory O
protein O
- O
1 O
alpha O
gene O
( O
boMIP O
- O
1 O
alpha O
/ O
CCL3 O
) O
isoform O
2 O
( O
lacking O
three O
NH B
2 I
- O
terminal O
amino B
acids I
) O
, O
belonging O
to O
the O
MIP O
subfamily O
of O
CC O
chemokines O
. O

Monocyte O
chemotactic O
activity O
of O
boCCL3 O
isoform O
2 O
was O
completely O
desensitized O
by O
human O
CCL3 O
and O
CCL5 O
, O
partially O
by O
CCL7 O
and O
not O
by O
CCL2 O
. O

Its O
activity O
was O
better O
inhibited O
by O
CCR1 O
than O
by O
CCR5 O
blockade O
. O

BoCCL3 O
isoform O
2 O
, O
present O
in O
bovine O
serum O
at O
about O
10 O
ng O
/ O
ml O
, O
functioned O
as O
a O
most O
potent O
chemoattractant O
for O
immature O
( O
but O
not O
mature O
) O
dendritic O
cells O
with O
a O
minimal O
effective O
concentration O
of O
0 O
. O
03 O
ng O
/ O
ml O
and O
a O
maximal O
chemotactic O
index O
of O
30 O
at O
0 O
. O
3 O
ng O
/ O
ml O
. O

Its O
chemotactic O
activity O
on O
immature O
dendritic O
cells O
was O
significantly O
desensitized O
by O
human O
CCL3 O
, O
CCL5 O
and O
CCL7 O
. O

Blockade O
of O
CCR5 O
rather O
than O
CCR1 O
partially O
prevented O
chemotactic O
activity O
, O
whereas O
blockade O
of O
both O
further O
enhanced O
this O
inhibition O
. O

BoCCL3 B
isoform O
2 O
was O
not O
chemokinetic O
but O
, O
like O
human O
CCL3 O
, O
synergized O
with O
CXCL12 O
in O
monocytic O
cell O
chemotaxis O
. O

Since O
it O
cannot O
be O
deduced O
which O
is O
the O
exact O
human O
homolog O
of O
boCCL3 O
isoform O
2 O
, O
further O
research O
is O
required O
to O
study O
the O
biology O
of O
other O
boCCL3 O
family O
members O
. O

A O
naonoporous O
cell O
- O
therapy O
device O
with O
controllable O
biodegradation O
for O
long O
- O
term O
drug O
release O
. O

Herein O
we O
describe O
the O
development O
and O
implementation O
of O
a O
nanoporous O
cell O
- O
therapy O
device O
with O
controllable O
biodegradation O
. O

Dopamine B
- O
secreting O
PC12 O
cells O
were O
housed O
within O
newly O
formulated O
alginate O
- O
glutamine B
degradable O
polylysine B
( O
A O
- O
GD B
- O
PLL B
) O
microcapsules O
. O

The O
A O
- O
GD O
- O
PLL B
microcapsules O
provided O
a O
3 O
- O
D O
microenvironment O
for O
good O
spatial O
cell O
growth O
, O
viability O
and O
proliferation O
. O

The O
microcapsules O
were O
subsequently O
placed O
within O
a O
poly B
( I
ethylene I
glycol I
) I
( O
PEG B
) O
- O
coated O
poly B
( I
epsilon I
- I
caprolactone I
) I
( O
PCL B
) O
chamber O
covered O
with O
a O
PEG B
- O
grafted O
PCL B
nanoporous O
membrane O
formed O
by O
phase O
inversion O
. O

To O
enhance O
PC12 O
cell O
growth O
and O
to O
assist O
in O
controlled O
degradation O
of O
both O
the O
PC12 O
cells O
and O
the O
device O
construct O
, O
small O
PCL B
capsules O
containing O
neural O
growth O
factor O
( O
PCL B
- O
NGF O
) O
and O
a O
poly B
( I
lactic I
- I
co I
- I
glycolic I
acid I
) I
pellet O
containing O
glutamine B
( O
PLGA B
- O
GLN O
) O
were O
also O
placed O
within O
the O
PCL B
chamber O
. O

Release O
of O
NGF O
from O
the O
PCL B
- O
NGF O
capsules O
facilitated O
cell O
proliferation O
and O
viability O
, O
while O
the O
controlled O
release O
of O
GLN O
from O
the O
PLGA B
- O
GLN O
pellet O
resulted O
in O
A O
- O
GD O
- O
PLL B
microcapsule O
degradation O
and O
eventual O
PC12 O
cell O
death O
following O
a O
pre O
- O
specified O
period O
of O
time O
( O
4 O
weeks O
in O
this O
study O
) O
. O

In O
vivo O
, O
our O
device O
was O
found O
to O
be O
well O
tolerated O
and O
we O
successfully O
demonstrated O
the O
controlled O
release O
of O
dopamine B
over O
a O
period O
of O
four O
weeks O
. O

This O
integrated O
biodegradable O
device O
holds O
great O
promise O
for O
the O
future O
treatment O
of O
a O
variety O
of O
diseases O
. O

Metals O
loads O
into O
the O
Mediterranean O
Sea O
: O
estimate O
of O
Sarno O
River O
inputs O
and O
ecological O
risk O
. O

The O
metals O
pollution O
in O
the O
Sarno O
River O
and O
its O
environmental O
impact O
on O
the O
Gulf O
of O
Naples O
( O
Tyrrhenian O
Sea O
, O
Central O
Mediterranean O
Sea O
) O
were O
estimated O
. O

Eight O
selected O
metals O
( O
As B
, O
Hg B
, O
Cd B
, O
Cr B
, O
Cu B
, O
Ni B
, O
Pb B
and O
Zn B
) O
were O
determined O
in O
the O
water O
dissolved O
phase O
( O
DP O
) O
, O
suspended O
particulate O
matter O
( O
SPM O
) O
and O
sediment O
samples O
. O

Selected O
metals O
concentrations O
ranged O
from O
0 O
. O
32 O
to O
1 O
, O
680 O
. O
39 O
mu O
g O
l O
( O
- O
1 O
) O
in O
water O
DP O
, O
from O
103 O
. O
6 O
to O
7 O
, O
734 O
. O
6 O
mu O
g O
l O
( O
- O
1 O
) O
in O
SPM O
and O
from O
90 O
. O
7 O
to O
2 O
, O
470 O
. O
3 O
mg O
kg O
( O
- O
1 O
) O
in O
sediment O
samples O
. O

Contaminant O
discharges O
of O
selected O
metals O
into O
the O
sea O
were O
calculated O
in O
about O
13 O
, O
977 O
. O
6 O
kg O
year O
( O
- O
1 O
) O
showing O
that O
this O
river O
should O
account O
as O
one O
of O
the O
main O
contribution O
sources O
of O
metals O
to O
the O
Tyrrhenian O
Sea O
. O

Dynamic O
bioavailability O
of O
copper B
in O
soil O
estimated O
by O
uptake O
and O
elimination O
kinetics O
in O
the O
springtail O
Folsomia O
candida O
. O

This O
study O
aimed O
to O
assess O
the O
bioavailability O
of O
copper B
in O
soil O
, O
by O
measuring O
its O
uptake O
kinetics O
into O
a O
representative O
soil O
invertebrate O
, O
the O
collembolan O
Folsomia O
candida O
. O

The O
animals O
were O
exposed O
to O
25 O
or O
100 O
mu O
g O
Cu O
g O
( O
- O
1 O
) O
dry O
LUFA O
2 O
. O
2 O
soil O
at O
nominal O
pH O
( O
CaCl2 B
) O
4 O
. O
5 O
, O
5 O
. O
5 O
, O
or O
6 O
. O
5 O
during O
14 O
days O
after O
which O
they O
were O
transferred O
to O
clean O
soil O
for O
14 O
days O
elimination O
. O

Uptake O
and O
elimination O
rate O
constants O
were O
calculated O
based O
on O
total O
and O
extractable O
soil O
concentrations O
and O
porewater O
concentrations O
using O
one O
- O
compartment O
first O
- O
order O
kinetics O
modelling O
. O

Copper B
was O
present O
in O
the O
animals O
at O
a O
basal O
physiological O
level O
of O
40 O
- O
90 O
mu O
g O
g O
( O
- O
1 O
) O
dry O
weight O
, O
on O
top O
of O
this O
uptake O
and O
elimination O
kinetics O
were O
observed O
. O

Uptake O
rates O
constants O
varied O
between O
0 O
. O
02 O
and O
0 O
. O
17 O
g O
( O
soil O
) O
g O
( O
animal O
) O
( O
- O
1 O
) O
day O
( O
- O
1 O
) O
, O
being O
higher O
at O
lower O
exposure O
level O
, O
but O
did O
not O
differ O
significantly O
between O
different O
soil O
pH O
levels O
. O

Elimination O
rate O
constants O
ranged O
between O
0 O
. O
04 O
and O
0 O
. O
20 O
day O
( O
- O
1 O
) O
and O
were O
negligible O
( O
k O
( O
2 O
) O
< O
0 O
. O
001 O
day O
( O
- O
1 O
) O
) O
at O
pH O
4 O
. O
5 O
and O
6 O
. O
5 O
. O

Multiple O
linear O
regressions O
showed O
that O
the O
pH O
effect O
on O
copper B
uptake O
was O
only O
significant O
when O
taking O
into O
account O
cation O
exchange O
capacity O
, O
or O
calcium B
and O
dissolved O
organic O
carbon B
levels O
in O
the O
pore O
water O
. O

Copper B
concentrations O
in O
the O
animals O
however O
, O
never O
were O
higher O
than O
185 O
mu O
g O
g O
( O
- O
1 O
) O
dry O
weight O
, O
independent O
of O
exposure O
level O
and O
pH O
, O
suggesting O
homeostatic O
regulation O
. O

These O
results O
show O
that O
the O
chemical O
composition O
of O
the O
pore O
water O
does O
affect O
bioavailability O
of O
copper B
in O
soil O
, O
but O
that O
copper B
uptake O
in O
collembolans O
is O
dominated O
by O
homeostatic O
regulation O
rather O
than O
by O
soil O
properties O
like O
pH O
. O

A O
photoinduced O
charge O
transfer O
composite O
of O
graphene B
oxide I
and O
ferrocene B
. O

We O
demonstrate O
the O
formation O
of O
a O
photoinduced O
charge O
transfer O
composite O
with O
graphene B
oxide I
( O
GO O
) O
and O
ferrocene B
( O
Fc O
) O
molecules O
. O

Derived O
insulating O
GO O
was O
partially O
reduced O
to O
improve O
the O
conductivity O
and O
modified O
with O
the O
Fc O
molecules O
. O

Transmission O
electron O
microscopy O
( O
TEM O
) O
, O
elemental O
mapping O
, O
X O
- O
ray O
photoelectron O
and O
UV O
- O
visible O
spectroscopy O
studies O
confirm O
that O
the O
Fc O
molecules O
were O
well O
grafted O
to O
the O
surface O
of O
a O
GO O
sheet O
. O

Photoresponsivity O
of O
the O
prepared O
GO O
- O
Fc O
composite O
was O
investigated O
by O
fabricating O
a O
metal O
/ O
GO O
- O
Fc O
/ O
metal O
device O
. O

The O
fabricated O
device O
shows O
enhanced O
current O
density O
under O
light O
illumination O
, O
suggesting O
a O
photo O
- O
induced O
charge O
transfer O
process O
in O
the O
developed O
GO O
- O
Fc O
composite O
. O

Phase O
transition O
- O
induced O
elasticity O
of O
alpha O
- O
helical O
bioelastomeric O
fibres O
and O
networks O
. O

Natural O
elastomeric O
fibres O
play O
central O
structural O
and O
functional O
roles O
in O
a O
variety O
of O
tissues O
produced O
by O
many O
organisms O
from O
diverse O
Phyla O
. O

Most O
of O
these O
fibres O
feature O
amorphous O
structure O
and O
their O
long O
- O
range O
elastic O
response O
is O
well O
described O
within O
the O
framework O
of O
entropic O
( O
rubber O
- O
like O
) O
elasticity O
. O

Recently O
, O
it O
has O
been O
recognized O
that O
long O
- O
range O
reversible O
deformation O
can O
also O
occur O
in O
biomacromolecular O
fibres O
or O
networks O
that O
feature O
significant O
secondary O
structure O
and O
long O
- O
range O
order O
. O

Their O
elastomeric O
response O
is O
then O
associated O
with O
conformational O
changes O
of O
the O
backbone O
of O
the O
constitutive O
protein O
- O
based O
polymers O
. O

Under O
axially O
imposed O
loads O
, O
several O
groups O
of O
proteins O
whose O
structure O
is O
dominated O
by O
alpha O
- O
helical O
coiled O
- O
coil O
structures O
can O
undergo O
unfolding O
transitions O
and O
secondary O
structure O
transformations O
, O
for O
example O
from O
coiled O
- O
coil O
alpha O
- O
helices O
to O
beta O
- O
sheet O
strands O
. O

In O
contrast O
to O
rubber O
- O
like O
biopolymers O
, O
the O
retractive O
elastic O
force O
in O
these O
biomacromolecular O
materials O
is O
not O
dominated O
by O
a O
return O
to O
a O
maximum O
entropic O
state O
, O
but O
is O
mostly O
the O
result O
of O
variations O
in O
internal O
energy O
associated O
with O
the O
conformational O
changes O
. O

Here O
, O
a O
review O
of O
alpha O
- O
helix O
based O
elastomeric O
materials O
is O
presented O
that O
encompasses O
examples O
and O
experimental O
evidence O
across O
multiple O
length O
scales O
, O
from O
the O
molecular O
to O
the O
macroscopic O
scale O
. O

We O
begin O
by O
summarizing O
the O
basic O
thermodynamic O
formalism O
of O
thermoelasticity O
. O

While O
this O
formalism O
is O
well O
established O
for O
amorphous O
( O
entropically O
- O
dominated O
) O
fibres O
under O
tensile O
loading O
, O
its O
extension O
towards O
conformational O
( O
internal O
energy O
- O
dominated O
) O
elasticity O
is O
less O
known O
. O

Recent O
experimental O
evidence O
as O
well O
as O
corroborating O
computer O
simulations O
are O
then O
reviewed O
and O
discussed O
in O
the O
light O
of O
secondary O
structure O
and O
nano O
- O
scale O
features O
of O
these O
biopolymers O
. O

Comparisons O
are O
also O
drawn O
with O
physiologically O
important O
structural O
fibres O
that O
share O
common O
characteristics O
at O
the O
molecular O
and O
the O
nano O
- O
scale O
, O
including O
intermediate O
filament O
( O
IF O
) O
proteins O
from O
the O
cell O
cytoskeleton O
, O
myosins O
from O
motor O
proteins O
, O
and O
fibrin O
from O
blood O
clot O
. O

We O
conclude O
with O
a O
discussion O
on O
future O
directions O
and O
opportunities O
for O
these O
materials O
from O
a O
biomimetics O
engineering O
perspective O
. O

Regions O
on O
adenylyl B
cyclase O
VII O
required O
for O
selective O
regulation O
by O
the O
G13 O
pathway O
. O

Regulation O
of O
multiple O
adenylyl B
cyclases O
( O
AC O
) O
provides O
unique O
inputs O
to O
mediate O
the O
synthesis O
of O
cAMP B
, O
a O
ubiquitous O
second O
messenger O
that O
controls O
many O
aspects O
of O
cellular O
function O
. O

On O
stimulation O
by O
G O
( O
s O
) O
, O
the O
activities O
of O
ACs O
can O
be O
further O
selectively O
modulated O
by O
other O
pathways O
to O
ensure O
precise O
control O
of O
intracellular O
cAMP B
responses O
to O
specific O
stimuli O
. O

Recently O
, O
we O
reported O
that O
one O
of O
the O
AC O
isoforms O
, O
AC7 O
, O
is O
uniquely O
regulated O
by O
the O
G O
( O
13 O
) O
pathway O
. O

To O
understand O
more O
fully O
the O
molecular O
mechanism O
of O
this O
regulation O
, O
we O
compared O
the O
regulation O
of O
AC7 O
with O
that O
of O
AC2 O
in O
bone O
marrow O
- O
derived O
macrophages O
devoid O
of O
AC7 O
. O

Although O
both O
enzymes O
could O
fully O
restore O
regulation O
of O
cAMP B
by O
G O
beta O
gamma O
, O
activation O
of O
the O
G O
( O
13 O
) O
pathway O
preferentially O
synergized O
with O
AC7 O
. O

Exchange O
of O
domains O
between O
the O
two O
isoforms O
indicates O
that O
the O
C1b O
domain O
and O
the O
N B
- O
terminus O
of O
the O
C1a O
domain O
are O
important O
for O
directing O
selective O
regulation O
of O
AC7 O
by O
the O
G O
( O
13 O
) O
pathway O
. O

A O
mutagenesis O
screen O
identified O
more O
specific O
regions O
of O
AC7 O
that O
differentially O
mediate O
its O
regulation O
by O
distinct O
pathways O
. O

Vitamin B
K2 I
covalently O
binds O
to O
Bak O
and O
induces O
Bak O
- O
mediated O
apoptosis O
. O

Vitamin B
K2 I
( O
VK2 B
, O
menaquinone B
) O
is O
known O
to O
have O
anticancer O
activity O
in O
vitro O
and O
in O
vivo O
. O

Although O
its O
effect O
is O
thought O
to O
be O
mediated O
, O
at O
least O
in O
part O
, O
by O
the O
induction O
of O
apoptosis O
, O
the O
underlying O
molecular O
mechanism O
remains O
elusive O
. O

Here O
, O
we O
identified O
Bcl O
- O
2 O
antagonist O
killer O
1 O
( O
Bak O
) O
as O
a O
molecular O
target O
of O
VK2 O
- O
induced O
apoptosis O
. O

VK2 O
directly O
interacts O
with O
Bak O
and O
induces O
mitochondrial O
- O
mediated O
apoptosis O
. O

Although O
Bak O
and O
Bcl O
- O
2 O
- O
associated O
X O
protein O
( O
Bax O
) O
, O
another O
member O
of O
the O
Bcl O
- O
2 O
family O
, O
are O
generally O
thought O
to O
be O
functionally O
redundant O
, O
only O
Bak O
is O
necessary O
and O
sufficient O
for O
VK2 O
- O
induced O
cytochrome O
c O
( O
cyt O
c O
) O
release O
and O
cell O
death O
. O

Moreover O
, O
VK2 B
- I
2 I
, I
3 I
epoxide I
, O
an O
intracellular O
metabolite O
of O
VK2 O
, O
was O
shown O
to O
covalently O
bind O
to O
the O
cysteine B
- O
166 O
residue O
of O
Bak O
. O

Several O
lines O
of O
evidence O
suggested O
that O
the O
covalent O
attachment O
of O
VK2 O
is O
critical O
for O
apoptosis O
induction O
. O

Thus O
this O
study O
reveals O
a O
specific O
role O
for O
Bak O
in O
mitochondria O
- O
mediated O
apoptosis O
. O

This O
study O
also O
provides O
insight O
into O
the O
anticancer O
effects O
of O
VK2 O
and O
suggests O
that O
Bak O
may O
be O
a O
potential O
target O
of O
cancer O
therapy O
. O

Relative O
oral O
bioavailability O
of O
3 B
- I
MCPD I
from O
3 B
- I
MCPD I
fatty I
acid I
esters I
in O
rats O
. O

In O
order O
to O
quantify O
the O
relative O
oral O
bioavailability O
of O
3 B
- I
chloropropane I
- I
1 I
, I
2 I
- I
diol I
( O
3 B
- I
MCPD I
) O
from O
3 B
- I
MCPD I
fatty I
acid I
diesters I
in O
vivo O
, O
1 B
, I
2 I
- I
dipalmitoyl I
- I
3 I
- I
chloropropane I
- I
1 I
, I
2 I
- I
diol I
( O
3 B
- I
MCPD I
diester I
) O
and O
3 B
- I
MCPD I
were O
orally O
applied O
to O
rats O
in O
equimolar O
doses O
. O

In O
both O
cases O
, O
the O
time O
courses O
of O
3 B
- I
MCPD I
concentrations O
were O
measured O
in O
blood O
, O
various O
organs O
, O
tissues O
and O
intestinal O
luminal O
contents O
. O

The O
results O
show O
that O
3 B
- I
MCPD I
is O
released O
by O
enzymatic O
hydrolysis O
from O
the O
3 B
- I
MCPD I
diester I
in O
the O
gastrointestinal O
tract O
and O
distributed O
to O
blood O
, O
organs O
and O
tissues O
. O

Based O
on O
the O
measurements O
in O
blood O
, O
the O
areas O
under O
the O
curve O
( O
AUC O
) O
for O
3 B
- I
MCPD I
were O
calculated O
. O

By O
comparing O
both O
AUC O
, O
the O
relative O
amount O
of O
3 B
- I
MCPD I
bioavailable O
from O
the O
3 B
- I
MCPD I
diester I
was O
calculated O
to O
be O
86 O
% O
on O
average O
of O
the O
amount O
bioavailable O
following O
administration O
of O
3 B
- I
MCPD I
. O

In O
view O
of O
limited O
experimental O
data O
, O
it O
is O
justified O
for O
the O
purpose O
of O
risk O
assessment O
to O
assume O
complete O
hydrolysis O
of O
the O
diesters O
in O
the O
gastro O
- O
intestinal O
tract O
. O

Therefore O
, O
assessment O
of O
the O
extent O
of O
exposure O
to O
3 B
- I
MCPD I
released O
from O
its O
fatty B
acid I
esters I
should O
be O
performed O
in O
the O
same O
way O
as O
exposure O
to O
the O
same O
molar O
quantity O
of O
3 B
- I
MCPD I
. O

Enantioresolution O
of O
chiral O
derivatives O
of O
xanthones B
on O
( O
S I
, I
S I
) I
- I
Whelk O
- O
O1 O
and O
L B
- I
phenylglycine I
stationary O
phases O
and O
chiral O
recognition O
mechanism O
by O
docking O
approach O
for O
( O
S I
, I
S I
) I
- I
Whelk O
- O
O1 O
. O

The O
resolution O
of O
seven O
enantiomeric O
pairs O
of O
chiral O
derivatives O
of O
xanthones B
( O
CDXs O
) O
on O
( O
S O
, O
S O
) O
- O
Whelk O
- O
O1 O
and O
L B
- I
phenylglycine I
chiral O
stationary O
phases O
( O
CSPs O
) O
was O
systematically O
investigated O
using O
multimodal O
elution O
conditions O
( O
normal O
- O
phase O
, O
polar O
- O
organic O
, O
and O
reversed O
- O
phase O
) O
. O

The O
( O
S O
, O
S O
) O
- O
Whelk O
- O
O1 O
CSP O
, O
under O
polar O
- O
organic O
conditions O
, O
demonstrated O
a O
very O
good O
power O
of O
resolution O
for O
the O
CDXs O
possessing O
an O
aromatic O
moiety O
linked O
to O
the O
stereogenic O
center O
with O
separation O
factor O
and O
resolution O
factor O
ranging O
from O
1 O
. O
91 O
to O
7 O
. O
55 O
and O
from O
6 O
. O
71 O
to O
24 O
. O
16 O
, O
respectively O
. O

The O
chiral O
recognition O
mechanisms O
were O
also O
investigated O
for O
( O
S O
, O
S O
) O
- O
Whelk O
- O
O1 O
CSP O
by O
molecular O
docking O
technique O
. O

Data O
regarding O
the O
CSP O
- O
CDX O
molecular O
conformations O
and O
interactions O
were O
retrieved O
. O

These O
results O
were O
in O
accordance O
with O
the O
experimental O
chromatographic O
parameters O
regarding O
enantioselectivity O
and O
enantiomer O
elution O
order O
. O

The O
results O
of O
the O
present O
study O
fulfilled O
the O
initial O
objectives O
of O
enantioselective O
studies O
of O
CDXs O
and O
elucidation O
of O
intermolecular O
CSP O
- O
CDX O
interactions O
. O

The O
Midregional O
Fragment O
of O
Pro O
- O
A O
- O
Type O
Natriuretic O
Peptide O
, O
Blood O
Pressure O
, O
and O
Mortality O
in O
a O
Prospective O
Cohort O
Study O
of O
Patients O
With O
Type O
2 O
Diabetes O
( O
ZODIAC O
- O
25 O
) O
. O

OBJECTIVE O
Evidence O
that O
midregional O
fragment O
of O
pro O
- O
A O
- O
type O
natriuretic O
peptide O
( O
MR O
- O
proANP O
) O
is O
a O
marker O
of O
mortality O
in O
patients O
with O
type O
2 O
diabetes O
is O
limited O
. O

Therefore O
, O
we O
aimed O
to O
investigate O
the O
capabilities O
of O
MR O
- O
proANP O
in O
predicting O
mortality O
. O

We O
also O
investigated O
whether O
MR O
- O
proANP O
influences O
the O
relationship O
between O
blood O
pressure O
and O
mortality O
in O
old O
age O
. O

RESEARCH O
DESIGN O
AND O
METHODS O
In O
1998 O
, O
1 O
, O
143 O
primary O
care O
patients O
with O
type O
2 O
diabetes O
participated O
in O
the O
ZODIAC O
study O
. O

Because O
blood O
was O
drawn O
for O
867 O
patients O
( O
76 O
% O
) O
and O
confounders O
were O
missing O
for O
19 O
patients O
, O
the O
final O
study O
sample O
comprised O
848 O
patients O
. O

After O
a O
follow O
- O
up O
time O
of O
10 O
years O
, O
we O
used O
Cox O
proportional O
hazard O
models O
to O
evaluate O
the O
relationship O
between O
MR O
- O
proANP O
and O
( O
cardiovascular O
) O
mortality O
. O

Harrell O
C O
statistic O
was O
used O
to O
compare O
models O
with O
and O
without O
MR O
- O
proANP O
. O

The O
regression O
analyses O
were O
repeated O
without O
MR O
- O
proANP O
for O
patients O
aged O
older O
than O
75 O
years O
. O

RESULTS O
Median O
MR O
- O
proANP O
in O
the O
total O
study O
sample O
was O
75 O
pmol O
/ O
L O
( O
interquartile O
range O
, O
48 O
- O
124 O
pmol O
/ O
L O
) O
. O

During O
follow O
- O
up O
, O
354 O
( O
42 O
% O
) O
out O
of O
848 O
patients O
had O
died O
, O
of O
whom O
152 O
( O
43 O
% O
) O
deaths O
were O
attributable O
to O
cardiovascular O
factors O
. O

MR O
- O
proANP O
was O
independently O
associated O
with O
all O
- O
cause O
and O
cardiovascular O
mortality O
, O
irrespective O
of O
age O
. O

During O
old O
age O
, O
there O
was O
a O
significant O
inverse O
relationship O
between O
blood O
pressure O
and O
mortality O
. O

This O
relationship O
did O
not O
change O
after O
adjustment O
for O
MR O
- O
proANP O
. O

CONCLUSIONS O
MR O
- O
proANP O
is O
independently O
associated O
with O
mortality O
in O
patients O
with O
type O
2 O
diabetes O
. O

MR O
- O
proANP O
did O
not O
influence O
the O
inverse O
relationship O
between O
blood O
pressure O
and O
mortality O
in O
elderly O
patients O
. O

Involvement O
of O
UDP B
- O
glucuronosyltransfer O
UGT1A9 O
and O
UGT2B7 O
in O
ethanol B
glucuronidation O
, O
and O
interactions O
with O
common O
drugs O
of O
abuse O
. O

Ethyl B
glucuronide I
( O
EtG B
) O
determination O
is O
increasingly O
used O
in O
clinical O
and O
forensic O
toxicology O
to O
document O
ethanol B
consumption O
. O

The O
enzymes O
involved O
in O
EtG O
production O
, O
as O
well O
as O
potential O
interactions O
with O
common O
drugs O
of O
abuse O
, O
have O
not O
been O
extensively O
studied O
. O

Activities O
of O
human O
liver O
( O
HLM O
) O
, O
kidney O
( O
HKM O
) O
, O
and O
intestinal O
( O
HIM O
) O
microsomes O
, O
as O
well O
as O
of O
12 O
major O
human O
recombinant O
UDP B
- O
glucuronosyltransfer O
( O
UGTs O
) O
, O
toward O
ethanol B
( O
50 O
and O
500 O
mM O
) O
were O
evaluated O
in O
vitro O
using O
liquid O
chromatography O
- O
tandem O
mass O
spectrometry O
. O

Enzyme O
kinetic O
parameters O
were O
determined O
for O
pooled O
microsomes O
and O
recombinant O
UGTs O
with O
significant O
activity O
. O

Individual O
contributions O
of O
UGTs O
were O
estimated O
using O
the O
relative O
activity O
factor O
approach O
, O
proposed O
for O
scaling O
activities O
obtained O
with O
cDNA O
- O
expressed O
enzymes O
to O
HLM O
. O

Interaction O
of O
morphine B
, O
codeine B
, O
lorazepam B
, O
oxazepam B
, O
nicotine B
, O
cotinine B
, O
cannabinol B
, O
and O
cannabidiol B
( O
5 O
, O
10 O
, O
15 O
mg O
/ O
l O
) O
with O
ethanol B
( O
1 O
. O
15 O
, O
4 O
. O
6 O
, O
11 O
. O
5 O
g O
/ O
l O
; O
i O
. O
e O
. O
, O
25 O
, O
100 O
, O
250 O
mM O
) O
glucuronidation O
was O
assessed O
using O
pooled O
HLM O
. O

Ethanol B
glucuronidation O
intrinsic O
clearance O
( O
Cl O
( O
int O
) O
) O
was O
4 O
and O
12 O
. O
7 O
times O
higher O
for O
HLM O
than O
for O
HKM O
and O
HIM O
, O
respectively O
. O

All O
recombinant O
UGTs O
, O
except O
UGT1A1 O
, O
1A6 O
, O
and O
1A10 O
, O
produced O
EtG B
in O
detectable O
amounts O
. O

UGT1A9 O
and O
2B7 O
were O
the O
most O
active O
enzymes O
, O
each O
accounting O
for O
17 O
and O
33 O
% O
of O
HLM O
Cl O
( O
int O
) O
, O
respectively O
. O

Only O
cannabinol B
and O
cannabidiol B
significantly O
affected O
ethanol B
glucuronidation O
. O

Cannabinol B
increased O
ethanol B
glucuronidation O
in O
a O
concentration O
- O
dependent O
manner O
, O
whereas O
cannabidiol B
significantly O
inhibited O
EtG B
formation O
in O
a O
noncompetitive O
manner O
( O
IC O
( O
50 O
) O
= O
1 O
. O
17 O
mg O
/ O
l O
; O
inhibition O
constant O
( O
K O
( O
i O
) O
) O
= O
3 O
. O
1 O
mg O
/ O
l O
) O
. O

UGT1A9 O
and O
2B7 O
are O
the O
main O
enzymes O
involved O
in O
ethanol B
glucuronidation O
. O

In O
addition O
, O
our O
results O
suggest O
that O
cannabinol B
and O
cannabidiol B
could O
significantly O
alter O
ethanol B
glucuronidation O
. O

Mutation O
of O
a O
zinc B
- O
binding O
residue O
in O
the O
glycine B
receptor O
alpha O
1 O
subunit O
changes O
ethanol B
sensitivity O
in O
vitro O
and O
alcohol B
consumption O
in O
vivo O
. O

Ethanol B
is O
a O
widely O
used O
drug O
, O
yet O
an O
understanding O
of O
its O
sites O
and O
mechanisms O
of O
action O
remains O
incomplete O
. O

Among O
the O
protein O
targets O
of O
ethanol B
are O
glycine B
receptors O
( O
GlyRs O
) O
, O
which O
are O
potentiated O
by O
millimolar O
concentrations O
of O
ethanol B
. O

In O
addition O
, O
zinc B
ions O
also O
modulate O
GlyR O
function O
, O
and O
recent O
evidence O
suggests O
that O
physiologic O
concentrations O
of O
zinc B
enhance O
ethanol B
potentiation O
of O
GlyRs O
. O

Here O
, O
we O
first O
built O
a O
homology O
model O
of O
a O
zinc B
- O
bound O
GlyR O
using O
the O
D80 O
position O
as O
a O
coordination O
site O
for O
a O
zinc B
ion O
. O

Next O
, O
we O
investigated O
in O
vitro O
the O
effects O
of O
zinc B
on O
ethanol B
action O
at O
recombinant O
wild O
- O
type O
( O
WT O
) O
and O
mutant O
alpha O
1 O
GlyRs O
containing O
the O
D80A O
substitution O
, O
which O
eliminates O
zinc B
potentiation O
. O

At O
D80A O
GlyRs O
, O
the O
effects O
of O
50 O
and O
200 O
mM O
ethanol B
were O
reduced O
as O
compared O
with O
WT O
receptors O
. O

Also O
, O
in O
contrast O
to O
what O
was O
seen O
with O
WT O
GlyRs O
, O
neither O
adding O
nor O
chelating O
zinc B
changed O
the O
magnitude O
of O
ethanol B
enhancement O
of O
mutant O
D80A O
receptors O
. O

Next O
, O
we O
evaluated O
the O
in O
vivo O
effects O
of O
the O
D80A O
substitution O
by O
using O
heterozygous O
Glra1 O
( O
D80A O
) O
knock O
- O
in O
( O
KI O
) O
mice O
. O

The O
KI O
mice O
showed O
decreased O
ethanol B
consumption O
and O
preference O
, O
and O
they O
displayed O
increased O
startle O
responses O
compared O
with O
their O
WT O
littermates O
. O

Other O
behavioral O
tests O
, O
including O
ethanol B
- O
induced O
motor O
incoordination O
and O
strychnine B
- O
induced O
convulsions O
, O
revealed O
no O
differences O
between O
the O
KI O
and O
WT O
mice O
. O

Together O
, O
our O
findings O
indicate O
that O
zinc B
is O
critical O
in O
determining O
the O
effects O
of O
ethanol B
at O
GlyRs O
and O
suggest O
that O
zinc B
binding O
at O
the O
D80 O
position O
may O
be O
important O
for O
mediating O
some O
of O
the O
behavioral O
effects O
of O
ethanol B
action O
at O
GlyRs O
. O

Expression O
and O
activity O
of O
nitric B
oxide I
synthase O
isoforms O
in O
methamphetamine B
- O
induced O
striatal O
dopamine B
toxicity O
. O

Nitric B
oxide I
is O
implicated O
in O
methamphetamine B
( O
METH B
) O
- O
induced O
neurotoxicity O
; O
however O
, O
the O
source O
of O
the O
nitric B
oxide I
has O
not O
been O
identified O
. O

Previous O
work O
has O
also O
revealed O
that O
animals O
with O
partial O
dopamine B
loss O
induced O
by O
a O
neurotoxic O
regimen O
of O
methamphetamine B
fail O
to O
exhibit O
further O
decreases O
in O
striatal O
dopamine B
when O
re O
- O
exposed O
to O
methamphetamine B
7 O
- O
30 O
days O
later O
. O

The O
current O
study O
examined O
nitric B
oxide I
synthase O
expression O
and O
activity O
and O
protein O
nitration O
in O
striata O
of O
animals O
administered O
saline O
or O
neurotoxic O
regimens O
of O
methamphetamine B
at O
postnatal O
days O
60 O
and O
/ O
or O
90 O
, O
resulting O
in O
four O
treatment O
groups O
: O
Saline O
: O
Saline O
, O
METH B
: O
Saline O
, O
Saline O
: O
METH B
, O
and O
METH B
: O
METH B
. O

Acute O
administration O
of O
methamphetamine B
on O
postnatal O
day O
90 O
( O
Saline O
: O
METH B
and O
METH B
: O
METH B
) O
increased O
nitric B
oxide I
production O
, O
as O
evidenced O
by O
increased O
protein O
nitration O
. O

Methamphetamine B
did O
not O
, O
however O
, O
change O
the O
expression O
of O
endothelial O
or O
inducible O
isoforms O
of O
nitric B
oxide I
synthase O
, O
nor O
did O
it O
change O
the O
number O
of O
cells O
positive O
for O
neuronal O
nitric B
oxide I
synthase O
mRNA O
expression O
or O
the O
amount O
of O
neuronal O
nitric B
oxide I
synthase O
mRNA O
per O
cell O
. O

However O
, O
nitric B
oxide I
synthase O
activity O
in O
striatal O
interneurons O
was O
increased O
in O
the O
Saline O
: O
METH B
and O
METH B
: O
METH B
animals O
. O

These O
data O
suggest O
that O
increased O
nitric B
oxide I
production O
after O
a O
neurotoxic O
regimen O
of O
methamphetamine B
results O
from O
increased O
nitric B
oxide I
synthase O
activity O
, O
rather O
than O
an O
induction O
of O
mRNA O
, O
and O
that O
constitutively O
expressed O
neuronal O
nitric B
oxide I
synthase O
is O
the O
most O
likely O
source O
of O
nitric B
oxide I
after O
methamphetamine B
administration O
. O

Of O
interest O
, O
animals O
rendered O
resistant O
to O
further O
methamphetamine B
- O
induced O
dopamine B
depletions O
still O
show O
equivalent O
degrees O
of O
methamphetamine B
- O
induced O
nitric B
oxide I
production O
, O
suggesting O
that O
nitric B
oxide I
production O
alone O
in O
response O
to O
methamphetamine B
is O
not O
sufficient O
to O
induce O
acute O
neurotoxic O
injury O
. O

The O
yeast O
cap O
binding O
complex O
modulates O
transcription O
factor O
recruitment O
and O
establishes O
proper O
histone O
H3K36 O
trimethylation O
during O
active O
transcription O
. O

Recent O
studies O
have O
revealed O
a O
close O
relationship O
between O
transcription O
, O
histone O
modification O
, O
and O
RNA O
processing O
. O

In O
fact O
, O
genome O
- O
wide O
analyses O
that O
correlate O
histone O
marks O
with O
RNA O
processing O
signals O
raise O
the O
possibility O
that O
specific O
RNA O
processing O
factors O
may O
modulate O
transcription O
and O
help O
to O
" O
write O
" O
chromatin O
marks O
. O

Here O
we O
show O
that O
the O
nuclear O
cap O
binding O
complex O
( O
CBC O
) O
directs O
recruitment O
of O
transcription O
elongation O
factors O
and O
establishes O
proper O
histone O
marks O
during O
active O
transcription O
. O

A O
directed O
genetic O
screen O
revealed O
that O
deletion O
of O
either O
subunit O
of O
the O
CBC O
confers O
a O
synthetic O
growth O
defect O
when O
combined O
with O
deletion O
of O
genes O
encoding O
either O
Ctk2 O
or O
Bur2 O
, O
a O
component O
of O
the O
Saccharomyces O
cerevisiae O
ortholog O
of O
P O
- O
TEFb O
. O

The O
CBC O
physically O
associates O
with O
these O
complexes O
to O
recruit O
them O
during O
transcription O
and O
mediates O
phosphorylation O
at O
Ser B
- O
2 O
of O
the O
C B
- O
terminal O
domain O
( O
CTD O
) O
of O
RNA O
polymerase O
II O
. O

To O
understand O
how O
these O
interactions O
influence O
downstream O
events O
, O
histone O
H3K36me3 O
was O
examined O
, O
and O
we O
demonstrate O
that O
CBC O
Delta O
affects O
proper O
Set2 O
- O
dependent O
H3K36me3 O
. O

Consistent O
with O
this O
, O
the O
CBC O
and O
Set2 O
have O
similar O
effects O
on O
the O
ability O
to O
rapidly O
induce O
and O
sustain O
activated O
gene O
expression O
, O
and O
these O
effects O
are O
distinct O
from O
other O
histone O
methyltransferases O
. O

This O
work O
provides O
evidence O
for O
an O
emerging O
model O
that O
RNA O
processing O
factors O
can O
modulate O
the O
recruitment O
of O
transcription O
factors O
and O
influence O
histone O
modification O
during O
elongation O
. O

Continuum O
- O
and O
particle O
- O
based O
modeling O
of O
shapes O
and O
dynamics O
of O
red O
blood O
cells O
in O
health O
and O
disease O
. O

We O
review O
recent O
advances O
in O
multiscale O
modeling O
of O
the O
mechanics O
of O
healthy O
and O
diseased O
red O
blood O
cells O
( O
RBCs O
) O
, O
and O
blood O
flow O
in O
the O
microcirculation O
. O

We O
cover O
the O
traditional O
continuum O
- O
based O
methods O
but O
also O
particle O
- O
based O
methods O
used O
to O
model O
both O
the O
RBCs O
and O
the O
blood O
plasma O
. O

We O
highlight O
examples O
of O
successful O
simulations O
of O
blood O
flow O
including O
malaria O
and O
sickle O
cell O
anemia O
. O

Surfactant O
- O
free O
microemulsion O
composed O
of O
oleic B
acid I
, O
n B
- I
propanol I
, O
and O
H2O B
. O

Generally O
, O
a O
microemulsion O
consists O
of O
oil O
, O
water O
, O
surfactant O
, O
and O
sometimes O
cosurfactant O
. O

Herein O
, O
we O
report O
a O
surfactant O
- O
free O
microemulsion O
( O
denoted O
as O
SFME O
) O
, O
consisting O
of O
oleic B
acid I
( O
oil O
phase O
) O
, O
water O
, O
and O
n B
- I
propanol I
without O
the O
amphiphilic O
molecular O
structure O
of O
a O
traditional O
surfactant O
. O

The O
phase O
behavior O
of O
the O
ternary O
system O
was O
investigated O
, O
showing O
that O
there O
were O
a O
single O
- O
phase O
microemulsion O
region O
and O
a O
multiphase O
region O
in O
the O
ternary O
phase O
diagram O
. O

The O
electrical O
conductivity O
measurement O
was O
employed O
to O
investigate O
the O
microregions O
of O
the O
single O
- O
phase O
microemulsion O
region O
, O
and O
three O
different O
microregions O
, O
that O
is O
, O
water O
- O
in O
- O
oleic B
acid I
( O
W O
/ O
O O
) O
, O
a O
bicontinuous O
( O
B O
. O
C O
. O
) O
region O
, O
and O
oleic B
acid I
- O
in O
- O
water O
( O
O O
/ O
W O
) O
, O
were O
identified O
, O
which O
were O
further O
confirmed O
by O
freeze O
- O
fracture O
and O
cryogenic O
transmission O
electron O
microscopy O
( O
FF O
- O
TEM O
and O
Cryo O
- O
TEM O
) O
observations O
. O

The O
polarity O
and O
the O
salt O
solubility O
of O
water O
domains O
in O
the O
W O
/ O
O O
SFME O
were O
investigated O
by O
UV O
- O
visible O
spectroscopy O
using O
methyl B
orange I
and O
potassium B
ferricyanide I
as O
probes O
, O
respectively O
. O

Experimental O
results O
showed O
that O
the O
water O
domains O
in O
the O
W O
/ O
O O
microemulsion O
had O
a O
lower O
polarity O
than O
bulk O
water O
and O
a O
normal O
solubility O
for O
salt O
species O
, O
indicating O
that O
the O
SFMEs O
have O
much O
significance O
in O
the O
preparation O
of O
various O
nanomaterials O
. O

An O
optimized O
RAD51 O
inhibitor O
that O
disrupts O
homologous O
recombination O
without O
requiring O
Michael O
acceptor O
reactivity O
. O

Homologous O
recombination O
( O
HR O
) O
is O
an O
essential O
process O
in O
cells O
that O
provides O
repair O
of O
DNA O
double O
- O
strand O
breaks O
and O
lesions O
that O
block O
DNA O
replication O
. O

RAD51 O
is O
an O
evolutionarily O
conserved O
protein O
that O
is O
central O
to O
HR O
. O

Overexpression O
of O
RAD51 O
protein O
is O
common O
in O
cancer O
cells O
and O
represents O
a O
potential O
therapeutic O
target O
in O
oncology O
. O

We O
previously O
described O
a O
chemical O
inhibitor O
of O
RAD51 O
, O
called O
RI O
- I
1 O
( O
referred O
to O
as O
compound O
1 O
in O
this O
report O
) O
. O

The O
chloromaleimide B
group O
of O
this O
compound O
is O
thought O
to O
act O
as O
a O
Michael O
acceptor O
and O
react O
with O
the O
thiol B
group O
on O
C319 O
of O
RAD51 O
, O
using O
a O
conjugate O
addition O
- O
elimination O
mechanism O
. O

In O
order O
to O
reduce O
the O
likelihood O
of O
off O
- O
target O
effects O
and O
to O
improve O
compound O
stability O
in O
biological O
systems O
, O
we O
developed O
an O
analogue O
of O
compound O
1 O
that O
lacks O
maleimide B
- O
based O
reactivity O
but O
retains O
RAD51 O
inhibitory O
activity O
. O

This O
compound O
, O
1 B
- I
( I
3 I
, I
4 I
- I
dichlorophenyl I
) I
- I
3 I
- I
( I
4 I
- I
methoxyphenyl I
) I
- I
4 I
- I
morpholino I
- I
1H I
- I
pyrrole I
- I
2 I
, I
5 I
- I
dione I
, O
named O
RI B
- I
2 I
( O
referred O
to O
as O
compound O
7a O
in O
this O
report O
) O
, O
appears O
to O
bind O
reversibly O
to O
the O
same O
site O
on O
the O
RAD51 O
protein O
as O
does O
compound O
1 O
. O

Like O
compound O
1 O
, O
compound O
7a O
specifically O
inhibits O
HR O
repair O
in O
human O
cells O
. O

Tilting O
the O
balance O
between O
canonical O
and O
noncanonical O
conformations O
for O
the O
H1 O
hypervariable O
loop O
of O
a O
llama O
VHH O
through O
point O
mutations O
. O

Nanobodies O
are O
single O
- O
domain O
antibodies O
found O
in O
camelids O
. O

These O
are O
the O
smallest O
naturally O
occurring O
binding O
domains O
and O
derive O
functionality O
via O
three O
hypervariable O
loops O
( O
H1 O
- O
H3 O
) O
that O
form O
the O
binding O
surface O
. O

They O
are O
excellent O
candidates O
for O
antibody O
engineering O
because O
of O
their O
favorable O
characteristics O
like O
small O
size O
, O
high O
solubility O
, O
and O
stability O
. O

To O
rationally O
engineer O
antibodies O
with O
affinity O
for O
a O
specific O
target O
, O
the O
hypervariable O
loops O
can O
be O
tailored O
to O
obtain O
the O
desired O
binding O
surface O
. O

As O
a O
first O
step O
toward O
such O
a O
goal O
, O
we O
consider O
the O
design O
of O
loops O
with O
a O
desired O
conformation O
. O

In O
this O
study O
, O
we O
focus O
on O
the O
H1 O
loop O
of O
the O
anti O
- O
hCG O
llama O
nanobody O
that O
exhibits O
a O
noncanonical O
conformation O
. O

We O
aim O
to O
" O
tilt O
" O
the O
stability O
of O
the O
H1 O
loop O
structure O
from O
a O
noncanonical O
conformation O
to O
a O
( O
humanized O
) O
type O
1 O
canonical O
conformation O
by O
studying O
the O
effect O
of O
selected O
mutations O
to O
the O
amino B
acid I
sequence O
of O
the O
H1 O
, O
H2 O
, O
and O
proximal O
residues O
. O

We O
use O
all O
- O
atomistic O
, O
explicit O
- O
solvent O
, O
biased O
molecular O
dynamic O
simulations O
to O
simulate O
the O
wild O
- O
type O
and O
mutant O
loops O
in O
a O
prefolded O
framework O
. O

We O
thus O
find O
mutants O
with O
increasing O
propensity O
to O
form O
a O
stable O
type O
1 O
canonical O
conformation O
of O
the O
H1 O
loop O
. O

Free O
energy O
landscapes O
reveal O
the O
existence O
of O
conformational O
isomers O
of O
the O
canonical O
conformation O
that O
may O
play O
a O
role O
in O
binding O
different O
antigenic O
surfaces O
. O

We O
also O
elucidate O
the O
approximate O
mechanism O
and O
kinetics O
of O
transitions O
between O
such O
conformational O
isomers O
by O
using O
a O
Markovian O
model O
. O

We O
find O
that O
a O
particular O
three O
- O
point O
mutant O
has O
the O
strongest O
thermodynamic O
propensity O
to O
form O
the O
H1 O
type O
1 O
canonical O
structure O
but O
also O
to O
exhibit O
transitions O
between O
conformational O
isomers O
, O
while O
a O
different O
, O
more O
rigid O
three O
- O
point O
mutant O
has O
the O
strongest O
propensity O
to O
be O
kinetically O
trapped O
in O
such O
a O
canonical O
structure O
. O

Peptidyl O
- O
prolyl B
cis O
/ O
trans O
- O
isomerase O
A1 O
( O
Pin1 O
) O
is O
a O
target O
for O
modification O
by O
lipid O
electrophiles O
. O

Oxidation O
of O
membrane O
phospholipids O
is O
associated O
with O
inflammation O
, O
neurodegenerative O
disease O
, O
and O
cancer O
. O

Oxyradical O
damage O
to O
phospholipids O
results O
in O
the O
production O
of O
reactive O
aldehydes B
that O
adduct O
proteins O
and O
modulate O
their O
function O
. O

4 B
- I
Hydroxynonenal I
( O
HNE B
) O
, O
a O
common O
product O
of O
oxidative O
damage O
to O
lipids O
, O
adducts O
proteins O
at O
exposed O
Cys B
, O
His B
, O
or O
Lys B
residues O
. O

Here O
, O
we O
demonstrate O
that O
peptidyl O
- O
prolyl B
cis O
/ O
trans O
- O
isomerase O
A1 O
( O
Pin1 O
) O
, O
an O
enzyme O
that O
catalyzes O
the O
conversion O
of O
the O
peptide O
bond O
of O
pSer B
/ O
pThr B
- I
Pro I
moieties O
in O
signaling O
proteins O
from O
cis O
to O
trans O
, O
is O
highly O
susceptible O
to O
HNE B
modification O
. O

Incubation O
of O
purified O
Pin1 O
with O
HNE B
followed O
by O
MALDI O
- O
TOF O
/ O
TOF O
mass O
spectrometry O
resulted O
in O
detection O
of O
Michael O
adducts O
at O
the O
active O
site O
residues O
His B
- O
157 O
and O
Cys B
- O
113 O
. O

Time O
and O
concentration O
dependencies O
indicate O
that O
Cys B
- O
113 O
is O
the O
primary O
site O
of O
HNE B
modification O
. O

Pin1 O
was O
adducted O
in O
MDA O
- O
MB O
- O
231 O
breast O
cancer O
cells O
treated O
with O
8 B
- I
alkynyl I
- I
HNE I
as O
judged O
by O
click O
chemistry O
conjugation O
with O
biotin B
followed O
by O
streptavidin O
- O
based O
pulldown O
and O
Western O
blotting O
with O
anti O
- O
Pin1 O
antibody O
. O

Furthermore O
, O
orbitrap O
MS O
data O
support O
the O
adduction O
of O
Cys B
- O
113 O
in O
the O
Pin1 O
active O
site O
upon O
HNE B
treatment O
of O
MDA O
- O
MB O
- O
231 O
cells O
. O

siRNA O
knockdown O
of O
Pin1 O
in O
MDA O
- O
MB O
- O
231 O
cells O
partially O
protected O
the O
cells O
from O
HNE B
- O
induced O
toxicity O
. O

Recent O
studies O
indicate O
that O
Pin1 O
is O
an O
important O
molecular O
target O
for O
the O
chemopreventive O
effects O
of O
green O
tea O
polyphenols B
. O

The O
present O
study O
establishes O
that O
it O
is O
also O
a O
target O
for O
electrophilic O
modification O
by O
products O
of O
lipid O
peroxidation O
. O

New O
iridoid B
glycoside I
and O
triterpenoid B
glycoside I
from O
Premna O
fulva O
. O

Liquid O
chromatography O
- O
photodiode O
array O
detector O
- O
mass O
spectrometry O
- O
based O
chemical O
investigation O
of O
the O
leaves O
and O
stems O
of O
Premna O
fulva O
yielded O
one O
new O
iridoid B
glycoside I
( O
1 O
) O
, O
one O
new O
triterpenoid B
glycoside I
( O
2 O
) O
along O
with O
six O
known O
compounds O
isolated O
for O
the O
first O
time O
from O
the O
genus O
. O

Their O
structures O
were O
established O
on O
the O
basis O
of O
extensive O
spectroscopic O
data O
analyses O
and O
chemical O
methods O
. O

Acetazolamide B
impairs O
fear O
memory O
consolidation O
in O
rodents O
. O

Acetazolamide B
( O
AZ O
) O
is O
an O
carbonic O
anhydrase O
inhibitor O
, O
which O
has O
been O
used O
in O
the O
treatment O
of O
seizures O
, O
mountain O
sickness O
and O
glaucoma O
. O

Memory O
impairment O
by O
AZ O
has O
been O
reported O
in O
patient O
interviews O
; O
however O
, O
the O
related O
mechanism O
is O
unclear O
. O

We O
applied O
two O
fear O
conditioning O
paradigms O
, O
shuttle O
avoidance O
and O
passive O
avoidance O
, O
in O
both O
rats O
and O
mice O
to O
investigate O
this O
clinical O
anecdote O
. O

Adult O
Wistar O
rats O
receiving O
AZ O
1 O
h O
before O
the O
shuttle O
avoidance O
test O
showed O
decreased O
avoidance O
rates O
, O
especially O
at O
high O
dosage O
. O

Adult O
ICR O
mice O
receiving O
AZ O
both O
before O
and O
after O
acquisition O
trials O
showed O
the O
decreased O
step O
- O
through O
latencies O
during O
the O
passive O
avoidance O
test O
. O

This O
impairment O
of O
fear O
memory O
was O
corroborated O
with O
decreased O
LTP O
by O
AZ O
in O
the O
amygdala O
. O

AZ O
only O
inhibited O
fear O
conditioning O
- O
induced O
ERK O
phosphorylation O
and O
had O
no O
effect O
on O
Akt O
phosphorylation O
. O

In O
conclusion O
, O
our O
study O
confirmed O
the O
adverse O
cognitive O
effect O
of O
AZ O
in O
animal O
and O
electrophysiological O
studies O
. O

In O
clinical O
practice O
, O
clinicians O
should O
be O
aware O
of O
this O
side O
effect O
in O
patients O
taking O
AZ O
. O

In O
addition O
, O
this O
inhibition O
of O
fear O
memory O
by O
AZ O
could O
potentially O
be O
applied O
to O
patients O
with O
posttraumatic O
stress O
disorder O
. O

Structure O
- O
based O
optimization O
of O
angiostatic O
agent O
6DBF7 B
, O
an O
allosteric O
antagonist O
of O
galectin O
- O
1 O
. O

Galectin O
- O
1 O
( O
gal O
- O
1 O
) O
, O
which O
binds O
beta B
- I
galactoside I
groups O
on O
various O
cell O
surface O
receptors O
, O
is O
crucial O
to O
cell O
adhesion O
and O
migration O
, O
and O
is O
found O
to O
be O
elevated O
in O
several O
cancers O
. O

Previously O
, O
we O
reported O
on O
6DBF7 B
, O
a O
dibenzofuran B
( O
DBF B
) O
- O
based O
peptidomimetic O
of O
the O
gal O
- O
1 O
antagonist O
anginex B
. O

In O
the O
present O
study O
, O
we O
used O
a O
structure O
- O
based O
approach O
to O
optimize O
6DBF7 O
. O

Initial O
NMR O
studies O
showed O
that O
6DBF7 O
binds O
to O
gal O
- O
1 O
on O
one O
side O
of O
the O
beta O
- O
sandwich O
away O
from O
the O
lectin O
' O
s O
carbohydrate B
binding O
site O
. O

Although O
an O
alanine B
scan O
of O
6DBF7 O
showed O
that O
the O
two O
cationic O
groups O
( O
lysines B
) O
in O
the O
partial O
peptide O
are O
crucial O
to O
its O
angiostatic O
activity O
, O
it O
is O
the O
hydrophobic O
face O
of O
the O
amphipath O
that O
appears O
to O
interact O
directly O
with O
the O
surface O
of O
gal O
- O
1 O
. O

Based O
on O
this O
structural O
information O
, O
we O
designed O
and O
tested O
additional O
DBF B
analogs O
. O

In O
particular O
, O
substitution O
of O
the O
C B
- O
terminal O
Asp B
for O
alanine B
and O
branched O
alkyl B
side O
chains O
( O
Val B
, O
Leu B
, O
Ile B
) O
for O
linear O
ones O
( O
Nle B
, O
Nva B
) O
rendered O
the O
greatest O
improvements O
in O
activity O
. O

Flow O
cytometry O
with O
gal O
- O
1 O
( O
- O
/ O
- O
) O
splenocytes O
showed O
that O
6DBF7 B
and O
two O
of O
its O
more O
potent O
analogs O
( O
DB16 B
and O
DB21 B
) O
can O
fully O
inhibit O
fluorescein B
isothiocyanate I
- O
gal O
- O
1 O
binding O
. O

Moreover O
, O
heteronuclear O
single O
- O
quantum O
coherence O
NMR O
titrations O
showed O
that O
the O
presence O
of O
DB16 O
decreases O
gal O
- O
1 O
affinity O
for O
lactose B
, O
indicating O
that O
the O
peptidomimetic O
targets O
gal O
- O
1 O
as O
a O
noncompetitive O
, O
allosteric O
inhibitor O
of O
glycan O
binding O
. O

Using O
tumor O
mouse O
models O
( O
B16F10 O
melanoma O
, O
LS174 O
lung O
, O
and O
MA148 O
ovarian O
) O
, O
we O
found O
that O
DB21 B
inhibits O
tumor O
angiogenesis O
and O
tumor O
growth O
significantly O
better O
than O
6DBF7 O
, O
DB16 B
, O
or O
anginex B
. O

DB21 O
is O
currently O
being O
developed O
further O
and O
holds O
promise O
for O
the O
management O
of O
human O
cancer O
in O
the O
clinic O
. O

An O
integrated O
assessment O
of O
sediment O
remediation O
in O
a O
midwestern O
U O
. O
S O
. O
stream O
using O
sediment O
chemistry O
, O
water O
quality O
, O
bioassessment O
, O
and O
fish O
biomarkers O
. O

A O
comprehensive O
biological O
, O
sediment O
, O
and O
water O
quality O
study O
of O
the O
lower O
Little O
Scioto O
River O
near O
Marion O
, O
Ohio O
, O
USA O
, O
was O
undertaken O
to O
evaluate O
the O
changes O
or O
improvements O
in O
biotic O
measurements O
following O
the O
removal O
of O
creosote O
- O
contaminated O
sediment O
. O

The O
study O
area O
covered O
7 O
. O
5 O
river O
miles O
( O
RMs O
) O
, O
including O
a O
remediated O
section O
between O
RMs O
6 O
. O
0 O
and O
6 O
. O
8 O
. O

Fish O
and O
macroinvertebrate O
assemblages O
, O
fish O
biomarkers O
( O
i O
. O
e O
. O
, O
polycyclic B
aromatic I
hydrocarbon I
[ O
PAH B
] O
metabolite O
levels O
in O
white O
sucker O
[ O
Castostomus O
commersoni O
] O
and O
common O
carp O
[ O
Cyprinus O
carpio O
] O
bile O
and O
DNA O
damage O
) O
, O
sediment O
chemistry O
, O
and O
water O
quality O
were O
assessed O
at O
five O
locations O
relative O
to O
the O
primary O
source O
of O
historical O
PAH B
contamination O
- O
upstream O
( O
RM O
9 O
. O
2 O
) O
, O
adjacent O
( O
RM O
6 O
. O
5 O
) O
, O
and O
downstream O
( O
RMs O
5 O
. O
7 O
, O
4 O
. O
4 O

, O
and O
2 O
. O
7 O
) O
. O

Overall O
, O
the O
biomarker O
results O
were O
consistent O
with O
the O
sediment O
PAH O
results O
, O
showing O
a O
pattern O
of O
low O
levels O
of O
PAH B
bile O
metabolites O
and O
DNA O
damage O
at O
the O
upstream O
( O
reference O
or O
background O
location O
) O
, O
as O
well O
as O
the O
remediated O
section O
, O
high O
levels O
at O
the O
two O
immediate O
downstream O
sites O
, O
and O
somewhat O
lower O
levels O
at O
the O
furthest O
downstream O
site O
. O

Results O
show O
that O
remediation O
was O
effective O
in O
reducing O
sediment O
contaminant O
concentrations O
and O
exposure O
of O
fish O
to O
PAHs B
and O
in O
improving O
fish O
assemblages O
( O
60 O
% O
increase O
in O
index O
of O
biotic O
integrity O
scores O
) O
in O
remediated O
river O
sections O
. O

Additional O
remedial O
investigation O
and O
potentially O
further O
remediation O
is O
needed O
to O
improve O
the O
downstream O
benthic O
fish O
community O
, O
which O
is O
still O
heavily O
exposed O
to O
PAH O
contaminants O
. O

A O
maternal O
" O
junk O
- O
food O
" O
diet O
reduces O
sensitivity O
to O
the O
opioid O
antagonist O
naloxone B
in O
offspring O
postweaning O
. O

Perinatal O
exposure O
to O
a O
maternal O
" O
junk O
- O
food O
" O
diet O
has O
been O
demonstrated O
to O
increase O
the O
preference O
for O
palatable O
diets O
in O
adult O
offspring O
. O

We O
aimed O
to O
determine O
whether O
this O
increased O
preference O
could O
be O
attributed O
to O
changes O
in O
mu O
- O
opioid O
receptor O
expression O
within O
the O
mesolimbic O
reward O
pathway O
. O

We O
report O
here O
that O
mRNA O
expression O
of O
the O
mu O
- O
opioid O
receptor O
in O
the O
ventral O
tegmental O
area O
( O
VTA O
) O
at O
weaning O
was O
1 O
. O
4 O
- O
fold O
( O
males O
) O
and O
1 O
. O
9 O
- O
fold O
( O
females O
) O
lower O
in O
offspring O
of O
junk O
- O
food O
( O
JF O
) O
- O
fed O
rat O
dams O
than O
in O
offspring O
of O
dams O
fed O
a O
standard O
rodent O
diet O
( O
control O
) O
( O
P O
< O
0 O
. O
05 O
) O
. O

Administration O
of O
the O
opioid O
antagonist O
naloxone B
to O
offspring O
given O
a O
palatable O
diet O
postweaning O
significantly O
reduced O
fat O
intake O
in O
control O
offspring O
( O
males O
: O
7 O
. O
7 O
+ O
/ O
- O
0 O
. O
7 O
vs O
. O
5 O
. O
4 O
+ O
/ O
- O
0 O
. O
6 O
g O
/ O
kg O
/ O
d O
; O
females O
: O
6 O
. O
9 O
+ O
/ O
- O
0 O
. O
3 O
vs O
. O
3 O
. O
9 O
+ O
/ O
- O
0 O
. O
5 O
g O
/ O
kg O
/ O
d O
; O
P O
< O
0 O
. O
05 O
) O
, O
but O
not O
in O
male O
JF O
offspring O
( O
8 O
. O
6 O
+ O
/ O
- O
0 O
. O
6 O
vs O
. O
7 O
. O
1 O
+ O
/ O
- O
0 O
. O
5 O
g O
/ O
kg O
/ O

d O
) O
and O
was O
less O
effective O
at O
reducing O
fat O
intake O
in O
JF O
females O
( O
42 O
. O
2 O
+ O
/ O
- O
6 O
. O
0 O
vs O
. O
23 O
. O
1 O
+ O
/ O
- O
4 O
. O
1 O
% O
reduction O
, O
P O
< O
0 O
. O
05 O
) O
. O

Similar O
findings O
were O
observed O
for O
total O
energy O
intake O
. O

Naloxone B
treatment O
did O
not O
affect O
intake O
of O
standard O
rodent O
feed O
in O
control O
or O
JF O
offspring O
. O

These O
findings O
suggest O
that O
exposure O
to O
a O
maternal O
junk O
- O
food O
diet O
results O
in O
early O
desensitization O
of O
the O
opioid O
system O
which O
may O
explain O
the O
increased O
preference O
for O
junk O
food O
in O
these O
offspring O
. O

Short O
- O
peptide O
fusion O
inhibitors O
with O
high O
potency O
against O
wild O
- O
type O
and O
enfuvirtide O
- O
resistant O
HIV O
- O
1 O
. O

Peptides O
derived O
from O
the O
C B
- O
terminal O
heptad O
repeat O
( O
C O
peptides O
) O
of O
HIV O
- O
1 O
gp41 O
are O
potent O
inhibitors O
against O
virus O
entry O
. O

However O
, O
development O
of O
a O
short O
C O
peptide O
possessing O
high O
anti O
- O
HIV O
potency O
is O
considered O
a O
daunting O
challenge O
. O

We O
recently O
discovered O
that O
the O
residues O
Met626 B
and O
Thr627 B
preceding O
the O
pocket O
- O
binding O
domain O
of O
the O
C O
peptide O
adopt O
a O
unique O
M O
- O
T O
hook O
structure O
that O
is O
crucial O
for O
the O
design O
of O
HIV O
- O
1 O
fusion O
inhibitors O
. O

In O
this O
study O
, O
we O
first O
presented O
a O
proof O
- O
of O
- O
concept O
prototype O
that O
the O
M O
- O
T O
hook O
residues O
can O
dramatically O
improve O
the O
antiviral O
activity O
and O
thermostability O
of O
a O
short O
C O
peptide O
. O

We O
then O
generated O
a O
24 O
- O
mer O
peptide O
termed O
MT O
- O
SC22EK O
by O
incorporating O
the O
M O
- O
T O
hook O
structure O
to O
the O
N B
terminus O
of O
the O
poorly O
active O
short O
C O
peptide O
SC22EK O
. O

Amazingly O
, O
MT O
- O
SC22EK O
inhibited O
HIV O
- O
1 O
- O
mediated O
cell O
fusion O
and O
infection O
at O
a O
level O
comparable O
to O
C34 O
, O
T1249 O
, O
SC29EK O
, O
and O
sifuvirtide O
, O
and O
it O
was O
highly O
active O
against O
diverse O
HIV O
- O
1 O
subtypes O
and O
variants O
, O
including O
those O
T20 O
( O
enfuvirtide O
) O
and O
SC29EK O
- O
resistant O
viruses O
. O

The O
high O
- O
resolution O
crystal O
structure O
of O
MT O
- O
SC22EK O
reveals O
the O
N B
- O
terminal O
M O
- O
T O
hook O
conformation O
folded O
by O
incorporated O
Met626 B
and O
Thr627 B
and O
identifies O
the O
C B
- O
terminal O
boundary O
critical O
for O
the O
anti O
- O
HIV O
activity O
. O

Collectively O
, O
our O
studies O
provide O
new O
insights O
into O
the O
mechanisms O
of O
HIV O
- O
1 O
fusion O
and O
its O
inhibition O
. O

Design O
and O
assessment O
of O
a O
microfluidic O
network O
system O
for O
oxygen B
transport O
in O
engineered O
tissue O
. O

Oxygen B
and O
nutrients O
cannot O
be O
delivered O
to O
cells O
residing O
in O
the O
interior O
of O
large O
- O
volume O
scaffolds O
via O
diffusion O
alone O
. O

Several O
efforts O
have O
been O
made O
to O
meet O
the O
metabolic O
needs O
of O
cells O
in O
a O
scaffold O
by O
constructing O
mass O
transport O
channels O
, O
particularly O
in O
the O
form O
of O
bifurcated O
networks O
. O

In O
contrast O
to O
progress O
in O
fabrication O
technologies O
, O
however O
, O
an O
approach O
to O
designing O
an O
optimal O
network O
based O
on O
experimental O
evaluation O
has O
not O
been O
actively O
reported O
. O

The O
main O
objective O
of O
this O
study O
was O
to O
establish O
a O
procedure O
for O
designing O
an O
effective O
microfluidic O
network O
system O
for O
a O
cell O
- O
seeded O
scaffold O
and O
to O
develop O
an O
experimental O
model O
to O
evaluate O
the O
design O
. O

We O
proposed O
a O
process O
to O
design O
a O
microfluidic O
network O
by O
combining O
an O
oxygen B
transport O
simulation O
with O
biomimetic O
principles O
governing O
biological O
vascular O
trees O
. O

The O
simulation O
was O
performed O
with O
the O
effective O
diffusion O
coefficient O
( O
D O
( O
e O
, O
s O
) O
) O
, O
which O
was O
experimentally O
measured O
in O
our O
previous O
study O
. O

Porous O
scaffolds O
containing O
an O
embedded O
microfluidic O
network O
were O
fabricated O
using O
the O
lost O
mold O
shape O
- O
forming O
process O
and O
salt O
leaching O
method O
. O

The O
reliability O
of O
the O
procedure O
was O
demonstrated O
by O
experiments O
using O
the O
scaffolds O
. O

This O
approach O
established O
a O
practical O
basis O
for O
designing O
an O
effective O
microfluidic O
network O
in O
a O
cell O
- O
seeded O
scaffold O
. O

Mapping O
the O
ion O
current O
distribution O
in O
nanopore O
/ O
electrode O
devices O
. O

Solid O
- O
state O
nanopores O
with O
integrated O
electrodes O
have O
interesting O
prospects O
in O
next O
- O
generation O
single O
- O
molecule O
biosensing O
and O
sequencing O
. O

These O
include O
" O
gated O
" O
nanopores O
with O
a O
single O
electrode O
integrated O
into O
the O
membrane O
, O
as O
well O
as O
two O
- O
electrode O
designs O
, O
such O
as O
a O
transversal O
tunneling O
junction O
. O

Here O
we O
report O
the O
first O
comprehensive O
analysis O
of O
current O
flow O
in O
a O
three O
- O
electrode O
device O
as O
a O
model O
for O
this O
class O
of O
sensors O
. O

As O
a O
new O
feature O
, O
we O
observe O
apparent O
rectification O
in O
the O
pore O
current O
that O
is O
rooted O
in O
the O
current O
distribution O
of O
the O
cell O
, O
rather O
than O
the O
geometry O
or O
electrostatics O
of O
the O
pore O
. O

We O
benchmark O
our O
results O
against O
a O
recently O
developed O
theoretical O
model O
and O
define O
operational O
parameters O
for O
nanopore O
/ O
electrode O
structures O
. O

Our O
findings O
thus O
facilitate O
the O
rational O
design O
of O
such O
sensor O
devices O
. O

Novobiocin B
analogues O
with O
second O
- O
generation O
noviose B
surrogates O
. O

Hsp90 O
is O
a O
promising O
therapeutic O
target O
for O
the O
treatment O
of O
cancer O
. O

Novobiocin B
is O
the O
first O
Hsp90 O
C B
- O
terminal O
inhibitor O
ever O
identified O
and O
recent O
structure O
- O
activity O
relationship O
studies O
on O
the O
noviose B
sugar I
identified O
several O
commercially O
available O
amines B
as O
suitable O
surrogates O
. O

In O
an O
effort O
to O
further O
understand O
this O
region O
of O
the O
molecule O
, O
analogues O
containing O
various O
N B
' I
- I
amino I
substituents O
were O
prepared O
and O
evaluated O
against O
two O
breast O
cancer O
cell O
lines O
for O
determination O
of O
their O
efficacy O
. O

Compound O
37j O
manifested O
the O
most O
potent O
anti O
- O
proliferative O
activity O
from O
these O
studies O
and O
induced O
Hsp90 O
- O
dependent O
client O
protein O
degradation O
at O
mid O
nano O
- O
molar O
concentrations O
. O

Enhancement O
of O
electrical O
and O
thermomechanical O
properties O
of O
silver B
nanowire O
composites O
by O
the O
introduction O
of O
nonconductive O
nanoparticles O
: O
experiment O
and O
simulation O
. O

Electrically O
conductive O
polymer O
nanocomposites O
have O
been O
applied O
extensively O
in O
many O
fields O
to O
develop O
the O
next O
generation O
of O
devices O
. O

Large O
amounts O
of O
conductive O
nanofillers O
in O
polymer O
matrices O
are O
, O
however O
, O
often O
required O
for O
a O
sufficiently O
high O
electrical O
conductivity O
, O
which O
in O
turn O
deteriorates O
the O
desired O
thermomechanical O
properties O
. O

We O
illustrate O
a O
novel O
but O
facile O
strategy O
to O
improve O
the O
electrical O
conductivity O
and O
the O
thermomechanical O
property O
of O
silver B
nanowire O
/ O
polymer O
nanocomposites O
. O

We O
find O
that O
one O
may O
increase O
the O
electrical O
conductivity O
of O
silver B
nanowire O
/ O
polymer O
nanocomposites O
by O
up O
to O
about O
8 O
orders O
of O
magnitude O
by O
introducing O
silica B
nanoparticles O
with O
nanocomposites O
. O

The O
electrical O
percolation O
threshold O
volume O
fraction O
of O
silver B
nanowires O
decreases O
from O
0 O
. O
12 O
to O
0 O
. O
02 O
. O

Thermomechanical O
properties O
also O
improve O
as O
silica B
nanoparticles O
are O
introduced O
. O

We O
carry O
out O
extensive O
Monte O
Carlo O
simulations O
to O
elucidate O
the O
effects O
of O
silica B
nanoparticles O
at O
a O
molecular O
level O
and O
find O
that O
van O
der O
Waals O
attractive O
interaction O
between O
silica B
nanoparticles O
and O
silver B
nanowires O
dominates O
over O
the O
depletion O
- O
induced O
interaction O
between O
silver B
nanowires O
, O
thus O
improving O
the O
dispersion O
of O
silver B
nanowires O
. O

Without O
silica B
nanoparticles O
, O
silver B
nanowires O
tend O
to O
aggregate O
, O
which O
is O
why O
additional O
silver B
nanowires O
are O
required O
for O
a O
desired O
electrical O
conductivity O
. O

On O
the O
other O
hand O
, O
with O
silica B
nanoparticles O
mixed O
, O
the O
electrical O
percolating O
network O
is O
likely O
to O
form O
at O
a O
smaller O
volume O
fraction O
of O
silver B
nanowires O
. O

Impact O
of O
the O
redox O
- O
cycling O
herbicide O
diquat B
on O
transcript O
expression O
and O
antioxidant O
enzymatic O
activities O
of O
the O
freshwater O
snail O
Lymnaea O
stagnalis O
. O

The O
presence O
of O
pesticides O
in O
the O
environment O
results O
in O
potential O
unwanted O
effects O
on O
non O
- O
target O
species O
. O

Freshwater O
organisms O
inhabiting O
water O
bodies O
adjacent O
to O
agricultural O
areas O
, O
such O
as O
ditches O
, O
ponds O
and O
marshes O
, O
are O
good O
models O
to O
test O
such O
effects O
as O
various O
pesticides O
may O
reach O
these O
habitats O
through O
several O
ways O
, O
including O
aerial O
drift O
, O
run O
- O
off O
, O
and O
drainage O
. O

Diquat B
is O
a O
non O
- O
selective O
herbicide O
used O
for O
crop O
protection O
or O
for O
weed O
control O
in O
such O
water O
bodies O
. O

In O
this O
study O
, O
we O
investigated O
the O
effects O
of O
diquat B
on O
a O
widely O
spread O
aquatic O
invertebrate O
, O
the O
holarctic O
freshwater O
snail O
Lymnaea O
stagnalis O
. O

Due O
to O
the O
known O
redox O
- O
cycling O
properties O
of O
diquat B
, O
we O
studied O
transcript O
expression O
and O
enzymatic O
activities O
relative O
to O
oxidative O
and O
general O
stress O
in O
the O
haemolymph O
and O
gonado O
- O
digestive O
complex O
( O
GDC O
) O
. O

As O
diquat B
is O
not O
persistent O
, O
snails O
were O
exposed O
for O
short O
times O
( O
5 O
, O
24 O
, O
and O
48 O
h O
) O
to O
ecologically O
relevant O
concentrations O
( O
22 O
. O
2 O
, O
44 O
. O
4 O
, O
and O
222 O
. O
2 O
mu O
g O
l O
( O
- O
1 O
) O
) O
of O
diquat B
dibromide I
. O

RT O
- O
qPCR O
was O
used O
to O
quantify O
the O
transcription O
of O
genes O
encoding O
catalase O
( O
cat O
) O
, O
a O
cytosolic O
superoxide B
dismutase O
( O
Cu B
/ O
Zn B
- O
sod O
) O
, O
a O
selenium B
- O
dependent O
glutathione B
peroxidase O
( O
gpx O
) O
, O
a O
glutathione B
reductase O
( O
gred O
) O
, O
the O
retinoid B
X O
receptor O
( O
rxr O
) O
, O
two O
heat O
shock O
proteins O
( O
hsp40 O
and O
hsp70 O
) O
, O
cortactin O
( O
cor O
) O
and O
the O
two O
ribosomal O
genes O
r18S O
and O

r28s O
. O

Enzymatic O
activities O
of O
SOD O
, O
Gpx O
, O
Gred O
and O
glutathione B
S B
- O
transferase O
( O
GST O
) O
were O
investigated O
in O
the O
GDC O
using O
spectrophoto O
/ O
fluorometric O
methods O
. O

Opposite O
trends O
were O
obtained O
in O
the O
haemolymph O
depending O
on O
the O
herbicide O
concentration O
. O

At O
the O
lowest O
concentration O
, O
effects O
were O
mainly O
observed O
after O
24 O
h O
of O
exposure O
, O
with O
over O
- O
transcription O
of O
cor O
, O
hsp40 O
, O
rxr O
, O
and O
sod O
, O
whereas O
higher O
concentrations O
down O
- O
regulated O
the O
expression O
of O
most O
of O
the O
studied O
transcripts O
, O
especially O
after O
48 O
h O
of O
exposure O
. O

In O
the O
GDC O
, O
earlier O
responses O
were O
observed O
and O
the O
fold O
- O
change O
magnitude O
was O
generally O
much O
higher O
: O
transcription O
of O
all O
target O
genes O
increased O
significantly O
( O
or O
non O
- O
significantly O
for O
cat O
) O
after O
5 O
h O
of O
exposure O
, O
and O
went O
back O
to O
control O
levels O
afterwards O
, O
suggesting O
the O
onset O
of O
an O
early O
response O
to O
oxidative O
stress O
associated O
to O
the O
unbalance O
of O
reactive O
oxygen B
species O
( O
ROS O
) O
in O
hepatocytes O
. O

Although O
increases O
obtained O
for O
Gred O
and O
SOD O
activities O
were O
globally O
consistent O
with O
their O
respective O
transcript O
expressions O
, O
up O
- O
regulation O
of O
transcription O
was O
not O
always O
correlated O
with O
increase O
of O
enzymatic O
activity O
, O
indicating O
that O
diquat B
might O
affect O
steps O
downstream O
of O
transcription O
. O

However O
, O
constitutive O
levels O
of O
enzymatic O
activities O
were O
at O
least O
maintained O
. O

In O
conclusion O
, O
diquat B
was O
shown O
to O
affect O
expression O
of O
the O
whole O
set O
of O
studied O
transcripts O
, O
reflecting O
their O
suitability O
as O
markers O
of O
early O
response O
to O
oxidative O
stress O
in O
L O
. O
stagnalis O
. O

Synthesis O
and O
SAR O
of O
aminothiazole B
fused O
benzazepines B
as O
selective O
dopamine B
D2 O
partial O
agonists O
. O

Dopamine B
( O
D O
( O
2 O
) O
) O
partial O
agonists O
( O
D2PAs O
) O
have O
been O
regarded O
as O
a O
potential O
treatment O
for O
schizophrenia O
patients O
with O
expected O
better O
side O
effect O
profiles O
than O
currently O
marketed O
antipsychotics O
. O

Herein O
we O
report O
the O
synthesis O
and O
SAR O
of O
a O
series O
of O
aminothiazole B
fused O
benzazepines B
as O
selective O
D O
( O
2 O
) O
partial O
agonists O
. O

These O
compounds O
have O
good O
selectivity O
, O
CNS O
drug O
- O
like O
properties O
and O
tunable O
D O
( O
2 O
) O
partial O
agonism O
. O

One O
of O
the O
key O
compounds O
, O
8h O
, O
has O
good O
in O
vitro O
/ O
in O
vivo O
ADME O
characteristics O
, O
and O
is O
active O
in O
a O
rat O
amphetamine B
- O
induced O
locomotor O
activity O
model O
. O

Synthesis O
and O
antimycobacterial O
evaluation O
of O
pyrazinamide B
derivatives O
with O
benzylamino B
substitution O
. O

A O
series O
of O
19 O
new O
compounds O
related O
to O
pyrazinamide B
were O
synthesized O
, O
characterized O
with O
analytical O
data O
and O
screened O
for O
in O
vitro O
whole O
cell O
antimycobacterial O
activity O
against O
Mycobacterium O
tuberculosis O
H37Rv O
, O
Mycobacterium O
kansasii O
and O
two O
types O
of O
Mycobacterium O
avium O
. O

The O
series O
consisted O
of O
3 B
- I
( I
benzylamino I
) I
- I
5 I
- I
cyanopyrazine I
- I
2 I
- I
carboxamides I
and O
3 B
- I
( I
benzylamino I
) I
pyrazine I
- I
2 I
, I
5 I
- I
dicarbonitriles I
with O
various O
substituents O
on O
the O
phenyl B
ring O
. O

RP O
- O
HPLC O
method O
was O
used O
to O
determine O
the O
lipophilicity O
of O
the O
prepared O
compounds O
. O

Nine O
compounds O
exerted O
similar O
or O
better O
activity O
against O
Mycobacterium O
tuberculosis O
compared O
to O
pyrazinamide B
( O
MIC O
= O
6 O
. O
25 O
- O
12 O
. O
5 O
mu O
g O
/ O
mL O
) O
. O

3 B
- I
( I
Benzylamino I
) I
pyrazine I
- I
2 I
, I
5 I
- I
dicarbonitrile I
inhibited O
all O
of O
the O
tested O
mycobacterial O
strains O
with O
MIC O
within O
the O
range O
12 O
. O
5 O
- O
25 O
mu O
g O
/ O
mL O
. O

Although O
not O
the O
most O
active O
, O
4 B
- I
NH I
( I
2 I
) I
substituted O
compounds O
possessed O
the O
lowest O
in O
vitro O
cytotoxicity O
( O
hepatotoxicity O
) O
, O
leading O
to O
selectivity O
index O
SI O
= O
5 O
. O
5 O
and O
SI O
> O
21 O
. O

2 B
' I
- I
Fluoro I
- I
6 I
' I
- I
methylene I
- I
carbocyclic I
adenosine I
phosphoramidate I
( O
FMCAP B
) O
prodrug O
: O
in O
vitro O
anti O
- O
HBV O
activity O
against O
the O
lamivudine B
- O
entecavir B
resistant O
triple O
mutant O
and O
its O
mechanism O
of O
action O
. O

Novel O
2 B
' I
- I
fluoro I
- I
6 I
' I
- I
methylene I
- I
carbocyclic I
adenosine I
( O
FMCA B
) O
monophosphate B
prodrug O
( O
FMCAP B
) O
was O
synthesized O
and O
evaluated O
for O
its O
in O
vitro O
anti O
- O
HBV O
potency O
against O
a O
lamivudine B
- O
entecavir B
resistant O
clone O
( O
L180M O
+ O
M204V O
+ O
S202G O
) O
. O

FMCA B
demonstrated O
significant O
antiviral O
activity O
against O
wild O
- O
type O
as O
well O
as O
lamivudine B
- O
entecavir B
resistant O
triple O
mutant O
( O
L180M O
+ O
M204V O
+ O
S202G O
) O
. O

The O
monophosphate B
prodrug O
( O
FMCAP O
) O
demonstrated O
greater O
than O
12 O
- O
fold O
( O
12 O
x O
) O
increase O
in O
anti O
- O
HBV O
activity O
without O
increased O
cellular O
toxicity O
. O

Mitochondrial O
and O
cellular O
toxicity O
studies O
of O
FMCA O
indicated O
that O
there O
is O
no O
significant O
toxicity O
up O
to O
100 O
mu O
M O
. O

Mode O
of O
action O
studies O
by O
molecular O
modeling O
indicate O
that O
the O
2 B
' I
- I
fluoro I
moiety O
by O
hydrogen B
bond O
as O
well O
as O
the O
Van O
der O
Waals O
interaction O
of O
the O
carbocyclic B
ring O
with O
the O
phenylalanine B
moiety O
of O
the O
polymerase O
promote O
the O
positive O
binding O
, O
even O
in O
the O
drug O
- O
resistant O
mutants O
. O

Osteocyte O
apoptosis O
. O

Apoptotic O
death O
of O
osteocytes O
was O
recognized O
over O
15years O
ago O
, O
but O
its O
significance O
for O
bone O
homeostasis O
has O
remained O
elusive O
. O

A O
new O
paradigm O
has O
emerged O
that O
invokes O
osteocyte O
apoptosis O
as O
a O
critical O
event O
in O
the O
recruitment O
of O
osteoclasts O
to O
a O
specific O
site O
in O
response O
to O
skeletal O
unloading O
, O
fatigue O
damage O
, O
estrogen B
deficiency O
and O
perhaps O
in O
other O
states O
where O
bone O
must O
be O
removed O
. O

This O
is O
accomplished O
by O
yet O
to O
be O
defined O
signals O
emanating O
from O
dying O
osteocytes O
, O
which O
stimulate O
neighboring O
viable O
osteocytes O
to O
produce O
osteoclastogenic O
cytokines O
. O

The O
osteocyte O
apoptosis O
caused O
by O
chronic O
glucocorticoid O
administration O
does O
not O
increase O
osteoclasts O
; O
however O
, O
it O
does O
negatively O
impact O
maintenance O
of O
bone O
hydration O
, O
vascularity O
, O
and O
strength O
. O

This O
article O
is O
part O
of O
a O
Special O
Issue O
entitled O
" O
The O
Osteocyte O
" O
. O

Bisphenol B
A I
interferes O
with O
thyroid O
specific O
gene O
expression O
. O

Bisphenol B
A I
( O
BPA B
) O
is O
an O
endocrine O
- O
disrupting O
chemical O
that O
leads O
to O
low O
- O
dose O
human O
exposure O
due O
to O
its O
ability O
to O
leach O
from O
chemically O
derived O
products O
, O
as O
polycarbonate B
plastics O
and O
epoxy B
resin O
. O

In O
addition O
to O
its O
known O
xeno O
- O
endocrine O
action O
, O
BPA B
exerts O
a O
wide O
range O
of O
metabolic O
effects O
. O

Despite O
the O
documented O
BPA B
exposure O
outcomes O
on O
synthesis O
of O
thyroid O
hormones O
, O
there O
are O
not O
any O
data O
available O
on O
its O
actions O
on O
the O
thyroid O
follicular O
cells O
, O
site O
of O
synthesis O
of O
the O
thyroid O
hormones O
. O

Recently O
, O
it O
has O
been O
shown O
that O
several O
environmental O
pollutants O
, O
as O
BPA B
, O
can O
exert O
a O
thyroid O
disrupting O
activity O
. O

In O
this O
study O
, O
we O
employed O
in O
vitro O
and O
in O
vivo O
( O
zebrafish O
) O
models O
to O
examine O
the O
effects O
of O
BPA B
in O
regulating O
the O
expression O
of O
genes O
involved O
in O
the O
thyroid O
hormone O
synthesis O
and O
of O
their O
transcriptional O
regulators O
at O
BPA B
doses O
as O
low O
as O
10 O
( O
- O
9 O
) O
M O
, O
a O
dose O
that O
is O
environmentally O
pertinent O
and O
far O
below O
the O
one O
detected O
in O
infants O
plasma O
. O

In O
both O
systems O
we O
could O
detect O
an O
altered O
expression O
of O
the O
genes O
involved O
in O
thyroid O
hormones O
synthesis O
and O
of O
thyroid O
specific O
transcriptional O
factors O
in O
BPA B
dose O
and O
time O
dependent O
manner O
. O

Our O
results O
suggest O
that O
BPA B
exerts O
a O
direct O
effect O
on O
thyroid O
follicular O
cell O
. O

We O
show O
that O
these O
cells O
can O
" O
sense O
" O
very O
low O
amount O
of O
BPA B
. O

Thus O
they O
, O
potentially O
, O
represent O
an O
ideal O
in O
vitro O
system O
to O
develop O
assays O
to O
detect O
BPA B
and O
other O
pollutants O
with O
thyroid O
disrupting O
activity O
at O
level O
far O
below O
the O
ones O
considered O
to O
be O
environmental O
relevant O
. O

Moreover O
, O
this O
report O
may O
provide O
new O
insight O
into O
the O
mode O
of O
BPA B
- O
induced O
deregulation O
of O
physiological O
processes O
as O
well O
as O
on O
the O
extensively O
debated O
molecular O
pathways O
underlying O
its O
biological O
activities O
. O

A O
re O
- O
evaluation O
of O
fifteen O
years O
of O
European O
risk O
assessment O
using O
effect O
models O
. O

Ecological O
risk O
assessments O
of O
chemicals O
can O
be O
informed O
by O
a O
suite O
of O
effect O
models O
, O
including O
population O
and O
food O
web O
models O
. O

In O
the O
risk O
assessments O
conducted O
under O
EU O
regulation O
793 O
/ O
93 O
/ O
EC O
, O
however O
, O
applications O
of O
such O
effect O
models O
are O
extremely O
scarce O
and O
toxicity O
- O
extrapolation O
approaches O
are O
often O
used O
instead O
. O

The O
objective O
of O
the O
present O
study O
was O
to O
re O
- O
evaluate O
these O
risk O
assessments O
using O
two O
types O
of O
effect O
models O
: O
species O
sensitivity O
distributions O
( O
SSDs O
, O
non O
- O
mechanistic O
) O
, O
and O
food O
web O
models O
( O
mechanistic O
) O
. O

Species O
sensitivity O
distributions O
significantly O
fitted O
the O
available O
toxicity O
data O
for O
up O
to O
35 O
% O
of O
the O
chemicals O
, O
depending O
on O
the O
trophic O
levels O
included O
and O
the O
amount O
of O
data O
available O
. O

Median O
hazardous O
concentrations O
for O
5 O
% O
of O
the O
species O
( O
HC5 O
- O
50 O
) O
estimated O
by O
the O
SSDs O
were O
less O
accurate O
predictors O
of O
measured O
community O
- O
level O
no O
observed O
effect O
concentration O
than O
food O
web O
model O
- O
derived O
HC5 O
- O
50s O
, O
albeit O
data O
were O
available O
for O
seven O
chemicals O
only O
. O

For O
datasets O
with O
more O
than O
10 O
data O
points O
, O
the O
90 O
% O
confidence O
interval O
of O
the O
estimated O
HC5s O
was O
narrower O
for O
the O
food O
web O
modeling O
approach O
than O
for O
the O
SSD O
approach O
. O

The O
HC5 O
- O
50s O
predicted O
by O
the O
two O
approaches O
were O
two O
to O
five O
times O
( O
metals O
) O
and O
10 O
to O
100 O
times O
( O
organic O
chemicals O
) O
higher O
than O
the O
predicted O
no O
effect O
concentrations O
( O
PNECs O
) O
for O
the O
aquatic O
environment O
listed O
in O
the O
risk O
assessment O
reports O
. O

This O
suggests O
that O
the O
derived O
PNECs O
are O
protective O
for O
aquatic O
ecosystems O
. O

Threshold O
collision O
- O
induced O
dissociation O
of O
hydrated B
magnesium I
: O
experimental O
and O
theoretical O
investigation O
of O
the O
binding O
energies O
for O
Mg B
( I
2 I
+ I
) I
( I
H2O I
) I
x I
complexes O
( O
x O
= O
2 O
- O
10 O
) O
. O

The O
sequential O
bond O
energies O
of O
Mg B
( I
2 I
+ I
) I
( I
H2O I
) I
x I
complexes O
, O
in O
which O
x O
= O
2 O
- O
10 O
, O
are O
measured O
by O
threshold O
collision O
- O
induced O
dissociation O
in O
a O
guided O
ion O
beam O
tandem O
mass O
spectrometer O
. O

From O
an O
electrospray O
ionization O
source O
that O
produces O
an O
initial O
distribution O
of O
Mg B
( I
2 I
+ I
) I
( I
H2O I
) I
x I
complexes O
in O
which O
x O
= O
7 O
- O
10 O
, O
complexes O
down O
to O
x O
= O
3 O
are O
formed O
by O
using O
an O
in O
- O
source O
fragmentation O
technique O
. O

Complexes O
smaller O
than O
Mg B
( I
2 I
+ I
) I
( I
H2O I
) I
3 I
cannot O
be O
formed O
in O
this O
source O
because O
charge O
separation O
into O
MgOH B
( I
+ I
) I
( I
H2O I
) I
and O
H3O B
( I
+ I
) I
is O
a O
lower O
- O
energy O
pathway O
than O
simple O
water O
loss O
from O
Mg B
( I
2 I
+ I
) I
( I
H2O I
) I
3 I
. O

The O
kinetic O
energy O
dependent O
cross O
sections O
for O
dissociation O
of O
Mg B
( I
2 I
+ I
) I
( I
H2O I
) I
x I
complexes O
, O
in O
which O
x O
= O
3 O
- O
10 O
, O
are O
examined O
over O
a O
wide O
energy O
range O
to O
monitor O
all O
dissociation O
products O
and O
are O
modeled O
to O
obtain O
0 O
and O
298 O
K O
binding O
energies O
. O

Analysis O
of O
both O
primary O
and O
secondary O
water O
molecule O
losses O
from O
each O
sized O
complex O
provides O
thermochemistry O
for O
the O
sequential O
hydration O
energies O
of O
Mg B
( I
2 I
+ I
) I
for O
x O
= O
2 O
- O
10 O
and O
the O
first O
experimental O
values O
for O
x O
= O
2 O
- O
4 O
. O

Additionally O
, O
the O
thermodynamic O
onsets O
leading O
to O
the O
charge O
- O
separation O
products O
from O
Mg B
( I
2 I
+ I
) I
( I
H2O I
) I
3 I
and O
Mg B
( I
2 I
+ I
) I
( I
H2O I
) I
4 I
are O
determined O
for O
the O
first O
time O
. O

Our O
experimental O
results O
for O
x O
= O
3 O
- O
7 O
agree O
well O
with O
quantum O
chemical O
calculations O
performed O
here O
and O
previously O
calculated O
binding O
enthalpies O
, O
as O
well O
as O
previous O
measurements O
for O
x O
= O
6 O
. O

The O
present O
values O
for O
x O
= O
7 O
- O
10 O
are O
slightly O
lower O
than O
previous O
experimental O
results O
and O
theory O
, O
but O
within O
experimental O
uncertainties O
. O

Boron B
- O
based O
inhibitors O
of O
acyl B
protein O
thioesterases O
1 O
and O
2 O
. O

Ras O
proteins O
are O
of O
importance O
in O
cell O
proliferation O
, O
and O
hence O
their O
mutated O
forms O
play O
causative O
roles O
in O
many O
kinds O
of O
cancer O
in O
different O
tissues O
. O

Inhibition O
of O
the O
Ras O
- O
depalmitoylating O
enzyme O
acyl B
protein O
thioesterases O
APT1 O
and O
- O
2 O
is O
a O
new O
approach O
to O
modulating O
the O
Ras O
cycle O
. O

Here O
we O
present O
boronic B
and I
borinic I
acid I
derivatives O
as O
a O
new O
class O
of O
potent O
and O
nontoxic O
APT O
inhibitors O
. O

These O
compounds O
were O
detected O
by O
extensive O
library O
screening O
using O
chemical O
arrays O
and O
turned O
out O
to O
inhibit O
human O
APT1 O
and O
- O
2 O
in O
a O
competitive O
mode O
. O

Furthermore O
, O
one O
of O
the O
molecules O
was O
demonstrated O
to O
inhibit O
Erk1 O
/ O
2 O
phosphorylation O
significantly O
. O

Three O
- O
Dimensional O
CdS B
- O
Titanate B
Composite O
Nanomaterials O
for O
Enhanced O
Visible O
- O
Light O
- O
Driven O
Hydrogen B
Evolution O
. O

3D O
Hierarchical O
echinus O
- O
like O
titanate B
spheres O
( O
HETSs O
) O
, O
serving O
as O
the O
supporting O
material O
for O
CdS O
nanoparticles O
, O
are O
synthesized O
via O
a O
fast O
one O
- O
step O
hydrothermal O
method O
. O

The O
obtained O
3D O
CdS B
- O
HETS B
composite O
materials O
show O
enhanced O
H2 B
generation O
under O
visible O
light O
irradiation O
. O

Enzyme O
- O
catalyzed O
crosslinking O
in O
a O
partly O
frozen O
state O
: O
a O
new O
way O
to O
produce O
supermacroporous O
protein O
structures O
. O

In O
this O
study O
a O
new O
way O
to O
produce O
supermacroporous O
protein O
structures O
was O
investigated O
. O

Enzyme O
- O
mediated O
crosslinking O
of O
gelatin O
or O
casein O
was O
performed O
in O
a O
partly O
frozen O
state O
, O
which O
yielded O
stable O
, O
protein O
- O
based O
cryogels O
. O

The O
reaction O
kinetics O
for O
the O
formation O
of O
cryogels O
were O
found O
to O
be O
fairly O
slow O
, O
most O
likely O
due O
to O
the O
low O
temperature O
( O
- O
12 O
degrees O
C O
) O
used O
or O
due O
to O
an O
increased O
viscosity O
owing O
to O
the O
cryo O
- O
concentration O
taking O
place O
. O

The O
produced O
cryogels O
were O
characterized O
with O
regards O
to O
their O
physical O
properties O
and O
in O
vitro O
degradation O
. O

Furthermore O
, O
cryogels O
produced O
from O
gelatin O
and O
casein O
were O
evaluated O
as O
potential O
scaffolds O
by O
fibroblast O
cultivation O
to O
confirm O
their O
in O
vitro O
biocompatibility O
. O

Gelatin O
- O
and O
casein O
- O
based O
scaffolds O
both O
supported O
cell O
proliferation O
and O
migration O
through O
the O
scaffold O
. O

Molecular O
insights O
into O
vesicle O
tethering O
at O
the O
Golgi O
by O
the O
conserved O
oligomeric O
Golgi O
( O
COG O
) O
complex O
and O
the O
golgin O
TATA O
element O
modulatory O
factor O
( O
TMF O
) O
. O

Protein O
sorting O
between O
eukaryotic O
compartments O
requires O
vesicular O
transport O
, O
wherein O
tethering O
provides O
the O
first O
contact O
between O
vesicle O
and O
target O
membranes O
. O

Here O
we O
map O
and O
start O
to O
functionally O
analyze O
the O
interaction O
network O
of O
the O
conserved O
oligomeric O
Golgi O
( O
COG O
) O
complex O
that O
mediates O
retrograde O
tethering O
at O
the O
Golgi O
. O

The O
interactions O
of O
COG O
subunits O
with O
members O
of O
transport O
factor O
families O
assign O
the O
individual O
subunits O
as O
specific O
interaction O
hubs O
. O

Functional O
analysis O
of O
selected O
interactions O
suggests O
a O
mechanistic O
tethering O
model O
. O

We O
find O
that O
the O
COG O
complex O
interacts O
with O
two O
different O
Rabs O
in O
addition O
to O
each O
end O
of O
the O
golgin O
" O
TATA O
element O
modulatory O
factor O
" O
( O
TMF O
) O
. O

This O
allows O
COG O
to O
potentially O
bridge O
the O
distance O
between O
the O
distal O
end O
of O
the O
golgin O
and O
the O
target O
membrane O
thereby O
promoting O
tighter O
docking O
. O

Concurrently O
we O
show O
that O
the O
central O
portion O
of O
TMF O
can O
bind O
to O
Golgi O
membranes O
that O
are O
liberated O
of O
their O
COPI O
cover O
. O

This O
latter O
interaction O
could O
serve O
to O
bring O
vesicle O
and O
target O
membranes O
into O
close O
apposition O
prior O
to O
fusion O
. O

A O
target O
selection O
mechanism O
, O
in O
which O
a O
hetero O
- O
oligomeric O
tethering O
factor O
organizes O
Rabs O
and O
coiled O
transport O
factors O
to O
enable O
protein O
sorting O
specificity O
, O
could O
be O
applicable O
to O
vesicle O
targeting O
throughout O
eukaryotic O
cells O
. O

FINDSITE O
( O
comb O
) O
: O
a O
threading O
/ O
structure O
- O
based O
, O
proteomic O
- O
scale O
virtual O
ligand O
screening O
approach O
. O

Virtual O
ligand O
screening O
is O
an O
integral O
part O
of O
the O
modern O
drug O
discovery O
process O
. O

Traditional O
ligand O
- O
based O
, O
virtual O
screening O
approaches O
are O
fast O
but O
require O
a O
set O
of O
structurally O
diverse O
ligands O
known O
to O
bind O
to O
the O
target O
. O

Traditional O
structure O
- O
based O
approaches O
require O
high O
- O
resolution O
target O
protein O
structures O
and O
are O
computationally O
demanding O
. O

In O
contrast O
, O
the O
recently O
developed O
threading O
/ O
structure O
- O
based O
FINDSITE O
- O
based O
approaches O
have O
the O
advantage O
that O
they O
are O
as O
fast O
as O
traditional O
ligand O
- O
based O
approaches O
and O
yet O
overcome O
the O
limitations O
of O
traditional O
ligand O
- O
or O
structure O
- O
based O
approaches O
. O

These O
new O
methods O
can O
use O
predicted O
low O
- O
resolution O
structures O
and O
infer O
the O
likelihood O
of O
a O
ligand O
binding O
to O
a O
target O
by O
utilizing O
ligand O
information O
excised O
from O
the O
target O
' O
s O
remote O
or O
close O
homologous O
proteins O
and O
/ O
or O
libraries O
of O
ligand O
binding O
databases O
. O

Here O
, O
we O
develop O
an O
improved O
version O
of O
FINDSITE O
, O
FINDSITE O
( O
filt O
) O
, O
that O
filters O
out O
false O
positive O
ligands O
in O
threading O
identified O
templates O
by O
a O
better O
binding O
site O
detection O
procedure O
that O
includes O
information O
about O
the O
binding O
site O
amino B
acid I
similarity O
. O

We O
then O
combine O
FINDSITE O
( O
filt O
) O
with O
FINDSITE O
( O
X O
) O
that O
uses O
publicly O
available O
binding O
databases O
ChEMBL O
and O
DrugBank O
for O
virtual O
ligand O
screening O
. O

The O
combined O
approach O
, O
FINDSITE O
( O
comb O
) O
, O
is O
compared O
to O
two O
traditional O
docking O
methods O
, O
AUTODOCK O
Vina O
and O
DOCK O
6 O
, O
on O
the O
DUD O
benchmark O
set O
. O

It O
is O
shown O
to O
be O
significantly O
better O
in O
terms O
of O
enrichment O
factor O
, O
dependence O
on O
target O
structure O
quality O
, O
and O
speed O
. O

FINDSITE O
( O
comb O
) O
is O
then O
tested O
for O
virtual O
ligand O
screening O
on O
a O
large O
set O
of O
3576 O
generic O
targets O
from O
the O
DrugBank O
database O
as O
well O
as O
a O
set O
of O
168 O
Human O
GPCRs O
. O

Excluding O
close O
homologues O
, O
FINDSITE O
( O
comb O
) O
gives O
an O
average O
enrichment O
factor O
of O
52 O
. O
1 O
for O
generic O
targets O
and O
22 O
. O
3 O
for O
GPCRs O
within O
the O
top O
1 O
% O
of O
the O
screened O
compound O
library O
. O

Around O
65 O
% O
of O
the O
targets O
have O
better O
than O
random O
enrichment O
factors O
. O

The O
performance O
is O
insensitive O
to O
target O
structure O
quality O
, O
as O
long O
as O
it O
has O
a O
TM O
- O
score O
> O
= O
0 O
. O
4 O
to O
native O
. O

Thus O
, O
FINDSITE O
( O
comb O
) O
makes O
the O
screening O
of O
millions O
of O
compounds O
across O
entire O
proteomes O
feasible O
. O

The O
FINDSITE O
( O
comb O
) O
web O
service O
is O
freely O
available O
for O
academic O
users O
at O
http O
: O
/ O
/ O
cssb O
. O
biology O
. O
gatech O
. O
edu O
/ O
skolnick O
/ O
webservice O
/ O
FINDSITE O
- O
COMB O
/ O
index O
. O
html O
. O

Optimization O
of O
brush O
- O
like O
cationic O
copolymers O
for O
nonviral O
gene O
delivery O
. O

Polyethylenimine B
( O
PEI B
) O
is O
one O
of O
the O
most O
broadly O
used O
polycations O
for O
gene O
delivery O
due O
to O
its O
high O
transfection O
efficiency O
and O
commercial O
availability O
but O
materials O
are O
cytotoxic O
and O
often O
polydisperse O
. O

The O
goal O
of O
current O
work O
is O
to O
develop O
an O
alternative O
family O
of O
polycations O
based O
on O
controlled O
living O
radical O
polymerization O
( O
CLRP O
) O
and O
to O
optimize O
the O
polymer O
structure O
for O
efficient O
gene O
delivery O
. O

In O
this O
study O
, O
well O
- O
defined O
poly B
( I
glycidyl I
methacrylate I
) I
( O
P B
( I
GMA I
) I
) O
homopolymers O
were O
synthesized O
using O
reversible O
addition O
- O
fragmentation O
chain O
transfer O
( O
RAFT O
) O
polymerization O
followed O
by O
decoration O
using O
three O
different O
types O
of O
oligoamines B
, O
i O
. O
e O
. O
, O
tetraethylenepentami B
( O
TEPA B
) O
, O
pentaethylenehexamin B
( O
PEHA B
) O
, O
and O
tris B
( I
2 I
- I
aminoethyl I
) I
amine I
( O
TREN B
) O
, O
respectively O
, O
to O
generate O
various O
P B
( I
GMA I
- I
oligoamine I
) I

homopolycations O
. O

The O
effect O
of O
P B
( I
GMA I
) I
backbone O
length O
and O
structure O
of O
oligoamine O
on O
gene O
transfer O
efficiency O
was O
then O
determined O
. O

The O
optimal O
polymer O
, O
P B
( I
GMA I
- I
TEPA I
) I
( O
50 O
) O
, O
provided O
comparable O
transfection O
efficiency O
but O
lower O
cytotoxicity O
than O
PEI B
. O

P B
( I
GMA I
- I
TEPA I
) I
( O
50 O
) O
was O
then O
used O
as O
the O
cationic O
block O
in O
diblock O
copolymers O
containing O
hydrophilic O
N B
- I
( I
2 I
- I
hydroxypropyl I
) I
methacrylamide I
( O
HPMA B
) O
and O
oligo B
( I
ethylene I
glycol I
) I
monomethyl I
ether I
methacrylate I
( O
OEGMA B
) O
. O

Polyplexes O
of O
block O
copolymers O
were O
stable O
against O
aggregation O
in O
physiological O
salt O
condition O
and O
in O
Opti O
- O
MEM O
due O
to O
the O
shielding O
effect O
of O
P B
( I
HPMA I
) I
and O
P B
( I
OEGMA I
) I
. O

However O
, O
the O
presence O
of O
the O
HPMA B
/ O
OEGMA B
block O
significantly O
decreased O
the O
transfection O
efficacy O
of O
P O
( O
GMA O
- O
TEPA O
) O
( O
50 O
) O
homopolycation O
. O

To O
compensate O
for O
reduced O
cell O
uptake O
caused O
by O
the O
hydrophilic O
shell O
of O
polyplex O
, O
the O
integrin O
- O
binding O
peptide O
, O
RGD O
, O
was O
conjugated O
to O
the O
hydrophilic O
chain O
end O
of O
P B
( I
OEGMA I
) I
( I
15 I
) I
- I
b I
- I
P I
( I
GMA I
- I
TEPA I
) I
( I
50 I
) I
copolymer O
by O
Michael O
- O
type O
addition O
reaction O
. O

At O
low O
polymer O
to O
DNA O
ratios O
, O
the O
RGD O
- O
functionalized O
polymer O
showed O
increased O
gene O
delivery O
efficiency O
to O
HeLa O
cells O
compared O
to O
analogous O
polymers O
lacking O
RGD O
. O

Optomechanical O
Shutter O
Modulated O
Broad O
- O
Band O
Cavity O
- O
Enhanced O
Absorption O
Spectroscopy O
of O
Molecular O
Transients O
of O
Astrophysical O
Interest O
. O

We O
describe O
a O
sensitive O
spectroscopic O
instrument O
capable O
of O
measuring O
broad O
- O
band O
absorption O
spectra O
through O
supersonically O
expanding O
planar O
plasma O
pulses O
. O

The O
instrument O
utilizes O
incoherent O
broad O
- O
band O
cavity O
- O
enhanced O
absorption O
spectroscopy O
( O
IBBCEAS O
) O
and O
incorporates O
an O
optomechanical O
shutter O
to O
modulate O
light O
from O
a O
continuous O
incoherent O
light O
source O
, O
enabling O
measurements O
of O
durations O
as O
low O
as O
~ O
400 O
mu O
s O
. O

The O
plasma O
expansion O
is O
used O
to O
mimic O
conditions O
in O
translucent O
interstellar O
clouds O
. O

The O
new O
setup O
is O
particularly O
applicable O
to O
test O
proposed O
carriers O
of O
the O
diffuse O
interstellar O
bands O
, O
as O
it O
permits O
swift O
measurements O
over O
a O
broad O
spectral O
range O
with O
a O
resolution O
comparable O
to O
astronomical O
observations O
. O

The O
sensitivity O
is O
estimated O
to O
be O
better O
than O
10 O
ppm O
/ O
pass O
, O
measured O
with O
an O
effective O
exposure O
time O
of O
only O
1 O
s O
. O

Acid O
- O
degradable O
cationic O
poly B
( I
ketal I
amidoamine I
) I
for O
enhanced O
RNA O
interference O
in O
vitro O
and O
in O
vivo O
. O

Efficient O
delivery O
of O
small O
interfering O
RNA O
( O
siRNA O
) O
is O
one O
of O
major O
challenges O
in O
the O
successful O
applications O
of O
siRNA O
in O
clinic O
. O

In O
the O
present O
study O
, O
we O
report O
a O
new O
acid O
- O
degradable O
poly B
( I
ketal I
amidoamine I
) I
( O
PKAA B
) O
as O
a O
siRNA O
carrier O
, O
which O
has O
high O
delivery O
efficiency O
and O
low O
cytotoxicity O
. O

PKAA O
was O
designed O
to O
have O
acid O
- O
cleavable O
ketal B
linkages O
in O
the O
backbone O
of O
cationic O
biodegradable O
poly B
( I
amidoamine I
) I
. O

PKAA O
efficiently O
self O
- O
assembled O
with O
siRNA O
to O
form O
nanocomplexes O
with O
a O
diameter O
of O
~ O
200 O
nm O
and O
slightly O
positive O
charges O
, O
which O
are O
stable O
under O
physiological O
conditions O
, O
but O
rapidly O
release O
siRNA O
at O
acidic O
pH O
. O

PKAA O
exhibited O
sufficient O
buffering O
capability O
and O
endosomolytic O
activity O
due O
mainly O
to O
the O
presence O
of O
secondary B
amine I
groups O
in O
its O
backbone O
and O
rapid O
degradation O
in O
acidic O
endosomes O
, O
leading O
to O
the O
enhanced O
release O
of O
siRNA O
to O
cytoplasm O
. O

Cell O
culture O
studies O
demonstrated O
that O
PKAA O
is O
capable O
of O
delivering O
anti O
- O
TNF O
( O
tumor O
necrosis O
factor O
) O
- O
alpha O
siRNA O
to O
lipopolysaccharide O
( O
LPS O
) O
- O
stimulated O
macrophages O
and O
significantly O
inhibits O
the O
expression O
of O
TNF O
- O
alpha O
. O

A O
mouse O
model O
of O
acetaminophen B
( O
APAP B
) O
- O
induced O
acute O
liver O
failure O
was O
used O
to O
evaluate O
in O
vivo O
siRNA O
delivery O
efficacy O
of O
PKAA O
. O

PKAA O
/ O
anti O
- O
TNF O
- O
alpha O
siRNA O
nanocomplexes O
significantly O
reduced O
the O
ALT O
( O
alanine B
transaminase O
) O
and O
the O
hepatic O
cellular O
damages O
in O
APAP B
- O
intoxicated O
mice O
. O

We O
anticipate O
that O
acid O
- O
degradable O
PKAA O
has O
great O
potential O
as O
siRNA O
carriers O
based O
on O
its O
excellent O
biocompatibility O
, O
pH O
sensitivity O
, O
potential O
endosomolytic O
activity O
, O
and O
high O
delivery O
efficiency O
. O

Lysozyme O
hydration O
in O
concentrated O
aqueous O
solutions O
. O

Effect O
of O
an O
equilibrium O
cluster O
phase O
. O

Water O
close O
to O
proteins O
plays O
a O
key O
role O
in O
determining O
their O
structural O
and O
functional O
properties O
. O

Despite O
being O
a O
subject O
of O
considerable O
interest O
, O
the O
characterization O
of O
hydration O
water O
, O
as O
far O
as O
its O
total O
amount O
is O
concerned O
, O
is O
still O
controversial O
and O
its O
influence O
on O
protein O
structure O
and O
folding O
is O
not O
yet O
fully O
understood O
. O

In O
this O
work O
, O
we O
have O
investigated O
the O
dielectric O
properties O
of O
lysozyme O
aqueous O
solutions O
over O
the O
frequency O
range O
where O
the O
orientational O
polarization O
relaxation O
of O
the O
aqueous O
phase O
occurs O
( O
from O
500 O
MHz O
to O
50 O
GHz O
) O
. O

Measurements O
extend O
over O
a O
wide O
concentration O
range O
, O
up O
to O
300 O
mg O
/ O
mL O
, O
corresponding O
to O
a O
volume O
fraction O
of O
the O
order O
of O
0 O
. O
4 O
. O

The O
analysis O
of O
the O
dielectric O
spectra O
, O
based O
on O
the O
decrease O
of O
the O
dielectric O
increment O
of O
the O
gamma O
- O
dispersion O
as O
a O
function O
of O
protein O
concentration O
, O
allows O
us O
to O
estimate O
the O
total O
amount O
of O
hydration O
water O
( O
both O
bound O
water O
and O
loosely O
bound O
water O
) O
present O
in O
the O
system O
investigated O
. O

We O
observe O
a O
decrease O
of O
the O
hydration O
number O
as O
a O
function O
of O
the O
protein O
concentration O
. O

This O
behavior O
is O
well O
accounted O
for O
by O
considering O
the O
formation O
of O
small O
equilibrium O
clusters O
with O
aggregation O
number O
of O
some O
units O
, O
as O
recently O
reported O
by O
Stradner O
et O
al O
. O

( O
1 O
) O
on O
the O
basis O
of O
small O
- O
angle O
X O
- O
ray O
and O
neutron O
scattering O
measurements O
. O

5 B
- I
Benzylglycinyl I
- I
amiloride I
kills O
proliferating O
and O
nonproliferating O
malignant O
glioma O
cells O
through O
caspase O
- O
independent O
necroptosis O
mediated O
by O
apoptosis O
- O
inducing O
factor O
. O

5 B
' I
- I
Beta I
enzylglycinyl I
- I
amiloride I
( O
UCD38B B
) O
and O
glycinyl B
- I
amiloride I
( O
UCD74A B
) O
are O
cell O
- O
permeant O
and O
cell O
- O
impermeant O
derivatives O
of O
amiloride B
, O
respectively O
, O
and O
used O
here O
to O
identify O
the O
cellular O
mechanisms O
of O
action O
underlying O
their O
antiglioma O
effects O
. O

UCD38B O
comparably O
kills O
proliferating O
and O
nonproliferating O
gliomas O
cells O
when O
cell O
cycle O
progression O
is O
arrested O
either O
by O
cyclin O
D1 O
siRNA O
or O
by O
acidification O
. O

Cell O
impermeant O
UCD74A B
inhibits O
plasmalemmal O
urokinase O
plasminogen O
activator O
( O
uPA O
) O
and O
the O
type O
1 O
sodium B
- O
proton O
exchanger O
with O
potencies O
analogous O
to O
UCD38B B
, O
but O
is O
cytostatic O
. O

In O
contrast O
, O
UCD38B O
targets O
intracellular O
uPA O
causing O
mistrafficking O
of O
uPA O
into O
perinuclear O
mitochondria O
, O
reducing O
the O
mitochondrial O
membrane O
potential O
, O
and O
followed O
by O
the O
release O
of O
apoptotic O
inducible O
factor O
( O
AIF O
) O
. O

AIF O
nuclear O
translocation O
is O
followed O
by O
a O
caspase O
- O
independent O
necroptotic O
cell O
death O
. O

Reduction O
in O
AIF O
expression O
by O
siRNA O
reduces O
the O
antiglioma O
cytotoxic O
effects O
of O
UCD38B O
, O
while O
not O
activating O
the O
caspase O
pathway O
. O

Ultrastructural O
changes O
shortly O
following O
treatment O
with O
UCD38B B
demonstrate O
dilation O
of O
endoplasmic O
reticulum O
( O
ER O
) O
and O
mitochondrial O
swelling O
followed O
by O
nuclear O
condensation O
within O
hours O
consistent O
with O
a O
necroptotic O
cell O
death O
differing O
from O
apoptosis O
and O
from O
autophagy O
. O

These O
drug O
mechanism O
of O
action O
studies O
demonstrate O
that O
UCD38B B
induces O
a O
cell O
cycle O
- O
independent O
, O
caspase O
- O
independent O
necroptotic O
glioma O
cell O
death O
that O
is O
mediated O
by O
AIF O
and O
independent O
of O
poly B
( I
ADP I
- I
ribose I
) I
polymerase O
and O
H2AX O
activation O
. O

Polyazamacrocycles B
as O
potential O
antitumor O
agents O
for O
human O
prostate O
cancer O
cells O
. O

Polyazamacrocycles B
are O
currently O
being O
studied O
and O
used O
in O
a O
variety O
of O
applications O
beyond O
their O
traditional O
place O
in O
supramolecular O
and O
co O
- O
ordination O
chemistry O
. O

This O
study O
suggests O
additional O
applications O
of O
these O
compounds O
with O
particular O
emphasis O
on O
their O
use O
as O
antiproliferative O
agents O
that O
could O
be O
potentially O
used O
to O
treat O
cancer O
. O

Four O
polyazamacrocycles O
were O
tested O
in O
human O
prostate O
cancer O
LNCaP O
and O
prostate O
epithelial O
PNTA1 O
cells O
to O
analyze O
changes O
in O
cell O
proliferation O
and O
cell O
death O
capabilities O
. O

Their O
intracellular O
localization O
was O
also O
evaluated O
by O
confocal O
microscopy O
. O

The O
results O
show O
a O
decrease O
in O
proliferation O
rate O
and O
cell O
viability O
of O
LNCaP O
and O
PNTA1 O
, O
after O
treatment O
with O
these O
compounds O
. O

The O
decrease O
in O
the O
number O
of O
viable O
cells O
is O
similar O
for O
the O
majority O
of O
the O
compounds O
studied O
, O
and O
at O
higher O
concentration O
, O
the O
proliferation O
efficiency O
decreased O
significantly O
in O
the O
cell O
lines O
studied O
. O

Also O
, O
our O
results O
suggest O
that O
L O
and O
L2 O
induce O
early O
apoptosis O
in O
PNTA1 O
cells O
and O
late O
apoptosis O
/ O
necrosis O
in O
LNCaP O
cells O
. O

The O
compounds O
did O
not O
induce O
a O
significant O
increase O
in O
necrosis O
of O
both O
cell O
types O
. O

Although O
the O
compounds O
did O
not O
localize O
in O
a O
unique O
organelle O
, O
all O
of O
them O
have O
as O
main O
target O
the O
Golgi O
apparatus O
and O
other O
localization O
profiles O
differed O
depending O
on O
the O
cell O
line O
. O

PreCisIon O
: O
PREdiction O
of O
CIS O
- O
regulatory O
elements O
improved O
by O
gene O
' O
s O
positION O
. O

Conventional O
approaches O
to O
predict O
transcriptional O
regulatory O
interactions O
usually O
rely O
on O
the O
definition O
of O
a O
shared O
motif O
sequence O
on O
the O
target O
genes O
of O
a O
transcription O
factor O
( O
TF O
) O
. O

These O
efforts O
have O
been O
frustrated O
by O
the O
limited O
availability O
and O
accuracy O
of O
TF O
binding O
site O
motifs O
, O
usually O
represented O
as O
position O
- O
specific O
scoring O
matrices O
, O
which O
may O
match O
large O
numbers O
of O
sites O
and O
produce O
an O
unreliable O
list O
of O
target O
genes O
. O

To O
improve O
the O
prediction O
of O
binding O
sites O
, O
we O
propose O
to O
additionally O
use O
the O
unrelated O
knowledge O
of O
the O
genome O
layout O
. O

Indeed O
, O
it O
has O
been O
shown O
that O
co O
- O
regulated O
genes O
tend O
to O
be O
either O
neighbors O
or O
periodically O
spaced O
along O
the O
whole O
chromosome O
. O

This O
study O
demonstrates O
that O
respective O
gene O
positioning O
carries O
significant O
information O
. O

This O
novel O
type O
of O
information O
is O
combined O
with O
traditional O
sequence O
information O
by O
a O
machine O
learning O
algorithm O
called O
PreCisIon O
. O

To O
optimize O
this O
combination O
, O
PreCisIon O
builds O
a O
strong O
gene O
target O
classifier O
by O
adaptively O
combining O
weak O
classifiers O
based O
on O
either O
local O
binding O
sequence O
or O
global O
gene O
position O
. O

This O
strategy O
generically O
paves O
the O
way O
to O
the O
optimized O
incorporation O
of O
any O
future O
advances O
in O
gene O
target O
prediction O
based O
on O
local O
sequence O
, O
genome O
layout O
or O
on O
novel O
criteria O
. O

With O
the O
current O
state O
of O
the O
art O
, O
PreCisIon O
consistently O
improves O
methods O
based O
on O
sequence O
information O
only O
. O

This O
is O
shown O
by O
implementing O
a O
cross O
- O
validation O
analysis O
of O
the O
20 O
major O
TFs O
from O
two O
phylogenetically O
remote O
model O
organisms O
. O

For O
Bacillus O
subtilis O
and O
Escherichia O
coli O
, O
respectively O
, O
PreCisIon O
achieves O
on O
average O
an O
area O
under O
the O
receiver O
operating O
characteristic O
curve O
of O
70 O
and O
60 O
% O
, O
a O
sensitivity O
of O
80 O
and O
70 O
% O
and O
a O
specificity O
of O
60 O
and O
56 O
% O
. O

The O
newly O
predicted O
gene O
targets O
are O
demonstrated O
to O
be O
functionally O
consistent O
with O
previously O
known O
targets O
, O
as O
assessed O
by O
analysis O
of O
Gene O
Ontology O
enrichment O
or O
of O
the O
relevant O
literature O
and O
databases O
. O

Primary O
hepatocyte O
cultures O
for O
pharmaco O
- O
toxicological O
studies O
: O
at O
the O
busy O
crossroad O
of O
various O
anti O
- O
dedifferentiation O
strategies O
. O

Continuously O
increasing O
understanding O
of O
the O
molecular O
triggers O
responsible O
for O
the O
onset O
of O
diseases O
, O
paralleled O
by O
an O
equally O
dynamic O
evolution O
of O
chemical O
synthesis O
and O
screening O
methods O
, O
offers O
an O
abundance O
of O
pharmacological O
agents O
with O
a O
potential O
to O
become O
new O
successful O
drugs O
. O

However O
, O
before O
patients O
can O
benefit O
of O
newly O
developed O
pharmaceuticals O
, O
stringent O
safety O
filters O
need O
to O
be O
applied O
to O
weed O
out O
unfavourable O
drug O
candidates O
. O

Cost O
effectiveness O
and O
the O
need O
to O
identify O
compound O
liabilities O
, O
without O
exposing O
humans O
to O
unnecessary O
risks O
, O
has O
stimulated O
the O
shift O
of O
the O
safety O
studies O
to O
the O
earliest O
stages O
of O
drug O
discovery O
and O
development O
. O

In O
this O
regard O
, O
in O
vivo O
relevant O
organotypic O
in O
vitro O
models O
have O
high O
potential O
to O
revolutionize O
the O
preclinical O
safety O
testing O
. O

They O
can O
enable O
automation O
of O
the O
process O
, O
to O
match O
the O
requirements O
of O
high O
- O
throughput O
screening O
approaches O
, O
while O
satisfying O
ethical O
considerations O
. O

Cultures O
of O
primary O
hepatocytes O
became O
already O
an O
inherent O
part O
of O
the O
preclinical O
pharmaco O
- O
toxicological O
testing O
battery O
, O
yet O
their O
routine O
use O
, O
particularly O
for O
long O
- O
term O
assays O
, O
is O
limited O
by O
the O
progressive O
deterioration O
of O
liver O
- O
specific O
features O
. O

The O
availability O
of O
suitable O
hepatic O
and O
other O
organ O
- O
specific O
in O
vitro O
models O
is O
, O
however O
, O
of O
paramount O
importance O
in O
the O
light O
of O
changing O
European O
legal O
regulations O
in O
the O
field O
of O
chemical O
compounds O
of O
different O
origin O
, O
which O
gradually O
restrict O
the O
use O
of O
animal O
studies O
for O
safety O
assessment O
, O
as O
currently O
witnessed O
in O
cosmetic O
industry O
. O

Fortunately O
, O
research O
groups O
worldwide O
spare O
no O
effort O
to O
establish O
hepatic O
in O
vitro O
systems O
. O

In O
the O
present O
review O
, O
both O
classical O
and O
innovative O
methodologies O
to O
stabilize O
the O
in O
vivo O
- O
like O
hepatocyte O
phenotype O
in O
culture O
of O
primary O
hepatocytes O
are O
presented O
and O
discussed O
. O

Profiling O
genome O
- O
wide O
chromatin O
methylation O
with O
engineered O
posttranslation O
apparatus O
within O
living O
cells O
. O

Protein O
methyltransferases O
( O
PMTs O
) O
have O
emerged O
as O
important O
epigenetic O
regulators O
in O
myriad O
biological O
processes O
in O
both O
normal O
physiology O
and O
disease O
conditions O
. O

However O
, O
elucidating O
PMT O
- O
regulated O
epigenetic O
processes O
has O
been O
hampered O
by O
ambiguous O
knowledge O
about O
in O
vivo O
activities O
of O
individual O
PMTs O
particularly O
because O
of O
their O
overlapping O
but O
nonredundant O
functions O
. O

To O
address O
limitations O
of O
conventional O
approaches O
in O
mapping O
chromatin O
modification O
of O
specific O
PMTs O
, O
we O
have O
engineered O
the O
chromatin O
- O
modifying O
apparatus O
and O
formulated O
a O
novel O
technology O
, O
termed O
clickable O
chromatin O
enrichment O
with O
parallel O
DNA O
sequencing O
( O
CliEn O
- O
seq O
) O
, O
to O
probe O
genome O
- O
wide O
chromatin O
modification O
within O
living O
cells O
. O

The O
three O
- O
step O
approach O
of O
CliEn O
- O
seq O
involves O
in O
vivo O
synthesis O
of O
S B
- I
adenosyl I
- I
L I
- I
methionine I
( O
SAM B
) O
analogues O
from O
cell O
- O
permeable O
methionine B
analogues O
by O
engineered O
SAM B
synthetase O
( O
methionine B
adenosyltransferase O
or O
MAT O
) O
, O
in O
situ O
chromatin O
modification O
by O
engineered O
PMTs O
, O
subsequent O
enrichment O
and O
sequencing O
of O
the O
uniquely O
modified O
chromatins O
. O

Given O
critical O
roles O
of O
the O
chromatin O
- O
modifying O
enzymes O
in O
epigenetics O
and O
structural O
similarity O
among O
many O
PMTs O
, O
we O
envision O
that O
the O
CliEn O
- O
seq O
technology O
is O
generally O
applicable O
in O
deciphering O
chromatin O
methylation O
events O
of O
individual O
PMTs O
in O
diverse O
biological O
settings O
. O

Self O
- O
assembly O
of O
segmented O
anisotropic O
particles O
: O
tuning O
compositional O
anisotropy O
to O
form O
vertical O
or O
horizontal O
arrays O
. O

Columnar O
arrays O
of O
anisotropic O
nano O
- O
and O
microparticles O
, O
in O
which O
the O
long O
axes O
of O
the O
particles O
are O
oriented O
perpendicular O
to O
the O
substrate O
, O
are O
of O
interest O
for O
photovoltaics O
and O
other O
applications O
. O

Array O
assembly O
typically O
requires O
applied O
electric O
or O
magnetic O
fields O
and O
/ O
or O
controlled O
drying O
, O
which O
are O
challenging O
over O
large O
areas O
. O

Here O
, O
we O
describe O
a O
scalable O
approach O
to O
self O
- O
assemble O
multicomponent O
nanowires O
into O
columnar O
arrays O
. O

Self O
- O
assembly O
of O
partially O
etched O
nanowires O
( O
PENs O
) O
occurred O
spontaneously O
during O
sedimentation O
from O
suspension O
, O
without O
drying O
or O
applied O
fields O
. O

PENs O
, O
which O
have O
segments O
that O
are O
either O
gold O
or O
" O
empty O
" O
( O
solvent O
- O
filled O
) O
surrounded O
by O
a O
silica B
shell O
, O
were O
produced O
from O
striped O
metal O
nanowires O
by O
first O
coating O
with O
silica B
and O
then O
removing O
sacrificial O
segments O
by O
acid O
etching O
. O

Electrostatic O
repulsion O
between O
the O
particles O
was O
necessary O
for O
array O
assembly O
; O
however O
, O
details O
of O
PEN O
surface O
chemistry O
were O
relatively O
unimportant O
. O

The O
aspect O
ratio O
and O
relative O
center O
of O
mass O
( O
COM O
) O
of O
the O
PENs O
were O
important O
for O
determining O
whether O
the O
PEN O
long O
axes O
were O
vertically O
or O
horizontally O
aligned O
with O
respect O
to O
the O
underlying O
substrate O
. O

Arrays O
with O
predominantly O
vertically O
aligned O
particles O
were O
achieved O
for O
PENs O
with O
a O
large O
offset O
in O
COM O
relative O
to O
the O
geometric O
center O
, O
while O
other O
types O
of O
PENs O
formed O
horizontal O
arrays O
. O

Assemblies O
were O
formed O
over O
> O
10 O
cm O
( O
2 O
) O
areas O
, O
with O
over O
60 O
% O
of O
particles O
standing O
. O

We O
assessed O
array O
uniformity O
and O
reproducibility O
by O
imaging O
many O
positions O
within O
each O
sample O
and O
performing O
multiple O
assemblies O
of O
differently O
segmented O
PENs O
. O

This O
work O
demonstrates O
the O
versatility O
of O
gravity O
- O
driven O
PEN O
array O
assembly O
and O
provides O
a O
framework O
for O
designing O
other O
anisotropic O
particle O
systems O
that O
self O
- O
assemble O
into O
columnar O
arrays O
. O

Xyloglucan O
- O
derivatized O
films O
for O
the O
culture O
of O
adherent O
cells O
and O
their O
thermocontrolled O
detachment O
: O
a O
promising O
alternative O
to O
cells O
sensitive O
to O
protease O
treatment O
. O

By O
taking O
advantage O
of O
a O
natural O
and O
abundant O
polymer O
as O
well O
as O
a O
straightforward O
film O
formation O
technique O
, O
this O
paper O
focuses O
on O
the O
conception O
and O
use O
of O
a O
new O
alternative O
tool O
for O
thermo O
- O
controlled O
cell O
detachment O
. O

Thermoresponsive O
xyloglucan O
was O
produced O
after O
partial O
galactose B
removal O
by O
a O
24 O
h O
reaction O
with O
beta O
- O
galactosidase O
. O

The O
obtained O
polymer O
( O
T24 O
) O
was O
then O
activated O
by O
reaction O
with O
4 B
- I
nitrophenyl I
chloroformate I
( O
NPC B
) O
in O
order O
to O
graft O
a O
cyclic O
peptide O
presenting O
an O
arginine B
- O
glycine B
- O
aspartic B
acid I
( O
RGD O
) O
motif O
. O

The O
effect O
of O
RGD O
grafting O
on O
the O
sol O
- O
gel O
transition O
temperature O
of O
T24 O
is O
evaluated O
by O
rheological O
measurements O
. O

Solvent O
- O
casted O
films O
of O
T24 O
- O
RGD O
successfully O
promoted O
cell O
adhesion O
, O
proliferation O
, O
and O
thermo O
- O
controlled O
detachment O
. O

The O
presented O
approach O
is O
a O
new O
alternative O
for O
cells O
sensitive O
to O
the O
proteolytic O
treatment O
routinely O
used O
for O
cell O
detachment O
. O

Because O
the O
RGD O
sequence O
used O
herein O
is O
widely O
recognized O
by O
different O
cell O
types O
, O
this O
protocol O
may O
be O
extended O
to O
other O
cells O
. O

Besides O
, O
the O
presented O
chemical O
route O
can O
be O
applied O
to O
different O
peptide O
sequences O
. O

Anion O
- O
pi O
interactions O
: O
generality O
, O
binding O
strength O
, O
and O
structure O
. O

Anion O
- O
pi O
interactions O
have O
been O
systematically O
studied O
using O
tetraoxacalix B
[ I
2 I
] I
arene I
[ I
2 I
] I
triazine I
1 O
, O
an O
electron O
- O
deficient O
and O
cavity O
self O
- O
tunable O
macrocyclic O
host O
, O
as O
an O
electron O
- O
neutral O
molecular O
probe O
. O

As O
revealed O
by O
electrospray O
ionization O
mass O
spectrometry O
( O
ESI O
- O
MS O
) O
, O
fluorescence O
titration O
and O
X O
- O
ray O
crystallography O
, O
tetraoxacalix B
[ I
2 I
] I
arene I
[ I
2 I
] I
triazine I
has O
been O
found O
to O
form O
1 O
: O
1 O
complexes O
with O
four O
typical O
polyatomic O
anions O
of O
different O
geometries O
and O
shapes O
in O
the O
gaseous O
phase O
, O
in O
solution O
, O
and O
in O
the O
solid O
state O
. O

The O
association O
constants O
for O
the O
formation O
of O
anion O
- O
pi O
complexes O
in O
acetonitrile B
are O
in O
the O
range O
of O
239 O
to O
16950 O
M O
( O
- O
1 O
) O
, O
following O
the O
order O
of O
1 O
. O
NO B
( I
3 I
) I
( I
- I
) I
> O
1 O
. O
BF B
( I
4 I
) I
( I
- I
) I
> O
1 O
. O
PF B
( I
6 I
) I
( I
- I
) I
> O
1 O
. O
SCN B
( I
- I
) I
. O

X O
- O
ray O
molecular O
structures O
of O
the O
complexes O
showed O
that O
two O
opposing O
triazine B
rings O
of O
tetraoxacalix B
[ I
2 I
] I
arene I
[ I
2 I
] I
triazine I
act O
as O
a O
pair O
of O
tweezers O
to O
interact O
with O
the O
included O
anions O
through O
cooperative O
anion O
- O
pi O
and O
lone O
- O
pair O
electron O
- O
pi O
interactions O
. O

The O
generality O
of O
anion O
- O
pi O
interactions O
and O
diverse O
anion O
- O
pi O
interaction O
motifs O
can O
provide O
a O
new O
dimension O
in O
the O
study O
of O
molecular O
recognition O
and O
self O
- O
assembly O
. O

Moreover O
, O
this O
study O
potentiates O
the O
effect O
of O
anion O
- O
pi O
interactions O
in O
chemical O
and O
biological O
systems O
, O
especially O
those O
involving O
anion O
and O
electron O
- O
deficient O
aromatic O
species O
. O

Effects O
and O
mechanism O
of O
organ O
protection O
by O
cardiotrophin B
- I
1 I
. O

Cardiotrophin B
- I
1 I
( O
CT O
- O
1 O
) O
, O
a O
member O
of O
the O
interleukin O
( O
IL O
) O
- O
6 O
family O
, O
is O
reported O
to O
exhibit O
a O
plethora O
of O
pleiotropic O
effects O
in O
the O
heart O
such O
as O
cytoprotective O
, O
pro O
- O
proliferative O
and O
pro O
- O
fibrotic O
ones O
. O

An O
extensive O
research O
has O
been O
devoted O
on O
proliferative O
and O
profibrotic O
effects O
of O
CT O
- O
1 O
on O
the O
heart O
. O

Thus O
the O
present O
review O
has O
been O
aimed O
to O
critically O
define O
the O
cytoprotective O
effects O
of O
CT O
- O
1 O
and O
the O
cellular O
and O
molecular O
mechanisms O
involved O
in O
them O
. O

Although O
many O
effects O
of O
CT O
- O
1 O
have O
been O
described O
on O
the O
heart O
, O
CT O
- O
1 O
has O
now O
also O
been O
reported O
to O
exhibit O
important O
protective O
effects O
in O
other O
organs O
such O
as O
liver O
, O
kidney O
or O
nervous O
system O
. O

CT O
- O
1 O
produces O
its O
effects O
through O
a O
unique O
receptor O
system O
comprising O
LIF O
receptor O
( O
LIFR O
beta O
) O
and O
a O
common O
signal O
transducer O
, O
the O
glycoprotein O
130 O
( O
gp130 O
) O
. O

The O
signaling O
pathway O
downstream O
from O
gp130 O
is O
based O
on O
at O
least O
, O
three O
distinct O
pathways O
: O
1 O
) O
the O
janus O
kinase O
/ O
signal O
transducer O
and O
activator O
of O
transcription O
( O
JAK O
/ O
STAT O
) O
pathway O
, O
2 O
) O
the O
p42 O
/ O
44 O
mitogen O
- O
activated O
protein O
kinase O
( O
p42 O
/ O
44 O
MAPK O
) O
pathway O
, O
also O
known O
as O
the O
extracellular O
receptor O
kinase O
- O
1 O
/ O
2 O
( O
ERK1 O
/ O
2 O
) O
pathway O
, O
and O
3 O
) O
the O
phosphatidylinositol B
3 I
- I
OH I
kinase O
( O
PI3K O
) O
/ O
Akt O
pathway O
. O

Since O
CT O
- O
1 O
easily O
achieves O
its O
cytoprotective O
effects O
via O
a O
combination O
of O
the O
above O
three O
signaling O
pathways O
, O
it O
becomes O
quite O
necessary O
to O
determine O
which O
pathway O
( O
s O
) O
is O
involved O
in O
each O
particular O
effect O
of O
CT O
- O
1 O
. O

In O
each O
of O
its O
target O
organs O
, O
CT O
- O
1 O
may O
also O
display O
differential O
mechanisms O
of O
cytoprotection O
, O
and O
thus O
it O
is O
relevant O
to O
understand O
how O
these O
mechanisms O
are O
locally O
regulated O
. O

Assessment O
of O
the O
antineoplastic O
potential O
of O
chalcones B
in O
animal O
models O
. O

One O
part O
of O
chemical O
space O
that O
is O
endowed O
with O
interesting O
biological O
properties O
is O
the O
area O
of O
the O
chalcones B
. O

With O
this O
review O
, O
we O
provide O
a O
comprehensive O
overview O
of O
the O
numerous O
in O
vivo O
animal O
studies O
on O
the O
antineoplastic O
potential O
of O
both O
natural O
and O
synthetic O
members O
of O
this O
flavonoid B
subclass O
( O
covering O
: O
up O
to O
mid O
- O
2011 O
) O
. O

The O
thus O
far O
identified O
modes O
of O
action O
of O
these O
compounds O
are O
also O
discussed O
. O

We O
hope O
that O
this O
overview O
may O
stimulate O
deeper O
investigations O
into O
the O
biochemical O
mechanisms O
by O
which O
chalcones B
exert O
their O
antineoplastic O
action O
. O

As O
a O
result O
, O
in O
the O
foreseeable O
future O
, O
chalcones B
may O
prove O
suitable O
lead O
molecules O
or O
early O
drug O
candidates O
for O
the O
prevention O
or O
treatment O
of O
various O
neoplastic O
diseases O
. O

Band O
gap O
engineering O
via O
controlling O
donor O
- O
acceptor O
compositions O
in O
conjugated O
copolymers O
. O

Varying O
composition O
of O
pi O
- O
donor O
/ O
acceptor O
moieties O
has O
been O
considered O
as O
an O
effective O
strategy O
for O
fine O
- O
tuning O
of O
the O
electronic O
properties O
of O
D O
- O
A O
conjugated O
copolymers O
. O

In O
this O
study O
, O
the O
change O
of O
optoelectronic O
properties O
with O
the O
change O
of O
donor O
/ O
acceptor O
ratios O
is O
investigated O
on O
the O
basis O
of O
first O
- O
principles O
density O
functional O
calculations O
. O

Copolymers O
containing O
moieties O
of O
similar O
pi O
- O
electron O
donating O
and O
/ O
or O
accepting O
capabilities O
, O
e O
. O
g O
. O
, O
thiophene B
( B
T I
) I
- I
methoxythiophene I
( O
OT B
) O
, O
exhibit O
a O
linear O
dependence O
of O
electronic O
properties O
( O
especially O
, O
HOMO O
/ O
LUMO O
, O
band O
gap O
, O
and O
bandwidth O
) O
on O
the O
D O
/ O
A O
content O
. O

In O
contrast O
, O
for O
strong O
D O
/ O
A O
contrast O
systems O
, O
e O
. O
g O
. O
, O
thiophene B
( B
T I
) I
- I
thienopyrazine I
( O
TP O
) O
, O
the O
electronic O
properties O
vary O
nonlinearly O
with O
D O
/ O
A O
compositions O
. O

However O
, O
when O
the O
block O
size O
of O
one O
parent O
monomer O
in O
a O
strong O
D O
/ O
A O
contrast O
system O
is O
fixed O
, O
the O
variation O
of O
electronic O
properties O
shows O
a O
remarkable O
linear O
correlation O
against O
D O
/ O
A O
compositions O
. O

We O
found O
that O
the O
deviation O
of O
electronic O
properties O
from O
a O
linear O
composition O
dependence O
is O
dominated O
by O
the O
strength O
of O
orbital O
interactions O
between O
D O
and O
A O
. O

Weak O
orbital O
interactions O
between O
D O
and O
A O
moieties O
tend O
to O
lead O
to O
a O
nonlinear O
composition O
dependence O
. O

Our O
results O
provide O
useful O
insights O
for O
band O
gap O
tuning O
through O
the O
adjustment O
of O
D O
/ O
A O
compositions O
in O
D O
- O
A O
conjugated O
copolymers O
. O

Microarray O
analysis O
of O
isolated O
human O
islet O
transcriptome O
in O
type O
2 O
diabetes O
and O
the O
role O
of O
the O
ubiquitin O
- O
proteasome O
system O
in O
pancreatic O
beta O
cell O
dysfunction O
. O

To O
shed O
light O
on O
islet O
cell O
molecular O
phenotype O
in O
human O
type O
2 O
diabetes O
( O
T2D O
) O
, O
we O
studied O
the O
transcriptome O
of O
non O
- O
diabetic O
( O
ND O
) O
and O
T2D O
islets O
to O
then O
focus O
on O
the O
ubiquitin O
- O
proteasome O
system O
( O
UPS O
) O
, O
the O
major O
protein O
degradation O
pathway O
. O

We O
assessed O
gene O
expression O
, O
amount O
of O
ubiquitinated O
proteins O
, O
proteasome O
activity O
, O
and O
the O
effects O
of O
proteasome O
inhibition O
and O
prolonged O
exposure O
to O
palmitate B
. O

Microarray O
analysis O
identified O
more O
than O
one O
thousand O
genes O
differently O
expressed O
in O
T2D O
islets O
, O
involved O
in O
many O
structures O
and O
functions O
, O
with O
consistent O
alterations O
of O
the O
UPS O
. O

Quantitative O
RT O
- O
PCR O
demonstrated O
downregulation O
of O
selected O
UPS O
genes O
in O
T2D O
islets O
and O
beta O
cell O
fractions O
, O
with O
greater O
ubiquitin O
accumulation O
and O
reduced O
proteasome O
activity O
. O

Chemically O
induced O
reduction O
of O
proteasome O
activity O
was O
associated O
with O
lower O
glucose B
- O
stimulated O
insulin O
secretion O
, O
which O
was O
partly O
reproduced O
by O
palmitate B
exposure O
. O

These O
results O
show O
the O
presence O
of O
many O
changes O
in O
islet O
transcriptome O
in O
T2D O
islets O
and O
underline O
the O
importance O
of O
the O
association O
between O
UPS O
alterations O
and O
beta O
cell O
dysfunction O
in O
human O
T2D O
. O

Dual O
action O
spirobicycloimidazol B
- I
2 I
, I
4 I
- I
diones I
: O
antidiabetic O
agents O
and O
inhibitors O
of O
aldose B
reductase O
- O
an O
enzyme O
involved O
in O
diabetic O
complications O
. O

The O
desired O
3 B
- I
( I
arylsulfonyl I
) I
spiroimidazolidine I
- I
2 I
, I
4 I
- I
diones I
were O
synthesized O
by O
reacting O
spiroiminoimidazolid B
- I
2 I
, I
4 I
- I
dione I
with O
arylsulfonyl B
chlorides I
. O

Spiroimidazolidine B
- I
2 I
, I
4 I
- I
dione I
was O
in O
turn O
synthesized O
from O
norcamphor O
. O

Structures O
of O
the O
synthesized O
molecules O
were O
established O
by O
modern O
spectroscopic O
techniques O
. O

The O
synthesized O
compounds O
were O
screened O
for O
in O
vivo O
antidiabetic O
activity O
and O
aldose B
reductase O
inhibition O
. O

Compounds O
2a O
, O
2b O
and O
2g O
exhibited O
excellent O
dual O
activity O
, O
compound O
2a O
being O
most O
prominent O
. O

These O
results O
reveal O
that O
the O
synthesized O
compounds O
may O
serve O
as O
the O
molecule O
of O
choice O
to O
treat O
diabetes O
and O
diabetic O
complications O
using O
a O
single O
medication O
. O

A O
SWI O
/ O
SNF O
chromatin O
- O
remodeling O
complex O
acts O
in O
noncoding O
RNA O
- O
mediated O
transcriptional O
silencing O
. O

RNA O
- O
mediated O
transcriptional O
silencing O
prevents O
deleterious O
effects O
of O
transposon O
activity O
and O
controls O
the O
expression O
of O
protein O
- O
coding O
genes O
. O

It O
involves O
long O
noncoding O
RNAs O
( O
lncRNAs O
) O
. O

In O
Arabidopsis O
thaliana O
, O
some O
of O
those O
lncRNAs O
are O
produced O
by O
a O
specialized O
RNA O
Polymerase O
V O
( O
Pol O
V O
) O
. O

The O
mechanism O
by O
which O
lncRNAs O
affect O
chromatin O
structure O
and O
mRNA O
production O
remains O
mostly O
unknown O
. O

Here O
we O
identify O
the O
SWI O
/ O
SNF O
ATP B
- O
dependent O
nucleosome O
- O
remodeling O
complex O
as O
a O
component O
of O
the O
RNA O
- O
mediated O
transcriptional O
silencing O
pathway O
. O

We O
found O
that O
SWI3B O
, O
an O
essential O
subunit O
of O
the O
SWI O
/ O
SNF O
complex O
, O
physically O
interacts O
with O
a O
lncRNA O
- O
binding O
protein O
, O
IDN2 O
. O

SWI O
/ O
SNF O
subunits O
contribute O
to O
lncRNA O
- O
mediated O
transcriptional O
silencing O
. O

Moreover O
, O
Pol O
V O
mediates O
stabilization O
of O
nucleosomes O
on O
silenced O
regions O
. O

We O
propose O
that O
Pol O
V O
- O
produced O
lncRNAs O
mediate O
transcriptional O
silencing O
by O
guiding O
the O
SWI O
/ O
SNF O
complex O
and O
establishing O
positioned O
nucleosomes O
on O
specific O
genomic O
loci O
. O

We O
further O
propose O
that O
guiding O
ATP B
- O
dependent O
chromatin O
- O
remodeling O
complexes O
may O
be O
a O
more O
general O
function O
of O
lncRNAs O
. O

Dendritic O
cell O
activation O
by O
polysaccharide O
isolated O
from O
Angelica O
dahurica O
. O

Angelica O
dahurica O
is O
used O
in O
functional O
foods O
for O
the O
prevention O
and O
treatment O
of O
various O
diseases O
, O
such O
as O
inflammation O
and O
cancer O
. O

In O
the O
present O
study O
, O
we O
examined O
the O
effect O
of O
A O
. O
dahurica O
polysaccharide O
( O
ADP O
) O
on O
dendritic O
cell O
( O
DC O
) O
maturation O
. O

ADP B
increased O
the O
expressions O
of O
CD86 O
and O
MHC O
- O
II O
molecules O
, O
the O
production O
of O
IL O
- O
12 O
, O
IL O
- O
1 O
beta O
, O
and O
TNF O
- O
alpha O
, O
and O
allogeneic O
T O
cell O
activation O
ability O
of O
DCs O
, O
and O
reduced O
DC O
endocytosis O
. O

As O
a O
mechanism O
of O
action O
, O
the O
knockdown O
of O
TLR4 O
with O
small O
interfering O
RNA O
decreased O
the O
ADP B
- O
induced O
production O
of O
nitric B
oxide I
and O
IL O
- O
12 O
by O
DCs O
, O
suggesting O
the O
membrane O
receptor O
candidate O
of O
ADP B
. O

After O
binding O
to O
TLR4 O
, O
ADP B
increased O
the O
phosphorylation O
of O
ERK O
, O
JNK O
, O
and O
p38 O
MAPKs O
, O
and O
the O
nuclear O
translocation O
of O
NF O
- O
kappa O
B O
p50 O
/ O
p65 O
. O

These O
results O
indicate O
that O
ADP B
activates O
DCs O
through O
TLR4 O
and O
downstream O
signalings O
. O

Poly B
( I
ethylene I
glycol I
) I
- I
block I
- I
poly I
( I
epsilon I
- I
caprolactone I
) I
micelles O
for O
combination O
drug O
delivery O
: O
evaluation O
of O
paclitaxel B
, O
cyclopamine B
and O
gossypol B
in O
intraperitoneal O
xenograft O
models O
of O
ovarian O
cancer O
. O

Ovarian O
cancer O
is O
the O
most O
lethal O
gynecological O
malignancy O
, O
characterized O
by O
a O
high O
rate O
of O
chemoresistance O
. O

Current O
treatment O
strategies O
for O
ovarian O
cancer O
focus O
on O
novel O
drug O
combinations O
of O
cytotoxic O
agents O
and O
molecular O
targeted O
agents O
or O
novel O
drug O
delivery O
strategies O
that O
often O
involve O
intraperitoneal O
( O
IP O
) O
injection O
. O

Poly B
( I
ethylene I
glycol I
) I
- I
block I
- I
poly I
( I
epsilon I
- I
caprolactone I
) I
( O
PEG B
- I
b I
- I
PCL I
) O
micelles O
were O
loaded O
with O
paclitaxel B
( O
cytotoxic O
agent O
) O
, O
cyclopamine B
( O
hedgehog O
inhibitor O
) O
, O
and O
gossypol B
( O
Bcl O
- O
2 O
inhibitor O
) O
. O

After O
physicochemical O
studies O
focusing O
on O
combination O
drug O
solubilization O
, O
3 O
- O
drug O
PEG B
- O
b O
- O
PCL B
micelles O
were O
evaluated O
in O
vitro O
in O
2 O
- O
D O
and O
3 O
- O
D O
cell O
culture O
and O
in O
vivo O
in O
xenograft O
models O
of O
ovarian O
cancer O
, O
tracking O
bioluminescence O
signals O
from O
ES O
- O
2 O
and O
SKOV3 O
human O
ovarian O
cancer O
cell O
lines O
after O
IP O
injection O
. O

3 O
- O
Drug O
PEG B
- I
b I
- I
PCL B
micelles O
were O
not O
significantly O
more O
potent O
in O
2 O
- O
D O
cell O
culture O
in O
comparison O
to O
paclitaxel B
; O
however O
, O
they O
disaggregated O
ES O
- O
2 O
tumor O
spheroids O
, O
whereas O
single O
drugs O
or O
2 O
- O
drug O
combinations O
only O
slowed O
growth O
of O
ES O
- O
2 O
tumor O
spheroids O
or O
had O
no O
noticeable O
effects O
. O

In O
ES O
- O
2 O
and O
SKOV3 O
xenograft O
models O
, O
3 O
- O
drug O
PEG B
- O
b O
- O
PCL O
micelles O
had O
significantly O
less O
tumor O
burden O
than O
paclitaxel B
based O
on O
bioluminescence O
imaging O
, O
3 B
' I
- I
deoxy I
- I
3 I
' I
- I
( I
18 I
) I
F I
- I
fluorothymidine I
( O
( B
18 I
) I
F I
- I
FLT I
) O
PET O
imaging O
, O
and O
overall O
survival O
. O

( B
18 I
) I
F I
- I
FLT I
- O
PET O
images O
clearly O
showed O
that O
3 O
- O
drug O
PEG B
- O
b O
- O
PCL B
micelles O
dramatically O
reduce O
tumor O
volumes O
over O
paclitaxel B
and O
vehicle O
controls O
. O

In O
summary O
, O
PEG B
- O
b O
- O
PCL B
micelles O
enable O
the O
IP O
combination O
drug O
delivery O
of O
paclitaxel B
, O
cyclopamine B
and O
gossypol B
, O
resulting O
in O
tumor O
growth O
inhibition O
and O
prolonged O
survival O
over O
paclitaxel B
alone O
. O

These O
results O
validate O
a O
novel O
treatment O
strategy O
for O
ovarian O
cancer O
based O
on O
drug O
combinations O
of O
cytotoxic O
agents O
and O
molecular O
targeted O
agents O
, O
delivered O
concurrently O
by O
a O
nanoscale O
drug O
delivery O
system O
, O
e O
. O
g O
. O
PEG B
- O
b O
- O
PCL B
micelles O
. O

Torching O
the O
Haystack O
: O
modelling O
fast O
- O
fail O
strategies O
in O
drug O
development O
. O

By O
quickly O
clearing O
the O
development O
pipeline O
of O
failing O
or O
marginal O
products O
, O
fast O
- O
fail O
strategies O
release O
resources O
to O
focus O
on O
more O
promising O
molecules O
. O

The O
Quick O
- O
Kill O
model O
of O
drug O
development O
demonstrates O
that O
fast O
- O
fail O
strategies O
will O
: O
( O
1 O
) O
reduce O
the O
expected O
time O
to O
market O
; O
( O
2 O
) O
reduce O
expected O
R O
& O
D O
costs O
; O
and O
( O
3 O
) O
increase O
R O
& O
D O
productivity O
. O

This O
paper O
outlines O
the O
model O
and O
demonstrates O
the O
impact O
of O
fast O
- O
fail O
strategies O
. O

The O
model O
is O
illustrated O
with O
costs O
and O
risks O
data O
from O
pharmaceutical O
and O
biopharmaceutical O
companies O
. O

Mechanisms O
underlying O
induction O
of O
LTP O
- O
associated O
changes O
in O
short O
- O
term O
dynamics O
of O
transmission O
at O
immature O
synapses O
. O

While O
the O
activity O
- O
dependent O
mechanisms O
guiding O
functional O
maturation O
of O
synaptic O
transmission O
postsynaptically O
are O
well O
characterized O
, O
less O
is O
known O
about O
the O
corresponding O
presynaptic O
mechanisms O
. O

Here O
we O
show O
that O
during O
the O
first O
postnatal O
week O
, O
a O
subset O
of O
CA3 O
- O
CA1 O
synapses O
express O
postsynaptically O
induced O
LTP O
that O
is O
tightly O
associated O
with O
a O
robust O
decrease O
in O
synaptic O
facilitation O
, O
consistent O
with O
an O
increase O
in O
release O
probability O
( O
P O
( O
r O
) O
) O
. O

The O
loss O
of O
facilitation O
is O
readily O
induced O
by O
physiologically O
relevant O
pairing O
protocols O
at O
immature O
synapses O
and O
is O
dependent O
on O
activation O
of O
NMDA B
- O
receptors O
but O
not O
L O
- O
type O
calcium B
channels O
. O

The O
putative O
pre O
- O
and O
postsynaptic O
components O
of O
neonatal O
LTP O
were O
distinguished O
in O
their O
downstream O
signaling O
requirements O
, O
PKC O
activity O
being O
selectively O
needed O
for O
the O
decrease O
in O
facilitation O
but O
not O
for O
synaptic O
potentiation O
per O
se O
. O

These O
data O
suggest O
that O
maturation O
of O
glutamatergic O
synapses O
involves O
a O
critical O
period O
during O
which O
presynaptic O
function O
is O
highly O
susceptible O
to O
activity O
- O
dependent O
regulation O
via O
a O
PKC O
- O
dependent O
mechanism O
. O

In O
vitro O
neurotoxic O
effects O
of O
Pseudechis O
spp O
. O
venoms O
: O
A O
comparison O
of O
avian O
and O
murine O
skeletal O
muscle O
preparations O
. O

Two O
common O
in O
vitro O
skeletal O
muscle O
preparations O
used O
for O
the O
study O
of O
venom O
neurotoxicity O
are O
the O
indirectly O
stimulated O
chick O
isolated O
biventer O
cervicis O
nerve O
- O
muscle O
preparation O
and O
the O
rat O
isolated O
phrenic O
nerve O
- O
diaphragm O
preparation O
. O

The O
aim O
of O
the O
current O
study O
was O
to O
compare O
the O
in O
vitro O
neurotoxicity O
of O
six O
Pseudechis O
spp O
. O

( O
Black O
snakes O
) O
venoms O
in O
both O
avian O
( O
chicken O
) O
and O
mammalian O
( O
rat O
) O
skeletal O
muscle O
preparations O
to O
determine O
differences O
in O
sensitivity O
. O

All O
Pseudechis O
spp O
. O
venoms O
significantly O
inhibited O
indirect O
twitches O
, O
in O
both O
preparations O
, O
indicating O
the O
presence O
of O
post O
synaptic O
neurotoxins O
. O

The O
inhibitory O
effects O
of O
all O
venoms O
were O
more O
rapid O
in O
the O
avian O
preparation O
, O
except O
for O
Pseudechis O
colletti O
venom O
where O
no O
significant O
difference O
was O
seen O
between O
the O
murine O
and O
avian O
muscles O
. O

Time O
taken O
to O
produce O
50 O
% O
reduction O
in O
stimulated O
twitches O
( O
i O
. O
e O
. O
t O
( O
50 O
) O
) O
was O
markedly O
shorter O
in O
the O
avian O
preparation O
. O

We O
have O
shown O
that O
the O
avian O
in O
vitro O
preparation O
is O
more O
sensitive O
to O
the O
neurotoxic O
activity O
of O
Pseudechis O
spp O
. O
than O
the O
murine O
preparation O
. O

This O
difference O
is O
likely O
to O
be O
due O
to O
species O
differences O
in O
the O
interaction O
between O
the O
neurotoxins O
and O
the O
nicotinic O
receptor O
binding O
sites O
as O
well O
as O
differences O
in O
the O
' O
safety O
factor O
' O
between O
the O
preparations O
. O

Development O
and O
evaluation O
of O
colloidal O
modified O
nanolipid O
carrier O
: O
Application O
to O
topical O
delivery O
of O
tacrolimus B
, O
Part O
II O
- O
In O
vivo O
assessment O
, O
drug O
targeting O
, O
efficacy O
, O
and O
safety O
in O
treatment O
for O
atopic O
dermatitis O
. O

In O
atopic O
dermatitis O
( O
AD O
) O
, O
topical O
anti O
- O
inflammatory O
therapy O
with O
skin O
barrier O
restoration O
to O
prevent O
repeated O
inflammatory O
episodes O
leads O
to O
long O
- O
term O
therapeutic O
success O
. O

Tacrolimus B
, O
although O
effective O
against O
AD O
, O
is O
a O
challenging O
molecule O
due O
to O
low O
solubility O
, O
low O
- O
penetration O
, O
poor O
- O
bioavailability O
, O
and O
toxicity O
. O

Part O
I O
of O
this O
paper O
, O
reported O
novel O
modified O
nanolipid O
carrier O
system O
for O
topical O
delivery O
of O
tacrolimus B
( O
T O
- O
MNLC O
) O
, O
offering O
great O
opportunity O
to O
load O
low O
- O
solubility O
drug O
with O
improved O
entrapment O
efficiency O
, O
enhanced O
stability O
and O
improved O
skin O
deposition O
. O

Present O
investigation O
focused O
on O
restoration O
of O
skin O
barrier O
, O
site O
- O
specific O
delivery O
, O
therapeutic O
effectiveness O
, O
and O
safety O
of O
novel O
T O
- O
MNLC O
. O

T O
- O
MNLC O
greatly O
enhanced O
occlusive O
properties O
, O
skin O
hydration O
potential O
and O
reduced O
transepidermal O
water O
loss O
. O

This O
might O
help O
to O
reduce O
the O
number O
of O
flares O
and O
better O
control O
the O
disease O
. O

Cutaneous O
uptake O
and O
drug O
deposition O
in O
albino O
rats O
by O
HPLC O
and O
confocal O
laser O
scanning O
microscopy O
revealed O
prominently O
elevated O
drug O
levels O
in O
all O
skin O
strata O
with O
T O
- O
MNLC O
as O
compared O
to O
reference O
. O

T O
- O
MNLC O
demonstrated O
efficient O
suppression O
of O
inflammatory O
responses O
in O
BALB O
/ O
c O
mice O
model O
of O
AD O
. O

Safety O
assessment O
by O
acute O
and O
repeated O
- O
dose O
dermal O
toxicity O
demonstrated O
mild O
keratosis O
and O
collagenous O
mass O
infiltration O
at O
the O
treatment O
area O
with O
repeated O
application O
of O
reference O
. O

Interestingly O
, O
T O
- O
MNLC O
showed O
no O
evident O
toxicity O
exhibiting O
safe O
drug O
delivery O
. O

Thus O
, O
novel O
T O
- O
MNLC O
would O
be O
a O
safe O
, O
effective O
, O
and O
esthetically O
appealing O
alternative O
to O
conventional O
vehicles O
for O
treatment O
for O
AD O
. O

Size O
- O
dependent O
toxicity O
and O
cell O
interaction O
mechanisms O
of O
gold O
nanoparticles O
on O
mouse O
fibroblasts O
. O

Gold O
nanoparticles O
( O
AuNPs O
) O
are O
currently O
used O
in O
several O
fields O
including O
biomedical O
applications O
, O
although O
no O
conclusive O
information O
on O
their O
cytotoxicity O
is O
available O
. O

For O
this O
reason O
this O
work O
has O
investigated O
the O
effects O
of O
AuNPs O
in O
vitro O
on O
Balb O
/ O
3T3 O
mouse O
fibroblasts O
. O

Results O
obtained O
exposing O
cells O
for O
72 O
h O
to O
AuNPs O
5 O
and O
15 O
nm O
citrate B
stabilized O
, O
revealed O
cytotoxic O
effects O
only O
for O
AuNPs O
5 O
nm O
at O
concentration O
> O
= O
50 O
mu O
M O
if O
measured O
by O
colony O
forming O
efficiency O
( O
CFE O
) O
. O

To O
understand O
the O
differences O
in O
cytotoxicity O
observed O
for O
the O
two O
AuNPs O
sizes O
, O
we O
investigated O
the O
uptake O
and O
the O
intracellular O
distribution O
of O
the O
nanoparticles O
. O

By O
TEM O
it O
was O
observed O
that O
5 O
and O
15 O
nm O
AuNPs O
are O
internalized O
by O
Balb O
/ O
3T3 O
cells O
and O
located O
within O
intracellular O
endosomal O
compartments O
. O

Quantification O
of O
the O
uptake O
by O
ICP O
- O
MS O
showed O
that O
AuNPs O
internalization O
enhanced O
even O
up O
to O
72 O
h O
. O

Disruption O
of O
the O
actin O
cytoskeleton O
was O
evident O
, O
with O
cell O
footprints O
narrow O
and O
contracted O
; O
effects O
more O
remarkable O
in O
cells O
exposed O
to O
5 O
nm O
AuNP O
. O

The O
mechanism O
of O
NPs O
cell O
internalization O
was O
investigated O
using O
immunocytochemistry O
and O
western O
blot O
. O

No O
significant O
effect O
was O
observed O
in O
the O
expression O
level O
of O
caveolin O
, O
while O
reduction O
of O
the O
expression O
and O
degradation O
of O
the O
clathrin O
heavy O
chain O
was O
observed O
in O
cells O
exposed O
for O
72 O
h O
to O
AuNPs O
. O

Failure O
to O
generate O
bone O
marrow O
adipocytes O
does O
not O
protect O
mice O
from O
ovariectomy O
- O
induced O
osteopenia O
. O

A O
reciprocal O
association O
between O
bone O
marrow O
fat O
and O
bone O
mass O
has O
been O
reported O
in O
ovariectomized O
rodents O
, O
suggesting O
that O
bone O
marrow O
adipogenesis O
has O
a O
negative O
effect O
on O
bone O
growth O
and O
turnover O
balance O
. O

Mice O
with O
loss O
of O
function O
mutations O
in O
kit O
receptor O
( O
kit O
( O
W O
/ O
W O
- O
v O
) O
) O
have O
no O
bone O
marrow O
adipocytes O
in O
tibia O
or O
lumbar O
vertebra O
. O

We O
therefore O
tested O
the O
hypothesis O
that O
marrow O
fat O
contributes O
to O
the O
development O
of O
osteopenia O
by O
comparing O
the O
skeletal O
response O
to O
ovariectomy O
( O
ovx O
) O
in O
growing O
wild O
type O
( O
WT O
) O
and O
bone O
marrow O
adipocyte O
- O
deficient O
kit O
( O
W O
/ O
W O
- O
v O
) O
mice O
. O

Mice O
were O
ovx O
at O
4 O
weeks O
of O
age O
and O
sacrificed O
4 O
or O
10 O
weeks O
post O
- O
surgery O
. O

Body O
composition O
was O
measured O
at O
necropsy O
by O
dual O
- O
energy O
X O
- O
ray O
absorptiometry O
. O

Cortical O
( O
tibia O
) O
and O
cancellous O
( O
tibia O
and O
lumbar O
vertebra O
) O
bone O
architecture O
were O
evaluated O
by O
microcomputed O
tomography O
. O

Bone O
marrow O
adipocyte O
size O
and O
density O
, O
osteoblast O
- O
and O
osteoclast O
- O
lined O
bone O
perimeters O
, O
and O
bone O
formation O
were O
determined O
by O
histomorphometry O
. O

Ovx O
resulted O
in O
an O
increase O
in O
total O
body O
fat O
mass O
at O
10 O
weeks O
post O
- O
ovx O
in O
both O
genotypes O
, O
but O
the O
response O
was O
attenuated O
in O
the O
in O
kit O
( O
W O
/ O
W O
- O
v O
) O
mice O
. O

Adipocytes O
were O
present O
in O
bone O
marrow O
of O
tibia O
and O
lumbar O
vertebra O
in O
WT O
mice O
and O
bone O
marrow O
adiposity O
increased O
following O
ovx O
. O

In O
contrast O
, O
marrow O
adipocytes O
were O
not O
detected O
in O
either O
intact O
or O
ovx O
kit O
( O
W O
/ O
W O
- O
v O
) O
mice O
. O

However O
, O
ovx O
in O
WT O
and O
kit O
( O
W O
/ O
W O
- O
v O
) O
mice O
resulted O
in O
statistically O
indistinguishable O
changes O
in O
cortical O
and O
cancellous O
bone O
mass O
, O
cortical O
and O
cancellous O
bone O
formation O
rate O
, O
and O
cancellous O
osteoblast O
and O
osteoclast O
- O
lined O
bone O
perimeters O
. O

In O
conclusion O
, O
our O
findings O
do O
not O
support O
a O
causal O
role O
for O
increased O
bone O
marrow O
fat O
as O
a O
mediator O
of O
ovx O
- O
induced O
osteopenia O
in O
mice O
. O

Ameliorating O
effects O
of O
extracellular O
polymeric O
substances O
excreted O
by O
Thalassiosira O
pseudonana O
on O
algal O
toxicity O
of O
CdSe B
quantum O
dots O
. O

Quantum O
dots O
( O
QDs O
) O
are O
engineered O
nanoparticles O
( O
ENs B
) O
that O
have O
found O
increasing O
applications O
and O
shown O
great O
potential O
in O
drug O
delivery O
, O
biological O
imaging O
and O
industrial O
products O
. O

Knowledge O
of O
their O
stability O
, O
fate O
and O
transport O
in O
the O
aquatic O
environment O
is O
still O
lacking O
, O
including O
details O
of O
how O
these O
nanomaterials O
interact O
with O
marine O
phytoplankton O
. O

Here O
, O
we O
examined O
the O
toxicity O
of O
functionalized O
CdSe B
/ O
ZnS B
QDs O
( O
amine B
- O
and O
carboxyl B
- O
) O
by O
exposing O
them O
for O
five O
days O
to O
Thalassiosira O
pseudonana O
( O
marine O
diatom O
) O
grown O
under O
different O
nutrient O
- O
conditions O
( O
enriched O
versus O
nitrogen B
- O
limited O
media O
) O
. O

The O
released O
polysaccharides O
and O
proteins O
, O
the O
major O
components O
of O
extracellular O
polymeric O
substances O
( O
EPS O
) O
, O
were O
measured O
to O
assess O
their O
potential O
effects O
on O
the O
interactions O
between O
QDs O
and O
T O
. O
pseudonana O
. O

The O
partitioning O
of O
QDs O
was O
analyzed O
by O
monitoring O
the O
concentration O
of O
Cd B
in O
different O
size O
fractions O
of O
the O
cultures O
( O
i O
. O
e O
. O
, O
filtrate O
, O
< O
0 O
. O
22 O
mu O
m O
and O
permeate O
, O
< O
3 O
kDa O
) O
. O

We O
found O
that O
the O
Cd B
release O
of O
QDs O
in O
the O
T O
. O
pseudonana O
culture O
was O
dependent O
on O
the O
nutrient O
conditions O
and O
nature O
of O
QDs O
' O
surface O
coating O
. O

Both O
amine B
- O
and O
carboxyl B
- O
functionalized O
QDs O
exhibited O
higher O
rates O
of O
Cd B
release O
in O
N B
- O
limited O
cultures O
than O
in O
nutrient O
enriched O
cultures O
. O

The O
results O
also O
showed O
that O
amine B
- O
functionalized O
QDs O
aggregate O
with O
minimal O
Cd B
release O
, O
independent O
of O
nutrient O
conditions O
. O

Laser O
scanning O
confocal O
microscopy O
images O
confirmed O
that O
aggregates O
are O
composed O
of O
QDs O
and O
the O
culture O
matrix O
( O
EPS O
) O
. O

In O
addition O
, O
both O
types O
of O
QDs O
showed O
limited O
toxicity O
to O
T O
. O
pseudonana O
. O

The O
increasing O
production O
of O
proteins O
induced O
by O
QDs O
suggests O
that O
extracellular O
proteins O
might O
be O
involved O
in O
the O
detoxification O
of O
QDs O
to O
T O
. O
pseudonana O
via O
the O
Cd B
release O
of O
QDs O
. O

Our O
results O
here O
demonstrated O
that O
EPS O
can O
play O
an O
ameliorating O
role O
in O
QD O
toxicity O
, O
fate O
and O
transport O
in O
the O
aquatic O
environment O
. O

17 B
beta I
estradiol I
regulation O
of O
connexin O
43 O
- O
based O
gap O
junction O
and O
mechanosensitivity O
through O
classical O
estrogen B
receptor O
pathway O
in O
osteocyte O
- O
like O
MLO O
- O
Y4 O
cells O
. O

Connexin O
43 O
( O
Cx43 O
) O
plays O
an O
essential O
role O
in O
osteocyte O
mechanotransduction O
. O

Although O
estrogen B
involves O
in O
the O
adaptive O
responses O
of O
bone O
cells O
to O
mechanical O
loadings O
, O
its O
effects O
on O
osteocytic O
Cx43 O
- O
based O
gap O
junction O
intercellular O
communication O
( O
GJIC O
) O
remain O
obscure O
. O

We O
found O
that O
17 B
beta I
estradiol I
( O
E2 O
) O
up O
- O
regulated O
Cx43 O
, O
and O
enhanced O
GJIC O
in O
osteocyte O
- O
like O
MLO O
- O
Y4 O
cells O
in O
fluorescence O
recovery O
after O
photobleaching O
( O
FRAP O
) O
assay O
. O

Combination O
of O
E2 O
pre O
- O
treatment O
and O
oscillating O
fluid O
flow O
( O
OFF O
) O
further O
enhanced O
Cx43 O
expression O
and O
mitogen O
- O
activated O
protein O
kinase O
( O
MAPK O
) O
phosphorylation O
, O
comparing O
to O
E2 O
or O
OFF O
treatment O
alone O
. O

Both O
blocking O
of O
classical O
estrogen B
receptors O
( O
ER O
alpha O
/ O
beta O
) O
by O
fulvestrant B
and O
ER O
alpha O
knockdown O
by O
small O
interfering O
RNA O
inhibited O
E2 O
- O
mediated O
Cx43 O
increase O
, O
while O
a O
GPR30 O
- O
specific O
agonist O
G O
- O
1 O
failed O
to O
promote O
Cx43 O
expression O
. O

Our O
results O
suggest O
that O
the O
presence O
of O
E2 O
enhanced O
Cx43 O
- O
based O
GJIC O
mainly O
via O
ER O
alpha O
/ O
beta O
pathway O
, O
and O
sensitized O
osteocytes O
to O
mechanical O
loading O
. O

Phase O
separation O
as O
a O
key O
to O
a O
thermoelectric O
high O
efficiency O
. O

This O
work O
elucidates O
the O
possible O
reasons O
for O
the O
outstanding O
, O
but O
never O
reproduced O
thermoelectric O
properties O
of O
the O
doped O
Ti B
( I
0 I
. I
5 I
) I
Zr I
( I
0 I
. I
25 I
) I
Hf I
( I
0 I
. I
25 I
) I
NiSn I
Heusler O
compounds O
. O

The O
structural O
investigations O
done O
via O
synchrotron O
X O
- O
ray O
diffraction O
measurements O
and O
scanning O
electron O
microscope O
measurements O
, O
which O
clearly O
show O
that O
the O
microstructure O
consists O
of O
three O
temperature O
stable O
C1 O
( O
b O
) O
phases O
with O
possible O
semi O
- O
coherent O
interfaces O
, O
are O
presented O
. O

The O
exceptional O
thermoelectric O
properties O
are O
due O
to O
this O
intrinsic O
phase O
separation O
. O

It O
is O
possible O
to O
reproduce O
the O
high O
Figure O
of O
Merit O
values O
with O
ZT O
= O
1 O
. O
2 O
at O
830 O
K O
. O

Furthermore O
, O
the O
influence O
of O
doping O
different O
elements O
on O
the O
Sn B
position O
in O
this O
Heusler O
material O
system O
is O
investigated O
. O

Halogen B
- O
bonding O
- O
triggered O
supramolecular O
gel O
formation O
. O

Supramolecular O
gels O
are O
topical O
soft O
materials O
involving O
the O
reversible O
formation O
of O
fibrous O
aggregates O
using O
non O
- O
covalent O
interactions O
. O

There O
is O
significant O
interest O
in O
controlling O
the O
properties O
of O
such O
materials O
by O
the O
formation O
of O
multicomponent O
systems O
, O
which O
exhibit O
non O
- O
additive O
properties O
emerging O
from O
interaction O
of O
the O
components O
. O

The O
use O
of O
hydrogen B
bonding O
to O
assemble O
supramolecular O
gels O
in O
organic O
solvents O
is O
well O
established O
. O

In O
contrast O
, O
the O
use O
of O
halogen B
bonding O
to O
trigger O
supramolecular O
gel O
formation O
in O
a O
two O
- O
component O
gel O
( O
' O
co O
- O
gel O
' O
) O
is O
essentially O
unexplored O
, O
and O
forms O
the O
basis O
for O
this O
study O
. O

Here O
, O
we O
show O
that O
halogen B
bonding O
between O
a O
pyridyl B
substituent O
in O
a O
bis B
( I
pyridyl I
urea I
) I
and O
1 B
, I
4 I
- I
diiodotetrafluoroben I
brings O
about O
gelation O
, O
even O
in O
polar O
media O
such O
as O
aqueous O
methanol B
and O
aqueous O
dimethylsulfoxide B
. O

This O
demonstrates O
that O
halogen B
bonding O
is O
sufficiently O
strong O
to O
interfere O
with O
competing O
gel O
- O
inhibitory O
interactions O
and O
create O
a O
' O
tipping O
point O
' O
in O
gel O
assembly O
. O

Using O
this O
concept O
, O
we O
have O
prepared O
a O
halogen B
bond O
donor O
bis B
( I
urea I
) I
gelator O
that O
forms O
co O
- O
gels O
with O
halogen B
bond O
acceptors O
. O

Translational O
research O
: O
the O
changing O
landscape O
of O
drug O
discovery O
. O

Drug O
discovery O
represents O
the O
first O
step O
in O
the O
creation O
of O
new O
drugs O
, O
and O
takes O
place O
in O
academic O
institutions O
, O
biotech O
companies O
, O
and O
large O
pharmaceutical O
corporations O
. O

Until O
recently O
, O
these O
sectors O
have O
each O
operated O
independently O
with O
little O
collaboration O
between O
those O
at O
the O
forefront O
of O
discovery O
research O
and O
those O
with O
experience O
in O
developing O
drugs O
. O

With O
the O
rise O
of O
translational O
research O
these O
relationships O
are O
shifting O
and O
new O
hubs O
are O
emerging O
, O
as O
key O
players O
seek O
to O
pool O
the O
expertise O
necessary O
to O
generate O
new O
therapies O
by O
linking O
laboratory O
discoveries O
directly O
to O
unmet O
clinical O
needs O
. O

In O
this O
article O
I O
discuss O
how O
the O
increasing O
adoption O
of O
translational O
research O
is O
leading O
to O
novel O
integrated O
discovery O
nexuses O
that O
may O
change O
the O
landscape O
of O
drug O
discovery O
. O

Drug O
- O
drug O
interactions O
between O
rosuvastatin B
and O
oral O
antidiabetic O
drugs O
occurring O
at O
the O
level O
of O
OATP1B1 O
. O

Organic O
anion O
- O
transporting O
polypeptide O
1B1 O
( O
OATP1B1 O
) O
is O
an O
important O
hepatic O
uptake O
transporter O
, O
of O
which O
the O
polymorphic O
variant O
OATP1B1 O
* O
15 O
( O
Asn130Asp O
and O
Val174Ala O
) O
has O
been O
associated O
with O
decreased O
transport O
activity O
. O

Rosuvastatin B
is O
an O
OATP1B1 O
substrate O
and O
often O
concomitantly O
prescribed O
with O
oral O
antidiabetics O
in O
the O
clinic O
. O

The O
aim O
of O
this O
study O
was O
to O
investigate O
possible O
drug O
- O
drug O
interactions O
between O
these O
drugs O
at O
the O
level O
of O
OATP1B1 O
and O
OATP1B1 O
* O
15 O
. O

We O
generated O
human O
embryonic O
kidney O
( O
HEK O
) O
293 O
cells O
stably O
overexpressing O
OATP1B1 O
or O
OATP1B1 O
* O
15 O
that O
showed O
similar O
protein O
expression O
levels O
of O
OATP1B1 O
and O
OATP1B1 O
* O
15 O
at O
the O
cell O
membrane O
as O
measured O
by O
liquid O
chromatography O
- O
tandem O
mass O
spectrometry O
. O

In O
HEK O
- O
OATP1B1 O
* O
15 O
cells O
, O
the O
V O
( O
max O
) O
for O
OATP1B1 O
- O
mediated O
transport O
of O
E O
( O
2 O
) O
17 B
beta I
- I
G I
( O
estradiol B
17 I
beta I
- I
d I
- I
glucuronide I
) O
was O
decreased O
> O
60 O
% O
, O
whereas O
K O
( O
m O
) O
values O
( O
Michaelis O
constant O
) O
were O
comparable O
. O

Uptake O
of O
rosuvastatin B
in O
HEK O
- O
OATP1B1 O
cells O
( O
K O
( O
m O
) O
13 O
. O
1 O
+ O
/ O
- O
0 O
. O
43 O
mu O
M O
) O
was O
nearly O
absent O
in O
HEK O
- O
OATP1B1 O
* O
15 O
cells O
. O

Interestingly O
, O
several O
oral O
antidiabetics O
( O
glyburide B
, O
glimepiride B
, O
troglitazone B
, O
pioglitazone B
, O
glipizide B
, O
gliclazide B
, O
and O
tolbutamide B
) O
, O
but O
not O
metformin B
, O
were O
identified O
as O
significant O
inhibitors O
of O
the O
OATP1B1 O
- O
mediated O
transport O
of O
rosuvastatin B
. O

The O
IC O
( O
50 O
) O
values O
for O
inhibition O
of O
E B
( I
2 I
) I
17 I
beta I
- I
G I
uptake O
were O
similar O
between O
OATP1B1 O
and O
OATP1B1 O
* O
15 O
. O

In O
conclusion O
, O
these O
studies O
indicate O
that O
several O
oral O
antidiabetic O
drugs O
affect O
the O
OATP1B1 O
- O
mediated O
uptake O
of O
rosuvastatin B
in O
vitro O
. O

The O
next O
step O
will O
be O
to O
translate O
these O
data O
to O
the O
clinical O
situation O
, O
as O
it O
remains O
to O
be O
established O
whether O
the O
studied O
oral O
antidiabetics O
indeed O
affect O
the O
clinical O
pharmacokinetic O
profile O
of O
rosuvastatin B
in O
patients O
. O

Optical O
and O
electrical O
detection O
of O
single O
- O
molecule O
translocation O
through O
carbon B
nanotubes O
. O

Ion O
current O
through O
a O
single O
- O
walled O
carbon B
nanotube O
( O
SWCNT O
) O
was O
monitored O
at O
the O
same O
time O
as O
fluorescence O
was O
recorded O
from O
charged O
dye O
molecules O
translocating O
through O
the O
SWCNT O
. O

Fluorescence O
bursts O
generally O
follow O
ion O
current O
peaks O
with O
a O
delay O
time O
consistent O
with O
diffusion O
from O
the O
end O
of O
the O
SWCNT O
to O
the O
fluorescence O
collection O
point O
. O

The O
fluorescence O
amplitude O
distribution O
of O
the O
bursts O
is O
consistent O
with O
single O
- O
molecule O
signals O
. O

Thus O
each O
peak O
in O
the O
ion O
current O
flowing O
through O
the O
SWCNT O
is O
associated O
with O
the O
translocation O
of O
a O
single O
molecule O
. O

Ion O
current O
peaks O
( O
as O
opposed O
to O
blockades O
) O
were O
produced O
by O
both O
positively O
( O
Rhodamine B
6G I
) O
and O
negatively O
( O
Alexa B
546 I
) O
charged O
molecules O
, O
showing O
that O
the O
charge O
filtering O
responsible O
for O
the O
current O
bursts O
is O
caused O
by O
the O
molecules O
themselves O
. O

Reduced O
antinociception O
of O
opioids O
in O
rats O
and O
mice O
by O
vaccination O
with O
immunogens O
containing O
oxycodone B
and O
hydrocodone B
haptens O
. O

Prescription O
opioids O
abuse O
and O
associated O
deaths O
are O
an O
emerging O
concern O
in O
the O
USA O
. O

Vaccination O
against O
prescription O
opioids O
may O
provide O
an O
alternative O
to O
pharmacotherapy O
. O

An O
oxycodone B
hapten O
containing O
a O
tetraglycine B
linker O
at O
the O
C6 O
position O
( O
6OXY B
( I
Gly I
) I
( I
4 I
) I
OH I
) O
conjugated O
to O
keyhole O
limpet O
hemocyanin O
( O
KLH O
) O
has O
shown O
early O
proof O
- O
of O
- O
efficacy O
in O
rodents O
as O
a O
candidate O
immunogen O
( O
6OXY B
( I
Gly I
) I
( O
4 O
) O
- O
KLH O
) O
for O
the O
treatment O
of O
oxycodone B
abuse O
. O

In O
this O
study O
, O
oxycodone B
- O
based O
and O
hydrocodone B
- O
based O
haptens O
were O
conjugated O
to O
KLH O
to O
generate O
immunogens O
that O
would O
recognize O
both O
oxycodone B
and O
hydrocodone B
. O

Vaccination O
with O
6OXY B
( I
Gly I
) I
( I
4 I
) I
- O
KLH O
increased O
drug O
binding O
in O
serum O
, O
reduced O
drug O
distribution O
to O
brain O
, O
and O
blunted O
analgesia O
for O
both O
oxycodone B
and O
hydrocodone B
. O

An O
analogous O
C6 B
- O
linked O
hydrocodone B
vaccine O
blocked O
hydrocodone B
effects O
but O
less O
so O
than O
6OXY B
( I
Gly I
) I
( I
4 I
) I
- I
KLH O
. O

C8 O
- O
Linked O
hydrocodone B
immunogens O
had O
only O
limited O
efficacy O
. O

Amide B
conjugation O
showed O
higher O
haptenation O
ratios O
and O
greater O
efficacy O
than O
thioether B
conjugation O
to O
maleimide B
activated O
KLH O
( O
mKLH O
) O
. O

The O
6OXY B
( I
Gly I
) I
( I
4 I
) I
- O
KLH O
vaccine O
may O
be O
used O
for O
treatment O
of O
prescription O
opioid O
abuse O
. O

Interactions O
of O
NO2 B
with O
Zr B
- O
based O
MOF O
: O
effects O
of O
the O
size O
of O
organic O
linkers O
on O
NO2 B
adsorption O
at O
ambient O
conditions O
. O

Zirconium B
- O
based O
metal O
organic O
framework O
( O
Zr B
- O
MOF O
) O
, O
UiO B
- I
66 I
and O
UiO B
- I
67 I
, O
were O
synthesized O
and O
used O
as O
adsorbents O
of O
NO B
( I
2 I
) I
at O
ambient O
temperatures O
in O
either O
dry O
or O
moist O
conditions O
. O

The O
samples O
were O
characterized O
before O
and O
after O
exposure O
to O
NO B
( I
2 I
) I
by O
X O
- O
ray O
diffraction O
, O
scanning O
electron O
microscopy O
, O
N O
( O
2 O
) O
- O
adsorption O
at O
77 O
K O
, O
thermal O
analysis O
, O
and O
infrared O
spectroscopy O
. O

The O
results O
indicate O
the O
important O
effect O
of O
a O
ligand O
size O
on O
the O
adsorption O
of O
NO B
( I
2 I
) I
on O
Zr B
- O
MOF O
materials O
. O

While O
the O
large O
size O
of O
the O
4 B
, I
4 I
- I
benzenebiphenyldicar I
acid I
( O
BDPC B
) O
ligand O
has O
a O
positive O
impact O
on O
the O
adsorption O
of O
NO B
( I
2 I
) I
on O
UiO B
- I
67 I
in O
moist O
conditions O
, O
the O
opposite O
effect O
is O
found O
in O
dry O
conditions O
. O

The O
large O
pore O
volume O
of O
UiO B
- I
67 I
enhances O
the O
adsorption O
of O
moisture O
and O
formation O
of O
nitric B
and I
nitrous I
acids I
. O

The O
small O
pore O
sizes O
of O
UiO B
- I
66 I
favor O
the O
NO B
( I
2 I
) I
removal O
in O
dry O
conditions O
via O
dispersive O
forces O
. O

Upon O
interaction O
of O
NO B
( I
2 I
) I
molecules O
with O
the O
Zr B
- O
MOF O
in O
dry O
conditions O
, O
the O
bond O
between O
the O
organic O
linker O
and O
metallic O
oxide B
center O
is O
broken O
, O
leading O
to O
the O
formation O
of O
nitrate B
and O
nitrite B
species O
. O

Moreover O
, O
organic O
ligands O
also O
contribute O
to O
the O
NO B
( I
2 I
) I
reactive O
adsorption O
via O
nitration O
reaction O
. O

Potent O
microRNA O
suppression O
by O
RNA O
Pol O
II O
- O
transcribed O
' O
Tough O
Decoy O
' O
inhibitors O
. O

MicroRNAs O
( O
miRNAs O
) O
are O
key O
regulators O
of O
gene O
expression O
and O
modulators O
of O
diverse O
biological O
pathways O
. O

Analyses O
of O
miRNA O
function O
as O
well O
as O
therapeutic O
managing O
of O
miRNAs O
rely O
on O
cellular O
administration O
of O
miRNA O
inhibitors O
which O
may O
be O
achieved O
by O
the O
use O
of O
viral O
vehicles O
. O

This O
study O
explores O
the O
miRNA O
- O
suppressive O
capacity O
of O
inhibitors O
expressed O
intracellularly O
from O
lentivirus O
- O
derived O
gene O
vectors O
. O

Superior O
activity O
of O
two O
decoy O
- O
type O
inhibitors O
, O
a O
" O
Bulged O
Sponge O
" O
with O
eight O
miRNA O
recognition O
sites O
and O
a O
hairpin O
- O
shaped O
" O
Tough O
Decoy O
" O
containing O
two O
miRNA O
recognition O
sites O
, O
is O
demonstrated O
in O
a O
side O
- O
by O
- O
side O
comparison O
of O
seven O
types O
of O
miRNA O
inhibitors O
transcribed O
as O
short O
RNAs O
from O
an O
RNA O
Pol O
III O
promoter O
. O

We O
find O
that O
lentiviral O
vectors O
expressing O
Tough O
Decoy O
inhibitors O
are O
less O
vulnerable O
than O
Bulged O
Sponge O
- O
encoding O
vectors O
to O
targeting O
by O
the O
cognate O
miRNA O
and O
less O
prone O
, O
therefore O
, O
to O
reductions O
in O
transfer O
efficiency O
. O

Importantly O
, O
it O
is O
demonstrated O
that O
Tough O
Decoy O
inhibitors O
retain O
their O
miRNA O
suppression O
capacity O
in O
the O
context O
of O
longer O
RNA O
transcripts O
expressed O
from O
an O
RNA O
Pol O
II O
promoter O
. O

Such O
RNA O
Pol O
II O
- O
transcribed O
Tough O
Decoy O
inhibitors O
are O
new O
tools O
in O
managing O
of O
miRNAs O
and O
may O
have O
potential O
for O
temporal O
and O
spatial O
regulation O
of O
miRNA O
activity O
as O
well O
as O
for O
therapeutic O
targeting O
of O
miRNAs O
that O
are O
aberrantly O
expressed O
in O
human O
disease O
. O

Androgens B
promote O
prostate O
cancer O
cell O
growth O
through O
induction O
of O
autophagy O
. O

Androgens B
regulate O
both O
the O
physiological O
development O
of O
the O
prostate O
and O
the O
pathology O
of O
prostatic O
diseases O
. O

However O
, O
the O
mechanisms O
by O
which O
androgens B
exert O
their O
regulatory O
activities O
on O
these O
processes O
are O
poorly O
understood O
. O

In O
this O
study O
, O
we O
have O
determined O
that O
androgens B
regulate O
overall O
cell O
metabolism O
and O
cell O
growth O
, O
in O
part O
, O
by O
increasing O
autophagy O
in O
prostate O
cancer O
cells O
. O

Importantly O
, O
inhibition O
of O
autophagy O
using O
either O
pharmacological O
or O
molecular O
inhibitors O
significantly O
abrogated O
androgen B
- O
induced O
prostate O
cancer O
cell O
growth O
. O

Mechanistically O
, O
androgen B
- O
mediated O
autophagy O
appears O
to O
promote O
cell O
growth O
by O
augmenting O
intracellular O
lipid O
accumulation O
, O
an O
effect O
previously O
demonstrated O
to O
be O
necessary O
for O
prostate O
cancer O
cell O
growth O
. O

Further O
, O
autophagy O
and O
subsequent O
cell O
growth O
is O
potentiated O
, O
in O
part O
, O
by O
androgen B
- O
mediated O
increases O
in O
reactive O
oxygen B
species O
. O

These O
findings O
demonstrate O
a O
role O
for O
increased O
fat O
metabolism O
and O
autophagy O
in O
prostatic O
neoplasias O
and O
highlight O
the O
potential O
of O
targeting O
underexplored O
metabolic O
pathways O
for O
the O
development O
of O
novel O
therapeutics O
. O

Regulation O
of O
H2O2 B
stress O
- O
responsive O
genes O
through O
a O
novel O
transcription O
factor O
in O
the O
protozoan O
pathogen O
Entamoeba O
histolytica O
. O

Outcome O
of O
infection O
depends O
upon O
complex O
interactions O
between O
the O
invading O
pathogen O
and O
the O
host O
. O

As O
part O
of O
the O
host O
' O
s O
innate O
immune O
response O
, O
the O
release O
of O
reactive O
oxygen B
and O
nitrogen B
species O
by O
phagocytes O
represents O
a O
major O
obstacle O
to O
the O
establishment O
of O
infection O
. O

The O
ability O
of O
the O
human O
parasite O
Entamoeba O
histolytica O
to O
survive O
reactive O
oxygen B
and O
nitrogen B
species O
is O
central O
to O
its O
pathogenic O
potential O
and O
contributes O
to O
disease O
outcome O
. O

In O
order O
to O
define O
the O
transcriptional O
network O
associated O
with O
oxidative O
stress O
, O
we O
utilized O
the O
MEME O
and O
MAST O
programs O
to O
analyze O
the O
promoter O
regions O
of O
57 O
amoebic O
genes O
that O
had O
increased O
expression O
specifically O
in O
response O
to O
H B
( I
2 I
) I
O I
( I
2 I
) I
exposure O
. O

We O
functionally O
characterized O
an O
H B
( I
2 I
) I
O I
( I
2 I
) I
- O
regulatory O
motif O
( O
HRM O
) O
( O
( O
1 O
) O
AAACCTCAATGAAGA O
( O
15 O
) O
) O
, O
which O
was O
enriched O
in O
these O
promoters O
and O
specifically O
bound O
amoebic O
nuclear O
protein O
( O
s O
) O
. O

Assays O
with O
promoter O
- O
luciferase O
fusions O
established O
the O
importance O
of O
key O
residues O
and O
that O
the O
HRM O
motif O
directly O
impacted O
the O
ability O
of O
H B
( I
2 I
) I
O I
( I
2 I
) I
- O
responsive O
promoters O
to O
drive O
gene O
expression O
. O

DNA O
affinity O
chromatography O
and O
mass O
spectrometry O
identified O
EHI O
_ O
108720 O
as O
an O
HRM O
DNA O
- O
binding O
protein O
. O

Overexpression O
and O
down O
- O
regulation O
of O
EHI O
_ O
108720 O
demonstrated O
the O
specificity O
of O
EHI O
_ O
108720 O
protein O
binding O
to O
the O
HRM O
, O
and O
overexpression O
increased O
basal O
expression O
from O
an O
H B
( I
2 I
) I
O I
( I
2 I
) I
- O
responsive O
wild O
- O
type O
promoter O
but O
not O
from O
its O
mutant O
counterpart O
. O

Thus O
, O
EHI O
_ O
108720 O
, O
or O
HRM O
- O
binding O
protein O
, O
represents O
a O
new O
stress O
- O
responsive O
transcription O
factor O
in O
E O
. O
histolytica O
that O
controls O
a O
transcriptional O
regulatory O
network O
associated O
with O
oxidative O
stress O
. O

Overexpression O
of O
EHI O
_ O
108720 O
increased O
parasite O
virulence O
. O

Insight O
into O
how O
E O
. O
histolytica O
responds O
to O
oxidative O
stress O
increases O
our O
understanding O
of O
how O
this O
important O
human O
pathogen O
establishes O
invasive O
disease O
. O

Palmitate B
and O
lipopolysaccharide O
trigger O
synergistic O
ceramide B
production O
in O
primary O
macrophages O
. O

Macrophages O
play O
a O
key O
role O
in O
host O
defense O
and O
in O
tissue O
repair O
after O
injury O
. O

Emerging O
evidence O
suggests O
that O
macrophage O
dysfunction O
in O
states O
of O
lipid O
excess O
can O
contribute O
to O
the O
development O
of O
insulin O
resistance O
and O
may O
underlie O
inflammatory O
complications O
of O
diabetes O
. O

Ceramides B
are O
sphingolipids B
that O
modulate O
a O
variety O
of O
cellular O
responses O
including O
cell O
death O
, O
autophagy O
, O
insulin O
signaling O
, O
and O
inflammation O
. O

In O
this O
study O
we O
investigated O
the O
intersection O
between O
TLR4 O
- O
mediated O
inflammatory O
signaling O
and O
saturated B
fatty I
acids I
with O
regard O
to O
ceramide B
generation O
. O

Primary O
macrophages O
treated O
with O
lipopolysaccharide O
( O
LPS O
) O
did O
not O
produce O
C16 B
ceramide I
, O
whereas O
palmitate B
exposure O
led O
to O
a O
modest O
increase O
in O
this O
sphingolipid B
. O

Strikingly O
, O
the O
combination O
of O
LPS O
and O
palmitate B
led O
to O
a O
synergistic O
increase O
in O
C16 B
ceramide I
. O

This O
response O
occurred O
via O
cross O
- O
talk O
at O
the O
level O
of O
de O
novo O
ceramide B
synthesis O
in O
the O
ER O
. O

The O
synergistic O
response O
required O
TLR4 O
signaling O
via O
MyD88 O
and O
TIR O
- O
domain O
- O
containing O
adaptor O
- O
inducing O
interferon O
beta O
( O
TRIF O
) O
, O
whereas O
palmitate B
- O
induced O
ceramide B
production O
occurred O
independent O
of O
these O
inflammatory O
molecules O
. O

This O
ceramide B
response O
augmented O
IL O
- O
1 O
beta O
and O
TNF O
alpha O
release O
, O
a O
process O
that O
may O
contribute O
to O
the O
enhanced O
inflammatory O
response O
in O
metabolic O
diseases O
characterized O
by O
dyslipidemia O
. O

Substituent O
effect O
in O
2 B
- I
benzoylmethylenequin I
difluoroborates I
exhibiting O
through O
- O
space O
couplings O
. O

Multinuclear O
magnetic O
resonance O
, O
X O
- O
ray O
diffraction O
, O
and O
computational O
study O
. O

The O
series O
of O
nine O
2 B
- I
benzoylmethylenequin I
difluoroborates I
have O
been O
synthesized O
and O
characterized O
by O
multinuclear O
magnetic O
resonance O
, O
X O
- O
ray O
diffraction O
( O
XRD O
) O
, O
and O
computational O
methods O
. O

The O
through O
- O
space O
spin O
- O
spin O
couplings O
between O
( B
19 I
) I
F I
and O
( B
1 I
) I
H I
/ O
( B
13 I
) I
C I
nuclei O
have O
been O
observed O
in O
solution O
. O

The O
NMR O
chemical O
shifts O
have O
been O
correlated O
to O
the O
Hammett O
substituent O
constants O
. O

The O
crystal O
structures O
of O
six O
compounds O
have O
been O
solved O
by O
XRD O
. O

For O
two O
derivatives O
the O
X O
- O
ray O
wave O
function O
refinement O
was O
performed O
to O
evaluate O
the O
character O
of O
bonds O
in O
the O
NBF B
( I
2 I
) I
O I
moiety O
by O
topological O
and O
integrated O
bond O
descriptors O
. O

Dynamic O
or O
nondynamic O
? O

Helical O
trajectory O
in O
hexabenzocoronene B
nanotubes O
biased O
by O
a O
detachable O
chiral O
auxiliary O
. O

When O
ether O
vapor O
was O
allowed O
to O
diffuse O
into O
a O
CH B
( I
2 I
) I
Cl I
( I
2 I
) I
solution O
of O
an O
enantiomer O
of O
a O
hexa B
- I
peri I
- I
hexabenzocoronene I
( O
HBC B
) O
derivative O
carrying O
a O
chiral O
( O
BINAP O
) O
Pt B
( I
II I
) I
- O
appended O
coordination O
metallacycle O
( O
HBC B
( I
Py I
) I
( O
[ B
( I
R I
) I
- I
Pt I
] I
) O
or O
HBC B
( I
Py I
) I
( O
[ B
( I
S I
) I
- I
Pt I
] I
) O
) O
, O
screw O
- O
sense O
- O
selective O
assembly O
took O
place O
to O
give O
optically O
active O
nanotubes O
( O
NT O
( O

Py I
) I
( O
[ B
( I
R I
) I
- I
Pt I
] I
) O
or O
NT B
( I
Py I
) I
( O
[ B
( I
S I
) I
- I
Pt I
] I
) O
) O
with O
helical O
chirality O
, O
which O
were O
enriched O
in O
either O
left O
- O
handed O
( B
M I
) I
- I
NT I
( I
Py I
) I
( O
[ B
( I
R I
) I
- I
Pt I
] I
) O
or O
right O
- O
handed O
( B
P I
) I
- I
NT I
( I
Py I
) I
( O
[ B
( I
S I
) I
- I
Pt I
] I
) O
, O
depending O
on O
the O
absolute O
configuration O
of O
the O
( B
BINAP I
) I
Pt I
( I
II I
) I
pendant O
. O

When O
MeOH B
was O
used O
instead O
of O
ether B
for O
the O
vapor O
- O
diffusion O
- O
induced O
assembly O
, O
nanocoils O
formed O
along O
with O
the O
nanotubes O
. O

As O
determined O
by O
scanning O
electron O
microscopy O
, O
the O
diastereomeric O
excess O
of O
the O
nanocoils O
was O
60 O
% O
( O
80 O
: O
20 O
diastereomeric O
ratio O
) O
. O

Removal O
of O
the O
( B
BINAP I
) I
Pt I
( I
II I
) I
pendants O
from O
NT B
( I
Py I
) I
( O
[ B
( I
R I
) I
- I
Pt I
] I
) O
or O
NT B
( I
Py I
) I
( O
[ B
( I
S I
) I
- I
Pt I
] I
) O
with O
ethylenediamine B
yielded O
metal O
- O
free O
nanotubes O
( O
NT B
( I
Py I
) I
) O
that O
remained O
optically O
active O
even O
upon O
heating O
without O
any O
change O
in O
the O
circular O
dichroism O
spectral O
profile O
. O

No O
helical O
inversion O
took O
place O
when O
NT B
( I
Py I
) I
derived O
from O
HBC B
( I
Py I
) I
( O
[ B
( I
R I
) I
- I
Pt I
] I
) O
or O
HBC B
( I
Py I
) I
( O
[ B
( I
S I
) I
- I
Pt I
] I
) O
was O
allowed O
to O
complex O
with O
( B
BINAP I
) I
Pt I
( I
II I
) I
with O
an O
absolute O
configuration O
opposite O
to O
the O
original O
one O
. O

Cooperative O
effects O
of O
drug O
- O
resistance O
mutations O
in O
the O
flap O
region O
of O
HIV O
- O
1 O
protease O
. O

Understanding O
the O
interdependence O
of O
multiple O
mutations O
in O
conferring O
drug O
resistance O
is O
crucial O
to O
the O
development O
of O
novel O
and O
robust O
inhibitors O
. O

As O
HIV O
- O
1 O
protease O
continues O
to O
adapt O
and O
evade O
inhibitors O
while O
still O
maintaining O
the O
ability O
to O
specifically O
recognize O
and O
efficiently O
cleave O
its O
substrates O
, O
the O
problem O
of O
drug O
resistance O
has O
become O
more O
complicated O
. O

Under O
the O
selective O
pressure O
of O
therapy O
, O
correlated O
mutations O
accumulate O
throughout O
the O
enzyme O
to O
compromise O
inhibitor O
binding O
, O
but O
characterizing O
their O
energetic O
interdependency O
is O
not O
straightforward O
. O

A O
particular O
drug O
resistant O
variant O
( O
L10I O
/ O
G48V O
/ O
I54V O
/ O
V82A O
) O
displays O
extreme O
entropy O
- O
enthalpy O
compensation O
relative O
to O
wild O
- O
type O
enzyme O
but O
a O
similar O
variant O
( O
L10I O
/ O
G48V O
/ O
I54A O
/ O
V82A O
) O
does O
not O
. O

Individual O
mutations O
of O
sites O
in O
the O
flaps O
( O
residues O
48 O
and O
54 O
) O
of O
the O
enzyme O
reveal O
that O
the O
thermodynamic O
effects O
are O
not O
additive O
. O

Rather O
, O
the O
thermodynamic O
profile O
of O
the O
variants O
is O
interdependent O
on O
the O
cooperative O
effects O
exerted O
by O
a O
particular O
combination O
of O
mutations O
simultaneously O
present O
. O

Exploring O
the O
sequence O
- O
structure O
relationship O
for O
amyloid O
peptides O
. O

Amyloid O
fibril O
formation O
is O
associated O
with O
misfolding O
diseases O
, O
as O
well O
as O
fulfilling O
a O
functional O
role O
. O

The O
cross O
- O
beta O
molecular O
architecture O
has O
been O
reported O
in O
increasing O
numbers O
of O
amyloid O
- O
like O
fibrillar O
systems O
. O

The O
Waltz O
algorithm O
is O
able O
to O
predict O
ordered O
self O
- O
assembly O
of O
amyloidogenic O
peptides O
by O
taking O
into O
account O
the O
residue O
type O
and O
position O
. O

This O
algorithm O
has O
expanded O
the O
amyloid O
sequence O
space O
, O
and O
in O
the O
present O
study O
we O
characterize O
the O
structures O
of O
amyloid O
- O
like O
fibrils O
formed O
by O
three O
peptides O
identified O
by O
Waltz O
that O
form O
fibrils O
but O
not O
crystals O
. O

The O
structural O
challenge O
is O
met O
by O
combining O
electron O
microscopy O
, O
linear O
dichroism O
, O
CD O
and O
X O
- O
ray O
fibre O
diffraction O
. O

We O
propose O
structures O
that O
reveal O
a O
cross O
- O
beta O
conformation O
with O
' O
steric O
- O
zipper O
' O
features O
, O
giving O
insights O
into O
the O
role O
for O
side O
chains O
in O
peptide O
packing O
and O
stability O
within O
fibrils O
. O

The O
amenity O
of O
these O
peptides O
to O
structural O
characterization O
makes O
them O
compelling O
model O
systems O
to O
use O
for O
understanding O
the O
relationship O
between O
sequence O
, O
self O
- O
assembly O
, O
stability O
and O
structure O
of O
amyloid O
fibrils O
. O

Chemical O
Modification O
of O
Lysozyme O
, O
Glucose B
6 I
- I
Phosphate I
Dehydrogenase O
, O
and O
Bovine O
Eye O
Lens O
Proteins O
Induced O
by O
Peroxyl B
Radicals O
: O
Role O
of O
Oxidizable O
Amino B
Acid I
Residues O
. O

Chemical O
and O
structural O
alterations O
to O
lysozyme O
( O
LYSO O
) O
, O
glucose B
6 I
- I
phosphate I
dehydrogenase O
( O
G6PD O
) O
, O
and O
bovine O
eye O
lens O
proteins O
( O
BLP O
) O
promoted O
by O
peroxyl B
radicals O
generated O
by O
the O
thermal O
decomposition O
of O
2 B
, I
2 I
' I
- I
azobis I
( I
2 I
- I
amidinopropane I
) I
hydrochloride I
( O
AAPH B
) O
under O
aerobic O
conditions O
were O
investigated O
. O

SDS B
- O
PAGE O
analysis O
of O
the O
AAPH B
- O
treated O
proteins O
revealed O
the O
occurrence O
of O
protein O
aggregation O
, O
cross O
- O
linking O
, O
and O
fragmentation O
; O
BLP O
, O
which O
are O
naturally O
organized O
in O
globular O
assemblies O
, O
were O
the O
most O
affected O
proteins O
. O

Transmission O
electron O
microscopy O
( O
TEM O
) O
analysis O
of O
BLP O
shows O
the O
formation O
of O
complex O
protein O
aggregates O
after O
treatment O
with O
AAPH B
. O

These O
structural O
modifications O
were O
accompanied O
by O
the O
formation O
of O
protein O
carbonyl B
groups O
and O
protein O
hydroperoxides B
. O

The O
yield O
of O
carbonyls B
was O
lower O
than O
that O
for O
protein O
hydroperoxide B
generation O
and O
was O
unrelated O
to O
protein O
fragmentation O
. O

The O
oxidized O
proteins O
were O
also O
characterized O
by O
significant O
oxidation O
of O
Met B
, O
Trp B
, O
and O
Tyr B
( O
but O
not O
other O
) O
residues O
, O
and O
low O
levels O
of O
dityrosine B
. O

As O
the O
dityrosine B
yield O
is O
too O
low O
to O
account O
for O
the O
observed O
cross O
- O
linking O
, O
we O
propose O
that O
aggregation O
is O
associated O
with O
tryptophan B
oxidation O
and O
Trp B
- O
derived O
cross O
- O
links O
. O

It O
is O
also O
proposed O
that O
Trp B
oxidation O
products O
play O
a O
fundamental O
role O
in O
nonrandom O
fragmentation O
and O
carbonyl B
group O
formation O
particularly O
for O
LYSO O
and O
G6PD O
. O

These O
data O
point O
to O
a O
complex O
mechanism O
of O
peroxyl B
- O
radical O
mediated O
modification O
of O
proteins O
with O
monomeric O
( O
LYSO O
) O
, O
dimeric O
( O
G6PD O
) O
, O
and O
multimeric O
( O
BLP O
) O
structural O
organization O
, O
which O
not O
only O
results O
in O
oxidation O
of O
protein O
side O
chains O
but O
also O
gives O
rise O
to O
radical O
- O
mediated O
protein O
cross O
- O
links O
and O
fragmentation O
, O
with O
Trp B
species O
being O
critical O
intermediates O
. O

Comparative O
structural O
and O
functional O
studies O
of O
4 B
- I
( I
thiazol I
- I
5 I
- I
yl I
) I
- I
2 I
- I
( I
phenylamino I
) I
pyrimidine I
- I
5 I
- I
carbonitrile I
CDK9 O
inhibitors O
suggest O
the O
basis O
for O
isotype O
selectivity O
. O

Cyclin O
- O
dependent O
kinase O
9 O
/ O
cyclin O
T O
, O
the O
protein O
kinase O
heterodimer O
that O
constitutes O
positive O
transcription O
elongation O
factor O
b O
, O
is O
a O
well O
- O
validated O
target O
for O
treatment O
of O
several O
diseases O
, O
including O
cancer O
and O
cardiac O
hypertrophy O
. O

In O
order O
to O
aid O
inhibitor O
design O
and O
rationalize O
the O
basis O
for O
CDK9 O
selectivity O
, O
we O
have O
studied O
the O
CDK O
- O
binding O
properties O
of O
six O
different O
members O
of O
a O
4 B
- I
( I
thiazol I
- I
5 I
- I
yl I
) I
- I
2 I
- I
( I
phenylamino I
) I
pyrimidine I
- I
5 I
- I
carbonitrile I
series O
that O
bind O
to O
both O
CDK9 O
/ O
cyclin O
T O
and O
CDK2 O
/ O
cyclin O
A O
. O

We O
find O
that O
for O
a O
given O
CDK O
, O
the O
melting O
temperature O
of O
a O
CDK O
/ O
cyclin O
/ O
inhibitor O
complex O
correlates O
well O
with O
inhibitor O
potency O
, O
suggesting O
that O
differential O
scanning O
fluorimetry O
( O
DSF O
) O
is O
a O
useful O
orthogonal O
measure O
of O
inhibitory O
activity O
for O
this O
series O
. O

We O
have O
used O
DSF O
to O
demonstrate O
that O
the O
binding O
of O
these O
compounds O
is O
independent O
of O
the O
presence O
or O
absence O
of O
the O
C B
- O
terminal O
tail O
region O
of O
CDK9 O
, O
unlike O
the O
binding O
of O
the O
CDK9 O
- O
selective O
inhibitor O
5 B
, I
6 I
- I
dichlorobenzimidazon I
- I
1 I
- I
beta I
- I
d I
- I
ribofuranoside I
( O
DRB B
) O
. O

Finally O
, O
on O
the O
basis O
of O
11 O
cocrystal O
structures O
bound O
to O
CDK9 O
/ O
cyclin O
T O
or O
CDK2 O
/ O
cyclin O
A O
, O
we O
conclude O
that O
selective O
inhibition O
of O
CDK9 O
/ O
cyclin O
T O
by O
members O
of O
the O
4 B
- I
( I
thiazol I
- I
5 I
- I
yl I
) I
- I
2 I
- I
( I
phenylamino I
) I
pyrimidine I
- I
5 I
- I
carbonitrile I
series O
results O
from O
the O
relative O
malleability O
of O
the O
CDK9 O
active O
site O
rather O
than O
from O
the O
formation O
of O
specific O
polar O
contacts O
. O

Development O
of O
new O
cathepsin O
B O
inhibitors O
: O
combining O
bioisosteric O
replacements O
and O
structure O
- O
based O
design O
to O
explore O
the O
structure O
- O
activity O
relationships O
of O
nitroxoline B
derivatives O
. O

Human O
cathepsin O
B O
has O
many O
house O
- O
keeping O
functions O
, O
such O
as O
protein O
turnover O
in O
lysosomes O
. O

However O
, O
dysregulation O
of O
its O
activity O
is O
associated O
with O
numerous O
diseases O
, O
including O
cancers O
. O

We O
present O
here O
the O
structure O
- O
based O
design O
and O
synthesis O
of O
new O
cathepsin O
B O
inhibitors O
using O
the O
cocrystal O
structure O
of O
5 B
- I
nitro I
- I
8 I
- I
hydroxyquinoline I
in O
the O
cathepsin O
B O
active O
site O
. O

A O
focused O
library O
of O
over O
50 O
compounds O
was O
prepared O
by O
modifying O
positions O
5 O
, O
7 O
, O
and O
8 O
of O
the O
parent O
compound O
nitroxoline B
. O

The O
kinetic O
parameters O
and O
modes O
of O
inhibition O
were O
characterized O
, O
and O
the O
selectivities O
of O
the O
most O
promising O
inhibitors O
were O
determined O
. O

The O
best O
performing O
inhibitor O
17 O
was O
effective O
in O
cell O
- O
based O
in O
vitro O
models O
of O
tumor O
invasion O
, O
where O
it O
significantly O
abrogated O
invasion O
of O
MCF O
- O
10A O
neoT O
cells O
. O

These O
data O
show O
that O
we O
have O
successfully O
explored O
the O
structure O
- O
activity O
relationships O
of O
nitroxoline B
derivatives O
to O
provide O
new O
inhibitors O
that O
could O
eventually O
lead O
to O
compounds O
with O
clinical O
usefulness O
against O
the O
deleterious O
effects O
of O
cathepsin O
B O
in O
cancer O
progression O
. O

Adverse O
events O
associated O
with O
mTOR O
inhibitors O
. O

INTRODUCTION O
: O
The O
mTOR O
( O
mechanistic O
target O
of O
rapamycin B
, O
formerly O
known O
as O
mammalian O
target O
of O
rapamycin B
) O
kinase O
is O
centrally O
involved O
in O
the O
regulation O
of O
cell O
growth O
and O
metabolism O
in O
response O
to O
intra O
- O
and O
extracellular O
energetic O
stimuli O
and O
growth O
factors O
. O

The O
importance O
of O
mTOR O
in O
health O
and O
diseases O
has O
fueled O
the O
development O
of O
molecules O
that O
inhibit O
mTOR O
signaling O
, O
including O
rapalogs O
( O
sirolimus B
, O
temsirolimus B
, O
everolimus B
and O
deforolimus B
) O
, O
which O
complex O
with O
FK506 B
- O
binding O
protein O
12 O
( O
FK O
- O
BP12 O
) O
to O
inhibit O
mTOR O
complex O
1 O
( O
MTORC1 O
) O
activity O
in O
an O
allosteric O
manner O
, O
or O
the O
more O
recent O
ATP B
- O
competitive O
mTOR O
inhibitors O
( O
mTORi O
) O
, O
which O
target O
the O
catalytic O
site O
of O
the O
enzyme O
. O

However O
, O
clinical O
development O
of O
these O
mTORi O
has O
revealed O
that O
these O
drugs O
produced O
numerous O
side O
effects O
that O
could O
be O
serious O
and O
/ O
or O
debilitating O
. O

Despite O
pharmacological O
efforts O
to O
develop O
drugs O
with O
an O
improved O
safety O
profile O
, O
these O
side O
effects O
are O
often O
unpredictable O
and O
may O
frequently O
preclude O
the O
efficiency O
of O
mTORi O
. O

AREAS O
COVERED O
: O
The O
objective O
of O
this O
review O
is O
to O
perform O
a O
comprehensive O
survey O
of O
the O
safety O
profiles O
of O
various O
rapalog O
- O
based O
therapies O
from O
the O
available O
clinical O
literature O
. O

The O
authors O
will O
discuss O
the O
potential O
mechanisms O
of O
these O
therapies O
, O
taking O
into O
account O
the O
knowledge O
of O
the O
biological O
pathways O
regulated O
by O
mTOR O
. O

EXPERT O
OPINION O
: O
A O
better O
prevention O
and O
management O
of O
mTORi O
- O
related O
side O
effects O
requires O
the O
identification O
of O
alterations O
in O
related O
biological O
pathways O
that O
will O
help O
to O
delineate O
therapeutic O
targets O
. O

Dependence O
of O
QSAR O
models O
on O
the O
selection O
of O
trial O
descriptor O
sets O
: O
a O
demonstration O
using O
nanotoxicity O
endpoints O
of O
decorated O
nanotubes O
. O

Little O
attention O
has O
been O
given O
to O
the O
selection O
of O
trial O
descriptor O
sets O
when O
designing O
a O
QSAR O
analysis O
even O
though O
a O
great O
number O
of O
descriptor O
classes O
, O
and O
often O
a O
greater O
number O
of O
descriptors O
within O
a O
given O
class O
, O
are O
now O
available O
. O

This O
paper O
reports O
an O
effort O
to O
explore O
interrelationships O
between O
QSAR O
models O
and O
descriptor O
sets O
. O

Zhou O
and O
co O
- O
workers O
( O
Zhou O
et O
al O
. O
, O
Nano O
Lett O
. O
2008 O
, O
8 O
( O
3 O
) O
, O
859 O
- O
865 O
) O
designed O
, O
synthesized O
, O
and O
tested O
a O
combinatorial O
library O
of O
80 O
surface O
modified O
, O
that O
is O
decorated O
, O
multi O
- O
walled O
carbon B
nanotubes O
for O
their O
composite O
nanotoxicity O
using O
six O
endpoints O
all O
based O
on O
a O
common O
0 O
to O
100 O
activity O
scale O
. O

Each O
of O
the O
six O
endpoints O
for O
the O
29 O
most O
nanotoxic O
decorated O
nanotubes O
were O
incorporated O
as O
the O
training O
set O
for O
this O
study O
. O

The O
study O
reported O
here O
includes O
trial O
descriptor O
sets O
for O
all O
possible O
combinations O
of O
MOE O
, O
VolSurf O
, O
and O
4D O
- O
fingerprints O
( O
FP O
) O
descriptor O
classes O
, O
as O
well O
as O
including O
and O
excluding O
explicit O
spatial O
contributions O
from O
the O
nanotube O
. O

Optimized O
QSAR O
models O
were O
constructed O
from O
these O
multiple O
trial O
descriptor O
sets O
. O

It O
was O
found O
that O
( O
a O
) O
both O
the O
form O
and O
quality O
of O
the O
best O
QSAR O
models O
for O
each O
of O
the O
endpoints O
are O
distinct O
and O
( O
b O
) O
some O
endpoints O
are O
quite O
dependent O
upon O
4D O
- O
FP O
descriptors O
of O
the O
entire O
nanotube O
- O
decorator O
complex O
. O

However O
, O
other O
endpoints O
yielded O
equally O
good O
models O
only O
using O
decorator O
descriptors O
with O
and O
without O
the O
decorator O
- O
only O
4D O
- O
FP O
descriptors O
. O

Lastly O
, O
and O
most O
importantly O
, O
the O
quality O
, O
significance O
, O
and O
interpretation O
of O
a O
QSAR O
model O
were O
found O
to O
be O
critically O
dependent O
on O
the O
trial O
descriptor O
sets O
used O
within O
a O
given O
QSAR O
endpoint O
study O
. O

Towards O
a O
balanced O
value O
business O
model O
for O
personalized O
medicine O
: O
an O
outlook O
. O

Novel O
targeted O
drugs O
, O
mainly O
in O
oncology O
, O
have O
commanded O
substantial O
price O
premiums O
in O
the O
recent O
past O
. O

Consequently O
, O
the O
attention O
of O
pharmaceutical O
companies O
has O
shifted O
away O
from O
the O
traditional O
low O
- O
price O
and O
high O
- O
volume O
blockbuster O
business O
model O
to O
drugs O
that O
command O
high O
, O
and O
sometimes O
extremely O
high O
, O
prices O
in O
limited O
markets O
defined O
by O
targeted O
patient O
populations O
. O

This O
model O
may O
have O
already O
passed O
its O
zenith O
, O
as O
the O
impact O
of O
more O
and O
more O
high O
- O
priced O
drugs O
coming O
to O
market O
substantially O
increases O
their O
combined O
burden O
on O
payors O
and O
public O
health O
finances O
. O

This O
article O
introduces O
a O
new O
' O
balanced O
value O
' O
business O
model O
for O
personalized O
medicine O
, O
leveraging O
the O
emerging O
opportunities O
to O
reduce O
drug O
development O
cost O
and O
time O
for O
targeted O
therapies O
. O

This O
model O
allows O
pharmaceutical O
companies O
to O
charge O
prices O
for O
targeted O
therapy O
below O
the O
likely O
future O
thresholds O
for O
payors O
' O
willingness O
to O
pay O
, O
at O
the O
same O
time O
preserving O
attractive O
margins O
for O
the O
drug O
developers O
. O

Improving O
clinical O
trial O
sampling O
for O
future O
research O
- O
an O
international O
approach O
: O
outcomes O
and O
next O
steps O
from O
the O
DIA O
future O
use O
sampling O
workshop O
2011 O
. O

Clinical O
trial O
samples O
collected O
for O
pharmacogenomic O
and O
future O
research O
are O
vital O
resources O
for O
the O
development O
of O
safe O
and O
effective O
drugs O
, O
yet O
collecting O
adequate O
, O
representative O
sample O
sets O
in O
global O
trials O
is O
challenging O
. O

The O
Drug O
Information O
Association O
( O
DIA O
) O
sponsored O
a O
workshop O
on O
future O
use O
sampling O
in O
September O
2011 O
, O
bringing O
together O
experts O
from O
regulatory O
agencies O
, O
academia O
and O
industry O
to O
discuss O
challenges O
to O
future O
use O
sample O
collection O
and O
identify O
actions O
to O
improve O
collection O
. O

Several O
common O
themes O
and O
associated O
action O
items O
emerged O
, O
including O
the O
need O
for O
international O
guidance O
on O
the O
collection O
of O
samples O
for O
future O
research O
; O
additional O
discussion O
related O
to O
coding O
, O
scope O
of O
research O
, O
and O
return O
of O
research O
results O
; O
and O
additional O
education O
about O
pharmacogenomic O
/ O
future O
research O
and O
the O
importance O
of O
long O
- O
term O
storage O
of O
specimens O
. O

Expanding O
the O
number O
of O
' O
druggable O
' O
targets O
: O
non O
- O
enzymes O
and O
protein O
- O
protein O
interactions O
. O

Following O
sequencing O
and O
assembly O
of O
the O
human O
genome O
, O
the O
preferred O
methods O
for O
identification O
of O
new O
drug O
targets O
have O
changed O
dramatically O
. O

Modern O
tactics O
such O
as O
genome O
- O
wide O
association O
studies O
( O
GWAS O
) O
and O
deep O
sequencing O
are O
fundamentally O
different O
from O
the O
pharmacology O
- O
guided O
approaches O
used O
previously O
, O
in O
which O
knowledge O
of O
small O
molecule O
ligands O
acting O
at O
their O
cellular O
targets O
was O
the O
primary O
discovery O
engine O
. O

A O
consequence O
of O
the O
' O
target O
- O
first O
, O
pharmacology O
- O
second O
' O
strategy O
is O
that O
many O
predicted O
drug O
targets O
are O
non O
- O
enzymes O
, O
such O
as O
scaffolding O
, O
regulatory O
or O
structural O
proteins O
, O
and O
their O
activities O
are O
often O
dependent O
on O
protein O
- O
protein O
interactions O
( O
PPIs O
) O
. O

These O
types O
of O
targets O
create O
unique O
challenges O
to O
drug O
discovery O
efforts O
because O
enzymatic O
turnover O
cannot O
be O
used O
as O
a O
convenient O
surrogate O
for O
compound O
potency O
. O

Moreover O
, O
it O
is O
often O
challenging O
to O
predict O
how O
ligand O
binding O
to O
non O
- O
enzymes O
might O
affect O
changes O
in O
protein O
function O
and O
/ O
or O
pathobiology O
. O

Thus O
, O
in O
the O
postgenomic O
era O
, O
targets O
might O
be O
strongly O
implicated O
by O
molecular O
biology O
- O
based O
methods O
, O
yet O
they O
often O
later O
earn O
the O
designation O
of O
' O
undruggable O
' O
. O

Can O
the O
scope O
of O
available O
targets O
be O
widened O
to O
include O
these O
promising O
, O
but O
challenging O
, O
non O
- O
enzymes O
? O

In O
this O
review O
, O
we O
discuss O
advances O
in O
high O
- O
throughput O
screening O
( O
HTS O
) O
technology O
and O
chemical O
library O
design O
that O
are O
emerging O
to O
deal O
with O
these O
challenges O
. O

Antibody O
- O
drug O
conjugates O
for O
the O
treatment O
of O
cancer O
. O

With O
over O
20 O
antibody O
- O
drug O
conjugates O
in O
clinical O
trials O
as O
well O
as O
a O
recently O
FDA O
- O
approved O
drug O
, O
it O
is O
clear O
that O
this O
is O
becoming O
an O
important O
and O
viable O
approach O
for O
selectively O
delivering O
highly O
cytotoxic O
agents O
to O
tumor O
cells O
while O
sparing O
normal O
tissue O
. O

This O
review O
discusses O
the O
critical O
aspects O
for O
this O
approach O
with O
an O
emphasis O
on O
the O
properties O
of O
the O
linker O
between O
the O
antibody O
and O
the O
cytotoxic O
payload O
that O
are O
required O
for O
an O
effective O
antibody O
- O
drug O
conjugate O
. O

Different O
linkers O
are O
illustrated O
with O
attention O
focused O
on O
( O
i O
) O
the O
specifics O
of O
attachment O
to O
the O
antibody O
, O
( O
ii O
) O
the O
polarity O
of O
the O
linker O
, O
( O
iii O
) O
the O
trigger O
on O
the O
linker O
that O
initiates O
cleavage O
from O
the O
drug O
, O
and O
( O
iv O
) O
the O
self O
- O
immolative O
spacer O
that O
liberates O
the O
active O
payload O
. O

Future O
directions O
in O
the O
field O
are O
proposed O
. O

Peptide O
scanning O
for O
studying O
structure O
- O
activity O
relationships O
in O
drug O
discovery O
. O

Peptide O
- O
based O
therapeutics O
have O
grown O
in O
importance O
over O
the O
last O
few O
decades O
. O

Furthermore O
, O
peptides O
have O
been O
extensively O
used O
as O
lead O
compounds O
in O
the O
drug O
discovery O
process O
to O
investigate O
the O
nature O
of O
chemical O
space O
required O
for O
molecular O
recognition O
and O
activity O
at O
a O
variety O
of O
targets O
. O

This O
critical O
commentary O
reviews O
scanning O
techniques O
, O
which O
employ O
natural O
and O
non O
- O
proteinogenic O
amino B
acids I
to O
facilitate O
understanding O
of O
structural O
requirements O
for O
peptide O
biological O
activity O
. O

The O
value O
of O
sequence O
analysis O
by O
such O
methods O
is O
highlighted O
by O
examples O
, O
in O
which O
the O
elements O
for O
peptide O
affinity O
and O
activity O
have O
been O
elucidated O
and O
employed O
to O
prepare O
peptidomimetic O
leads O
for O
drug O
development O
. O

Neurochemical O
control O
of O
rapid O
stress O
- O
induced O
changes O
in O
brain O
aromatase O
activity O
. O

In O
the O
male O
brain O
, O
the O
medial O
preoptic O
nucleus O
( O
POM O
) O
is O
known O
to O
be O
a O
critical O
relay O
for O
the O
activation O
of O
sexual O
behaviour O
, O
with O
the O
aromatisation O
of O
testosterone B
into O
17 B
beta I
- I
oestradiol I
( O
E2 O
) O
playing O
a O
key O
role O
. O

Acute O
stress O
has O
been O
shown O
to O
differentially O
modulate O
the O
aromatase O
enzyme O
in O
this O
and O
other O
brain O
nuclei O
in O
a O
sex O
- O
specific O
manner O
. O

In O
POM O
specifically O
, O
stress O
induces O
increases O
in O
aromatase O
activity O
( O
AA O
) O
that O
are O
both O
rapid O
and O
reversible O
. O

How O
the O
physiological O
processes O
initiated O
during O
an O
acute O
stress O
response O
mediate O
sex O
- O
and O
nuclei O
- O
specific O
changes O
in O
AA O
and O
which O
stress O
response O
hormones O
are O
involved O
remains O
to O
be O
determined O
. O

By O
examining O
the O
relative O
effects O
of O
corticosterone B
( O
CORT B
) O
, O
arginine B
vasotocin I
( O
AVT B
, O
the O
avian O
homologue O
to O
arginine B
vasopressin I
) O
and O
corticotrophin O
- O
releasing O
factor O
( O
CRF O
) O
, O
the O
present O
study O
aimed O
to O
define O
the O
hormone O
profile O
regulating O
stress O
- O
induced O
increases O
in O
AA O
in O
the O
POM O
. O

We O
found O
that O
CORT B
, O
AVT B
and O
CRF O
all O
appear O
to O
play O
some O
role O
in O
these O
changes O
in O
the O
male O
brain O
. O

In O
addition O
, O
these O
effects O
occur O
in O
a O
targeted O
manner O
, O
such O
that O
modulation O
of O
the O
enzyme O
by O
these O
hormones O
only O
occurs O
in O
the O
POM O
rather O
than O
in O
all O
aromatase O
- O
expressing O
nuclei O
. O

Similarly O
, O
in O
the O
female O
brain O
, O
the O
experimental O
effects O
were O
restricted O
to O
the O
POM O
but O
only O
CRF O
was O
capable O
of O
inducing O
the O
stress O
- O
like O
increases O
in O
AA O
. O

These O
data O
further O
demonstrate O
the O
high O
degree O
of O
specificity O
( O
nuclei O
- O
, O
sex O
- O
and O
hormone O
- O
specific O
effects O
) O
in O
this O
system O
, O
highlighting O
the O
complexity O
of O
the O
stress O
- O
aromatase O
link O
and O
suggesting O
modes O
through O
which O
the O
nongenomic O
modulation O
of O
this O
enzyme O
can O
result O
in O
targeted O
, O
rapid O
changes O
in O
local O
oestrogen B
concentrations O
. O

Assessment O
of O
the O
usefulness O
of O
the O
murine O
cytotoxic O
T O
cell O
line O
CTLL O
- O
2 O
for O
immunotoxicity O
screening O
by O
transcriptomics O
. O

A O
toxicogenomics O
approach O
was O
applied O
to O
assess O
the O
usefulness O
of O
the O
mouse O
cytotoxic O
T O
cell O
line O
CTLL O
- O
2 O
for O
in O
vitro O
immunotoxicity O
testing O
. O

CTLL O
- O
2 O
cells O
were O
exposed O
for O
6 O
h O
to O
two O
model O
immunotoxic O
compounds O
: O
( O
1 O
) O
the O
mycotoxin O
deoxynivalenol B
( O
DON B
, O
1 O
and O
2 O
mu O
M O
) O
, O
a O
ribotoxic O
stress O
inducer O
, O
and O
( O
2 O
) O
the O
organotin B
compound O
tributyltin B
oxide I
( O
TBTO B
, O
100 O
and O
200 O
nM O
) O
, O
an O
endoplasmic O
reticulum O
( O
ER O
) O
stress O
inducer O
. O

Effects O
on O
whole O
- O
genome O
mRNA O
expression O
were O
assessed O
by O
microarray O
analysis O
. O

The O
biological O
interpretation O
of O
the O
microarray O
data O
indicated O
that O
TBTO B
( O
200 O
nM O
) O
induced O
genes O
involved O
in O
T O
cell O
activation O
, O
ER O
stress O
, O
NF O
kappa O
B O
activation O
and O
apoptosis O
, O
which O
agreed O
very O
well O
with O
results O
obtained O
before O
on O
TBTO B
exposed O
Jurkat O
cells O
and O
mouse O
primary O
thymocytes O
. O

Remarkably O
, O
DON B
( O
2 O
mu O
M O
) O
downregulated O
genes O
involved O
in O
T O
cell O
activation O
, O
ER O
stress O
and O
apoptosis O
, O
which O
is O
opposite O
to O
results O
obtained O
before O
for O
DON B
- O
exposed O
Jurkat O
cells O
and O
mouse O
primary O
thymocytes O
. O

Furthermore O
, O
the O
results O
for O
DON B
in O
CTLL O
- O
2 O
cells O
are O
also O
opposite O
to O
the O
results O
obtained O
for O
TBTO B
in O
CTLL O
- O
2 O
cells O
. O

In O
agreement O
with O
the O
lack O
of O
induction O
of O
ER O
stress O
and O
apoptosis O
, O
viability O
assays O
showed O
that O
CTLL O
- O
2 O
cells O
are O
much O
more O
resistant O
to O
the O
toxicity O
of O
DON B
than O
Jurkat O
cells O
and O
primary O
thymocytes O
. O

We O
propose O
that O
CTLL O
- O
2 O
cells O
lack O
the O
signal O
transduction O
that O
induces O
ER O
stress O
and O
apoptosis O
in O
response O
to O
ribotoxic O
stress O
. O

Based O
on O
the O
results O
for O
TBTO B
and O
DON B
, O
the O
CTLL O
- O
2 O
cell O
line O
does O
not O
yield O
an O
added O
value O
for O
immunotoxicity O
compared O
to O
the O
human O
Jurkat O
T O
cell O
line O
. O

Effect O
of O
lactation O
on O
postpartum O
cardiac O
function O
of O
pregnancy O
- O
associated O
hypertensive O
mice O
. O

Preeclampsia O
is O
a O
serious O
complication O
during O
pregnancy O
, O
and O
recent O
epidemiological O
studies O
indicate O
the O
association O
between O
preeclampsia O
and O
cardiac O
morbidity O
and O
mortality O
during O
the O
postpartum O
period O
. O

Although O
the O
risk O
of O
cardiovascular O
diseases O
in O
the O
postpartum O
period O
is O
affected O
by O
lactation O
, O
its O
role O
in O
maternal O
heart O
with O
a O
history O
of O
preeclampsia O
remains O
unclear O
. O

In O
this O
study O
, O
we O
investigated O
postpartum O
change O
in O
cardiac O
remodeling O
and O
function O
of O
pregnancy O
- O
associated O
hypertensive O
( O
PAH O
) O
mice O
with O
and O
without O
lactation O
. O

The O
systolic O
blood O
pressure O
was O
increased O
in O
PAH O
mice O
at O
day O
19 O
of O
gestation O
( O
E19 O
) O
and O
was O
reduced O
to O
normal O
levels O
in O
both O
lactating O
and O
nonlactating O
( O
NL O
) O
groups O
in O
the O
postpartum O
period O
. O

Histological O
analyses O
revealed O
that O
cardiac O
hypertrophy O
and O
macrophage O
infiltration O
in O
PAH O
mice O
at O
E19 O
were O
improved O
in O
both O
lactating O
and O
NL O
groups O
at O
4 O
weeks O
postpartum O
( O
4W O
- O
PP O
) O
, O
while O
marked O
fibrosis O
remained O
. O

Increased O
mRNA O
expression O
of O
profibrotic O
genes O
and O
proinflammatory O
cytokines O
in O
PAH O
mice O
at O
E19 O
was O
significantly O
reduced O
in O
both O
lactating O
and O
NL O
groups O
at O
4W O
- O
PP O
. O

Echocardiographic O
analysis O
found O
no O
significant O
differences O
in O
fractional O
shortening O
between O
PAH O
mice O
and O
C57BL O
/ O
6J O
mice O
at O
E19 O
. O

On O
the O
other O
hand O
, O
at O
4W O
- O
PP O
, O
NL O
PAH O
mice O
showed O
normal O
fractional O
shortening O
, O
but O
lactating O
PAH O
mice O
exhibited O
significant O
decreases O
in O
cardiac O
contractility O
compared O
with O
NL O
PAH O
mice O
. O

These O
results O
show O
that O
cardiac O
remodeling O
induced O
by O
hypertension O
during O
pregnancy O
are O
improved O
in O
the O
postpartum O
period O
except O
fibrosis O
, O
whereas O
lactation O
induces O
cardiac O
contractile O
dysfunction O
in O
mice O
with O
a O
history O
of O
pregnancy O
- O
associated O
hypertension O
. O

Focal O
adhesion O
size O
uniquely O
predicts O
cell O
migration O
. O

Focal O
adhesions O
are O
large O
protein O
complexes O
organized O
at O
the O
basal O
surface O
of O
cells O
, O
which O
physically O
connect O
the O
extracellular O
matrix O
to O
the O
cytoskeleton O
and O
have O
long O
been O
speculated O
to O
mediate O
cell O
migration O
. O

However O
, O
whether O
clustering O
of O
these O
molecular O
components O
into O
focal O
adhesions O
is O
actually O
required O
for O
these O
proteins O
to O
regulate O
cell O
motility O
is O
unclear O
. O

Here O
we O
use O
quantitative O
microscopy O
to O
characterize O
descriptors O
of O
focal O
adhesion O
and O
cell O
motility O
for O
mouse O
embryonic O
fibroblasts O
and O
human O
fibrosarcoma O
cells O
, O
across O
a O
wide O
range O
of O
matrix O
compliance O
and O
following O
genetic O
manipulations O
of O
focal O
adhesion O
proteins O
( O
vinculin O
, O
talin O
, O
zyxin O
, O
FAK O
, O
and O
paxilin O
) O
. O

This O
analysis O
reveals O
a O
tight O
, O
biphasic O
gaussian O
relationship O
between O
mean O
size O
of O
focal O
adhesions O
( O
not O
their O
number O
, O
surface O
density O
, O
or O
shape O
) O
and O
cell O
speed O
. O

The O
predictive O
power O
of O
this O
relationship O
is O
comprehensively O
validated O
by O
disrupting O
nonfocal O
adhesion O
proteins O
( O
alpha O
- O
actinin O
, O
F O
- O
actin O
, O
and O
myosin O
II O
) O
and O
subcellular O
organelles O
( O
mitochondria O
, O
nuclear O
DNA O
, O
etc O
. O
) O
not O
known O
to O
affect O
either O
focal O
adhesions O
or O
cell O
migration O
. O

This O
study O
suggests O
that O
the O
mean O
size O
of O
focal O
adhesions O
robustly O
and O
precisely O
predicts O
cell O
speed O
independently O
of O
focal O
adhesion O
surface O
density O
and O
molecular O
composition O
. O
- O
Kim O
, O
D O
. O
- O
H O
. O
, O
Wirtz O
, O
D O
. O

Focal O
adhesion O
size O
uniquely O
predicts O
cell O
migration O
. O

Formation O
and O
infrared O
absorption O
of O
protonated O
naphthalenes B
( O
1 B
- I
C10H9 I
+ I
and O
2 B
- I
C10H9 I
+ I
) O
and O
their O
neutral O
counterparts O
in O
solid O
para B
- I
hydrogen I
. O

Protonated O
naphthalene B
( O
C B
( I
10 I
) I
H I
( I
9 I
) I
( I
+ I
) I
) O
and O
its O
neutral O
counterparts O
( O
hydronaphthyl B
radicals O
, O
C B
( I
10 I
) I
H I
( I
9 I
) I
) O
are O
important O
intermediates O
in O
the O
reactions O
of O
aromatic O
compounds O
and O
in O
understanding O
the O
unidentified O
infrared O
( O
IR O
) O
emissions O
from O
interstellar O
media O
. O

We O
report O
the O
IR O
spectra O
of O
1 B
- I
C I
( I
10 I
) I
H I
( I
9 I
) I
( I
+ I
) I
, O
2 B
- I
C I
( I
10 I
) I
H I
( I
9 I
) I
( I
+ I
) I
, O
1 B
- I
C I
( I
10 I
) I
H I
( I
9 I
) I
, O
and O
2 B
- I
C I
( I
10 I
) I
H I
( I
9 I
) I
trapped O
in O
solid O
para B
- I
hydrogen I
( O
p B
- I
H I
( I
2 I
) I
) O
; O
the O
latter O
three O
are O
new O
. O

These O
species O
were O
produced O
upon O
electron O
bombardment O
of O
a O
mixture O
of O
naphthalene B
( O
C B
( I
10 I
) I
H I
( I
8 I
) I
) O
and O
p B
- I
H I
( I
2 I
) I
during O
matrix O
deposition O
. O

The O
intensities O
of O
IR O
features O
of O
1 B
- I
C I
( I
10 I
) I
H I
( I
9 I
) I
( I
+ I
) I
decreased O
after O
the O
matrix O
was O
maintained O
in O
darkness O
for O
19 O
h O
, O
whereas O
those O
of O
1 B
- I
C I
( I
10 I
) I
H I
( I
9 I
) I
and O
2 B
- I
C I
( I
10 I
) I
H I
( I
9 I
) I
increased O
. O

Irradiation O
of O
this O
matrix O
sample O
with O
light O
at O
365 O
nm O
diminished O
lines O
of O
1 B
- I
C I
( I
10 I
) I
H I
( I
9 I
) I
( I
+ I
) I
and O
2 B
- I
C I
( I
10 I
) I
H I
( I
9 I
) I
and O
enhanced O
lines O
of O
1 B
- I
C I
( I
10 I
) I
H I
( I
9 I
) I
and O
2 B
- I
C I
( I
10 I
) I
H I
( I
9 I
) I
( I
+ I
) I
; O
the O
latter O
species O
was O
unstable O
and O
converted O
to O
1 B
- I
C I
( I
10 I
) I
H I
( I
9 I
) I
( I
+ I
) I
in O
less O
than O
30 O
min O
and O
2 B
- I
C I
( I
10 I
) I
H I
( I
9 I
) I
was O
converted O
to O
1 B
- I
C I
( I
10 I
) I
H I
( I
9 I
) I
at O
365 O
nm O
. O

Observed O
wavenumbers O
and O
relative O
intensities O
of O
these O
species O
agree O
satisfactorily O
with O
the O
anharmonic O
vibrational O
wavenumbers O
and O
IR O
intensities O
predicted O
with O
the O
B3PW91 O
/ O
6 O
- O
311 O
+ O
+ O
G O
( O
2d O
, O
2p O
) O
method O
. O

Compared O
with O
spectra O
recorded O
previously O
with O
IR O
photodissociation O
of O
Ar B
- O
tagged O
C B
( I
10 I
) I
H I
( I
9 I
) I
( I
+ I
) I
or O
IR O
multiphoton O
dissociation O
of O
C B
( I
10 I
) I
H I
( I
9 I
) I
( I
+ I
) I
, O
our O
method O
has O
the O
advantages O
of O
producing O
high O
- O
resolution O
IR O
spectra O
with O
a O
wide O
spectral O
coverage O
, O
true O
IR O
intensity O
and O
excellent O
ratio O
of O
signal O
to O
noise O
; O
both O
protonated O
species O
and O
their O
neutral O
counterparts O
are O
produced O
with O
little O
interference O
from O
other O
fragments O
. O

With O
these O
advantages O
, O
the O
IR O
spectra O
of O
1 B
- I
C I
( I
10 I
) I
H I
( I
9 I
) I
( I
+ I
) I
, O
2 B
- I
C I
( I
10 I
) I
H I
( I
9 I
) I
( I
+ I
) I
, O
1 B
- I
C I
( I
10 I
) I
H I
( I
9 I
) I
, O
and O
2 B
- I
C I
( I
10 I
) I
H I
( I
9 I
) I
are O
here O
clearly O
characterized O
. O

Identification O
of O
multiple O
binding O
sites O
for O
substrate O
transport O
in O
bovine O
organic O
anion O
transporting O
polypeptide O
1a2 O
. O

Organic O
anion O
transporting O
polypeptides O
( O
OATP O
) O
have O
been O
extensively O
recognized O
as O
key O
determinants O
of O
absorption O
, O
distribution O
, O
metabolism O
, O
and O
excretion O
of O
various O
drugs O
because O
of O
their O
broad O
substrate O
specificity O
, O
wide O
tissue O
distribution O
, O
and O
the O
involvement O
of O
drug O
- O
drug O
interaction O
. O

As O
the O
first O
cloned O
human O
OATP O
, O
OATP1A2 O
has O
been O
found O
to O
transport O
a O
wide O
spectrum O
of O
endogenous O
and O
exogenous O
compounds O
. O

Bovine O
Oapt1a2 O
shared O
high O
homology O
with O
the O
human O
transporter O
and O
is O
considered O
as O
its O
functional O
ortholog O
. O

In O
the O
present O
study O
, O
we O
expressed O
bovine O
Oatp1a2 O
in O
human O
embryonic O
kidney O
293 O
cells O
and O
found O
that O
, O
unlike O
human O
OATP1A2 O
, O
the O
transport O
of O
estrone B
- I
3 I
- I
sulfate I
( O
E B
- I
3 I
- I
S I
) O
exhibited O
biphasic O
saturation O
kinetics O
. O

The O
K O
( O
m O
) O
values O
are O
0 O
. O
25 O
+ O
/ O
- O
0 O
. O
08 O
and O
46 O
. O
6 O
+ O
/ O
- O
18 O
. O
5 O
micro O
M O
, O
and O
V O
( O
max O
) O
values O
were O
24 O
. O
5 O
+ O
/ O
- O
4 O
. O
4 O
and O
375 O
+ O
/ O
- O
142 O
pmol O
/ O
mg O
protein O
/ O
min O
for O
high O
- O
and O
low O
- O
affinity O
sites O
, O
respectively O
, O
suggesting O
the O
presence O
of O
multiple O
binding O
sites O
. O

Further O
study O
on O
other O
Oatp1a2 O
substrates O
showed O
that O
the O
high O
affinity O
component O
for O
E O
- O
3 O
- O
S O
is O
responsible O
for O
the O
interaction O
with O
taurocholate B
, O
bromsulphthalein B
, O
and O
rifampicin B
and O
is O
sensitive O
to O
proton O
concentration O
change O
, O
whereas O
the O
low O
affinity O
binding O
site O
is O
only O
involved O
in O
the O
binding O
of O
the O
antitumor O
drug O
methotrexate B
and O
had O
no O
response O
to O
change O
of O
pH O
. O

Bamboo O
salt O
has O
in O
vitro O
anticancer O
activity O
in O
HCT O
- O
116 O
cells O
and O
exerts O
anti O
- O
metastatic O
effects O
in O
vivo O
. O

Bamboo O
salt O
is O
a O
traditional O
food O
widely O
used O
in O
Korea O
. O

The O
in O
vitro O
anticancer O
effects O
of O
this O
salt O
were O
evaluated O
in O
HCT O
- O
116 O
human O
colon O
cancer O
cells O
using O
a O
3 B
- I
( I
4 I
, I
5 I
- I
dimethyl I
- I
2 I
- I
thiazolyl I
) I
- I
2 I
, I
5 I
- I
diphenyltetrazolium I
bromide I
( O
MTT B
) O
assay O
. O

A O
1 O
% O
salt O
concentration O
of O
bamboo O
salt O
baked O
nine O
times O
( O
9 O
x O
) O
inhibited O
the O
growth O
of O
HCT O
- O
116 O
cells O
by O
53 O
% O
, O
which O
was O
higher O
than O
salt O
baked O
three O
times O
( O
3 O
x O
) O
or O
once O
( O
1 O
x O
; O
44 O
% O
and O
41 O
% O
, O
respectively O
) O
and O
much O
higher O
than O
solar O
sea O
salt O
( O
Korean O
sea O
salt O
) O
and O
purified O
salt O
( O
22 O
% O
and O
18 O
% O
, O
respectively O
) O
. O

To O
elucidate O
the O
inhibitory O
mechanisms O
underlying O
the O
anticancer O
effect O
of O
the O
salt O
samples O
in O
cancer O
cells O
, O
expression O
of O
genes O
associated O
with O
apoptosis O
, O
inflammation O
, O
and O
metastasis O
was O
measured O
with O
reverse O
transcription O
- O
polymerase O
chain O
reaction O
and O
Western O
blotting O
. O

Bamboo O
salt O
( O
9 O
x O
) O
significantly O
induced O
apoptosis O
in O
cancer O
cells O
( O
P O
< O
. O
05 O
) O
by O
upregulating O
Bax O
, O
caspase O
- O
9 O
, O
and O
caspase O
- O
3 O
, O
and O
downregulating O
Bcl O
- O
2 O
. O

The O
expression O
of O
genes O
associated O
with O
inflammation O
( O
NF O
- O
kappa O
B O
, O
iNOS O
, O
and O
COX O
- O
2 O
) O
was O
significantly O
downregulated O
( O
P O
< O
. O
05 O
) O
by O
9 O
x O
bamboo O
salt O
, O
demonstrating O
its O
anti O
- O
inflammatory O
properties O
. O

The O
9 O
x O
bamboo O
salt O
also O
exerted O
a O
greater O
anti O
- O
metastatic O
effect O
on O
cancer O
cells O
than O
the O
other O
salts O
as O
demonstrated O
by O
decreased O
mRNA O
expression O
of O
MMP O
genes O
and O
increased O
expression O
of O
tissue O
inhibitors O
of O
metalloproteinases O
, O
which O
was O
confirmed O
by O
the O
inhibition O
of O
tumor O
metastasis O
induced O
in O
colon O
26 O
- O
M3 O
. O
1 O
cells O
in O
BALB O
/ O
c O
mice O
. O

In O
contrast O
, O
purified O
and O
solar O
salts O
increased O
metastasis O
in O
the O
mice O
. O

Our O
results O
demonstrated O
that O
9 O
x O
bamboo O
salt O
had O
the O
most O
potent O
in O
vitro O
anticancer O
effect O
, O
induced O
apoptosis O
, O
had O
anti O
- O
inflammatory O
activities O
, O
and O
exerted O
in O
vivo O
anti O
- O
metastatic O
effects O
. O

Additionally O
, O
the O
anticancer O
, O
anti O
- O
inflammatory O
, O
and O
anti O
- O
metastatic O
effects O
of O
the O
1 O
x O
and O
3 O
x O
bamboo O
salts O
were O
stronger O
than O
those O
of O
the O
purified O
and O
solar O
salts O
. O

Iodine B
- I
129 I
microdosing O
for O
protein O
and O
peptide O
drug O
development O
: O
erythropoietin O
as O
a O
case O
study O
. O

BACKGROUND O
: O
Microdosing O
is O
a O
technique O
for O
studying O
the O
behavior O
of O
compounds O
in O
vivo O
at O
1 O
/ O
100th O
of O
the O
dose O
of O
a O
test O
substance O
calculated O
, O
based O
on O
animal O
data O
, O
to O
yield O
a O
pharmacologic O
effect O
. O

In O
microdosing O
, O
use O
is O
made O
of O
accelerator O
MS O
( O
AMS O
) O
. O

In O
this O
study O
, O
we O
investigated O
whether O
( B
129 I
) I
I I
- O
labeling O
of O
proteins O
with O
subsequent O
AMS O
measurements O
is O
a O
suitable O
method O
to O
perform O
microdose O
studies O
with O
therapeutic O
proteins O
. O

We O
used O
erythropoietin O
( O
EPO O
) O
as O
a O
case O
study O
. O

RESULTS O
: O
In O
an O
animal O
study O
with O
( B
129 I
) I
I I
- O
labeled O
EPO O
in O
Han O
- O
Wistar O
rats O
, O
an O
increase O
of O
( B
129 I
) I
I I
- O
EPO O
is O
observed O
after O
dose O
administration O
. O

The O
half O
- O
life O
was O
found O
to O
be O
2 O
and O
5 O
. O
5 O
h O
for O
two O
different O
EPOs O
. O

These O
results O
are O
in O
accordance O
with O
expected O
values O
. O

CoNCLUSION O
: O
Although O
further O
research O
is O
required O
, O
( B
129 I
) I
I I
- O
labeling O
of O
proteins O
seems O
a O
feasible O
method O
for O
AMS O
microdose O
studies O
with O
peptide O
and O
protein O
drugs O
, O
such O
as O
biosimilars O
. O

Structural O
- O
Functional O
Studies O
of O
Burkholderia O
cenocepaciad O
- I
Glycero I
- I
beta I
- I
d I
- I
manno I
- I
heptose I
7 I
- I
Phosphate I
Kinase O
( O
HldA O
) O
and O
Characterization O
of O
Inhibitors O
with O
Antibiotic O
Adjuvant O
and O
Antivirulence O
Properties O
. O

As O
an O
essential O
constituent O
of O
the O
outer O
membrane O
of O
Gram O
- O
negative O
bacteria O
, O
lipopolysaccharide O
contributes O
significantly O
to O
virulence O
and O
antibiotic O
resistance O
. O

The O
lipopolysaccharide O
biosynthetic O
pathway O
therefore O
serves O
as O
a O
promising O
therapeutic O
target O
for O
antivirulence O
drugs O
and O
antibiotic O
adjuvants O
. O

Here O
we O
report O
the O
structural O
- O
functional O
studies O
of O
d B
- I
glycero I
- I
beta I
- I
d I
- I
manno I
- I
heptose I
7 I
- I
phosphate I
kinase O
( O
HldA O
) O
, O
an O
absolutely O
conserved O
enzyme O
in O
this O
pathway O
, O
from O
Burkholderia O
cenocepacia O
. O

HldA O
is O
structurally O
similar O
to O
members O
of O
the O
PfkB O
carbohydrate B
kinase O
family O
and O
appears O
to O
catalyze O
heptose B
phosphorylation O
via O
an O
in O
- O
line O
mechanism O
mediated O
mainly O
by O
a O
conserved O
aspartate B
, O
Asp270 B
. O

Moreover O
, O
we O
report O
the O
structures O
of O
HldA O
in O
complex O
with O
two O
potent O
inhibitors O
in O
which O
both O
inhibitors O
adopt O
a O
folded O
conformation O
and O
occupy O
the O
nucleotide B
- O
binding O
sites O
. O

Together O
, O
these O
results O
provide O
important O
insight O
into O
the O
mechanism O
of O
HldA O
- O
catalyzed O
heptose B
phosphorylation O
and O
necessary O
information O
for O
further O
development O
of O
HldA O
inhibitors O
. O

Application O
of O
a O
liquid O
chromatography O
- O
electrospray O
mass O
spectrometry O
( O
LC O
/ O
MS O
) O
method O
to O
the O
biodistribution O
and O
excretion O
studies O
of O
novel O
5 B
' I
- I
chloro I
- I
2 I
, I
3 I
- I
didehydroindolo I
( I
2 I
' I
, I
3 I
' I
: I
2 I
, I
3 I
) I
betulinic I
acid I
( O
DRF B
- I
4012 I
) O
in O
tumour O
- O
bearing O
mice O
. O

Novel O
betulinic B
acid I
derivative O
5 B
' I
- I
chloro I
- I
2 I
, I
3 I
- I
didehydroindolo I
[ I
2 I
' I
, I
3 I
' I
: I
2 I
, I
3 I
] I
betulinic I
acid I
( O
DRF B
- I
4012 I
) O
is O
a O
new O
effective O
lupane B
type O
triterpenes B
with O
greater O
anticancer O
activity O
and O
efficacy O
than O
betulinic B
acid I
and O
currently O
under O
advanced O
preclinical O
investigation O
phase O
. O

In O
this O
study O
, O
a O
sensitive O
and O
rapid O
liquid O
chromatography O
- O
electrospray O
mass O
spectrometric O
( O
LC O
/ O
MS O
) O
method O
has O
been O
developed O
for O
the O
determination O
of O
DRF B
- I
4012 I
in O
tumour O
- O
bearing O
mice O
plasma O
, O
urine O
, O
feces O
and O
tissues O
( O
liver O
, O
brain O
, O
lungs O
, O
heart O
, O
spleen O
, O
stomach O
, O
thigh O
muscle O
, O
kidneys O
, O
urinary O
bladder O
, O
small O
intestine O
and O
tumour O
) O
. O

Biodistribution O
and O
excretion O
studies O
were O
performed O
for O
DRF O
- O
4012 O
nanoparticle O
( O
30 O
mg O
/ O
kg O
body O
weight O
) O
after O
intravenous O
( O
i O
. O
v O
. O
) O
injection O
in O
tumour O
- O
bearing O
mice O
. O

DRF B
- I
4012 I
rapidly O
distributed O
throughout O
the O
body O
. O

After O
0 O
. O
5 O
h O
, O
tumour O
showed O
the O
second O
highest O
concentration O
, O
which O
was O
nearly O
half O
of O
the O
liver O
. O

After O
4 O
and O
24 O
h O
, O
the O
highest O
concentration O
of O
DRF B
- I
4012 I
was O
found O
in O
tumour O
indicating O
its O
retention O
in O
tumour O
site O
for O
a O
longer O
time O
. O

Excretion O
studies O
revealed O
that O
very O
low O
amount O
of O
unchanged O
DRF B
- I
4012 I
was O
observed O
in O
urine O
and O
primarily O
excreted O
through O
fecal O
route O
. O

This O
study O
may O
be O
useful O
to O
explain O
the O
manner O
in O
which O
DRF B
- I
4012 I
can O
inhibit O
tumour O
growth O
without O
apparent O
toxicity O
and O
preclinical O
/ O
clinical O
evaluation O
of O
this O
potential O
antitumour O
agent O
. O

Characterization O
of O
in O
vitro O
metabolites O
of O
luotonin B
A I
in O
human O
liver O
microsomes O
using O
electrospray O
/ O
tandem O
mass O
spectrometry O
. O

1 O
. O

The O
pharmacological O
activity O
of O
luotonin B
A I
varies O
, O
depending O
on O
the O
type O
of O
functional O
group O
and O
the O
site O
of O
derivatization O
. O

To O
understand O
the O
in O
vivo O
efficacy O
of O
luotonin B
A I
, O
the O
in O
vitro O
metabolism O
of O
luotonin B
A I
was O
investigated O
in O
human O
liver O
microsomes O
and O
recombinant O
cDNA O
- O
expressed O
cytochromeP450 O
( O
CYP O
) O
. O

2 O
. O

Incubation O
of O
luotonin B
A I
with O
pooled O
human O
liver O
microsomes O
in O
the O
presence O
of O
NADPH B
- O
generating O
system O
resulted O
in O
the O
formation O
of O
four O
metabolites O
and O
the O
structures O
of O
each O
metabolite O
were O
tentatively O
characterized O
on O
the O
basis O
of O
electrospray O
tandem O
mass O
spectra O
. O

3 O
. O

The O
main O
metabolic O
pathway O
of O
luotonin B
A I
in O
human O
liver O
microsomes O
was O
hydroxylation O
, O
resulting O
in O
the O
generation O
of O
two O
mono B
- I
hydroxyl I
metabolites O
( O
M1 O
and O
M2 O
) O
and O
two O
di B
- I
hydroxyl I
metabolites O
( O
M3 O
and O
M4 O
) O
. O

CYP1A2 O
was O
primarily O
involved O
in O
hydroxylation O
of O
the O
quinolone B
moiety O
( O
M1 O
andM3 O
) O
, O
while O
CYP3A4 O
was O
mainly O
responsible O
for O
hydroxylation O
of O
the O
quinazoline B
moiety O
of O
luotonin B
A I
( O
M2 O
and O
M4 O
) O
in O
human O
liver O
microsomes O
. O

Evaluation O
of O
low O
background O
liquid O
scintillation O
counter O
for O
non O
- O
clinical O
ADME O
studies O
. O

1 O
. O
The O
performance O
of O
low O
background O
( O
BG O
) O
liquid O
scintillation O
counter O
( O
LSC O
) O
was O
evaluated O
for O
practical O
purposes O
of O
non O
- O
clinical O
drug O
absorption O
, O
distribution O
, O
metabolism O
and O
excretion O
( O
ADME O
) O
studies O
. O

The O
measurement O
conditions O
for O
the O
radioactivity O
for O
low O
BG O
LSC O
were O
investigated O
and O
metabolite O
profiling O
in O
rat O
plasma O
after O
single O
oral O
administration O
of O
( B
14 I
) I
C I
- O
labeled O
compounds O
was O
performed O
. O

Metabolite O
profiling O
was O
also O
conducted O
using O
conventional O
LSC O
and O
accelerator O
mass O
spectrometer O
( O
AMS O
) O
, O
and O
the O
performances O
of O
these O
measuring O
instruments O
were O
compared O
. O

2 O
. O
The O
established O
measurement O
conditions O
showed O
good O
linearity O
of O
the O
calibration O
curve O
over O
the O
concentration O
range O
from O
3 O
to O
300 O
dpm O
/ O
vial O
. O

Metabolite O
profiling O
using O
low O
BG O
LSC O
for O
the O
plasma O
samples O
diluted O
to O
5 O
- O
55 O
times O
was O
comparable O
to O
that O
using O
conventional O
LSC O
for O
the O
undiluted O
plasma O
samples O
. O

Meanwhile O
, O
metabolite O
profiling O
using O
AMS O
for O
the O
plasma O
samples O
diluted O
to O
250 O
- O
2000 O
times O
was O
comparable O
to O
that O
using O
conventional O
LSC O
. O

3 O
. O
These O
results O
suggest O
that O
the O
application O
of O
low O
BG O
LSC O
is O
one O
of O
the O
useful O
tools O
for O
non O
- O
clinical O
ADME O
studies O
and O
that O
it O
is O
possible O
to O
select O
conventional O
LSC O
, O
low O
BG O
LSC O
or O
AMS O
for O
radioactivity O
measurement O
by O
considering O
the O
specific O
radioactivity O
of O
the O
compounds O
and O
the O
predicted O
concentrations O
of O
radioactivity O
in O
biological O
samples O
in O
ADME O
studies O
. O

The O
effects O
of O
kisspeptin O
in O
human O
reproductive O
function O
- O
therapeutic O
implications O
. O

Kisspeptin O
is O
a O
54 O
- O
amino B
acid I
peptide O
which O
is O
encoded O
by O
the O
KiSS O
- O
1 O
gene O
and O
activates O
the O
G O
protein O
- O
coupled O
receptor O
GPR54 O
. O

Evidence O
suggests O
that O
this O
system O
is O
a O
key O
regulator O
of O
mammalian O
and O
human O
reproduction O
. O

Animal O
studies O
have O
shown O
that O
GPR54 O
- O
deficient O
mice O
have O
abnormal O
sexual O
development O
. O

Central O
and O
peripheral O
administration O
of O
kisspeptin O
stimulates O
the O
hypothalamic O
- O
pituitary O
- O
gonadal O
( O
HPG O
) O
axis O
whilst O
pre O
- O
administration O
of O
a O
gonadotrophin B
releasing I
hormone I
( O
GnRH B
) O
antagonist O
abolishes O
this O
effect O
. O

In O
humans O
, O
inactivating O
GPR54 O
mutations O
cause O
normosmic O
hypogonadotrophic O
hypogonadism O
whilst O
activation O
of O
GPR54 O
signalling O
is O
associated O
with O
premature O
puberty O
. O

In O
healthy O
human O
volunteers O
, O
the O
acute O
intravenous O
administration O
of O
kisspeptin O
potently O
increases O
plasma O
luteinising O
hormone O
( O
LH O
) O
levels O
and O
significantly O
increases O
plasma O
follicle O
stimulating O
hormone O
( O
FSH O
) O
and O
testosterone B
without O
side O
effects O
in O
both O
males O
and O
in O
females O
particularly O
in O
the O
preovulatatory O
phase O
of O
the O
menstrual O
cycle O
. O

In O
infertility O
due O
to O
hypothalamic O
amenorrhoea O
acute O
administration O
of O
kisspeptin O
results O
in O
stimulation O
of O
reproductive O
hormones O
. O

The O
kisspeptin O
/ O
GPR54 O
system O
therefore O
appears O
to O
play O
an O
important O
role O
in O
the O
regulation O
of O
reproduction O
in O
humans O
. O

Hence O
kisspeptin O
has O
potential O
as O
a O
novel O
tool O
for O
the O
manipulation O
of O
the O
HPG O
axis O
and O
treatment O
of O
infertility O
in O
humans O
. O

This O
review O
discusses O
the O
evidence O
highlighting O
kisspeptin O
' O
s O
key O
role O
in O
human O
reproduction O
. O

Construction O
and O
Characterization O
of O
Molecular O
Nonwoven O
Fabrics O
Consisting O
of O
Cross O
- O
Linked O
Poly B
( I
gamma I
- I
methyl I
- I
l I
- I
glutamate I
) I
. O

Molecular O
nonwoven O
fabrics O
in O
the O
form O
of O
ultrathin O
layer O
- O
by O
- O
layer O
( O
LbL O
) O
helical O
polymer O
films O
with O
covalent O
cross O
- O
linking O
were O
assembled O
on O
substrates O
by O
an O
alternate O
ester B
- O
amide B
exchange O
reaction O
between O
poly B
( I
gamma I
- I
methyl I
l I
- I
glutamate I
) I
( O
PMLG B
) O
and O
cross O
- O
linking O
agent O
ethylene B
diamine I
or O
4 B
, I
4 I
' I
- I
diamino I
azobenzene I
. O

The O
regular O
growth O
of O
helical O
monolayers O
without O
excessive O
adsorption O
and O
the O
formation O
of O
amide B
bonds O
were O
confirmed O
by O
ultraviolet O
- O
visible O
( O
UV O
- O
vis O
) O
spectrophotometry O
, O
quartz B
crystal O
microbalance O
( O
QCM O
) O
, O
ellipsometry O
, O
and O
infrared O
reflection O
- O
absorption O
spectroscopy O
( O
IR O
- O
RAS O
) O
measurements O
. O

Nanostructures O
with O
high O
uniformity O
and O
ultrathin O
films O
with O
few O
defects O
formed O
by O
helical O
rod O
segments O
of O
PMLG O
were O
characterized O
by O
atomic O
force O
microscopy O
( O
AFM O
) O
and O
Kelvin O
probe O
force O
microscopy O
( O
KFM O
) O
. O

Dating O
an O
impressive O
Neotropical O
radiation O
: O
Molecular O
time O
estimates O
for O
the O
Sigmodontinae O
( O
Rodentia O
) O
provide O
insights O
into O
its O
historical O
biogeography O
. O

With O
about O
400 O
living O
species O
and O
82 O
genera O
, O
rodents O
of O
the O
subfamily O
Sigmodontinae O
comprise O
one O
of O
the O
most O
diverse O
and O
more O
broadly O
distributed O
Neotropical O
mammalian O
clades O
. O

There O
has O
been O
much O
debate O
on O
the O
origin O
of O
the O
lineage O
or O
the O
lineages O
of O
sigmodontines O
that O
entered O
South O
America O
, O
the O
timing O
of O
entrance O
and O
different O
aspects O
of O
further O
diversification O
within O
South O
America O
. O

The O
ages O
of O
divergence O
of O
the O
main O
lineages O
and O
the O
crown O
age O
of O
the O
subfamily O
were O
estimated O
by O
using O
sequences O
of O
the O
interphotoreceptor O
retinoid B
binding O
protein O
and O
cytochrome O
b O
genes O
for O
a O
dense O
sigmodontine O
and O
muroid O
sampling O
. O

Bayesian O
inference O
using O
three O
fossil O
calibration O
points O
and O
a O
relaxed O
molecular O
clock O
estimated O
a O
middle O
Miocene O
origin O
for O
Sigmodontinae O
( O
~ O
12Ma O
) O
, O
with O
most O
tribes O
diversifying O
throughout O
the O
Late O
Miocene O
( O
6 O
. O
9 O
- O
9 O
. O
4Ma O
) O
. O

These O
estimates O
together O
results O
of O
analyses O
of O
ancestral O
area O
reconstructions O
suggest O
a O
distribution O
for O
the O
most O
recent O
common O
ancestor O
of O
Sigmodontinae O
in O
Central O
- O
South O
America O
and O
a O
South O
American O
distribution O
for O
the O
most O
recent O
common O
ancestor O
of O
Oryzomyalia O
. O

Fragile O
X O
syndrome O
: O
from O
targets O
to O
treatments O
. O

Fragile O
X O
syndrome O
( O
FXS O
) O
is O
one O
of O
the O
most O
prevalent O
and O
well O
- O
studied O
monogenetic O
causes O
of O
intellectual O
disability O
and O
autism O
and O
, O
although O
rare O
, O
its O
high O
penetrance O
makes O
it O
a O
desirable O
model O
for O
the O
study O
of O
neurodevelopmental O
disorders O
more O
generally O
. O

Indeed O
recent O
studies O
suggest O
that O
there O
is O
functional O
convergence O
of O
a O
number O
of O
genes O
that O
are O
implicated O
in O
intellectual O
disability O
and O
autism O
indicating O
that O
an O
understanding O
of O
the O
cellular O
and O
biochemical O
dysfunction O
that O
occurs O
in O
monogenic O
forms O
of O
these O
disorders O
are O
likely O
to O
reveal O
common O
targets O
for O
therapeutic O
intervention O
. O

Fundamental O
research O
into O
FXS O
has O
provided O
a O
wealth O
of O
information O
about O
how O
the O
loss O
of O
function O
of O
the O
fragile O
X O
mental O
retardation O
protein O
results O
in O
biochemical O
, O
anatomical O
and O
physiological O
dysfunction O
leading O
to O
the O
discovery O
of O
interventions O
that O
correct O
many O
of O
the O
core O
pathological O
phenotypes O
associated O
with O
animal O
models O
of O
FXS O
. O

Most O
promisingly O
such O
strategies O
have O
led O
to O
development O
of O
drugs O
that O
are O
now O
in O
clinical O
trials O
. O

This O
review O
highlights O
how O
progress O
in O
understanding O
disorders O
such O
as O
FXS O
has O
led O
to O
a O
new O
era O
in O
which O
targeted O
molecular O
treatment O
towards O
neurodevelopmental O
disorders O
is O
becoming O
a O
reality O
. O

This O
article O
is O
part O
of O
the O
Special O
Issue O
entitled O
' O
Neurodevelopmental O
Disorders O
' O
. O

Genipin B
stimulates O
glucose B
transport O
in O
C2C12 O
myotubes O
via O
an O
IRS O
- O
1 O
and O
calcium B
- O
dependent O
mechanism O
. O

Genipin B
, O
a O
compound O
derived O
from O
Gardenia O
jasminoides O
Ellis O
fruits O
, O
has O
been O
used O
over O
the O
years O
in O
traditional O
Chinese O
medicine O
to O
treat O
symptoms O
of O
type O
2 O
diabetes O
. O

However O
, O
the O
molecular O
basis O
for O
its O
antidiabetic O
effect O
has O
not O
been O
fully O
revealed O
. O

In O
this O
study O
, O
we O
investigated O
the O
effects O
of O
genipin B
on O
glucose B
uptake O
and O
signaling O
pathways O
in O
C B
( I
2 I
) I
C I
( I
12 I
) I
myotubes O
. O

Our O
study O
demonstrates O
that O
genipin B
stimulated O
glucose B
uptake O
in O
a O
time O
- O
and O
dose O
- O
dependent O
manner O
. O

The O
maximal O
effect O
was O
achieved O
at O
2 O
h O
with O
a O
concentration O
of O
10 O
mu O
M O
. O

In O
myotubes O
, O
genipin B
promoted O
glucose B
transporter O
4 O
( O
GLUT4 O
) O
translocation O
to O
the O
cell O
surface O
, O
which O
was O
observed O
by O
analyzing O
their O
distribution O
in O
subcellular O
membrane O
fraction O
, O
and O
increased O
the O
phosphorylation O
of O
insulin O
receptor O
substrate O
- O
1 O
( O
IRS O
- O
1 O
) O
, O
AKT O
, O
and O
GSK3 O
beta O
. O

Meanwhile O
, O
genipin B
increased O
ATP B
levels O
, O
closed O
K B
( O
ATP B
) O
channels O
, O
and O
then O
increased O
the O
concentration O
of O
calcium B
in O
the O
cytoplasm O
in O
C O
( O
2 O
) O
C O
( O
12 O
) O
myotubes O
. O

Genipin B
- O
stimulated O
glucose B
uptake O
could O
be O
blocked O
by O
both O
the O
PI3 O
- O
K O
inhibitor O
wortmannin B
and O
calcium B
chelator O
EGTA B
. O

Moreover O
, O
genipin B
increases O
the O
level O
of O
reactive O
oxygen B
species O
and O
ATP B
in O
C O
( I
2 I
) I
C I
( I
12 I
) I
myotubes O
. O

These O
results O
suggest O
that O
genipin B
activates O
IRS O
- O
1 O
, O
PI3 O
- O
K O
, O
and O
downstream O
signaling O
pathway O
and O
increases O
concentrations O
of O
calcium B
, O
resulting O
in O
GLUT4 O
translocation O
and O
glucose B
uptake O
increase O
in O
C O
( O
2 O
) O
C O
( O
12 O
) O
myotubes O
. O

Electrophoresis O
of O
randomly O
and O
vertically O
embedded O
graphene B
nanosheets O
in O
activated O
carbon B
film O
as O
a O
counter O
electrode O
for O
dye O
- O
sensitized O
solar O
cells O
. O

A O
new O
approach O
has O
been O
developed O
to O
randomly O
and O
vertically O
embed O
the O
graphene B
nanosheets O
( O
GNs O
) O
in O
the O
activated O
carbon B
( O
AC O
) O
film O
in O
an O
applied O
electric O
field O
. O

The O
activated O
carbon B
( O
AC O
) O
nanoparticles O
in O
suspension O
during O
electrophoresis O
play O
an O
important O
role O
in O
supporting O
the O
GNs O
perpendicular O
to O
the O
FTO B
( O
fluorine B
- I
doped I
tin I
oxide I
) O
glass O
. O

Insufficient O
amount O
of O
AC O
nanoparticles O
might O
result O
in O
a O
deposition O
of O
GNs O
parallel O
to O
the O
FTO O
glass O
, O
leading O
to O
incomplete O
utilization O
of O
the O
surface O
area O
accessible O
to O
electrolyte O
ions O
. O

An O
AC O
cathode O
with O
randomly O
and O
vertically O
embedded O
GNs O
facilitated O
electrolyte O
penetration O
and O
electron O
conduction O
. O

The O
photoelectron O
conversion O
efficiency O
of O
the O
cell O
was O
increased O
to O
7 O
. O
50 O
% O
by O
employing O
the O
AC O
cathode O
with O
randomly O
and O
vertically O
embedded O
GNs O
. O

Heterogeneous O
oxidation O
of O
a O
phosphocholine B
on O
synthetic O
sea O
salt O
by O
ozone B
at O
room O
temperature O
. O

The O
ozonolysis O
of O
1 B
- I
palmitoyl I
- I
2 I
- I
oleoyl I
- I
sn I
- I
glycero I
- I
3 I
- I
phosphocholine I
( O
POPC B
) O
adsorbed O
on O
salt O
mixtures O
as O
models O
for O
sea O
- O
salt O
particles O
was O
studied O
in O
real O
time O
using O
diffuse O
reflection O
infrared O
Fourier O
transform O
spectrometry O
( O
DRIFTS O
) O
at O
room O
temperature O
with O
and O
without O
added O
water O
vapor O
. O

The O
salt O
substrates O
were O
a O
mixture O
of O
MgCl B
( I
2 I
) I
. I
6H I
( I
2 I
) I
O I
with O
NaCl B
or O
a O
commercially O
available O
synthetic O
sea O
salt O
. O

Ozone B
concentrations O
ranged O
from O
( O
0 O
. O
25 O
to O
3 O
. O
9 O
) O
x O
10 O
( O
13 O
) O
molecules O
cm O
( O
- O
3 O
) O
( O
0 O
. O
1 O
- O
1 O
. O
6 O
ppm O
) O
. O

The O
major O
products O
identified O
by O
FTIR O
and O
confirmed O
using O
matrix O
- O
assisted O
laser O
desorption O
/ O
ionization O
( O
MALDI O
) O
mass O
spectrometry O
were O
the O
secondary B
ozonide I
( O
SOZ B
) O
and O
a O
phospholipid O
aldehyde B
and O
carboxylic B
acid I
formed O
by O
scission O
of O
the O
double O
bond O
. O

The O
reaction O
probabilities O
for O
the O
two O
substrates O
were O
similar O
, O
gamma O
= O
( O
6 O
- O
7 O
) O
x O
10 O
( O
- O
7 O
) O
, O
with O
an O
estimated O
overall O
uncertainty O
of O
a O
factor O
of O
two O
. O

The O
presence O
of O
water O
vapor O
decreased O
the O
yield O
of O
SOZ B
relative O
to O
the O
products O
formed O
by O
C B
[ O
double O
bond O
, O
length O
as O
m O
- O
dash O
] O
C B
scission O
, O
but O
also O
increased O
the O
availability O
of O
the O
double O
bond O
for O
reaction O
, O
particularly O
on O
the O
less O
hygroscopic O
commercial O
sea O
- O
salt O
substrate O
. O

Thus O
, O
water O
not O
only O
affects O
the O
mechanisms O
and O
products O
, O
but O
also O
the O
structure O
of O
the O
phospholipid O
on O
the O
salt O
in O
a O
manner O
that O
affects O
its O
reactivity O
. O

The O
results O
of O
these O
studies O
suggest O
that O
the O
reactivity O
and O
products O
of O
oxidation O
of O
unsaturated O
phospholipids O
on O
sea O
- O
salt O
particles O
in O
air O
will O
be O
very O
sensitive O
to O
the O
nature O
and O
phase O
of O
the O
substrate O
, O
the O
amount O
of O
water O
present O
, O
and O
whether O
there O
is O
phase O
separation O
between O
the O
organics O
and O
the O
inorganic O
salt O
mixture O
. O

Prediction O
of O
( B
TiO2 I
) I
x I
( I
Cu2O I
) I
y I
alloys O
for O
efficient O
photoelectrochemical O
water O
splitting O
. O

The O
formation O
of O
( B
TiO I
( I
2 I
) I
) I
( I
x I
) I
( I
Cu I
( I
2 I
) I
O I
) I
( I
y I
) I
solid O
- O
solutions O
is O
investigated O
using O
a O
global O
optimization O
evolutionary O
algorithm O
. O

First O
- O
principles O
calculations O
based O
on O
density O
functional O
theory O
are O
then O
used O
to O
gain O
insight O
into O
the O
electronic O
properties O
of O
these O
alloys O
. O

We O
find O
that O
: O
( I
i I
) I
Ti B
and O
Cu B
in I
( I
TiO I
( I
2 I
) I
) I
( I
x I
) I
( I
Cu I
( I
2 I
) I
O I
) I
( I
y I
) I
alloys O
have O
similar O
local O
environments O
as O
in O
bulk O
TiO B
( I
2 I
) I
and O
Cu B
( I
2 I
) I
O I
except O
for O
( B
TiO I
( I
2 I
) I
) I
( I
Cu I
( I
2 I
) I
O I
) I
which O
has O
some O
trigonal O
- O
planar O
Cu B
ions O
. O

( O
ii O
) O
The O
predicted O
optical O
band O
gaps O
are O
around O
2 O
. O
1 O
eV O
( O
590 O
nm O
) O
, O
thus O
having O
much O
better O
performance O
in O
the O
absorption O
of O
visible O
light O
compared O
with O
both O
binary O
oxides B
. O

( I
iii I
) I
( I
TiO I
( I
2 I
) I
) I
( I
2 I
) I
( O
Cu B
( I
2 I
) I
O I
) O
has O
the O
lowest O
formation O
energy O
amongst O
all O
studied O
alloys O
and O
the O
positions O
of O
its O
band O
edges O
are O
found O
to O
be O
suitable O
for O
solar O
- O
driven O
water O
splitting O
applications O
. O

pH O
tuning O
of O
DNA O
translocation O
time O
through O
organically O
functionalized O
nanopores O
. O

Controlling O
DNA O
translocation O
speed O
is O
critically O
important O
for O
nanopore O
sequencing O
as O
free O
electrophoretic O
threading O
is O
far O
too O
rapid O
to O
resolve O
individual O
bases O
. O

A O
number O
of O
promising O
strategies O
have O
been O
explored O
in O
recent O
years O
, O
largely O
driven O
by O
the O
demands O
of O
next O
- O
generation O
sequencing O
. O

Engineering O
DNA O
- O
nanopore O
interactions O
( O
known O
to O
dominate O
translocation O
dynamics O
) O
with O
organic O
coatings O
is O
an O
attractive O
method O
as O
it O
does O
not O
require O
sample O
modification O
, O
processive O
enzymes O
, O
or O
complicated O
and O
expensive O
fabrication O
steps O
. O

In O
this O
work O
, O
we O
show O
for O
the O
first O
time O
4 O
- O
fold O
tuning O
of O
unfolded O
, O
single O
- O
file O
translocation O
time O
through O
small O
, O
amine B
- O
functionalized O
solid O
- O
state O
nanopores O
by O
varying O
the O
solution O
pH O
in O
situ O
. O

Additionally O
, O
we O
develop O
a O
simple O
analytical O
model O
based O
on O
electrostatic O
interactions O
to O
explain O
this O
effect O
which O
will O
be O
a O
useful O
tool O
in O
designing O
future O
devices O
and O
experiments O
. O

Visualization O
and O
virtual O
screening O
of O
the O
chemical O
universe O
database O
GDB O
- O
17 O
. O

The O
chemical O
universe O
database O
GDB O
- O
17 O
contains O
166 O
. O
4 O
billion O
molecules O
of O
up O
to O
17 O
atoms O
of O
C B
, O
N B
, O
O B
, O
S B
, O
and O
halogens B
obeying O
rules O
for O
chemical O
stability O
, O
synthetic O
feasibility O
, O
and O
medicinal O
chemistry O
. O

GDB O
- O
17 O
was O
analyzed O
using O
42 O
integer O
value O
descriptors O
of O
molecular O
structure O
which O
we O
term O
" O
Molecular O
Quantum O
Numbers O
" O
( O
MQN O
) O
. O

Principal O
component O
analysis O
and O
representation O
of O
the O
( O
PC1 O
, O
PC2 O
) O
- O
plane O
provided O
a O
graphical O
overview O
of O
the O
GDB O
- O
17 O
chemical O
space O
. O

Rapid O
ligand O
- O
based O
virtual O
screening O
( O
LBVS O
) O
of O
GDB B
- I
17 I
using O
the O
city O
- O
block O
distance O
CBD O
( O
MQN O
) O
as O
a O
similarity O
search O
measure O
was O
enabled O
by O
a O
hashed O
MQN O
- O
fingerprint O
. O

LBVS O
of O
the O
entire O
GDB B
- I
17 I
and O
of O
selected O
subsets O
identified O
shape O
similar O
, O
scaffold O
hopping O
analogs O
( O
ROCS O
> O
1 O
. O
6 O
and O
T O
( O
SF O
) O
< O
0 O
. O
5 O
) O
of O
15 O
drugs O
. O

Over O
97 O
% O
of O
these O
analogs O
occurred O
within O
CBD B
( O
MQN O
) O
< O
= O
12 O
from O
each O
drug O
, O
a O
constraint O
which O
might O
help O
focus O
advanced O
virtual O
screening O
. O

An O
MQN O
- O
searchable O
50 O
million O
subset O
of O
GDB O
- O
17 O
is O
publicly O
available O
at O
www O
. O
gdb O
. O
unibe O
. O
ch O
. O

Tailorable O
cell O
culture O
platforms O
from O
enzymatically O
cross O
- O
linked O
multifunctional O
poly B
( I
ethylene I
glycol I
) I
- O
based O
hydrogels O
. O

As O
stem O
- O
cell O
- O
based O
therapies O
rapidly O
advance O
toward O
clinical O
applications O
, O
there O
is O
a O
need O
for O
cheap O
, O
easily O
manufactured O
, O
injectable O
gels O
that O
can O
be O
tailored O
to O
carry O
stem O
cells O
and O
impart O
function O
to O
such O
cells O
. O

Herein O
we O
describe O
a O
process O
for O
making O
hydrogels O
composed O
of O
hydroxyphenyl B
propionic I
acid I
( O
HPA B
) O
conjugated O
, O
branched O
poly B
( I
ethylene I
glycol I
) I
( O
PEG B
) O
via O
an O
enzyme O
mediated O
, O
oxidative O
cross O
- O
linking O
method O
. O

Functionalization O
of O
the O
branched O
PEG B
with O
HPA B
at O
varying O
degrees O
of O
substitution O
was O
confirmed O
via O
attenuated O
total O
reflectance O
Fourier O
transform O
infrared O
spectroscopy O
( O
ATR O
- O
FTIR O
) O
and O
( B
1 I
) I
H I
NMR O
. O

The O
versatility O
of O
this O
hydrogel O
system O
was O
exemplified O
through O
variations O
in O
the O
degree O
of O
HPA O
substitution O
, O
polymer O
concentration O
, O
and O
the O
concentration O
of O
cross O
- O
linking O
reagents O
( O
horseradish O
peroxidase O
and O
H B
( I
2 I
) I
O I
( I
2 I
) I
) O
, O
which O
resulted O
in O
a O
range O
of O
mechanical O
properties O
and O
gelation O
kinetics O
for O
these O
gels O
. O

Cross O
- O
linking O
of O
the O
PEG B
- I
HPA I
conjugate O
with O
a O
recombinantly O
produced O
Fibronectin O
fragment O
( O
Type O
III O
domains O
7 O
- O
10 O
) O
encouraged O
attachment O
and O
spreading O
of O
human O
mesenchymal O
stem O
cells O
( O
hMSCs O
) O
when O
assessed O
in O
both O
two O
- O
dimensional O
and O
three O
- O
dimensional O
formats O
. O

Interestingly O
, O
when O
encapsulated O
in O
both O
nonfunctionalized O
and O
functionalized O
cross O
- O
linked O
PEG B
- O
HPA B
gels O
, O
MSCs O
showed O
good O
viability O
over O
all O
time O
periods O
assessed O
. O

With O
tunable O
gelation O
kinetics O
and O
mechanical O
properties O
, O
these O
hydrogels O
provide O
a O
flexible O
in O
vitro O
cell O
culture O
platform O
that O
will O
likely O
have O
significant O
utility O
in O
tissue O
engineering O
as O
an O
injectable O
delivery O
platform O
for O
cells O
to O
sites O
of O
tissue O
damage O
. O

Discovery O
of O
a O
new O
series O
of O
[ B
1 I
, I
2 I
, I
4 I
] I
triazolo I
[ I
4 I
, I
3 I
- I
a I
] I
quinoxalines I
as O
dual O
phosphodiesterase O
2 O
/ O
phosphodiesterase O
10 O
( O
PDE2 O
/ O
PDE10 O
) O
inhibitors O
. O

The O
synthesis O
, O
preliminary O
evaluation O
and O
structure O
- O
activity O
relationship O
( O
SAR O
) O
of O
a O
series O
of O
1 B
- I
aryl I
- I
4 I
- I
methyl I
[ I
1 I
, I
2 I
, I
4 I
] I
triazolo I
[ I
4 I
, I
3 I
- I
a I
] I
quinoxalines I
as O
dual O
phosphodiesterase O
2 O
/ O
phosphodiesterase O
10 O
( O
PDE2 O
/ O
PDE10 O
) O
inhibitors O
are O
described O
. O

From O
this O
investigation O
compound O
31 O
was O
identified O
, O
showing O
good O
combined O
potency O
, O
acceptable O
brain O
uptake O
and O
high O
selectivity O
for O
both O
PDE2 O
and O
PDE10 O
enzymes O
. O

Compound O
31 O
was O
subjected O
to O
a O
microdosing O
experiment O
in O
rats O
, O
showing O
preferential O
distribution O
in O
brain O
areas O
where O
both O
PDE2 O
and O
PDE10 O
are O
highly O
expressed O
. O

These O
promising O
results O
may O
drive O
the O
further O
development O
of O
highly O
potent O
combined O
PDE2 O
/ O
PDE10 O
inhibitors O
, O
or O
even O
of O
selective O
inhibitors O
of O
PDE2 O
and O
/ O
or O
PDE10 O
. O

Discovering O
gene O
- O
environment O
interactions O
in O
Glioblastoma O
through O
a O
comprehensive O
data O
integration O
bioinformatics O
method O
. O

Glioblastoma O
multiforme O
( O
GBM O
) O
is O
the O
most O
common O
and O
aggressive O
type O
of O
human O
brain O
tumor O
. O

Although O
considerable O
efforts O
to O
delineate O
the O
underlying O
pathophysiological O
pathways O
have O
been O
made O
during O
the O
last O
decades O
, O
only O
very O
limited O
progress O
on O
treatment O
have O
been O
achieved O
because O
molecular O
pathways O
that O
drive O
the O
aggressive O
nature O
of O
GBM O
are O
largely O
unknown O
. O

Recent O
studies O
have O
emphasized O
the O
importance O
of O
environmental O
factors O
and O
the O
role O
of O
gene O
- O
environment O
interactions O
( O
GEI O
) O
in O
the O
development O
of O
GBM O
. O

Factors O
such O
as O
small O
sample O
sizes O
and O
study O
costs O
have O
limited O
the O
conduct O
of O
GEI O
studies O
in O
brain O
tumors O
however O
. O

Additionally O
, O
advances O
in O
high O
- O
throughput O
microarrays O
have O
produced O
a O
wealth O
of O
information O
concerning O
molecular O
biology O
of O
glioma O
. O

In O
particular O
, O
microarrays O
have O
been O
used O
to O
obtain O
genetic O
and O
epigenetic O
changes O
between O
normal O
non O
- O
tumor O
tissue O
and O
glioma O
tissue O
. O

Due O
to O
the O
relative O
rarity O
of O
gliomas O
, O
microarray O
data O
for O
these O
tumors O
is O
often O
the O
product O
of O
small O
studies O
, O
and O
thus O
pooling O
this O
data O
becomes O
desirable O
. O

To O
address O
the O
challenge O
of O
small O
sample O
sizes O
and O
GEI O
study O
difficulties O
, O
we O
introduce O
a O
comprehensive O
bioinformatics O
method O
using O
genetic O
variations O
( O
copy O
number O
variations O
and O
small O
- O
scale O
variations O
) O
and O
environmental O
data O
integration O
that O
links O
with O
Glioblastoma O
( O
GEG O
) O
to O
identify O
: O
( O
1 O
) O
genes O
that O
interact O
with O
chemicals O
and O
have O
genetic O
variants O
linked O
to O
the O
development O
of O
GBM O
, O
( O
2 O
) O
important O
pathways O
that O
may O
be O
influenced O
by O
environmental O
exposures O
( O
or O
endogenous O
chemicals O
) O
, O
and O
( O
3 O
) O
genes O
with O
variants O
in O
GBM O
that O
have O
been O
understudied O
in O
relation O
to O
GBM O
development O
. O

The O
first O
step O
in O
our O
GEG O
method O
identified O
genes O
responsive O
to O
environmental O
exposures O
using O
the O
Environmental O
Genome O
Project O
, O
Comparative O
Toxicology O
, O
and O
Seattle O
SNPs O
databases O
. O

These O
environmentally O
responsive O
genes O
were O
then O
compared O
to O
a O
curated O
list O
of O
genes O
containing O
copy O
number O
variation O
and O
/ O
or O
mutations O
in O
GBM O
. O

This O
comparison O
produced O
a O
list O
of O
genes O
responsive O
to O
the O
environment O
and O
important O
to O
GBM O
that O
was O
then O
further O
analyzed O
using O
gene O
networking O
tools O
such O
as O
RSpider O
, O
Cytoscape O
, O
and O
DAVID O
. O

Using O
this O
GEG O
bioinformatics O
method O
we O
were O
able O
to O
identify O
173 O
genes O
with O
the O
potential O
to O
be O
involved O
in O
GEI O
that O
may O
be O
important O
to O
the O
development O
of O
GBM O
. O

Sixty O
five O
of O
these O
environmentally O
responsive O
genes O
have O
not O
been O
reported O
as O
important O
to O
GBM O
development O
, O
despite O
several O
of O
them O
having O
substantial O
potential O
for O
response O
to O
chemicals O
and O
subsequent O
disease O
related O
actions O
. O

The O
main O
biological O
functions O
of O
these O
173 O
genes O
include O
signaling O
by O
Nerve O
Growth O
Factor O
, O
DNA O
Repair O
, O
Integrin O
Cell O
Surface O
Interactions O
, O
Biological O
Oxidations O
, O
Apoptosis O
, O
Synaptic O
Transmission O
, O
Cell O
Cycle O
Checkpoints O
, O
and O
Arachidonic B
Acid I
Metabolism O
. O

Importantly O
, O
some O
of O
these O
functions O
have O
been O
implicated O
in O
the O
development O
of O
several O
cancers O
, O
including O
glioma O
. O

In O
summary O
, O
our O
GEG O
bioinformatics O
approach O
revealed O
potential O
gene O
- O
environment O
interactions O
, O
and O
generated O
new O
data O
for O
hypothesis O
generation O
, O
in O
GBM O
. O

Central O
nervous O
system O
damage O
due O
to O
acute O
paraquat B
poisoning O
: O
an O
experimental O
study O
with O
rat O
model O
. O

Paraquat B
( O
PQ O
) O
is O
a O
common O
herbicide O
and O
PQ O
poisoning O
is O
a O
major O
medical O
problem O
in O
Asia O
. O

However O
, O
few O
studies O
have O
focused O
on O
the O
acute O
neurotoxic O
changes O
caused O
by O
PQ O
. O

Here O
we O
report O
the O
acute O
neurotoxicological O
findings O
of O
rats O
treated O
with O
lethal O
dose O
of O
PQ O
. O

In O
substantia O
nigra O
( O
SN O
) O
and O
striatum O
we O
found O
obvious O
microglia O
( O
labeled O
by O
Iba O
- O
1 O
) O
activation O
within O
one O
week O
. O

In O
SN O
and O
hippocampus O
, O
we O
detected O
increased O
oxidative O
stress O
in O
the O
neurons O
based O
on O
NeuN O
/ O
8 B
- I
OHdG I
immunofluorescence O
double O
labeling O
and O
laser O
cofocal O
microscopy O
. O

Moreover O
, O
we O
provided O
ultrastructural O
evidences O
of O
astrocyte O
edema O
and O
neurons O
apoptosis O
in O
rat O
brain O
by O
electron O
microscopy O
. O

Further O
studies O
will O
be O
needed O
with O
non O
- O
lethal O
dose O
of O
PQ O
to O
confirm O
these O
results O
and O
demonstrate O
the O
direct O
CNS O
toxicity O
of O
PQ O
. O

The O
uptake O
and O
distribution O
of O
selenium B
in O
three O
aquatic O
plants O
grown O
in O
Se B
( I
IV I
) I
solution O
. O

The O
uptake O
of O
Se B
( I
IV I
) I
by O
Myriophyllum O
spicatum O
, O
Ceratophyllum O
demersum O
and O
Potamogeton O
perfoliatus O
, O
and O
the O
effects O
of O
Se B
( I
IV I
) I
on O
their O
physiological O
and O
biochemical O
characteristics O
were O
studied O
. O

Plants O
were O
cultivated O
outdoors O
under O
semi O
- O
controlled O
conditions O
in O
water O
solution O
containing O
Na B
selenite I
( O
20 O
mu O
g O
Se B
L O
( O
- O
1 O
) O
and O
10 O
mg O
Se B
L O
( O
- O
1 O
) O
) O
. O

The O
higher O
concentration O
of O
Se B
lowered O
the O
photochemical O
efficiency O
of O
PSII O
in O
all O
species O
studied O
, O
while O
the O
lower O
concentration O
had O
no O
effect O
on O
any O
species O
. O

The O
higher O
concentration O
of O
Se B
lowered O
respiratory O
potential O
in O
M O
. O
spicatum O
. O

The O
response O
of O
M O
. O
spicatum O
and O
C O
. O
demersum O
to O
Se B
( I
IV I
) I
regarding O
chlorophylls B
was O
variable O
, O
however O
in O
the O
majority O
of O
cases O
, O
there O
was O
a O
trend O
of O
increasing O
the O
amount O
of O
chlorophylls B
, O
while O
in O
P O
. O
perfoliatus O
the O
amount O
of O
chlorophyll B
a I
decreased O
. O

The O
concentration O
of O
Se B
in O
plants O
cultured O
in O
10 O
mg O
Se B
( I
IV I
) I
L O
( O
- O
1 O
) O
ranged O
from O
436 O
to O
839 O
mu O
g O
Se B
g O
( O
- O
1 O
) O
DM O
in O
M O
. O
spicatum O
, O
319 O
to O
988 O
mu O
g O
Se B
g O
( O
- O
1 O
) O
DM O
in O
C O
. O
demersum O
and O
310 O
to O
661 O
mu O
g O
Se B
g O
( O
- O
1 O
) O
DM O
in O
P O
. O
perfoliatus O
. O

The O
amount O
of O
soluble O
Se B
compounds O
in O
enzyme O
extracts O
of O
high O
Se B
treatment O
was O
27 O
% O
in O
M O
. O
spicatum O
, O
41 O
% O
in O
C O
. O
demersum O
and O
35 O
% O
in O
P O
. O
perfoliatus O
. O

Se B
compounds O
were O
determined O
using O
HPLC O
- O
ICP O
- O
MS O
. O

It O
was O
observed O
that O
the O
applied O
Se B
( I
IV I
) I
was O
mainly O
transformed O
to O
insoluble O
Se B
. O

Qalibra O
: O
a O
general O
model O
for O
food O
risk O
- O
benefit O
assessment O
that O
quantifies O
variability O
and O
uncertainty O
. O

The O
EU O
project O
BRAFO O
proposed O
a O
framework O
for O
risk O
- O
benefit O
assessment O
of O
foods O
, O
or O
changes O
in O
diet O
, O
that O
present O
both O
potential O
risks O
and O
potential O
benefits O
to O
consumers O
( O
Hoekstra O
et O
al O
. O
, O
2012a O
) O
. O

In O
higher O
tiers O
of O
the O
BRAFO O
framework O
, O
risks O
and O
benefits O
are O
integrated O
quantitatively O
to O
estimate O
net O
health O
impact O
measured O
in O
DALYs O
or O
QALYs O
( O
disability O
- O
or O
quality O
- O
adjusted O
life O
years O
) O
. O

This O
paper O
describes O
a O
general O
model O
that O
was O
developed O
by O
a O
second O
EU O
project O
, O
Qalibra O
, O
to O
assist O
users O
in O
conducting O
these O
assessments O
. O

Its O
flexible O
design O
makes O
it O
applicable O
to O
a O
wide O
range O
of O
dietary O
questions O
involving O
different O
nutrients O
, O
contaminants O
and O
health O
effects O
. O

Account O
can O
be O
taken O
of O
variation O
between O
consumers O
in O
their O
diets O
and O
also O
other O
characteristics O
relevant O
to O
the O
estimation O
of O
risk O
and O
benefit O
, O
such O
as O
body O
weight O
, O
gender O
and O
age O
. O

Uncertainty O
in O
any O
input O
parameter O
may O
be O
quantified O
probabilistically O
, O
using O
probability O
distributions O
, O
or O
deterministically O
by O
repeating O
the O
assessment O
with O
alternative O
assumptions O
. O

Uncertainties O
that O
are O
not O
quantified O
should O
be O
evaluated O
qualitatively O
. O

Outputs O
produced O
by O
the O
model O
are O
illustrated O
using O
results O
from O
a O
simple O
assessment O
of O
fish O
consumption O
. O

More O
detailed O
case O
studies O
on O
oily O
fish O
and O
phytosterols B
are O
presented O
in O
companion O
papers O
. O

The O
model O
can O
be O
accessed O
as O
web O
- O
based O
software O
at O
www O
. O
qalibra O
. O
eu O
. O

Shikonin B
induces O
programmed O
necrosis O
- O
like O
cell O
death O
through O
the O
formation O
of O
receptor O
interacting O
protein O
1 O
and O
3 O
complex O
. O

An O
alternative O
cell O
demise O
programmed O
necrosis O
has O
also O
been O
proposed O
when O
apoptotic O
machinery O
is O
impaired O
or O
blocked O
during O
tumor O
necrosis O
factor O
alpha O
( O
TNF O
alpha O
) O
stimulation O
. O

Shikonin B
( O
SKN B
) O
, O
an O
herbal O
extract O
from O
the O
Chinese O
plant O
, O
has O
been O
reported O
to O
induce O
either O
apoptosis O
or O
necrosis O
depending O
on O
cell O
types O
or O
its O
concentrations O
. O

In O
this O
presentation O
, O
SKN O
caused O
cell O
death O
of O
NIH3T3 O
in O
a O
dose O
- O
dependent O
manner O
. O

Intriguingly O
, O
SKN O
- O
mediated O
cell O
death O
was O
in O
part O
protected O
by O
necrostatin B
- I
1 I
( O
Nec B
- I
1 I
) O
, O
a O
specific O
inhibitor O
of O
programmed O
necrosis O
, O
but O
not O
zVAD O
a O
pan O
- O
caspase O
inhibitor O
. O

SKN O
directly O
mediated O
cell O
death O
via O
receptor O
interacting O
protein1 O
and O
3 O
( O
RIP1 O
- O
RIP3 O
) O
complex O
formation O
, O
which O
is O
required O
for O
TNF O
alpha O
- O
mediated O
programmed O
necrosis O
. O

Additionally O
, O
SKN O
- O
caused O
cell O
death O
was O
reversed O
by O
a O
reactive O
oxygen B
species O
( O
ROS O
) O
scavenger O
N B
- I
acetylcysteine I
( O
NAC B
) O
whereas O
TNF O
alpha O
- O
mediated O
necrosis O
was O
successfully O
protected O
by O
butylated B
hydroxyanisole I
( O
BHA B
) O
, O
implying O
that O
ROS O
may O
be O
differentially O
derived O
from O
death O
inducing O
agents O
. O

Concurrently O
with O
the O
protective O
effect O
of O
the O
ROS O
scavenger O
or O
Nec B
- I
1 I
on O
TNF O
alpha O
or O
SKN O
, O
the O
RIP1 O
- O
RIP3 O
complex O
was O
significantly O
affected O
in O
the O
presence O
of O
those O
agents O
. O

Here O
, O
it O
is O
highlighted O
that O
SKN O
as O
well O
as O
TNF O
alpha O
can O
directly O
mediate O
cell O
death O
via O
a O
pronecrotic O
complex O
, O
but O
ROS O
were O
generated O
via O
different O
routes O
depending O
on O
cell O
death O
- O
inducing O
agents O
. O

Comparative O
analysis O
of O
genetic O
toxicity O
of O
antiretroviral O
combinations O
in O
somatic O
cells O
of O
Drosophila O
melanogaster O
. O

Nucleoside B
reverse O
- O
transcriptase O
inhibitor O
( O
NRTI O
) O
drugs O
are O
a O
major O
component O
of O
highly O
- O
active O
antiretroviral O
therapy O
( O
HAART O
) O
. O

NRTI O
combinations O
have O
been O
demonstrated O
as O
producing O
a O
sustained O
reduction O
in O
plasma O
viremia O
with O
an O
increased O
CD4 O
count O
, O
thereby O
showing O
clear O
clinical O
benefits O
. O

Therefore O
, O
the O
secondary O
effects O
caused O
by O
the O
combination O
of O
two O
NRTIs O
, O
mainly O
those O
related O
to O
amplification O
of O
genotoxic O
effects O
, O
due O
to O
increased O
risk O
of O
DNA O
damage O
caused O
by O
these O
drugs O
, O
should O
be O
carefully O
examined O
. O

We O
employed O
the O
standard O
version O
of O
the O
wing O
SMART O
in O
Drosophila O
melanogaster O
to O
obtain O
more O
detailed O
knowledge O
about O
the O
genotoxic O
profile O
of O
NRTI O
combinations O
of O
AZT B
+ O
ddI B
, O
AZT B
+ O
3TC B
and O
AZT B
+ O
d4T B
. O

Our O
results O
showed O
that O
all O
combinations O
increased O
the O
frequencies O
of O
induction O
of O
mutant O
spots O
. O

The O
combinations O
AZT B
+ O
ddI B
and O
AZT B
+ O
3TC B
were O
shown O
to O
induce O
recombination O
rates O
ranging O
from O
86 O
. O
38 O
% O
to O
98 O
. O
36 O
% O
while O
AZT B
+ O
d4T B
showed O
a O
large O
discrepancy O
between O
recombination O
and O
mutation O
percentages O
. O

The O
combination O
index O
demonstrated O
that O
3TC B
and O
d4T B
produced O
antagonism O
while O
ddI B
showed O
synergistic O
effects O
in O
combination O
with O
AZT B
. O

New O
enzymatic O
assay O
for O
the O
AKR1C O
enzymes O
. O

The O
imbalance O
in O
expression O
of O
the O
human O
aldo O
- O
keto O
reductases O
AKR1C1 O
- O
AKR1C3 O
is O
related O
to O
different O
hormone O
dependent O
and O
independent O
cancers O
and O
some O
other O
diseases O
. O

The O
AKR1C1 O
- O
3 O
enzymes O
thus O
represent O
emerging O
targets O
for O
the O
development O
of O
new O
drugs O
. O

Currently O
, O
various O
enzymatic O
assays O
are O
used O
in O
the O
search O
for O
AKR1C O
inhibitors O
, O
and O
consequently O
the O
results O
of O
different O
research O
groups O
are O
not O
necessarily O
comparable O
. O

During O
our O
recent O
search O
for O
AKR1C O
inhibitors O
, O
we O
found O
a O
cyclopentanol B
derivative O
( O
2 B
- I
( I
4 I
- I
chlorobenzylidene I
) I
cyclopentanol I
, O
CBCP B
- I
ol I
) O
and O
its O
respective O
cyclopentanone B
counterpart O
( O
2 B
- I
( I
4 I
- I
chlorobenzylidene I
) I
cyclopentanone I
, O
CBCP B
- I
one I
) O
that O
acted O
as O
AKR1C O
substrates O
. O

We O
determined O
the O
kinetic O
parameters O
KM O
, O
kcat O
and O
kcat O
/ O
KM O
for O
oxidation O
of O
CBCP B
- I
ol I
and O
reduction O
of O
CBCP B
- I
one I
by O
AKR1C O
enzymes O
in O
the O
presence O
of O
NAD B
( I
+ I
) I
/ O
NADP B
( I
+ I
) I
and O
NADH B
/ O
NADPH B
, O
respectively O
. O

The O
catalytic O
efficiencies O
for O
the O
oxidation O
of O
CBCP B
- I
ol I
in O
the O
presence O
of O
NAD B
( I
+ I
) I
or O
NADP B
( I
+ I
) I
were O
in O
general O
higher O
when O
compared O
to O
the O
catalytic O
efficiencies O
for O
reduction O
of O
CBCP B
- I
one I
in O
the O
presence O
of O
NADH B
or O
NADPH B
. O

When O
NADPH B
was O
used O
, O
as O
compared O
to O
NADH B
, O
the O
reductions O
of O
CBCP O
- O
one O
by O
AKR1C1 O
, O
AKR1C2 O
and O
AKR1C3 O
were O
14 O
- O
, O
51 O
- O
and O
31 O
- O
fold O
more O
efficient O
, O
respectively O
. O

When O
comparing O
to O
oxidations O
of O
the O
well O
- O
known O
artificial O
substrates O
, O
1 B
- I
acenaphthenol I
and O
S B
- I
tetralol I
, O
we O
observed O
similar O
catalytic O
efficiencies O
as O
for O
CBCP B
- I
ol I
oxidation O
with O
NAD B
( I
+ I
) I
and O
NADP B
( I
+ I
) I
. O

The O
comparison O
of O
CBCP B
- I
one I
reduction O
with O
NADPH B
to O
reductions O
of O
physiological O
substrates O
revealed O
in O
general O
higher O
efficiencies O
, O
except O
for O
reduction O
of O
9 B
- I
cis I
- I
retinaldehyde I
by O
AKR1C3 O
. O

This O
NADPH B
- O
dependent O
reduction O
of O
CBCP B
- I
one I
was O
then O
used O
to O
re O
- O
evaluate O
inhibitory O
potencies O
of O
the O
known O
inhibitors O
of O
the O
target O
AKR1C3 O
and O
the O
anti O
- O
target O
AKR1C2 O
, O
medroxyprogesterone B
acetate I
and O
ursodeoxycholic B
acid I
, O
respectively O
, O
showing O
Ki O
constants O
similar O
to O
the O
reported O
values O
. O

Our O
data O
thus O
confirm O
that O
the O
new O
enzymatic O
assays O
with O
two O
cyclopentane B
substrates O
CBP O
- O
ol O
and O
CBP O
- O
one O
, O
and O
especially O
reduction O
of O
CBCP O
- O
one O
with O
NADPH B
, O
are O
appropriate O
for O
the O
evaluation O
of O
AKR1C O
inhibitors O
. O

Effects O
of O
p53 O
knockout O
on O
ochratoxin B
A I
- O
induced O
genotoxicity O
in O
p53 O
- O
deficient O
gpt O
delta O
mice O
. O

Ochratoxin B
A I
( O
OTA B
) O
is O
a O
mycotoxin O
produced O
by O
fungal O
species O
and O
is O
carcinogenic O
targeting O
the O
S3 O
segment O
of O
the O
renal O
proximal O
tubules O
in O
rodents O
. O

We O
previously O
reported O
that O
exposure O
of O
gpt O
delta O
rats O
to O
OTA B
induced O
both O
mutations O
in O
the O
red O
/ O
gam O
gene O
( O
Spi O
( O
- O
) O
) O
, O
suggesting O
large O
deletion O
mutations O
, O
and O
fluctuations O
in O
genes O
transcribed O
by O
p53 O
in O
the O
kidneys O
, O
which O
were O
associated O
with O
DNA O
double O
- O
strand O
break O
( O
DSB O
) O
repair O
, O
particularly O
homologous O
recombination O
( O
HR O
) O
repair O
. O

In O
the O
present O
study O
, O
to O
investigate O
the O
effects O
of O
p53 O
knockout O
on O
OTA B
- O
induced O
mutagenicity O
, O
apoptosis O
, O
and O
karyomegaly O
in O
renal O
tubular O
cells O
, O
p53 O
- O
proficient O
and O
p53 O
- O
deficient O
gpt O
delta O
mice O
were O
given O
1 O
and O
5mg O
/ O
kg O
of O
OTA B
for O
4 O
weeks O
. O

Significant O
increases O
in O
Spi O
( O
- O
) O
mutant O
frequencies O
( O
MFs O
) O
were O
observed O
in O
the O
kidneys O
of O
p53 O
- O
deficient O
gpt O
delta O
mice O
given O
5 O
mg O
/ O
kg O
of O
OTA B
, O
but O
not O
in O
the O
kidneys O
of O
p53 O
- O
proficient O
gpt O
delta O
mice O
given O
the O
same O
dose O
. O

There O
were O
no O
changes O
in O
gpt O
MFs O
in O
both O
genotypes O
of O
mice O
treated O
with O
OTA O
. O

Western O
blotting O
analysis O
demonstrated O
that O
p53 O
protein O
levels O
in O
the O
kidneys O
of O
p53 O
- O
proficient O
mice O
given O
OTA B
were O
significantly O
increased O
compared O
with O
the O
control O
. O

Incidences O
of O
apoptosis O
and O
karyomegaly O
in O
not O
only O
the O
outer O
stripe O
of O
outer O
medulla O
but O
also O
the O
cortex O
were O
significantly O
higher O
in O
p53 O
- O
deficient O
at O
5mg O
/ O
kg O
than O
in O
p53 O
- O
proficient O
gpt O
delta O
mice O
at O
same O
dose O
, O
which O
had O
no O
change O
in O
the O
cortex O
, O
the O
inner O
stripe O
of O
outer O
stripe O
, O
and O
the O
inner O
medulla O
. O

Given O
that O
p53 O
regulates O
HR O
repair O
in O
DSBs O
, O
these O
results O
suggest O
that O
OTA B
may O
promote O
large O
deletion O
mutations O
in O
the O
process O
of O
HR O
repair O
for O
DSBs O
. O

Additionally O
, O
the O
lower O
incidence O
of O
karyomegaly O
and O
apoptosis O
found O
in O
the O
p53 O
- O
proficient O
gpt O
delta O
mice O
suggests O
that O
these O
phenomena O
may O
arise O
from O
OTA B
- O
induced O
DNA O
damage O
. O

Sex O
hormones O
and O
mental O
rotation O
: O
an O
intensive O
longitudinal O
investigation O
. O

The O
present O
study O
used O
an O
intensive O
longitudinal O
design O
to O
examine O
whether O
mental O
rotation O
performance O
varies O
according O
to O
a O
monthly O
cycle O
in O
both O
males O
and O
females O
and O
whether O
these O
variations O
are O
related O
to O
variations O
in O
progesterone B
, O
estradiol B
, O
and O
testosterone B
levels O
. O

We O
collected O
reaction O
time O
and O
accuracy O
data O
for O
10 O
males O
and O
seven O
females O
each O
workday O
over O
eight O
weeks O
using O
136 O
pairs O
of O
mental O
rotation O
stimuli O
/ O
day O
, O
and O
measured O
sexual O
hormones O
concentrations O
in O
the O
saliva O
twice O
a O
week O
. O

A O
mixed O
linear O
model O
statistical O
analysis O
revealed O
that O
all O
females O
and O
seven O
males O
showed O
significant O
cycle O
effects O
in O
mental O
rotation O
performance O
. O

The O
female O
cycle O
showed O
an O
amplitude O
that O
was O
twice O
as O
large O
compared O
with O
the O
amplitude O
found O
in O
males O
. O

For O
males O
and O
females O
, O
estradiol B
and O
testosterone B
were O
significantly O
linearly O
and O
quadratically O
related O
to O
interindividual O
variation O
in O
performance O
at O
the O
beginning O
of O
the O
study O
( O
progesterone B
was O
linearly O
related O
to O
performance O
for O
females O
) O
. O

The O
association O
between O
testosterone B
and O
performance O
differed O
across O
sexes O
: O
for O
males O
, O
it O
had O
an O
inverse O
U O
- O
shape O
, O
for O
females O
it O
was O
U O
- O
shaped O
. O

Towards O
the O
end O
of O
the O
study O
, O
none O
of O
the O
hormones O
were O
significantly O
related O
to O
performance O
anymore O
. O

Thus O
, O
the O
relationship O
between O
hormones O
and O
mental O
rotation O
performance O
disappeared O
with O
repeated O
testing O
. O

Only O
estradiol B
levels O
were O
significantly O
elevated O
at O
the O
lowest O
point O
of O
the O
cycle O
in O
mental O
rotation O
performance O
in O
females O
. O

In O
conclusion O
, O
in O
this O
intensive O
longitudinal O
study O
spanning O
two O
months O
, O
a O
monthly O
cycle O
in O
mental O
rotation O
performance O
was O
found O
among O
both O
males O
and O
females O
, O
with O
a O
larger O
cycle O
' O
s O
amplitude O
for O
females O
. O

Effects O
of O
oxygen B
and O
glucose B
deprivation O
on O
synaptic O
transmission O
in O
rat O
dentate O
gyrus O
: O
role O
of O
A O
( O
2A O
) O
adenosine B
receptors O
. O

The O
hippocampus O
is O
comprised O
of O
two O
distinct O
subfields O
that O
show O
different O
responses O
to O
hypoxic O
- O
ischemic O
brain O
injury O
: O
the O
CA1 O
region O
is O
particularly O
susceptible O
whereas O
the O
dentate O
gyrus O
( O
DG O
) O
is O
quite O
resistant O
. O

Our O
aim O
was O
to O
determine O
the O
synaptic O
and O
proliferative O
response O
of O
the O
DG O
to O
severe O
oxygen B
and O
glucose B
deprivation O
( O
OGD O
) O
in O
acute O
rat O
hippocampal O
slices O
and O
to O
investigate O
the O
contribution O
of O
A O
( O
2A O
) O
adenosine B
receptor O
antagonism O
to O
recovery O
of O
synaptic O
activity O
after O
OGD O
. O

Extracellular O
recordings O
of O
field O
excitatory O
post O
- O
synaptic O
potentials O
( O
fEPSPs O
) O
in O
granule O
cells O
of O
the O
DG O
in O
brain O
slices O
prepared O
from O
male O
Wistar O
rats O
were O
used O
. O

A O
9 O
- O
min O
OGD O
is O
needed O
in O
the O
DG O
to O
always O
induce O
the O
appearance O
of O
anoxic O
depolarization O
( O
AD O
) O
and O
the O
irreversible O
block O
of O
synaptic O
activity O
, O
as O
recorded O
up O
to O
24 O
h O
from O
the O
end O
of O
the O
insult O
, O
whereas O
only O
7 O
- O
min O
OGD O
is O
required O
in O
the O
CA1 O
region O
. O

Selective O
antagonism O
of O
A O
( O
2A O
) O
adenosine B
receptors O
by O
ZM241385 B
significantly O
prevents O
or O
delays O
the O
appearance O
of O
AD O
and O
protects O
from O
the O
irreversible O
block O
of O
neurotransmission O
induced O
by O
9 O
- O
min O
OGD O
in O
the O
DG O
. O

The O
effects O
of O
9 O
- O
min O
OGD O
on O
proliferation O
and O
maturation O
of O
cells O
localized O
in O
the O
subgranular O
zone O
of O
DG O
in O
slices O
prepared O
from O
5 B
- I
bromo I
- I
2 I
' I
- I
deoxyuridine I
( O
BrdU B
) O
treated O
rats O
was O
investigated O
. O

Slices O
were O
further O
incubated O
with O
an O
immature O
neuronal O
marker O
, O
doublecortin O
( O
DCX O
) O
. O

The O
number O
of O
BrdU O
( O
+ O
) O
cells O
was O
significantly O
decreased O
6 O
h O
after O
9 O
- O
min O
OGD O
and O
this O
effect O
was O
antagonized O
by O
ZM241385 B
. O

After O
24 O
h O
from O
the O
end O
of O
9 O
- O
min O
OGD O
, O
the O
number O
of O
BrdU B
( O
+ O
) O
cells O
returned O
to O
that O
found O
before O
OGD O
and O
increased O
arborization O
of O
tertiary O
dendrites O
of O
DCX O
( O
+ O
) O
cells O
was O
observed O
. O

The O
adenosine B
A O
( O
2A O
) O
antagonist O
ZM241385 B
protects O
from O
synaptic O
failure O
and O
from O
decreased O
proliferation O
of O
immature O
neuronal O
cells O
at O
a O
precocious O
time O
after O
OGD O
. O

Psychostimulant O
pharmacological O
profile O
of O
paraxanthine B
, O
the O
main O
metabolite O
of O
caffeine B
in O
humans O
. O

Caffeine B
induces O
locomotor O
activation O
by O
its O
ability O
to O
block O
adenosine B
receptors O
. O

Caffeine B
is O
metabolized O
to O
several O
methylxanthines B
, O
with O
paraxanthine B
being O
the O
main O
metabolite O
in O
humans O
. O

In O
this O
study O
we O
show O
that O
in O
rats O
paraxanthine B
has O
a O
stronger O
locomotor O
activating O
effect O
than O
caffeine B
or O
the O
two O
other O
main O
metabolites O
of O
caffeine B
, O
theophylline B
and O
theobromine B
. O

As O
previously O
described O
for O
caffeine B
, O
the O
locomotor O
activating O
doses O
of O
paraxanthine B
more O
efficiently O
counteract O
the O
locomotor O
depressant O
effects O
of O
an O
adenosine B
A O
( O
1 O
) O
than O
an O
adenosine B
A O
( O
2A O
) O
receptor O
agonist O
. O

In O
drug O
discrimination O
experiments O
in O
rats O
trained O
to O
discriminate O
a O
maximal O
locomotor O
activating O
dose O
of O
caffeine B
, O
paraxanthine B
, O
unlike O
theophylline B
, O
generalized O
poorly O
to O
caffeine B
suggesting O
the O
existence O
of O
additional O
mechanisms O
other O
than O
adenosine B
antagonism O
in O
the O
behavioral O
effects O
of O
paraxanthine B
. O

Pretreatment O
with O
the O
nitric B
oxide I
inhibitor O
N B
( I
G I
) I
- I
nitro I
- I
l I
- I
arginine I
methyl I
ester I
( O
l B
- I
NAME I
) O
reduced O
the O
locomotor O
activating O
effects O
of O
paraxanthine B
, O
but O
not O
caffeine B
. O

On O
the O
other O
hand O
, O
pretreatment O
with O
the O
selective O
cGMP B
- O
preferring O
phosphodiesterase O
PDE9 O
inhibitor O
BAY B
73 I
- I
6691 I
, O
increased O
locomotor O
activity O
induced O
by O
caffeine B
, O
but O
not O
paraxanthine B
. O

Ex O
vivo O
experiments O
demonstrated O
that O
paraxanthine B
, O
but O
not O
caffeine B
, O
can O
induce O
cGMP B
accumulation O
in O
the O
rat O
striatum O
. O

Finally O
, O
in O
vivo O
microdialysis O
experiments O
showed O
that O
paraxanthine B
, O
but O
not O
caffeine B
, O
significantly O
increases O
extracellular O
levels O
of O
dopamine B
in O
the O
dorsolateral O
striatum O
, O
which O
was O
blocked O
by O
l B
- I
NAME I
. O

These O
findings O
indicate O
that O
inhibition O
of O
cGMP B
- O
preferring O
PDE O
is O
involved O
in O
the O
locomotor O
activating O
effects O
of O
the O
acute O
administration O
of O
paraxanthine B
. O

The O
present O
results O
demonstrate O
a O
unique O
psychostimulant O
profile O
of O
paraxanthine B
, O
which O
might O
contribute O
to O
the O
reinforcing O
effects O
of O
caffeine B
in O
humans O
. O

Site O
- O
specific O
modulation O
of O
brain O
glucocorticoid O
receptor O
and O
corticotropin O
- O
releasing O
hormone O
expression O
using O
lentiviral O
vectors O
. O

The O
glucocorticoid O
receptor O
( O
GR O
) O
and O
corticotropin O
- O
releasing O
hormone O
( O
CRH O
) O
are O
important O
molecular O
regulators O
of O
an O
individual O
' O
s O
ability O
to O
respond O
to O
stressful O
stimuli O
in O
an O
adaptive O
manner O
. O

Impaired O
signaling O
of O
both O
GR O
and O
CRH O
often O
leads O
to O
dysfunction O
of O
the O
hypothalamic O
- O
pituitary O
- O
adrenal O
axis O
, O
which O
underlies O
the O
etiology O
of O
many O
affective O
disorders O
such O
as O
anxiety O
and O
depression O
. O

Studies O
focusing O
on O
how O
GR O
and O
CRH O
influence O
the O
stress O
response O
are O
limited O
as O
they O
generalize O
to O
broad O
brain O
regions O
, O
thus O
hindering O
identification O
of O
how O
specific O
CNS O
nuclei O
contribute O
to O
maladaptive O
stress O
responses O
. O

Our O
objective O
is O
to O
distinguish O
the O
site O
- O
specific O
involvement O
of O
GR O
and O
CRH O
in O
limbic O
regions O
involved O
in O
the O
stress O
response O
. O

With O
that O
intent O
, O
we O
use O
lentiviral O
( O
LV O
) O
vectors O
in O
combination O
with O
transgenic O
mouse O
lines O
, O
enabling O
us O
to O
modify O
expression O
of O
GR O
or O
CRH O
in O
a O
very O
localized O
manner O
. O

This O
paper O
describes O
the O
generation O
of O
several O
distinct O
LV O
vectors O
and O
transgenic O
mice O
models O
that O
will O
help O
further O
elucidate O
the O
site O
- O
specific O
actions O
of O
GR O
and O
CRH O
. O

The O
molecular O
mystique O
of O
tetrodotoxin B
. O

In O
many O
respects O
tetrodotoxin B
( O
TTX B
) O
is O
the O
quintessential O
natural O
toxin O
. O

It O
is O
unequivocally O
toxic O
to O
mammals O
with O
LD O
( O
50 O
) O
values O
for O
mice O
in O
the O
range O
of O
10 O
mu O
g O
/ O
kg O
( O
intraperitoneal O
) O
, O
16 O
mu O
g O
/ O
kg O
( O
subcutaneous O
) O
, O
and O
332 O
mu O
g O
/ O
kg O
( O
oral O
) O
( O
Kao O
, O
1966 O
) O
. O

Its O
biothreat O
status O
is O
recognized O
by O
its O
listing O
as O
a O
" O
Select O
Agent O
" O
by O
the O
US O
Department O
of O
Health O
and O
Human O
Services O
which O
includes O
regulated O
agents O
" O
determined O
to O
have O
the O
potential O
to O
pose O
a O
severe O
threat O
to O
both O
human O
and O
animal O
health O
" O
( O
http O
: O
/ O
/ O
www O
. O
selectagents O
. O
gov O
/ O
) O
. O

It O
has O
a O
well O
- O
defined O
cellular O
target O
( O
i O
. O
e O
. O
, O
NaV O
channels O
) O
and O
pharmacological O
mode O
of O
action O
( O
i O
. O
e O
. O
, O
block O
of O
nerve O
and O
muscle O
action O
potentials O
) O
, O
and O
it O
is O
an O
indispensable O
chemical O
tool O
in O
neuroscience O
. O

It O
is O
widely O
distributed O
in O
marine O
and O
terrestrial O
ecosystems O
where O
it O
plays O
a O
role O
in O
the O
chemical O
ecology O
of O
predator O
- O
prey O
relationships O
and O
drives O
evolutionary O
selection O
of O
TTX B
- O
resistance O
( O
Hanifin O
, O
2010 O
; O
Williams O
, O
2010 O
; O
Zimmer O
and O
Ferrer O
, O
2007 O
) O
. O

Lastly O
, O
TTX B
has O
acquired O
a O
certain O
mystique O
in O
scientific O
lore O
attributable O
to O
many O
fascinating O
aspects O
of O
its O
natural O
history O
and O
molecular O
interactions O
as O
presented O
in O
selected O
summary O
below O
. O

Additional O
information O
may O
be O
found O
in O
other O
excellent O
reviews O
( O
Fozzard O
and O
Lipkind O
, O
2010 O
; O
Kao O
, O
1966 O
; O
Lee O
and O
Ruben O
, O
2008 O
; O
Narahashi O
, O
2001 O
, O
2008 O
) O
. O

Glast O
- O
expressing O
progenitor O
cells O
contribute O
to O
heterotopic O
ossification O
. O

Heterotopic O
ossification O
( O
HO O
) O
, O
acquired O
or O
hereditary O
, O
is O
the O
formation O
of O
true O
bone O
outside O
the O
normal O
skeleton O
. O

Although O
the O
lineages O
of O
cells O
contributing O
to O
bone O
formation O
during O
normal O
development O
are O
well O
defined O
, O
the O
precise O
lineages O
of O
cells O
that O
contribute O
to O
HO O
are O
not O
clear O
. O

This O
study O
utilized O
Cre O
- O
lox O
based O
genetic O
lineage O
tracing O
to O
examine O
the O
contribution O
to O
HO O
of O
cells O
that O
expressed O
either O
FoxD1 O
or O
Glast O
. O

Both O
lineages O
contributed O
broadly O
to O
different O
normal O
tissues O
, O
and O
FoxD1 O
- O
cre O
labeled O
cells O
contributed O
to O
normal O
bone O
formation O
. O

Despite O
the O
similarity O
in O
labeling O
patterns O
of O
normal O
tissues O
, O
and O
the O
significant O
contribution O
of O
FoxD1 O
- O
cre O
labeled O
cells O
to O
normal O
bone O
, O
only O
Glast O
- O
creERT O
labeled O
progenitors O
contributed O
significantly O
to O
HO O
at O
all O
stages O
, O
suggesting O
that O
the O
cell O
populations O
that O
normally O
contribute O
to O
physiological O
bone O
formation O
, O
such O
as O
the O
Foxd1 O
- O
cre O
labeled O
cells O
, O
may O
not O
participate O
in O
pathological O
HO O
. O

Further O
, O
identification O
of O
Glast O
- O
expressing O
cells O
as O
precursors O
that O
give O
rise O
to O
HO O
should O
help O
with O
the O
molecular O
targeting O
of O
this O
population O
both O
for O
the O
prevention O
and O
for O
the O
treatment O
of O
HO O
. O

Anti O
- O
tumor O
efficacy O
of O
chitosan O
- O
g O
- O
poly B
( I
ethylene I
glycol I
) I
nanocapsules O
containing O
docetaxel B
: O
anti O
- O
TMEFF O
- O
2 O
functionalized O
nanocapsules O
vs O
. O
non O
- O
functionalized O
nanocapsules O
. O

The O
development O
and O
evaluation O
of O
PEGylated O
chitosan O
( O
CS O
) O
nanocapsules O
( O
NCs O
) O
conjugated O
to O
a O
monoclonal O
antibody O
anti O
- O
TMEFF O
- O
2 O
( O
CS O
- O
PEG B
- O
anti O
- O
TMEFF O
- O
2 O
mAb O
NCs O
) O
for O
targeted O
delivery O
of O
docetaxel B
( O
DCX B
) O
is O
presented O
. O

CS O
- O
PEG B
- O
Biotin B
NCs O
, O
displaying O
biotin B
tags O
at O
their O
surface O
, O
were O
obtained O
and O
efficiently O
functionalized O
with O
an O
anti O
- O
TMEFF O
- O
2 O
mAb O
through O
a O
convenient O
avidin O
- O
biotin B
approach O
. O

Cell O
cycle O
analysis O
after O
treatment O
with O
different O
DCX B
- O
loaded O
CS O
- O
PEG B
NC O
formulations O
indicated O
that O
the O
encapsulated O
drug O
remained O
fully O
active O
, O
showing O
a O
similar O
functional O
behavior O
to O
free O
DCX B
. O

In O
vivo O
efficacy O
studies O
using O
a O
non O
- O
small O
cell O
lung O
carcinoma O
xenograft O
revealed O
that O
CS O
- O
PEG B
- O
anti O
- O
TMEFF O
- O
2 O
NCs O
resulted O
as O
effective O
as O
free O
DCX B
( O
Taxotere B
( O
R O
) O
) O
. O

Interestingly O
, O
differences O
on O
the O
pharmacodynamic O
behavior O
among O
the O
different O
DCX B
formulations O
were O
observed O
. O

Thus O
, O
while O
free O
DCX B
exhibited O
a O
fast O
and O
short O
effect O
on O
tumor O
volume O
reduction O
, O
CS O
- O
PEG B
- O
anti O
- O
TMEFF O
- O
2 O
mAb O
NCs O
showed O
a O
delayed O
and O
prolonged O
action O
, O
with O
no O
significant O
side O
effects O
of O
treatments O
. O

Phenylethanoid B
glycosides I
from O
the O
stems O
of O
Callicarpa O
peii O
( O
hemostatic O
drug O
) O
. O

Two O
new O
trisaccharide B
intermediates O
of O
phenylethanoid B
glycosides I
, O
peiioside B
A I
( I
1 I
) I
/ I
A I
( O
2 O
) O
( O
1a O
/ O
1b O
) O
and O
peiioside B
B I
( O
2 O
) O
, O
were O
isolated O
from O
the O
n B
- I
BuOH I
fraction O
of O
MeOH B
extract O
of O
the O
stems O
of O
Callicarpa O
peii O
H O
. O
T O
. O

Chang O
, O
together O
with O
five O
biogenetic O
relevant O
known O
compounds O
3 O
- O
7 O
. O

The O
structures O
of O
compounds O
1 O
and O
2 O
were O
elucidated O
by O
extensive O
spectroscopic O
methods O
( O
especially O
2D O
- O
NMR O
techniques O
) O
and O
acid O
- O
catalyzed O
hydrolysis O
as O
O B
- I
alpha I
- I
l I
- I
rhamnopyranosyl I
- I
( I
1 I
' I
' I
- I
- I
> I
3 I
' I
) I
- I
O I
- I
[ I
beta I
- I
d I
- I
apiofuranosyl I
- I
( I
1 I
' I
' I
' I
- I
- I
> I
6 I
' I
) I
] I
- I
4 I
' I
- I
O I
- I
[ I
( I
E I
) I
- I
caffeoyl I
] I
- I
d I
- I
glucopyranoside I
] I
( O
1a O
/ O
1b O
) O
, O
3 B
, I
4 I
- I

dihydroxy I
- I
beta I
- I
phenylethoxy I
- I
O I
- I
[ I
beta I
- I
d I
- I
apiofuranosyl I
- I
( I
1 I
' I
' I
' I
- I
- I
> I
6 I
' I
) I
- I
alpha I
- I
l I
- I
rhamnopyranosyl I
- I
( I
1 I
' I
' I
- I
- I
> I
3 I
' I
) I
- I
O I
- I
beta I
- I
d I
- I
glucopyranoside I
] I
( O
2 O
) O
, O
respectively O
. O

On O
the O
basis O
of O
the O
isolated O
compounds O
, O
a O
presumable O
biogenetic O
pathway O
of O
the O
biologically O
interesting O
phenylethanoid B
glycosides I
about O
forsythoside B
B I
( O
3 O
) O
and O
acteoside B
( O
4 O
) O
isolated O
from O
this O
species O
was O
proposed O
. O

Isolation O
of O
five O
related O
intermediates O
( O
1 O
- O
2 O
, O
5 O
- O
7 O
) O
provided O
further O
support O
for O
the O
biogenetic O
path O
. O

This O
is O
the O
first O
report O
about O
phytochemical O
research O
on O
C O
. O
peii O
and O
the O
biogenetic O
hypothesis O
of O
forsythoside B
B I
and O
acteoside B
. O

Reducing O
effect O
of O
an O
extract O
of O
Phaseolus O
vulgaris O
on O
food O
intake O
in O
mice O
- O
- O
focus O
on O
highly O
palatable O
foods O
. O

Different O
lines O
of O
experimental O
evidence O
indicate O
that O
treatment O
with O
extracts O
from O
and O
derivatives O
of O
Phaseolus O
vulgaris O
reduces O
intake O
of O
food O
, O
including O
highly O
palatable O
foods O
and O
beverages O
, O
in O
rats O
. O

The O
present O
study O
was O
designed O
to O
extend O
to O
mice O
these O
lines O
of O
evidence O
. O

To O
this O
end O
, O
CD1 O
mice O
were O
treated O
acutely O
with O
a O
standardized O
extract O
of O
P O
. O
vulgaris O
and O
then O
exposed O
to O
unlimited O
access O
to O
regular O
food O
pellets O
( O
Experiment O
1 O
) O
or O
1 O
- O
hour O
limited O
access O
to O
three O
different O
palatable O
foods O
/ O
beverages O
, O
such O
as O
butter O
cookies O
( O
Experiment O
2 O
) O
, O
a O
condensed O
- O
milk O
beverage O
( O
Experiment O
3 O
) O
, O
and O
a O
chocolate O
- O
flavored O
beverage O
( O
Experiment O
4 O
) O
. O

Treatment O
with O
P O
. O
vulgaris O
extract O
resulted O
in O
a O
significant O
reduction O
in O
the O
intake O
of O
regular O
food O
pellets O
, O
that O
was O
still O
evident O
24h O
later O
, O
as O
well O
as O
of O
the O
three O
palatable O
nourishments O
. O

Together O
, O
these O
results O
( O
a O
) O
extend O
to O
mice O
several O
previous O
findings O
on O
the O
capacity O
of O
P O
. O
vulgaris O
extracts O
to O
suppress O
food O
intake O
in O
rats O
, O
( O
b O
) O
suggest O
that O
P O
. O
vulgaris O
extracts O
may O
interfere O
with O
the O
central O
mechanisms O
regulating O
appetite O
, O
food O
intake O
, O
palatability O
, O
and O
/ O
or O
the O
rewarding O
and O
hedonic O
properties O
of O
food O
, O
and O
( O
c O
) O
P O
. O
vulgaris O
extracts O
may O
represent O
a O
potentially O
effective O
therapy O
for O
overeating O
, O
obesity O
, O
and O
food O
craving O
. O

Characterization O
of O
tyrosinase O
inhibitors O
in O
the O
twigs O
of O
Cudrania O
tricuspidata O
and O
their O
structure O
- O
activity O
relationship O
study O
. O

The O
twigs O
of O
Cudrania O
tricuspidata O
were O
found O
to O
show O
strong O
tyrosinase O
inhibitory O
activity O
, O
and O
further O
detailed O
component O
analysis O
resulted O
in O
the O
isolation O
of O
a O
new O
flavanol B
glucoside I
, O
( B
2S I
, I
3S I
) I
- I
2 I
, I
3 I
- I
trans I
- I
dihydromorin I
- I
7 I
- I
O I
- I
beta I
- I
d I
- I
glucoside I
( O
1 O
) O
, O
plus O
twenty O
- O
seven O
known O
compounds O
( O
2 O
- O
28 O
) O
. O

Their O
structures O
were O
elucidated O
on O
the O
basis O
of O
ESI O
- O
MS O
and O
NMR O
spectral O
data O
. O

Among O
the O
isolated O
compounds O
, O
trans B
- I
dihydromorin I
( O
8 O
) O
, O
oxyresveratrol B
( O
9 O
) O
, O
and O
steppogenin B
( O
12 O
) O
were O
found O
to O
exhibit O
significant O
tyrosinase O
inhibition O
activities O
. O

Moreover O
, O
the O
structure O
- O
activity O
relationship O
of O
these O
isolated O
compounds O
was O
also O
discussed O
. O

Design O
, O
synthesis O
, O
inhibition O
studies O
, O
and O
molecular O
modeling O
of O
pepstatin B
analogues O
addressing O
different O
secreted O
aspartic O
proteinases O
of O
Candida O
albicans O
. O

The O
family O
of O
secreted O
aspartic O
proteinases O
is O
known O
as O
an O
important O
virulence O
factor O
of O
yeast O
infections O
by O
Candida O
albicans O
in O
particular O
, O
which O
is O
the O
most O
common O
fungal O
pathogen O
for O
humans O
with O
respect O
to O
systemic O
disease O
. O

Due O
to O
the O
continuing O
increase O
of O
drug O
resistant O
strains O
, O
these O
proteinases O
are O
currently O
considered O
as O
promising O
drug O
target O
candidates O
. O

Based O
on O
the O
known O
Sap2 O
- O
substrate O
specificity O
data O
and O
X O
- O
ray O
analyses O
of O
Sap O
/ O
inhibitor O
complexes O
, O
three O
libraries O
of O
inhibitors O
were O
designed O
and O
synthesized O
by O
modifying O
the O
structure O
of O
pepstatin B
A I
, O
a O
common O
non O
- O
selective O
aspartic O
proteinase O
inhibitor O
, O
at O
the O
P3 O
, O
P2 O
, O
or O
P2 O
' O
position O
. O

These O
novel O
inhibitors O
showed O
high O
inhibitory O
potencies O
for O
the O
isoenzymes O
Sap1 O
, O
Sap3 O
, O
Sap5 O
and O
Sap6 O
. O

Then O
, O
the O
affinity O
and O
selectivity O
of O
the O
peptide O
ligands O
were O
investigated O
by O
molecular O
modeling O
, O
highlighting O
new O
key O
structural O
information O
for O
the O
design O
of O
potent O
and O
selective O
anti O
- O
virulence O
agents O
targeting O
Candida O
albicans O
. O

FluidFM O
as O
a O
lithography O
tool O
in O
liquid O
: O
spatially O
controlled O
deposition O
of O
fluorescent O
nanoparticles O
. O

The O
atomic O
force O
microscope O
( O
AFM O
) O
is O
a O
powerful O
instrument O
for O
nanolithography O
, O
which O
is O
well O
characterized O
in O
air O
where O
the O
deposition O
process O
is O
steered O
by O
capillary O
action O
. O

In O
contrast O
, O
AFM O
patterning O
has O
been O
seldom O
achieved O
in O
liquid O
, O
mostly O
via O
electrochemical O
deposition O
. O

This O
study O
investigates O
the O
pressure O
- O
controlled O
local O
deposition O
of O
nanoparticles O
in O
a O
liquid O
environment O
using O
a O
FluidFM O
. O

Fluorescent O
25 O
nm O
polystyrene B
nanospheres O
were O
chosen O
as O
nanoobjects O
to O
be O
dispensed O
because O
they O
enable O
both O
the O
in O
situ O
monitoring O
of O
the O
process O
by O
optical O
microscopy O
and O
the O
ex O
situ O
high O
- O
resolution O
characterization O
of O
the O
pattern O
by O
e O
. O
g O
. O
scanning O
electron O
microscopy O
. O

The O
FluidFM O
microchannel O
was O
filled O
with O
an O
aqueous O
solution O
of O
negatively O
charged O
nanoparticles O
to O
be O
delivered O
onto O
a O
glass O
surface O
coated O
with O
a O
polycation O
. O

An O
overpressure O
in O
the O
internal O
fluidic O
circuit O
leads O
to O
the O
deposition O
of O
nanoparticle O
dots O
and O
lines O
under O
the O
tip O
, O
while O
the O
force O
control O
regulates O
the O
contact O
between O
the O
probe O
and O
the O
surface O
. O

The O
nanoparticle O
adsorption O
process O
depends O
both O
on O
applied O
pressure O
and O
contact O
time O
( O
respectively O
tip O
velocity O
) O
and O
can O
be O
described O
using O
the O
Langmuir O
approximation O
for O
the O
random O
sequential O
adsorption O
model O
. O

Moreover O
, O
we O
observed O
that O
the O
force O
setpoint O
, O
which O
does O
not O
influence O
the O
capillary O
- O
driven O
mechanism O
in O
air O
, O
indeed O
affects O
the O
hydrodynamic O
resistance O
at O
the O
tip O
aperture O
and O
therefore O
the O
volumetric O
flow O
. O

The O
described O
method O
demonstrates O
the O
potential O
of O
FluidFM O
in O
depositing O
nano O
- O
sized O
objects O
in O
liquid O
with O
nanometre O
precision O
. O

Both O
CpG B
methylation O
and O
activation O
- O
induced O
deaminase O
are O
required O
for O
the O
fragility O
of O
the O
human O
bcl O
- O
2 O
major O
breakpoint O
region O
: O
implications O
for O
the O
timing O
of O
the O
breaks O
in O
the O
t O
( O
14 O
; O
18 O
) O
translocation O
. O

The O
t O
( O
14 O
; O
18 O
) O
chromosomal O
translocation O
typically O
involves O
breakage O
at O
the O
bcl O
- O
2 O
major O
breakpoint O
region O
( O
MBR O
) O
to O
cause O
human O
follicular O
lymphoma O
. O

A O
theory O
to O
explain O
the O
striking O
propensity O
of O
the O
MBR O
breaks O
at O
three O
CpG B
clusters O
within O
the O
175 O
- O
bp O
MBR O
region O
invoked O
activation O
- O
induced O
deaminase O
( O
AID O
) O
. O

In O
a O
test O
of O
that O
theory O
, O
we O
used O
here O
minichromosomal O
substrates O
in O
human O
pre O
- O
B O
cell O
lines O
. O

Consistent O
with O
the O
essential O
elements O
of O
the O
theory O
, O
we O
found O
that O
the O
MBR O
breakage O
process O
is O
indeed O
highly O
dependent O
on O
DNA O
methylation O
at O
the O
CpG B
sites O
and O
highly O
dependent O
on O
the O
AID O
enzyme O
to O
create O
lesions O
at O
peak O
locations O
within O
the O
MBR O
. O

Interestingly O
, O
breakage O
of O
the O
phosphodiester B
bonds O
at O
the O
AID O
- O
initiated O
MBR O
lesions O
is O
RAG O
dependent O
, O
but O
, O
unexpectedly O
, O
most O
are O
also O
dependent O
on O
Artemis O
. O

We O
found O
that O
Artemis O
is O
capable O
of O
nicking O
small O
heteroduplex O
structures O
and O
is O
even O
able O
to O
nick O
single O
- O
base O
mismatches O
. O

This O
raises O
the O
possibility O
that O
activated O
Artemis O
, O
derived O
from O
the O
unjoined O
D O
to O
J O
( O
H O
) O
DNA O
ends O
at O
the O
IgH O
locus O
on O
chromosome O
14 O
, O
nicks O
AID O
- O
generated O
TG O
mismatches O
at O
methyl B
CpG I
sites O
, O
and O
this O
would O
explain O
why O
the O
breaks O
at O
the O
chromosome O
18 O
MBR O
occur O
within O
the O
same O
time O
window O
as O
those O
on O
chromosome O
14 O
. O

Quantitative O
analysis O
of O
chromosome O
condensation O
in O
fission O
yeast O
. O

Chromosomes O
undergo O
extensive O
conformational O
rearrangements O
in O
preparation O
for O
their O
segregation O
during O
cell O
divisions O
. O

Insights O
into O
the O
molecular O
mechanisms O
behind O
this O
still O
poorly O
understood O
condensation O
process O
require O
the O
development O
of O
new O
approaches O
to O
quantitatively O
assess O
chromosome O
formation O
in O
vivo O
. O

In O
this O
study O
, O
we O
present O
a O
live O
- O
cell O
microscopy O
- O
based O
chromosome O
condensation O
assay O
in O
the O
fission O
yeast O
Schizosaccharomyces O
pombe O
. O

By O
automatically O
tracking O
the O
three O
- O
dimensional O
distance O
changes O
between O
fluorescently O
marked O
chromosome O
loci O
at O
high O
temporal O
and O
spatial O
resolution O
, O
we O
analyze O
chromosome O
condensation O
during O
mitosis O
and O
meiosis O
and O
deduct O
defined O
parameters O
to O
describe O
condensation O
dynamics O
. O

We O
demonstrate O
that O
this O
method O
can O
determine O
the O
contributions O
of O
condensin O
, O
topoisomerase O
II O
, O
and O
Aurora O
kinase O
to O
mitotic O
chromosome O
condensation O
. O

We O
furthermore O
show O
that O
the O
assay O
can O
identify O
proteins O
required O
for O
mitotic O
chromosome O
formation O
de O
novo O
by O
isolating O
mutants O
in O
condensin O
, O
DNA O
polymerase O
epsilon O
, O
and O
F O
- O
box O
DNA O
helicase O
I O
that O
are O
specifically O
defective O
in O
pro O
- O
/ O
metaphase O
condensation O
. O

Thus O
, O
the O
chromosome O
condensation O
assay O
provides O
a O
direct O
and O
sensitive O
system O
for O
the O
discovery O
and O
characterization O
of O
components O
of O
the O
chromosome O
condensation O
machinery O
in O
a O
genetically O
tractable O
eukaryote O
. O

The O
conserved O
PHD1 O
- O
PHD2 O
domain O
of O
ZFP O
- O
1 O
/ O
AF10 O
is O
a O
discrete O
functional O
module O
essential O
for O
viability O
in O
Caenorhabditis O
elegans O
. O

Plant O
homeodomain O
( O
PHD O
) O
- O
type O
zinc B
fingers O
play O
an O
important O
role O
in O
recognizing O
chromatin O
modifications O
and O
recruiting O
regulatory O
proteins O
to O
specific O
genes O
. O

A O
specific O
module O
containing O
a O
conventional O
PHD O
finger O
followed O
by O
an O
extended O
PHD O
finger O
exists O
in O
the O
mammalian O
AF10 O
protein O
, O
among O
a O
few O
others O
. O

AF10 O
has O
mostly O
been O
studied O
in O
the O
context O
of O
the O
leukemic O
MLL O
- O
AF10 O
fusion O
protein O
, O
which O
lacks O
the O
N B
- O
terminal O
PHD O
fingers O
of O
AF10 O
. O

Although O
this O
domain O
of O
AF10 O
is O
the O
most O
conserved O
region O
of O
the O
protein O
, O
its O
biological O
significance O
has O
not O
been O
elucidated O
. O

In O
this O
study O
, O
we O
used O
genetic O
and O
biochemical O
approaches O
to O
examine O
the O
PHD1 O
- O
PHD2 O
region O
of O
the O
Caenorhabditis O
elegans O
ortholog O
of O
AF10 O
, O
zinc O
finger O
protein O
1 O
( O
ZFP O
- O
1 O
) O
. O

We O
demonstrate O
that O
the O
PHD1 O
- O
PHD2 O
region O
is O
essential O
for O
viability O
and O
that O
the O
first O
PHD O
finger O
contributes O
to O
the O
preferred O
binding O
of O
PHD1 O
- O
PHD2 O
to O
lysine B
4 O
- O
methylated O
histone O
H3 O
tails O
. O

Moreover O
, O
we O
show O
that O
ZFP O
- O
1 O
localization O
peaks O
overlap O
with O
H3K4 O
methylation O
- O
enriched O
promoters O
of O
actively O
expressed O
genes O
genomewide O
and O
that O
H3K4 O
methylation O
is O
important O
for O
ZFP O
- O
1 O
localization O
to O
promoters O
in O
the O
embryo O
. O

We O
predict O
that O
the O
essential O
biological O
role O
of O
the O
PHD1 O
- O
PHD2 O
module O
of O
ZFP O
- O
1 O
/ O
AF10 O
is O
connected O
to O
the O
regulation O
of O
actively O
expressed O
genes O
during O
early O
development O
. O

Interferon O
beta O
and O
glatiramer B
acetate I
therapy O
. O

Interferon O
beta O
and O
glatiramer B
acetate I
have O
been O
mainstays O
of O
treatment O
in O
relapsingremitting O
multiple O
sclerosis O
for O
two O
decades O
. O

Remarkable O
advances O
in O
our O
understanding O
of O
immune O
function O
and O
dysfunction O
as O
well O
as O
increasingly O
sophisticated O
clinical O
trial O
design O
have O
stemmed O
from O
efforts O
to O
better O
understand O
these O
drugs O
. O

In O
this O
chapter O
, O
we O
review O
the O
history O
of O
their O
development O
and O
elaborate O
on O
known O
and O
theorized O
mechanisms O
of O
action O
. O

We O
describe O
the O
pivotal O
clinical O
trials O
that O
have O
led O
to O
their O
widespread O
use O
. O

We O
evaluate O
the O
clinical O
use O
of O
the O
drugs O
including O
tolerability O
, O
side O
effects O
, O
and O
efficacy O
measures O
. O

Finally O
, O
we O
look O
to O
the O
future O
of O
interferon O
beta O
and O
glatiramer B
acetate I
in O
the O
context O
of O
an O
ever O
growing O
armamentarium O
of O
treatments O
for O
relapsing O
remitting O
multiple O
sclerosis O
. O

Long O
- O
lasting O
inhibitory O
effect O
of O
apple O
and O
orange O
juices O
, O
but O
not O
grapefruit O
juice O
, O
on O
OATP2B1 O
- O
mediated O
drug O
absorption O
. O

Enzyme O
- O
based O
grapefruit O
juice O
( O
GFJ O
) O
- O
drug O
interactions O
are O
mainly O
due O
to O
mechanism O
- O
based O
irreversible O
inhibition O
of O
metabolizing O
enzyme O
CYP3A4 O
by O
GFJ O
components O
, O
but O
the O
transporter O
organic O
anion O
transporting O
polypeptide O
( O
OATP O
) O
2B1 O
is O
also O
a O
putative O
site O
of O
interaction O
between O
drugs O
and O
fruit O
juices O
( O
FJ O
) O
in O
the O
absorption O
process O
. O

Here O
we O
aimed O
to O
investigate O
the O
effect O
of O
preincubation O
with O
FJ O
on O
OATP2B1 O
- O
mediated O
transport O
of O
drugs O
in O
vitro O
. O

When O
OATP2B1 O
- O
expressing O
Xenopus O
oocytes O
were O
preincubated O
with O
GFJ O
, O
orange O
juice O
( O
OJ O
) O
, O
or O
apple O
juice O
( O
AJ O
) O
, O
AJ O
induced O
a O
remarkable O
decrease O
in O
OATP2B1 O
- O
mediated O
estrone B
- I
3 I
- I
sulfate I
uptake O
in O
a O
concentration O
- O
dependent O
manner O
( O
IC O
( O
50 O
) O
= O
1 O
. O
5 O
% O
) O
. O

A O
similar O
but O
less O
potent O
effect O
was O
observed O
with O
OJ O
( O
IC O
( O
50 O
) O
= O
21 O
% O
) O
, O
whereas O
GFJ O
had O
no O
effect O
. O

Similar O
results O
were O
obtained O
in O
preincubation O
studies O
using O
fexofenadine B
. O

Preincubation O
with O
OJ O
and O
AJ O
resulted O
in O
time O
- O
dependent O
inhibition O
of O
OATP2B1 O
. O

Again O
, O
AJ O
had O
the O
more O
potent O
effect O
; O
its O
action O
lasted O
for O
at O
least O
240 O
minutes O
, O
suggesting O
that O
AJ O
irreversibly O
inhibits O
OATP2B1 O
- O
mediated O
drug O
uptake O
. O

Kinetic O
analysis O
revealed O
that O
coincubation O
and O
preincubation O
with O
AJ O
reduced O
OATP2B1 O
- O
mediated O
estrone B
- I
3 I
- I
sulfate I
uptake O
via O
competitive O
and O
noncompetitive O
mechanisms O
, O
respectively O
. O

Thus O
, O
OATP2B1 O
is O
functionally O
impaired O
through O
both O
competitive O
and O
long O
- O
lasting O
inhibition O
mechanisms O
by O
AJ O
and O
OJ O
, O
but O
not O
GFJ O
. O

Interestingly O
, O
although O
GFJ B
but O
not O
AJ O
is O
able O
to O
irreversibly O
inhibit O
CYP3A4 O
, O
in O
the O
case O
of O
OATP2B1 O
, O
AJ O
but O
not O
GFJ B
has O
a O
long O
- O
lasting O
inhibitory O
effect O
. O

Accordingly O
, O
complex O
FJ O
- O
drug O
interactions O
may O
occur O
in O
vivo O
, O
and O
their O
clinical O
significance O
should O
be O
examined O
. O

Vicilin O
and O
the O
basic O
subunit O
of O
legumin O
are O
putative O
chickpea O
allergens O
. O

IgE O
- O
mediated O
reactions O
to O
food O
allergens O
constitute O
a O
major O
health O
problem O
in O
industrialized O
countries O
. O

Chickpea O
is O
consumed O
in O
Mediterranean O
countries O
, O
and O
reportedly O
associated O
with O
IgE O
- O
mediated O
hypersensitivity O
reactions O
. O

However O
, O
the O
nature O
of O
allergic O
reactions O
to O
chickpea O
has O
not O
been O
characterized O
. O

A O
serum O
pool O
from O
paediatric O
patients O
allergic O
to O
chickpeas O
was O
used O
to O
detect O
IgE O
- O
binding O
proteins O
from O
chickpea O
seeds O
by O
immunoassay O
and O
immunoblot O
inhibition O
assay O
. O

Protein O
samples O
enriched O
in O
chickpea O
legumin O
and O
vicilin O
were O
obtained O
by O
anion O
exchange O
chromatography O
, O
and O
were O
identified O
by O
mass O
spectrometric O
analysis O
. O

IgE O
- O
immunoassays O
of O
globulin O
fractions O
from O
chickpeas O
revealed O
that O
vicilin O
( O
50 O
kDa O
) O
and O
the O
basic O
subunit O
of O
legumin O
( O
20 O
kDa O
) O
were O
bound O
by O
IgE O
from O
patient O
sera O
. O

Pea O
and O
lentil O
protein O
extracts O
strongly O
inhibited O
the O
IgE O
binding O
to O
chickpea O
globulin O
. O

We O
speculate O
that O
vicilin O
and O
the O
basic O
subunit O
of O
legumin O
are O
major O
chickpea O
allergens O
. O

Also O
, O
the O
globulin O
fraction O
of O
chickpea O
likely O
cross O
- O
reacts O
with O
the O
allergenic O
proteins O
of O
pea O
and O
lentil O
. O

Antioxidant O
and O
immunomodulatory O
activity O
of O
selenium B
exopolysaccharide O
produced O
by O
Lactococcus O
lactis O
subsp O
. O
lactis O
. O

Exopolysaccharide O
( O
EPS O
) O
was O
isolated O
and O
purified O
from O
Lactococcus O
lactis O
subsp O
. O

Lactis O
culture O
broth O
. O

Selenium B
chloride I
oxide I
( O
SeCl B
( I
2 I
) I
O I
) O
was O
added O
to O
the O
EPS O
to O
synthesize O
selenium B
- O
exopolysaccharide O
( O
Se B
- O
EPS O
) O
. O

The O
in O
vitro O
and O
in O
vivo O
antioxidant O
and O
in O
vivo O
immunomodulatory O
activity O
of O
EPS O
and O
Se B
- O
EPS O
were O
compared O
. O

EPS O
and O
Se O
- O
EPS O
scavenged O
superoxide B
anions O
and O
hydroxyl B
radicals O
. O

They O
also O
increased O
catalase O
( O
CAT O
) O
, O
superoxide B
dismutase O
( O
SOD O
) O
and O
glutathione B
peroxidase O
( O
GSH B
- O
Px O
) O
activity O
, O
while O
decreasing O
malondialdehyde B
( O
MDA B
) O
levels O
in O
serum O
and O
in O
the O
livers O
of O
mice O
. O

Se B
- O
EPS O
showed O
stronger O
in O
vitro O
and O
in O
vivo O
antioxidant O
activity O
than O
were O
shown O
by O
EPS O
. O

The O
in O
vivo O
immunoenhancement O
activity O
of O
EPS O
and O
Se B
- O
EPS O
induced O
by O
cyclophosphamide B
( O
CY O
) O
treatment O
in O
immunosuppressed O
mice O
was O
researched O
. O

EPS O
and O
Se B
- O
EPS O
treatments O
increased O
macrophage O
phagocytosis O
, O
spleen O
and O
thymus O
indices O
and O
haemolytic O
complement O
activity O
( O
HC O
( O
50 O
) O
) O
. O

Se B
- O
EPS O
showed O
stronger O
immunomodulatory O
activity O
than O
did O
EPS O
. O

Apoptosis O
during O
postmortem O
conditioning O
and O
its O
relationship O
to O
duck O
meat O
quality O
. O

The O
aim O
of O
this O
work O
was O
to O
examine O
the O
relationship O
of O
skeletal O
muscle O
apoptosis O
and O
postmortem O
development O
of O
meat O
quality O
. O

Colour O
, O
cooking O
loss O
, O
myofibril O
fragmentation O
index O
( O
MFI O
) O
and O
shear O
force O
of O
duck O
breast O
and O
thigh O
meat O
postmortem O
were O
measured O
, O
and O
changes O
of O
positive O
nuclei O
were O
assessed O
with O
Terminal O
deoxynucleotidyl O
transferase O
- O
mediated O
deoxyuridine B
triphosphophate I
nick O
end O
- O
labelling O
method O
( O
TUNEL O
) O
. O

Correlation O
analysis O
revealed O
that O
apoptosis O
were O
positively O
correlated O
with O
colour O
( O
L O
( O
* O
) O
, O
a O
( O
* O
) O
and O
b O
( O
* O
) O
) O
, O
cooking O
loss O
and O
MFI O
( O
P O
< O
0 O
. O
05 O
) O
, O
while O
it O
is O
negatively O
correlated O
with O
shear O
force O
( O
P O
< O
0 O
. O
05 O
) O
. O

Our O
results O
indicate O
the O
growing O
level O
of O
duck O
skeletal O
muscle O
cell O
apoptosis O
was O
associated O
with O
the O
postmortem O
development O
of O
meat O
quality O
traits O
such O
as O
meat O
colour O
, O
water O
holding O
capacity O
and O
tenderness O
. O

Biochemical O
characterisation O
of O
Alaska O
pollock O
, O
Pacific O
whiting O
, O
and O
threadfin O
bream O
surimi O
as O
affected O
by O
comminution O
conditions O
. O

Salt O
- O
soluble O
protein O
, O
surface O
reactive O
sulfhydryl B
content O
, O
and O
surface O
hydrophobicity O
of O
Alaska O
pollock O
, O
Pacific O
whiting O
, O
and O
threadfin O
bream O
surimi O
were O
characterised O
, O
as O
affected O
by O
various O
comminution O
conditions O
. O

Chopping O
time O
/ O
temperatures O
were O
explored O
in O
consideration O
of O
their O
habitat O
temperatures O
. O

Salt O
- O
soluble O
protein O
( O
SSP O
) O
significantly O
decreased O
when O
chopping O
time O
was O
extended O
. O

Corresponding O
to O
our O
follow O
- O
up O
study O
, O
no O
relationship O
between O
SSP O
and O
gel O
texture O
was O
found O
. O

Surface O
hydrophobicity O
was O
inversely O
proportional O
to O
SSP O
concentration O
, O
indicating O
the O
unfolding O
of O
protein O
upon O
comminution O
. O

Alaska O
pollock O
surimi O
demonstrated O
aggregation O
during O
chopping O
at O
10 O
and O
20 O
degrees O
C O
, O
based O
on O
the O
surface O
hydrophobicity O
. O

Surface O
reactive O
sulfhydryl B
( O
SRSH O
) O
contents O
of O
the O
three O
fish O
species O
behaved O
differently O
. O

The O
SH B
groups O
were O
oxidized O
to O
disulphide B
bonds O
when O
higher O
chopping O
temperature O
was O
applied O
. O

As O
a O
result O
, O
increased O
SRSH B
content O
was O
not O
observed O
in O
Alaska O
pollock O
( O
10 O
and O
20 O
degrees O
C O
chopping O
) O
and O
threadfin O
bream O
paste O
( O
25 O
and O
30 O
degrees O
C O
chopping O
) O
. O

Characterization O
of O
modified O
high O
- O
amylose O
maize O
starch O
- O
alpha B
- I
naphthol I
complexes O
and O
their O
influence O
on O
rheological O
properties O
of O
wheat O
starch O
. O

Amylose O
can O
form O
inclusion O
complexes O
with O
diverse O
small O
molecules O
. O

Modified O
starch O
has O
different O
and O
unique O
properties O
compared O
with O
its O
native O
counterpart O
. O

In O
this O
study O
, O
chemically O
/ O
enzymatically O
modified O
high O
- O
amylose O
maize O
starches O
were O
used O
to O
make O
inclusion O
complexes O
with O
alpha B
- I
naphthol I
, O
and O
the O
physical O
properties O
of O
complexes O
and O
their O
influences O
on O
the O
rheology O
of O
wheat O
starch O
were O
characterized O
. O

The O
results O
showed O
that O
modification O
of O
starch O
had O
little O
influence O
on O
the O
wide O
angle O
X O
- O
ray O
diffraction O
pattern O
of O
complex O
( O
eightfold O
single O
helix O
) O
, O
but O
did O
so O
on O
the O
complexation O
index O
and O
precipitation O
yield O
. O

Inclusion O
complexes O
with O
chemically O
modified O
starch O
showed O
a O
lower O
range O
of O
thermostability O
and O
recrystallization O
temperatures O
. O

Addition O
of O
complex O
considerably O
influenced O
the O
rheological O
properties O
of O
wheat O
starch O
, O
and O
the O
effect O
was O
dependent O
on O
the O
type O
of O
modified O
starch O
used O
. O

It O
may O
be O
concluded O
that O
starch O
inclusion O
complexes O
, O
with O
a O
range O
of O
properties O
and O
potential O
food O
applications O
, O
may O
be O
feasibly O
prepared O
by O
using O
diverse O
modified O
high O
- O
amylose O
maize O
starches O
. O

Retention O
of O
aroma O
compounds O
from O
Mentha O
piperita O
essential O
oil O
by O
cyclodextrins O
and O
crosslinked O
cyclodextrin O
polymers O
. O

In O
this O
paper O
, O
the O
controlled O
release O
of O
aroma O
compounds O
from O
cyclodextrins O
( O
CDs O
) O
and O
CD O
polymers O
was O
studied O
by O
multiple O
headspace O
extraction O
( O
MHE O
) O
experiments O
. O

Mentha O
piperita O
essential O
oil O
was O
obtained O
by O
Soxhlet O
extraction O
and O
identification O
of O
the O
major O
compounds O
was O
performed O
by O
GC O
- O
MS O
analysis O
. O

Menthol B
, O
menthone B
, O
pulegone B
and O
eucalyptol B
were O
identified O
as O
the O
major O
components O
. O

Retention O
of O
standard O
compounds O
in O
the O
presence O
of O
different O
CDs B
and O
CD B
polymers O
has O
been O
realised O
by O
static O
headspace O
gas O
chromatography O
( O
SH O
- O
GC O
) O
at O
25 O
degrees O
C O
in O
the O
aqueous O
or O
gaseous O
phase O
. O

Stability O
constants O
for O
standard O
compounds O
and O
for O
compounds O
in O
essential O
oil O
have O
been O
also O
determined O
with O
monomeric O
CD O
derivatives O
. O

The O
obtained O
results O
indicated O
the O
formation O
of O
a O
1 O
: O
1 O
inclusion O
complex O
for O
all O
the O
studied O
compounds O
. O

Molecular O
modelling O
was O
used O
to O
investigate O
the O
complementarities O
between O
host O
and O
guest O
. O

This O
study O
showed O
that O
beta O
- O
CDs I
were O
the O
most O
versatile O
CDs O
and O
that O
beta B
- I
CD I
polymers O
could O
perform O
the O
controlled O
release O
of O
aroma O
compounds O
. O

Effects O
of O
ozone B
microbubble O
treatment O
on O
removal O
of O
residual O
pesticides O
and O
quality O
of O
persimmon O
leaves O
. O

This O
study O
investigated O
the O
effects O
of O
ozone B
microbubble O
( O
OMCB O
) O
treatment O
on O
the O
removal O
of O
residual O
fenitrothion B
( O
FT O
) O
and O
benomyl B
pesticides O
from O
red O
and O
green O
persimmon O
leaves O
, O
and O
also O
the O
treatment O
effect O
on O
the O
leaf O
colours O
, O
physical O
properties O
and O
flavour O
. O

The O
continuous O
bubbling O
OMCB B
treatment O
was O
more O
effective O
than O
the O
non O
- O
bubbling O
OMCB B
treatments O
at O
reducing O
the O
FT O
and O
benomyl B
agricultural O
pesticide O
residues O
from O
both O
the O
red O
and O
green O
persimmon O
leaves O
. O

Moreover O
, O
the O
bubbling O
OMCB B
treatment O
had O
no O
effect O
on O
the O
colour O
and O
pulling O
strength O
of O
the O
leaves O
. O

These O
results O
indicate O
that O
the O
treatment O
by O
bubbling O
OMCB O
is O
an O
extremely O
effective O
method O
for O
removing O
the O
residues O
of O
FT O
and O
benomyl B
in O
persimmon O
leaves O
and O
has O
relatively O
little O
effect O
on O
leaf O
quality O
characteristics O
. O

The O
influence O
of O
pectolytic O
enzyme O
addition O
and O
prefermentative O
mash O
heating O
during O
the O
winemaking O
process O
on O
the O
phenolic B
composition O
of O
Okuzgozu O
red O
wine O
. O

The O
effects O
of O
pectolytic O
enzyme O
addition O
and O
mash O
heating O
prior O
to O
fermentation O
on O
the O
phenolic B
component O
of O
Okuzgozu O
red O
wine O
during O
the O
winemaking O
and O
ageing O
processes O
were O
investigated O
. O

In O
general O
, O
the O
highest O
concentration O
of O
total O
phenolics B
was O
found O
in O
the O
mash O
- O
heated O
wines O
, O
whereas O
the O
total O
flavan B
- I
3 I
- I
ol I
and O
total O
anthocyanin B
contents O
in O
all O
of O
the O
wines O
, O
decreased O
notably O
during O
the O
winemaking O
and O
ageing O
processes O
. O

As O
determined O
by O
HPLC O
, O
hydroxycinnamic B
acids I
were O
the O
major O
phenolic B
acids I
in O
the O
red O
wines O
. O

After O
6 O
months O
in O
the O
bottle O
, O
the O
enzyme O
- O
treated O
wines O
had O
lower O
phenolic B
acid I
concentrations O
than O
had O
the O
control O
and O
mash O
- O
heated O
wines O
, O
but O
no O
significant O
( O
p O
< O
0 O
. O
05 O
) O
differences O
were O
found O
in O
the O
concentration O
of O
total O
phenolic B
acids I
between O
the O
control O
and O
mash O
- O
heated O
wines O
. O

All O
of O
the O
phenolic B
acid I
levels O
decreased O
with O
the O
winemaking O
and O
ageing O
processes O
whereas O
only O
gallic B
acid I
increased O
. O

The O
wines O
treated O
by O
the O
pectolytic O
enzyme O
addition O
had O
a O
lower O
monomeric O
flavan B
- I
3 I
- I
ol I
content O
than O
had O
the O
other O
wines O
, O
and O
the O
amount O
of O
monomeric O
anthocyanins B
extracted O
did O
not O
increase O
with O
the O
addition O
of O
enzymes O
. O

Identification O
of O
xyloglucan O
endotransglucosylase O
/ O
hydrolase O
genes O
( O
XTHs O
) O
and O
their O
expression O
in O
persimmon O
fruit O
as O
influenced O
by O
1 B
- I
methylcyclopropene I
and O
gibberellic B
acid I
during O
storage O
at O
ambient O
temperature O
. O

Xyloglucan O
endotransglucosylase O
/ O
hydrolase O
( O
XTH O
) O
is O
thought O
to O
contribute O
to O
fruit O
softening O
by O
degrading O
xyloglucan O
that O
is O
a O
predominant O
hemicellulose O
in O
the O
cell O
wall O
. O

In O
this O
study O
, O
two O
full O
- O
length O
XTH O
genes O
( O
DKXTH1 O
and O
DKXTH2 O
) O
were O
identified O
from O
' O
Fupingjianshi O
' O
persimmon O
fruit O
, O
and O
the O
expression O
level O
of O
both O
XTH O
genes O
was O
investigated O
during O
softening O
for O
18 O
- O
24 O
d O
using O
RT O
- O
qPCR O
. O

Sequence O
analysis O
showed O
that O
DKXTH1 O
and O
DKXTH2 O
contained O
a O
putative O
open O
reading O
frame O
of O
861 O
and O
876 O
bp O
encoding O
polypeptides O
of O
287 O
and O
292 O
amino B
acid I
residues O
, O
respectively O
, O
which O
contained O
the O
conserved O
DEIDFEFLG O
motif O
of O
XTH O
, O
a O
potential O
N B
- O
linked O
glycosylation O
signal O
site O
. O

RT O
- O
qPCR O
analysis O
showed O
that O
DKXTH1 O
and O
DKXTH2 O
in O
untreated O
fruit O
had O
different O
expression O
patterns O
during O
fruit O
softening O
, O
in O
which O
maximum O
expression O
occurred O
on O
days O
3 O
and O
12 O
of O
ripening O
, O
respectively O
. O

1 B
- I
Methylcyclopropene I
( O
1 B
- I
MCP I
) O
and O
gibberellic B
acid I
( O
GA B
( I
3 I
) I
) O
treatments O
delayed O
the O
softening O
and O
ethylene B
peak O
of O
persimmon O
fruit O
, O
as O
well O
as O
suppressed O
the O
expression O
of O
both O
XTH O
genes O
, O
especially O
DKXTH1 O
. O

These O
results O
indicated O
that O
the O
expression O
of O
both O
XTH O
genes O
might O
be O
ethylene B
dependent O
action O
, O
and O
closely O
related O
to O
softening O
of O
persimmon O
in O
the O
early O
( O
DKXTH1 O
) O
and O
later O
( O
DKXTH2 O
) O
ripening O
stages O
. O

Production O
of O
the O
alpha O
- O
glycosidase O
inhibitor O
1 B
- I
deoxynojirimycin I
from O
Bacillus O
species O
. O

1 B
- I
Deoxynojirimycin I
( O
DNJ B
) O
, O
a O
potent O
alpha O
- O
glycosidase O
inhibitor O
, O
has O
therapeutic O
applications O
in O
treatments O
of O
HIV O
, O
Gaucher O
' O
s O
disease O
, O
and O
diabetes O
. O

DNJ B
has O
been O
extracted O
from O
natural O
sources O
( O
mulberry O
leaves O
) O
for O
therapeutic O
purposes O
; O
however O
, O
DNJ B
ingredients O
are O
in O
limited O
supply O
and O
are O
costly O
to O
obtain O
on O
a O
large O
scale O
. O

Since O
certain O
strains O
of O
Bacillus O
and O
Streptomyces O
species O
reportedly O
produce O
DNJ B
, O
they O
may O
serve O
as O
potential O
sources O
for O
high O
- O
yield O
DNJ B
production O
. O

In O
this O
study O
, O
we O
obtained O
evidence O
for O
a O
DNJ B
production O
in O
Bacillus O
subtilis O
DSM704 O
by O
hydrophilic O
interaction O
chromatography O
- O
tandem O
mass O
spectrometry O
. O

In O
addition O
, O
from O
a O
screen O
of O
750 O
microorganisms O
, O
we O
identified O
additional O
Bacillus O
strains O
( O
Bacillus O
amyloliquefaciens O
AS385 O
and O
Bacillus O
subtilis O
B4 O
) O
that O
produce O
DNJ B
in O
large O
quantities O
. O

Investigation O
of O
the O
effect O
of O
various O
culture O
conditions O
, O
using O
Bacillus O
subtilis O
DSM704 O
and O
the O
DNJ B
high O
- O
production O
Bacillus O
strains O
, O
provided O
evidence O
for O
the O
importance O
of O
sorbitol B
supplementation O
on O
the O
yield O
of O
the O
DNJ B
precursor O
, O
2 B
- I
amino I
- I
2 I
- I
deoxy I
- I
D I
- I
mannitol I
, O
thereby O
increasing O
DNJ B
production O
. O

The O
role O
of O
sorbitol B
in O
increased O
DNJ B
production O
was O
supported O
by O
an O
observed O
increase O
in O
mRNA O
expression O
of O
the O
biosynthetic O
gene O
, O
gabT1 O
. O

When O
Bacillus O
amyloliquefaciens O
AS385 O
was O
cultured O
in O
medium O
supplemented O
with O
sorbitol B
, O
extracellular O
DNJ B
concentration O
reached O
a O
maximum O
of O
460 O
mg O
/ O
l O
of O
medium O
( O
equivalent O
to O
9 O
. O
20mg O
/ O
g O
of O
freeze O
- O
dried O
medium O
) O
, O
indicating O
that O
this O
strain O
can O
serve O
as O
a O
source O
for O
food O
- O
and O
drug O
- O
grade O
products O
. O

These O
findings O
not O
only O
lead O
to O
a O
further O
understanding O
of O
the O
DNJ B
biosynthetic O
pathway O
, O
but O
also O
suggest O
a O
method O
for O
microbial O
mass O
production O
of O
DNJ B
for O
therapeutic O
applications O
. O

Grape O
seed O
procyanidin B
extract O
modulates O
proliferation O
and O
apoptosis O
of O
pancreatic O
beta O
- O
cells O
. O

Grape O
seed O
procyanidin B
extract O
( O
GSPE O
) O
modulates O
glucose B
homeostasis O
and O
insulinemia O
in O
several O
animal O
models O
. O

Under O
pathological O
conditions O
, O
insulin O
levels O
are O
dependent O
on O
pancreatic O
beta O
- O
cell O
functionality O
, O
as O
well O
as O
on O
the O
beta O
- O
cell O
mass O
expansion O
or O
apoptosis O
in O
the O
pancreas O
. O

In O
this O
study O
, O
we O
analysed O
the O
effects O
of O
GSPE O
on O
modulating O
apoptosis O
and O
proliferation O
in O
beta O
- O
cells O
. O

We O
tested O
the O
effects O
of O
GSPE O
in O
the O
INS O
- O
1E O
pancreatic O
beta O
- O
cell O
line O
, O
either O
under O
basal O
or O
altered O
conditions O
with O
high O
glucose B
, O
insulin O
or O
palmitate B
levels O
. O

GSPE O
enhanced O
the O
pro O
- O
apoptotic O
effect O
of O
high O
glucose B
and O
showed O
clear O
antiproliferative O
effects O
under O
high O
glucose B
, O
insulin O
and O
palmitate B
conditions O
. O

These O
antiproliferative O
effects O
are O
likely O
due O
to O
high O
molecular O
weight O
compounds O
contained O
in O
the O
extract O
. O

GSPE O
also O
modulated O
pro O
- O
and O
anti O
- O
apoptotic O
markers O
in O
the O
pancreas O
of O
rats O
fed O
a O
cafeteria O
diet O
, O
with O
the O
effect O
depending O
on O
the O
dose O
of O
GSPE O
and O
duration O
of O
treatment O
. O

Thus O
, O
GSPE O
is O
able O
to O
modulate O
apoptosis O
and O
proliferation O
of O
beta O
- O
cells O
under O
altered O
, O
but O
not O
basal O
, O
conditions O
. O

Physicochemical O
properties O
of O
lard O
- O
based O
diacylglycerols B
in O
blends O
with O
lard O
. O

The O
objective O
of O
the O
study O
was O
to O
investigate O
how O
blending O
of O
triacylglycerols B
and O
diacylglycerols B
affected O
the O
melting O
and O
crystallisation O
properties O
in O
a O
solid O
fat O
system O
. O

Lard O
- O
based O
diacylglycerols B
( O
DAGs B
) O
were O
blended O
with O
lard O
in O
various O
concentrations O
( O
0 O
% O
, O
1 O
% O
, O
5 O
% O
, O
10 O
% O
, O
20 O
% O
, O
50 O
% O
, O
60 O
% O
, O
70 O
% O
, O
80 O
% O
, O
90 O
% O
, O
and O
100 O
% O
) O
. O

The O
melting O
and O
crystallisation O
properties O
were O
investigated O
by O
the O
determination O
of O
dropping O
point O
( O
DP O
) O
, O
solid O
fat O
content O
( O
SFC O
) O
, O
differential O
scanning O
calorimetry O
( O
DSC O
) O
and O
X O
- O
ray O
diffraction O
( O
XRD O
) O
. O

In O
general O
, O
the O
effects O
of O
DAGs B
were O
found O
to O
be O
dependent O
on O
concentration O
. O

The O
DP O
was O
significantly O
( O
P O
< O
0 O
. O
0001 O
) O
decreased O
when O
DAGs B
were O
added O
to O
the O
lard O
from O
5 O
- O
50 O
% O
, O
whereas O
the O
DP O
was O
increased O
( O
P O
< O
0 O
. O
0001 O
) O
when O
the O
blends O
contained O
more O
than O
60 O
% O
DAGs B
. O

The O
DSC O
thermograms O
showed O
that O
DAGs B
changed O
the O
melting O
and O
crystallisation O
profiles O
of O
lard O
. O

The O
crystallisation O
onset O
point O
increased O
( O
P O
< O
0 O
. O
05 O
) O
with O
increasing O
the O
DAG B
concentrations O
( O
10 O
- O
100 O
% O
) O
. O

The O
melting O
peaks O
and O
off O
- O
set O
points O
generally O
shifted O
slightly O
towards O
higher O
temperatures O
as O
the O
content O
of O
DAGs B
increased O
above O
50 O
% O
. O

DAG B
content O
of O
5 O
% O
and O
10 O
% O
resulted O
in O
lowering O
of O
the O
off O
- O
set O
point O
. O

The O
lard O
contained O
both O
beta O
and O
beta O
' O
crystals O
. O

The O
beta O
form O
was O
more O
pronounced O
in O
the O
blends O
with O
high O
concentrations O
of O
DAGs B
. O

Blending O
of O
TAGs B
and O
DAGs B
may O
serve O
as O
a O
solution O
to O
achieve O
specific O
functional O
properties O
in O
products O
containing O
solid O
fats O
. O

Reduction O
of O
acrylamide B
formation O
by O
vanadium B
salt O
in O
potato O
French O
fries O
and O
chips O
. O

The O
effects O
of O
vanadyl B
sulphate I
on O
the O
formation O
of O
acrylamide B
have O
been O
studied O
in O
fried O
potato O
products O
, O
such O
as O
French O
fries O
and O
chips O
. O

Acrylamide B
formation O
was O
inhibited O
by O
30 O
. O
3 O
% O
, O
53 O
. O
3 O
% O
and O
89 O
. O
3 O
% O
when O
the O
sliced O
potato O
strips O
were O
soaked O
in O
0 O
. O
001 O
, O
0 O
. O
01 O
and O
0 O
. O
1 O
M O
vanadyl B
sulphate I
( O
VOSO B
( I
4 I
) I
) O
solutions O
, O
respectively O
, O
for O
60 O
min O
before O
frying O
. O

Moreover O
, O
57 O
. O
7 O
% O
, O
71 O
. O
4 O
% O
and O
92 O
. O
5 O
% O
inhibition O
of O
acrylamide B
formation O
was O
observed O
when O
chips O
were O
soaked O
in O
the O
respective O
vanadyl B
sulphate I
solution O
before O
frying O
. O

In O
a O
separate O
model O
reaction O
, O
a O
solution O
containing O
an O
equimolar O
concentration O
of O
L B
- I
asparagine I
and O
D B
- I
glucose I
showed O
a O
significant O
inhibition O
of O
acrylamide B
formation O
when O
heated O
at O
150 O
degrees O
C O
for O
30 O
min O
in O
the O
presence O
of O
vanadyl B
sulphate I
( O
VOSO B
( I
4 I
) I
) O
. O

The O
results O
indicate O
that O
the O
binding O
of O
VO B
( I
2 I
+ I
) I
to O
asparagine B
and O
the O
decrease O
in O
the O
pH O
of O
the O
potato O
samples O
resulted O
in O
a O
significant O
reduction O
of O
acrylamide B
formation O
in O
fried O
potato O
products O
. O

Determination O
of O
fluorine B
in O
milk O
samples O
via O
calcium B
- I
monofluoride I
by O
electrothermal O
molecular O
absorption O
spectrometry O
. O

The O
determination O
of O
fluorine B
in O
milk O
samples O
via O
the O
molecular O
absorption O
of O
calcium B
mono I
- I
fluoride I
( O
CaF B
) O
was O
performed O
using O
a O
HR O
- O
CS O
- O
ETAAS O
. O

For O
this O
purpose O
, O
calcium B
was O
pipetted O
to O
graphite B
furnace O
together O
with O
samples O
. O

The O
amount O
of O
Ca O
and O
the O
graphite B
furnace O
program O
were O
optimised O
. O

Fluorine B
was O
determined O
in O
pyrolytically O
coated O
platforms O
at O
606 O
. O
440 O
nm O
applying O
a O
pyrolysis O
temperature O
of O
700 O
degrees O
C O
and O
a O
molecule O
forming O
temperature O
of O
2250 O
degrees O
C O
. O

Finally O
, O
applying O
standard O
addition O
technique O
, O
F O
contents O
of O
several O
milk O
samples O
were O
determined O
. O

The O
results O
obtained O
by O
linear O
calibration O
and O
standard O
addition O
techniques O
were O
significantly O
different O
which O
can O
be O
attributed O
to O
non O
- O
spectral O
interferences O
in O
milk O
due O
to O
matrix O
concomitants O
. O

Therefore O
, O
in O
order O
to O
tolerate O
the O
errors O
, O
the O
F O
contents O
of O
several O
milk O
samples O
were O
determined O
applying O
standard O
addition O
technique O
. O

However O
, O
since O
the O
ingredients O
of O
milk O
samples O
change O
for O
different O
kinds O
, O
the O
F O
in O
each O
sample O
was O
determined O
from O
its O
own O
standard O
addition O
curve O
. O

The O
range O
of O
F O
content O
for O
the O
milk O
samples O
were O
0 O
. O
027 O
- O
0 O
. O
543 O
mu O
g O
mL O
( O
- O
1 O
) O
. O

The O
limit O
of O
detection O
and O
characteristic O
mass O
of O
the O
method O
were O
0 O
. O
26 O
and O
0 O
. O
13 O
ng O
of O
F O
, O
respectively O
. O

Characterising O
protein O
, O
salt O
and O
water O
interactions O
with O
combined O
vibrational O
spectroscopic O
techniques O
. O

In O
this O
paper O
a O
combination O
of O
NIR O
spectroscopy O
and O
FTIR O
and O
Raman O
microspectroscopy O
was O
used O
to O
elucidate O
the O
effects O
of O
different O
salts O
( O
NaCl B
, O
KCl B
and O
MgSO B
( I
4 I
) I
) O
on O
structural O
proteins O
and O
their O
hydration O
in O
muscle O
tissue O
. O

Multivariate O
multi O
- O
block O
technique O
Consensus O
Principal O
Component O
Analysis O
enabled O
integration O
of O
different O
vibrational O
spectroscopic O
techniques O
: O
macroscopic O
information O
obtained O
by O
NIR O
spectroscopy O
is O
directly O
related O
to O
microscopic O
information O
obtained O
by O
FTIR O
and O
Raman O
microspectroscopy O
. O

Changes O
in O
protein O
secondary O
structure O
observed O
at O
different O
concentrations O
of O
salts O
were O
linked O
to O
changes O
in O
protein O
hydration O
affinity O
. O

The O
evidence O
for O
this O
was O
given O
by O
connecting O
the O
underlying O
FTIR O
bands O
of O
the O
amide B
I O
region O
( O
1700 O
- O
1600 O
cm O
( O
- O
1 O
) O
) O
and O
the O
water O
region O
( O
3500 O
- O
3000 O
cm O
( O
- O
1 O
) O
) O
with O
water O
vibrations O
obtained O
by O
NIR O
spectroscopy O
. O

In O
addition O
, O
Raman O
microspectroscopy O
demonstrated O
that O
different O
cations O
affected O
structures O
of O
aromatic B
amino I
acid I
residues O
differently O
, O
which O
indicates O
that O
cation O
- O
pi O
interactions O
play O
an O
important O
role O
in O
determination O
of O
the O
final O
structure O
of O
protein O
molecules O
. O

Influence O
of O
nitrogen B
supply O
on O
the O
production O
of O
higher O
alcohols B
/ O
esters B
and O
expression O
of O
flavour O
- O
related O
genes O
in O
cacha O
c O
a O
fermentation O
. O

This O
study O
provides O
the O
first O
attempt O
to O
analyse O
the O
influence O
of O
ammonium B
supplements O
on O
sugar B
- O
cane O
juice O
fermentation O
and O
the O
flavour O
profile O
in O
a O
cacha O
c O
a O
industrial O
process O
. O

The O
objective O
was O
to O
find O
a O
relationship O
between O
higher O
alcohol B
/ O
ester B
content O
and O
the O
transcription O
levels O
of O
the O
main O
genes O
involved O
in O
production O
of O
these O
compounds O
under O
cacha O
c O
a O
fermentation O
. O

Sugar B
- O
cane O
juice O
with O
a O
low O
amount O
of O
assimilable O
nitrogen B
( O
81 O
mg O
N B
/ O
L O
) O
, O
was O
further O
supplemented O
with O
mid O
- O
range O
or O
high O
concentrations O
of O
ammonium B
sulfate I
. O

Overall O
, O
higher O
alcohol O
production O
was O
reduced O
by O
ammonium B
supplementation O
, O
and O
this O
can O
be O
correlated O
with O
a O
general O
downregulation O
of O
genes O
encoding O
decarboxylases O
and O
dehydrogenases O
of O
the O
Ehrlich O
pathway O
. O

The O
production O
of O
acetate B
esters I
was O
enhanced O
by O
mid O
- O
range O
ammonium B
supplementation O
and O
the O
production O
of O
acyl B
esters I
by O
high O
ammonium B
supplementation O
. O

The O
acyl B
esters I
could O
be O
correlated O
with O
expression O
of O
alcohol B
acyl B
- O
transferase O
EEB1 O
and O
the O
acyl B
esterase O
IAH1 O
. O

Near O
native O
binding O
of O
a O
fluorescent O
serotonin B
conjugate O
to O
serotonin B
type O
3 O
receptors O
. O

Described O
is O
the O
synthesis O
of O
5 B
- I
hydroxytryptamine I
- O
tetramethylrhodamine B
( O
5HT B
* O
) O
; O
an O
indole B
nitrogen I
linked O
fluorescent O
conjugate O
of O
serotonin B
. O

Through O
a O
series O
fluorescence O
quenching O
experiments O
and O
experiments O
in O
the O
presence O
of O
a O
known O
competitive O
antagonist O
( O
Granisetron B
) O
, O
it O
was O
shown O
that O
5HT B
* O
specifically O
binds O
to O
purified O
homo O
- O
pentameric O
type O
- O
3 O
human O
serotonin B
receptors O
( O
5HT O
( O
3A O
) O
) O
. O

The O
measured O
dissociation O
constant O
and O
Hill O
coefficient O
are O
K O
( O
d O
) O
= O
83 O
+ O
/ O
- O
3 O
nM O
and O
n O
= O
3 O
. O
1 O
+ O
/ O
- O
0 O
. O
3 O
, O
respectively O
which O
is O
indicative O
of O
multi O
- O
ligand O
binding O
and O
cooperativity O
similar O
to O
that O
of O
unconjugated O
serotonin B
. O

Design O
and O
synthesis O
of O
tricyclic O
cores O
for O
kinase O
inhibition O
. O

Interest O
in O
therapeutic O
kinase O
inhibitors O
continues O
to O
grow O
beyond O
success O
in O
oncology O
. O

To O
date O
, O
ATP B
- O
mimetic O
kinase O
inhibitors O
have O
focused O
primarily O
on O
monocyclic O
and O
bicyclic O
heterocyclic O
cores O
. O

We O
sought O
to O
expand O
on O
the O
repertoire O
of O
potential O
cores O
for O
kinase O
inhibition O
by O
exploring O
tricyclic O
variants O
of O
classical O
bicyclic O
hinge O
binding O
motifs O
such O
as O
pyrrolopyridine B
and O
pyrrolopyrazine B
. O

Herein O
we O
describe O
the O
syntheses O
of O
eight O
alternative O
tricyclic O
cores O
as O
well O
as O
in O
vitro O
screening O
results O
for O
representative O
kinases O
of O
potential O
therapeutic O
interest O
. O

3 O
' O
- O
Modified O
oligodeoxyribonucleo O
for O
the O
study O
of O
2 B
- I
deoxyribose I
damage O
in O
DNA O
. O

Well O
- O
defined O
substrates O
for O
the O
study O
of O
oxidative O
processes O
are O
important O
for O
the O
elucidation O
of O
the O
role O
of O
DNA O
damage O
in O
the O
etiology O
of O
diseases O
such O
as O
cancer O
. O

We O
have O
synthesized O
3 O
' O
- O
modified O
oligodeoxyribonucleo O
( O
ODNs O
) O
using O
5 O
' O
- O
- O
> O
3 O
' O
' O
reverse O
' O
DNA O
synthesis O
for O
the O
study O
of O
2 B
- I
deoxyribose I
oxidative O
damage O
to O
DNA O
. O

The O
modified O
monomers O
designed O
for O
these O
studies O
all O
share O
a O
common O
feature O
, O
they O
lack O
the O
naturally O
occurring O
3 B
' I
- I
hydroxyl I
group O
found O
in O
2 B
- I
deoxyribonucleosides I
. O

Modified O
H B
- I
phosphonates I
containing O
3 B
' I
- I
phenyl I
selenides I
as O
well O
as O
saturated B
and I
unsaturated I
sugars I
were O
obtained O
and O
incorporated O
in O
ODNs O
. O

These O
ODNs O
were O
used O
to O
investigate O
the O
fate O
of O
C3 B
' I
- I
dideoxyribonucleotid I
radicals O
in O
DNA O
. O

Discovery O
of O
nosokophic B
acid I
, O
a O
predicted O
intermediate O
of O
moenomycins B
, O
from O
nosokomycin B
- O
producing O
Streptomyces O
sp O
. O

K04 O
- O
0144 O
. O

A O
new O
actinomycete O
metabolite O
designated O
nosokophic B
acid I
was O
isolated O
from O
the O
culture O
broth O
of O
nosokomycin B
- O
producing O
Streptomyces O
sp O
. O

K04 O
- O
0144 O
, O
and O
the O
structure O
was O
elucidated O
by O
various O
NMR O
experiments O
. O

Nosokophic B
acid I
was O
found O
to O
be O
3 B
- I
phosphoglycosyl I
- I
2 I
- I
sesquiterpenyl I
dihydroxypropionic I
acid I
, O
a O
predicted O
biosynthetic O
intermediate O
of O
nosokomycin B
- O
related O
moenomycins B
. O

The O
compound O
showed O
no O
activity O
against O
MRSA O
, O
but O
potentiated O
imipenem O
activity O
against O
MRSA O
by O
512 O
- O
fold O
. O

Synthesis O
of O
new O
N B
- I
( I
arylcyclopropyl I
) I
acetamides I
and O
N B
- I
( I
arylvinyl I
) I
acetamides I
as O
conformationally O
- O
restricted O
ligands O
for O
melatonin B
receptors O
. O

N B
- I
( I
Arylcyclopropyl I
) I
acetamides I
and O
N B
- I
( I
arylvinyl I
) I
acetamides I
or O
methyl B
ureas I
have O
been O
prepared O
as O
constrained O
analogues O
of O
melatonin B
. O

The O
affinity O
of O
these O
new O
compounds O
for O
chicken O
brain O
melatonin B
receptors O
and O
recombinant O
human O
MT O
( O
1 O
) O
and O
MT O
( O
2 O
) O
receptors O
was O
evaluated O
using O
2 B
- I
[ I
( I
125 I
) I
I I
] I
- I
iodomelatonin I
as O
radioligand O
. O

Strict O
ethylenic B
or O
cyclopropyl B
analogues O
of O
the O
commercialized O
agonist O
agomelatine B
( O
Valdoxan B
( O
R O
) O
) O
were O
equipotent O
to O
agomelatine B
in O
binding O
bioassays O
. O

However O
, O
the O
ethylenic B
analogue O
was O
more O
effective O
than O
the O
cyclopropyl B
one O
in O
the O
melanophore O
aggregation O
bioassay O
, O
but O
was O
still O
less O
potent O
than O
the O
disubstituted O
2 B
, I
7 I
- I
dimethoxy I
- I
naphtalenic I
compounds O
. O

Non O
- O
benzimidazole B
containing O
inhibitors O
of O
respiratory O
syncytial O
virus O
. O

Several O
non O
- O
benzimidazole B
containing O
inhibitors O
of O
respiratory O
syncytial O
virus O
are O
described O
. O

Core O
template O
modification O
, O
analysis O
of O
antiviral O
activity O
, O
physicochemistry O
and O
optimisation O
of O
properties O
led O
to O
the O
thiazole B
- I
imidazole I
13 O
, O
that O
showed O
a O
good O
potency O
and O
pharmacokinetic O
profile O
in O
the O
rat O
. O

Design O
and O
synthesis O
of O
novel O
2 B
- I
methyl I
- I
4 I
, I
5 I
- I
substitutedbenzo I
[ I
f I
] I
- I
3 I
, I
3a I
, I
4 I
, I
5 I
- I
tetrahydro I
- I
pyrazolo I
[ I
1 I
, I
5 I
- I
d I
] I
[ I
1 I
, I
4 I
] I
oxazepin I
- I
8 I
( I
7H I
) I
- I
one I
derivatives O
as O
telomerase O
inhibitors O
. O

Eight O
novel O
4 B
, I
5 I
- I
tetrahydropyrazolo I
[ I
1 I
, I
5 I
- I
d I
] I
[ I
1 I
, I
4 I
] I
oxazepine I
derivatives O
have O
been O
synthesized O
and O
purified O
to O
be O
screened O
for O
anticancer O
activity O
. O

By O
a O
modified O
TRAP O
assay O
, O
some O
titled O
compounds O
were O
tested O
against O
telomerase O
, O
and O
compound O
4a O
showed O
the O
most O
potent O
inhibitory O
activity O
with O
IC O
( O
50 O
) O
value O
at O
0 O
. O
78 O
+ O
/ O
- O
0 O
. O
22 O
mu O
M O
. O

Western O
blot O
assays O
showed O
that O
compounds O
4a O
and O
4b O
could O
inhibit O
expression O
of O
Cyclin O
D1 O
, O
TERT O
, O
phospho O
- O
AKT O
and O
PI3K O
/ O
AKT O
pathway O
. O

Triazole B
- O
based O
inhibitors O
of O
geranylgeranyltransf B
II O
. O

A O
small O
set O
of O
triazole B
bisphosphonates I
has O
been O
prepared O
and O
tested O
for O
the O
ability O
to O
inhibit O
geranylgeranyltransf O
II O
( O
GGTase O
II O
) O
. O

The O
compounds O
were O
prepared O
through O
use O
of O
click O
chemistry O
to O
assemble O
a O
central O
triazole B
that O
links O
a O
polar O
head O
group O
to O
a O
hydrophobic O
tail O
. O

The O
resulting O
compounds O
were O
tested O
for O
their O
ability O
to O
inhibit O
GGTase O
II O
in O
an O
in O
vitro O
enzyme O
assay O
and O
also O
were O
tested O
for O
cytotoxic O
activity O
in O
an O
MTT B
assay O
with O
the O
human O
myeloma O
RPMI O
- O
8226 O
cell O
line O
. O

The O
most O
potent O
enzyme O
inhibitor O
was O
the O
triazole B
with O
a O
geranylgeranyl B
tail O
, O
which O
suggests O
that O
inhibitors O
that O
can O
access O
the O
enzyme O
region O
that O
holds O
the O
isoprenoid B
tail O
will O
display O
greater O
activity O
. O

Protective O
effect O
of O
ganodermanondiol B
isolated O
from O
the O
Lingzhi O
mushroom O
against O
tert B
- I
butyl I
hydroperoxide I
- O
induced O
hepatotoxicity O
through O
Nrf2 O
- O
mediated O
antioxidant O
enzymes O
. O

Ganodermanondiol B
, O
a O
biologically O
active O
compound O
, O
was O
isolated O
from O
the O
Lingzhi O
mushroom O
( O
Ganoderma O
lucidum O
) O
. O

The O
present O
study O
examined O
the O
protective O
effects O
of O
ganodermanondiol B
against O
tert B
- I
butyl I
hydroperoxide I
( O
t B
- I
BHP I
) O
- O
induced O
hepatotoxicity O
. O

Ganodermanondiol B
protected O
human O
liver O
- O
derived O
HepG2 O
cells O
through O
nuclear O
factor O
- O
E2 O
- O
related O
factor O
2 O
( O
Nrf2 O
) O
pathway O
- O
dependent O
heme O
oxygenase O
- O
1 O
expressions O
. O

Moreover O
, O
ganodermanondiol B
increased O
cellular O
glutathione B
levels O
and O
the O
expression O
of O
the O
glutamine B
- O
cysteine B
ligase O
gene O
in O
a O
dose O
- O
dependent O
manner O
. O

Furthermore O
, O
ganodermanondiol B
exposure O
enhanced O
the O
phosphorylation O
of O
adenosine B
monophosphate I
- O
activated O
protein O
kinase O
( O
AMPK O
) O
and O
its O
upstream O
kinase O
activators O
, O
LKB1 O
and O
Ca B
( I
2 I
+ I
) I
/ O
calmodulin O
- O
dependent O
protein O
kinase O
- O
II O
( O
CaMKII O
) O
. O

This O
study O
indicates O
that O
ganodermanondiol B
exhibits O
potent O
cytoprotective O
effects O
on O
t B
- I
BHP I
- O
induced O
hepatotoxicity O
in O
human O
liver O
- O
derived O
HepG2 O
cells O
, O
presumably O
through O
Nrf2 O
- O
mediated O
antioxidant O
enzymes O
and O
AMPK O
. O

Anti O
- O
inflammatory O
effects O
of O
trans B
- I
1 I
, I
3 I
- I
diphenyl I
- I
2 I
, I
3 I
- I
epoxypropane I
- I
1 I
- I
one I
mediated O
by O
suppression O
of O
inflammatory O
mediators O
in O
LPS O
- O
stimulated O
RAW O
264 O
. O
7 O
macrophages O
. O

To O
assess O
the O
potential O
therapeutic O
properties O
of O
trans B
- I
1 I
, I
3 I
- I
diphenyl I
- I
2 I
, I
3 I
- I
epoxypropane I
- I
1 I
- I
one I
( O
DPEP B
) O
, O
its O
anti O
- O
inflammatory O
effects O
were O
investigated O
in O
lipopolysaccharide O
( O
LPS O
) O
- O
stimulated O
mouse O
macrophage O
( O
RAW O
264 O
. O
7 O
) O
cells O
. O

DPEP O
induced O
dose O
- O
dependent O
reduction O
of O
the O
protein O
levels O
of O
inducible O
nitric B
oxide I
synthase O
( O
iNOS O
) O
and O
cyclooxygenase O
- O
2 O
( O
COX O
- O
2 O
) O
and O
concomitant O
reduction O
in O
the O
production O
of O
NO B
and O
prostaglandin B
E I
( I
2 I
) I
( O
PGE B
( I
2 I
) I
) O
. O

Additionally O
, O
DPEP O
suppressed O
the O
production O
of O
inflammatory O
cytokines O
, O
including O
tumor O
necrosis O
factor O
- O
alpha O
( O
TNF O
- O
alpha O
) O
, O
interleukin O
( O
IL O
) O
- O
1 O
beta O
, O
and O
IL O
- O
6 O
. O

We O
investigated O
the O
mechanism O
by O
which O
DPEP O
inhibits O
NO B
and O
PGE B
( I
2 I
) I
by O
examining O
the O
level O
of O
nuclear O
factor O
- O
kappa O
B O
( O
NF O
- O
kappa O
B O
) O
activation O
within O
the O
mitogen O
- O
activated O
protein O
kinase O
( O
MAPK O
) O
pathway O
, O
which O
is O
an O
inflammation O
- O
induced O
signaling O
pathway O
in O
RAW O
264 O
. O
7 O
cells O
. O

DPEP O
inhibited O
LPS O
- O
induced O
phosphorylation O
of O
ERK O
, O
JNK O
, O
and O
p38 O
. O

Furthermore O
, O
DPEP O
inhibited O
the O
LPS O
- O
induced O
phosphorylation O
of O
inhibitor O
kappa O
B O
( O
I O
kappa O
B O
) O
- O
alpha O
and O
NF O
- O
kappa O
B O
p50 O
. O

Taken O
together O
, O
the O
results O
of O
this O
study O
demonstrate O
that O
DPEP O
inhibits O
LPS O
- O
stimulated O
inflammation O
by O
blocking O
the O
NF O
- O
kappa O
B O
and O
MAPK O
pathways O
in O
macrophages O
. O

Radioprotection O
by O
two O
phenolic B
compounds O
: O
chlorogenic B
and I
quinic I
acid I
, O
on O
X O
- O
ray O
induced O
DNA O
damage O
in O
human O
blood O
lymphocytes O
in O
vitro O
. O

The O
present O
study O
was O
designed O
to O
determine O
the O
radioprotective O
effect O
of O
two O
phytochemicals O
, O
namely O
, O
quinic B
acid I
and O
chlorogenic B
acid I
, O
against O
X O
- O
ray O
irradiation O
- O
induced O
genomic O
instability O
in O
non O
- O
tumorigenic O
human O
blood O
lymphocytes O
. O

The O
protective O
ability O
of O
two O
phenolic B
acids I
against O
radiation O
- O
induced O
DNA O
damage O
was O
assessed O
using O
the O
alkaline O
comet O
assay O
in O
human O
blood O
lymphocytes O
isolated O
from O
two O
healthy O
human O
donors O
. O

A O
Siemens O
Mevatron O
MD2 O
( O
Siemens O
AG O
, O
USA O
, O
1994 O
) O
linear O
accelerator O
was O
used O
for O
irradiation O
. O

The O
results O
of O
the O
alkaline O
comet O
assay O
revealed O
that O
quinic B
acid I
and O
chlorogenic B
acid I
decreased O
the O
DNA O
damage O
induced O
by O
X O
- O
ray O
irradiation O
and O
provided O
a O
significant O
radioprotective O
effect O
. O

Quinic B
acid I
decreased O
the O
presence O
of O
irradiation O
- O
induced O
DNA O
damage O
by O
5 O
. O
99 O
- O
53 O
. O
57 O
% O
and O
chlorogenic B
acid I
by O
4 O
. O
49 O
- O
48 O
. O
15 O
% O
, O
as O
determined O
by O
the O
alkaline O
comet O
assay O
. O

The O
results O
show O
that O
quinic B
acid I
and O
chlorogenic B
acid I
may O
act O
as O
radioprotective O
compounds O
. O

Future O
studies O
should O
focus O
on O
determining O
the O
mechanism O
by O
which O
these O
phenolic B
acids I
provide O
radioprotection O
. O

Additive O
inhibition O
of O
human O
alpha O
1 O
beta O
2 O
gamma O
2 O
GABAA O
receptors O
by O
mixtures O
of O
commonly O
used O
drugs O
of O
abuse O
. O

Yearly O
, O
exposure O
to O
drugs O
of O
abuse O
results O
in O
~ O
1 O
million O
emergency O
department O
visits O
in O
the O
US O
. O

In O
~ O
50 O
% O
of O
the O
visits O
, O
stimulant O
drugs O
like O
cocaine B
and O
amphetamine B
- O
like O
substances O
( O
e O
. O
g O
. O
3 B
, I
4 I
- I
methylenedioxymetham I
( O
MDMA B
, O
the O
main O
active O
ingredient O
of O
ecstasy B
) O
) O
are O
involved O
, O
whereas O
in O
~ O
60 O
% O
multiple O
drugs O
are O
involved O
. O

These O
drugs O
induce O
higher O
dopamine B
and O
serotonin B
levels O
resulting O
in O
drug O
- O
induced O
toxicity O
. O

Since O
GABA B
receptors O
( O
GABA B
- O
R O
) O
provide O
the O
main O
inhibitory O
input O
on O
dopaminergic O
and O
serotonergic O
neurons O
, O
drug O
- O
induced O
inhibition O
of O
GABA B
- O
R O
could O
contribute O
to O
higher O
neurotransmitter O
levels O
and O
thus O
toxicity O
. O

We O
therefore O
investigated O
the O
effects O
of O
combinations O
of O
commonly O
abused O
stimulant O
drugs O
( O
cocaine B
, O
MDMA B
, O
3 B
, I
4 I
- I
methylenedioxyamphet I
( O
MDA B
) O
and O
meta B
- I
chlorophenylpiperazi I
( O
mCPP B
) O
) O
on O
the O
function O
of O
the O
human O
alpha O
1 O
beta O
2 O
gamma O
2 O
GABAA O
receptor O
( O
hGABAA O
- O
R O
) O
, O
expressed O
in O
Xenopus O
oocytes O
, O
using O
the O
two O
- O
electrode O
voltage O
- O
clamp O
technique O
. O

These O
drugs O
concentration O
- O
dependently O
inhibited O
the O
GABA B
- O
evoked O
current O
( O
mCPP B
> O
cocaine B
> O
MDMA B
> O
MDA B
) O
. O

Most O
drug O
combinations O
decreased O
the O
GABA B
- O
evoked O
current O
stronger O
than O
the O
single O
drug O
. O

Additivity O
was O
observed O
during O
combined O
exposure O
to O
low O
concentrations O
of O
cocaine B
and O
mCPP B
as O
well O
as O
during O
combined O
exposure O
to O
MDA B
with O
cocaine B
or O
mCPP B
. O

However O
, O
combinations O
containing O
MDMA B
mainly O
resulted O
in O
sub O
- O
additivity O
or O
no O
additivity O
. O

At O
drug O
concentrations O
relevant O
for O
clinical O
toxicology O
, O
co O
- O
exposure O
to O
> O
= O
2 O
drugs O
can O
decrease O
the O
GABA B
- O
evoked O
current O
in O
an O
additive O
manner O
. O

Thus O
, O
in O
patients O
exposed O
to O
multiple O
drugs O
, O
inhibitory O
GABA B
- O
ergic O
input O
is O
reduced O
more O
prominently O
, O
likely O
resulting O
in O
higher O
brain O
dopamine B
levels O
. O

As O
this O
will O
increase O
the O
risk O
for O
drug O
- O
induced O
toxicity O
, O
treatment O
of O
drug O
- O
intoxicated O
patients O
with O
drugs O
that O
enhance O
GABA B
- O
ergic O
input O
should O
be O
further O
optimized O
. O

A O
self O
- O
assembled O
nanocarrier O
loading O
teniposide B
improves O
the O
oral O
delivery O
and O
drug O
concentration O
in O
tumor O
. O

We O
attempted O
to O
improve O
the O
oral O
delivery O
of O
lipophilic O
teniposide B
to O
achieve O
higher O
drug O
concentration O
in O
tumor O
by O
self O
- O
assembled O
nanocarrier O
for O
further O
oral O
chemotherapy O
. O

The O
teniposide B
loaded O
self O
- O
assembled O
nanocarrier O
( O
TSN O
) O
was O
spherical O
nanometric O
particles O
with O
narrow O
size O
distribution O
. O

The O
intestinal O
absorption O
of O
teniposide B
from O
TSN O
was O
obviously O
improved O
4 O
. O
09 O
- O
and O
6 O
. O
35 O
- O
fold O
in O
duodenum O
and O
jejunum O
at O
0 O
. O
5h O
after O
oral O
administration O
, O
then O
significantly O
decreased O
with O
the O
prolongation O
of O
time O
. O

The O
cellular O
uptake O
of O
TSN O
in O
Caco O
- O
2 O
cell O
monolayer O
was O
significantly O
enhanced O
over O
3 O
folds O
and O
increased O
with O
incubation O
time O
. O

Moreover O
, O
TSN O
could O
be O
internalized O
into O
Caco O
- O
2 O
cell O
monolayer O
through O
clathrin O
- O
mediated O
endocytosis O
pathway O
, O
and O
then O
mainly O
transported O
into O
the O
systemic O
circulation O
via O
portal O
vein O
and O
intestinal O
lymphatic O
pathway O
. O

The O
pharmacokinetic O
results O
indicated O
that O
the O
AUC O
( O
0 O
- O
t O
) O
value O
of O
TSN O
in O
rats O
was O
significantly O
improved O
5 O
. O
41 O
- O
fold O
than O
that O
of O
teniposide B
solution O
, O
moreover O
, O
the O
teniposide B
concentration O
in O
tumor O
from O
TSN O
was O
obviously O
improved O
over O
7 O
- O
fold O
in O
tumor O
bearing O
mice O
. O

The O
captured O
image O
indicated O
that O
the O
oral O
administered O
TSN B
could O
specifically O
accumulate O
in O
tumor O
in O
the O
xenograft O
model O
. O

Therefore O
, O
the O
self O
- O
assembled O
nanocarrier O
was O
promising O
to O
enhance O
the O
oral O
delivery O
of O
lipophilic O
teniposide B
and O
its O
concentration O
in O
tumor O
for O
oral O
chemotherapy O
. O

Combined O
delivery O
of O
BMP O
- O
2 O
and O
bFGF O
from O
nanostructured O
colloidal O
gelatin O
gels O
and O
its O
effect O
on O
bone O
regeneration O
in O
vivo O
. O

During O
the O
process O
of O
bone O
regeneration O
, O
a O
multitude O
of O
morphogenetic O
signaling O
factors O
regulate O
cellular O
behavior O
and O
ultimately O
tissue O
response O
. O

These O
factors O
are O
presented O
to O
cells O
under O
strong O
spatial O
and O
temporal O
control O
, O
which O
stresses O
the O
relevance O
of O
controlled O
delivery O
of O
multiple O
growth O
factors O
for O
bone O
tissue O
regeneration O
. O

This O
demand O
for O
biomimetic O
delivery O
has O
prompted O
the O
development O
of O
a O
novel O
generation O
of O
biomaterials O
that O
is O
capable O
of O
delivering O
multiple O
growth O
factors O
in O
a O
controlled O
manner O
. O

Therefore O
, O
the O
current O
study O
has O
exploited O
the O
strong O
capacity O
of O
colloidal O
gels O
solely O
made O
of O
oppositely O
charged O
gelatin O
nanospheres O
to O
obtain O
controlled O
release O
of O
angiogenic O
and O
osteogenic O
growth O
factors O
. O

The O
release O
kinetics O
of O
dual O
delivery O
of O
osteogenic O
bone O
morphogenetic O
protein O
- O
2 O
( O
BMP O
- O
2 O
) O
and O
angiogenic O
basic O
fibroblast O
growth O
factor O
( O
bFGF O
) O
were O
investigated O
in O
vitro O
by O
radiolabeling O
the O
respective O
growth O
factors O
and O
monitoring O
their O
release O
in O
vitro O
. O

Furthermore O
, O
the O
effect O
of O
single O
or O
dual O
delivery O
of O
BMP O
- O
2 O
and O
bFGF O
on O
bone O
regeneration O
was O
evaluated O
in O
vivo O
using O
a O
rat O
femoral O
condyle O
defect O
model O
. O

The O
in O
vitro O
results O
confirmed O
that O
the O
delivery O
kinetics O
of O
BMP O
- O
2 O
and O
/ O
or O
bFGF O
are O
more O
dependent O
on O
the O
degree O
of O
crosslinking O
than O
on O
the O
type O
of O
gelatin O
. O

Sequential O
release O
characterized O
by O
rapid O
release O
of O
angiogenic O
bFGF O
and O
more O
sustained O
release O
of O
BMP O
- O
2 O
was O
obtained O
by O
loading O
bFGF O
onto O
cationic O
nanospheres O
of O
low O
crosslinking O
density O
and O
BMP O
- O
2 O
onto O
anionic O
nanospheres O
of O
high O
crosslinking O
density O
. O

The O
in O
vivo O
study O
demonstrated O
the O
biocompatibility O
and O
biodegradability O
of O
bare O
colloidal O
gelatin O
gels O
, O
and O
did O
not O
show O
any O
adverse O
effects O
on O
the O
process O
of O
bone O
healing O
after O
4 O
week O
of O
implantation O
since O
the O
volumes O
of O
new O
bone O
formation O
were O
comparable O
to O
empty O
control O
defects O
. O

An O
obvious O
stimulatory O
effect O
on O
bone O
regeneration O
was O
observed O
for O
the O
colloidal O
gels O
loaded O
with O
BMP O
- O
2 O
, O
whereas O
bFGF O
- O
loaded O
colloidal O
gelatin O
gels O
did O
not O
influence O
the O
rate O
of O
bone O
regeneration O
. O

In O
contrast O
, O
the O
combined O
delivery O
of O
BMP O
- O
2 O
and O
bFGF O
resulted O
into O
an O
inhibitory O
effect O
on O
osteogenesis O
under O
the O
current O
experimental O
conditions O
. O

Summarizing O
, O
the O
current O
study O
proved O
that O
nanostructured O
colloidal O
gelatin O
gels O
are O
suitable O
carriers O
for O
programmed O
and O
sustained O
release O
of O
multiple O
therapeutic O
proteins O
for O
tissue O
regeneration O
. O

Influence O
of O
drying O
and O
cooking O
process O
on O
the O
phytochemical O
content O
, O
antioxidant O
and O
hypoglycaemic O
properties O
of O
two O
bell O
Capsicum O
annum O
L O
. O
cultivars O
. O

The O
present O
study O
evaluates O
the O
influence O
of O
drying O
and O
cooking O
processes O
on O
the O
health O
properties O
of O
two O
bell O
Capsicum O
annuum O
L O
. O
cultivars O
Roggiano O
and O
Senise O
compared O
with O
fresh O
peppers O
. O

The O
content O
of O
phytochemicals O
decreased O
in O
the O
order O
fresh O
> O
dried O
> O
dried O
frying O
processes O
. O

HPLC O
analysis O
was O
applied O
to O
quantify O
five O
flavonoids B
from O
peppers O
. O

Apigenin B
was O
identified O
as O
main O
constituent O
. O

Its O
content O
was O
affected O
by O
drying O
and O
dried O
frying O
processes O
. O

The O
antioxidant O
activity O
was O
evaluated O
by O
DPPH B
, O
ABTS B
, O
beta B
- I
carotene I
bleaching O
test O
and O
Fe B
- O
chelating O
activity O
assay O
. O

A O
comparable O
radical O
scavenging O
activity O
was O
observed O
for O
both O
cultivars O
. O

Interestingly O
, O
frying O
process O
did O
not O
influenced O
this O
property O
. O

Roggiano O
peppers O
exhibited O
the O
highest O
antioxidant O
activity O
using O
beta B
- I
carotene I
bleaching O
test O
with O
IC O
( O
50 O
) O
values O
of O
38 O
. O
1 O
and O
24 O
. O
9 O
mu O
g O
/ O
mL O
for O
total O
extract O
and O
n B
- I
hexane I
fraction O
, O
respectively O
. O

GC O
- O
MS O
analysis O
of O
lipophilic O
fraction O
revealed O
the O
presence O
of O
fatty B
acids I
and O
vitamin B
E I
as O
major O
components O
. O

In O
the O
inhibition O
of O
the O
carbohydrate B
- O
hydrolyzing O
enzymes O
fresh O
Senise O
peppers O
exerted O
the O
strongest O
activity O
against O
alpha O
- O
amylase O
with O
an O
IC O
( O
50 O
) O
value O
of O
55 O
. O
3 O
mu O
g O
/ O
mL O
. O

Our O
results O
indicate O
that O
C O
. O
annuum O
cultivars O
Roggiano O
and O
Senise O
have O
an O
interestingly O
potential O
health O
benefits O
not O
influenced O
by O
processes O
that O
are O
used O
before O
consumption O
. O

Activation O
of O
an O
apoptotic O
signal O
transduction O
pathway O
involved O
in O
the O
upregulation O
of O
calpain O
and O
apoptosis O
- O
inducing O
factor O
in O
aldosterone B
- O
induced O
primary O
cultured O
cardiomyocytes O
. O

In O
this O
study O
, O
aldosterone B
( O
ALD B
) O
- O
induced O
apoptosis O
of O
cardiomyocyte O
was O
evaluated O
based O
on O
the O
previous O
studies O
, O
and O
the O
roles O
of O
calpain O
signaling O
were O
clarified O
. O

Primary O
cultured O
rat O
cardiomyocytes O
were O
injured O
by O
ALD O
( O
0 O
. O
01 O
- O
10 O
mu O
M O
) O
for O
varying O
time O
periods O
. O

Then O
, O
the O
effects O
of O
ethylene B
glycol I
tetraacetic I
acid I
( O
EGTA B
) O
( O
0 O
. O
5 O
mM O
) O
, O
calpeptin O
( O
2 O
. O
5 O
mu O
M O
) O
, O
and O
spironoclactone B
( O
10 O
mu O
M O
) O
were O
evaluated O
on O
cardiomyocytes O
activated O
by O
ALD O
. O

Cardiomyocytes O
that O
were O
injured O
by O
ALD O
were O
assayed O
by O
the O
MTT B
and O
LDH O
leakage O
ratio O
. O

Apoptosis O
was O
evaluated O
by O
a O
TUNEL O
assay O
, O
annexin O
V O
/ O
PI O
staining O
, O
and O
caspase O
- O
3 O
activity O
. O

The O
expression O
of O
cleavage O
of O
Bid O
( O
tBid O
) O
, O
calpain O
and O
apoptosis O
- O
inducing O
factor O
( O
AIF O
) O
was O
evaluated O
by O
western O
blot O
analysis O
. O

ALD O
increased O
calpain O
expression O
and O
caspase O
- O
3 O
activity O
and O
promoted O
Bid O
cleavage O
. O

It O
also O
induced O
the O
release O
of O
AIF O
from O
mitochondria O
into O
the O
cytosol O
. O

The O
upregulation O
of O
calpain O
, O
tBid O
and O
caspase O
- O
3 O
activity O
were O
further O
inhibited O
by O
treatment O
with O
EGTA B
in O
the O
presence O
of O
ALD O
. O

Additionally O
, O
AIF O
levels O
in O
the O
cytosol O
decreased O
due O
to O
EGTA B
but O
not O
due O
to O
calpeptin O
. O

This O
was O
also O
accompanied O
by O
a O
significant O
decrease O
in O
apoptosis O
. O

Furthermore O
, O
treatment O
with O
spironoclactone B
not O
only O
attenuated O
the O
pro O
- O
apoptotic O
effect O
of O
ALD O
but O
reversed O
the O
ALD O
- O
induced O
increase O
of O
calpain O
and O
AIF O
levels O
. O

DHA B
supplementation O
: O
current O
implications O
in O
pregnancy O
and O
childhood O
. O

Dietary O
supplementation O
with O
omega O
- O
3 O
long O
chain O
fatty B
acids I
including O
docosahexaenoic B
acid I
( O
DHA B
) O
has O
increased O
in O
popularity O
in O
recent O
years O
and O
adequate O
DHA B
supplementation O
during O
pregnancy O
and O
early O
childhood O
is O
of O
clinical O
importance O
. O

Some O
evidence O
has O
been O
built O
for O
the O
neuro O
- O
cognitive O
benefits O
of O
supplementation O
with O
long O
chain O
polyunsaturated B
fatty I
acids I
( O
LCPUFA O
) O
such O
as O
DHA B
during O
pregnancy O
; O
however O
, O
recent O
data O
indicate O
that O
the O
anti O
- O
inflammatory O
properties O
may O
be O
of O
at O
least O
equal O
significance O
. O

Adequate O
DHA B
availability O
in O
the O
fetus O
/ O
infant O
optimizes O
brain O
and O
retinal O
maturation O
in O
part O
by O
influencing O
neurotransmitter O
pathways O
. O

The O
anti O
- O
inflammatory O
properties O
of O
LCPUFA B
are O
largely O
mediated O
through O
modulation O
of O
signaling O
either O
directly O
through O
binding O
to O
receptors O
or O
through O
changes O
in O
lipid O
raft O
formation O
and O
receptor O
presentation O
. O

Our O
goal O
is O
to O
review O
the O
current O
findings O
on O
DHA B
supplementation O
, O
specifically O
in O
pregnancy O
and O
infant O
neurodevelopment O
, O
as O
a O
pharmacologic O
agent O
with O
both O
preventative O
and O
therapeutic O
value O
. O

Given O
the O
overall O
benefits O
of O
DHA B
, O
maternal O
and O
infant O
supplementation O
may O
improve O
neurological O
outcomes O
especially O
in O
vulernable O
populations O
. O

However O
, O
optimal O
composition O
of O
the O
supplement O
and O
dosing O
and O
treatment O
strategies O
still O
need O
to O
be O
determined O
to O
lend O
support O
for O
routine O
supplementation O
. O

Expression O
profiles O
of O
hippocampal O
regenerative O
sprouting O
- O
related O
genes O
and O
their O
regulation O
by O
E B
- I
64d I
in O
a O
developmental O
rat O
model O
of O
penicillin B
- O
induced O
recurrent O
epilepticus O
. O

E B
- I
64d I
( O
a O
calpain O
and O
autophagy O
inhibitor O
) O
has O
previously O
been O
shown O
safe O
for O
the O
treatment O
of O
Alzheimer O
' O
s O
disease O
in O
humans O
. O

In O
the O
present O
study O
, O
the O
potential O
protective O
mechanism O
of O
E B
- I
64d I
on O
hippocampal O
aberrant O
mossy O
fiber O
sprouting O
was O
examined O
in O
a O
developmental O
rat O
model O
of O
penicillin B
- O
induced O
recurrent O
epilepticus O
. O

A O
seizure O
was O
induced O
by O
penicillin B
every O
other O
day O
in O
Sprague O
- O
Dawley O
rats O
from O
postnatal O
day O
21 O
( O
P21 O
) O
. O

The O
rats O
were O
randomly O
assigned O
into O
the O
control O
group O
( O
CONT1 O
) O
, O
the O
control O
plus O
E B
- I
64d I
( O
CONT2 O
) O
, O
the O
seizure O
group O
( O
EXP1 O
) O
and O
the O
seizure O
plus O
E B
- I
64d I
( O
EXP2 O
) O
. O

On O
P51 O
, O
mossy O
fiber O
sprouting O
and O
related O
gene O
expression O
in O
hippocampus O
were O
assessed O
by O
Timm O
staining O
and O
real O
- O
time O
RT O
- O
PCR O
methods O
, O
respectively O
. O

To O
validate O
the O
RT O
- O
PCR O
results O
, O
western O
blot O
analysis O
was O
performed O
on O
selected O
genes O
. O

E B
- I
64d I
obviously O
suppressed O
the O
aberrant O
mossy O
fiber O
sprouting O
in O
the O
supragranular O
region O
of O
dentate O
gyrus O
and O
CA3 O
subfield O
of O
hippocampus O
. O

Among O
the O
total O
twelve O
genes O
, O
six O
genes O
were O
strongly O
up O
- O
( O
MT O
- O
3 O
, O
ACAT1 O
, O
clusterin O
and O
ApoE O
) O
or O
down O
- O
( O
ZnT O
- O
1 O
and O
PRG O
- O
3 O
) O
regulated O
by O
developmental O
seizures O
( O
EXP1 O
) O
compared O
with O
that O
in O
the O
CONT1 O
. O

Up O
- O
regulation O
of O
ApoE O
and O
Clusterin O
was O
blocked O
by O
pretreatment O
with O
E B
- I
64d I
both O
in O
mRNA O
and O
protein O
levels O
. O

Further O
, O
E B
- I
64d I
- O
pretreated O
seizure O
rats O
( O
EXP2 O
) O
showed O
a O
significant O
downregulation O
of O
mRNA O
expression O
of O
PRG O
- O
1 O
, O
PRG O
- O
3 O
and O
PRG O
- O
5 O
, O
cathepsin O
B O
and O
ApoE O
, O
as O
well O
as O
up O
- O
regulated O
nSMase O
and O
ANX7 O
in O
hippocampus O
when O
compared O
with O
EXP1 O
rats O
. O

The O
results O
of O
the O
present O
study O
suggest O
that O
E B
- I
64d I
, O
an O
elective O
inhibitor O
of O
calpain O
and O
autophagy O
, O
is O
potentially O
useful O
in O
the O
treatment O
of O
developmental O
seizure O
- O
induced O
brain O
damage O
both O
by O
regulating O
abnormal O
zinc B
signal O
transduction O
and O
through O
the O
modulation O
of O
altered O
lipid O
metabolism O
via O
ApoE O
/ O
clusterin O
pathway O
in O
hippocampus O
. O

Studies O
on O
a O
rhein O
- O
producing O
endophytic O
fungus O
isolated O
from O
Rheum O
palmatum O
L O
. O

Rheum O
palmatum O
L O
. O

( O
Chinese O
rhubarb O
) O
is O
a O
highly O
regarded O
medicinal O
plant O
. O

Its O
dominant O
active O
constituents O
are O
anthraquinones B
including O
emodin B
, O
aloe O
- O
emodin B
, O
rhein B
, O
etc O
. O

Rhein B
naturally O
occurs O
in O
anthraquinone B
( O
1 B
, I
3 I
, I
8 I
- I
trihydroxy I
- I
6 I
- I
methyl I
anthraquinone I
) O
, O
which O
is O
found O
in O
R O
. O
palmatum O
L O
. O
and O
related O
plants O
such O
as O
rhubarb O
. O

It O
has O
good O
antitumor O
, O
anti O
- O
inflammatory O
, O
anticancer O
, O
antimicrobial O
and O
hemostatic O
properties O
. O

In O
this O
study O
, O
a O
total O
of O
14 O
strains O
of O
endophytic O
fungi O
were O
isolated O
from O
R O
. O
palmatum O
L O
. O

All O
fungal O
isolates O
were O
fermented O
in O
liquid O
PDA O
medium O
and O
their O
extracts O
were O
preliminarily O
analyzed O
by O
antibacterial O
reactions O
, O
magnesium B
acetate I
- O
methanol B
reagent O
and O
Borntraiger O
' O
s O
reaction O
, O
and O
the O
strain O
reselection O
was O
made O
by O
thin O
- O
layer O
chromatography O
( O
TLC O
) O
, O
high O
- O
performance O
liquid O
chromatography O
( O
HPLC O
) O
and O
LC O
- O
MS O
to O
identify O
the O
fermentation O
products O
of O
the O
selected O
strains O
and O
confirmed O
through O
a O
comparison O
with O
authentic O
standards O
. O

Extract O
from O
one O
strain O
, O
R13 O
, O
showed O
positive O
reactions O
with O
both O
reagents O
. O

The O
strain O
R13 O
had O
a O
component O
with O
the O
same O
TLC O
( O
Rf O
) O
value O
and O
HPLC O
, O
LC O
- O
MS O
retention O
time O
as O
authentic O
rhein B
standards O
. O

The O
yield O
of O
rhein O
in O
R13 O
can O
reach O
5 O
. O
672mgl O
( O
- O
1 O
) O
. O

The O
fungi O
were O
identified O
as O
Fusarium O
solani O
by O
using O
both O
ITS O
rDNA O
sequencing O
and O
spore O
morphology O
. O

Phytochemical O
analysis O
of O
the O
triterpenoids B
with O
cytotoxicity O
and O
QR O
inducing O
properties O
from O
the O
total O
tea O
seed O
saponin B
of O
Camellia O
sinensis O
. O

The O
tea O
seed O
triterpene B
saponin I
( O
TS O
) O
from O
Camellia O
sinensis O
was O
found O
to O
exhibit O
better O
antitumor O
activity O
in O
vivo O
in O
S180 O
implanted O
ICR O
mice O
and O
QR O
inducing O
activity O
for O
hepa O
lclc7 O
cells O
respectively O
compared O
with O
the O
total O
tea O
seed O
saponin B
( O
TTS O
) O
, O
hydrolysate O
of O
the O
TTS O
and O
tea O
seed O
flavonoid B
glycosides I
( O
TF O
) O
. O

By O
bioassay O
- O
guided O
isolation O
, O
the O
TS O
fraction O
was O
separated O
and O
seven O
major O
components O
were O
purified O
and O
identified O
as O
theasaponin B
E1 I
( O
1 O
) O
, O
theasaponin B
E2 I
( O
2 O
) O
, O
theasaponin B
C1 I
( O
3 O
) O
, O
assamsaponin B
C I
( O
4 O
) O
, O
theasaponin B
H1 I
( O
5 O
) O
, O
theasaponin B
A9 I
( O
6 O
) O
, O
and O
theasaponin B
A8 I
( O
7 O
) O
, O
among O
which O
compounds O
4 O
and O
5 O
were O
isolated O
from O
this O
genus O
for O
the O
first O
time O
. O

The O
antitumor O
bioassay O
of O
the O
isolated O
compounds O
showed O
that O
compounds O
1 O
, O
2 O
and O
3 O
exhibited O
potential O
activities O
against O
the O
human O
tumor O
cell O
lines O
K562 O
and O
HL60 O
. O

Furthermore O
, O
compound O
1 O
( O
the O
major O
constituent O
with O
a O
mass O
content O
of O
over O
1 O
% O
) O
showed O
significant O
QR O
inducing O
activity O
with O
an O
IR O
value O
of O
4 O
. O
2 O
at O
4 O
mu O
g O
/ O
ml O
. O

So O
it O
can O
be O
concluded O
that O
tea O
seed O
especially O
the O
compound O
1 O
( O
theasaponin B
E1 I
) O
could O
be O
used O
as O
an O
antitumor O
agent O
and O
a O
chemoprevention O
agent O
of O
cancer O
. O

The O
preliminary O
structure O
- O
activity O
relationship O
in O
the O
anti O
- O
tumor O
activity O
and O
QR B
inducing O
activity O
of O
tea O
saponins B
was O
discussed O
briefly O
. O

On O
the O
structure O
of O
aspongopusin B
recently O
isolated O
from O
Aspongopus O
chinensis O
. O

The O
2 B
, I
5 I
- I
disubstituted I
oxazole I
recently O
proposed O
for O
aspongopusin B
, O
a O
natural O
product O
isolated O
from O
Aspongopus O
chinensis O
, O
was O
synthesized O
through O
an O
unambiguous O
route O
. O

The O
synthetic O
sample O
showed O
( B
1 I
) I
H I
and O
( B
13 I
) I
C I
NMR O
entirely O
different O
from O
those O
in O
the O
literature O
, O
revealing O
that O
the O
initially O
assigned O
structure O
was O
incorrect O
. O

The O
spectroscopic O
data O
for O
the O
given O
structure O
are O
thus O
made O
available O
for O
the O
first O
time O
. O

DNA O
polymerase O
minor O
groove O
interactions O
modulate O
mutagenic O
bypass O
of O
a O
templating O
8 B
- I
oxoguanine I
lesion O
. O

A O
major O
base O
lesion O
resulting O
from O
oxidative O
stress O
is O
8 B
- I
oxo I
- I
7 I
, I
8 I
- I
dihydro I
- I
2 I
' I
- I
deoxyguanosine I
( O
8 B
- I
oxoG I
) O
that O
has O
ambiguous O
coding O
potential O
. O

Error O
- O
free O
DNA O
synthesis O
involves O
8 B
- I
oxoG I
adopting O
an O
anti O
- O
conformation O
to O
base O
pair O
with O
cytosine B
whereas O
mutagenic O
bypass O
involves O
8 B
- I
oxoG I
adopting O
a O
syn O
- O
conformation O
to O
base O
pair O
with O
adenine B
. O

Left O
unrepaired O
the O
syn B
- I
8 I
- I
oxoG I
/ O
dAMP I
base O
pair O
results O
in O
a O
G O
- O
C O
to O
T O
- O
A O
transversion O
. O

During O
base O
excision O
repair O
of O
this O
mispair O
, O
DNA O
polymerase O
( O
pol O
) O
beta O
is O
confronted O
with O
gap O
filling O
opposite O
8 B
- I
oxoG I
. O

To O
determine O
how O
pol O
beta O
discriminates O
between O
anti O
- I
and I
syn I
- I
8 I
- I
oxoG I
, O
we O
introduced O
a O
point O
mutation O
( O
R283K O
) O
to O
alter O
insertion O
specificity O
. O

Kinetic O
studies O
demonstrate O
that O
this O
substitution O
results O
in O
an O
increased O
fidelity O
opposite O
8 B
- I
oxoG I
. O

Structural O
studies O
with O
R283K O
pol O
beta O
show O
that O
the O
binary O
DNA O
complex O
has O
8 B
- I
oxoG I
in O
equilibrium O
between O
anti O
- O
and O
syn O
- O
forms O
. O

Ternary O
complexes O
with O
incoming O
dCTP B
resemble O
the O
wild O
- O
type O
enzyme O
, O
with O
templating O
anti O
- O
8 B
- I
oxoG I
base O
pairing O
with O
incoming O
cytosine B
. O

In O
contrast O
to O
wild O
- O
type O
pol O
beta O
, O
the O
ternary O
complex O
of O
the O
R283K O
mutant O
with O
an O
incoming O
dATP B
- O
analogue O
and O
templating O
8 B
- I
oxoG I
resembles O
a O
G O
- O
A O
mismatched O
structure O
with O
8 B
- I
oxoG I
adopting O
an O
anti O
- O
conformation O
. O

These O
results O
demonstrate O
that O
the O
incoming O
nucleotide B
is O
unable O
to O
induce O
a O
syn O
- O
8 B
- I
oxoG I
conformation O
without O
minor O
groove O
DNA O
polymerase O
interactions O
that O
influence O
templating O
( O
anti O
- O
/ O
syn O
- O
equilibrium O
) O
of O
8 B
- I
oxoG I
while O
modulating O
fidelity O
. O

Effect O
of O
long O
- O
term O
co O
- O
administration O
of O
Wuzhi O
tablet O
( O
Schisandra O
sphenanthera O
extract O
) O
and O
prednisone B
on O
the O
pharmacokinetics O
of O
tacrolimus B
. O

Tacrolimus B
( O
TAC B
) O
is O
an O
immunosuppressant O
that O
has O
been O
widely O
used O
alone O
or O
in O
combination O
with O
prednisone B
( O
PRED B
) O
to O
prevent O
acute O
rejection O
after O
organ O
transplantation O
. O

Wuzhi O
tablet O
( O
WZ O
, O
Schisandra O
sphenanthera O
extract O
) O
is O
often O
prescribed O
with O
TAC O
to O
prevent O
drug O
- O
induced O
hepatitis O
. O

We O
recently O
reported O
that O
WZ O
could O
significantly O
increase O
TAC B
blood O
exposure O
by O
inhibiting O
P O
- O
gp O
- O
mediated O
efflux O
and O
CYP3A O
- O
mediated O
metabolism O
of O
TAC B
. O

PRED B
is O
also O
a O
substrate O
of O
P O
- O
gp O
and O
is O
a O
weak O
inducer O
of O
CYP3A O
, O
and O
drug O
- O
drug O
interactions O
within O
this O
combination O
therapy O
might O
occur O
. O

Therefore O
, O
the O
purpose O
of O
this O
study O
was O
to O
investigate O
the O
effect O
of O
long O
- O
term O
treatment O
of O
WZ O
and O
PRED B
on O
the O
pharmacokinetics O
of O
TAC B
in O
rats O
. O

After O
14 O
days O
of O
co O
- O
administration O
of O
WZ O
and O
PRED O
, O
the O
AUC O
( O
0 O
- O
24h O
) O
of O
oral O
TAC B
was O
increased O
( O
from O
59 O
. O
6 O
+ O
/ O
- O
37 O
. O
3 O
to O
95 O
. O
3 O
+ O
/ O
- O
39 O
. O
4 O
ng O
h O
/ O
ml O
, O
p O
= O
0 O
. O
18 O
) O
and O
the O
clearance O
was O
decreased O
( O
from O
38 O
. O
4 O
+ O
/ O
- O
28 O
. O
4 O
to O
17 O
. O
7 O
+ O
/ O
- O
6 O
. O
4 O
l O
/ O
h O
/ O
kg O
, O
p O
= O
0 O
. O
15 O
) O
. O

When O
only O
co O
- O
administered O
with O
WZ O
, O
AUC O
( O
0 O
- O
24h O
) O
of O
TAC B
was O
demonstrated O
a O
significantly O
increase O
( O
from O
59 O
. O
6 O
+ O
/ O
- O
37 O
. O
3 O
to O
135 O
. O
9 O
+ O
/ O
- O
34 O
. O
8 O
ng O
h O
/ O
ml O
, O
p O
< O
0 O
. O
05 O
) O
. O

The O
concomitant O
administration O
of O
PRED B
resulted O
in O
a O
reduction O
in O
the O
systemic O
exposure O
of O
TAC B
and O
an O
increase O
in O
its O
clearance O
, O
though O
neither O
was O
statistically O
significant O
. O

Thus O
, O
our O
study O
suggested O
that O
the O
presence O
of O
WZ O
and O
PRED B
still O
could O
increase O
the O
systemic O
exposure O
of O
TAC B
in O
rats O
. O

The O
drug O
- O
drug O
interactions O
among O
this O
combination O
therapy O
should O
still O
be O
taken O
into O
consideration O
in O
clinical O
practice O
. O

Naturally O
occurring O
HCA1 O
missense O
mutations O
result O
in O
loss O
of O
function O
: O
potential O
impact O
on O
lipid O
deposition O
. O

The O
hydroxy B
- I
carboxylic I
acid I
receptor O
( O
HCA1 O
) O
is O
a O
G O
protein O
- O
coupled O
receptor O
that O
is O
highly O
expressed O
on O
adipocytes O
and O
considered O
a O
potential O
target O
for O
the O
treatment O
of O
dyslipidemia O
. O

In O
the O
current O
study O
, O
we O
investigated O
the O
pharmacological O
properties O
of O
naturally O
occurring O
variants O
in O
this O
receptor O
( O
H43Q O
, O
A110V O
, O
S172L O
, O
and O
D253H O
) O
. O

After O
transient O
expression O
of O
these O
receptors O
into O
human O
embryonic O
kidney O
293 O
cells O
, O
basal O
and O
ligand O
- O
induced O
signaling O
were O
assessed O
using O
luciferase O
reporter O
gene O
assays O
. O

The O
A110V O
, O
S172L O
, O
and O
D253 O
variants O
showed O
reduced O
basal O
activity O
; O
the O
S172L O
mutant O
displayed O
a O
decrease O
in O
potency O
to O
the O
endogenous O
ligand O
L B
- I
lactate I
. O

Both O
the O
S172L O
and O
D253H O
variants O
also O
showed O
impaired O
cell O
surface O
expression O
, O
which O
may O
in O
part O
explain O
the O
reduced O
activity O
of O
these O
receptors O
. O

The O
impact O
of O
a O
loss O
in O
HCA1 O
function O
on O
lipid O
accumulation O
was O
investigated O
in O
the O
adipocyte O
cell O
line O
, O
OP9 O
. O

In O
these O
cells O
, O
endogenous O
HCA1 O
transcript O
levels O
rapidly O
increased O
and O
reached O
maximal O
levels O
3 O
days O
after O
the O
addition O
of O
differentiation O
media O
. O

Knockdown O
of O
HCA1 O
using O
siRNA O
resulted O
in O
an O
increase O
in O
lipid O
accumulation O
as O
assessed O
by O
quantification O
of O
Nile B
Red I
staining O
and O
TLC O
analysis O
. O

Our O
data O
suggest O
that O
lipid O
homeostasis O
may O
be O
altered O
in O
carriers O
of O
selected O
HCA1 O
missense O
variants O
. O

Anti O
- O
inflammatory O
sesquiterpene B
derivatives O
from O
the O
leaves O
of O
Tripterygium O
wilfordii O
. O

Twelve O
new O
dihydroagarofuran B
sesquiterpene I
polyol I
esters I
, O
triptersinines B
A I
- I
L I
( O
1 O
- O
12 O
) O
, O
and O
eight O
known O
sesquiterpene B
pyridine I
alkaloids I
were O
isolated O
from O
the O
leaves O
of O
Tripterygium O
wilfordii O
. O

Their O
structures O
were O
elucidated O
on O
the O
basis O
of O
spectroscopic O
analyses O
, O
including O
UV O
, O
IR O
, O
and O
NMR O
experiments O
( O
( B
1 I
) I
H I
- O
( B
1 I
) I
H I
COSY O
, O
NOESY O
, O
HSQC O
, O
and O
HMBC O
) O
. O

Furthermore O
, O
in O
an O
in O
vitro O
bioassay O
, O
compounds O
1 O
, O
9 O
, O
11 O
, O
13 O
, O
14 O
, O
and O
18 O
showed O
moderate O
inhibitory O
effects O
on O
nitric B
oxide I
production O
in O
LPS O
- O
induced O
macrophages O
at O
5 O
mu O
M O
; O
all O
compounds O
were O
inactive O
when O
tested O
against O
five O
human O
cancer O
cell O
lines O
( O
IC O
( O
50 O
) O
values O
> O
1 O
mu O
M O
) O
. O

Bioassay O
- O
guided O
isolation O
of O
proanthocyanidins B
with O
antiangiogenic O
activities O
. O

The O
proangiogenic O
members O
of O
the O
vascular O
endothelial O
growth O
factor O
( O
VEGF O
) O
family O
and O
related O
receptors O
play O
a O
central O
role O
in O
the O
modulation O
of O
pathological O
angiogenesis O
. O

In O
order O
to O
identify O
plant O
compounds O
able O
to O
interfere O
in O
the O
VEGFs O
/ O
VEGFR O
- O
1 O
( O
Flt O
- O
1 O
) O
recognition O
by O
VEGF O
family O
members O
, O
the O
extracts O
of O
the O
aerial O
parts O
of O
Campsiandra O
guayanensis O
and O
Feretia O
apodanthera O
were O
screened O
by O
a O
competitive O
ELISA O
- O
based O
assay O
. O

By O
using O
this O
bioassay O
- O
oriented O
approach O
five O
proanthocyanindins B
, O
including O
the O
new O
natural O
compounds O
( B
2S I
) I
- I
4 I
' I
, I
5 I
, I
7 I
- I
trihydroxyflavan I
- I
( I
4 I
beta I
- I
- I
> I
8 I
) I
- I
afzelechin I
( O
1 O
) O
and O
( B
2S I
) I
- I
4 I
' I
, I
5 I
, I
7 I
- I
trihydroxyflavan I
- I
( I
4 I
beta I
- I
- I
> I
8 I
) I
- I
epiafzelechin I
( O
2 O
) O
and O
the O
known O
geranin B
B I
( O
3 O
) O
, O
proanthocyanidin B
A2 I
( O
4 O
) O
, O
and O

proanthocyanidin B
A1 I
( O
5 O
) O
, O
were O
isolated O
. O

The O
study O
of O
the O
antiangiogenic O
activities O
of O
compounds O
1 O
- O
5 O
using O
ELISA O
and O
SPR O
assays O
showed O
compound O
1 O
as O
being O
the O
most O
active O
. O

The O
antiangiogenic O
activity O
of O
1 O
was O
also O
confirmed O
in O
vivo O
by O
the O
chicken O
chorioallantoic O
membrane O
assay O
. O

Our O
results O
indicated O
1 O
as O
a O
new O
antiangiogenic O
compound O
inhibiting O
the O
interaction O
between O
VEGF O
- O
A O
or O
PlGF O
and O
their O
receptor O
VEGRF O
- O
1 O
. O

Highly O
ordered O
cobalt B
- O
phthalocyanine B
chains O
on O
fractional O
atomic O
steps O
: O
one O
- O
dimensionality O
and O
electron O
hybridization O
. O

Precisely O
controlled O
fabrication O
of O
low O
- O
dimensional O
molecular O
structures O
with O
tailored O
morphologies O
and O
electronic O
properties O
is O
at O
the O
heart O
of O
the O
nanotechnology O
research O
. O

Especially O
, O
the O
formation O
of O
one O
- O
dimensional O
( O
1D O
) O
structures O
has O
been O
strongly O
desired O
due O
to O
their O
expected O
high O
performance O
for O
information O
processing O
in O
electronic O
/ O
magnetic O
devices O
. O

So O
far O
, O
however O
, O
they O
have O
been O
obtained O
by O
tough O
and O
slow O
methods O
such O
as O
manipulation O
of O
individual O
molecules O
, O
which O
are O
totally O
unsuited O
for O
mass O
production O
. O

Here O
we O
show O
that O
highly O
ordered O
cobalt B
- O
phthalocyanine B
chains O
can O
be O
self O
- O
assembled O
on O
a O
metal O
surface O
using O
fractional O
atomic O
steps O
as O
a O
template O
. O

We O
also O
demonstrate O
that O
the O
substrate O
surface O
electrons O
, O
which O
can O
be O
confined O
by O
cobalt B
- O
phthalocyanine B
molecules O
, O
can O
propagate O
along O
the O
step O
arrays O
and O
can O
hybridize O
with O
the O
molecular O
orbitals O
. O

These O
findings O
provide O
a O
significant O
step O
toward O
readily O
realization O
of O
1D O
charge O
/ O
spin O
transport O
, O
which O
can O
be O
mediated O
either O
directly O
by O
the O
molecules O
or O
by O
the O
surface O
electrons O
. O

Discovery O
of O
small O
molecule O
vanin B
inhibitors O
: O
new O
tools O
to O
study O
metabolism O
and O
disease O
. O

Vanins O
are O
enzymes O
with O
pantetheinase O
activity O
and O
are O
presumed O
to O
play O
a O
role O
in O
the O
recycling O
of O
pantothenic B
acid I
( O
vitamin B
B5 I
) O
from O
pantetheine B
. O

Pantothenic B
acid I
is O
an O
essential O
nutrient O
required O
to O
synthesize O
coenzyme O
A O
, O
a O
cofactor O
involved O
in O
many O
biological O
processes O
such O
as O
fatty B
acid I
synthesis O
and O
oxidation O
of O
pyruvate B
to O
fuel O
the O
citric B
acid I
cycle O
. O

Hydrolysis O
of O
pantetheine B
also O
liberates O
cysteamine B
, O
a O
known O
antioxidant O
. O

Vanin B
- O
1 O
is O
highly O
expressed O
in O
liver O
and O
is O
under O
transcriptional O
control O
of O
PPAR O
- O
alpha O
and O
nutritional O
status O
, O
suggesting O
a O
role O
in O
energy O
metabolism O
. O

The O
lack O
of O
potent O
and O
specific O
inhibitors O
of O
vanins O
has O
hampered O
detailed O
investigation O
of O
their O
function O
. O

We O
hereby O
report O
the O
design O
, O
synthesis O
, O
and O
characterization O
of O
a O
novel O
pantetheine B
analogue O
, O
RR6 B
, O
that O
acts O
as O
a O
selective O
, O
reversible O
, O
and O
competitive O
vanin O
inhibitor O
at O
nanomolar O
concentration O
. O

Oral O
administration O
of O
RR6 O
in O
rats O
completely O
inhibited O
plasma O
vanin B
activity O
and O
caused O
alterations O
of O
plasma O
lipid O
concentrations O
upon O
fasting O
, O
thereby O
illustrating O
its O
potential O
use O
in O
chemical O
biology O
research O
. O

Theoretical O
characterization O
of O
X O
- O
ray O
absorption O
, O
emission O
, O
and O
photoelectron O
spectra O
of O
nitrogen B
doped O
along O
graphene B
edges O
. O

K O
- O
edge O
X O
- O
ray O
absorption O
( O
XAS O
) O
, O
emission O
( O
XES O
) O
, O
and O
photoelectron O
( O
XPS O
) O
spectra O
of O
nitrogen B
doped O
along O
graphene B
edges O
are O
systematically O
investigated O
by O
using O
first O
- O
principles O
methods O
. O

In O
this O
study O
we O
considered O
pyridinium B
- O
like O
, O
pyridine B
- O
like O
, O
cyanide B
- O
like O
, O
and O
amine B
- O
like O
nitrogens B
at O
armchair O
and O
zigzag O
edges O
and O
pyrrole B
- O
like O
nitrogen B
at O
armchair O
edge O
as O
well O
as O
graphite B
- O
like O
nitrogen B
at O
graphene B
interior O
site O
. O

Our O
results O
indicate O
that O
nitrogen B
configuration O
and O
its O
location O
( O
armchair O
or O
zigzag O
edge O
) O
in O
nitrogen B
- O
doped O
graphene B
can O
be O
identified O
via O
the O
spectral O
analysis O
. O

Furthermore O
, O
some O
controversial O
spectral O
features O
observed O
in O
experiment O
for O
N B
- I
doped I
graphene I
- O
like O
materials O
are O
unambiguously O
assigned O
. O

The O
present O
analysis O
gives O
an O
explanation O
to O
the O
reason O
why O
the O
peak O
assignment O
is O
usually O
made O
differently O
between O
XPS O
and O
XAS O
. O

Study O
of O
the O
potential O
oxidative O
stress O
induced O
by O
six O
solvents O
in O
the O
rat O
brain O
. O

The O
mechanisms O
of O
action O
involved O
in O
the O
neurotoxicity O
of O
solvents O
are O
poorly O
understood O
. O

In O
vitro O
studies O
have O
suggested O
that O
the O
effects O
of O
some O
solvents O
might O
be O
due O
to O
the O
formation O
of O
reactive O
oxygen B
species O
( O
ROS O
) O
. O

This O
study O
assesses O
hydroxyl B
radical O
( O
OH B
) O
generation O
and O
measures O
malondialdehyde B
( O
MDA B
) O
levels O
in O
the O
cerebral O
tissue O
of O
rats O
exposed O
to O
six O
solvents O
( O
n B
- I
hexane I
, O
n B
- I
octane I
, O
toluene B
, O
n B
- I
butylbenzene I
, O
cyclohexane B
and O
1 B
, I
2 I
, I
4 I
- I
trimethylcyclohexane I
) O
. O

Three O
of O
these O
solvents O
have O
been O
shown O
to O
generate O
ROS O
in O
studies O
carried O
out O
in O
vitro O
on O
granular O
cell O
cultures O
from O
rat O
cerebellum O
. O

We O
assessed O
OH B
production O
by O
quantifying O
the O
rate O
of O
formation O
of O
3 B
, I
4 I
- I
dihydroxybenzoic I
acid I
using O
a O
trapping O
agent O
, O
4 B
- I
hydroxybenzoic I
acid I
, O
infused O
via O
the O
microdialysis O
probe O
, O
into O
the O
prefrontal O
cortex O
of O
rats O
exposed O
intraperitoneally O
to O
the O
solvents O
. O

Extracellular O
MDA B
was O
quantified O
in O
microdialysates O
collected O
from O
the O
prefrontal O
cortex O
of O
rats O
exposed O
, O
6h O
/ O
day O
for O
ten O
days O
, O
to O
1000ppm O
of O
the O
solvents O
( O
except O
for O
n B
- I
butylbenzene I
, O
generated O
at O
830ppm O
) O
in O
inhalation O
chambers O
. O

Tissue O
levels O
of O
free O
and O
total O
MDA B
were O
measured O
in O
different O
brain O
structures O
for O
rats O
acutely O
( O
intraperitoneal O
route O
) O
and O
sub O
- O
acutely O
( O
inhalation O
) O
exposed O
to O
solvents O
. O

None O
of O
the O
six O
solvents O
studied O
increased O
the O
production O
of O
hydroxyl B
radicals O
in O
the O
prefrontal O
cortex O
after O
acute O
administration O
. O

Nor O
did O
they O
increase O
extracellular O
or O
tissue O
levels O
of O
MDA B
after O
10 O
days O
' O
inhalation O
exposure O
. O

On O
the O
other O
hand O
, O
a O
decrease O
in O
the O
concentrations O
of O
free O
MDA B
in O
brain O
structures O
was O
observed O
after O
acute O
administration O
of O
n B
- I
hexane I
, O
1 B
, I
2 I
, I
4 I
- I
trimethylcyclohexane I
, O
toluene B
and O
n B
- I
butylbenzene I
. O

Therefore O
, O
data O
of O
this O
study O
carried O
out O
in O
vivo O
did O
not O
confirm O
observations O
made O
in O
vitro O
on O
cell O
cultures O
. O

Antivirals O
: O
past O
, O
present O
and O
future O
. O

Vaccination O
is O
possible O
to O
prevent O
infections O
with O
some O
viruses O
: O
hepatitis O
B O
virus O
( O
HBV O
) O
, O
varicella O
- O
zoster O
virus O
( O
VZV O
) O
, O
influenza O
A O
and O
B O
viruses O
, O
Yellow O
fever O
virus O
and O
poliovirus O
; O
but O
not O
for O
others O
: O
human O
immunodeficiency O
virus O
( O
HIV O
) O
, O
hepatitis O
C O
virus O
( O
HCV O
) O
, O
herpes O
simplex O
virus O
( O
HSV O
) O
, O
cytomegalovirus O
( O
CMV O
) O
, O
and O
most O
hemorrhagic O
fever O
viruses O
( O
HFV O
) O
( O
except O
for O
Yellow O
fever O
virus O
) O
. O

Antiviral O
therapy O
is O
obviously O
needed O
to O
control O
those O
infections O
that O
are O
not O
amenable O
to O
prophylaxis O
by O
vaccination O
, O
but O
is O
also O
highly O
desirable O
for O
those O
infections O
where O
vaccination O
has O
not O
been O
implemented O
or O
did O
not O
fulfill O
its O
premises O
for O
complete O
protection O
. O

The O
vasorelaxant O
effects O
of O
1 B
- I
nitro I
- I
2 I
- I
phenylethane I
involve O
stimulation O
of O
the O
soluble O
guanylate B
cyclase O
- O
cGMP B
pathway O
. O

1 B
- I
Nitro I
- I
2 I
- I
phenylethane I
is O
the O
first O
organic O
NO B
2 O
- O
containing O
molecule O
isolated O
from O
plants O
. O

It O
possesses O
interesting O
hypotensive O
, O
bradycardic O
, O
and O
vasodilator O
properties O
, O
but O
the O
mode O
by O
which O
it O
induces O
vasorelaxation O
is O
still O
unknown O
. O

The O
underlying O
mechanism O
involved O
in O
the O
vasodilator O
effect O
of O
1 B
- I
nitro I
- I
2 I
- I
phenylethane I
was O
investigated O
in O
rat O
aorta O
. O

The O
vasorelaxant O
effects O
of O
1 B
- I
nitro I
- I
2 I
- I
phenylethane I
did O
not O
depend O
on O
endothelial O
layer O
integrity O
, O
and O
the O
effects O
were O
refractory O
to O
L B
- I
N I
( I
G I
) I
- I
nitroarginine I
methyl I
ester I
( O
L B
- I
NAME I
) O
- O
induced O
nitric B
oxide I
synthase O
inhibition O
. O

Vasorelaxation O
was O
similarly O
resistant O
to O
treatment O
with O
indomethacin B
, O
cis B
- I
N I
- I
( I
2 I
- I
phenylcyclopentyl I
) I
- I
azacyclotridec I
- I
1 I
- I
en I
- I
2 I
- I
amine I
hydrochloride I
( O
MDL B
- I
12330A I
) O
, O
and O
KT5720 B
, O
indicating O
that O
neither O
prostaglandin B
release O
nor O
adenylyl O
cyclase O
activation O
is O
involved O
. O

Conversely O
, O
methylene B
blue I
- O
and O
ODQ B
- O
induced O
guanylate B
cyclase O
inhibition O
reduced O
the O
vasorelaxation O
induced O
by O
1 B
- I
nitro I
- I
2 I
- I
phenylethane I
. O

The O
pharmacological O
blockade O
of O
K B
( I
+ I
) I
channels O
with O
tetraethylammonium B
, O
glybenclamide B
, O
and O
4 B
- I
aminopyridine I
also O
blunted O
vasorelaxation O
induced O
by O
1 B
- I
nitro I
- I
2 I
- I
phenylethane I
. O

The O
effects O
of O
1 B
- I
nitro I
- I
2 I
- I
phenylethane I
were O
reversed O
by O
1H B
- I
[ I
1 I
, I
2 I
, I
4 I
] I
oxadiazolo I
[ I
4 I
, I
3 I
- I
a I
] I
quinoxalin I
- I
1 I
- I
one I
( O
ODQ B
) O
and O
comparable O
to O
the O
effects O
induced O
by O
sodium B
nitroprusside I
. O

In O
silico O
analysis O
using O
an O
Ns O
H O
- O
NOX O
subunit O
of O
guanylate B
cyclase O
revealed O
a O
pocket O
on O
the O
macromolecule O
surface O
where O
1 B
- I
nitro I
- I
2 I
- I
phenylethane I
preferentially O
docked O
. O

In O
vitro O
, O
1 B
- I
nitro I
- I
2 I
- I
phenylethane I
increased O
cyclic B
guanosine I
3 I
' I
, I
5 I
' I
- I
monophosphate I
( O
cGMP B
) O
levels O
in O
rat O
aortic O
rings O
, O
an O
effect O
also O
reversed O
by O
ODQ B
. O

In O
conclusion O
, O
1 B
- I
nitro I
- I
2 I
- I
phenylethane I
produces O
vasodilator O
effects O
by O
stimulating O
the O
soluble O
guanylate B
cyclase O
- O
cGMP B
pathway O
. O

Antidiabetic O
effect O
of O
secoisolariciresinol B
diglucoside I
in O
streptozotocin B
- O
induced O
diabetic O
rats O
. O

Diabetes O
mellitus O
is O
a O
chronic O
metabolic O
disorder O
characterized O
by O
hyperglycaemia O
. O

Its O
complications O
such O
as O
neuropathy O
, O
cardiopathy O
, O
nephropathy O
, O
and O
micro O
and O
macro O
vascular O
diseases O
are O
believed O
to O
be O
due O
to O
the O
increase O
in O
oxidative O
stress O
and O
decrease O
in O
the O
level O
of O
antioxidants O
. O

The O
aim O
of O
this O
study O
was O
to O
determine O
the O
antihyperglycemic O
activity O
of O
synthetic O
Secoisolariciresinol B
diglucoside I
( O
SDG B
) O
in O
streptozotocin B
( O
STZ B
) O
- O
induced O
diabetic O
rats O
. O

The O
synthetic O
SDG B
in O
a O
single O
- O
dose O
( O
20 O
mg O
/ O
kg O
b O
. O
w O
. O
) O
two O
- O
day O
study O
showed O
dose O
- O
dependent O
reduction O
in O
glucose B
levels O
with O
maximum O
effect O
of O
64 O
. O
62 O
% O
at O
48 O
h O
post O
drug O
treatment O
( O
p O
< O
0 O
. O
05 O
) O
, O
which O
is O
comparable O
to O
that O
of O
the O
standard O
drug O
tolbutamide B
( O
20 O
mg O
/ O
kg O
b O
. O
w O
. O
) O
. O

In O
a O
multi O
- O
dose O
fourteen O
- O
day O
study O
, O
lower O
doses O
of O
SDG B
( O
5 O
and O
10 O
mg O
/ O
kg O
b O
. O
w O
. O
) O
exhibited O
moderate O
reduction O
in O
glucose B
levels O
, O
lipid O
profile O
, O
restoration O
of O
antioxidant O
enzymes O
and O
improvement O
of O
the O
insulin O
and O
c O
- O
peptide O
levels O
which O
shows O
the O
regeneration O
of O
beta O
- O
cell O
which O
secretes O
insulin O
. O

Altered O
levels O
of O
lipids O
and O
enzymatic O
antioxidants O
were O
also O
restored O
by O
the O
SDG B
to O
the O
considerable O
levels O
in O
diabetic O
rats O
. O

Results O
of O
the O
present O
investigation O
suggest O
that O
diabetes O
is O
associated O
with O
an O
increase O
in O
oxidative O
stress O
as O
shown O
by O
increase O
in O
serum O
malondialdehyde B
( O
MDA B
) O
, O
decreased O
levels O
of O
catalase O
( O
CAT O
) O
, O
superoxide B
dismutase O
( O
SOD O
) O
, O
and O
glutathione B
( O
GSH B
) O
. O

Also O
, O
diabetes O
is O
associated O
with O
an O
increase O
in O
serum O
total O
cholesterol B
as O
well O
as O
triglycerides B
levels O
and O
decrease O
in O
insulin O
and O
c O
- O
peptide O
levels O
. O

SDG B
is O
effective O
in O
retarding O
the O
development O
of O
diabetic O
complications O
. O

We O
propose O
that O
synthetic O
SDG B
exerts O
anti O
hyperglycemic O
effect O
by O
preventing O
the O
liver O
from O
peroxidation O
damage O
through O
inhibition O
of O
ROS O
level O
mediated O
increased O
level O
of O
enzymatic O
and O
non O
- O
enzymatic O
antioxidants O
. O

And O
, O
also O
maintaining O
tissue O
function O
which O
results O
in O
improving O
the O
sensitivity O
and O
response O
of O
target O
cells O
in O
STZ B
- O
induced O
diabetic O
rats O
to O
insulin O
. O

Feeding O
of O
selenium B
alone O
or O
in O
combination O
with O
glucoraphanin B
differentially O
affects O
intestinal O
and O
hepatic O
antioxidant O
and O
phase O
II O
enzymes O
in O
growing O
rats O
. O

The O
anti O
- O
carcinogenic O
effects O
of O
sulforaphane B
( O
SFN B
) O
are O
based O
on O
the O
up O
- O
regulation O
of O
antioxidant O
enzymes O
( O
AE O
) O
and O
phase O
II O
enzymes O
( O
PIIE O
) O
through O
the O
transcription O
factor O
Nrf2 O
. O

Current O
knowledge O
on O
the O
roles O
of O
the O
SFN O
precursor O
glucoraphanin B
( O
GRA B
) O
on O
these O
processes O
is O
limited O
. O

Anti O
- O
carcinogenic O
effects O
of O
Se B
depending O
on O
glutathione B
peroxidase O
( O
GPx O
) O
activity O
have O
also O
been O
reported O
. O

We O
studied O
effects O
and O
possible O
synergisms O
of O
Se B
and O
GRA O
on O
the O
expression O
and O
activity O
of O
a O
broad O
spectrum O
of O
AE O
and O
PIIE O
in O
jejunum O
, O
colon O
and O
the O
liver O
of O
rats O
fed O
diets O
differing O
in O
Se B
and O
GRA O
concentration O
. O

In O
all O
organs O
, O
GPx1 O
mRNA O
expression O
was O
70 O
% O
to O
90 O
% O
lower O
in O
Se B
deficiency O
than O
in O
Se B
sufficiency O
. O

GPx2 O
expression O
increased O
in O
jejunum O
and O
liver O
under O
Se B
deficiency O
and O
decreased O
in O
the O
colon O
. O

Se B
deficiency O
increased O
most O
colonic O
AE O
and O
PIIE O
compared O
to O
Se B
adequacy O
. O

Adequate O
and O
in O
particular O
supranutritive O
Se O
combined O
with O
GRA O
increased O
colonic O
AE O
and O
PIIE O
expression O
up O
to O
3 O
. O
72 O
- O
fold O
. O

In O
the O
liver O
Se B
deficiency O
raised O
the O
expression O
of O
AE O
and O
PIIE O
up O
to O
4 O
. O
49 O
- O
fold O
. O

GRA O
attenuated O
liver O
AE O
and O
PIIE O
response O
in O
Se B
deficiency O
. O

Expression O
- O
and O
correlation O
analyses O
revealed O
that O
Keap1 O
mRNA O
better O
reflects O
AE O
and O
PIIE O
gene O
expression O
than O
Nrf2 O
mRNA O
. O

We O
conclude O
that O
: O
( O
1 O
) O
GPx1 O
sensitively O
indicates O
Se B
deficiency O
; O
( O
2 O
) O
the O
influence O
of O
Se B
and O
Nrf2 O
/ O
Keap1 O
on O
GPx2 O
expression O
depends O
on O
the O
organ O
; O
( O
3 O
) O
GRA O
combined O
with O
supranutritive O
Se B
may O
effectively O
protect O
against O
inflammation O
and O
colon O
cancer O
; O
( O
4 O
) O
future O
investigations O
on O
AE O
and O
PIIE O
expression O
should O
consider O
the O
role O
of O
Keap1 O
to O
a O
higher O
extent O
. O

Specific O
conserved O
C B
- O
terminal O
amino B
acids I
of O
Caenorhabditis O
elegans O
HMP O
- O
1 O
/ O
alpha O
- O
catenin O
modulate O
F O
- O
actin O
binding O
independently O
of O
vinculin O
. O

Stable O
intercellular O
adhesions O
formed O
through O
the O
cadherin O
- O
catenin O
complex O
are O
important O
determinants O
of O
proper O
tissue O
architecture O
and O
help O
maintain O
tissue O
integrity O
during O
morphogenetic O
movements O
in O
developing O
embryos O
. O

A O
key O
regulator O
of O
this O
stability O
is O
alpha O
- O
catenin O
, O
which O
connects O
the O
cadherin O
- O
catenin O
complex O
to O
the O
actin O
cytoskeleton O
. O

Although O
the O
C B
- O
terminal O
F O
- O
actin O
- O
binding O
domain O
of O
alpha O
- O
catenin O
has O
been O
shown O
to O
be O
crucial O
for O
its O
function O
, O
a O
more O
detailed O
in O
vivo O
analysis O
of O
discrete O
regions O
and O
residues O
required O
for O
actin O
binding O
has O
not O
been O
performed O
. O

Using O
Caenorhabditis O
elegans O
as O
a O
model O
system O
, O
we O
have O
characterized O
mutations O
in O
hmp O
- O
1 O
/ O
alpha O
- O
catenin O
that O
identify O
HMP O
- O
1 O
residues O
687 O
- O
742 O
and O
826 O
- O
927 O
, O
as O
well O
as O
amino B
acid I
802 O
, O
as O
critical O
to O
the O
localization O
of O
junctional O
proximal O
actin O
during O
epidermal O
morphogenesis O
. O

We O
also O
find O
that O
the O
S823F O
transition O
in O
a O
hypomorphic O
allele O
, O
hmp O
- O
1 O
( O
fe4 O
) O
, O
decreases O
actin O
binding O
in O
vitro O
. O

Using O
hmp O
- O
1 O
( O
fe4 O
) O
animals O
in O
a O
mutagenesis O
screen O
, O
we O
were O
then O
able O
to O
identify O
11 O
intragenic O
suppressors O
of O
hmp O
- O
1 O
( O
fe4 O
) O
that O
revert O
actin O
binding O
to O
wild O
- O
type O
levels O
. O

Using O
homology O
modeling O
, O
we O
show O
that O
these O
amino B
acids I
are O
positioned O
at O
key O
conserved O
sites O
within O
predicted O
alpha O
- O
helices O
in O
the O
C O
terminus O
. O

Through O
the O
use O
of O
transgenic O
animals O
, O
we O
also O
demonstrate O
that O
HMP O
- O
1 O
residues O
315 O
- O
494 O
, O
which O
correspond O
to O
a O
putative O
mechanotransduction O
domain O
that O
binds O
vinculin O
in O
vertebrate O
alpha O
E O
- O
catenin O
, O
are O
not O
required O
during O
epidermal O
morphogenesis O
but O
may O
aid O
efficient O
recruitment O
of O
HMP O
- O
1 O
to O
the O
junction O
. O

Our O
studies O
are O
the O
first O
to O
identify O
key O
conserved O
amino B
acids I
in O
the O
C B
terminus O
of O
alpha O
- O
catenin O
that O
modulate O
F O
- O
actin O
binding O
in O
living O
embryos O
of O
a O
simple O
metazoan O
. O

Nanoscale O
stabilization O
of O
new O
phases O
in O
the O
PbTe B
- O
Sb2Te3 B
system O
: O
Pb B
( I
m I
) I
Sb I
( I
2n I
) I
Te I
( I
m I
+ I
3n I
) I
nanocrystals O
. O

A O
series O
of O
novel O
rock O
- O
salt O
- O
type O
Pb B
( I
m I
) I
Sb I
( I
2n I
) I
Te I
( O
m O
+ O
3n O
) O
nanocrystals O
( O
m O
= O
2 O
, O
3 O
, O
4 O
, O
6 O
, O
8 O
, O
and O
10 O
; O
n O
= O
1 O
and O
2 O
) O
were O
successfully O
prepared O
using O
a O
colloidal O
synthesis O
route O
. O

These O
materials O
are O
stable O
only O
on O
the O
nanoscale O
and O
have O
no O
bulk O
analogues O
. O

Elemental O
compositions O
were O
determined O
using O
scanning O
transmission O
electron O
microscopy O
/ O
energy O
- O
dispersive O
X O
- O
ray O
spectroscopy O
( O
STEM O
/ O
EDS O
) O
and O
inductively O
coupled O
plasma O
atomic O
emission O
spectroscopy O
( O
ICP O
- O
AES O
) O
. O

The O
nanocrystals O
exhibit O
well O
- O
defined O
band O
energies O
in O
the O
mid O
- O
IR O
region O
that O
are O
nearly O
independent O
of O
their O
atomic O
compositions O
. O

Pb B
( I
m I
) I
Sb I
( I
2n I
) I
Te I
( I
m I
+ I
3n I
) I
nanocrystals O
behave O
as O
metastable O
homogeneous O
solid O
solutions O
at O
room O
temperature O
and O
tend O
to O
phase O
separate O
into O
the O
respective O
binary O
PbTe B
+ O
Sb B
( I
2 I
) I
Te I
( I
3 I
) I
at O
300 O
degrees O
C O
. O

Furthermore O
, O
pair O
distribution O
function O
( O
PDF O
) O
analysis O
suggests O
that O
the O
local O
structure O
of O
these O
Pb B
( I
m I
) I
Sb I
( I
2n I
) I
Te I
( I
m I
+ I
3n I
) I
nanocrystals O
is O
distorted O
with O
respect O
to O
the O
rock O
- O
salt O
structure O
. O

N B
- I
cinnamoylated I
chloroquine I
analogues O
as O
dual O
- O
stage O
antimalarial O
leads O
. O

The O
control O
of O
malaria O
is O
challenged O
by O
drug O
resistance O
, O
and O
new O
antimalarial O
drugs O
are O
needed O
. O

New O
drug O
discovery O
efforts O
include O
consideration O
of O
hybrid O
compounds O
as O
potential O
multitarget O
antimalarials O
. O

Previous O
work O
from O
our O
group O
has O
demonstrated O
that O
hybrid O
structures O
resulting O
from O
cinnamic B
acid I
conjugation O
with O
heterocyclic O
moieties O
from O
well O
- O
known O
antimalarials O
present O
improved O
antimalarial O
activity O
. O

Now O
, O
we O
report O
the O
synthesis O
and O
SAR O
analysis O
of O
an O
expanded O
series O
of O
cinnamic B
acid I
derivatives O
displaying O
remarkably O
high O
activities O
against O
both O
blood O
- O
and O
liver O
- O
stage O
malaria O
parasites O
. O

Two O
compounds O
judged O
most O
promising O
, O
based O
on O
their O
in O
vitro O
activity O
and O
druglikeness O
according O
to O
the O
Lipinski O
rules O
and O
Veber O
filter O
, O
were O
active O
in O
vivo O
against O
blood O
- O
stage O
rodent O
malaria O
parasites O
. O

Therefore O
, O
the O
compounds O
reported O
represent O
a O
new O
entry O
as O
promising O
dual O
- O
stage O
antimalarial O
leads O
. O

Bistable O
magnetoresistance O
switching O
in O
exchange O
- O
coupled O
CoFe B
2 I
O I
4 I
- O
- O
Fe B
3 I
O I
4 I
binary O
nanocrystal O
superlattices O
by O
self O
- O
assembly O
and O
thermal O
annealing O
. O

Self O
- O
assembly O
of O
multicomponent O
nanocrystal O
superlattices O
provides O
a O
modular O
approach O
to O
the O
design O
of O
metamaterials O
by O
choosing O
constituent O
nanocrystal O
building O
blocks O
with O
desired O
physical O
properties O
and O
engineering O
the O
interparticle O
coupling O
. O

In O
this O
work O
, O
we O
report O
the O
self O
- O
assembly O
of O
binary O
nanocrystal O
superlattices O
composed O
of O
magnetically O
hard O
CoFe B
2 I
O I
4 I
nanocrystals O
and O
magnetically O
soft O
Fe B
3 I
O I
4 I
nanocrystals O
. O

Both O
NaZn B
1 I
3 O
- O
and O
MgZn B
2 I
- O
type O
CoFe B
2 I
O I
4 I
- O
- O
Fe B
3 I
O I
4 I
binary O
nanocrystal O
superlattices O
have O
been O
formed O
by O
the O
liquid O
- O
air O
interfacial O
assembly O
approach O
. O

Exchange O
coupling O
is O
achieved O
in O
both O
types O
of O
binary O
superlattices O
after O
thermal O
annealing O
under O
vacuum O
at O
400 O
degrees O
C O
. O

The O
exchange O
- O
coupled O
CoFe B
2 I
O I
4 I
- O
- O
Fe B
3 I
O I
4 I
binary O
nanocrystal O
superlattices O
show O
single O
- O
phase O
magnetization O
switching O
behavior O
and O
magnetoresistance O
switching O
behavior O
below O
200 O
K O
. O

The O
NaZn B
1 O
3 I
- O
type O
CoFe B
2 I
O I
4 I
- O
- O
Fe B
3 I
O I
4 I
binary O
nanocrystal O
superlattices O
annealed O
at O
500 O
degrees O
C O
even O
exhibit O
bistable O
magnetoresistance O
switching O
behavior O
at O
room O
temperature O
constituting O
a O
simple O
nonvolatile O
memory O
function O
. O

Synthesis O
, O
molecular O
modeling O
and O
evaluation O
of O
novel O
N B
' I
- I
2 I
- I
( I
4 I
- I
benzylpiperidin I
- I
/ I
piperazin I
- I
1 I
- I
yl I
) I
acylhydrazone I
derivatives O
as O
dual O
inhibitors O
for O
cholinesterases O
and O
A O
beta O
aggregation O
. O

To O
develop O
new O
drugs O
for O
treatment O
of O
Alzheimer O
' O
s O
disease O
, O
a O
group O
of O
N B
' I
- I
2 I
- I
( I
4 I
- I
Benzylpiperidin I
- I
/ I
piperazin I
- I
1 I
- I
yl I
) I
acylhydrazones I
was O
designed O
, O
synthesized O
and O
tested O
for O
their O
ability O
to O
inhibit O
acetylcholinesterase O
, O
butyrylcholinesteras O
and O
aggregation O
of O
amyloid O
beta O
peptides O
( O
1 O
- O
40 O
, O
1 O
- O
42 O
and O
1 O
- O
40 O
_ O
1 O
- O
42 O
) O
. O

The O
enzyme O
inhibition O
assay O
results O
indicated O
that O
compounds O
moderately O
inhibit O
both O
acetylcholinesterase O
and O
butyrylcholinesteras O
. O

beta O
- O
Amyloid O
aggregation O
results O
showed O
that O
all O
compounds O
exhibited O
remarkable O
A O
beta O
fibril O
aggregation O
inhibition O
activity O
with O
a O
nearly O
similar O
potential O
as O
the O
reference O
compound O
rifampicin B
, O
which O
makes O
them O
promising O
anti O
- O
Alzheimer O
drug O
candidates O
. O

Docking O
experiments O
were O
carried O
out O
with O
the O
aim O
to O
understand O
the O
interactions O
of O
the O
most O
active O
compounds O
with O
the O
active O
site O
of O
the O
cholinesterase O
enzymes O
. O

Synthesis O
and O
biological O
evaluation O
of O
analogues O
of O
the O
kinase O
inhibitor O
nilotinib B
as O
Abl O
and O
Kit O
inhibitors O
. O

The O
importance O
of O
the O
trifluoromethyl B
group O
in O
the O
polypharmacological O
profile O
of O
nilotinib B
was O
investigated O
. O

Molecular O
editing O
of O
nilotinib B
led O
to O
the O
design O
, O
synthesis O
and O
biological O
evaluation O
of O
analogues O
where O
the O
trifluoromethyl B
group O
was O
replaced O
by O
a O
proton O
, O
fluorine B
and O
a O
methyl B
group O
. O

While O
these O
analogues O
were O
less O
active O
than O
nilotinib B
toward O
Abl O
, O
their O
activity O
toward O
Kit O
was O
comparable O
, O
with O
the O
monofluorinated O
analogue O
being O
the O
most O
active O
. O

Docking O
of O
nilotinib B
and O
of O
analogues O
2a O
- O
c O
to O
the O
binding O
pocket O
of O
Abl O
and O
of O
Kit O
showed O
that O
the O
lack O
of O
shape O
complementarity O
in O
Kit O
is O
compensated O
by O
the O
stabilizing O
effect O
from O
its O
juxtamembrane O
region O
. O

HCV O
NS5A O
replication O
complex O
inhibitors O
. O

Part O
3 O
: O
discovery O
of O
potent O
analogs O
with O
distinct O
core O
topologies O
. O

In O
a O
recent O
disclosure O
, O
we O
described O
the O
discovery O
of O
dimeric O
, O
prolinamide B
- O
based O
NS5A O
replication O
complex O
inhibitors O
exhibiting O
excellent O
potency O
towards O
an O
HCV O
genotype O
1b O
replicon O
. O

That O
disclosure O
dealt O
with O
the O
SAR O
exploration O
of O
the O
peripheral O
region O
of O
our O
lead O
chemotype O
, O
and O
herein O
is O
described O
the O
SAR O
uncovered O
from O
a O
complementary O
effort O
that O
focused O
on O
the O
central O
core O
region O
. O

From O
this O
effort O
, O
the O
contribution O
of O
the O
core O
region O
to O
the O
overall O
topology O
of O
the O
pharmacophore O
, O
primarily O
vector O
orientation O
and O
planarity O
, O
was O
determined O
, O
with O
a O
set O
of O
analogs O
exhibiting O
< O
10 O
nM O
EC O
( O
50 O
) O
in O
a O
genotype O
1b O
replicon O
assay O
. O

Endophytic O
fungi O
from O
Miquelia O
dentata O
Bedd O
. O
, O
produce O
the O
anti O
- O
cancer O
alkaloid O
, O
camptothecine B
. O

Camptothecine B
( O
Campothecin B
, O
CPT B
) O
, O
a O
quinoline B
alkaloid I
, O
is O
a O
potent O
inhibitor O
of O
eukaryotic O
topoisomerase O
I O
. O

Several O
semi O
- O
synthetic O
derivatives O
of O
CPT B
are O
in O
clinical O
use O
against O
ovarian O
, O
small O
lung O
and O
refractory O
ovarian O
cancers O
. O

While O
CPT O
is O
produced O
by O
several O
plant O
species O
belonging O
to O
the O
Asterid O
clade O
, O
in O
recent O
years O
, O
efforts O
have O
been O
made O
to O
isolate O
endophytic O
fungi O
from O
some O
of O
these O
plants O
as O
possible O
alternative O
sources O
of O
CPT O
. O

In O
this O
study O
we O
report O
the O
isolation O
of O
three O
endophytic O
fungi O
from O
fruit O
and O
seed O
regions O
of O
Miquelia O
dentata O
( O
Icacinaceae O
) O
, O
that O
produce O
CPT B
, O
9 B
- I
methoxy I
CPT I
( O
9 B
- I
MeO I
- I
CPT I
) O
and O
10 B
- I
hydroxy I
CPT I
( O
10 B
- I
OH I
- I
CPT I
) O
. O

All O
the O
three O
fungi O
identified O
as O
, O
Fomitopsis O
sp O
. O

P O
. O

Karst O
( O
MTCC O
10177 O
) O
, O
Alternaria O
alternata O
( O
Fr O
. O
) O
Keissl O
( O
MTCC O
5477 O
) O
and O
Phomposis O
sp O
. O

( O
Sacc O
. O
) O
produced O
CPT B
, O
9 B
- I
MeO I
- I
CPT I
and O
10 B
- I
OH I
- I
CPT I
in O
mycelial O
mats O
in O
shake O
flasks O
containing O
potato O
dextrose B
broth O
. O

Methanolic O
and O
ethyl B
acetate I
extracts O
of O
these O
fungal O
species O
were O
cytotoxic O
to O
colon O
and O
breast O
cancer O
cell O
lines O
. O

We O
discuss O
these O
results O
in O
the O
context O
of O
the O
recent O
interest O
in O
endophytic O
fungi O
as O
possible O
alternative O
sources O
of O
plant O
secondary O
metabolites O
. O

A O
link O
between O
the O
cytoplasmic O
engulfment O
protein O
Elmo1 O
and O
the O
Mediator O
complex O
subunit O
Med31 O
. O

The O
cytoplasmic O
Elmo1 O
: O
Dock180 O
complex O
acts O
as O
a O
guanine B
nucleotide I
exchange O
factor O
( O
GEF O
) O
for O
the O
small O
GTPase O
Rac O
and O
functions O
downstream O
of O
the O
phagocytic O
receptor O
BAI1 O
during O
apoptotic O
cell O
clearance O
, O
and O
in O
the O
entry O
of O
Salmonella O
and O
Shigella O
into O
cells O
. O

We O
discovered O
an O
unexpected O
binding O
between O
Elmo1 O
and O
the O
Mediator O
complex O
subunit O
Med31 O
. O

The O
Mediator O
complex O
is O
a O
regulatory O
hub O
for O
nearly O
all O
gene O
transcription O
via O
RNA O
polymerase O
II O
, O
bridging O
the O
general O
transcription O
machinery O
with O
gene O
- O
specific O
regulatory O
proteins O
. O

Med31 O
is O
the O
smallest O
and O
the O
most O
evolutionarily O
conserved O
Mediator O
subunit O
, O
and O
knockout O
of O
Med31 O
results O
in O
embryonic O
lethality O
in O
mice O
; O
however O
, O
Med31 O
function O
in O
specific O
biological O
contexts O
is O
poorly O
understood O
. O

We O
observed O
that O
in O
primary O
macrophages O
, O
during O
Salmonella O
infection O
, O
Elmo1 O
and O
Med31 O
specifically O
affected O
expression O
of O
the O
cytokine O
genes O
Il10 O
and O
Il33 O
among O
the O
> O
25 O
genes O
monitored O
. O

Although O
endogenous O
Med31 O
is O
predominantly O
nuclear O
localized O
, O
Elmo1 O
increased O
the O
cytoplasmic O
localization O
of O
Med31 O
. O

We O
identify O
ubiquitination O
as O
a O
novel O
posttranslational O
modification O
of O
Med31 O
, O
with O
the O
cytoplasmic O
monoubiquitinated O
form O
of O
Med31 O
being O
enhanced O
by O
Elmo1 O
. O

These O
data O
identify O
Elmo1 O
as O
a O
novel O
regulator O
of O
Med31 O
, O
revealing O
a O
previously O
unrecognized O
link O
between O
cytoplasmic O
signaling O
proteins O
and O
the O
Mediator O
complex O
. O

Jaceosidin B
, O
isolated O
from O
dietary O
mugwort O
( O
Artemisia O
princeps O
) O
, O
induces O
G2 O
/ O
M O
cell O
cycle O
arrest O
by O
inactivating O
cdc25C O
- O
cdc2 O
via O
ATM O
- O
Chk1 O
/ O
2 O
activation O
. O

Jaceosidin B
, O
a O
flavonoid B
derived O
from O
Artemisia O
princeps O
( O
Japanese O
mugwort O
) O
, O
has O
been O
shown O
to O
inhibit O
the O
growth O
of O
several O
human O
cancer O
cells O
, O
However O
, O
the O
exact O
mechanism O
for O
the O
cytotoxic O
effect O
of O
jaceosidin B
is O
not O
completely O
understood O
. O

In O
this O
study O
, O
we O
investigated O
the O
molecular O
mechanism O
involved O
in O
the O
antiproliferative O
effect O
of O
jaceosidin B
in O
human O
endometrial O
cancer O
cells O
. O

We O
demonstrated O
that O
jaceosidin B
is O
a O
more O
potent O
inhibitor O
of O
cell O
growth O
than O
cisplatin B
in O
human O
endometrial O
cancer O
cells O
. O

In O
contrast O
, O
jaceosidin B
- O
induced O
cytotoxicity O
in O
normal O
endometrial O
cells O
was O
lower O
than O
that O
observed O
for O
cisplatin B
. O

Jaceosidin B
induced O
G2 O
/ O
M O
phase O
cell O
cycle O
arrest O
and O
modulated O
the O
levels O
of O
cyclin O
B O
and O
p O
- O
Cdc2 O
in O
Hec1A O
cells O
. O

Knockdown O
of O
p21 O
using O
specific O
siRNAs O
partially O
abrogated O
jaceosidin B
- O
induced O
cell O
growth O
inhibition O
. O

Additional O
mechanistic O
studies O
revealed O
that O
jaceosidin B
treatment O
resulted O
in O
an O
increase O
in O
phosphorylation O
of O
Cdc25C O
and O
ATM O
- O
Chk1 O
/ O
2 O
. O

Ku55933 B
, O
an O
ATM O
inhibitor O
, O
reversed O
jaceosidin B
- O
induced O
cell O
growth O
inhibition O
, O
in O
part O
. O

Moreover O
, O
jaceosidin B
treatment O
resulted O
in O
phosphorylation O
of O
ERK O
, O
and O
pretreatment O
with O
the O
ERK O
inhibitor O
, O
PD98059 B
, O
attenuated O
cell O
growth O
inhibition O
by O
jaceosidin B
. O

These O
data O
suggest O
that O
jaceosidin B
, O
isolated O
from O
Japanese O
mugwort O
, O
modulates O
the O
ERK O
/ O
ATM O
/ O
Chk1 O
/ O
2 O
pathway O
, O
leading O
to O
inactivation O
of O
the O
Cdc2 O
- O
cyclin O
B1 O
complex O
, O
followed O
by O
G2 O
/ O
M O
cell O
cycle O
arrest O
in O
endometrial O
cancer O
cells O
. O

AMPK O
is O
a O
negative O
regulator O
of O
the O
Warburg O
effect O
and O
suppresses O
tumor O
growth O
in O
vivo O
. O

AMPK O
is O
a O
metabolic O
sensor O
that O
helps O
maintain O
cellular O
energy O
homeostasis O
. O

Despite O
evidence O
linking O
AMPK O
with O
tumor O
suppressor O
functions O
, O
the O
role O
of O
AMPK O
in O
tumorigenesis O
and O
tumor O
metabolism O
is O
unknown O
. O

Here O
we O
show O
that O
AMPK O
negatively O
regulates O
aerobic O
glycolysis O
( O
the O
Warburg O
effect O
) O
in O
cancer O
cells O
and O
suppresses O
tumor O
growth O
in O
vivo O
. O

Genetic O
ablation O
of O
the O
alpha O
1 O
catalytic O
subunit O
of O
AMPK O
accelerates O
Myc O
- O
induced O
lymphomagenesis O
. O

Inactivation O
of O
AMPK O
alpha O
in O
both O
transformed O
and O
nontransformed O
cells O
promotes O
a O
metabolic O
shift O
to O
aerobic O
glycolysis O
, O
increased O
allocation O
of O
glucose B
carbon B
into O
lipids O
, O
and O
biomass O
accumulation O
. O

These O
metabolic O
effects O
require O
normoxic O
stabilization O
of O
the O
hypoxia O
- O
inducible O
factor O
- O
1 O
alpha O
( O
HIF O
- O
1 O
alpha O
) O
, O
as O
silencing O
HIF O
- O
1 O
alpha O
reverses O
the O
shift O
to O
aerobic O
glycolysis O
and O
the O
biosynthetic O
and O
proliferative O
advantages O
conferred O
by O
reduced O
AMPK O
alpha O
signaling O
. O

Together O
our O
findings O
suggest O
that O
AMPK O
activity O
opposes O
tumor O
development O
and O
that O
its O
loss O
fosters O
tumor O
progression O
in O
part O
by O
regulating O
cellular O
metabolic O
pathways O
that O
support O
cell O
growth O
and O
proliferation O
. O

Ptaquiloside B
reduces O
NK O
cell O
activities O
by O
enhancing O
metallothionein O
expression O
, O
which O
is O
prevented O
by O
selenium B
. O

Pteridium O
aquilinum O
, O
one O
of O
the O
most O
important O
poisonous O
plants O
in O
the O
world O
, O
is O
known O
to O
be O
carcinogenic O
to O
animals O
and O
humans O
. O

Moreover O
, O
our O
previous O
studies O
showed O
that O
the O
immunosuppressive O
effects O
of O
ptaquiloside B
, O
its O
main O
toxic O
agent O
, O
were O
prevented O
by O
selenium B
in O
mouse O
natural O
killer O
( O
NK O
) O
cells O
. O

We O
also O
verified O
that O
this O
immunosuppression O
facilitated O
development O
of O
cancer O
. O

Here O
, O
we O
performed O
gene O
expression O
microarray O
analysis O
in O
splenic O
NK O
cells O
from O
mice O
treated O
for O
14 O
days O
with O
ptaquiloside B
( O
5 O
. O
3 O
mg O
/ O
kg O
) O
and O
/ O
or O
selenium B
( O
1 O
. O
3 O
mg O
/ O
kg O
) O
to O
identify O
gene O
transcripts O
altered O
by O
ptaquiloside B
that O
could O
be O
linked O
to O
the O
immunosuppression O
and O
that O
would O
be O
prevented O
by O
selenium B
. O

Transcriptome O
analysis O
of O
ptaquiloside B
samples O
revealed O
that O
872 O
transcripts O
were O
expressed O
differentially O
( O
fold O
change O
> O
2 O
and O
p O
< O
0 O
. O
05 O
) O
, O
including O
77 O
up O
- O
regulated O
and O
795 O
down O
- O
regulated O
transcripts O
. O

Gene O
ontology O
analysis O
mapped O
these O
up O
- O
regulated O
transcripts O
to O
three O
main O
biological O
processes O
( O
cellular O
ion O
homeostasis O
, O
negative O
regulation O
of O
apoptosis O
and O
regulation O
of O
transcription O
) O
. O

Considering O
the O
immunosuppressive O
effect O
of O
ptaquiloside B
, O
we O
hypothesized O
that O
two O
genes O
involved O
in O
cellular O
ion O
homeostasis O
, O
metallothionein O
1 O
( O
Mt1 O
) O
and O
metallothionein O
2 O
( O
Mt2 O
) O
, O
could O
be O
implicated O
because O
Mt1 O
and O
Mt2 O
are O
responsible O
for O
zinc B
homeostasis O
, O
and O
a O
reduction O
of O
free O
intracellular O
zinc B
impairs O
NK O
functions O
. O

We O
confirm O
these O
hypotheses O
and O
show O
increased O
expression O
of O
metallothionein O
in O
splenic O
NK O
cells O
and O
reduction O
in O
free O
intracellular O
zinc B
following O
treatment O
with O
ptaquiloside B
that O
were O
completely O
prevented O
by O
selenium B
co O
- O
treatment O
. O

These O
findings O
could O
help O
avoid O
the O
higher O
susceptibility O
to O
cancer O
that O
is O
induced O
by O
P O
. O
aquilinum O
- O
mediated O
immunosuppressive O
effects O
. O

Interference O
of O
a O
novel O
indolylmaleimide B
with O
microtubules O
induces O
mitotic O
arrest O
and O
apoptosis O
in O
human O
progenitor O
and O
cancer O
cells O
. O

Indolylmaleimides B
display O
a O
broad O
spectrum O
of O
biological O
activity O
and O
offer O
great O
opportunity O
to O
influence O
several O
aspects O
of O
cell O
fate O
, O
as O
proliferation O
and O
differentiation O
. O

In O
this O
study O
we O
describe O
the O
effect O
of O
PDA B
- I
66 I
, O
a O
newly O
synthesised O
indolylmaleimide B
, O
showing O
a O
strong O
dose O
dependent O
anti O
- O
proliferative O
effect O
on O
immortalised O
human O
progenitor O
and O
cancer O
cells O
. O

We O
demonstrated O
a O
highly O
depolymerizing O
effect O
on O
in O
vitro O
tubulin O
assembly O
and O
conclude O
that O
PDA B
- I
66 I
acts O
as O
microtubule O
destabilising O
agent O
. O

In O
addition O
we O
found O
that O
PDA B
- I
66 I
induces O
mitotic O
arrest O
of O
cells O
in O
the O
G O
2 O
/ O
M O
phase O
of O
the O
cell O
cycle O
. O

Subsequently O
cells O
undergo O
apoptosis O
, O
indicating O
the O
major O
mechanism O
of O
the O
anti O
- O
proliferative O
effect O
. O

To O
prove O
a O
potential O
anti O
- O
cancer O
activity O
of O
PDA B
- I
66 I
we O
examined O
the O
effect O
of O
PDA B
- I
66 I
on O
human O
SH O
- O
SY5Y O
neuroblastoma O
and O
A O
- O
459 O
lung O
cancer O
cells O
, O
showing O
a O
significant O
reduction O
in O
cancer O
cell O
proliferation O
in O
a O
dose O
dependent O
manner O
. O

Thus O
PDA B
- I
66 I
is O
a O
new O
anti O
- O
mitotic O
compound O
with O
an O
indole B
- O
core O
with O
the O
potential O
to O
be O
used O
for O
cancer O
therapy O
. O

alpha B
- I
Terpineol I
induces O
fatty O
liver O
in O
mice O
mediated O
by O
the O
AMP B
- O
activated O
kinase O
and O
sterol B
response O
element O
binding O
protein O
pathway O
. O

The O
use O
of O
herbal O
medicines O
in O
disease O
prevention O
and O
treatment O
is O
growing O
rapidly O
worldwide O
, O
without O
careful O
consideration O
of O
safety O
issues O
. O

alpha B
- I
Terpineol I
is O
a O
monoterpene B
alcoholic I
component O
of O
Melaleuca O
alternifolia O
, O
Salvia O
officinalis O
and O
Carthamus O
tinctorius O
that O
is O
used O
widely O
as O
a O
flavor O
and O
essential O
oil O
in O
food O
. O

The O
present O
study O
showed O
that O
alpha B
- I
terpineol I
induces O
fatty O
liver O
via O
the O
AMP B
- O
activated O
protein O
kinase O
( O
AMPK O
) O
- O
mTOR O
- O
sterol B
regulatory O
element O
- O
binding O
protein O
- O
1 O
( O
SREBP O
- O
1 O
) O
pathway O
. O

alpha B
- I
Terpineol I
- O
treated O
hepatocytes O
had O
significantly O
increased O
neutral O
lipid O
accumulation O
. O

alpha B
- I
Terpineol I
suppressed O
AMPK O
phosphorylation O
, O
and O
increased O
p70S6 O
kinase O
( O
p70S6K O
) O
phosphorylation O
and O
SREBP O
- O
1 O
activation O
. O

It O
also O
increased O
luciferase O
activity O
in O
cells O
transfected O
with O
LXRE O
- O
tk O
- O
Luc O
and O
SRE O
- O
tk O
- O
Luc O
. O

Inhibition O
of O
mTOR O
signaling O
by O
co O
- O
treatment O
with O
rapamycin B
or O
co O
- O
transfection O
with O
dominant O
negative O
p70S6K O
blocked O
completely O
the O
effects O
of O
alpha B
- I
terpineol I
. O

alpha B
- I
Terpineol I
oral O
administration O
to O
mice O
for O
2weeks O
led O
to O
decreased O
AMPK O
phosphorylation O
and O
increased O
SREBP O
- O
1 O
activation O
in O
the O
liver O
, O
followed O
by O
hepatic O
lipid O
accumulation O
. O

Conversely O
, O
rapamycin B
co O
- O
treatment O
reversed O
alpha B
- I
terpineol I
- O
induced O
SREBP O
- O
1 O
activation O
and O
fatty O
liver O
in O
mice O
. O

These O
data O
provide O
evidence O
that O
alpha B
- I
terpineol I
causes O
fatty O
liver O
, O
an O
effect O
mediated O
by O
the O
AMPK O
/ O
mTOR O
/ O
SREBP O
- O
1 O
pathway O
. O

Multi O
- O
walled O
carbon B
nanotube O
increases O
the O
excitability O
of O
hippocampal O
CA1 O
neurons O
through O
inhibition O
of O
potassium B
channels O
in O
rat O
' O
s O
brain O
slices O
. O

This O
study O
was O
to O
investigate O
the O
neurotoxicity O
of O
multi O
- O
walled O
carbon B
nanotube O
( O
MWCNT O
) O
by O
measuring O
neuronal O
excitability O
in O
rat O
hippocampal O
neurons O
and O
exploring O
the O
underlying O
mechanism O
. O

Whole O
cell O
patch O
- O
clamp O
technique O
was O
used O
. O

Action O
potential O
properties O
and O
the O
pattern O
of O
repetitive O
firing O
rate O
were O
assessed O
. O

Our O
data O
showed O
that O
spike O
half O
- O
width O
and O
repetitive O
firing O
rate O
were O
significantly O
increased O
in O
a O
concentration O
- O
dependent O
manner O
. O

Furthermore O
, O
voltage O
- O
activated O
potassium B
currents O
were O
recorded O
. O

It O
was O
found O
that O
MWCNT O
produced O
a O
concentration O
- O
dependent O
inhibition O
in O
amplitudes O
of O
I O
( O
A O
) O
and O
I O
( O
K B
) O
. O

In O
addition O
, O
MWCNT O
had O
effect O
on O
the O
activation O
kinetics O
of O
I O
( O
A O
) O
and O
I O
( O
K B
) O
with O
V O
( O
h O
) O
being O
shifted O
to O
the O
negative O
potential O
at O
high O
concentration O
, O
while O
I O
( O
A O
) O
inactivation O
curve O
was O
considerably O
shifted O
to O
the O
hyperpolarize O
potential O
with O
V O
( O
h O
) O
being O
increased O
. O

However O
, O
no O
effect O
was O
found O
on O
the O
recovery O
from O
inactivation O
of O
I O
( O
A O
) O
. O

The O
results O
suggest O
that O
MWCNT O
increases O
the O
excitability O
of O
hippocampal O
CA1 O
neurons O
by O
inhibiting O
voltage O
- O
gated O
potassium B
current O
. O

Bile B
acids I
in O
the O
colon O
, O
from O
healthy O
to O
cytotoxic O
molecules O
. O

Bile B
acids I
are O
natural O
detergents O
mainly O
involved O
in O
facilitating O
the O
absorption O
of O
dietary O
fat O
in O
the O
intestine O
. O

In O
addition O
to O
this O
absorptive O
function O
, O
bile B
acids I
are O
also O
essential O
in O
the O
maintenance O
of O
the O
intestinal O
epithelium O
homeostasis O
. O

To O
accomplish O
this O
regulatory O
function O
, O
bile B
acids I
may O
induce O
programmed O
cell O
death O
fostering O
the O
renewal O
of O
the O
epithelium O
. O

Here O
we O
first O
discuss O
on O
the O
different O
molecular O
pathways O
of O
cell O
death O
focusing O
on O
apoptosis O
in O
colon O
epithelial O
cells O
. O

Bile B
acids I
may O
induce O
apoptosis O
in O
colonocytes O
through O
different O
mechanisms O
. O

In O
contrast O
to O
hepatocytes O
, O
the O
extrinsic O
apoptotic O
pathway O
seems O
to O
have O
a O
low O
relevance O
regarding O
bile B
acid I
cytotoxicity O
in O
the O
colon O
. O

On O
the O
contrary O
, O
these O
molecules O
mainly O
trigger O
apoptosis O
through O
direct O
or O
indirect O
mitochondrial O
perturbations O
, O
where O
oxidative O
stress O
plays O
a O
key O
role O
. O

In O
addition O
, O
bile B
acids I
may O
also O
act O
as O
regulatory O
molecules O
involved O
in O
different O
cell O
signaling O
pathways O
in O
colon O
cells O
. O

On O
the O
other O
hand O
, O
there O
is O
increasing O
evidence O
that O
the O
continuous O
exposure O
to O
certain O
hydrophobic O
bile B
acids I
, O
due O
to O
a O
fat O
- O
rich O
diet O
or O
pathological O
conditions O
, O
may O
induce O
oxidative O
DNA O
damage O
that O
, O
in O
turn O
, O
may O
lead O
to O
colorectal O
carcinogenesis O
as O
a O
consequence O
of O
the O
appearance O
of O
cell O
populations O
resistant O
to O
bile B
acid I
- O
induced O
apoptosis O
. O

Finally O
, O
some O
bile B
acids I
, O
such O
as O
UDCA B
, O
or O
low O
concentrations O
of O
hydrophobic O
bile B
acids I
, O
can O
protect O
colon O
cells O
against O
apoptosis O
induced O
by O
high O
concentrations O
of O
cytotoxic O
bile B
acids I
, O
suggesting O
a O
dual O
behavior O
of O
these O
agents O
as O
pro O
- O
death O
or O
pro O
- O
survival O
molecules O
. O

In O
vitro O
evaluation O
of O
cytochrome O
P450 O
induction O
and O
the O
inhibition O
potential O
of O
mitragynine B
, O
a O
stimulant O
alkaloid O
. O

CYP450 O
enzymes O
are O
key O
determinants O
in O
drug O
toxicities O
, O
reduced O
pharmacological O
effect O
and O
adverse O
drug O
reactions O
. O

Mitragynine B
, O
an O
euphoric O
compound O
was O
evaluated O
for O
its O
effects O
on O
the O
expression O
of O
mRNAs O
encoding O
CYP1A2 O
, O
CYP2D6 O
and O
CYP3A4 O
and O
protein O
expression O
and O
resultant O
enzymatic O
activity O
. O

The O
mRNA O
and O
protein O
expression O
of O
CYP450 O
isoforms O
were O
carried O
out O
using O
an O
optimized O
multiplex O
qRT O
- O
PCR O
assay O
and O
Western O
blot O
analysis O
. O

CYP1A2 O
and O
CYP3A4 O
enzyme O
activities O
were O
evaluated O
using O
P450 O
- O
Glo O
( O
TM O
) O
assays O
. O

The O
effects O
of O
mitragynine B
on O
human O
CYP3A4 O
protein O
expression O
were O
determined O
using O
an O
optimized O
hCYP3A4 O
- O
HepG2 O
cell O
- O
based O
assay O
. O

An O
in O
silico O
computational O
method O
to O
predict O
the O
binding O
conformation O
of O
mitragynine B
to O
the O
active O
site O
of O
the O
CYP3A4 O
enzyme O
was O
performed O
and O
further O
validated O
using O
in O
vitro O
CYP3A4 O
inhibition O
assays O
. O

Mitragynine B
was O
found O
to O
induce O
mRNA O
and O
protein O
expression O
of O
CYP1A2 O
. O

For O
the O
highest O
concentration O
of O
25 O
mu O
M O
, O
induction O
of O
mRNA O
was O
approximately O
70 O
% O
that O
of O
the O
positive O
control O
and O
was O
consistent O
with O
the O
increased O
CYP1A2 O
enzymatic O
activity O
. O

Thus O
, O
mitragynine B
is O
a O
significant O
in O
vitro O
CYP1A2 O
inducer O
. O

However O
, O
it O
appeared O
to O
be O
a O
weak O
CYP3A4 O
inducer O
at O
the O
transcriptional O
level O
and O
a O
weak O
CYP3A4 O
enzyme O
inhibitor O
. O

It O
is O
therefore O
, O
unlikely O
to O
have O
any O
significant O
clinical O
effects O
on O
CYP3A4 O
activity O
. O

NF O
- O
kappa O
B O
- O
associated O
mechanisms O
underlying O
the O
response O
of O
embryonic O
cells O
to O
Doxorubicin B
. O

The O
involvement O
of O
NF O
- O
kappa O
B O
in O
the O
regulation O
of O
teratogen O
- O
induced O
apoptosis O
has O
not O
been O
established O
yet O
. O

Therefore O
, O
we O
tried O
to O
assess O
the O
involvement O
of O
the O
p65 O
subunit O
of O
NF O
- O
kappa O
B O
in O
the O
embryonic O
response O
to O
the O
anti O
- O
cancer O
drug O
Doxorubicin B
( O
DOX B
) O
. O

Thus O
, O
exposure O
of O
p65 O
knockout O
( O
p65 O
( O
- O
/ O
- O
) O
) O
or O
wild O
type O
( O
WT O
) O
mouse O
embryonic O
fibroblasts O
( O
MEFs O
) O
to O
DOX B
resulted O
in O
a O
decrease O
in O
cell O
survival O
, O
culture O
density O
and O
cell O
proliferation O
, O
which O
was O
found O
to O
be O
more O
prominent O
in O
p65 O
( O
- O
/ O
- O
) O
MEFs O
. O

Those O
phenomena O
were O
accompanied O
by O
a O
DOX B
- O
induced O
increase O
in O
the O
proportion O
of O
apoptotic O
cells O
, O
which O
was O
demonstrated O
only O
in O
p65 O
( O
- O
/ O
- O
) O
cells O
and O
a O
G2 O
/ O
M O
arrest O
, O
which O
was O
found O
to O
be O
more O
prominent O
in O
WT O
cells O
. O

Furthermore O
, O
DOX B
- O
treated O
WT O
and O
p65 O
( O
- O
/ O
- O
) O
MEFs O
differed O
in O
their O
expression O
of O
various O
apoptosis O
- O
associated O
molecules O
, O
when O
the O
former O
demonstrated O
a O
decrease O
in O
the O
percentage O
of O
p65 O
- O
positive O
and O
a O
more O
prominent O
decrease O
in O
the O
percentage O
of O
p53 O
- O
positive O
cells O
, O
while O
a O
decreased O
percentage O
of O
I O
kappa O
B O
alpha O
- O
positive O
and O
a O
more O
prominent O
decrease O
in O
the O
percentage O
of O
bcl O
- O
2 O
- O
positive O
cells O
was O
detected O
among O
the O
latter O
. O

The O
fact O
that O
the O
response O
of O
the O
cells O
to O
the O
teratogen O
was O
clearly O
p65 O
- O
dependent O
implicates O
this O
molecule O
to O
be O
involved O
in O
the O
response O
of O
the O
embryonic O
cells O
to O
DOX B
. O

Chemical O
constituents O
from O
the O
fibrous O
root O
of O
Ophiopogon O
japonicus O
, O
and O
their O
effect O
on O
tube O
formation O
in O
human O
myocardial O
microvascular O
endothelial O
cells O
. O

In O
an O
effort O
to O
identify O
novel O
active O
constituents O
on O
the O
cardiovascular O
system O
, O
a O
systematic O
study O
on O
macroporous O
resin O
adsorption O
of O
extracts O
from O
the O
fibrous O
root O
of O
Ophiopogon O
japonicus O
was O
performed O
in O
a O
human O
myocardial O
microvascular O
endothelial O
cell O
line O
( O
HMMEC O
) O
based O
assay O
. O

One O
novel O
spirostan B
, O
named O
ophiogenin B
( O
1 O
) O
, O
together O
with O
six O
known O
spirostans B
( O
4 O
- O
8 O
, O
10 O
) O
, O
and O
one O
new O
sesquiterpene B
glycoside I
, O
named O
ophioside B
A I
( O
2 O
) O
, O
together O
with O
one O
known O
monoterpene B
glycoside I
( O
9 O
) O
were O
isolated O
from O
the O
active O
fractions O
, O
and O
the O
aglycone O
of O
compound O
2 O
that O
was O
a O
new O
natural O
compound O
was O
obtained O
from O
the O
acid O
hydrolysis O
of O
2 O
, O
named O
ophiopogonol B
( O
3 O
) O
. O

Their O
structures O
were O
determined O
by O
spectral O
and O
chemical O
analyses O
. O

Furthermore O
, O
their O
effect O
on O
HMMEC O
tube O
formation O
was O
also O
determined O
. O

Our O
results O
indicated O
that O
compounds O
4 O
and O
8 O
could O
significantly O
improve O
the O
tube O
formation O
and O
2 O
showed O
moderate O
increasing O
effect O
, O
while O
compound O
5 O
exhibited O
potent O
inhibitory O
effect O
. O

Fetal O
PGC O
- O
1 O
alpha O
overexpression O
programs O
adult O
pancreatic O
beta O
- O
cell O
dysfunction O
. O

Adult O
beta O
- O
cell O
dysfunction O
, O
a O
hallmark O
of O
type O
2 O
diabetes O
, O
can O
be O
programmed O
by O
adverse O
fetal O
environment O
. O

We O
have O
shown O
that O
fetal O
glucocorticoids O
( O
GCs O
) O
participate O
in O
this O
programming O
through O
inhibition O
of O
beta O
- O
cell O
development O
. O

Here O
we O
have O
investigated O
the O
molecular O
mechanisms O
underlying O
this O
regulation O
. O

We O
showed O
that O
GCs O
stimulate O
the O
expression O
of O
peroxisome O
proliferator O
- O
activated O
receptor O
- O
gamma O
coactivator O
- O
1 O
alpha O
( O
PGC O
- O
1 O
alpha O
) O
, O
a O
coregulator O
of O
the O
GCs O
receptor O
( O
GR O
) O
, O
and O
that O
the O
overexpression O
of O
PGC O
- O
1 O
alpha O
represses O
genes O
important O
for O
beta O
- O
cell O
development O
and O
function O
. O

More O
precisely O
, O
PGC O
- O
1 O
alpha O
inhibited O
the O
expression O
of O
the O
key O
beta O
- O
cell O
transcription O
factor O
pancreatic O
duodenal O
homeobox O
1 O
( O
Pdx1 O
) O
. O

This O
repression O
required O
the O
GR O
and O
was O
mediated O
through O
binding O
of O
a O
GR O
/ O
PGC O
- O
1 O
alpha O
complex O
to O
the O
Pdx1 O
promoter O
. O

To O
explore O
PGC O
- O
1 O
alpha O
function O
, O
we O
generated O
mice O
with O
inducible O
beta O
- O
cell O
PGC O
- O
1 O
alpha O
overexpression O
. O

Mice O
overexpressing O
PGC O
- O
1 O
alpha O
exhibited O
at O
adult O
age O
impaired O
glucose B
tolerance O
associated O
with O
reduced O
insulin O
secretion O
, O
decreased O
beta O
- O
cell O
mass O
, O
and O
beta O
- O
cell O
hypotrophy O
. O

Interestingly O
, O
PGC O
- O
1 O
alpha O
expression O
in O
fetal O
life O
only O
was O
sufficient O
to O
impair O
adult O
beta O
- O
cell O
function O
whereas O
beta O
- O
cell O
PGC O
- O
1 O
alpha O
overexpression O
from O
adult O
age O
had O
no O
consequence O
on O
beta O
- O
cell O
function O
. O

Altogether O
, O
our O
results O
demonstrate O
that O
the O
GR O
and O
PGC O
- O
1 O
alpha O
participate O
in O
the O
fetal O
programming O
of O
adult O
beta O
- O
cell O
function O
through O
inhibition O
of O
Pdx1 O
expression O
. O

G6PC2 O
: O
A O
Negative O
Regulator O
of O
Basal O
Glucose B
- O
Stimulated O
Insulin O
Secretion O
. O

Elevated O
fasting O
blood O
glucose B
( O
FBG O
) O
is O
associated O
with O
increased O
risk O
for O
the O
development O
of O
type O
2 O
diabetes O
and O
cardiovascular O
- O
associated O
mortality O
. O

Genome O
- O
wide O
association O
studies O
( O
GWAS O
) O
have O
linked O
polymorphisms O
in O
G6PC2 O
with O
variations O
in O
FBG O
and O
body O
fat O
, O
although O
not O
insulin O
sensitivity O
or O
glucose B
tolerance O
. O

G6PC2 O
encodes O
an O
islet O
- O
specific O
, O
endoplasmic O
reticulum O
- O
resident O
glucose B
- O
6 O
- O
phosphatase O
catalytic O
subunit O
. O

A O
combination O
of O
in O
situ O
perfused O
pancreas O
, O
in O
vitro O
isolated O
islet O
, O
and O
in O
vivo O
analyses O
were O
used O
to O
explore O
the O
function O
of O
G6pc2 O
in O
mice O
. O

G6pc2 O
deletion O
had O
little O
effect O
on O
insulin O
sensitivity O
and O
glucose B
tolerance O
, O
whereas O
body O
fat O
was O
reduced O
in O
female O
G6pc2 O
knockout O
( O
KO O
) O
mice O
on O
both O
a O
chow O
and O
high O
- O
fat O
diet O
, O
observations O
that O
are O
all O
consistent O
with O
human O
GWAS O
data O
. O

G6pc2 O
deletion O
resulted O
in O
a O
leftward O
shift O
in O
the O
dose O
- O
response O
curve O
for O
glucose B
- O
stimulated O
insulin O
secretion O
( O
GSIS O
) O
. O

As O
a O
consequence O
, O
under O
fasting O
conditions O
in O
which O
plasma O
insulin O
levels O
were O
identical O
, O
blood O
glucose B
levels O
were O
reduced O
in O
G6pc2 O
KO O
mice O
, O
again O
consistent O
with O
human O
GWAS O
data O
. O

Glucose B
- O
6 O
- O
phosphatase O
activity O
was O
reduced O
, O
whereas O
basal O
cytoplasmic O
calcium B
levels O
were O
elevated O
in O
islets O
isolated O
from O
G6pc2 O
KO O
mice O
. O

These O
data O
suggest O
that O
G6pc2 O
represents O
a O
novel O
, O
negative O
regulator O
of O
basal O
GSIS O
that O
acts O
by O
hydrolyzing O
glucose B
- I
6 I
- I
phosphate I
, O
thereby O
reducing O
glycolytic O
flux O
. O

Congenital O
Hyperinsulinism O
Caused O
by O
Hexokinase O
I O
Expression O
or O
Glucokinase O
- O
Activating O
Mutation O
in O
a O
Subset O
of O
beta O
- O
Cells O
. O

Congenital O
hyperinsulinism O
causes O
persistent O
hypoglycemia O
in O
neonates O
and O
infants O
. O

Most O
often O
, O
uncontrolled O
insulin O
secretion O
( O
IS O
) O
results O
from O
a O
lack O
of O
functional O
KATP O
channels O
in O
all O
beta O
- O
cells O
or O
only O
in O
beta O
- O
cells O
within O
a O
resectable O
focal O
lesion O
. O

In O
more O
rare O
cases O
, O
without O
KATP O
channel O
mutations O
, O
hyperfunctional O
islets O
are O
confined O
within O
few O
lobules O
, O
whereas O
hypofunctional O
islets O
are O
present O
throughout O
the O
pancreas O
. O

They O
also O
can O
be O
cured O
by O
selective O
partial O
pancreatectomy O
; O
however O
, O
unlike O
those O
with O
a O
KATP O
focal O
lesion O
, O
they O
show O
clinical O
sensitivity O
to O
diazoxide B
. O

Here O
, O
we O
characterized O
in O
vitro O
IS O
by O
fragments O
of O
pathological O
and O
adjacent O
normal O
pancreas O
from O
six O
such O
cases O
. O

Responses O
of O
normal O
pancreas O
were O
unremarkable O
. O

In O
pathological O
region O
, O
IS O
was O
elevated O
at O
1 O
mmol O
/ O
L O
and O
was O
further O
increased O
by O
15 O
mmol O
/ O
L O
glucose B
. O

Diazoxide B
suppressed O
IS O
and O
tolbutamide B
antagonized O
the O
inhibition O
. O

The O
most O
conspicuous O
anomaly O
was O
a O
large O
stimulation O
of O
IS O
by O
1 O
mmol O
/ O
L O
glucose B
. O

In O
five O
of O
six O
cases O
, O
immunohistochemistry O
revealed O
undue O
presence O
of O
low O
- O
Km O
hexokinase O
- O
I O
in O
beta O
- O
cells O
of O
hyperfunctional O
islets O
only O
. O

In O
one O
case O
, O
an O
activating O
mutation O
of O
glucokinase O
( O
I211F O
) O
was O
found O
in O
pathological O
islets O
only O
. O

Both O
abnormalities O
, O
attributed O
to O
somatic O
genetic O
events O
, O
may O
account O
for O
inappropriate O
IS O
at O
low O
glucose B
levels O
by O
a O
subset O
of O
beta O
- O
cells O
. O

They O
represent O
a O
novel O
cause O
of O
focal O
congenital O
hyperinsulinism O
. O

The O
naphthoquinone B
diospyrin I
is O
an O
inhibitor O
of O
DNA O
gyrase O
with O
a O
novel O
mechanism O
of O
action O
. O

Tuberculosis O
and O
other O
bacterial O
diseases O
represent O
a O
significant O
threat O
to O
human O
health O
. O

The O
DNA O
topoisomerases O
are O
excellent O
targets O
for O
chemotherapy O
, O
and O
DNA O
gyrase O
in O
particular O
is O
a O
well O
- O
validated O
target O
for O
antibacterial O
agents O
. O

Naphthoquinones B
( O
e O
. O
g O
. O
diospyrin B
and O
7 B
- I
methyljuglone I
) O
have O
been O
shown O
to O
have O
therapeutic O
potential O
, O
particularly O
against O
Mycobacterium O
tuberculosis O
. O

We O
have O
found O
that O
these O
compounds O
are O
inhibitors O
of O
the O
supercoiling O
reaction O
catalyzed O
by O
M O
. O
tuberculosis O
gyrase O
and O
other O
gyrases O
. O

Our O
evidence O
strongly O
suggests O
that O
the O
compounds O
bind O
to O
the O
N B
- O
terminal O
domain O
of O
GyrB O
, O
which O
contains O
the O
ATPase O
active O
site O
, O
but O
are O
not O
competitive O
inhibitors O
of O
the O
ATPase O
reaction O
. O

We O
propose O
that O
naphthoquinones B
bind O
to O
GyrB O
at O
a O
novel O
site O
close O
to O
the O
ATPase O
site O
. O

This O
novel O
mode O
of O
action O
could O
be O
exploited O
to O
develop O
new O
antibacterial O
agents O
. O

Structure O
, O
stability O
and O
function O
of O
5 B
- I
chlorouracil I
modified O
A O
: O
U O
and O
G O
: O
U O
base O
pairs O
. O

The O
thymine B
analog O
5 B
- I
chlorouridine I
, O
first O
reported O
in O
the O
1950s O
as O
anti O
- O
tumor O
agent O
, O
is O
known O
as O
an O
effective O
mutagen O
, O
clastogen O
and O
toxicant O
as O
well O
as O
an O
effective O
inducer O
of O
sister O
- O
chromatid O
exchange O
. O

Recently O
, O
the O
first O
microorganism O
with O
a O
chemically O
different O
genome O
was O
reported O
; O
the O
selected O
Escherichia O
coli O
strain O
relies O
on O
the O
four O
building O
blocks O
5 B
- I
chloro I
- I
2 I
' I
- I
deoxyuridine I
( O
ClU B
) O
, O
A O
, O
C O
and O
G O
instead O
of O
the O
standard O
T O
, O
A O
, O
C O
, O
G O
alphabet O
[ O
Marli O
e O
re O
, O
P O
. O
, O
Patrouix O
, O
J O
. O
, O
D O
o O
ring O
, O
V O
. O
, O
Herdewijn O
, O
P O
. O
, O
Tricot O
, O
S O
. O
, O
Cruveiller O
, O
S O
. O
, O
Bouzon O
, O
M O
. O
and O
Mutzel O
, O

R O
. O
( O
2011 O
) O
Chemical O
evolution O
of O
a O
bacterium O
' O
s O
genome O
. O
Angew O
. O
Chem O
. O
Int O
. O
Ed O
. O
, O
50 O
, O
7109 O
- O
7114 O
] O
. O

The O
residual O
fraction O
of O
T O
in O
the O
DNA O
of O
adapted O
bacteria O
was O
< O
2 O
% O
and O
the O
switch O
from O
T O
to O
ClU O
was O
accompanied O
by O
a O
massive O
number O
of O
mutations O
, O
including O
> O
1500 O
A O
to O
G O
or O
G O
to O
A O
transitions O
in O
a O
culture O
. O

The O
former O
is O
most O
likely O
due O
to O
wobble O
base O
pairing O
between O
ClU O
and O
G O
, O
which O
may O
be O
more O
common O
for O
ClU O
than O
T O
. O

To O
identify O
potential O
changes O
in O
the O
geometries O
of O
base O
pairs O
and O
duplexes O
as O
a O
result O
of O
replacement O
of O
T O
by O
ClU B
, O
we O
determined O
four O
crystal O
structures O
of O
a O
B O
- O
form O
DNA O
dodecamer O
duplex O
containing O
ClU B
: O
A O
or O
ClU B
: O
G O
base O
pairs O
. O

The O
structures O
reveal O
nearly O
identical O
geometries O
of O
these O
pairs O
compared O
with O
T O
: O
A O
or O
T O
: O
G O
, O
respectively O
, O
and O
no O
consequences O
for O
stability O
and O
cleavage O
by O
an O
endonuclease O
( O
EcoRI O
) O
. O

The O
lack O
of O
significant O
changes O
in O
the O
geometry O
of O
ClU O
: O
A O
and O
ClU O
: O
G O
base O
pairs O
relative O
to O
the O
corresponding O
native O
pairs O
is O
consistent O
with O
the O
sustained O
unlimited O
self O
- O
reproduction O
of O
E O
. O
coli O
strains O
with O
virtually O
complete O
T O
- O
- O
> O
ClU O
genome O
substitution O
. O

Circularized O
synthetic O
oligodeoxynucleotide O
serve O
as O
promoterless O
RNA O
polymerase O
III O
templates O
for O
small O
RNA O
generation O
in O
human O
cells O
. O

Synthetic O
RNA O
formulations O
and O
viral O
vectors O
are O
the O
two O
main O
approaches O
for O
delivering O
small O
therapeutic O
RNA O
to O
human O
cells O
. O

Here O
we O
report O
findings O
supporting O
an O
alternative O
strategy O
in O
which O
an O
endogenous O
human O
RNA O
polymerase O
( O
RNAP O
) O
is O
harnessed O
to O
make O
RNA O
hairpin O
- O
containing O
small O
RNA O
from O
synthetic O
single O
- O
stranded O
DNA O
oligonucleotides O
. O

We O
report O
that O
circularizing O
a O
DNA O
template O
strand O
encoding O
a O
pre O
- O
microRNA O
hairpin O
mimic O
can O
trigger O
its O
circumtranscription O
by O
human O
RNAP O
III O
in O
vitro O
and O
in O
human O
cells O
. O

Sequence O
and O
secondary O
structure O
preferences O
that O
appear O
to O
promote O
productive O
transcription O
are O
described O
. O

The O
circular O
topology O
of O
the O
template O
is O
required O
for O
productive O
transcription O
, O
at O
least O
in O
part O
, O
to O
stabilize O
the O
template O
against O
exonucleases O
. O

In O
contrast O
to O
bacteriophage O
and O
Escherichia O
coli O
RNAPs O
, O
human O
RNAPs O
do O
not O
carry O
out O
rolling O
circle O
transcription O
on O
circularized O
templates O
. O

While O
transfected O
DNA O
circles O
distribute O
between O
the O
nucleus O
and O
cytosol O
, O
their O
transcripts O
are O
found O
mainly O
in O
the O
cytosol O
. O

Circularized O
oligonucleotides O
are O
synthetic O
, O
free O
of O
the O
hazards O
of O
viral O
vectors O
and O
maintain O
small O
RNA O
information O
in O
a O
stable O
form O
that O
RNAP O
III O
can O
access O
in O
a O
cellular O
context O
with O
, O
in O
some O
cases O
, O
near O
promoter O
- O
like O
precision O
and O
biologically O
relevant O
efficiency O
. O

Melanocortins O
as O
innovative O
drugs O
for O
ischemic O
diseases O
and O
neurodegenerative O
disorders O
: O
established O
data O
and O
perspectives O
. O

Ischemic O
insults O
and O
neurodegenerative O
diseases O
are O
by O
far O
the O
leading O
cause O
of O
mortality O
and O
disability O
. O

Whole O
- O
body O
hypoperfusion O
, O
as O
it O
occurs O
in O
polytraumatic O
and O
hemorrhagic O
shock O
, O
is O
alike O
an O
increasingly O
frequent O
condition O
, O
especially O
due O
to O
traffic O
accidents O
, O
wars O
and O
acts O
of O
terrorism O
. O

It O
is O
now O
clearly O
established O
that O
inflammatory O
processes O
play O
a O
fundamental O
role O
in O
the O
pathophysiology O
of O
both O
hypoperfusion O
/ O
ischemia O
damage O
( O
be O
it O
generalized O
to O
the O
whole O
body O
, O
as O
in O
the O
case O
of O
shock O
, O
or O
limited O
to O
individual O
organs O
) O
and O
neurodegenerative O
diseases O
( O
Alzheimer O
' O
s O
disease O
, O
Parkinson O
' O
s O
disease O
, O
multiple O
sclerosis O
, O
amyotrophic O
lateral O
sclerosis O
) O
. O

On O
the O
other O
hand O
, O
concurrent O
animal O
and O
human O
data O
show O
that O
melanocortin O
peptides O
with O
agonist O
activity O
at O
melanocortin O
MC3 O
/ O
MC4 O
receptors O
are O
highly O
effective O
in O
different O
shock O
conditions O
as O
well O
as O
in O
conditions O
of O
ischemia O
/ O
ischemia O
- O
reperfusion O
of O
individual O
organs O
( O
heart O
, O
brain O
, O
intestine O
, O
kidney O
, O
etc O
. O
) O
, O
and O
accumulating O
evidence O
indicates O
that O
such O
effects O
of O
melanocortins O
are O
mostly O
due O
to O
quite O
peculiar O
antiinflammatory O
mechanisms O
. O

Melanocortins O
have O
also O
long O
been O
known O
( O
i O
) O
to O
exert O
important O
neurotrophic O
effects O
, O
not O
only O
during O
fetal O
development O
but O
also O
in O
adulthood O
, O
in O
different O
animal O
models O
of O
brain O
lesions O
; O
( O
ii O
) O
to O
reduce O
the O
morphological O
correlates O
of O
brain O
aging O
; O
( O
iii O
) O
to O
retard O
the O
behavioral O
deficits O
that O
develop O
during O
the O
aging O
process O
. O

Moreover O
, O
recent O
data O
from O
different O
laboratories O
show O
that O
after O
brain O
ischemic O
episodes O
melanocortins O
activate O
the O
transcription O
of O
neurotrophins O
and O
their O
receptors O
in O
the O
cerebral O
cortex O
and O
in O
the O
hippocampus O
, O
and O
increase O
the O
proliferation O
of O
progenitor O
neuron O
cells O
. O

The O
above O
arguments O
support O
the O
view O
that O
pharmacokinetically O
suitable O
agonists O
at O
MC3 O
/ O
MC4 O
melanocortin O
receptors O
may O
represent O
a O
completely O
innovative O
class O
of O
drugs O
for O
an O
effective O
treatment O
of O
both O
ischemic O
and O
neurodegenerative O
diseases O
. O

Histone O
deacetylase O
inhibitors O
: O
an O
attractive O
strategy O
for O
cancer O
therapy O
. O

Histone O
deacetylases O
are O
able O
to O
catalyze O
the O
hydrolysis O
of O
N B
- I
acetyl I
lysine I
residues O
of O
histones O
which O
package O
chromosomal O
DNA O
. O

Therefore O
they O
play O
an O
important O
role O
in O
mediating O
gene O
expression O
and O
cell O
proliferation O
. O

HDAC O
inhibitors O
have O
not O
only O
shown O
promise O
as O
antiparasitic O
, O
antineurodegenerativ O
, O
antirheumatologic O
agents O
and O
immunosuppressant O
, O
but O
as O
potent O
anticancer O
agents O
by O
inducing O
cell O
cycle O
arrest O
, O
differentiation O
and O
apoptosis O
. O

This O
review O
highlights O
recent O
development O
in O
design O
, O
synthesis O
and O
biological O
evaluation O
of O
HDAC O
inhibitors O
for O
cancer O
therapy O
. O

Alkyl B
substituted I
2 I
' I
- I
benzoylpyridine I
thiosemicarbazone I
chelators O
with O
potent O
and O
selective O
anti O
- O
neoplastic O
activity O
: O
novel O
ligands O
that O
limit O
methemoglobin O
formation O
. O

Thiosemicarbazone B
chelators O
, O
including O
the O
2 B
' I
- I
benzoylpyridine I
thiosemicarbazones I
( O
BpT B
) O
class O
, O
show O
marked O
potential O
as O
anticancer O
agents O
. O

Importantly O
, O
3 B
- I
aminopyridine I
- I
2 I
- I
carboxaldehyde I
thiosemicarbazone I
( O
3 B
- I
AP I
) O
has O
been O
investigated O
in O
> O
20 O
phase O
I O
and O
II O
clinical O
trials O
. O

However O
, O
side O
effects O
associated O
with O
3 B
- I
AP I
administration O
include O
methemoglobinemia O
. O

Considering O
this O
problem O
, O
novel O
BpT B
analogues O
were O
designed O
bearing O
hydrophobic O
, O
electron O
- O
donating O
substituents O
at O
the O
para O
position O
of O
the O
phenyl B
group O
( O
RBpT B
) O
. O

Their O
Fe B
( I
III I
/ I
II I
) I
redox O
potentials O
were O
all O
within O
the O
range O
accessible O
to O
cellular O
oxidants O
and O
reductants O
, O
suggesting O
they O
can O
redox O
cycle O
. O

These O
RBpT O
ligands O
exhibited O
potent O
and O
selective O
antiproliferative O
activity O
, O
which O
was O
comparable O
or O
exceeded O
their O
BpT O
counterparts O
. O

Major O
findings O
include O
that O
methemoglobin O
formation O
mediated O
by O
the O
lipophilic O
t B
- I
BuBpT I
series O
was O
significantly O
( O
p O
< O
0 O
. O
05 O
- O
0 O
. O
001 O
) O
decreased O
in O
comparison O
to O
3 B
- I
AP I
in O
intact O
red O
blood O
cells O
and O
were O
generally O
comparable O
to O
the O
control O
. O

These O
data O
indicate O
the O
t O
- O
BuBpT O
ligands O
may O
minimize O
methemoglobinemia O
, O
which O
is O
a O
marked O
advantage O
over O
3 B
- I
AP I
and O
other O
potent O
thiosemicarbazones B
. O

Besting O
vitamin B
E I
: O
sidechain O
substitution O
is O
key O
to O
the O
reactivity O
of O
naphthyridinol B
antioxidants O
in O
lipid O
bilayers O
. O

A O
series O
of O
naphthyridinol B
analogs O
of O
alpha B
- I
tocopherol I
( O
alpha B
- I
TOH I
, O
right O
) O
with O
varying O
sidechain O
substitution O
was O
synthesized O
to O
determine O
how O
systematic O
changes O
in O
the O
lipophilicity O
of O
these O
potent O
antioxidants O
impact O
their O
radical O
- O
trapping O
activities O
in O
lipid O
bilayers O
, O
regenerability O
by O
water O
- O
soluble O
reductants O
, O
and O
binding O
to O
human O
tocopherol B
transport O
protein O
( O
TTP O
) O
. O

The O
activities O
of O
the O
naphthyridinols B
were O
assayed O
in O
phosphatidylcholine B
unilamellar O
liposomes O
using O
a O
recently O
developed O
high O
- O
throughput O
assay O
that O
employs O
a O
boron B
dipyrromethene I
conjugate O
of O
alpha O
- O
TOH O
( O
H B
( I
2 I
) I
B I
- I
PMHC I
) O
that O
undergoes O
fluorescence O
enhancement O
upon O
oxidation O
. O

The O
naphthyridinols B
afforded O
a O
dose O
- O
dependent O
protection O
of O
H B
( I
2 I
) I
B I
- I
PMHC I
consistent O
with O
unprecedented O
peroxyl B
radical O
- O
trapping O
activity O
in O
lipid O
bilayers O
. O

While O
sidechain O
length O
and O
/ O
or O
branching O
had O
no O
effect O
on O
their O
apparent O
reactivity O
, O
it O
dramatically O
impacted O
reaction O
stoichiometry O
, O
with O
more O
lipophilic O
compounds O
trapping O
two O
peroxyl B
radicals O
and O
more O
hydrophilic O
compounds O
trapping O
significantly O
less O
than O
one O
. O

It O
is O
suggested O
that O
the O
less O
lipophilic O
compounds O
autoxidize O
rapidly O
in O
the O
aqueous O
phase O
and O
that O
preferential O
partitioning O
of O
the O
more O
lipophilic O
compounds O
to O
the O
bilayer O
protects O
them O
from O
autoxidation O
. O

The O
cooperativity O
of O
a O
lipophilic O
naphthyridinol B
with O
water O
- O
soluble O
reducing O
agents O
was O
also O
studied O
in O
liposomes O
using O
H B
( I
2 I
) I
B I
- I
PMHC I
and O
revealed O
superior O
regenerability O
by O
each O
of O
ascorbate B
, O
N B
- I
acetylcysteine I
, O
and O
urate B
when O
compared O
to O
alpha B
- I
TOH I
. O

Binding O
assays O
with O
human O
TTP O
, O
a O
key O
determinant O
of O
the O
bioavailability O
of O
the O
tocopherols B
, O
reveal O
that O
the O
naphthyiridinols B
can O
be O
very O
good O
ligands O
for O
the O
protein O
. O

In O
fact O
, O
naphthyridinols B
with O
sidechains O
of O
eight O
or O
more O
carbons B
had O
affinities O
for O
TTP O
which O
were O
similar O
to O
, O
and O
in O
one O
case O
10 O
- O
fold O
better O
than O
, O
alpha O
- O
TOH O
. O

Potential O
antipsoriatic O
effect O
of O
chondroitin O
sulfate O
through O
inhibition O
of O
NF O
- O
kappa O
B O
and O
STAT3 O
in O
human O
keratinocytes O
. O

Chondroitin O
sulfate O
( O
CS O
) O
is O
a O
natural O
glycosaminoglycan O
, O
formed O
by O
the O
1 O
- O
3 O
linkage O
of O
d B
- I
glucuronic I
acid I
to O
N B
- I
acetylgalactosamine I
, O
present O
in O
the O
extracellular O
matrix O
. O

It O
is O
used O
as O
a O
slow O
acting O
disease O
modifying O
agent O
in O
the O
treatment O
of O
osteoarthritis O
, O
and O
part O
of O
its O
beneficial O
effects O
are O
due O
to O
its O
antiinflammatory O
properties O
that O
result O
from O
an O
inhibitory O
effect O
on O
NF O
- O
kappa O
B O
signaling O
pathway O
. O

This O
ability O
raises O
the O
hypothesis O
that O
CS O
might O
be O
effective O
in O
other O
chronic O
inflammatory O
processes O
such O
as O
psoriasis O
, O
in O
which O
a O
deregulation O
of O
NF O
- O
kappa O
B O
is O
a O
key O
feature O
. O

In O
addition O
, O
psoriasis O
is O
characterized O
by O
an O
upregulation O
of O
STAT3 O
signaling O
pathway O
that O
is O
related O
to O
the O
epidermal O
hyperplasia O
. O

In O
the O
present O
study O
we O
report O
the O
pharmacological O
modulation O
of O
the O
NF O
- O
kappa O
B O
and O
STAT3 O
signaling O
pathways O
by O
CS O
in O
normal O
human O
keratinocytes O
. O

CS O
inhibited O
NF O
- O
kappa O
B O
activation O
and O
the O
release O
of O
some O
of O
the O
key O
psoriatic O
cytokines O
such O
as O
TNF O
alpha O
, O
IL O
- O
8 O
, O
IL O
- O
6 O
and O
CCL27 O
. O

Moreover O
, O
it O
impaired O
STAT3 O
translocation O
to O
the O
nucleus O
and O
significantly O
reduced O
STAT3 O
transcriptional O
activity O
by O
a O
mechanism O
that O
was O
independent O
from O
STAT3 O
phosphorylation O
. O

Our O
results O
confirm O
the O
interest O
of O
CS O
as O
a O
candidate O
for O
future O
drug O
research O
in O
the O
therapeutics O
of O
psoriasis O
given O
the O
need O
of O
more O
effective O
and O
safer O
oral O
medications O
for O
these O
patients O
. O

Generating O
thermal O
stable O
variants O
of O
protein O
domains O
through O
phage O
display O
. O

Often O
in O
protein O
design O
research O
, O
one O
desires O
to O
generate O
thermally O
stable O
variants O
of O
a O
protein O
or O
domain O
. O

One O
route O
to O
identifying O
mutations O
that O
yield O
domains O
that O
remain O
folded O
and O
active O
at O
a O
higher O
temperature O
is O
through O
the O
use O
of O
directed O
evolution O
. O

A O
library O
of O
protein O
domain O
variants O
can O
be O
generated O
by O
mutagenic O
PCR O
, O
expressed O
on O
the O
surface O
of O
bacteriophage O
M13 O
, O
and O
subjected O
to O
heat O
, O
such O
that O
the O
unfolded O
forms O
of O
the O
domain O
, O
showing O
reduced O
or O
no O
binding O
activity O
, O
are O
lost O
during O
subsequent O
affinity O
selection O
, O
whereas O
variants O
that O
still O
retain O
binding O
to O
their O
target O
are O
selected O
and O
enriched O
with O
each O
subsequent O
round O
of O
affinity O
selection O
. O

This O
approach O
takes O
advantage O
of O
the O
fact O
that O
bacteriophage O
M13 O
particles O
are O
heat O
stable O
and O
resistant O
to O
many O
proteases O
and O
protein O
denaturants O
. O

We O
present O
the O
application O
of O
this O
general O
approach O
to O
generating O
thermally O
stable O
variants O
of O
a O
eukaryotic O
peptide O
- O
binding O
domain O
. O

The O
benefits O
of O
producing O
such O
variants O
are O
that O
they O
typically O
express O
at O
high O
levels O
in O
Escherichia O
coli O
( O
30 O
- O
60mg O
/ O
L O
shake O
flask O
) O
and O
remain O
soluble O
in O
solution O
at O
higher O
concentrations O
for O
longer O
periods O
of O
time O
than O
the O
wild O
- O
type O
form O
of O
the O
domain O
. O

The O
process O
of O
library O
generation O
and O
screening O
generally O
requires O
about O
one O
month O
of O
effort O
, O
and O
yields O
variants O
with O
> O
10 O
degrees O
C O
increase O
in O
thermal O
stability O
, O
as O
measured O
in O
a O
simple O
fluorescence O
- O
based O
thermal O
shift O
assay O
. O

It O
is O
anticipated O
that O
thermally O
stable O
variants O
will O
serve O
as O
excellent O
scaffolds O
for O
generating O
affinity O
reagents O
to O
a O
variety O
of O
targets O
of O
interest O
. O

Effects O
of O
glyphosate B
- O
based O
herbicides O
on O
embryo O
- O
larval O
development O
and O
metamorphosis O
in O
the O
Pacific O
oyster O
, O
Crassostrea O
gigas O
. O

Pesticides O
may O
be O
involved O
in O
oyster O
summer O
mortality O
events O
, O
not O
necessarily O
as O
a O
single O
causative O
agent O
but O
as O
an O
additional O
stressor O
. O

In O
this O
context O
, O
the O
present O
study O
aimed O
to O
assess O
the O
toxicity O
of O
glyphosate B
, O
its O
by O
- O
product O
, O
aminomethylphosphoni B
acid I
( O
AMPA B
) O
and O
two O
commercial O
formulations O
, O
Roundup B
Express O
( O
( O
R O
) O
) O
( O
R O
( O
EX O
) O
) O
and O
Roundup B
All O
e O
es O
et O
Terrasses O
( O
( O
R O
) O
) O
( O
R O
( O
AT O
) O
) O
, O
containing O
glyphosate B
as O
the O
active O
ingredient O
, O
on O
the O
early O
life O
stages O
of O
the O
Pacific O
oyster O
, O
Crassostrea O
gigas O
. O

The O
embryotoxicity O
of O
these O
chemicals O
were O
quantified O
by O
considering O
both O
the O
rates O
of O
abnormalities O
and O
the O
arrested O
development O
or O
types O
of O
abnormalities O
in O
D O
- O
shaped O
larvae O
after O
48 O
h O
exposure O
. O

The O
success O
of O
metamorphosis O
was O
examined O
in O
pediveliger O
larvae O
exposed O
for O
24 O
h O
. O

Experiments O
involving O
both O
endpoints O
included O
range O
finding O
experiments O
for O
herbicide O
concentrations O
ranging O
from O
0 O
. O
1 O
to O
100 O
, O
000 O
mu O
g O
L O
( O
- O
1 O
) O
. O

This O
range O
was O
then O
narrowed O
down O
in O
order O
to O
determine O
precise O
EC O
( O
50 O
) O
values O
. O

Actual O
concentrations O
of O
the O
herbicide O
were O
determined O
at O
the O
beginning O
and O
after O
48 O
h O
( O
embryotoxicity O
) O
and O
24 O
h O
( O
metamorphosis O
) O
to O
evaluate O
the O
potential O
temporal O
variation O
in O
the O
concentrations O
. O

During O
embryo O
- O
larval O
development O
, O
no O
mortalities O
were O
recorded O
at O
any O
of O
the O
concentrations O
of O
glyphosate B
and O
AMPA B
, O
whereas O
no O
embryos O
or O
D O
- O
shaped O
larvae O
could O
be O
observed O
after O
exposure O
to O
10 O
, O
000 O
mu O
g O
L O
( O
- O
1 O
) O
of O
R O
( O
EX O
) O
or O
R O
( O
AT O
) O
. O

Compared O
with O
the O
controls O
, O
no O
effects O
on O
embryo O
- O
larval O
development O
were O
recorded O
between O
0 O
. O
1 O
and O
1000 O
mu O
g O
L O
( O
- O
1 O
) O
, O
regardless O
of O
the O
chemical O
tested O
. O

Above O
a O
threshold O
, O
which O
varied O
according O
to O
the O
chemical O
used O
, O
the O
gradient O
of O
herbicide O
concentrations O
correlated O
with O
a O
gradient O
of O
severity O
of O
abnormality O
ranging O
from O
normal O
larvae O
to O
arrested O
development O
( O
an O
" O
old O
embryo O
" O
stage O
) O
. O

The O
EC O
( O
50 O
) O
values O
were O
28 O
, O
315 O
and O
40 O
, O
617 O
mu O
g O
L O
( O
- O
1 O
) O
for O
glyphosate B
and O
its O
metabolite O
, O
respectively O
, O
but O
much O
lowered O
values O
of O
1133 O
and O
1675 O
mu O
g O
L O
( O
- O
1 O
) O
for O
R O
( O
EX O
) O
and O
R O
( O
AT O
) O
, O
respectively O
. O

Metamorphosis O
tests O
also O
revealed O
a O
significant O
difference O
between O
molecules O
, O
as O
the O
EC O
( O
50 O
) O
values O
exceeded O
100 O
, O
000 O
mu O
g O
L O
( O
- O
1 O
) O
for O
glyphosate B
and O
AMPA B
but O
were O
as O
low O
as O
6366 O
and O
6060 O
mu O
g O
L O
( O
- O
1 O
) O
for O
the O
commercial O
formulations O
, O
which O
appeared O
relatively O
more O
toxic O
. O

Overall O
, O
the O
embryo O
- O
larval O
development O
of O
C O
. O
gigas O
was O
more O
sensitive O
to O
glyphosate B
- O
based O
herbicides O
compared O
to O
various O
endpoints O
studied O
in O
regulatory O
model O
organisms O
, O
and O
embryos O
and O
D O
- O
shaped O
larvae O
were O
more O
sensitive O
compared O
to O
pediveliger O
larvae O
. O

Ly6C O
+ O
Ly6G O
- O
Myeloid O
- O
derived O
suppressor O
cells O
play O
a O
critical O
role O
in O
the O
resolution O
of O
acute O
inflammation O
and O
the O
subsequent O
tissue O
repair O
process O
after O
spinal O
cord O
injury O
. O

Acute O
inflammation O
is O
a O
prominent O
feature O
of O
central O
nervous O
system O
( O
CNS O
) O
insult O
and O
is O
detrimental O
to O
the O
CNS O
tissue O
. O

Although O
this O
reaction O
spontaneously O
diminishes O
within O
a O
short O
period O
of O
time O
, O
the O
mechanism O
underlying O
this O
inflammatory O
resolution O
remains O
largely O
unknown O
. O

In O
this O
study O
, O
we O
demonstrated O
that O
an O
initial O
infiltration O
of O
Ly6C O
( O
+ O
) O
Ly6G O
( O
- O
) O
immature O
monocyte O
fraction O
exhibited O
the O
same O
characteristics O
as O
myeloid O
- O
derived O
suppressor O
cells O
( O
MDSCs O
) O
, O
and O
played O
a O
critical O
role O
in O
the O
resolution O
of O
acute O
inflammation O
and O
in O
the O
subsequent O
tissue O
repair O
by O
using O
mice O
spinal O
cord O
injury O
( O
SCI O
) O
model O
. O

Complete O
depletion O
of O
Ly6C O
( O
+ O
) O
Ly6G O
( O
- O
) O
fraction O
prior O
to O
injury O
by O
anti O
- O
Gr O
- O
1 O
antibody O
( O
clone O
: O
RB6 O
- O
8C5 O
) O
treatment O
significantly O
exacerbated O
tissue O
edema O
, O
vessel O
permeability O
, O
and O
hemorrhage O
, O
causing O
impaired O
neurological O
outcomes O
. O

Functional O
recovery O
was O
barely O
impaired O
when O
infiltration O
was O
allowed O
for O
the O
initial O
24 O
h O
after O
injury O
, O
suggesting O
that O
MDSC O
infiltration O
at O
an O
early O
phase O
is O
critical O
to O
improve O
the O
neurological O
outcome O
. O

Moreover O
, O
intraspinal O
transplantation O
of O
ex O
vivo O
- O
generated O
MDSCs O
at O
sites O
of O
SCI O
significantly O
reduced O
inflammation O
and O
promoted O
tissue O
regeneration O
, O
resulting O
in O
better O
functional O
recovery O
. O

Our O
findings O
reveal O
the O
crucial O
role O
of O
an O
Ly6C O
( O
+ O
) O
Ly6G O
( O
- O
) O
fraction O
as O
MDSCs O
in O
regulating O
inflammation O
and O
tissue O
repair O
after O
SCI O
, O
and O
also O
suggests O
an O
MDSC O
- O
based O
strategy O
that O
can O
be O
applied O
to O
acute O
inflammatory O
diseases O
. O

Concentration O
of O
tacrolimus B
and O
major O
metabolites O
in O
kidney O
transplant O
recipients O
as O
a O
function O
of O
diabetes O
mellitus O
and O
cytochrome O
P450 O
3A O
gene O
polymorphism O
. O

Abstract O
1 O
. O

Disposition O
of O
tacrolimus B
and O
its O
major O
metabolites O
, O
13 B
- I
O I
- I
desmethyl I
tacrolimus I
and O
15 B
- I
O I
- I
desmethyl I
tacrolimus I
, O
was O
evaluated O
in O
stable O
kidney O
transplant O
recipients O
in O
relation O
to O
diabetes O
mellitus O
and O
genetic O
polymorphism O
of O
cytochrome O
P450 O
( O
CYP O
) O
3A O
. O

2 O
. O

Steady O
- O
state O
concentration O
- O
time O
profiles O
were O
obtained O
for O
12 O
- O
hour O
or O
2 O
- O
hour O
post O
- O
dose O
, O
in O
20 O
( O
11 O
with O
diabetes O
) O
and O
32 O
( O
24 O
with O
diabetes O
) O
patients O
, O
respectively O
. O

In O
addition O
, O
single O
nucleotide O
polymorphisms O
of O
the O
following O
genes O
: O
CYP3A4 O
( O
CYP3A4 O
: O
CYP3A4 O
* O
1B O
, O
- O
392A O
> O
G O
) O
, O
3A5 O
( O
CYP3A5 O
: O
CYP3A5 O
* O
3 O
, O
6986A O
> O
G O
) O
and O
P O
- O
glycoprotein O
( O
ABCB1 O
: O
3435C O
> O
T O
) O
were O
characterized O
. O

3 O
. O

Dose O
- O
normalized O
concentrations O
of O
tacrolimus B
or O
metabolites O
were O
higher O
in O
diabetic O
patients O
. O

CYP3A4 O
* O
1B O
carriers O
and O
CYP3A5 O
expressers O
, O
independently O
or O
when O
assessed O
as O
a O
combined O
CYP3A4 O
- O
3A5 O
genotype O
, O
had O
significantly O
lower O
dose O
- O
normalized O
pre O
- O
dose O
( O
C O
( O
0 O
) O
/ O
dose O
) O
and O
2 O
- O
hour O
post O
- O
dose O
( O
C O
( O
2 O
) O
/ O
dose O
) O
concentrations O
of O
tacrolimus B
and O
metabolites O
. O

Non O
- O
diabetic O
patients O
with O
at O
least O
one O
CYP3A4 O
* O
1B O
and O
CYP3A5 O
* O
1 O
allele O
had O
lower O
C O
( O
0 O
) O
/ O
dose O
as O
compared O
to O
the O
rest O
of O
the O
population O
. O

4 O
. O

Genetic O
polymorphism O
of O
CYP3A5 O
or O
CYP3A4 O
influence O
tacrolimus B
or O
metabolites O
dose O
- O
normalized O
concentrations O
but O
not O
metabolite O
to O
parent O
concentration O
ratios O
. O

The O
effect O
of O
diabetes O
on O
tacrolimus B
metabolism O
is O
subject O
to O
debate O
and O
requires O
a O
larger O
sample O
size O
of O
genetically O
stratified O
subjects O
. O

Adjuvant O
and O
neoadjuvant O
chemotherapy O
for O
soft O
tissue O
sarcomas O
. O

Sarcomas O
of O
the O
soft O
tissue O
are O
a O
heterogeneous O
, O
rare O
and O
complex O
group O
of O
mesenchymal O
malignant O
tumors O
, O
accounting O
for O
less O
than O
1 O
% O
of O
all O
adult O
malignancies O
and O
about O
10 O
- O
15 O
% O
of O
childhood O
cancer O
. O

Despite O
local O
disease O
control O
obtained O
with O
surgery O
and O
pre O
- O
or O
postoperative O
radiotherapy O
, O
roughly O
one O
half O
of O
patients O
with O
high O
- O
grade O
tumors O
experience O
metastatic O
disease O
. O

The O
adjunction O
of O
chemotherapy O
, O
either O
before O
or O
after O
resection O
, O
is O
not O
currently O
viewed O
as O
standard O
practice O
due O
to O
the O
lack O
of O
reproducible O
impact O
on O
survival O
. O

The O
1997 O
SMAC O
meta O
- O
analysis O
based O
on O
individual O
data O
from O
randomized O
studies O
confirmed O
a O
significant O
impact O
of O
adjuvant O
chemotherapy O
on O
both O
local O
and O
metastatic O
relapse O
, O
without O
any O
significant O
benefit O
on O
survival O
. O

Further O
meta O
- O
analyses O
demonstrated O
a O
significant O
benefit O
also O
in O
overall O
survival O
. O

Yet O
, O
the O
latest O
adjuvant O
EORTC O
trial O
was O
disappointedly O
negative O
. O

To O
date O
, O
adjuvant O
chemotherapy O
may O
be O
recommended O
as O
a O
reasonable O
option O
for O
the O
high O
- O
risk O
individual O
patient O
who O
should O
be O
well O
informed O
on O
the O
possible O
risks O
and O
benefits O
of O
treatment O
. O

Also O
the O
indications O
for O
neoadjuvant O
chemotherapy O
remain O
controversial O
. O

A O
local O
benefit O
may O
be O
gained O
, O
facilitating O
surgery O
, O
but O
data O
on O
survival O
are O
limited O
and O
affected O
by O
a O
strong O
patient O
selection O
bias O
. O

In O
order O
to O
improve O
our O
knowledge O
on O
sarcomas O
and O
to O
offer O
patients O
the O
best O
of O
current O
standards O
, O
we O
strongly O
recommend O
that O
all O
patients O
be O
referred O
to O
a O
sarcoma O
multidisciplinary O
group O
, O
under O
whose O
supervision O
they O
could O
receive O
the O
correct O
combined O
- O
modality O
management O
as O
well O
as O
have O
access O
to O
new O
clinical O
trials O
appropriately O
stratified O
for O
risk O
and O
histological O
and O
/ O
or O
molecular O
subtypes O
. O

Statistical O
analyses O
of O
protein O
sequence O
alignments O
identify O
structures O
and O
mechanisms O
in O
signal O
activation O
of O
sensor O
histidine O
kinases O
. O

Statistical O
analyses O
of O
genome O
sequence O
- O
derived O
protein O
sequence O
data O
can O
identify O
amino B
acid I
residues O
that O
interact O
between O
proteins O
or O
between O
domains O
of O
a O
protein O
. O

These O
statistical O
methods O
are O
based O
on O
evolution O
- O
directed O
amino B
acid I
variation O
responding O
to O
structural O
and O
functional O
constraints O
in O
proteins O
. O

The O
identified O
residues O
form O
a O
basis O
for O
determining O
structure O
and O
folding O
of O
proteins O
as O
well O
as O
inferring O
mechanisms O
of O
protein O
function O
. O

When O
applied O
to O
two O
- O
component O
systems O
, O
several O
research O
groups O
have O
shown O
they O
can O
be O
used O
to O
identify O
the O
amino B
acid I
interactions O
between O
response O
regulators O
and O
histidine B
kinases O
and O
the O
specificity O
therein O
. O

Recently O
, O
statistical O
studies O
between O
the O
HisKA O
and O
HATPase O
- O
ATP B
- O
binding O
domains O
of O
histidine B
kinases O
identified O
amino B
acid I
interactions O
for O
both O
the O
inactive O
and O
the O
active O
catalytic O
states O
of O
such O
kinases O
. O

The O
identified O
interactions O
generated O
a O
model O
structure O
for O
the O
domain O
conformation O
of O
the O
active O
state O
. O

This O
conformation O
requires O
an O
unwinding O
of O
a O
portion O
of O
the O
C B
- O
terminal O
helix O
of O
the O
HisKA O
domain O
that O
destroys O
the O
inactive O
state O
residue O
contacts O
and O
suggests O
how O
signal O
- O
binding O
determines O
the O
equilibrium O
between O
the O
inactive O
and O
active O
states O
of O
histidine B
kinases O
. O

The O
rapidly O
accumulating O
protein O
sequence O
databases O
from O
genome O
, O
metagenome O
and O
microbiome O
studies O
are O
an O
important O
resource O
for O
functional O
and O
structural O
understanding O
of O
proteins O
and O
protein O
complexes O
in O
microbes O
. O

Self O
- O
trimerization O
of O
ExsD O
limits O
inhibition O
of O
the O
Pseudomonas O
aeruginosa O
transcriptional O
activator O
ExsA O
in O
vitro O
. O

The O
opportunistic O
pathogen O
Pseudomonas O
aeruginosa O
ranks O
among O
the O
leading O
causes O
of O
nosocomial O
infection O
. O

The O
type O
III O
secretion O
system O
( O
T3SS O
) O
aids O
acute O
Pseudomonas O
aeruginosa O
infection O
by O
injecting O
potent O
cytotoxins O
into O
host O
cells O
to O
suppress O
the O
host O
' O
s O
innate O
immune O
response O
. O

Expression O
of O
all O
T3SS O
- O
related O
genes O
is O
strictly O
dependent O
on O
the O
transcription O
factor O
ExsA O
. O

Consequently O
, O
ExsA O
and O
the O
biological O
processes O
that O
regulate O
ExsA O
function O
are O
of O
great O
biomedical O
interest O
. O

The O
present O
study O
focused O
on O
the O
ExsA O
- O
ExsC O
- O
ExsD O
- O
ExsE O
signaling O
cascade O
, O
which O
ties O
host O
cell O
contact O
to O
the O
upregulation O
of O
T3SS O
gene O
expression O
. O

Prior O
to O
T3SS O
induction O
, O
the O
antiactivator O
protein O
ExsD O
binds O
to O
ExsA O
and O
blocks O
ExsA O
- O
dependent O
transcription O
by O
interfering O
with O
ExsA O
dimerization O
and O
promoter O
interactions O
. O

Upon O
host O
cell O
contact O
, O
ExsD O
is O
sequestered O
by O
the O
T3SS O
chaperone O
ExsC O
, O
resulting O
in O
the O
release O
of O
ExsA O
and O
upregulation O
of O
the O
T3SS O
. O

Previous O
studies O
have O
shown O
that O
the O
ExsD O
- O
ExsA O
interactions O
are O
not O
freely O
reversible O
. O

Because O
independently O
folded O
ExsD O
and O
ExsA O
were O
not O
found O
to O
interact O
, O
it O
has O
been O
hypothesized O
that O
folding O
intermediates O
of O
the O
two O
proteins O
form O
the O
complex O
. O

Here O
, O
we O
demonstrate O
, O
for O
the O
first O
time O
, O
that O
ExsD O
alone O
is O
sufficient O
to O
inhibit O
ExsA O
- O
dependent O
transcription O
in O
vitro O
and O
that O
no O
other O
cellular O
factors O
are O
required O
. O

More O
significantly O
, O
we O
show O
that O
independently O
folded O
ExsD O
and O
ExsA O
are O
capable O
of O
interacting O
, O
but O
only O
at O
37 O
degrees O
C O
and O
not O
at O
30 O
degrees O
C O
. O

Guided O
by O
the O
crystal O
structure O
of O
ExsD O
, O
we O
designed O
a O
monomeric O
variant O
of O
the O
protein O
, O
and O
demonstrated O
that O
ExsD O
trimerization O
prevents O
ExsD O
from O
inhibiting O
ExsA O
- O
dependent O
transcription O
at O
30 O
degrees O
C O
. O

We O
propose O
that O
this O
unique O
mechanism O
plays O
an O
important O
role O
in O
T3SS O
regulation O
. O

Morin O
inhibits O
STAT3 O
tyrosine B
705 O
phosphorylation O
in O
tumor O
cells O
through O
activation O
of O
protein O
tyrosine B
phosphatase O
SHP1 O
. O

The O
major O
goal O
of O
cancer O
drug O
discovery O
is O
to O
find O
an O
agent O
that O
is O
safe O
and O
affordable O
, O
yet O
effective O
against O
cancer O
. O

Here O
we O
show O
that O
morin B
( O
3 B
, I
5 I
, I
7 I
, I
2 I
' I
, I
4 I
' I
- I
pentahydroxyflavone I
) O
has O
potential O
against O
cancer O
cells O
through O
suppression O
of O
the O
signal O
transducer O
and O
activator O
of O
transcription O
3 O
( O
STAT3 O
) O
pathway O
, O
which O
is O
closely O
linked O
to O
the O
transformation O
, O
survival O
, O
proliferation O
, O
and O
metastasis O
of O
cancer O
. O

We O
found O
that O
morin B
completely O
suppressed O
inducible O
and O
constitutively O
activated O
STAT3 O
and O
blocked O
the O
nuclear O
translocation O
of O
STAT3 O
and O
its O
DNA O
binding O
in O
multiple O
myeloma O
and O
head O
and O
neck O
squamous O
carcinoma O
cells O
. O

Morin O
inhibited O
activated O
Src O
, O
JAK O
- O
1 O
, O
and O
JAK O
- O
2 O
, O
all O
of O
which O
are O
linked O
to O
STAT3 O
activation O
, O
while O
up O
- O
regulating O
a O
protein O
inhibitor O
of O
activated O
STAT3 O
, O
PIAS3 O
. O

Pervanadate B
reversed O
the O
effects O
of O
morin O
on O
STAT3 O
phosphorylation O
, O
indicating O
the O
role O
of O
a O
protein O
tyrosine B
phosphatase O
. O

Furthermore O
, O
morin O
induced O
SHP1 O
expression O
at O
both O
the O
mRNA O
and O
protein O
levels O
, O
and O
silencing O
of O
SHP1 O
abrogated O
the O
effect O
of O
morin O
on O
STAT3 O
phosphorylation O
, O
indicating O
that O
morin O
mediates O
its O
effects O
on O
STAT3 O
through O
SHP1 O
. O

Suppression O
of O
STAT3 O
correlated O
with O
the O
down O
- O
regulation O
of O
various O
gene O
products O
linked O
to O
tumor O
survival O
, O
proliferation O
, O
and O
angiogenesis O
and O
led O
to O
sensitization O
of O
tumor O
cells O
to O
thalidomide B
and O
bortezomib B
. O

Comparing O
the O
activities O
of O
morin B
with O
those O
of O
four O
structurally O
related O
flavonols B
demonstrated O
the O
importance O
of O
hydroxyl B
groups O
in O
the O
B O
ring O
in O
inhibiting O
STAT3 O
activation O
. O

These O
findings O
suggest O
that O
morin O
suppresses O
the O
STAT3 O
pathway O
, O
leading O
to O
the O
down O
- O
regulation O
of O
STAT3 O
- O
dependent O
gene O
expression O
and O
chemosensitization O
of O
tumor O
cells O
. O

Blood O
pressure O
and O
levels O
of O
Fe B
, O
Ca B
, O
Mg B
, O
Zn B
, O
Cu B
, O
Na B
and O
K B
in O
the O
hair O
of O
young O
Bantu O
men O
from O
Tanzania O
. O

Mineral O
imbalance O
in O
the O
body O
may O
significantly O
contribute O
to O
the O
development O
and O
course O
of O
hypertension O
. O

In O
this O
paper O
, O
blood O
pressure O
figures O
have O
been O
linked O
to O
the O
levels O
of O
Fe B
, O
Ca B
, O
Mg B
, O
Zn B
, O
Cu B
, O
Na B
and O
K B
in O
hair O
. O

The O
research O
sample O
was O
composed O
of O
young O
men O
( O
n O
= O
91 O
) O
aged O
13 O
- O
21 O
, O
from O
the O
town O
of O
Mafinga O
, O
Iringa O
District O
, O
Tanzania O
. O

The O
data O
collected O
included O
their O
age O
, O
tribal O
background O
and O
weekly O
diet O
. O

Based O
on O
body O
mass O
index O
, O
the O
participants O
were O
categorised O
into O
pre O
- O
defined O
subgroups O
. O

To O
examine O
how O
the O
minerals O
in O
question O
affect O
blood O
pressure O
, O
correlation O
analysis O
and O
multiple O
ridge O
regression O
analysis O
were O
performed O
. O

Analysis O
of O
ridge O
regression O
findings O
for O
the O
researched O
group O
( O
n O
= O
91 O
) O
shows O
that O
the O
minerals O
under O
scrutiny O
account O
for O
systolic O
blood O
pressure O
variation O
in O
13 O
% O
and O
in O
15 O
% O
for O
diastolic O
blood O
pressure O
variation O
. O

After O
including O
two O
additional O
variables O
- O
calendar O
age O
and O
body O
mass O
index O
- O
in O
regression O
analysis O
, O
the O
ultimate O
coefficient O
of O
determination O
( O
R O
( O
2 O
) O
) O
changes O
for O
systolic O
blood O
pressure O
and O
remains O
the O
same O
for O
diastolic O
blood O
pressure O
( O
R O
( O
2 O
) O
= O
0 O
. O
194 O
and O
R O
( O
2 O
) O
= O
0 O
. O
156 O
, O
respectively O
) O
. O

Nutritional O
analysis O
shows O
that O
the O
students O
included O
in O
the O
study O
received O
insufficient O
calories O
per O
day O
( O
1 O
, O
500 O
- O
2 O
, O
200 O
kcal O
) O
. O

The O
group O
of O
students O
with O
abnormal O
blood O
pressure O
were O
not O
aware O
of O
their O
poor O
health O
. O

Research O
findings O
may O
result O
from O
progressive O
environmental O
changes O
and O
poor O
nutrition O
in O
terms O
of O
food O
quantity O
and O
quality O
, O
which O
had O
an O
impact O
on O
the O
subjects O
' O
blood O
pressure O
. O

Hair O
analysis O
used O
to O
determine O
mineral O
content O
in O
the O
body O
may O
be O
an O
auxiliary O
tool O
in O
identifying O
the O
links O
between O
factors O
leading O
to O
the O
development O
of O
hypertension O
. O

Mussel O
- O
inspired O
adhesive O
binders O
for O
high O
- O
performance O
silicon B
nanoparticle O
anodes O
in O
lithium B
- O
ion O
batteries O
. O

Conjugation O
of O
mussel O
- O
inspired O
catechol B
groups O
to O
various O
polymer O
backbones O
results O
in O
materials O
suitable O
as O
silicon B
anode O
binders O
. O

The O
unique O
wetness O
- O
resistant O
adhesion O
provided O
by O
the O
catechol B
groups O
allows O
the O
silicon B
nanoparticle O
electrodes O
to O
maintain O
their O
structure O
throughout O
the O
repeated O
volume O
expansion O
and O
shrinkage O
during O
lithiation O
cycling O
, O
thus O
facilitating O
substantially O
improved O
specific O
capacities O
and O
cycle O
lives O
of O
lithium B
- O
ion O
batteries O
. O

Revising O
the O
absolute O
configurations O
of O
coatlines O
via O
density O
functional O
theory O
calculations O
of O
electronic O
circular O
dichroism O
spectra O
. O

Coatline B
A I
( O
1 O
) O
and O
alpha B
- I
epi I
- I
coatline I
A I
( O
4 O
) O
co O
- O
occur O
in O
the O
trunk O
extract O
of O
Andira O
coriacea O
. O

Inspection O
of O
their O
chiroptical O
properties O
led O
to O
intriguing O
results O
. O

After O
a O
careful O
examination O
of O
the O
experimental O
data O
used O
for O
the O
previously O
reported O
absolute O
configuration O
of O
these O
compounds O
, O
some O
uncertainties O
were O
identified O
. O

A O
combined O
theoretical O
approach O
including O
conformational O
analyses O
and O
calculation O
of O
electronic O
circular O
dichroism O
( O
ECD O
) O
spectra O
, O
in O
addition O
with O
experimental O
data O
obtained O
for O
schoepfin B
A I
( O
5 O
) O
and O
the O
new O
schoepfin B
D I
( O
6 O
) O
isolated O
from O
Senna O
quinquangulata O
, O
allowed O
the O
revision O
of O
the O
absolute O
configuration O
of O
coatlines B
A I
( I
1 I
) I
and I
B I
( O
2 O
) O
. O

Relative O
importance O
of O
direct O
and O
trophic O
uranium B
exposures O
in O
the O
crayfish O
Orconectes O
limosus O
: O
Implication O
for O
predicting O
uranium B
bioaccumulation O
and O
its O
associated O
toxicity O
. O

Pollutants O
that O
occur O
at O
sublethal O
concentrations O
in O
the O
environment O
may O
lead O
to O
chronic O
exposure O
in O
aquatic O
organisms O
. O

If O
these O
pollutants O
bioaccumulate O
, O
then O
organisms O
higher O
in O
the O
food O
chain O
may O
also O
be O
at O
risk O
. O

Increased O
attention O
has O
thus O
been O
focused O
on O
the O
relative O
importance O
of O
dietary O
uptake O
, O
but O
additional O
knowledge O
of O
the O
cellular O
distribution O
of O
metals O
after O
dietary O
exposure O
is O
required O
to O
assess O
the O
potential O
toxicity O
. O

The O
authors O
address O
concerns O
relating O
to O
increasing O
uranium B
( O
U O
) O
concentrations O
( O
from O
12 O
micro O
g O
/ O
L O
to O
2 O
mg O
/ O
L O
) O
in O
the O
freshwater O
ecosystem O
caused O
by O
anthropogenic O
activities O
. O

The O
objective O
of O
the O
present O
study O
is O
to O
compare O
uranium B
bioaccumulation O
levels O
in O
tissues O
and O
in O
the O
subcellular O
environment O
. O

The O
authors O
focused O
on O
the O
cytosol O
fraction O
and O
its O
microlocalization O
( O
TEM O
- O
EDX O
) O
in O
the O
gills O
and O
the O
hepatopancreas O
( O
HP O
) O
of O
the O
crayfish O
Orconectes O
limosus O
after O
10 O
d O
of O
direct O
exposure O
( O
at O
concentrations O
of O
20 O
, O
100 O
, O
and O
500 O
micro O
g O
/ O
L O
) O
and O
five O
trophic O
exposure O
treatments O
( O
at O
concentrations O
from O
1 O
to O
20 O
micro O
g O
/ O
g O
) O
. O

Results O
indicated O
that O
adsorption O
of O
uranium B
on O
the O
cuticle O
represents O
the O
main O
contribution O
of O
total O
uranium B
accumulation O
to O
the O
animal O
. O

Accumulation O
in O
the O
gills O
should O
be O
considered O
only O
as O
a O
marker O
of O
waterborne O
uranium B
exposure O
. O

Accumulation O
in O
the O
HP O
after O
trophic O
environmental O
exposure O
conditions O
was O
higher O
( O
18 O
. O
9 O
+ O
/ O
- O
3 O
. O
8 O
micro O
g O
/ O
g O
) O
than O
after O
direct O
exposure O
. O

Moreover O
, O
no O
significant O
difference O
in O
the O
subcellular O
distribution O
of O
uranium B
( O
50 O
% O
) O
in O
HP O
was O
observed O
between O
animals O
that O
had O
been O
exposed O
to O
both O
types O
of O
treatment O
. O

A O
potential O
toxic O
effect O
after O
uranium B
accumulation O
could O
therefore O
exist O
after O
trophic O
exposure O
. O

This O
confirms O
the O
need O
to O
focus O
further O
studies O
on O
the O
metal O
( O
uranium B
) O
risk O
assessment O
. O

Photoactivable O
amino B
acid I
bioisosteres O
and O
mass O
spectrometry O
: O
snapshots O
of O
in O
vivo O
3D O
protein O
structures O
. O

From O
folded O
to O
crosslinked O
proteins O
. O

A O
new O
promising O
photo O
- O
crosslinking O
/ O
mass O
spectrometry O
method O
for O
the O
structural O
characterisation O
of O
folded O
proteins O
is O
highlighted O
. O

A O
reactive O
photo O
- O
leucine B
can O
clamp O
the O
front O
residues O
in O
beta O
- O
turn O
and O
beta O
- O
hairpin O
domains O
, O
thus O
allowing O
us O
to O
look O
into O
the O
specific O
native O
3D O
structure O
of O
proteins O
. O

Assessment O
of O
density O
functional O
methods O
for O
reaction O
energetics O
: O
iridium B
- O
catalyzed O
water O
oxidation O
as O
case O
study O
. O

We O
investigate O
basis O
set O
convergence O
for O
a O
series O
of O
density O
functional O
theory O
( O
DFT O
) O
functionals O
( O
both O
hybrid O
and O
nonhybrid O
) O
and O
compare O
to O
coupled O
- O
cluster O
with O
single O
and O
double O
excitations O
and O
perturbative O
triples O
[ O
CCSD O
( O
T O
) O
] O
benchmark O
calculations O
. O

The O
case O
studied O
is O
the O
energetics O
of O
the O
water O
oxidation O
reaction O
by O
an O
iridium B
- I
oxo I
complex O
. O

Complexation O
energies O
for O
the O
reactants O
and O
products O
complexes O
as O
well O
as O
the O
transition O
state O
( O
TS O
) O
energy O
are O
considered O
. O

Contrary O
to O
the O
expectation O
of O
relatively O
weak O
basis O
set O
dependence O
for O
DFT O
, O
the O
basis O
set O
effects O
are O
large O
, O
for O
example O
, O
more O
than O
10 O
kcal O
mol O
( O
- O
1 O
) O
difference O
from O
converged O
basis O
for O
the O
activation O
energy O
with O
" O
small O
" O
basis O
sets O
( O
DZ O
/ O
6 O
- O
31G O
* O
* O
for O
Ir O
/ O
other O
atoms O
, O
or O
SVP O
) O
and O
still O
more O
than O
6 O
kcal O
mol O
( O
- O
1 O
) O
for O
def2 O
- O
TZVPP O
/ O
6 O
- O
31G O
* O
* O
. O

Inclusion O
of O
the O
dispersion O
correction O
in O
DFT O
- O
D3 O
schemes O
affects O
the O
energies O
of O
reactant O
complex O
( O
RC O
) O
, O
TS O
, O
and O
product O
complex O
( O
PC O
) O
by O
almost O
the O
same O
amount O
; O
it O
significantly O
improves O
the O
complexation O
energy O
( O
the O
formation O
of O
RC O
) O
, O
but O
has O
little O
effect O
on O
the O
activation O
energy O
with O
respect O
to O
RC O
. O

With O
converged O
basis O
, O
some O
pure O
GGAs O
( O
PBE O
- O
D3 O
, O
BP86 O
- O
D3 O
) O
as O
well O
as O
the O
hybrid O
functional O
B3LYP O
- O
D3 O
are O
very O
accurate O
compared O
to O
benchmark O
CCSD O
( O
T O
) O
calculations O
. O

Effect O
of O
molecular O
crowding O
on O
the O
temperature O
- O
pressure O
stability O
diagram O
of O
ribonuclease O
A O
. O

FT O
- O
IR O
spectroscopic O
and O
thermodynamic O
measurements O
were O
designed O
to O
explore O
the O
effect O
of O
a O
macromolecular O
crowder O
, O
dextran O
, O
on O
the O
temperature O
and O
pressure O
- O
dependent O
phase O
diagram O
of O
the O
protein O
Ribonuclease O
A O
( O
RNase O
A O
) O
, O
and O
we O
compare O
the O
experimental O
data O
with O
approximate O
theoretical O
predictions O
based O
on O
configuration O
entropy O
. O

Exploring O
the O
crowding O
effect O
on O
the O
pressure O
- O
induced O
unfolding O
of O
proteins O
provides O
insight O
in O
protein O
stability O
and O
folding O
under O
cell O
- O
like O
dense O
conditions O
, O
since O
pressure O
is O
a O
fundamental O
thermodynamic O
variable O
linked O
to O
molecular O
volume O
. O

Moreover O
, O
these O
studies O
are O
of O
relevance O
for O
understanding O
protein O
stability O
in O
deep O
- O
sea O
organisms O
, O
which O
have O
to O
cope O
with O
pressures O
in O
the O
kbar O
range O
. O

We O
found O
that O
not O
only O
temperature O
- O
induced O
equilibrium O
unfolding O
of O
RNase O
A O
, O
but O
also O
unfolding O
induced O
by O
pressure O
is O
markedly O
prohibited O
in O
the O
crowded O
dextran O
solutions O
, O
suggesting O
that O
crowded O
environments O
such O
as O
those O
found O
intracellularly O
, O
will O
also O
oppress O
high O
- O
pressure O
protein O
unfolding O
. O

The O
FT O
- O
IR O
spectroscopic O
measurements O
revealed O
a O
marked O
increase O
in O
unfolding O
pressure O
of O
2 O
kbar O
in O
the O
presence O
of O
30 O
wt O
% O
dextran O
. O

Whereas O
the O
structural O
changes O
upon O
thermal O
unfolding O
of O
the O
protein O
are O
not O
significantly O
influenced O
in O
the O
presence O
of O
the O
crowding O
agent O
, O
through O
stabilization O
by O
dextran O
the O
pressure O
- O
unfolded O
state O
of O
the O
protein O
retains O
more O
ordered O
secondary O
structure O
elements O
, O
which O
seems O
to O
be O
a O
manifestation O
of O
the O
entropic O
destabilization O
of O
the O
unfolded O
state O
by O
crowding O
. O

Proteome O
profiling O
of O
peripheral O
mononuclear O
cells O
from O
human O
blood O
. O

Peripheral O
blood O
mononuclear O
cells O
( O
MNCs O
) O
are O
accessible O
through O
blood O
collection O
and O
represent O
a O
useful O
source O
for O
investigations O
on O
disease O
mechanisms O
and O
treatment O
response O
. O

Aiming O
to O
build O
a O
reference O
proteome O
database O
, O
we O
generated O
three O
proteome O
data O
sets O
from O
MNCs O
using O
a O
combination O
of O
SDS B
- O
PAGE O
and O
nanoflow O
LC O
- O
MS O
. O

Experiments O
were O
performed O
in O
triplicates O
and O
514 O
unique O
proteins O
were O
identified O
by O
at O
least O
two O
non O
- O
redundant O
peptides O
with O
95 O
% O
confidence O
for O
all O
replicates O
. O

Identified O
proteins O
are O
associated O
with O
a O
range O
of O
dermatologic O
, O
inflammatory O
and O
neurological O
conditions O
as O
well O
as O
molecular O
processes O
, O
such O
as O
free O
radical O
scavenging O
and O
cellular O
growth O
and O
proliferation O
. O

Mapping O
the O
MNC O
proteome O
provides O
a O
valuable O
resource O
for O
studies O
on O
disease O
pathogenesis O
and O
the O
identification O
of O
therapeutic O
targets O
. O

Bifunctional O
nanoparticles O
constructed O
using O
one O
- O
pot O
encapsulation O
of O
a O
fluorescent O
polymer O
and O
magnetic O
( O
Fe3O4 B
) O
nanoparticles O
in O
a O
silica B
shell O
. O

Integration O
of O
biocompatible O
silica B
with O
a O
fluorescent O
polymer O
( O
PDDF B
) O
and O
superparamagnetic O
iron B
oxide I
nanoparticles O
( O
Fe3 B
O4 I
) O
to O
form O
uniform O
core O
- O
shell O
nanostructures O
has O
the O
great O
potential O
to O
form O
particles O
for O
use O
in O
multimodal O
bioimaging O
applications O
. O

Core O
- O
shell O
nanoparticles O
( O
PDDF B
/ O
Fe3 B
O4 I
@ O
SiO2 B
) O
exhibit O
fluorescent O
and O
magnetic O
properties O
that O
are O
favorable O
for O
their O
use O
in O
magnetic O
separation O
and O
guiding O
applications O
, O
as O
well O
as O
optical O
and O
magnetic O
resonance O
( O
MR O
) O
imaging O
capabilities O
. O

With O
the O
biological O
analysis O
in O
an O
in O
vitro O
intracellular O
permeation O
and O
cytotoxicity O
test O
, O
chemical O
conjugation O
of O
the O
surface O
using O
folic B
acid I
( O
FA O
) O
molecules O
can O
provide O
the O
nanoparticles O
with O
cell O
- O
targeting O
properties O
, O
localizing O
the O
nanoparticles O
to O
folate B
receptors O
( O
FRs O
) O
on O
target O
KB O
cells O
that O
over O
- O
express O
the O
FRs O
. O

Inclusion O
of O
pediatric O
samples O
in O
an O
opt O
- O
out O
biorepository O
linking O
DNA O
to O
de O
- O
identified O
medical O
records O
: O
pediatric O
BioVU O
. O

The O
Vanderbilt O
DNA O
repository O
, O
BioVU O
, O
links O
DNA O
from O
leftover O
clinical O
blood O
samples O
to O
de O
- O
identified O
electronic O
medical O
records O
( O
EMRs O
) O
. O

After O
initiating O
adult O
sample O
collection O
, O
pediatric O
extension O
required O
consideration O
of O
ethical O
concerns O
specific O
to O
pediatrics O
and O
implementation O
of O
specialized O
DNA O
extraction O
methods O
. O

In O
the O
first O
year O
of O
pediatric O
sample O
collection O
, O
more O
than O
11 O
, O
000 O
samples O
from O
individuals O
younger O
than O
18 O
years O
were O
included O
. O

We O
compared O
data O
from O
the O
pediatric O
BioVU O
cohort O
with O
those O
from O
the O
overall O
Vanderbilt O
University O
Medical O
Center O
pediatric O
population O
and O
found O
similar O
demographic O
characteristics O
; O
however O
, O
the O
BioVU O
cohort O
had O
higher O
rates O
of O
select O
diseases O
, O
medication O
exposures O
, O
and O
laboratory O
testing O
, O
demonstrating O
enriched O
representation O
of O
severe O
or O
chronic O
disease O
. O

The O
fact O
that O
the O
sample O
accumulation O
is O
not O
balanced O
may O
accelerate O
research O
in O
some O
cohorts O
while O
limiting O
the O
study O
of O
relatively O
benign O
conditions O
and O
the O
accrual O
of O
unaffected O
and O
unbiased O
control O
samples O
. O

BioVU O
represents O
a O
feasible O
model O
for O
pediatric O
DNA O
biobanking O
but O
involves O
both O
ethical O
and O
practical O
considerations O
specific O
to O
the O
pediatric O
population O
. O

Is O
this O
the O
dose O
for O
you O
? O
: O
the O
role O
of O
modeling O
. O

To O
make O
an O
informed O
benefit O
- O
risk O
evaluation O
of O
a O
drug O
, O
a O
range O
of O
doses O
needs O
to O
be O
evaluated O
and O
its O
dose O
- O
response O
and O
exposure O
- O
response O
relationships O
for O
safety O
and O
effectiveness O
assessed O
during O
drug O
development O
( O
International O
Conference O
on O
Harmonisation O
E4 O
) O
. O

Once O
a O
safe O
and O
effective O
population O
dose O
( O
or O
doses O
) O
has O
been O
determined O
for O
indicated O
use O
( O
s O
) O
, O
the O
individual O
patient O
dose O
can O
then O
be O
adjusted O
based O
on O
patient O
- O
specific O
factors O
( O
e O
. O
g O
. O
, O
age O
, O
race O
, O
genetics O
, O
organ O
functions O
, O
concomitant O
medications O
) O
. O

One O
- O
pot O
assembly O
of O
a O
hetero O
- O
dimeric O
DNA O
origami O
from O
chip O
- O
derived O
staples O
and O
double O
- O
stranded O
scaffold O
. O

Although O
structural O
DNA O
nanotechnology O
, O
and O
especially O
scaffolded O
DNA O
origami O
, O
hold O
great O
promise O
for O
bottom O
- O
up O
fabrication O
of O
novel O
nanoscale O
materials O
and O
devices O
, O
concerns O
about O
scalability O
have O
tempered O
widespread O
enthusiasm O
. O

Here O
we O
report O
a O
single O
- O
pot O
reaction O
where O
both O
strands O
of O
double O
- O
stranded O
M13 O
- O
bacteriophage O
DNA O
are O
simultaneously O
folded O
into O
two O
distinct O
shapes O
that O
then O
heterodimerize O
with O
high O
yield O
. O

The O
fully O
addressable O
, O
two O
- O
dimensional O
heterodimer O
DNA O
origami O
, O
with O
twice O
the O
surface O
area O
of O
standard O
M13 O
origami O
, O
formed O
in O
high O
yield O
( O
81 O
% O
of O
the O
well O
- O
formed O
monomers O
undergo O
dimerization O
) O
. O

We O
also O
report O
the O
concurrent O
production O
of O
entire O
sets O
of O
staple O
strands O
by O
a O
unique O
, O
nicking O
strand O
- O
displacement O
amplification O
( O
nSDA O
) O
involving O
reusable O
surface O
- O
bound O
template O
strands O
that O
were O
synthesized O
in O
situ O
using O
a O
custom O
piezoelectric O
inkjet O
system O
. O

The O
combination O
of O
chip O
- O
based O
staple O
strand O
production O
, O
double O
- O
sized O
origami O
, O
and O
high O
- O
yield O
one O
- O
pot O
assembly O
markedly O
increases O
the O
useful O
scale O
of O
DNA O
origami O
. O

In O
vivo O
biodistribution O
of O
mixed O
shell O
micelles O
with O
tunable O
hydrophilic O
/ O
hydrophobic O
surface O
. O

The O
miserable O
targeting O
performance O
of O
nanocarriers O
for O
cancer O
therapy O
arises O
largely O
from O
the O
rapid O
clearance O
from O
blood O
circulation O
and O
the O
major O
accumulation O
in O
the O
organs O
of O
the O
reticuloendothelial O
system O
( O
RES O
) O
, O
leading O
to O
inefficient O
enhanced O
permeability O
and O
retention O
( O
EPR O
) O
effect O
after O
intravenous O
injection O
( O
i O
. O
v O
. O
) O
. O

Herein O
, O
we O
reported O
an O
efficient O
method O
to O
prolong O
the O
blood O
circulation O
of O
nanoparticles O
and O
decrease O
their O
deposition O
in O
liver O
and O
spleen O
. O

In O
this O
work O
, O
we O
fabricated O
a O
series O
of O
mixed O
shell O
micelles O
( O
MSMs O
) O
with O
approximately O
the O
same O
size O
, O
charge O
and O
core O
composition O
but O
with O
varied O
hydrophilic O
/ O
hydrophobic O
ratios O
in O
the O
shell O
through O
spontaneously O
self O
- O
assembly O
of O
block O
copolymers O
poly B
( I
ethylene I
glycol I
) I
- I
block I
- I
poly I
( I
l I
- I
lysine I
) I
( O
PEG B
- I
b I
- I
PLys I
) O
and O
poly B
( I
N I
- I
isopropylacrylamide I
) I
- I
block I
- I
poly I
( I
aspartic I
acid I
) I
( O
PNIPAM B
- I
b I
- I
PAsp I
) O
in O

aqueous O
medium O
. O

The O
effect O
of O
the O
surface O
heterogeneity O
on O
the O
in O
vivo O
biodistribution O
was O
systematically O
investigated O
through O
in O
vivo O
tracking O
of O
the O
( B
125 I
) I
I I
- O
labeled O
MSMs O
determined O
by O
Gamma O
counter O
. O

Compared O
with O
single O
PEGylated O
micelles O
, O
some O
MSMs B
were O
proved O
to O
be O
significantly O
efficient O
with O
more O
than O
3 O
times O
lower O
accumulation O
in O
liver O
and O
spleen O
and O
about O
6 O
times O
higher O
concentration O
in O
blood O
at O
1 O
h O
after O
i O
. O
v O
. O
. O

The O
results O
provide O
us O
a O
novel O
strategy O
for O
future O
development O
of O
long O
- O
circulating O
nanocarriers O
for O
efficient O
cancer O
therapy O
. O

Tetrahydropyrroloqui B
type O
dual O
inhibitors O
of O
aromatase O
/ O
aldosterone B
synthase O
as O
a O
novel O
strategy O
for O
breast O
cancer O
patients O
with O
elevated O
cardiovascular O
risks O
. O

The O
application O
of O
aromatase O
inhibitors O
to O
postmenopausal O
breast O
cancer O
patients O
increases O
the O
risk O
of O
cardiovascular O
diseases O
( O
CVD O
) O
, O
which O
is O
believed O
to O
be O
caused O
by O
the O
abnormally O
high O
concentrations O
of O
aldosterone B
as O
a O
consequence O
of O
the O
estrogen B
deficiency O
. O

Dual O
inhibitors O
of O
aromatase O
( O
CYP19 O
) O
and O
aldosterone B
synthase O
( O
CYP11B2 O
) O
are O
therefore O
proposed O
as O
a O
novel O
strategy O
for O
the O
adjuvant O
therapy O
to O
reduce O
the O
CVD O
risk O
for O
these O
patients O
. O

By O
combining O
decisive O
structural O
features O
of O
CYP11B2 O
and O
CYP19 O
inhibitors O
into O
a O
common O
template O
, O
a O
series O
of O
pyridinylmethyl B
substituted I
1 I
, I
2 I
, I
5 I
, I
6 I
- I
tetrahydro I
- I
pyrrolo I
[ I
3 I
, I
2 I
, I
1 I
- I
ij I
] I
quinolin I
- I
4 I
- I
ones I
were O
designed O
and O
synthesized O
. O

Interestingly O
, O
the O
substituents O
on O
the O
methylene B
bridge O
showed O
strong O
influences O
on O
the O
inhibitory O
activities O
leading O
to O
opposite O
effects O
, O
that O
is O
, O
a O
given O
substituent O
showed O
an O
increase O
in O
inhibition O
of O
one O
enzyme O
, O
while O
it O
led O
to O
a O
decrease O
for O
the O
other O
enzyme O
. O

The O
compromise O
of O
this O
conflict O
led O
to O
compounds O
3j O
, O
3k O
, O
3n O
, O
and O
3p O
as O
potent O
and O
selective O
dual O
inhibitors O
of O
CYP19 O
and O
CYP11B2 O
, O
especially O
compound O
3p O
, O
which O
exhibited O
IC O
( O
50 O
) O
values O
of O
32 O
and O
41 O
nM O
for O
CYP19 O
and O
CYP11B2 O
, O
respectively O
, O
and O
a O
high O
selectivity O
toward O
CYP17 O
and O
CYP11B1 O
. O

This O
compound O
is O
considered O
as O
a O
candidate O
for O
further O
evaluation O
in O
vivo O
. O

Absolute O
configuration O
and O
conformational O
analysis O
of O
brevipolides B
, O
bioactive O
5 B
, I
6 I
- I
dihydro I
- I
alpha I
- I
pyrones I
from O
Hyptis O
brevipes O
. O

The O
( O
6 O
' O
S O
) O
- O
configuration O
of O
brevipolides B
A I
- I
J I
( O
1 O
- O
10 O
) O
, O
isolated O
from O
Hyptis O
brevipes O
, O
was O
established O
by O
X O
- O
ray O
diffraction O
analysis O
of O
9 O
in O
conjunction O
with O
Mosher O
' O
s O
ester O
analysis O
of O
the O
tetrahydro O
derivative O
11 O
obtained O
from O
both O
geometric O
isomers O
8 O
and O
9 O
as O
well O
as O
by O
chemical O
correlations O
. O

The O
structure O
of O
the O
new O
brevipolide B
J I
( O
10 O
) O
was O
characterized O
through O
NMR O
and O
MS O
data O
as O
having O
the O
same O
6 B
- I
heptyl I
- I
5 I
, I
6 I
- I
dihydro I
- I
2H I
- I
pyran I
- I
2 I
- I
one I
framework O
possessing O
the O
cyclopropane B
moiety O
of O
all O
brevipolides B
but O
substituted O
by O
an O
isoferuloyl B
group O
instead O
of O
the O
p B
- I
methoxycinnamoyl I
moiety O
found O
in O
8 O
and O
9 O
. O

Conformational O
analysis O
of O
these O
cytotoxic O
6 B
- I
heptyl I
- I
5 I
, I
6 I
- I
dihydro I
- I
alpha I
- I
pyrones I
was O
carried O
out O
on O
compound O
9 O
by O
application O
of O
a O
protocol O
based O
on O
comparison O
between O
experimental O
and O
DFT O
- O
calculated O
vicinal O
( B
1 I
) I
H I
- O
( B
1 I
) I
H I
NMR O
coupling O
constants O
. O

Molecular O
modeling O
was O
used O
to O
correlate O
minimum O
energy O
conformers O
and O
observed O
electronic O
circular O
dichroism O
transitions O
for O
the O
isomeric O
series O
of O
brevipolides B
. O

Compounds O
7 O
- O
10 O
exhibited O
moderate O
activity O
( O
ED O
( O
50 O
) O
0 O
. O
3 O
- O
8 O
. O
0 O
mu O
g O
/ O
mL O
) O
against O
a O
variety O
of O
tumor O
cell O
lines O
. O

Treatment O
and O
prevention O
of O
various O
therapeutic O
conditions O
using O
OX O
receptor O
antagonistic O
activity O
( O
WO2012081692 O
) O
. O

Application O
WO2012081692 O
from O
Taisho O
Pharmaceutical O
Co O
. O

Ltd O
. O
claims O
pyrazole B
- O
based O
antagonists O
of O
the O
orexin O
- O
1 O
and O
orexin O
- O
2 O
receptors O
. O

Utility O
in O
a O
number O
of O
therapeutic O
areas O
is O
claimed O
, O
including O
the O
treatment O
of O
sleep O
disorders O
; O
the O
most O
likely O
use O
of O
the O
claimed O
compounds O
. O

Data O
from O
in O
vitro O
functional O
assays O
are O
presented O
, O
with O
the O
claimed O
compounds O
typically O
being O
dual O
orexin O
receptor O
antagonists O
( O
DORAs O
) O
or O
having O
moderate O
selectivity O
for O
orexin O
- O
1 O
. O

Structurally O
, O
the O
claimed O
compounds O
represent O
a O
variation O
on O
established O
DORA O
SAR O
themes O
and O
translate O
features O
of O
clinical O
compounds O
into O
a O
pyrazole B
- O
based O
scaffold O
. O

Example O
52 O
, O
the O
most O
potent O
molecule O
in O
the O
application O
, O
has O
similar O
molecular O
weight O
and O
lipophilicity O
to O
suvorexant B
, O
the O
most O
advanced O
DORA O
, O
with O
broadly O
comparable O
potency O
in O
functional O
assays O
. O

Highly O
sensitive O
fluorescent O
and O
colorimetric O
pH O
sensor O
based O
on O
polyethylenimine B
- O
capped O
silver B
nanoclusters O
. O

Silver B
nanoclusters O
capped O
by O
hyperbranched O
polyethylenimine B
( O
PEI B
) O
have O
been O
developed O
as O
a O
highly O
sensitive O
fluorescent O
and O
colorimetric O
pH O
sensor O
. O

The O
probe O
responds O
rapidly O
to O
pH O
fluctuations O
and O
has O
such O
absorption O
characteristics O
that O
the O
color O
changes O
from O
the O
colorless O
or O
a O
nearly O
colorless O
state O
to O
a O
colored O
state O
with O
increasing O
acidity O
, O
so O
PEI B
- O
capped O
Ag B
nanoclusters O
could O
be O
used O
as O
a O
color O
indicator O
for O
colorimetric O
pH O
detection O
. O

Quantitatively O
, O
the O
fluorescence O
intensity O
of O
PEI B
- O
capped O
Ag B
nanoclusters O
exhibits O
a O
linear O
fashion O
over O
the O
pH O
range O
of O
5 O
. O
02 O
- O
7 O
. O
96 O
and O
increases O
by O
around O
10 O
- O
fold O
approximately O
with O
greater O
fluorescence O
at O
higher O
pH O
values O
. O

The O
repulsion O
development O
and O
conformational O
change O
of O
PEI B
with O
decreasing O
pH O
induce O
the O
aggregation O
of O
Ag B
nanoclusters O
, O
leading O
to O
an O
obvious O
color O
change O
and O
fluorescence O
quenching O
of O
Ag B
nanoclusters O
at O
low O
pH O
values O
. O

As O
expected O
, O
the O
pH O
probe O
is O
also O
sensitive O
to O
the O
different O
buffer O
solutions O
, O
except O
for O
those O
containing O
some O
anions O
that O
could O
react O
with O
Ag B
nanoclusters O
. O

Besides O
, O
the O
ionic O
strength O
of O
the O
buffers O
has O
a O
little O
influence O
on O
the O
pH O
- O
responsive O
behavior O
. O

Our O
pH O
sensor O
with O
nanoscaled O
physical O
dimensions O
would O
be O
a O
promising O
candidate O
in O
the O
applications O
in O
biological O
, O
medical O
, O
and O
pharmaceutical O
fields O
. O

Multicolor O
fluorescent O
semiconducting O
polymer O
dots O
with O
narrow O
emissions O
and O
high O
brightness O
. O

Fluorescent O
semiconducting O
polymer O
dots O
( O
Pdots O
) O
have O
attracted O
great O
interest O
because O
of O
their O
superior O
characteristics O
as O
fluorescent O
probes O
, O
such O
as O
high O
fluorescence O
brightness O
, O
fast O
radiative O
rates O
, O
and O
excellent O
photostability O
. O

However O
, O
currently O
available O
Pdots O
generally O
exhibit O
broad O
emission O
spectra O
, O
which O
significantly O
limit O
their O
usefulness O
in O
many O
biological O
applications O
involving O
multiplex O
detections O
. O

Here O
, O
we O
describe O
the O
design O
and O
development O
of O
multicolor O
narrow O
emissive O
Pdots O
based O
on O
different O
boron B
dipyrromethene I
( O
BODIPY B
) O
units O
. O

BODIPY B
- O
containing O
semiconducting O
polymers O
emitting O
at O
multiple O
wavelengths O
were O
synthesized O
and O
used O
as O
precursors O
for O
preparing O
the O
Pdots O
, O
where O
intraparticle O
energy O
transfer O
led O
to O
highly O
bright O
, O
narrow O
emissions O
. O

The O
emission O
full O
width O
at O
half O
- O
maximum O
of O
the O
resulting O
Pdots O
varies O
from O
40 O
to O
55 O
nm O
, O
which O
is O
1 O
. O
5 O
- O
2 O
times O
narrower O
than O
those O
of O
conventional O
semiconducting O
polymer O
dots O
. O

BODIPY B
520 O
Pdots O
were O
about O
an O
order O
of O
magnitude O
brighter O
than O
commercial O
Qdot O
525 O
under O
identical O
laser O
excitation O
conditions O
. O

Fluorescence O
imaging O
and O
flow O
cytometry O
experiments O
indicate O
that O
the O
narrow O
emissions O
from O
these O
bright O
Pdots O
are O
promising O
for O
multiplexed O
biological O
detections O
. O

Characterization O
of O
arsenic B
induced O
cytotoxicity O
in O
liver O
with O
stress O
in O
erythrocytes O
and O
its O
reversibility O
with O
Pleurotus O
florida O
lectin O
. O

Arsenic B
is O
one O
of O
the O
most O
hazardous O
substances O
in O
the O
environment O
known O
to O
cause O
toxicity O
in O
multiple O
organs O
. O

Cell O
adhesion O
, O
morphological O
alterations O
, O
cell O
proliferation O
, O
terminal O
deoxyuridine B
triphosphate I
nick O
- O
end O
labeling O
( O
TUNEL O
) O
and O
caspase O
- O
3 O
/ O
CPP32 O
fluorometric O
protease O
assay O
were O
important O
biomarkers O
to O
assess O
apoptosis O
in O
cells O
. O

This O
study O
aimed O
to O
evaluate O
arsenic B
- O
induced O
apoptosis O
in O
the O
hepatocytes O
of O
rat O
and O
its O
protective O
efficacy O
with O
coadministration O
of O
ascorbic B
acid I
( O
AA O
) O
and O
Pleurotus O
florida O
lectin O
( O
PFL O
) O
individually O
. O

Results O
of O
the O
present O
study O
also O
showed O
that O
arsenic B
caused O
cytotoxicity O
by O
elevating O
morphological O
alterations O
, O
TUNEL O
- O
positive O
nuclei O
, O
caspase O
- O
3 O
activity O
and O
DNA O
damage O
and O
reducing O
cell O
adhesion O
and O
cell O
proliferation O
in O
a O
time O
- O
dependent O
manner O
. O

The O
apoptosis O
in O
hepatocytes O
was O
reverted O
to O
normal O
value O
after O
coadministration O
of O
mushroom O
lectin O
in O
arsenic B
- O
exposed O
rat O
. O

The O
study O
provided O
significant O
evidence O
that O
PFL O
has O
antiapoptotic O
property O
against O
arsenic B
- O
induced O
toxicity O
. O

The O
beneficial O
effect O
of O
PFL O
was O
proportional O
to O
its O
duration O
of O
exposure O
. O

Retard O
activities O
of O
superoxide B
dismutase O
and O
catalase O
, O
enhanced O
lipid O
peroxidation O
as O
well O
as O
protein O
carbonyl B
in O
erythrocytes O
caused O
by O
arsenic B
could O
also O
be O
maintained O
toward O
normalcy O
by O
supplementation O
of O
AA O
and O
PFL O
. O

These O
antioxidative O
effects O
were O
exhibited O
in O
a O
time O
- O
dependant O
manner O
. O

In O
rat O
, O
treatment O
with O
AA O
and O
PFL O
prevented O
alteration O
of O
plasma O
enzyme O
activities O
caused O
by O
arsenic B
. O

The O
results O
concluded O
that O
treatment O
with O
PFL O
has O
significant O
role O
in O
protecting O
animals O
from O
arsenic B
- O
induced O
erythrocytic O
damage O
. O

This O
finding O
might O
be O
of O
therapeutic O
benefit O
in O
people O
suffering O
from O
chronic O
exposure O
to O
arsenic B
from O
natural O
sources O
, O
a O
global O
problem O
especially O
relevant O
to O
millions O
of O
people O
on O
the O
Indian O
subcontinent O
. O

Control O
of O
transcriptional O
fidelity O
by O
active O
center O
tuning O
as O
derived O
from O
RNA O
polymerase O
endonuclease O
reaction O
. O

Precise O
transcription O
by O
cellular O
RNA O
polymerase O
requires O
the O
efficient O
removal O
of O
noncognate O
nucleotide B
residues O
that O
are O
occasionally O
incorporated O
. O

Mis O
- O
incorporation O
causes O
the O
transcription O
elongation O
complex O
to O
backtrack O
, O
releasing O
a O
single O
strand O
3 O
' O
- O
RNA O
segment O
bearing O
a O
noncognate O
residue O
, O
which O
is O
hydrolyzed O
by O
the O
active O
center O
that O
carries O
two O
Mg B
( I
2 I
+ I
) I
ions O
. O

However O
, O
in O
most O
x O
- O
ray O
structures O
only O
one O
Mg B
( I
2 I
+ I
) I
is O
present O
. O

This O
Mg B
( I
2 I
+ I
) I
is O
tightly O
bound O
to O
the O
active O
center O
aspartates B
, O
creating O
an O
inactive O
stable O
state O
. O

The O
first O
residue O
of O
the O
single O
strand O
RNA O
segment O
in O
the O
backtracked O
transcription O
elongation O
complex O
strongly O
promotes O
transcript O
hydrolytic O
cleavage O
by O
establishing O
a O
network O
of O
interactions O
that O
force O
a O
shift O
of O
stably O
bound O
Mg B
( I
2 I
+ I
) I
to O
release O
some O
of O
its O
aspartate B
coordination O
valences O
for O
binding O
to O
the O
second O
Mg B
( I
2 I
+ I
) I
thus O
enabling O
catalysis O
. O

Such O
a O
rearrangement O
that O
we O
call O
active O
center O
tuning O
( O
ACT O
) O
occurs O
when O
all O
recognition O
contacts O
of O
the O
active O
center O
- O
bound O
RNA O
segment O
are O
established O
and O
verified O
by O
tolerance O
to O
stress O
. O

Transcription O
factor O
Gre O
builds O
on O
the O
ACT O
mechanism O
in O
the O
same O
reaction O
by O
increasing O
the O
retention O
of O
the O
second O
Mg B
( I
2 I
+ I
) I
and O
by O
activating O
the O
attacking O
water O
, O
causing O
3000 O
- O
4000 O
- O
fold O
reaction O
acceleration O
and O
strongly O
reinforcing O
proofreading O
. O

The O
unified O
mechanism O
for O
RNA O
synthesis O
and O
degradation O
by O
RNA O
polymerase O
predicts O
that O
ACT O
also O
executes O
NTP O
selection O
thereby O
contributing O
to O
high O
transcription O
fidelity O
. O

Discovery O
of O
5 B
- I
benzyl I
- I
3 I
- I
phenyl I
- I
4 I
, I
5 I
- I
dihydroisoxazoles I
and O
5 B
- I
benzyl I
- I
3 I
- I
phenyl I
- I
1 I
, I
4 I
, I
2 I
- I
dioxazoles I
as O
potent O
firefly O
luciferase O
inhibitors O
. O

Luciferase O
reporter O
assays O
are O
commonly O
used O
in O
high O
- O
throughput O
screening O
methods O
. O

Here O
, O
we O
report O
new O
firefly O
luciferase O
( O
FLuc O
) O
inhibitors O
based O
on O
5 B
- I
benzyl I
- I
3 I
- I
phenyl I
- I
4 I
, I
5 I
- I
dihydroisoxazoles I
and O
5 B
- I
benzyl I
- I
3 I
- I
phenyl I
- I
1 I
, I
4 I
, I
2 I
- I
dioxazoles I
, O
which O
showed O
up O
as O
" O
false O
positives O
" O
in O
a O
luciferase O
reporter O
gene O
- O
based O
assay O
for O
nuclear O
receptor O
antagonists O
. O

The O
inhibition O
was O
shown O
to O
be O
noncompetitive O
for O
both O
natural O
enzyme O
substrates O
( O
d B
- I
luciferin I
and O
ATP B
) O
and O
selective O
to O
FLuc O
and O
proven O
to O
arise O
from O
a O
direct O
interaction O
between O
the O
enzyme O
and O
the O
inhibitor O
. O

Of O
the O
63 O
evaluated O
compounds O
, O
28 O
showed O
significantly O
better O
inhibition O
potency O
than O
the O
well O
- O
known O
inhibitor O
resveratrol B
( O
IC O
( O
50 O
) O
= O
59 O
nM O
) O
, O
with O
five O
compounds O
having O
distinctly O
subnanomolar O
IC O
( O
50 O
) O
values O
. O

The O
most O
efficient O
compounds O
inhibited O
the O
luminescence O
at O
concentrations O
lower O
than O
( O
1 O
) O
/ O
( O
100 O
) O
in O
comparison O
to O
resveratrol B
( O
lowest O
IC O
( O
50 O
) O
= O
0 O
. O
26 O
nM O
) O
and O
can O
thus O
be O
considered O
to O
belong O
to O
the O
most O
potent O
FLuc O
inhibitors O
reported O
thus O
far O
. O

Overall O
, O
the O
novel O
inhibitors O
form O
a O
unique O
molecular O
library O
for O
structure O
- O
activity O
relationship O
( O
SAR O
) O
analyses O
. O

Design O
and O
implementation O
of O
two O
- O
dimensional O
polymer O
adsorption O
models O
: O
evaluating O
the O
stability O
of O
Candida O
antarctica O
lipase O
B O
/ O
solid O
- O
support O
interfaces O
by O
QCM O
- O
D O
. O

A O
two O
- O
dimensional O
model O
of O
a O
solid O
- O
supported O
enzyme O
catalyst O
bead O
is O
fabricated O
on O
a O
quartz B
crystal O
microbalance O
with O
dissipation O
monitoring O
( O
QCM O
- O
D O
) O
sensor O
to O
measure O
in O
situ O
interfacial O
stability O
and O
mechanical O
properties O
of O
Candida O
antarctica O
Lipase O
B O
( O
CAL O
B O
) O
under O
varied O
conditions O
relating O
to O
ring O
- O
opening O
polymerization O
. O

The O
model O
was O
fabricated O
using O
a O
dual O
photochemical O
approach O
, O
where O
poly B
( I
methyl I
methacrylate I
) I
( O
PMMA B
) O
thin O
films O
were O
cross O
- O
linked O
by O
a O
photoactive O
benzophenone B
monolayer O
and O
blended O
cross O
- O
linking O
agent O
. O

This O
process O
produces O
two O
- O
dimensional O
, O
homogeneous O
, O
rigid O
PMMA B
layers O
, O
which O
mimic O
commercial O
acrylic B
resins O
in O
a O
QCM O
- O
D O
experiment O
. O

Adsorption O
of O
CAL O
B O
to O
PMMA B
in O
QCM O
- O
D O
under O
varied O
buffer O
ionic O
strengths O
produces O
a O
viscoelastic O
enzyme O
surface O
that O
becomes O
more O
rigid O
as O
ionic O
strength O
increases O
. O

The O
rigid O
CAL O
B O
/ O
PMMA B
interface O
demonstrates O
up O
to O
20 O
% O
desorption O
of O
enzyme O
with O
increasing O
trace O
water O
content O
. O

Increased O
polycaprolactone B
( O
PCL B
) O
binding O
at O
the O
enzyme O
surface O
was O
also O
observed O
, O
indicating O
greater O
PCL B
affinity O
for O
a O
more O
hydrated O
enzyme O
surface O
. O

The O
enzyme O
layer O
destabilized O
with O
increasing O
temperature O
, O
yielding O
near O
complete O
reversible O
catalyst O
desorption O
in O
the O
model O
. O

Effects O
of O
the O
benzimidazole B
anthelmintic O
drug O
flubendazole B
on O
rat O
embryos O
in O
vitro O
. O

Filarial O
diseases O
affect O
millions O
of O
people O
in O
poverty O
- O
stricken O
areas O
. O

In O
2011 O
, O
an O
investigation O
of O
the O
potential O
of O
flubendazole B
as O
a O
safe O
, O
highly O
efficacious O
, O
and O
field O
- O
usable O
macrofilaricidal O
drug O
was O
begun O
by O
Drug O
for O
Neglected O
Diseases O
initiative O
. O

As O
part O
of O
the O
preclinical O
development O
program O
, O
whole O
embryo O
culture O
was O
used O
to O
investigate O
the O
potential O
embryotoxicity O
of O
flubendazole B
and O
its O
metabolites O
, O
reduced O
and O
hydrolyzed O
flubendazole B
. O

Albendazole B
was O
included O
as O
a O
comparator O
. O

Flubendazole B
and O
albendazole B
showed O
similar O
potency O
in O
affecting O
rat O
embryonic O
development O
in O
vitro O
, O
inducing O
retardation O
of O
growth O
and O
dysmorphogenic O
effects O
at O
concentrations O
> O
= O
0 O
. O
5 O
mu O
g O
/ O
mL O
. O

The O
head O
, O
optic O
and O
otic O
systems O
, O
branchial O
arches O
and O
posterior O
body O
portion O
were O
affected O
. O

Diffuse O
areas O
of O
cell O
death O
were O
seen O
in O
various O
embryonic O
districts O
. O

The O
No O
Observed O
Effect O
Level O
( O
NOEL O
) O
was O
0 O
. O
25 O
mu O
g O
/ O
mL O
for O
both O
drugs O
. O

Reduced O
and O
hydrolyzed O
flubendazole B
were O
less O
embryotoxic O
than O
the O
parent O
compound O
, O
with O
NOELs O
4 O
- O
fold O
and O
> O
40 O
- O
fold O
higher O
than O
that O
of O
flubendazole B
, O
respectively O
. O

Effect O
of O
pigeon B
pea I
( O
Cajanus O
cajan O
L O
. O
) O
on O
high O
- O
fat O
diet O
- O
induced O
hypercholesterolemia O
in O
hamsters O
. O

Obesity O
is O
associated O
with O
increased O
systemic O
and O
airway O
oxidative O
stress O
, O
which O
may O
result O
from O
a O
combination O
of O
adipokine O
imbalance O
and O
antioxidant O
defenses O
reduction O
. O

Obesity O
- O
mediated O
oxidative O
stress O
plays O
an O
important O
role O
in O
the O
pathogenesis O
of O
dyslipidemia O
, O
vascular O
disease O
, O
and O
nonalcoholic O
hepatic O
steatosis O
. O

The O
antidyslipidemic O
activity O
of O
pigeon O
pea O
were O
evaluated O
by O
high O
- O
fat O
diet O
( O
HFD O
) O
hamsters O
model O
, O
in O
which O
the O
level O
of O
high O
- O
density O
lipoprotein O
- O
cholesterol B
( O
HDL O
- O
C O
) O
, O
low O
- O
density O
lipoprotein O
- O
cholesterol B
( O
LDL O
- O
C O
) O
, O
total O
cholesterol B
( O
TC O
) O
, O
and O
total O
triglyceride B
( O
TG O
) O
were O
examined O
. O

We O
found O
that O
pigeon B
pea I
administration O
promoted O
cholesterol B
converting O
to O
bile B
acid I
in O
HFD O
- O
induced O
hamsters O
, O
thereby O
exerting O
hypolipidemic O
activity O
. O

In O
the O
statistical O
results O
, O
pigeon B
pea I
significantly O
increased O
hepatic O
carnitine B
palmitoyltransferase O
- O
1 O
( O
CPT O
- O
1 O
) O
, O
LDL O
receptor O
, O
and O
cholesterol B
7 O
alpha O
- O
hydroxylase O
( O
also O
known O
as O
cytochrome O
P450 O
7A1 O
, O
CYP7A1 O
) O
expression O
to O
attenuate O
dyslipidemia O
in O
HFD O
- O
fed O
hamsters O
; O
and O
markedly O
elevated O
antioxidant O
enzymes O
in O
the O
liver O
of O
HFD O
- O
induced O
hamsters O
, O
further O
alleviating O
lipid O
peroxidation O
. O

These O
effects O
may O
attribute O
to O
pigeon O
pea O
contained O
large O
of O
unsaturated B
fatty I
acids I
( O
UFA B
; O
C18 B
: I
2 I
) O
and O
phytosterol B
( O
beta B
- I
sitosterol I
, O
campesterol B
, O
and O
stigmasterol B
) O
. O

Moreover O
, O
the O
effects O
of O
pigeon O
pea O
on O
dyslipidemia O
were O
greater O
than O
beta B
- I
sitosterol I
administration O
( O
4 O
% O
) O
, O
suggesting O
that O
phytosterone B
in O
pigeon O
pea O
could O
prevent O
metabolic O
syndrome O
. O

Novel O
treatment O
options O
for O
epilepsy O
: O
focus O
on O
perampanel B
. O

Perampanel B
is O
a O
new O
chemical O
entity O
recently O
approved O
in O
the O
United O
States O
( O
US O
) O
and O
European O
Union O
( O
EU O
) O
as O
adjunctive O
treatment O
of O
partial O
- O
onset O
seizures O
with O
and O
without O
secondary O
generalization O
in O
patients O
with O
epilepsy O
aged O
12 O
years O
and O
older O
. O

Pharmacological O
studies O
suggest O
that O
perampanel B
acts O
with O
a O
new O
mechanism O
of O
action O
via O
non O
- O
competitive O
antagonism O
of O
the O
ionotropic O
alpha B
- I
amino I
- I
3 I
- I
hydroxy I
- I
5 I
- I
methyl I
- I
4 I
- I
isoxazoleproprionic I
acid I
( O
AMPA B
) O
receptor O
of O
glutamate B
, O
the O
main O
mediator O
of O
excitatory O
neurotransmission O
in O
the O
central O
nervous O
system O
. O

Perampanel B
is O
completely O
absorbed O
after O
oral O
administration O
. O

The O
drug O
is O
95 O
% O
bound O
to O
plasma O
proteins O
and O
is O
extensively O
metabolized O
by O
oxidation O
followed O
by O
glucuronidation O
. O

Perampanel B
has O
an O
elimination O
half O
- O
life O
of O
approximately O
52 O
- O
129h O
, O
allowing O
once O
daily O
dosing O
, O
with O
peak O
plasma O
levels O
observed O
0 O
. O
25 O
- O
2h O
post O
- O
dose O
. O

Randomized O
placebo O
- O
controlled O
trials O
of O
adjunctive O
treatment O
have O
demonstrated O
that O
once O
- O
daily O
perampanel B
doses O
of O
4 O
- O
12mg O
/ O
day O
significantly O
reduced O
partial O
- O
onset O
seizure O
frequency O
in O
patients O
with O
pharmacoresistant O
epilepsy O
along O
with O
a O
favorable O
tolerability O
profile O
. O

In O
perampanel B
pivotal O
trials O
, O
the O
most O
frequently O
reported O
treatment O
emergent O
adverse O
events O
( O
> O
10 O
% O
) O
included O
dizziness O
, O
somnolence O
, O
fatigue O
and O
headache O
. O

Perampanel B
therapeutic O
response O
was O
maintained O
in O
patients O
included O
in O
the O
long O
term O
open O
- O
label O
extension O
studies O
for O
up O
to O
4 O
years O
. O

Based O
on O
these O
data O
, O
perampanel B
offers O
a O
valuable O
option O
in O
the O
add O
- O
on O
treatment O
of O
partial O
- O
onset O
and O
secondarily O
generalized O
seizures O
. O

SAR O
analysis O
of O
novel O
non O
- O
peptidic O
NPBWR1 O
( O
GPR7 O
) O
antagonists O
. O

In O
this O
Letter O
we O
report O
on O
the O
advances O
in O
our O
NPBWR1 O
antagonist O
program O
aimed O
at O
optimizing O
the O
5 B
- I
chloro I
- I
2 I
- I
( I
3 I
, I
5 I
- I
dimethylphenyl I
) I
- I
4 I
- I
( I
4 I
- I
methoxyphenoxy I
) I
pyridazin I
- I
3 I
( I
2H I
) I
- I
one I
lead O
molecule O
previously O
obtained O
from O
a O
high O
- O
throughput O
screening O
( O
HTS O
) O
- O
derived O
hit O
. O

Synthesis O
and O
structure O
- O
activity O
relationships O
( O
SAR O
) O
studies O
around O
the O
3 B
, I
5 I
- I
dimethylphenyl I
and O
4 B
- I
methoxyphenyl I
regions O
resulted O
in O
the O
identification O
of O
a O
novel O
series O
of O
non O
- O
peptidic O
submicromolar O
NPBWR1 O
antagonists O
based O
on O
a O
5 B
- I
chloro I
- I
4 I
- I
( I
4 I
- I
alkoxyphenoxy I
) I
- I
2 I
- I
( I
benzyl I
) I
pyridazin I
- I
3 I
( I
2H I
) I
- I
one I
chemotype O
. O

Amongst O
them O
, O
5 B
- I
chloro I
- I
2 I
- I
( I
9H I
- I
fluoren I
- I
9 I
- I
yl I
) I
- I
4 I
- I
( I
4 I
- I
methoxyphenoxy I
) I
pyridazin I
- I
3 I
( I
2H I
) I
- I
one I
9h O
( O
CYM50769 B
) O
inhibited O
NPW O
activation O
of O
NPBWR1 O
with O
a O
submicromolar O
IC O
( O
50 O
) O
, O
and O
displayed O
high O
selectivity O
against O
a O
broad O
array O
of O
off O
- O
targets O
with O
pharmaceutical O
relevance O
. O

Our O
medicinal O
chemistry O
study O
provides O
innovative O
non O
- O
peptidic O
selective O
NPBWR1 O
antagonists O
that O
may O
enable O
to O
clarify O
the O
biological O
role O
and O
therapeutic O
utility O
of O
the O
target O
receptor O
in O
the O
regulation O
of O
feeding O
behavior O
, O
pain O
, O
stress O
, O
and O
neuroendocrine O
function O
. O

Evaluation O
of O
iodide B
deficiency O
in O
the O
lactating O
rat O
and O
pup O
using O
a O
biologically O
based O
dose O
- O
response O
model O
. O

A O
biologically O
based O
dose O
- O
response O
( O
BBDR O
) O
model O
for O
the O
hypothalamic O
- O
pituitary O
thyroid O
( O
HPT O
) O
axis O
in O
the O
lactating O
rat O
and O
nursing O
pup O
was O
developed O
to O
describe O
the O
perturbations O
caused O
by O
iodide B
deficiency O
on O
the O
HPT O
axis O
. O

Model O
calibrations O
, O
carried O
out O
by O
adjusting O
key O
model O
parameters O
, O
were O
used O
as O
a O
technique O
to O
evaluate O
HPT O
axis O
adaptations O
to O
dietary O
iodide B
intake O
in O
euthyroid O
( O
4 O
. O
1 O
- O
39 O
micro O
g O
iodide B
/ O
day O
) O
and O
iodide B
- O
deficient O
( O
0 O
. O
31 O
and O
1 O
. O
2 O
micro O
g O
iodide B
/ O
day O
) O
conditions O
. O

Iodide B
- O
deficient O
conditions O
in O
both O
the O
dam O
and O
the O
pup O
were O
described O
with O
increased O
blood O
flow O
to O
the O
thyroid O
gland O
, O
TSH O
- O
mediated O
increase O
in O
thyroidal O
uptake O
of O
iodide B
and O
binding O
of O
iodide B
in O
the O
thyroid O
gland O
( O
organification O
) O
, O
and O
, O
in O
general O
, O
reduced O
thyroid O
hormone O
production O
and O
metabolism O
. O

Alterations O
in O
thyroxine B
( O
T4 O
) O
homeostasis O
were O
more O
apparent O
than O
for O
triiodothyronine B
( O
T3 O
) O
. O

Model O
- O
predicted O
average O
daily O
area O
- O
under O
- O
the O
- O
serum O
- O
concentration O
- O
curve O
( O
nM O
- O
day O
) O
values O
for O
T4 O
at O
steady O
state O
in O
the O
dam O
and O
pup O
decreased O
by O
14 O
- O
15 O
% O
for O
the O
1 O
. O
2 O
micro O
g O
iodide B
/ O
day O
iodide B
- O
deficient O
diet O
and O
42 O
- O
52 O
% O
for O
the O
0 O
. O
31 O
micro O
g O
iodide B
/ O
day O
iodide B
- O
deficient O
diet O
. O

In O
rat O
pups O
that O
were O
iodide B
deficient O
during O
gestation O
and O
lactation O
, O
these O
decreases O
in O
serum O
T4 O
levels O
were O
associated O
with O
declines O
in O
thyroid O
hormone O
in O
the O
fetal O
brain O
and O
a O
suppression O
of O
synaptic O
responses O
in O
the O
hippocampal O
region O
of O
the O
brain O
of O
the O
adult O
offspring O
( O
Gilbert O
et O
al O
. O
, O
2013 O
) O
. O

Perspectives O
on O
the O
reaction O
force O
constant O
. O

A O
synchronous O
, O
concerted O
chemical O
process O
is O
rigorously O
divided O
by O
the O
reaction O
force O
F O
( O
R O
) O
, O
the O
negative O
gradient O
of O
V O
( O
R O
) O
, O
into O
" O
reactant O
" O
and O
" O
product O
" O
regions O
which O
are O
dominated O
by O
structural O
changes O
and O
an O
intervening O
" O
transition O
" O
region O
which O
is O
electronically O
intensive O
. O

The O
reaction O
force O
constant O
kappa O
( O
R O
) O
, O
the O
second O
derivative O
of O
V O
( O
R O
) O
, O
is O
negative O
throughout O
the O
transition O
region O
, O
not O
just O
at O
the O
nominal O
transition O
state O
, O
at O
which O
kappa O
( O
R O
) O
has O
a O
minimum O
. O

This O
is O
consistent O
with O
experimental O
evidence O
that O
there O
is O
a O
transition O
region O
, O
not O
simply O
a O
specific O
point O
. O

We O
show O
graphically O
that O
significant O
nonsynchronicity O
in O
the O
process O
is O
associated O
with O
the O
development O
of O
a O
maximum O
of O
kappa O
( O
R O
) O
in O
the O
transition O
region O
, O
which O
increases O
as O
the O
process O
becomes O
more O
nonsynchronous O
. O

( O
We O
speculate O
that O
for O
a O
nonconcerted O
process O
this O
maximum O
is O
actually O
positive O
. O
) O
Thus O
, O
kappa O
( O
R O
) O
can O
serve O
as O
an O
indicator O
of O
the O
level O
of O
nonsynchronicity O
. O

Inhibition O
of O
matrix O
metalloproteinase O
- O
9 O
expression O
by O
docosahexaenoic B
acid I
mediated O
by O
heme B
oxygenase O
1 O
in O
12 B
- I
O I
- I
tetradecanoylphorbol I
- I
13 I
- I
acetate I
- O
induced O
MCF O
- O
7 O
human O
breast O
cancer O
cells O
. O

Matrix O
metalloproteinase O
- O
9 O
( O
MMP O
- O
9 O
) O
plays O
a O
crucial O
role O
in O
tumor O
metastasis O
. O

Previous O
studies O
showed O
that O
polyunsaturated B
fatty I
acids I
exhibit O
an O
anti O
- O
cancer O
effect O
in O
various O
human O
carcinoma O
cells O
, O
but O
the O
effect O
of O
docosahexaenoic B
acid I
( O
DHA B
) O
and O
linoleic B
acid I
( O
LA O
) O
on O
metastasis O
of O
breast O
cancer O
cells O
is O
not O
fully O
clarified O
. O

We O
studied O
the O
anti O
- O
metastasis O
potential O
of O
DHA B
and O
LA O
in O
12 B
- I
O I
- I
tetradecanoylphorbol I
- I
13 I
- I
acetate I
( O
TPA B
) O
- O
induced O
MCF O
- O
7 O
cells O
. O

We O
found O
that O
TPA O
( O
100 O
ng O
/ O
ml O
) O
induced O
MMP O
- O
9 O
enzyme O
activity O
both O
dose O
- O
and O
time O
- O
dependently O
, O
and O
200 O
mu O
M O
DHA B
and O
LA O
significantly O
inhibited O
MMP O
- O
9 O
mRNA O
and O
protein O
expression O
, O
enzyme O
activity O
, O
cell O
migration O
, O
and O
invasion O
. O

Treatment O
with O
PD98059 B
( O
10 O
mu O
M O
) O
, O
wortmannin B
( O
10 O
mu O
M O
) O
, O
and O
GF109203X B
( O
0 O
. O
5 O
mu O
M O
) O
decreased O
TPA O
- O
induced O
MMP O
- O
9 O
protein O
expression O
and O
enzyme O
activity O
. O

TPA O
- O
induced O
activation O
of O
ERK1 O
, O
Akt O
, O
and O
PKC O
delta O
was O
attenuated O
by O
DHA B
, O
whereas O
LA O
attenuated O
only O
ERK1 O
activation O
. O

GF109203X B
also O
suppressed O
ERK1 O
activation O
. O

EMSA O
showed O
that O
DHA B
, O
LA O
, O
PD98059 B
, O
and O
wortmannin B
decreased O
TPA O
- O
induced O
NF O
- O
kappa O
B O
and O
AP O
- O
1 O
DNA O
- O
binding O
activity O
. O

Furthermore O
, O
DHA B
rather O
than O
LA O
dose O
- O
dependently O
increased O
HO O
- O
1 O
expression O
. O

HO O
- O
1 O
siRNA O
alleviated O
the O
inhibition O
by O
DHA B
of O
TPA O
- O
induced O
MMP O
- O
9 O
protein O
expression O
and O
enzyme O
activity O
in O
MCF O
- O
7 O
cells O
, O
and O
HO O
- O
1 O
knockdown O
reversed O
the O
DHA B
inhibition O
of O
cell O
migration O
. O

These O
results O
suggest O
that O
DHA B
and O
LA O
have O
both O
similar O
and O
divergent O
signaling O
pathways O
in O
the O
suppression O
of O
TPA O
- O
induced O
MCF O
- O
7 O
metastasis O
. O

Calculation O
of O
wave O
- O
functions O
with O
frozen O
orbitals O
in O
mixed O
quantum O
mechanics O
/ O
molecular O
mechanics O
methods O
. O

II O
. O

Application O
of O
the O
local O
basis O
equation O
. O

The O
application O
of O
the O
local O
basis O
equation O
( O
Ferenczy O
and O
Adams O
, O
J O
. O
Chem O
. O
Phys O
. O
2009 O
, O
130 O
, O
134108 O
) O
in O
mixed O
quantum O
mechanics O
/ O
molecular O
mechanics O
( O
QM O
/ O
MM O
) O
and O
quantum O
mechanics O
/ O
quantum O
mechanics O
( O
QM O
/ O
QM O
) O
methods O
is O
investigated O
. O

This O
equation O
is O
suitable O
to O
derive O
local O
basis O
nonorthogonal O
orbitals O
that O
minimize O
the O
energy O
of O
the O
system O
and O
it O
exhibits O
good O
convergence O
properties O
in O
a O
self O
- O
consistent O
field O
solution O
. O

These O
features O
make O
the O
equation O
appropriate O
to O
be O
used O
in O
mixed O
QM O
/ O
MM O
and O
QM O
/ O
QM O
methods O
to O
optimize O
orbitals O
in O
the O
field O
of O
frozen O
localized O
orbitals O
connecting O
the O
subsystems O
. O

Calculations O
performed O
for O
several O
properties O
in O
divers O
systems O
show O
that O
the O
method O
is O
robust O
with O
various O
choices O
of O
the O
frozen O
orbitals O
and O
frontier O
atom O
properties O
. O

With O
appropriate O
basis O
set O
assignment O
, O
it O
gives O
results O
equivalent O
with O
those O
of O
a O
related O
approach O
[ O
G O
. O
G O
. O
Ferenczy O
previous O
paper O
in O
this O
issue O
] O
using O
the O
Huzinaga O
equation O
. O

Thus O
, O
the O
local O
basis O
equation O
can O
be O
used O
in O
mixed O
QM O
/ O
MM O
methods O
with O
small O
size O
quantum O
subsystems O
to O
calculate O
properties O
in O
good O
agreement O
with O
reference O
Hartree O
- O
Fock O
- O
Roothaan O
results O
. O

It O
is O
shown O
that O
bond O
charges O
are O
not O
necessary O
when O
the O
local O
basis O
equation O
is O
applied O
, O
although O
they O
are O
required O
for O
the O
self O
- O
consistent O
field O
solution O
of O
the O
Huzinaga O
equation O
based O
method O
. O

Conversely O
, O
the O
deformation O
of O
the O
wave O
- O
function O
near O
to O
the O
boundary O
is O
observed O
without O
bond O
charges O
and O
this O
has O
a O
significant O
effect O
on O
deprotonation O
energies O
but O
a O
less O
pronounced O
effect O
when O
the O
total O
charge O
of O
the O
system O
is O
conserved O
. O

The O
local O
basis O
equation O
can O
also O
be O
used O
to O
define O
a O
two O
layer O
quantum O
system O
with O
nonorthogonal O
localized O
orbitals O
surrounding O
the O
central O
delocalized O
quantum O
subsystem O
. O

Materials O
for O
the O
active O
layer O
of O
organic O
photovoltaics O
: O
ternary O
solar O
cell O
approach O
. O

Power O
conversion O
efficiencies O
in O
excess O
of O
7 O
% O
have O
been O
achieved O
with O
bulk O
heterojunction O
( O
BHJ O
) O
- O
type O
organic O
solar O
cells O
using O
two O
components O
: O
p O
- O
and O
n O
- O
doped O
materials O
. O

The O
energy O
level O
and O
absorption O
profile O
of O
the O
active O
layer O
can O
be O
tuned O
by O
introduction O
of O
an O
additional O
component O
. O

Careful O
design O
of O
the O
additional O
component O
is O
required O
to O
achieve O
optimal O
panchromatic O
absorption O
, O
suitable O
energy O
- O
level O
offset O
, O
balanced O
electron O
and O
hole O
mobility O
, O
and O
good O
light O
- O
harvesting O
efficiency O
. O

This O
article O
reviews O
the O
recent O
progress O
on O
ternary O
organic O
photovoltaic O
systems O
, O
including O
polymer O
/ O
small O
molecule O
/ O
functional O
fullerene B
, O
polymer O
/ O
polymer O
/ O
functional O
fullerene B
, O
small O
molecule O
/ O
small O
molecule O
/ O
functional O
fullerene B
, O
polymer O
/ O
functional O
fullerene B
I O
/ O
functional O
fullerene B
II O
, O
and O
polymer O
/ O
quantum O
dot O
or O
metal O
/ O
functional O
fullerene B
systems O
. O

Cell O
wounding O
activates O
phospholipase O
D O
in O
primary O
mouse O
keratinocytes O
. O

Plasma O
membrane O
disruptions O
occur O
in O
mechanically O
active O
tissues O
such O
as O
the O
epidermis O
and O
can O
lead O
to O
cell O
death O
if O
the O
damage O
remains O
unrepaired O
. O

Repair O
occurs O
through O
fusion O
of O
vesicle O
patches O
to O
the O
damaged O
membrane O
region O
. O

The O
enzyme O
phospholipase O
D O
( O
PLD O
) O
is O
involved O
in O
membrane O
traffickiing O
; O
therefore O
, O
the O
role O
of O
PLD O
in O
membrane O
repair O
was O
investigated O
. O

Generation O
of O
membrane O
disruptions O
by O
lifting O
epidermal O
keratinocytes O
from O
the O
substratum O
induced O
PLD O
activation O
, O
whereas O
removal O
of O
cells O
from O
the O
substratum O
via O
trypsinization O
had O
no O
effect O
. O

Pretreatment O
with O
1 B
, I
25 I
- I
dihydroxyvitamin I
D I
3 I
, O
previously O
shown O
to O
increase O
PLD1 O
expression O
and O
activity O
, O
had O
no O
effect O
on O
, O
and O
a O
PLD2 O
- O
selective O
( O
but O
not O
a O
PLD1 O
- O
selective O
) O
inhibitor O
decreased O
, O
cell O
lifting O
- O
induced O
PLD O
activation O
, O
suggesting O
PLD2 O
as O
the O
isoform O
activated O
. O

PLD2 O
interacts O
functionally O
with O
the O
glycerol B
channel O
aquaporin O
- O
3 O
( O
AQP3 O
) O
to O
produce O
phosphatidylglycerol B
( O
PG O
) O
; O
however O
, O
wounding O
resulted O
in O
decreased O
PG O
production O
, O
suggesting O
a O
potential O
PG O
deficiency O
in O
wounded O
cells O
. O

Cell O
lifting O
- O
induced O
PLD O
activation O
was O
transient O
, O
consistent O
with O
a O
possible O
role O
in O
membrane O
repair O
, O
and O
PLD O
inhibitors O
inhibited O
membrane O
resealing O
upon O
laser O
injury O
. O

In O
an O
in O
vivo O
full O
- O
thickness O
mouse O
skin O
wound O
model O
, O
PG O
accelerated O
wound O
healing O
. O

These O
results O
suggest O
that O
PLD O
and O
the O
PLD2 O
/ O
AQP3 O
signaling O
module O
may O
be O
involved O
in O
membrane O
repair O
and O
wound O
healing O
. O

Bone O
marrow O
NR4A O
expression O
is O
not O
a O
dominant O
factor O
in O
the O
development O
of O
atherosclerosis O
or O
macrophage O
polarization O
in O
mice O
. O

The O
formation O
of O
the O
atherosclerotic O
lesion O
is O
a O
complex O
process O
influenced O
by O
an O
array O
of O
inflammatory O
and O
lipid O
metabolism O
pathways O
. O

We O
previously O
demonstrated O
that O
NR4A O
nuclear O
receptors O
are O
highly O
induced O
in O
macrophages O
in O
response O
to O
inflammatory O
stimuli O
and O
modulate O
the O
expression O
of O
genes O
linked O
to O
inflammation O
in O
vitro O
. O

Here O
we O
used O
mouse O
genetic O
models O
to O
assess O
the O
impact O
of O
NR4A O
expression O
on O
atherosclerosis O
development O
and O
macrophage O
polarization O
. O

Transplantation O
of O
wild O
- O
type O
, O
Nur77 O
- O
/ O
- O
, O
or O
Nor1 O
- O
/ O
- O
null O
hematopoetic O
precursors O
into O
LDL O
receptor O
( O
LDLR O
) O
- O
/ O
- O
recipient O
mice O
led O
to O
comparable O
development O
of O
atherosclerotic O
lesions O
after O
high O
- O
cholesterol B
diet O
. O

We O
also O
observed O
comparable O
induction O
of O
genes O
linked O
to O
M1 O
and O
M2 O
responses O
in O
wild O
- O
type O
and O
Nur77 O
- O
null O
macrophages O
in O
response O
to O
lipopolysaccharides O
and O
interleukin O
( O
IL O
) O
- O
4 O
, O
respectively O
. O

In O
contrast O
, O
activation O
of O
the O
nuclear O
receptor O
liver O
X O
receptor O
( O
LXR O
) O
strongly O
suppressed O
M1 O
responses O
, O
and O
ablation O
of O
signal O
transductor O
and O
activator O
of O
transcription O
6 O
( O
STAT6 O
) O
strongly O
suppressed O
M2 O
responses O
. O

Recent O
studies O
have O
suggested O
that O
alterations O
in O
levels O
of O
Ly6C O
( O
lo O
) O
monocytes O
may O
be O
a O
contributor O
to O
inflammation O
and O
atherosclerosis O
. O

In O
our O
study O
, O
loss O
of O
Nur77 O
, O
but O
not O
Nor1 O
, O
was O
associated O
with O
decreased O
abundance O
of O
Ly6C O
( O
lo O
) O
monocytes O
, O
but O
this O
change O
was O
not O
correlated O
with O
atherosclerotic O
lesion O
development O
. O

Collectively O
, O
our O
results O
suggest O
that O
alterations O
in O
the O
Ly6C O
( O
lo O
) O
monocyte O
population O
and O
bone O
marrow O
NR4A O
expression O
do O
not O
play O
dominant O
roles O
in O
macrophage O
polarization O
or O
the O
development O
of O
atherosclerosis O
in O
mice O
. O

Visualizing O
the O
perturbation O
of O
cellular O
cyclic B
di I
- I
GMP I
levels O
in O
bacterial O
cells O
. O

Cyclic B
di I
- I
GMP I
( O
c B
- I
di I
- I
GMP I
) O
has O
emerged O
as O
a O
prominent O
intracellular O
messenger O
that O
coordinates O
biofilm O
formation O
and O
pathogenicity O
in O
many O
bacterial O
species O
. O

Developing O
genetically O
encoded O
biosensors O
for O
c B
- I
di I
- I
GMP I
will O
help O
us O
understand O
how O
bacterial O
cells O
respond O
to O
environmental O
changes O
via O
the O
modulation O
of O
cellular O
c B
- I
di I
- I
GMP I
levels O
. O

Here O
we O
report O
the O
design O
of O
two O
genetically O
encoded O
c B
- I
di I
- I
GMP I
fluorescent O
biosensors O
with O
complementary O
dynamic O
ranges O
. O

By O
using O
the O
biosensors O
, O
we O
found O
that O
several O
compounds O
known O
to O
promote O
biofilm O
dispersal O
trigger O
a O
decline O
in O
c B
- I
di I
- I
GMP I
levels O
in O
Escherichia O
coli O
cells O
. O

In O
contrast O
, O
cellular O
c B
- I
di I
- I
GMP I
levels O
were O
elevated O
when O
the O
bacterial O
cells O
were O
treated O
with O
subinhibitory O
concentrations O
of O
biofilm O
- O
promoting O
antibiotics O
. O

The O
biosensors O
also O
revealed O
that O
E O
. O
coli O
cells O
engulfed O
by O
macrophages O
exhibit O
lower O
c B
- I
di I
- I
GMP I
levels O
, O
most O
likely O
as O
a O
response O
to O
the O
enormous O
pressures O
of O
survival O
during O
phagocytosis O
. O

On O
the O
azo B
/ O
hydrazo B
equilibrium O
in O
Sudan B
I I
azo B
dye O
derivatives O
. O

In O
this O
study O
, O
Raman O
, O
infrared O
, O
UV O
/ O
vis O
, O
NMR O
, O
and O
single O
crystal O
X O
- O
ray O
diffraction O
spectroscopies O
are O
used O
to O
elucidate O
the O
tautomeric O
equilibrium O
of O
azo B
dyes O
derived O
from O
1 B
- I
phenyl I
- I
azo I
- I
2 I
- I
naphthol I
( O
Sudan B
I I
) O
. O

A O
new O
crystallographic O
structure O
is O
described O
for O
Sudan B
I I
, O
revealing O
the O
presence O
of O
intramolecular O
hydrogen B
bonds O
and O
supramolecular O
interactions O
, O
such O
as O
the O
unconventional O
C B
- I
H I
. O
. O
. O
O B
hydrogen B
bond O
type O
, O
pi O
- O
stacking O
, O
and O
charge O
- O
dipole O
interactions O
. O

All O
of O
these O
weak O
intermolecular O
interactions O
play O
a O
role O
in O
the O
stability O
of O
the O
crystalline O
structure O
. O

Theoretical O
calculations O
are O
also O
reported O
for O
geometries O
, O
energy O
, O
and O
spectroscopic O
properties O
. O

The O
predicted O
spectra O
are O
in O
accordance O
with O
the O
experiments O
carried O
out O
in O
the O
solid O
state O
and O
in O
solution O
of O
dichloromethane B
, O
carbon B
tetrachloride I
, O
and O
chloroform B
, O
suggesting O
the O
hydrazo B
form O
as O
the O
preferable O
tautomer O
in O
gas O
and O
condensate O
phases O
for O
Sudan B
I I
and O
its O
derivatives O
. O

Stereoselective O
Rh2 B
( I
S I
- I
IBAZ I
) I
4 I
- O
catalyzed O
cyclopropanation O
of O
alkenes B
, O
alkynes B
, O
and O
allenes B
: O
asymmetric O
synthesis O
of O
diacceptor O
cyclopropylphosphona B
and O
alkylidenecyclopropa B
. O

A O
mild O
and O
highly O
stereoselective O
rhodium B
( I
II I
) I
- O
catalyzed O
cyclopropanation O
of O
alkenes B
, O
alkynes B
, O
and O
allenes B
with O
diacceptor O
diazo B
compounds O
is O
reported O
. O

Using O
the O
phosphonate B
moiety O
as O
an O
efficient O
trans O
- O
directing O
group O
, O
the O
first O
catalytic O
asymmetric O
route O
to O
diacceptor O
cycloprop B
( I
en I
) I
ylphosphonates I
was O
developed O
by O
employing O
an O
alpha B
- I
cyano I
diazophosphonate I
and O
Rh B
( I
2 I
) I
( I
S I
- I
IBAZ I
) I
( I
4 I
) I
as O
chiral O
catalyst O
. O

The O
isosteric O
character O
of O
phosphonic B
and I
carboxylic I
acid I
derivatives O
allowed O
the O
alternative O
use O
of O
an O
alpha B
- I
cyano I
diazo I
ester I
in O
the O
process O
, O
leading O
to O
alpha B
- I
cyano I
cycloprop I
( I
en I
) I
ylcarboxylates I
in O
high O
yields O
and O
stereoselectivities O
. O

Taking O
advantage O
of O
the O
particular O
reactivity O
of O
the O
cyanocarbene B
intermediates O
involved O
in O
this O
system O
, O
the O
scope O
of O
compatible O
substrates O
could O
be O
extended O
to O
substituted O
allenes B
, O
leading O
to O
the O
development O
of O
the O
first O
catalytic O
enantioselective O
method O
for O
the O
synthesis O
of O
diacceptor O
alkylidenecyclopropa B
. O

Discovery O
of O
thiazolidine B
- I
2 I
, I
4 I
- I
dione I
/ O
biphenylcarbonitrile B
hybrid O
as O
dual O
PPAR O
alpha O
/ O
gamma O
modulator O
with O
antidiabetic O
effect O
: O
in O
vitro O
, O
in O
silico O
and O
in O
vivo O
approaches O
. O

A O
small O
series O
of O
thiazolidine B
- I
2 I
, I
4 I
- I
dione I
and O
barbituric B
acid I
derivatives O
1 O
- O
4 O
was O
prepared O
using O
a O
short O
synthetic O
route O
, O
and O
all O
compounds O
were O
characterized O
by O
elemental O
analysis O
, O
mass O
spectrometry O
, O
and O
NMR O
( O
( B
1 I
) I
H I
, O
( B
13 I
) I
C I
) O
spectroscopy O
. O

Their O
in O
vitro O
relative O
expression O
of O
peroxisome O
proliferator O
- O
activated O
receptor O
alpha O
and O
peroxisome O
proliferator O
- O
activated O
receptor O
gamma O
was O
evaluated O
. O

Compound O
1 O
showed O
an O
increase O
in O
the O
mRNA O
expression O
of O
both O
peroxisome O
proliferator O
- O
activated O
receptor O
isoforms O
, O
as O
well O
as O
the O
GLUT O
- O
4 O
levels O
. O

The O
antidiabetic O
activity O
of O
compound O
1 O
was O
determined O
at O
50 O
mg O
/ O
kg O
single O
dose O
using O
a O
non O
- O
insulin O
- O
dependent O
diabetes O
mellitus O
rat O
model O
. O

The O
results O
indicated O
a O
significant O
decrease O
in O
plasma O
glucose B
levels O
. O

Additionally O
, O
we O
performed O
a O
molecular O
docking O
of O
compound O
1 O
into O
the O
ligand O
binding O
pocket O
of O
peroxisome O
proliferator O
- O
activated O
receptor O
alpha O
and O
peroxisome O
proliferator O
- O
activated O
receptor O
gamma O
. O

In O
these O
binding O
models O
, O
compound O
1 O
may O
bind O
into O
the O
active O
site O
of O
both O
isoforms O
showing O
important O
short O
contacts O
with O
the O
peroxisome O
proliferator O
- O
activated O
receptor O
gamma O
residues O
: O
Tyr B
473 O
, O
His B
449 O
, O
Ser B
289 O
, O
His B
323 O
; O
and O
peroxisome O
proliferator O
- O
activated O
receptor O
alpha O
residues O
: O
Tyr B
464 O
, O
His B
440 O
, O
Ser B
280 O
and O
Tyr B
314 O
. O

Anti O
- O
diabetic O
property O
of O
Tinospora O
cordifolia O
and O
its O
active O
compound O
is O
mediated O
through O
the O
expression O
of O
Glut O
- O
4 O
in O
L6 O
myotubes O
. O

Tinospora O
cordifolia O
is O
a O
well O
reported O
plant O
possessing O
numerous O
medicinal O
values O
including O
anti O
- O
diabetic O
property O
. O

Aim O
of O
the O
present O
study O
is O
to O
study O
the O
mechanism O
of O
action O
of O
Tinospora O
cordifolia O
and O
its O
active O
compound O
in O
differentiated O
myocytes O
, O
L6 O
cells O
. O

Key O
marker O
of O
diabetes O
in O
cells O
is O
the O
insulin O
dependent O
glucose B
transporter O
- O
4 O
( O
Glut O
- O
4 O
) O
which O
also O
responds O
to O
exogenous O
chemicals O
, O
and O
is O
over O
expressed O
up O
to O
5 O
- O
and O
4 O
- O
fold O
, O
by O
Tinospora O
cordifolia O
and O
palmatine O
, O
respectively O
. O

Next O
to O
Glut O
- O
4 O
, O
the O
predominant O
protein O
influencing O
glucose B
metabolism O
is O
PPAR O
alpha O
and O
gamma O
whose O
expressions O
were O
also O
positively O
modulated O
. O

Further O
, O
the O
inhibitors O
of O
insulin O
pathway O
prevented O
glucose B
uptake O
mediated O
by O
Tinospora O
cordifolia O
and O
palmatine O
which O
shows O
that O
the O
activity O
is O
majorly O
mediated O
through O
insulin O
pathway O
. O

Dissolution O
of O
tablet O
- O
in O
- O
tablet O
formulations O
studied O
with O
ATR O
- O
FTIR O
spectroscopic O
imaging O
. O

This O
work O
uses O
ATR O
- O
FTIR O
spectroscopic O
imaging O
to O
study O
the O
dissolution O
of O
delayed O
release O
and O
pH O
resistant O
compressed O
coating O
pharmaceutical O
tablets O
. O

Tablets O
with O
an O
inner O
core O
and O
outer O
shell O
were O
constructed O
using O
a O
custom O
designed O
compaction O
cell O
. O

The O
core O
of O
the O
delayed O
release O
tablets O
consisted O
of O
hydroxypropyl B
methylcellulose O
( O
HPMC O
) O
and O
caffeine B
. O

The O
shell O
consisted O
of O
microcrystalline O
cellulose O
( O
MCC O
) O
and O
glucose B
. O

The O
core O
of O
the O
pH O
resistant O
formulations O
was O
an O
ibuprofen B
and O
PEG B
melt O
and O
the O
shell O
was O
constructed O
from O
HPMC O
and O
a O
basic O
buffer O
. O

UV O
/ O
vis O
spectroscopy O
was O
used O
to O
monitor O
the O
lag O
- O
time O
of O
drug O
release O
and O
visible O
optical O
video O
imaging O
was O
used O
as O
a O
complementary O
imaging O
technique O
with O
a O
larger O
field O
of O
view O
. O

Two O
delayed O
release O
mechanisms O
were O
established O
. O

For O
tablets O
with O
soluble O
shell O
sections O
, O
lag O
- O
time O
was O
dependent O
upon O
rapid O
shell O
dissolution O
. O

For O
tablets O
with O
less O
soluble O
shells O
, O
the O
lag O
- O
time O
was O
controlled O
by O
the O
rate O
of O
dissolution O
medium O
ingress O
through O
the O
shell O
and O
the O
subsequent O
expansion O
of O
the O
wet O
HPMC O
core O
. O

The O
pH O
resistant O
formulations O
prevented O
crystallization O
of O
the O
ibuprofen B
in O
the O
core O
during O
dissolution O
despite O
an O
acidic O
dissolution O
medium O
. O

FTIR O
imaging O
produced O
important O
information O
about O
the O
physical O
and O
chemical O
processes O
occurring O
at O
the O
interface O
between O
tablet O
sections O
during O
dissolution O
. O

Study O
of O
the O
recrystallization O
in O
coated O
pellets O
- O
Effect O
of O
coating O
on O
API O
crystallinity O
. O

Coated O
diltiazem B
hydrochloride I
- O
containing O
pellets O
were O
prepared O
using O
the O
solution O
layering O
technique O
. O

Unusual O
thermal O
behavior O
was O
detected O
with O
differential O
scanning O
calorimetry O
( O
DSC O
) O
and O
its O
source O
was O
determined O
using O
thermogravimetry O
( O
TG O
) O
, O
X O
- O
ray O
powder O
diffraction O
( O
XRPD O
) O
and O
hot O
- O
stage O
microscopy O
. O

The O
coated O
pellets O
contained O
diltiazem B
hydrochloride I
both O
in O
crystalline O
and O
amorphous O
form O
. O

Crystallization O
occurs O
on O
heat O
treatment O
causing O
an O
exothermic O
peak O
on O
the O
DSC O
curves O
that O
only O
appears O
in O
pellets O
containing O
both O
diltiazem B
hydrochloride I
and O
the O
coating O
. O

Results O
indicate O
that O
the O
amorphous O
fraction O
is O
situated O
in O
the O
coating O
layer O
. O

The O
migration O
of O
drugs O
into O
the O
coating O
layer O
can O
cause O
changes O
in O
its O
degree O
of O
crystallinity O
. O

Polymeric O
coating O
materials O
should O
therefore O
be O
investigated O
as O
possible O
crystallization O
inhibitors O
. O

Substituted O
phenyl B
groups O
improve O
the O
pharmacokinetic O
profile O
and O
anti O
- O
inflammatory O
effect O
of O
urea B
- O
based O
soluble O
epoxide B
hydrolase O
inhibitors O
in O
murine O
models O
. O

Soluble O
epoxide B
hydrolase O
inhibitors O
( O
sEHIs O
) O
are O
anti O
- O
inflammatory O
, O
analgesic O
, O
anti O
- O
hypertensive O
, O
cardio O
- O
and O
renal O
- O
protective O
in O
multiple O
animal O
models O
. O

However O
, O
the O
earlier O
adamantyl B
- O
containing O
urea B
- O
based O
inhibitors O
are O
rapidly O
metabolized O
. O

Therefore O
, O
new O
potent O
inhibitors O
with O
the O
adamantyl B
group O
replaced O
by O
a O
substituted O
phenyl B
group O
were O
synthesized O
to O
presumptively O
offer O
better O
pharmacokinetic O
( O
PK O
) O
properties O
. O

Here O
we O
describe O
the O
improved O
PK O
profile O
of O
these O
inhibitors O
and O
the O
anti O
- O
inflammatory O
effect O
of O
the O
most O
promising O
one O
in O
a O
murine O
model O
. O

The O
PK O
profiles O
of O
inhibitors O
were O
determined O
following O
p O
. O
o O
. O
administration O
and O
serial O
bleeding O
in O
mice O
. O

The O
anti O
- O
inflammatory O
effect O
of O
1 B
- I
trifluoromethoxyphen I
- I
3 I
- I
( I
1 I
- I
propionylpiperidin I
- I
4 I
- I
yl I
) I
urea I
( O
TPPU B
) O
, O
the O
most O
promising O
inhibitor O
among O
the O
five O
sEHIs B
tested O
, O
was O
investigated O
in O
a O
lipopolysaccharide O
( O
LPS O
) O
- O
challenged O
murine O
model O
. O

The O
earlier O
broadly O
- O
used O
adamantyl B
- O
containing O
sEHI O
, O
trans B
- I
4 I
- I
[ I
4 I
- I
( I
3 I
- I
adamantan I
- I
1 I
- I
yl I
- I
ureido I
) I
- I
cyclohexyloxy I
] I
- I
benzoic I
acid I
( O
t B
- I
AUCB I
) O
, O
was O
used O
for O
comparison O
. O

Compared O
with O
the O
earlier O
adamantyl B
- O
containing O
urea B
- O
based O
inhibitors O
, O
substituted O
phenyl B
- O
containing O
urea B
- O
based O
inhibitors O
afford O
more O
favorable O
PK O
properties O
, O
such O
as O
higher O
Cmaxs O
, O
larger O
AUCs O
and O
longer O
t1 O
/ O
2s O
, O
which O
, O
as O
expected O
, O
show O
more O
stable O
metabolic O
stability O
. O

Moreover O
, O
oral O
administration O
of O
TPPU B
dramatically O
reversed O
the O
shifts O
caused O
by O
LPS O
- O
challenge O
in O
plasma O
levels O
of O
inflammatory O
cytokines O
, O
epoxides B
and O
corresponding O
diols B
, O
which O
is O
more O
potent O
than O
t B
- I
AUCB I
. O

The O
substituted O
phenyl B
- O
containing O
sEHIs B
are O
more O
metabolically O
stable O
than O
those O
with O
adamantyl B
group O
, O
resulting O
in O
more O
potent O
efficacy O
in O
vivo O
. O

This O
indicates O
a O
new O
strategy O
for O
development O
of O
sEHIs O
for O
further O
study O
toward O
clinical O
trials O
. O

The O
oral O
cavity O
as O
a O
biological O
barrier O
system O
: O
Design O
of O
an O
advanced O
buccal O
in O
vitro O
permeability O
model O
. O

An O
important O
area O
for O
future O
research O
lies O
in O
finding O
a O
drug O
delivery O
system O
across O
or O
into O
the O
oral O
mucosa O
. O

However O
, O
to O
design O
such O
systems O
, O
simplified O
biological O
models O
are O
necessary O
so O
that O
the O
mechanisms O
and O
/ O
or O
interactions O
of O
interest O
can O
readily O
be O
studied O
. O

The O
oral O
epithelium O
is O
covered O
by O
a O
complex O
mucus O
layer O
, O
which O
enables O
exchange O
of O
nutrients O
and O
provides O
lubrication O
. O

However O
, O
it O
has O
been O
demonstrated O
that O
mucus O
has O
an O
impact O
on O
the O
mobility O
of O
nanoparticles O
and O
drug O
molecules O
. O

Thus O
, O
we O
aimed O
to O
develop O
an O
advanced O
buccal O
in O
vitro O
model O
for O
studying O
transport O
of O
nanoparticles O
, O
taking O
the O
mucus O
layer O
into O
account O
. O

First O
, O
animal O
mucins O
( O
porcine O
gastric O
, O
bovine O
submaxillary O
) O
were O
compared O
with O
natural O
human O
mucin O
regarding O
chemical O
and O
morphological O
structure O
. O

Second O
, O
an O
" O
external O
" O
mucus O
layer O
was O
prepared O
by O
a O
film O
method O
and O
deposited O
onto O
an O
oral O
cell O
line O
( O
TR O
146 O
) O
, O
cultured O
on O
transwells O
( O
R O
) O
. O

Adherence O
of O
the O
mucin O
fibers O
was O
evaluated O
and O
the O
viability O
of O
the O
model O
was O
assessed O
. O

Nanoparticle O
transport O
studies O
were O
performed O
with O
this O
advanced O
in O
vitro O
model O
and O
an O
ex O
vivo O
diffusion O
system O
. O

The O
results O
revealed O
that O
porcine O
mucin O
is O
most O
similar O
to O
human O
natural O
mucin O
in O
chemical O
structure O
and O
morphology O
. O

Both O
the O
bovine O
and O
porcine O
mucin O
fibers O
adhered O
onto O
the O
oral O
cells O
: O
Due O
to O
the O
different O
morphology O
of O
bovine O
mucin O
, O
the O
viability O
of O
the O
oral O
cells O
decreased O
, O
whereas O
porcine O
mucin O
maintained O
the O
viability O
of O
the O
model O
for O
more O
than O
48h O
. O

Comparison O
of O
in O
vitro O
data O
with O
ex O
vivo O
data O
suggested O
reliability O
of O
the O
advanced O
buccal O
in O
vitro O
model O
. O

Additionally O
, O
it O
was O
demonstrated O
that O
the O
mucus O
layer O
in O
the O
oral O
cavity O
also O
acts O
as O
a O
strong O
barrier O
for O
the O
mobility O
of O
nanoparticles O
. O

Antioxidant O
activities O
of O
thiosemicarbazones B
from O
substituted O
benzaldehydes B
and O
N B
- I
( I
tetra I
- I
O I
- I
acetyl I
- I
beta I
- I
D I
- I
galactopyranosyl I
) I
thiosemicarbazide I
. O

Reaction O
of O
N B
- I
( I
2 I
, I
3 I
, I
4 I
, I
6 I
- I
tetra I
- I
O I
- I
acetyl I
- I
beta I
- I
d I
- I
galactopyranosyl I
) I
thiosemicarbazide I
and O
different O
substituted O
benzaldehydes B
gave O
some O
new O
substituted O
benzaldehyde B
N I
- I
( I
2 I
, I
3 I
, I
4 I
, I
6 I
- I
tetra I
- I
O I
- I
acetyl I
- I
beta I
- I
d I
- I
galactopyranosyl I
) I
thiosemicarbazones I
. O

The O
reaction O
was O
performed O
using O
conventional O
and O
microwave O
- O
assisted O
heating O
methods O
. O

The O
structures O
of O
thiosemicarbazones B
were O
confirmed O
by O
spectroscopic O
( O
IR O
, O
( B
1 I
) I
H I
NMR O
, O
( B
13 I
) I
C I
NMR O
and O
ESI O
- O
MS O
) O
method O
. O

The O
antioxidant O
activity O
of O
these O
thiosemicarbazones B
was O
evaluated O
in O
vitro O
and O
in O
vivo O
, O
and O
it O
' O
s O
shown O
that O
some O
of O
these O
compounds O
had O
significant O
antioxidant O
activity O
. O

Amongst O
the O
compounds O
screened O
for O
antioxidant O
activity O
, O
thiosemicarbazones B
4a O
, O
4b O
and O
4c O
showed O
good O
antioxidant O
activity O
on O
DPPH B
. O

The O
compounds O
4g O
, O
4i O
, O
4l O
caused O
significant O
elevation O
of O
SOD O
activity O
and O
4e O
, O
4g O
, O
4i O
, O
4l O
had O
higher O
catalase O
activity O
, O
and O
only O
compounds O
4c O
and O
4f O
expressed O
the O
GSH B
- O
Px O
activity O
. O

Cerebral O
and O
extracerebral O
cholesterol B
metabolism O
and O
CSF O
markers O
of O
Alzheimer O
' O
s O
disease O
. O

The O
disturbances O
of O
the O
cholesterol B
synthesis O
and O
metabolism O
described O
in O
Alzheimer O
' O
s O
disease O
( O
AD O
) O
may O
be O
both O
a O
consequence O
of O
the O
neurodegenerative O
process O
and O
a O
contributor O
to O
the O
pathogenesis O
. O

These O
putative O
relationships O
and O
their O
underlying O
mechanisms O
are O
not O
well O
understood O
. O

The O
aim O
of O
this O
study O
was O
to O
evaluate O
the O
relationship O
between O
the O
cerebral O
and O
extracerebral O
cholesterol B
synthesis O
and O
metabolism O
, O
and O
the O
AD O
pathology O
as O
reflected O
by O
CSF O
markers O
in O
humans O
. O

We O
evaluated O
the O
relationships O
between O
the O
plasma O
and O
the O
cerebrospinal O
fluid O
( O
CSF O
) O
concentrations O
of O
cholesterol B
, O
the O
cholesterol B
precursors O
lanosterol B
, O
lathosterol B
and O
desmosterol B
, O
and O
the O
cholesterol B
elimination O
products O
24S B
- I
hydroxycholesterol I
and O
27 B
- I
hydroxycholesterol I
, O
and O
the O
CSF O
markers O
for O
AD O
pathology O
A O
beta O
1 O
- O
42 O
and O
p O
- O
tau181 O
in O
86 O
subjects O
with O
normal O
cognition O
and O
in O
107 O
AD O
patients O
. O

CSF O
desmosterol B
, O
cholesterol B
and O
24S B
- I
hydroxycholesterol I
in O
the O
AD O
group O
, O
and O
CSF O
24S B
- I
hydroxycholesterol I
in O
the O
control O
group O
correlated O
with O
the O
p O
- O
tau181 O
levels O
. O

Neither O
CSF O
nor O
plasma O
concentrations O
of O
the O
included O
compounds O
correlated O
with O
the O
CSF O
A O
beta O
1 O
- O
42 O
levels O
. O

In O
multivariate O
regression O
tests O
including O
age O
, O
gender O
, O
albumin O
ratio O
, O
number O
of O
the O
APOE O
epsilon O
4 O
alleles O
, O
and O
diagnosis O
, O
p O
- O
tau181 O
levels O
independently O
predicted O
the O
CSF O
desmosterol B
, O
cholesterol B
and O
24S B
- I
hydroxycholesterol I
concentrations O
. O

The O
associations O
remained O
significant O
for O
CSF O
cholesterol B
and O
24S B
- I
hydroxycholesterol I
when O
analyses O
were O
separately O
performed O
in O
the O
AD O
group O
. O

The O
results O
suggest O
that O
alterations O
of O
CNS O
cholesterol B
de O
novo O
genesis O
and O
metabolism O
are O
related O
to O
neurodegeneration O
and O
in O
particular O
to O
the O
cerebral O
accumulation O
of O
phosphorylated O
tau O
. O

Toxic O
effects O
of O
lead O
exposure O
in O
Wistar O
rats O
: O
involvement O
of O
oxidative O
stress O
and O
the O
beneficial O
role O
of O
edible O
jute O
( O
Corchorus O
olitorius O
) O
leaves O
. O

Lead O
( O
Pb B
) O
is O
considered O
to O
be O
a O
multi O
- O
target O
toxicant O
. O

The O
present O
study O
was O
undertaken O
to O
evaluate O
the O
protective O
effect O
of O
aqueous O
extract O
of O
Corchorus O
olitorius O
leaves O
against O
Pb B
- I
acetate I
induced O
toxic O
manifestation O
in O
blood O
, O
liver O
, O
kidney O
, O
brain O
and O
heart O
of O
Wistar O
rats O
. O

The O
Pb B
- I
acetate I
( O
5mg O
/ O
kg O
body O
weight O
) O
treated O
rats O
exhibited O
a O
significant O
inhibition O
of O
co O
- O
enzymes O
Q O
, O
antioxidant O
enzymes O
and O
reduced B
glutathione I
levels O
in O
the O
tissues O
. O

In O
addition O
, O
the O
extent O
of O
lipid O
peroxidation O
, O
DNA O
fragmentation O
and O
haematological O
parameters O
were O
significantly O
altered O
in O
the O
Pb B
- I
acetate I
treated O
rats O
as O
compared O
to O
control O
. O

Simultaneous O
administration O
of O
test O
extract O
( O
25 O
, O
50 O
and O
100mg O
/ O
kg O
body O
weight O
) O
, O
could O
significantly O
restore O
the O
biochemical O
and O
haematological O
parameters O
near O
to O
the O
normal O
status O
through O
antioxidant O
activity O
and O
/ O
or O
by O
preventing O
bioaccumulation O
of O
Pb B
within O
the O
tissues O
of O
experimental O
rats O
. O

Presence O
of O
substantial O
quantity O
of O
phenolics B
and O
flavonoids B
in O
the O
extract O
may O
be O
responsible O
for O
the O
observed O
protective O
role O
against O
Pb B
- O
intoxication O
. O

Chemical O
composition O
and O
anticancer O
activity O
of O
essential O
oils O
of O
Mediterranean O
sage O
( O
Salvia O
officinalis O
L O
. O
) O
grown O
in O
different O
environmental O
conditions O
. O

Salvia O
officinalis O
L O
. O
can O
be O
found O
worldwide O
and O
its O
leaves O
are O
commonly O
used O
as O
ingredient O
in O
food O
industry O
. O

Sage O
essential O
oil O
is O
applied O
in O
the O
treatment O
of O
a O
range O
of O
diseases O
and O
has O
been O
shown O
to O
possess O
different O
biological O
activities O
. O

The O
objectives O
of O
our O
research O
were O
to O
study O
the O
effects O
of O
environment O
on O
crop O
, O
chemical O
composition O
and O
anticancer O
activity O
on O
S O
. O
officinalis O
essential O
oil O
. O

Sage O
was O
cultivated O
at O
eighteen O
experimental O
sites O
in O
south O
- O
central O
Italy O
( O
Molise O
) O
in O
different O
growing O
environments O
. O

The O
essential O
oils O
( O
S1 O
- O
S18 O
) O
, O
extracted O
by O
hydrodistillation O
, O
were O
analyzed O
by O
GC O
and O
CG O
/ O
MS O
. O

Results O
show O
that O
the O
main O
components O
were O
alpha B
- I
thujone I
, O
camphor B
, O
borneol B
, O
gamma B
- I
muurolene I
and O
sclareol B
for O
all O
the O
samples O
, O
but O
the O
percentages O
of O
these O
compounds O
varied O
depending O
on O
environmental O
factors O
such O
as O
altitude O
, O
water O
availability O
and O
pedo O
- O
climatic O
conditions O
. O

The O
growth O
- O
inhibitory O
and O
proapoptotic O
effects O
of O
the O
eighteen O
sage O
essential O
oils O
were O
evaluated O
in O
three O
human O
melanoma O
cell O
lines O
, O
A375 O
, O
M14 O
, O
and O
A2058 O
. O

Alkyl B
esters I
of O
gallic B
acid I
as O
anticancer O
agents O
: O
a O
review O
. O

The O
current O
review O
presents O
the O
antitumoral O
properties O
of O
gallic B
acid I
and O
its O
ester O
derivatives O
. O

Numerous O
studies O
have O
indicated O
that O
the O
alkyl B
esters I
are O
more O
effective O
against O
tumor O
cell O
lines O
than O
gallic B
acid I
, O
and O
that O
this O
activity O
is O
related O
to O
their O
hydrophobic O
moiety O
. O

All O
related O
studies O
have O
shown O
that O
the O
antitumor O
activity O
is O
interconnected O
to O
the O
induction O
of O
apoptosis O
by O
different O
mechanisms O
and O
it O
depends O
on O
the O
cell O
type O
. O

The O
results O
presented O
in O
this O
review O
may O
help O
to O
emphasize O
that O
these O
compounds O
could O
be O
promising O
as O
a O
new O
alternative O
for O
the O
treatment O
of O
cancer O
, O
either O
alone O
or O
in O
combination O
with O
other O
antitumor O
drugs O
to O
potentiate O
their O
effects O
. O

Chlamydophila O
pneumoniae O
endonuclease O
IV O
prefers O
to O
remove O
mismatched O
3 B
' I
ribonucleotides I
: O
implication O
in O
proofreading O
mismatched O
3 O
' O
- O
terminal O
nucleotides B
in O
short O
- O
patch O
repair O
synthesis O
. O

DNA O
polymerase O
I O
( O
DNApolI O
) O
catalyzes O
DNA O
synthesis O
during O
Okazaki O
fragment O
maturation O
, O
base O
excision O
repair O
, O
and O
nucleotide B
excision O
repair O
. O

Some O
bacterial O
DNApolIs O
are O
deficient O
in O
3 O
' O
- O
5 O
' O
exonuclease O
, O
which O
is O
required O
for O
removing O
an O
incorrectly O
incorporated O
3 O
' O
- O
terminal O
nucleotide B
during O
DNA O
elongation O
by O
DNA O
polymerase O
activity O
. O

The O
key O
amino B
acid I
residues O
in O
the O
exonuclease O
center O
of O
Chlamydophila O
pneumoniae O
DNApolI O
( O
CpDNApolI O
) O
are O
naturally O
mutated O
, O
resulting O
in O
the O
loss O
of O
3 O
' O
- O
5 O
' O
exonuclease O
. O

Hence O
, O
the O
manner O
by O
which O
CpDNApolI O
proofreads O
the O
incorrectly O
incorporated O
nucleotide B
during O
DNA O
synthesis O
warrants O
clarification O
. O

C O
. O
pneumoniae O
encodes O
three O
3 O
' O
- O
5 O
' O
exonuclease O
activities O
: O
one O
endonuclease O
IV O
and O
two O
homologs O
of O
the O
epsilon O
subunit O
of O
replicative O
DNA O
polymerase O
III O
. O

The O
three O
proteins O
were O
biochemically O
characterized O
using O
single O
- O
and O
double O
- O
stranded O
DNA O
substrate O
. O

Among O
them O
, O
C O
. O
pneumoniae O
endonuclease O
IV O
( O
CpendoIV O
) O
possesses O
3 O
' O
- O
5 O
' O
exonuclease O
activity O
that O
prefers O
to O
remove O
mismatched O
3 O
' O
- O
terminal O
nucleotides B
in O
the O
nick O
, O
gap O
, O
and O
3 O
' O
recess O
of O
a O
double O
- O
stranded O
DNA O
( O
dsDNA O
) O
. O

Finally O
, O
we O
reconstituted O
the O
proofreading O
reaction O
of O
the O
mismatched O
3 O
' O
- O
terminal O
nucleotide B
using O
the O
dsDNA O
with O
a O
nick O
or O
3 O
' O
recess O
as O
substrate O
. O

Upon O
proofreading O
of O
the O
mismatched O
3 O
' O
- O
terminal O
nucleotide B
by O
CpendoIV O
, O
CpDNApolI O
can O
correctly O
reincorporate O
the O
matched O
nucleotide B
and O
the O
nick O
is O
further O
sealed O
by O
DNA O
ligase O
. O

Based O
on O
our O
biochemical O
results O
, O
we O
proposed O
that O
CpendoIV O
was O
responsible O
for O
proofreading O
the O
replication O
errors O
of O
CpDNApolI O
. O

Nuclear O
receptor O
CAR O
specifically O
activates O
the O
two O
- O
pore O
K B
+ I
channel O
Kcnk1 O
gene O
in O
male O
mouse O
livers O
, O
which O
attenuates O
phenobarbital B
- O
induced O
hepatic O
hyperplasia O
. O

KCNK1 O
, O
a O
member O
of O
the O
family O
of O
two O
- O
pore O
K B
( I
+ I
) I
ion O
channels O
, O
is O
specifically O
induced O
in O
the O
livers O
of O
male O
mice O
after O
phenobarbital B
treatment O
. O

Here O
, O
we O
have O
determined O
the O
molecular O
mechanism O
of O
this O
male O
- O
specific O
activation O
of O
the O
Kcnk1 O
gene O
and O
characterized O
KCNK1 O
as O
a O
phenobarbital B
- O
inducible O
antihyperplasia O
factor O
. O

Upon O
activation O
by O
phenobarbital B
, O
nuclear O
receptor O
CAR O
binds O
the O
97 O
- O
bp O
response O
element O
( O
- O
2441 O
/ O
- O
2345 O
) O
within O
the O
Kcnk1 O
promoter O
. O

This O
binding O
is O
observed O
in O
the O
livers O
of O
male O
mice O
, O
but O
not O
in O
the O
livers O
of O
female O
mice O
and O
requires O
the O
pituitary O
gland O
, O
because O
hypophysectomy O
abrogates O
it O
. O

Hyperplasia O
further O
progressed O
in O
the O
livers O
of O
Kcnk1 O
( O
- O
/ O
- O
) O
male O
mice O
compared O
with O
those O
of O
Kcnk1 O
( O
+ O
/ O
+ O
) O
males O
after O
phenobarbital B
treatment O
. O

Thus O
, O
KCNK1 O
suppresses O
phenobarbital B
- O
induced O
hyperplasia O
. O

These O
results O
indicate O
that O
phenobarbital B
treatment O
induces O
KCNK1 O
to O
elicit O
a O
male O
- O
specific O
and O
growth O
- O
suppressing O
signal O
. O

Thus O
, O
KCNK1 O
and O
Kcnk1 O
( O
- O
/ O
- O
) O
mice O
provide O
an O
experimental O
tool O
for O
further O
investigation O
into O
the O
molecular O
mechanism O
of O
CAR O
- O
mediated O
promotion O
of O
the O
development O
of O
hepatocellular O
carcinoma O
in O
mice O
. O

Postweaning O
exposure O
to O
dietary O
zearalenone B
, O
a O
mycotoxin O
, O
promotes O
premature O
onset O
of O
puberty O
and O
disrupts O
early O
pregnancy O
events O
in O
female O
mice O
. O

Zearalenone B
( O
ZEA B
) O
is O
a O
mycotoxin O
commonly O
found O
in O
contaminated O
livestock O
feed O
and O
human O
food O
with O
levels O
in O
the O
range O
of O
ppb O
and O
low O
ppm O
. O

It O
was O
hypothesized O
that O
ZEA B
, O
an O
endocrine O
disruptor O
, O
could O
affect O
puberty O
and O
early O
pregnancy O
. O

To O
test O
this O
hypothesis O
, O
newly O
weaned O
( O
3 O
weeks O
old O
) O
C57BL O
/ O
6J O
female O
mice O
were O
exposed O
to O
0 O
, O
0 O
. O
002 O
, O
4 O
, O
10 O
, O
and O
40 O
ppm O
ZEA B
and O
0 O
. O
05 O
ppm O
diethylstilbestrol B
( O
positive O
control O
) O
in O
phytoestrogen O
- O
free O
AIN O
- O
93G O
diet O
. O

Females O
exposed O
to O
10 O
and O
40 O
ppm O
ZEA B
diets O
showed O
earlier O
onset O
of O
vaginal O
opening O
. O

Those O
treated O
with O
40 O
ppm O
ZEA B
diet O
also O
had O
earlier O
first O
copulation O
plug O
and O
irregular O
estrous O
cyclicity O
. O

At O
8 O
weeks O
old O
, O
all O
females O
were O
mated O
with O
untreated O
stud O
males O
on O
AIN O
- O
93G O
diet O
during O
mating O
. O

Treatment O
resumed O
upon O
identification O
of O
a O
vaginal O
plug O
on O
gestation O
day O
0 O
. O
5 O
( O
D0 O
. O
5 O
) O
. O

Embryo O
implantation O
was O
assessed O
on O
D4 O
. O
5 O
. O

Exposure O
to O
40 O
ppm O
ZEA B
diet O
resulted O
in O
reduced O
percentage O
of O
plugged O
mice O
with O
implantation O
sites O
, O
distended O
uterine O
appearance O
, O
and O
retained O
expression O
of O
progesterone B
receptor O
in O
D4 O
. O
5 O
uterine O
epithelium O
. O

To O
determine O
the O
exposure O
timing O
and O
mechanisms O
of O
disrupted O
embryo O
implantation O
, O
four O
groups O
of O
females O
were O
fed O
with O
0 O
or O
40 O
ppm O
ZEA B
diets O
during O
premating O
( O
weaning O
to O
mating O
) O
and O
postmating O
( O
D0 O
. O
5 O
- O
D4 O
. O
5 O
) O
, O
respectively O
. O

Premating O
exposure O
to O
40 O
ppm O
ZEA B
diet O
reduced O
fertilization O
rate O
, O
whereas O
postmating O
exposure O
to O
40 O
ppm O
ZEA B
diet O
delayed O
embryo O
transport O
and O
preimplantation O
embryo O
development O
, O
which O
subsequently O
affected O
embryo O
implantation O
. O

These O
data O
demonstrate O
that O
postweaning O
exposure O
to O
dietary O
ZEA B
can O
promote O
premature O
onset O
of O
puberty O
and O
disrupt O
early O
pregnancy O
events O
. O

Autophagy O
inhibition O
for O
chemosensitization O
and O
radiosensitization O
in O
cancer O
: O
do O
the O
preclinical O
data O
support O
this O
therapeutic O
strategy O
? O

Recognition O
of O
the O
cytoprotective O
functions O
of O
autophagy O
that O
occur O
in O
tumor O
cells O
exposed O
to O
various O
forms O
of O
chemotherapy O
or O
radiation O
has O
generated O
intense O
interest O
in O
the O
possibility O
that O
pharmacological O
interference O
with O
autophagy O
could O
provide O
a O
clinical O
strategy O
for O
overcoming O
therapeutic O
resistance O
. O

Multiple O
clinical O
trials O
are O
currently O
in O
progress O
to O
evaluate O
the O
antimalarial O
agent O
chloroquine B
( O
generally O
in O
its O
clinical O
formulation O
as O
hydroxychloroquine B
) O
and O
its O
impact O
on O
various O
forms O
of O
cancer O
therapy O
. O

In O
this O
commentary O
/ O
review O
, O
we O
focus O
on O
the O
relatively O
limited O
number O
of O
studies O
in O
the O
literature O
where O
chloroquine B
has O
been O
tested O
in O
combination O
with O
chemotherapy O
or O
radiation O
in O
experimental O
tumor O
- O
bearing O
animal O
models O
. O

We O
also O
present O
recent O
data O
from O
our O
own O
laboratories O
, O
in O
cell O
culture O
experiments O
as O
well O
as O
in O
vivo O
studies O
, O
which O
demonstrate O
that O
neither O
chloroquine B
nor O
silencing O
of O
an O
autophagy O
regulatory O
gene O
was O
effective O
in O
conferring O
radiation O
sensitivity O
in O
an O
experimental O
model O
of O
breast O
cancer O
. O

The O
capacity O
for O
sensitization O
by O
chloroquine B
appears O
to O
be O
quite O
wide O
- O
ranging O
, O
with O
dramatic O
effects O
for O
some O
drugs O
/ O
tumor O
models O
and O
modest O
or O
minimal O
effects O
in O
others O
. O

One O
possible O
caveat O
is O
that O
, O
with O
only O
a O
few O
exceptions O
, O
experiments O
have O
generally O
been O
performed O
in O
xenograft O
models O
, O
thereby O
eliminating O
the O
involvement O
of O
the O
immune O
system O
, O
which O
might O
ultimately O
be O
proven O
to O
play O
a O
central O
role O
in O
determining O
the O
effectiveness O
of O
autophagy O
inhibition O
in O
chemosensitization O
or O
radiosensitization O
. O

Nevertheless O
, O
a O
careful O
review O
of O
the O
current O
literature O
suggests O
that O
caution O
is O
likely O
to O
be O
warranted O
in O
translating O
preclinical O
findings O
relating O
to O
autophagy O
inhibition O
as O
an O
adjunctive O
therapeutic O
strategy O
. O

Synthesis O
of O
selenolate B
- O
protected O
Au18 B
( I
SeC6H5 I
) I
14 I
nanoclusters O
. O

This O
work O
reports O
the O
first O
synthesis O
of O
selenophenolate B
- O
protected O
Au B
( I
18 I
) I
( I
SePh I
) I
( I
14 I
) I
nanoclusters O
. O

This O
cluster O
exhibits O
distinct O
differences O
from O
its O
thiolate B
analogue O
in O
terms O
of O
optical O
absorption O
properties O
. O

The O
Au B
( I
18 I
) I
( I
SePh I
) I
( I
14 I
) I
nanoclusters O
were O
obtained O
via O
a O
controlled O
reaction O
of O
Au B
( I
25 I
) I
( I
SCH I
( I
2 I
) I
CH I
( I
2 I
) I
Ph I
) I
( I
18 I
) I
with O
selenophenol B
. O

Electrospray O
ionization O
time O
- O
of O
- O
flight O
mass O
spectrometry O
( O
ESI O
- O
TOF O
- O
MS O
) O
revealed O
the O
crude O
product O
to O
contain O
predominantly O
Au B
( O
18 O
) O
( O
SePh I
) O
( O
14 O
) O
nanoclusters O
, O
and O
side O
products O
include O
Au B
( O
15 O
) O
( O
SePh I
) O
( O
13 O
) O
, O
Au B
( O
19 O
) O
( O
SePh O
) O
( O
15 O
) O
and O
Au B
( O
20 O
) O
( O
SePh I
) O
( O
16 O
) O
. O

High O
- O
performance O
liquid O
chromatography O
( O
HPLC O
) O
was O
employed O
to O
isolate O
Au B
( I
18 I
) I
( I
SePh B
) I
( I
14 O
) O
nanoclusters O
. O

The O
results O
of O
thermogravimetric O
analysis O
( O
TGA O
) O
, O
elemental O
analysis O
( O
EA O
) O
, O
and O
( B
1 I
) I
H I
/ O
( B
13 I
) I
C I
NMR O
spectroscopy O
confirmed O
the O
cluster O
composition O
. O

To O
the O
best O
of O
our O
knowledge O
, O
this O
is O
the O
first O
report O
of O
selenolate B
- O
protected O
Au B
( I
18 I
) I
nanoclusters O
. O

Future O
theoretical O
and O
X O
- O
ray O
crystallographic O
work O
will O
reveal O
the O
geometric O
structure O
and O
the O
nature O
of O
selenolate B
- O
gold O
bonding O
in O
the O
nanocluster O
. O

The O
physico O
- O
chemical O
" O
anatomy O
" O
of O
the O
tautomerization O
through O
the O
DPT O
of O
the O
biologically O
important O
pairs O
of O
hypoxanthine B
with O
DNA O
bases O
: O
QM O
and O
QTAIM O
perspectives O
. O

The O
biologically O
important O
tautomerization O
of O
the O
Hyp B
. O
Cyt I
, O
Hyp B
* O
. O
Thy B
and O
Hyp B
. O
Hyp I
base O
pairs O
to O
the O
Hyp B
* O
. O
Cyt B
* O
, O
Hyp B
. O
Thy I
* O
and O
Hyp B
* O
. O
Hyp B
* O
base O
pairs O
, O
respectively O
, O
by O
the O
double O
proton O
transfer O
( O
DPT O
) O
was O
comprehensively O
studied O
in O
vacuo O
and O
in O
the O
continuum O
with O
a O
low O
dielectric O
constant O
( O
epsilon O
= O
4 O
) O
corresponding O
to O
hydrophobic O
interfaces O
of O
protein O
- O
nucleic O
acid O
interactions O
by O
combining O
theoretical O
investigations O
at O
the O

B3LYP O
/ O
6 O
- O
311 O
+ O
+ O
G O
( O
d O
, O
p O
) O
level O
of O
QM O
theory O
with O
QTAIM O
topological O
analysis O
. O

Based O
on O
the O
sweeps O
of O
the O
energetic O
, O
electron O
- O
topological O
, O
geometric O
and O
polar O
parameters O
, O
which O
describe O
the O
course O
of O
the O
tautomerization O
along O
the O
intrinsic O
reaction O
coordinate O
( O
IRC O
) O
, O
it O
was O
proved O
that O
the O
tautomerization O
through O
the O
DPT O
is O
concerted O
and O
asynchronous O
process O
for O
the O
Hyp B
. O
Cyt I
and O
Hyp B
* O
. I
Thy B
base O
pairs O
, O
while O
concerted O
and O
synchronous O
for O
the O
Hyp B
. I
Hyp I
homodimer O
. O

The O
continuum O
with O
epsilon O
= O
4 O
does O
not O
affect O
qualitatively O
the O
course O
of O
the O
tautomerization O
reaction O
for O
all O
studied O
complexes O
. O

The O
nine O
key O
points O
along O
the O
IRC O
of O
the O
Hyp B
. I
Cyt I
< I
- I
- I
> I
Hyp I
* O
. O
Cyt O
* O
and O
Hyp B
* O
. O
Thy I
< I
- I
- I
> I
Hyp I
. I
Thy I
* O
tautomerizations O
and O
the O
six O
key O
points O
of O
the O
Hyp B
. I
Hyp I
< I
- I
- I
> I
Hyp I
* I
. I
Hyp I
* O
tautomerization O
have O
been O
identified O
and O
fully O
characterized O
. O

These O
key O
points O
could O
be O
considered O
as O
electron O
- O
topological O
" O
fingerprints O
" O
of O
concerted O
asynchronous O
( O
for O
Hyp B
. O
Cyt I
and O
Hyp B
* I
. I
Thy I
) O
or O
synchronous O
( O
for O
Hyp B
. O
Hyp I
) O
tautomerization O
process O
via O
the O
DPT O
. O

It O
was O
found O
, O
that O
in O
the O
Hyp B
* O
. O
Cyt O
* O
, O
Hyp B
. O
Thy I
* O
, O
Hyp B
. O
Hyp I
and O
Hyp B
* O
. O
Hyp B
* O
base O
pairs O
all O
H B
- O
bonds O
are O
significantly O
cooperative O
and O
mutually O
reinforce O
each O
other O
, O
while O
the O
C2H B
. O
. O
. O
O2 B
H I
- O
bond O
in O
the O
Hyp B
. O
Cyt O
base O
pair O
and O
the O
O6H B
. O
. O
. O
O4 B
H I
- O
bond O
in O
the O
Hyp B
* O
. O
Thy B
base O
pair O
behave O
anti O
- O
cooperatively O
, O
i O
. O
e O
. O
, O
they O
become O
weakened O
, O
while O
two O
others O
become O
strengthened O
. O

Zinc B
deficiency O
induced O
in O
Swiss O
3T3 O
cells O
by O
a O
low O
- O
zinc B
medium O
impairs O
calcium B
entry O
and O
two O
mechanisms O
of O
entry O
are O
involved O
. O

Zinc B
deficiency O
in O
3T3 O
cells O
induced O
by O
the O
use O
of O
diethylenetriaminepe B
( O
DTPA B
) O
has O
been O
shown O
to O
impair O
calcium B
entry O
associated O
with O
failure O
of O
proliferation O
when O
the O
cells O
are O
stimulated O
with O
polypeptide O
growth O
factors O
( O
GF O
) O
. O

These O
functions O
of O
zinc B
have O
been O
evaluated O
here O
in O
the O
same O
clone O
of O
cells O
by O
simple O
depletion O
using O
a O
low O
- O
zinc B
medium O
( O
0 O
. O
05 O
mu O
mol O
/ O
L O
zinc B
) O
without O
chelator O
. O

Confluent O
cells O
were O
maintained O
for O
1 O
day O
in O
the O
low O
- O
zinc B
medium O
without O
GF O
, O
then O
loaded O
with O
Fluo B
- I
4 I
, O
and O
stimulated O
with O
GF O
. O

Calcium B
entry O
was O
measured O
by O
the O
increase O
in O
sustained O
fluorescence O
. O

It O
was O
preceded O
by O
the O
release O
of O
stored O
calcium B
as O
observed O
in O
the O
previous O
study O
using O
DTPA B
. O

Zinc B
deprivation O
decreased O
calcium B
entry O
when O
calcium B
was O
added O
at O
0 O
or O
0 O
. O
05 O
mmol O
/ O
L O
but O
not O
when O
0 O
. O
1 O
mmol O
/ O
L O
or O
higher O
. O

Cell O
proliferation O
reflected O
similar O
effects O
of O
zinc B
and O
calcium B
concentrations O
. O

In O
a O
newly O
acquired O
clone O
of O
3T3 O
cells O
, O
GF O
did O
not O
induce O
internal O
calcium B
release O
but O
thapsigargin B
( O
TG O
) O
did O
. O

When O
added O
in O
a O
low O
- O
calcium B
medium O
, O
both O
agonists O
stimulated O
calcium B
entry O
when O
external O
calcium B
was O
added O
, O
suggesting O
that O
two O
different O
mechanisms O
of O
entry O
were O
impaired O
by O
zinc B
deficiency O
. O

Zinc B
deficiency O
produced O
by O
DTPA B
in O
the O
newer O
clones O
gave O
similar O
results O
, O
decreasing O
calcium B
entry O
induced O
by O
both O
agonists O
. O

The O
effects O
of O
GF O
and O
TG O
were O
not O
additive O
. O

The O
results O
confirm O
the O
earlier O
observation O
that O
zinc B
deficiency O
impairs O
calcium B
entry O
into O
3T3 O
cells O
when O
stimulated O
by O
GF O
and O
show O
that O
the O
cells O
can O
take O
up O
calcium B
by O
either O
store O
- O
operated O
or O
receptor O
- O
operated O
mechanisms O
. O

Theoretical O
investigation O
into O
optical O
and O
electronic O
properties O
of O
1 B
, I
8 I
- I
naphthalimide I
derivatives O
. O

A O
series O
of O
1 B
, I
8 I
- I
naphthalimide I
derivatives O
has O
been O
designed O
to O
explore O
their O
optical O
, O
electronic O
, O
and O
charge O
transport O
properties O
as O
charge O
transport O
and O
/ O
or O
luminescent O
materials O
for O
organic O
light O
- O
emitting O
diodes O
( O
OLEDs O
) O
. O

The O
frontier O
molecular O
orbitals O
( O
FMOs O
) O
analysis O
have O
shown O
that O
the O
vertical O
electronic O
transitions O
of O
absorption O
and O
emission O
are O
characterized O
as O
intramolecular O
charge O
transfer O
( O
ICT O
) O
for O
electron O
- O
donating O
and O
aromatic O
groups O
substituted O
derivatives O
. O

However O
, O
the O
ICT O
character O
of O
the O
electron O
- O
withdrawing O
substituted O
derivatives O
is O
not O
significant O
. O

The O
calculated O
results O
show O
that O
their O
optical O
and O
electronic O
properties O
are O
affected O
by O
the O
substituent O
groups O
in O
4 O
- O
position O
of O
1 B
, I
8 I
- I
naphthalimide I
. O

Our O
results O
suggest O
that O
1 B
, I
8 I
- I
naphthalimide I
derivatives O
with O
electron O
- O
donating O
- O
OCH3 B
and O
- O
N B
( I
CH3 I
) I
2 I
( O
1 O
and O
2 O
) O
, O
electron O
- O
withdrawing O
- O
CN B
and O
- O
COCH3 B
( O
3 O
and O
4 O
) O
, O
2 B
- I
( I
thiophen I
- I
2 I
- I
yl I
) I
thiophene I
( O
5 O
) O
, O
2 B
, I
3 I
- I
dihydrothieno I
[ I
3 I
, I
4 I
- I
b I
] I
[ I
1 I
, I
4 I
] I
dioxine I
( O
6 O
) O
, O
2 B
- I
phenyl I
- I
1 I
, I
3 I
, I
4 I
- I
oxadiazole I
( O
7 O
) O
, O
and O

benzo B
[ I
c I
] I
[ I
1 I
, I
2 I
, I
5 I
] I
thiadiazole I
( O
8 O
) O
fragments O
are O
expected O
to O
be O
promising O
candidates O
for O
luminescent O
materials O
for O
OLEDs O
, O
particularly O
for O
5 O
and O
7 O
. O

In O
addition O
, O
3 O
and O
7 O
can O
be O
used O
as O
promising O
hole O
transport O
materials O
for O
OLEDs O
. O

This O
study O
should O
be O
helpful O
in O
further O
theoretical O
investigations O
on O
such O
kind O
of O
systems O
and O
also O
to O
the O
experimental O
study O
for O
charge O
transport O
and O
/ O
or O
luminescent O
materials O
for O
OLEDs O
. O

Polyethylene B
Glycol I
and O
Polyethylenimine B
Dual O
- O
Functionalized O
Nano O
- O
Graphene B
Oxide I
for O
Photothermally O
Enhanced O
Gene O
Delivery O
. O

Graphene B
oxide I
( O
GO O
) O
has O
been O
extensively O
explored O
in O
nanomedicine O
for O
its O
excellent O
physiochemical O
, O
electrical O
, O
and O
optical O
properties O
. O

Here O
, O
polyethylene B
glycol I
( O
PEG B
) O
and O
polyethylenimine B
( O
PEI B
) O
are O
covalently O
conjugated O
to O
GO O
via O
amide B
bonds O
, O
obtaining O
a O
physiologically O
stable O
dual O
- O
polymer O
- O
functionalized O
nano O
- O
GO O
conjugate O
( O
NGO O
- O
PEG B
- O
PEI B
) O
with O
ultra O
- O
small O
size O
. O

Compared O
with O
free O
PEI B
and O
the O
GO O
- O
PEI B
conjugate O
without O
PEGylation O
, O
NGO O
- O
PEG B
- O
PEI B
shows O
superior O
gene O
transfection O
efficiency O
without O
serum O
interference O
, O
as O
well O
as O
reduced O
cytotoxicity O
. O

Utilizing O
the O
NIR O
optical O
absorbance O
of O
NGO O
, O
the O
cellular O
uptake O
of O
NGO O
- O
PEG B
- O
PEI B
is O
shown O
to O
be O
enhanced O
under O
a O
low O
power O
NIR O
laser O
irradiation O
, O
owing O
to O
the O
mild O
photothermal O
heating O
that O
increases O
the O
cell O
membrane O
permeability O
without O
significantly O
damaging O
cells O
. O

As O
the O
results O
, O
remarkably O
enhanced O
plasmid O
DNA O
transfection O
efficiencies O
induced O
by O
the O
NIR O
laser O
are O
achieved O
using O
NGO O
- O
PEG B
- O
PEI B
as O
the O
light O
- O
responsive O
gene O
carrier O
. O

More O
importantly O
, O
it O
is O
shown O
that O
our O
NGO O
- O
PEG B
- O
PEI B
is O
able O
to O
deliver O
small O
interfering O
RNA O
( O
siRNA O
) O
into O
cells O
under O
the O
control O
of O
NIR O
light O
, O
resulting O
in O
obvious O
down O
- O
regulation O
of O
the O
target O
gene O
, O
Polo O
- O
like O
kinase O
1 O
( O
Plk1 O
) O
, O
in O
the O
presence O
of O
laser O
irradiation O
. O

This O
study O
is O
the O
first O
to O
use O
photothermally O
enhanced O
intracellular O
trafficking O
of O
nanocarriers O
for O
light O
- O
controllable O
gene O
delivery O
. O

This O
work O
also O
encourages O
further O
explorations O
of O
functionalized O
nano O
- O
GO O
as O
a O
photocontrollable O
nanovector O
for O
combined O
photothermal O
and O
gene O
therapies O
. O

Effects O
of O
smoking O
on O
the O
oxidant O
/ O
antioxidant O
balance O
and O
the O
blood O
lipids O
in O
pesticide O
sprayers O
. O

The O
present O
study O
was O
conducted O
on O
80 O
pesticide O
male O
sprayers O
( O
42 O
nonsmokers O
and O
38 O
smokers O
) O
. O

Our O
aim O
was O
to O
estimate O
the O
smoking O
effects O
on O
blood O
lipids O
and O
oxidant O
/ O
antioxidant O
status O
in O
pesticide O
sprayers O
. O

Results O
revealed O
that O
cholesterol B
, O
low O
- O
density O
lipoprotein O
( O
LDL O
) O
and O
glutathion B
peroxidase O
( O
GPx O
) O
enzyme O
were O
significantly O
higher O
in O
the O
38 O
smoker O
sprayers O
than O
in O
the O
42 O
nonsmoker O
sprayers O
. O

Cholesterol B
and O
LDL O
were O
correlated O
with O
smoking O
index O
and O
high O
- O
density O
lipoprotein O
( O
HDL O
) O
, O
superoxide B
dismutase O
( O
SOD O
) O
enzyme O
and O
zinc B
( O
Zn B
) O
were O
inversely O
correlated O
with O
duration O
of O
pesticides O
' O
exposure O
. O

In O
nonsmokers O
, O
LDL O
and O
cholesterol B
were O
negatively O
correlated O
with O
SOD O
and O
correlated O
with O
malondialdehyde B
( O
MDA B
) O
, O
and O
cholesterol B
was O
negatively O
correlated O
with O
Zn B
. O

HDL O
was O
negatively O
correlated O
with O
MDA B
in O
all O
the O
sprayers O
, O
but O
was O
correlated O
with O
GPx O
in O
smokers O
and O
with O
Zn B
in O
nonsmokers O
. O

In O
smokers O
, O
LDL O
was O
negatively O
correlated O
with O
GPx O
, O
HDL O
was O
negatively O
correlated O
with O
MDA B
and O
triglycerides B
and O
very O
- O
low O
- O
density O
lipoprotein O
were O
negatively O
correlated O
with O
Zn B
. O

MDA B
was O
negatively O
correlated O
with O
SOD O
, O
GPx O
and O
Zn B
. O

Smoking O
and O
pesticide O
exposure O
could O
be O
responsible O
for O
hyperlipidemia O
and O
oxidative O
stress O
. O

Therefore O
, O
improvement O
in O
the O
antioxidant O
status O
is O
mandatory O
for O
pesticide O
sprayers O
especially O
the O
ones O
who O
smoke O
. O

Agreement O
between O
chest O
radiography O
and O
high O
- O
resolution O
computed O
tomography O
in O
diagnosing O
dust O
- O
related O
interstitial O
lung O
fibrosis O
. O

Although O
it O
has O
been O
suggested O
that O
high O
- O
resolution O
computed O
tomography O
( O
HRCT O
) O
scans O
can O
be O
obtained O
when O
plain O
radiographs O
are O
equivocal O
for O
the O
presence O
of O
interstitial O
lung O
fibrosis O
( O
ILF O
) O
caused O
by O
inhalation O
of O
dust O
, O
such O
as O
silica B
, O
asbestos O
fibres O
, O
etc O
. O
, O
the O
specificity O
of O
the O
findings O
remains O
in O
question O
. O

The O
present O
study O
was O
carried O
out O
to O
compare O
the O
relative O
efficacy O
of O
chest O
radiography O
by O
conventional O
method O
and O
HRCT O
in O
evaluating O
ILF O
which O
included O
22 O
workers O
exposed O
to O
fibrogenic O
dust O
, O
who O
were O
subjected O
to O
clinical O
examination O
, O
pulmonary O
function O
testing O
, O
posteroanterior O
chest O
radiography O
and O
HRCT O
. O

In O
the O
six O
subjects O
who O
had O
findings O
suggestive O
of O
ILF O
on O
HRCT O
, O
four O
had O
normal O
chest O
x O
- O
ray O
( O
CXR O
) O
while O
one O
each O
has O
been O
diagnosed O
as O
having O
tuberculosis O
and O
ILF O
on O
CXR O
. O

The O
agreement O
analysis O
between O
HRCT O
and O
CXR O
suggests O
that O
there O
was O
a O
poor O
agreement O
between O
HRCT O
and O
CXR O
( O
kappa O
= O
0 O
. O
34 O
) O
. O

Serum O
mineral O
status O
of O
long O
- O
term O
cigarette O
smokers O
. O

This O
study O
was O
carried O
out O
to O
investigate O
comparatively O
some O
serum O
mineral O
levels O
of O
cigarette O
smokers O
. O

A O
total O
of O
25 O
nonsmokers O
( O
control O
group O
) O
and O
50 O
long O
- O
term O
cigarette O
smokers O
( O
smoking O
for O
at O
least O
15 O
years O
; O
smoker O
group O
) O
were O
participated O
in O
the O
study O
. O

Subjects O
were O
between O
25 O
and O
40 O
years O
old O
. O

Control O
and O
smoker O
groups O
were O
matched O
for O
age O
, O
sex O
and O
body O
mass O
index O
status O
. O

The O
blood O
samples O
were O
taken O
from O
smokers O
and O
nonsmokers O
after O
12 O
h O
of O
fasting O
period O
. O

The O
levels O
of O
zinc B
( O
Zn B
) O
, O
copper B
( O
Cu B
) O
, O
iron B
( O
Fe B
) O
, O
magnesium B
( O
Mg B
) O
, O
calcium B
( O
Ca B
) O
, O
potassium B
( O
K B
) O
, O
chlorine B
( O
Cl B
) O
, O
sodium B
( O
Na B
) O
and O
phosphorus B
( O
P B
) O
were O
measured O
by O
autoanalyzer O
using O
commercial O
kits O
. O

Student O
' O
s O
t O
test O
was O
used O
to O
compare O
the O
control O
and O
smoker O
groups O
, O
and O
p O
< O
0 O
. O
05 O
indicated O
a O
significant O
difference O
. O

Pearson O
' O
s O
correlation O
coefficient O
was O
used O
to O
demonstrate O
the O
relationship O
among O
parameters O
in O
smoker O
and O
control O
groups O
. O

Although O
there O
was O
no O
statistical O
difference O
( O
p O
> O
0 O
. O
05 O
) O
between O
the O
groups O
regarding O
the O
levels O
of O
K B
, O
P B
, O
Mg B
, O
Na B
, O
Cl B
, O
Zn B
, O
Fe B
, O
Ca B
and O
Cu B
, O
some O
positive O
correlations O
were O
observed O
in O
controls O
but O
not O
in O
smokers O
. O

Therefore O
, O
it O
was O
concluded O
that O
smoking O
does O
not O
affect O
the O
serum O
mineral O
levels O
. O

However O
, O
it O
may O
negatively O
affect O
some O
important O
positive O
correlations O
among O
minerals O
observed O
in O
healthy O
individuals O
. O

Occupational O
hazards O
control O
of O
hazardous O
substances O
in O
clean O
room O
of O
semiconductor O
manufacturing O
plant O
using O
CFD O
analysis O
. O

The O
manufacturing O
processes O
in O
chip O
industries O
are O
complex O
, O
and O
many O
kinds O
of O
raw O
materials O
and O
solvents O
of O
different O
nature O
are O
used O
, O
most O
of O
which O
are O
highly O
toxic O
and O
dangerous O
. O

During O
the O
machine O
preventive O
maintenance O
period O
, O
these O
toxic O
and O
harmful O
substances O
will O
escape O
from O
the O
sealed O
reaction O
chamber O
to O
the O
clean O
workshop O
environment O
and O
endanger O
the O
health O
of O
the O
workers O
on O
- O
site O
, O
resulting O
in O
occupational O
diseases O
. O

From O
the O
perspective O
of O
prevention O
, O
the O
spread O
and O
prediction O
of O
hydrochloric B
acid I
( O
HCl B
) O
that O
escaped O
from O
the O
metal O
- O
etching O
chamber O
during O
maintenance O
were O
studied O
in O
this O
article O
. O

The O
computational O
fluid O
dynamics O
technology O
was O
used O
for O
a O
three O
- O
dimensional O
numerical O
simulation O
of O
the O
indoor O
air O
velocity O
field O
and O
the O
HCl B
concentration O
field O
, O
and O
the O
simulation O
results O
were O
then O
compared O
with O
the O
on O
- O
site O
monitoring O
data O
to O
verify O
the O
correctness O
and O
feasibility O
. O

The O
occupational O
hazards O
and O
control O
measures O
were O
analyzed O
based O
on O
the O
numerical O
simulation O
, O
and O
the O
optimal O
control O
measure O
was O
obtained O
. O

In O
this O
article O
, O
using O
the O
method O
of O
ambient O
air O
to O
analyze O
the O
occupational O
exposure O
can O
provide O
a O
new O
idea O
to O
the O
field O
of O
occupational O
health O
research O
in O
the O
integrated O
circuit O
industry O
and O
had O
theoretical O
and O
practical O
significance O
. O

Plasmon O
dynamics O
in O
colloidal O
Au B
2 I
Cd I
alloy O
- O
CdSe B
core O
/ O
shell O
nanocrystals O
. O

Metal O
- O
semiconductor O
nanocrystal O
heterostructures O
are O
model O
systems O
for O
understanding O
the O
interplay O
between O
the O
localized O
surface O
plasmon O
resonances O
in O
the O
metal O
domain O
and O
the O
relaxation O
of O
the O
excited O
carriers O
in O
the O
semiconductor O
domain O
. O

Here O
we O
report O
the O
synthesis O
of O
colloidal O
Au B
2 I
Cd I
( O
core O
) O
/ O
CdSe B
( O
shell O
) O
nanocrystal O
heterostructures O
, O
which O
were O
characterized O
extensively O
with O
several O
structural O
and O
optical O
techniques O
, O
including O
time O
- O
resolved O
fluorescence O
and O
broad O
- O
band O
transient O
absorption O
spectroscopy O
( O
both O
below O
and O
above O
the O
CdSe B
band O
gap O
) O
. O

The O
dynamics O
of O
the O
transient O
plasmon O
peak O
was O
dominated O
by O
the O
relaxation O
of O
hot O
carriers O
in O
the O
metal O
core O
, O
its O
spectral O
shape O
was O
independent O
of O
the O
pump O
wavelength O
, O
and O
the O
bleaching O
lifetime O
was O
about O
half O
a O
picosecond O
, O
comparable O
with O
the O
value O
found O
in O
the O
AuCd O
seeds O
used O
for O
the O
synthesis O
. O

Thermodynamic O
studies O
of O
ionic O
hydration O
and O
interactions O
for O
amino B
acid I
ionic O
liquids O
in O
aqueous O
solutions O
at O
298 O
. O
15 O
K O
. O

Amino B
acid I
ionic O
liquids O
are O
a O
special O
class O
of O
ionic O
liquids O
due O
to O
their O
unique O
acid O
- O
base O
behavior O
, O
biological O
significance O
, O
and O
applications O
in O
different O
fields O
such O
as O
templates O
in O
synthetic O
chemistry O
, O
stabilizers O
for O
biological O
macromolecules O
, O
etc O
. O

The O
physicochemical O
properties O
of O
these O
ionic O
liquids O
can O
easily O
be O
altered O
by O
making O
the O
different O
combinations O
of O
amino B
acids I
as O
anion O
along O
with O
possible O
cation O
modification O
which O
makes O
amino B
acid I
ionic O
liquids O
more O
suitable O
to O
understand O
the O
different O
kinds O
of O
molecular O
and O
ionic O
interactions O
with O
sufficient O
depth O
so O
that O
they O
can O
provide O
fruitful O
information O
for O
a O
molecular O
level O
understanding O
of O
more O
complicated O
biological O
processes O
. O

In O
this O
context O
, O
volumetric O
and O
osmotic O
coefficient O
measurements O
for O
aqueous O
solutions O
containing O
1 B
- I
ethyl I
- I
3 I
- I
methylimidazolium I
( O
[ B
Emim I
] I
) O
based O
amino B
acid I
ionic O
liquids O
of O
glycine B
, O
alanine B
, O
valine B
, O
leucine B
, O
and O
isoleucine B
are O
reported O
at O
298 O
. O
15 O
K O
. O

From O
experimental O
osmotic O
coefficient O
data O
, O
mean O
molal O
activity O
coefficients O
of O
ionic O
liquids O
were O
estimated O
and O
analyzed O
using O
the O
Debye O
- O
H O
u O
ckel O
and O
Pitzer O
models O
. O

The O
hydration O
numbers O
of O
ionic O
liquids O
in O
aqueous O
solutions O
were O
obtained O
using O
activity O
data O
. O

Pitzer O
ion O
interaction O
parameters O
are O
estimated O
and O
compared O
with O
other O
electrolytes O
reported O
in O
the O
literature O
. O

The O
nonelectrolyte O
contribution O
to O
the O
aqueous O
solutions O
containing O
ionic O
liquids O
was O
studied O
by O
calculating O
the O
osmotic O
second O
virial O
coefficient O
through O
an O
application O
of O
the O
McMillan O
- O
Mayer O
theory O
of O
solution O
. O

It O
has O
been O
found O
that O
the O
second O
osmotic O
virial O
coefficient O
which O
includes O
volume O
effects O
correlates O
linearly O
with O
the O
Pitzer O
ion O
interaction O
parameter O
estimated O
independently O
from O
osmotic O
data O
as O
well O
as O
the O
hydrophobicity O
of O
ionic O
liquids O
. O

The O
enthalpy O
- O
entropy O
compensation O
effect O
, O
explained O
using O
the O
Starikov O
- O
Nord O
e O
n O
model O
of O
enthalpy O
- O
entropy O
compensation O
, O
and O
partial O
molar O
entropy O
analysis O
for O
aqueous O
[ B
Emim I
] I
[ I
Gly I
] I
solutions O
are O
made O
by O
using O
experimental O
Gibb O
' O
s O
free O
energy O
data O
and O
literature O
enthalpy O
data O
. O

This O
study O
highlights O
that O
the O
hydrophobic O
interaction O
persists O
even O
in O
the O
limit O
of O
infinite O
dilution O
where O
the O
hydration O
effects O
are O
usually O
dominant O
, O
implying O
importance O
of O
hydrophobic O
hydration O
. O

Analysis O
of O
the O
results O
further O
shows O
that O
the O
hydration O
of O
amino B
acid I
ionic O
liquids O
occurs O
through O
the O
cooperative O
H B
- O
bond O
formation O
with O
the O
kosmotropic O
effect O
in O
contrast O
to O
the O
usual O
inorganic O
salts O
or O
hydrophobic O
salts O
like O
tetraalkylammonium B
halides I
. O

Chemical O
warfare O
agent O
and O
biological O
toxin O
- O
induced O
pulmonary O
toxicity O
: O
could O
stem O
cells O
provide O
potential O
therapies O
? O

Chemical O
warfare O
agents O
( O
CWAs O
) O
as O
well O
as O
biological O
toxins O
present O
a O
significant O
inhalation O
injury O
risk O
to O
both O
deployed O
warfighters O
and O
civilian O
targets O
of O
terrorist O
attacks O
. O

Inhalation O
of O
many O
CWAs O
and O
biological O
toxins O
can O
induce O
severe O
pulmonary O
toxicity O
leading O
to O
the O
development O
of O
acute O
lung O
injury O
( O
ALI O
) O
as O
well O
as O
acute O
respiratory O
distress O
syndrome O
( O
ARDS O
) O
. O

The O
therapeutic O
options O
currently O
used O
to O
treat O
these O
conditions O
are O
very O
limited O
and O
mortality O
rates O
remain O
high O
. O

Recent O
evidence O
suggests O
that O
human O
stem O
cells O
may O
provide O
significant O
therapeutic O
options O
for O
ALI O
and O
ARDS O
in O
the O
near O
future O
. O

The O
threat O
posed O
by O
CWAs O
and O
biological O
toxins O
for O
both O
civilian O
populations O
and O
military O
personnel O
is O
growing O
, O
thus O
understanding O
the O
mechanisms O
of O
toxicity O
and O
potential O
therapies O
is O
critical O
. O

This O
review O
will O
outline O
the O
pulmonary O
toxic O
effects O
of O
some O
of O
the O
most O
common O
CWAs O
and O
biological O
toxins O
as O
well O
as O
the O
potential O
role O
of O
stem O
cells O
in O
treating O
these O
types O
of O
toxic O
lung O
injuries O
. O

Spiroketal O
formation O
and O
modification O
in O
avermectin B
biosynthesis O
involves O
a O
dual O
activity O
of O
AveC O
. O

Avermectins B
( O
AVEs B
) O
, O
which O
are O
widely O
used O
for O
the O
treatment O
of O
agricultural O
parasitic O
diseases O
, O
belong O
to O
a O
family O
of O
6 B
, I
6 I
- I
spiroketal I
moiety O
- O
containing O
, O
macrolide B
natural O
products O
. O

AVE O
biosynthesis O
is O
known O
to O
employ O
a O
type O
I O
polyketide O
synthase O
( O
PKS O
) O
system O
to O
assemble O
the O
molecular O
skeleton O
for O
further O
functionalization O
. O

It O
remains O
unknown O
how O
and O
when O
spiroketal B
formation O
proceeds O
, O
particularly O
regarding O
the O
role O
of O
AveC O
, O
a O
unique O
protein O
in O
the O
pathway O
that O
shares O
no O
sequence O
homology O
to O
any O
enzyme O
of O
known O
function O
. O

Here O
, O
we O
report O
the O
unprecedented O
, O
dual O
function O
of O
AveC O
by O
correlating O
its O
activity O
with O
spiroketal O
formation O
and O
modification O
during O
the O
AVE O
biosynthetic O
process O
. O

The O
findings O
in O
this O
study O
were O
supported O
by O
characterizing O
extremely O
unstable O
intermediates O
, O
products O
and O
their O
spontaneous O
derivative O
products O
from O
the O
simplified O
chemical O
profile O
and O
by O
comparative O
analysis O
of O
in O
vitro O
biotransformations O
and O
in O
vivo O
complementations O
mediated O
by O
AveC B
and O
MeiC B
( O
the O
counterpart O
in O
biosynthesizing O
the O
naturally O
occurring O
, O
AVE O
- O
like O
meilingmycins B
) O
. O

AveC O
catalyzes O
the O
stereospecific O
spiroketalization O
of O
a O
dihydroxy B
- I
ketone I
polyketide O
intermediate O
and O
the O
optional O
dehydration O
to O
determine O
the O
regiospecific O
saturation O
characteristics O
of O
spiroketal B
diversity O
. O

These O
reactions O
take O
place O
between O
the O
closures O
of O
the O
hexene B
ring O
and O
16 O
- O
membered O
macrolide O
and O
the O
formation O
of O
the O
hexahydrobenzofuran B
unit O
. O

MeiC B
can O
replace O
the O
spirocyclase O
activity O
of O
AveC O
, O
but O
it O
lacks O
the O
independent O
dehydratase O
activity O
. O

Elucidation O
of O
the O
generality O
and O
specificity O
of O
AveC O
- O
type O
proteins O
allows O
for O
the O
rationalization O
of O
previously O
published O
results O
that O
were O
not O
completely O
understood O
, O
suggesting O
that O
enzyme O
- O
mediated O
spiroketal B
formation O
was O
initially O
underestimated O
, O
but O
is O
, O
in O
fact O
, O
widespread O
in O
nature O
for O
the O
control O
of O
stereoselectivity O
. O

Attenuating O
Staphylococcus O
aureus O
Virulence O
Gene O
Regulation O
: O
A O
Medicinal O
Chemistry O
Perspective O
. O

Virulence O
gene O
expression O
in O
Staphylococcus O
aureus O
is O
tightly O
regulated O
by O
intricate O
networks O
of O
transcriptional O
regulators O
and O
two O
- O
component O
signal O
transduction O
systems O
. O

There O
is O
now O
an O
emerging O
body O
of O
evidence O
to O
suggest O
that O
the O
blockade O
of O
S O
. O
aureus O
virulence O
gene O
expression O
significantly O
attenuates O
infection O
in O
experimental O
models O
. O

In O
this O
Perspective O
, O
we O
will O
provide O
insights O
into O
medicinal O
chemistry O
strategies O
for O
the O
development O
of O
chemical O
reagents O
that O
have O
the O
capacity O
to O
inhibit O
staphylococcal O
virulence O
expression O
. O

These O
reagents O
can O
be O
broadly O
grouped O
into O
four O
categories O
: O
( O
1 O
) O
competitive O
inhibitors O
of O
the O
accessory O
gene O
regulator O
( O
agr O
) O
quorum O
sensing O
system O
, O
( O
2 O
) O
inhibitors O
of O
AgrA O
- O
DNA O
interactions O
, O
( O
3 O
) O
RNAIII O
transcription O
inhibitors O
, O
and O
( O
4 O
) O
inhibitors O
of O
the O
SarA O
family O
of O
transcriptional O
regulators O
. O

We O
discuss O
the O
potential O
of O
specific O
examples O
of O
antivirulence O
agents O
for O
the O
management O
and O
treatment O
of O
staphylococcal O
infections O
. O

Development O
of O
new O
cyclic O
plasmin O
inhibitors O
with O
excellent O
potency O
and O
selectivity O
. O

The O
trypsin O
- O
like O
serine B
protease O
plasmin O
is O
a O
target O
for O
the O
development O
of O
antifibrinolytic O
drugs O
for O
use O
in O
cardiac O
surgery O
with O
cardiopulmonary O
bypass O
or O
organ O
transplantations O
to O
reduce O
excessive O
blood O
loss O
. O

The O
optimization O
of O
our O
recently O
described O
substrate O
- O
analogue O
plasmin O
inhibitors O
, O
which O
were O
cyclized O
between O
their O
P3 O
and O
P2 O
side O
chains O
, O
provided O
a O
new O
series O
with O
improved O
efficacy O
and O
excellent O
selectivity O
. O

The O
most O
potent O
inhibitor O
8 O
binds O
to O
plasmin O
with O
an O
inhibition O
constant O
of O
0 O
. O
2 O
nM O
, O
whereas O
K O
( O
i O
) O
values O
> O
1 O
mu O
M O
were O
determined O
for O
nearly O
all O
other O
tested O
trypsin O
- O
like O
serine B
proteases O
, O
with O
the O
exception O
of O
trypsin O
, O
which O
is O
also O
inhibited O
in O
the O
nanomolar O
range O
. O

Docking O
studies O
revealed O
a O
potential O
binding O
mode O
in O
the O
widely O
open O
active O
site O
of O
plasmin O
that O
explains O
the O
strong O
potency O
and O
selectivity O
profile O
of O
these O
inhibitors O
. O

The O
dialkylated B
piperazine I
- O
linker O
segment O
contributes O
to O
an O
excellent O
solubility O
of O
all O
analogues O
. O

Based O
on O
their O
overall O
profile O
the O
presented O
inhibitors O
are O
well O
suited O
for O
further O
development O
as O
injectable O
antifibrinolytic O
drugs O
. O

Discovery O
of O
a O
potent O
and O
selective O
free O
fatty B
acid I
receptor O
1 O
agonist O
with O
low O
lipophilicity O
and O
high O
oral O
bioavailability O
. O

The O
free O
fatty B
acid I
receptor O
1 O
( O
FFA1 O
, O
also O
known O
as O
GPR40 O
) O
mediates O
enhancement O
of O
glucose B
- O
stimulated O
insulin O
secretion O
and O
is O
emerging O
as O
a O
new O
target O
for O
the O
treatment O
of O
type O
2 O
diabetes O
. O

Several O
FFA1 O
agonists O
are O
known O
, O
but O
the O
majority O
of O
these O
suffer O
from O
high O
lipophilicity O
. O

We O
have O
previously O
reported O
the O
FFA1 O
agonist O
3 O
( O
TUG B
- I
424 I
) O
. O

We O
here O
describe O
the O
continued O
structure O
- O
activity O
exploration O
and O
optimization O
of O
this O
compound O
series O
, O
leading O
to O
the O
discovery O
of O
the O
more O
potent O
agonist O
40 O
, O
a O
compound O
with O
low O
lipophilicity O
, O
excellent O
in O
vitro O
metabolic O
stability O
and O
permeability O
, O
complete O
oral O
bioavailability O
, O
and O
appreciable O
efficacy O
on O
glucose B
tolerance O
in O
mice O
. O

A O
safety O
study O
on O
single O
intravenous O
dose O
of O
tetrachloro B
- I
diphenyl I
glycoluril I
[ O
iodogen B
] O
dissolved O
in O
dimethyl B
sulphoxide I
( O
DMSO B
) O
. O

Abstract O
1 O
. O

Iodogen B
( O
tetrachloro B
- I
diphenyl I
glycoluril I
) O
dissolved O
in O
DMSO B
( O
dimethyl B
sulphoxide I
) O
appears O
indispensable O
in O
radioiodination O
of O
hypericin B
for O
a O
new O
anticancer O
strategy O
. O

We O
studied O
the O
safety O
of O
intravenously O
administered O
iodogen B
/ O
DMSO B
in O
mice O
( O
n O
= O
132 O
) O
. O

2 O
. O

Median O
lethal O
dose O
( O
LD O
( O
50 O
) O
) O
of O
iodogen B
/ O
DMSO B
was O
determined O
with O
doses O
of O
40 O
. O
0 O
, O
50 O
. O
0 O
, O
55 O
. O
0 O
, O
60 O
. O
0 O
, O
65 O
. O
0 O
and O
70 O
. O
0 O
mg O
/ O
kg O
. O

Next O
, O
toxicity O
of O
iodogen B
/ O
DMSO B
at O
30 O
. O
0 O
mg O
/ O
kg O
was O
evaluated O
using O
saline O
and O
DMSO B
as O
controls O
. O

Changes O
in O
behaviour O
, O
body O
weight O
and O
serum O
biochemistry O
were O
evaluated O
. O

Histopathology O
of O
lungs O
, O
heart O
, O
liver O
and O
kidney O
was O
performed O
. O

3 O
. O

LD O
( O
50 O
) O
values O
of O
iodogen B
/ O
DMSO B
were O
59 O
. O
5 O
mg O
/ O
kg O
( O
95 O
% O
confidence O
limits O
( O
CI O
) O
: O
54 O
. O
1 O
- O
65 O
. O
4 O
mg O
/ O
kg O
) O
and O
61 O
. O
0 O
mg O
/ O
kg O
( O
95 O
% O
CI O
: O
56 O
. O
2 O
- O
66 O
. O
2 O
mg O
/ O
kg O
) O
for O
female O
and O
male O
mice O
, O
respectively O
. O

Similar O
to O
that O
of O
control O
groups O
, O
no O
animal O
deaths O
were O
encountered O
after O
iodogen B
/ O
DMSO B
administration O
at O
30 O
. O
0 O
mg O
/ O
kg O
. O

Body O
weights O
over O
24 O
h O
were O
not O
altered O
in O
all O
groups O
, O
but O
significantly O
higher O
in O
iodogen B
/ O
DMSO B
and O
DMSO B
groups O
( O
p O
< O
0 O
. O
05 O
) O
14 O
d O
post O
- O
injection O
. O

Blood O
urea B
nitrogen B
and O
alkaline O
phosphatase O
increased O
( O
p O
< O
0 O
. O
05 O
) O
in O
iodogen B
/ O
DMSO B
group O
without O
clinical O
symptoms O
. O

No O
pathologies O
were O
found O
by O
gross O
and O
microscopic O
inspection O
. O

4 O
. O

A O
single O
dose O
of O
iodogen B
/ O
DMSO B
up O
to O
30 O
. O
0 O
mg O
/ O
kg O
, O
over O
3000 O
times O
the O
dose O
in O
potential O
human O
applications O
, O
appears O
safe O
, O
with O
an O
LD O
( O
50 O
) O
doubling O
that O
dose O
in O
mice O
. O

Fragment O
- O
based O
discovery O
of O
new O
highly O
substituted O
1H B
- I
pyrrolo I
[ I
2 I
, I
3 I
- I
b I
] I
- I
and I
3H I
- I
imidazolo I
[ I
4 I
, I
5 I
- I
b I
] I
- I
pyridines I
as O
focal O
adhesion O
kinase O
inhibitors O
. O

Focal O
adhesion O
kinase O
( O
FAK O
) O
is O
considered O
as O
an O
attractive O
target O
for O
oncology O
, O
and O
small O
- O
molecule O
inhibitors O
are O
reported O
to O
be O
in O
clinical O
testing O
. O

In O
a O
surface O
plasmon O
resonance O
( O
SPR O
) O
- O
mediated O
fragment O
screening O
campaign O
, O
we O
discovered O
bicyclic O
scaffolds O
like O
1H B
- I
pyrazolo I
[ I
3 I
, I
4 I
- I
d I
] I
pyrimidines I
binding O
to O
the O
hinge O
region O
of O
FAK O
. O

By O
an O
accelerated O
knowledge O
- O
based O
fragment O
growing O
approach O
, O
essential O
pharmacophores O
were O
added O
. O

The O
establishment O
of O
highly O
substituted O
unprecedented O
1H B
- I
pyrrolo I
[ I
2 I
, I
3 I
- I
b I
] I
pyridine I
derivatizations O
provided O
compounds O
with O
submicromolar O
cellular O
FAK O
inhibition O
potential O
. O

The O
combination O
of O
substituents O
on O
the O
bicyclic O
templates O
and O
the O
nature O
of O
the O
core O
structure O
itself O
have O
a O
significant O
impact O
on O
the O
compounds O
FAK O
selectivity O
. O

Structural O
analysis O
revealed O
that O
the O
appropriately O
substituted O
pyrrolo B
[ I
2 I
, I
3 I
- I
b I
] I
pyridine I
induced O
a O
rare O
helical O
DFG O
- O
loop O
conformation O
. O

The O
discovered O
synthetic O
route O
to O
introduce O
three O
different O
substituents O
independently O
paves O
the O
way O
for O
versatile O
applications O
of O
the O
7 B
- I
azaindole I
core O
. O

Melt O
granulation O
in O
fluidized O
bed O
: O
a O
comparative O
study O
of O
spray O
- O
on O
versus O
in O
situ O
procedure O
. O

Abstract O
Objective O
: O
The O
aim O
of O
this O
study O
was O
to O
investigate O
the O
influence O
of O
process O
parameters O
, O
binder O
content O
and O
binder O
addition O
method O
on O
characteristics O
of O
the O
granules O
obtained O
by O
melt O
granulation O
( O
MG O
) O
in O
fluidized O
bed O
. O

Methods O
: O
Spray O
- O
on O
experiments O
were O
performed O
according O
to O
2 O
( O
3 O
) O
full O
factorial O
design O
. O

The O
effect O
of O
binder O
content O
, O
molten O
binder O
feed O
rate O
, O
and O
spray O
air O
pressure O
on O
granule O
size O
and O
size O
distribution O
, O
granule O
shape O
, O
fl O
owability O
and O
drug O
release O
rate O
was O
investigated O
. O

In O
the O
in O
situ O
experiments O
, O
the O
influence O
of O
binder O
particle O
size O
and O
binder O
content O
was O
evaluated O
. O

Solid O
- O
state O
characterization O
was O
performed O
by O
means O
of O
differential O
scanning O
calorimetry O
, O
X O
- O
ray O
powder O
diffraction O
and O
Fourier O
transform O
infrared O
spectroscopy O
. O

Results O
: O
Size O
of O
the O
granules O
obtained O
by O
spray O
- O
on O
procedure O
was O
significantly O
influenced O
by O
binder O
content O
and O
spray O
air O
pressure O
, O
while O
the O
width O
of O
particle O
size O
distribution O
was O
mainly O
affected O
by O
binder O
feed O
rate O
. O

Spray O
air O
pressure O
showed O
the O
most O
significant O
influence O
on O
granule O
shape O
. O

It O
was O
shown O
that O
smooth O
and O
spherical O
particles O
with O
good O
flow O
properties O
may O
be O
obtained O
by O
both O
procedures O
, O
spray O
- O
on O
and O
in O
situ O
MG O
. O

The O
results O
obtained O
indicated O
the O
influence O
of O
agglomeration O
mechanism O
on O
granule O
sphericity O
, O
with O
higher O
degree O
of O
granule O
sphericity O
observed O
when O
immersion O
and O
layering O
was O
the O
dominant O
mechanism O
. O

Paracetamol B
release O
from O
granulates O
was O
very O
rapid O
, O
but O
after O
compression O
of O
the O
granules O
into O
tablets O
, O
drug O
release O
was O
considerably O
slower O
. O

Solid O
- O
state O
analysis O
confirmed O
that O
the O
physical O
form O
of O
the O
granulate O
components O
remained O
unaffected O
after O
the O
MG O
process O
. O

Conclusion O
: O
The O
results O
presented O
indicate O
that O
MG B
in O
fluidized O
bed O
could O
be O
a O
good O
alternative O
to O
conventional O
granulation O
techniques O
. O

The O
mechanism O
of O
discrimination O
between O
oxidized O
and O
reduced O
coenzyme O
in O
the O
aldehyde B
dehydrogenase O
domain O
of O
Aldh1l1 O
. O

Aldh1l1 O
, O
also O
known O
as O
10 B
- I
formyltetrahydrofola I
dehydrogenase O
( O
FDH O
) O
, O
contains O
the O
carboxy B
- O
terminal O
domain O
( O
Ct O
- O
FDH O
) O
, O
which O
is O
a O
structural O
and O
functional O
homolog O
of O
aldehyde B
dehydrogenases O
( O
ALDHs O
) O
. O

This O
domain O
is O
capable O
of O
catalyzing O
the O
NADP B
( I
+ I
) I
- O
dependent O
oxidation O
of O
short O
chain O
aldehydes B
to O
their O
corresponding O
acids O
, O
and O
similar O
to O
most O
ALDHs O
it O
has O
two O
conserved O
catalytic O
residues O
, O
Cys707 B
and O
Glu673 B
. O

Previously O
, O
we O
demonstrated O
that O
in O
the O
Ct O
- O
FDH O
mechanism O
these O
residues O
define O
the O
conformation O
of O
the O
bound O
coenzyme O
and O
the O
affinity O
of O
its O
interaction O
with O
the O
protein O
. O

Specifically O
, O
the O
replacement O
of O
Cys707 B
with O
an O
alanine B
resulted O
in O
the O
enzyme O
lacking O
the O
ability O
to O
differentiate O
between O
the O
oxidized O
and O
reduced O
coenzyme O
. O

We O
suggested O
that O
this O
was O
due O
to O
the O
loss O
of O
a O
covalent O
bond O
between O
the O
cysteine B
and O
the O
C4N B
atom O
of O
nicotinamide B
ring O
of O
NADP B
( I
+ I
) I
formed O
during O
Ct O
- O
FDH B
catalysis O
. O

To O
obtain O
further O
insight O
into O
the O
functional O
significance O
of O
the O
covalent O
bond O
between O
Cys707 B
and O
the O
coenzyme O
, O
and O
the O
overall O
role O
of O
the O
two O
catalytic O
residues O
in O
the O
coenzyme O
binding O
and O
positioning O
, O
we O
have O
now O
solved O
crystal O
structures O
of O
Ct O
- O
FDH O
in O
the O
complex O
with O
thio B
- I
NADP I
( I
+ I
) I
and O
the O
complexes O
of O
the O
C707S O
mutant O
with O
NADP B
( I
+ I
) I
and O
NADPH B
. O

This O
study O
has O
allowed O
us O
to O
trap O
the O
coenzyme O
in O
the O
contracted O
conformation O
, O
which O
provided O
a O
snapshot O
of O
the O
conformational O
processing O
of O
the O
coenzyme O
during O
the O
transition O
from O
oxidized O
to O
reduced O
form O
. O

Overall O
, O
the O
results O
of O
this O
study O
further O
support O
the O
previously O
proposed O
mechanism O
by O
which O
Cys707 B
helps O
to O
differentiate O
between O
the O
oxidized O
and O
reduced O
coenzyme O
during O
ALDH O
catalysis O
. O

X O
- O
ray O
structure O
of O
the O
V301L O
aldo O
- O
keto O
reductase O
1B10 O
complexed O
with O
NADP B
( I
+ I
) I
and O
the O
potent O
aldose B
reductase O
inhibitor O
fidarestat B
: O
implications O
for O
inhibitor O
binding O
and O
selectivity O
. O

Only O
one O
crystal O
structure O
is O
currently O
available O
for O
tumor O
marker O
AKR1B10 O
, O
complexed O
with O
NADP B
( I
+ I
) I
and O
tolrestat B
, O
which O
is O
an O
aldose B
reductase O
inhibitor O
( O
ARI O
) O
of O
the O
carboxylic B
acid I
type O
. O

Here O
, O
the O
X O
- O
ray O
structure O
of O
the O
complex O
of O
the O
V301L O
substituted O
AKR1B10 O
holoenzyme O
with O
fidarestat B
, O
an O
ARI O
of O
the O
cyclic B
imide I
type O
, O
was O
obtained O
at O
1 O
. O
60 O
A O
resolution O
by O
replacement O
soaking O
of O
crystals O
containing O
tolrestat B
. O

Previously O
, O
fidarestat B
was O
found O
to O
be O
safe O
in O
phase O
III O
trials O
for O
diabetic O
neuropathy O
and O
, O
consistent O
with O
its O
low O
in O
vivo O
side O
effects O
, O
was O
highly O
selective O
for O
aldose B
reductase O
( O
AR O
or O
AKR1B1 O
) O
versus O
aldehyde B
reductase O
( O
AKR1A1 O
) O
. O

Now O
, O
inhibition O
studies O
showed O
that O
fidarestat B
was O
indeed O
1300 O
- O
fold O
more O
selective O
for O
AR O
as O
compared O
to O
AKR1B10 O
, O
while O
the O
change O
of O
Val B
to O
Leu B
( O
found O
in O
AR O
) O
caused O
a O
20 O
- O
fold O
decrease O
in O
the O
IC50 O
value O
with O
fidarestat B
. O

Structural O
analysis O
of O
the O
V301L O
AKR1B10 O
- O
fidarestat O
complex O
displayed O
enzyme O
- O
inhibitor O
interactions O
similar O
to O
those O
of O
the O
AR O
- O
fidarestat O
complex O
. O

However O
, O
a O
close O
inspection O
of O
both O
the O
new O
crystal O
structure O
and O
a O
computer O
model O
of O
the O
wild O
- O
type O
AKR1B10 O
complex O
with O
fidarestat B
revealed O
subtle O
changes O
that O
could O
affect O
fidarestat B
binding O
. O

In O
the O
crystal O
structure O
, O
a O
significant O
motion O
of O
loop O
A O
was O
observed O
between O
AR O
and O
V301L O
AKR1B10 O
, O
linked O
to O
a O
Phe B
- O
122 O
/ O
Phe B
- O
123 O
side O
chain O
displacement O
. O

This O
was O
due O
to O
the O
presence O
of O
the O
more O
voluminous O
Gln B
- O
303 O
side O
chain O
( O
Ser B
- O
302 O
in O
AR O
) O
and O
of O
a O
water O
molecule O
buried O
in O
a O
subpocket O
located O
at O
the O
base O
of O
flexible O
loop O
A O
. O

In O
the O
wild O
- O
type O
AKR1B10 O
model O
, O
a O
short O
contact O
was O
predicted O
between O
the O
Val B
- O
301 O
side O
chain O
and O
fidarestat B
, O
but O
would O
not O
be O
present O
in O
AR O
or O
in O
V301L O
AKR1B10 O
. O

Overall O
, O
these O
changes O
could O
contribute O
to O
the O
difference O
in O
inhibitory O
potency O
of O
fidarestat B
between O
AR O
and O
AKR1B10 O
. O

Potential O
monovalent O
cation O
- O
binding O
sites O
in O
aldehyde B
dehydrogenases O
. O

Potassium B
ions O
are O
non O
- O
essential O
activators O
of O
several O
aldehyde B
dehydrogenases O
( O
ALDHs O
) O
, O
whereas O
a O
few O
others O
require O
the O
cation O
for O
activity O
. O

Two O
kinds O
of O
cation O
- O
binding O
sites O
, O
which O
we O
named O
intra O
- O
subunit O
and O
inter O
- O
subunit O
, O
have O
been O
observed O
in O
crystal O
structures O
of O
ALDHs O
, O
and O
based O
on O
reported O
crystallographic O
data O
, O
we O
here O
propose O
the O
existence O
of O
a O
third O
kind O
located O
in O
the O
central O
cavity O
of O
some O
tetrameric O
ALDHs O
. O

Given O
the O
high O
structural O
similarity O
between O
these O
enzymes O
, O
cation O
- O
binding O
sites O
may O
be O
present O
in O
many O
other O
members O
of O
this O
superfamily O
. O

To O
explore O
the O
prevalence O
of O
these O
sites O
, O
we O
compared O
37 O
known O
crystal O
structures O
from O
13 O
different O
ALDH O
families O
and O
evaluated O
the O
possible O
existence O
of O
a O
cation O
on O
the O
basis O
of O
the O
number O
, O
distance O
and O
geometry O
of O
its O
potential O
interactions O
, O
as O
well O
as O
of O
B O
- O
factor O
values O
of O
modeled O
cations O
obtained O
in O
new O
refinements O
of O
some O
reported O
crystal O
structures O
. O

Also O
, O
by O
performing O
multiple O
alignments O
of O
855 O
non O
- O
redundant O
amino B
acid I
sequences O
, O
we O
assessed O
the O
degree O
of O
conservation O
in O
their O
respective O
families O
of O
the O
amino B
acid I
residues O
putatively O
relevant O
for O
cation O
binding O
. O

Among O
the O
ALDH O
enzymes O
studied O
, O
and O
according O
to O
our O
analyses O
, O
potential O
intra O
- O
subunit O
cation O
- O
binding O
sites O
seem O
to O
be O
present O
in O
most O
members O
of O
ALDH2 O
, O
ALDH1L O
, O
ALDH4 O
, O
ALDH5 O
, O
ALDH7 O
, O
ALDH10 O
, O
and O
ALDH25 O
families O
, O
as O
well O
as O
in O
the O
bacterial O
and O
fungal O
members O
of O
the O
ALDH9 O
family O
and O
in O
a O
few O
ALDH1 O
, O
ALDH6 O
, O
ALDH11 O
and O
ALDH26 O
enzymes O
; O
potential O
inter O
- O
subunit O
sites O
in O
members O
of O
ALDH1L O
, O

ALDH3 O
, O
ALDH4 O
from O
bacillales O
, O
ALDH5 O
, O
ALDH7 O
, O
ALDH9 O
, O
ALDH10 O
, O
ALDH11 O
and O
ALDH25 O
families O
; O
and O
potential O
central O
- O
cavity O
sites O
only O
in O
some O
bacterial O
and O
animal O
ALDH9s O
and O
in O
most O
members O
of O
the O
ALDH1L O
family O
. O

Because O
potassium B
is O
the O
most O
abundant O
intracellular O
cation O
, O
we O
propose O
that O
these O
are O
potassium B
- O
binding O
sites O
, O
but O
the O
specific O
structural O
and O
/ O
or O
functional O
roles O
of O
the O
cation O
bound O
to O
these O
different O
sites O
remain O
to O
be O
investigated O
. O

Specific O
surface O
area O
of O
titanium B
dioxide I
( O
TiO2 B
) O
particles O
influences O
cyto O
- O
and O
photo O
- O
toxicity O
. O

The O
aim O
of O
this O
study O
is O
to O
examine O
how O
different O
specific O
surface O
areas O
of O
similar O
- O
sized O
titanium B
dioxide I
( O
TiO B
( I
2 I
) I
) O
particles O
could O
influence O
both O
cytotoxicity O
and O
phototoxicity O
. O

TiO B
( I
2 I
) I
particles O
of O
different O
specific O
surface O
areas O
were O
compared O
for O
their O
toxic O
effects O
on O
RAW264 O
. O
7 O
cells O
in O
the O
absence O
and O
presence O
of O
UV O
light O
. O

From O
the O
results O
, O
TiO B
( I
2 I
) I
particles O
with O
larger O
specific O
surface O
area O
were O
found O
to O
induce O
higher O
cyto O
- O
( O
UV O
absent O
) O
and O
photo O
- O
toxicity O
( O
UV O
activated O
) O
to O
cells O
after O
24h O
incubation O
. O

The O
observed O
cytotoxicity O
from O
TiO B
( I
2 I
) I
particles O
with O
larger O
surface O
area O
could O
be O
explained O
from O
their O
interactions O
with O
biomolecules O
. O

Upon O
photoactivation O
, O
a O
larger O
number O
of O
hydroxyl B
radicals O
were O
detected O
from O
TiO B
( I
2 I
) I
particles O
with O
larger O
surface O
area O
, O
again O
suggesting O
a O
surface O
area O
dependent O
phototoxic O
effect O
. O

On O
the O
other O
hand O
, O
pre O
- O
adsorbing O
TiO B
( I
2 I
) I
particles O
with O
extracellular O
proteins O
were O
found O
to O
decrease O
toxicity O
effects O
. O

Lack O
of O
transient O
receptor O
potential O
melastatin O
8 O
activation O
by O
phthalate B
esters I
that O
enhance O
contact O
hypersensitivity O
in O
mice O
. O

We O
studied O
the O
involvement O
of O
sensory O
neurons O
in O
skin O
sensitization O
to O
allergens O
using O
a O
mouse O
model O
in O
which O
the O
T O
- O
helper O
type O
2 O
response O
is O
essential O
. O

Skin O
sensitization O
to O
fluorescein B
isothiocyanate I
( O
FITC B
) O
has O
been O
shown O
to O
be O
enhanced O
by O
several O
phthalate B
esters I
, O
including O
dibutyl B
phthalate I
( O
DBP B
) O
. O

For O
different O
types O
of O
phthalate B
esters I
, O
we O
found O
a O
correlation O
between O
the O
ability O
of O
transient O
receptor O
potential O
( O
TRP O
) O
A1 O
activation O
and O
that O
of O
enhancing O
skin O
sensitization O
. O

A O
TRPA1 O
- O
specific O
antagonist O
, O
HC B
- I
030031 I
, O
was O
shown O
to O
suppress O
skin O
sensitization O
in O
the O
presence O
of O
DBP O
. O

However O
, O
since O
phthalate B
esters I
also O
activate O
TRPV1 O
, O
phthalate B
esters I
could O
activate O
other O
types O
of O
TRP O
channels O
non O
- O
selectively O
. O

Furthermore O
, O
sensitization O
to O
FITC B
is O
also O
enhanced O
by O
menthol B
, O
which O
activates O
TRPA1 O
and O
TRPM8 O
. O

Here O
we O
established O
an O
in O
vitro O
system O
for O
measuring O
TRPM8 O
activation O
. O

The O
selectivity O
for O
TRPM8 O
was O
established O
by O
the O
fact O
that O
two O
TRPM8 O
agonists O
( O
menthol B
and O
icilin B
) O
induced O
calcium B
mobilization O
, O
whereas O
agonists O
of O
TRPA1 O
and O
TRPV1 O
did O
not O
. O

We O
demonstrated O
that O
phthalate B
esters I
do O
not O
activate O
TRPM8 O
. O

TRPA1 O
- O
antagonist O
HC B
- I
030031 I
did O
not O
inhibit O
TRPM8 O
activation O
induced O
by O
menthol B
or O
icilin B
. O

These O
results O
show O
that O
phthalate B
esters I
activate O
TRPA1 O
and O
TRPV1 O
with O
selectivity O
. O

TRPM8 O
activation O
is O
not O
likely O
to O
be O
involved O
in O
the O
sensitization O
to O
FITC B
. O

The O
genotoxicity O
of O
PEI B
- O
based O
nanoparticles O
is O
reduced O
by O
acetylation O
of O
polyethylenimine B
amines I
in O
human O
primary O
cells O
. O

The O
ultrasmall O
size O
and O
unique O
properties O
of O
polymeric O
nanoparticles O
( O
NPs O
) O
have O
led O
to O
raising O
concerns O
about O
their O
potential O
cyto O
- O
and O
genotoxicity O
on O
biological O
systems O
. O

Polyethylenimine B
( O
PEI B
) O
is O
a O
highly O
positive O
charged O
polymer O
and O
is O
known O
to O
have O
varying O
degree O
of O
toxic O
effect O
to O
cells O
based O
on O
its O
chemical O
structure O
( O
i O
. O
e O
. O
, O
amount O
of O
primary B
and I
secondary I
amine I
) O
. O

Herein O
, O
drug O
delivery O
carriers O
such O
as O
PEI B
- O
PLGA B
nanoparticles O
( O
PEI B
- O
NPs O
) O
and O
acetylated B
PEI I
- O
PLGA B
nanoparticles O
( O
AcPEI O
- O
NPs O
) O
were O
utilized O
to O
examine O
the O
effect O
of O
acetylation O
on O
NPs O
biocompatibility O
and O
genotoxicity O
, O
using O
human O
primary O
cells O
as O
in O
vitro O
model O
. O

Cell O
uptake O
of O
NPs O
was O
characterized O
along O
with O
their O
effects O
on O
cellular O
viability O
. O

The O
results O
indicate O
that O
both O
NPs O
showed O
an O
equivalent O
behavior O
in O
terms O
of O
uptake O
and O
biocompatibility O
. O

In O
depth O
analysis O
of O
NP O
uptake O
on O
cell O
biology O
evidenced O
that O
these O
nanoparticles O
induced O
dose O
dependant O
genotoxic O
effects O
. O

This O
phenomenon O
was O
significantly O
reduced O
by O
PEI B
acetylation O
. O

Endocytosed O
PEI B
- O
NPs O
trigger O
an O
oxidative O
stress O
on O
cells O
by O
inducing O
the O
production O
of O
reactive O
oxygen B
species O
( O
ROS O
) O
, O
which O
cause O
DNA O
damage O
without O
apparently O
affecting O
cell O
viability O
. O

Thus O
, O
the O
genotoxicity O
of O
nanoparticles O
, O
that O
could O
be O
used O
as O
non O
- O
viral O
drug O
carriers O
, O
should O
be O
evaluated O
based O
on O
the O
intracellular O
level O
of O
ROS O
generation O
and O
DNA O
damage O
even O
in O
absence O
of O
a O
significant O
cell O
death O
. O

Graphene B
oxide I
for O
effective O
radionuclide O
removal O
. O

Here O
we O
show O
the O
efficacy O
of O
graphene B
oxide I
( O
GO O
) O
for O
rapid O
removal O
of O
some O
of O
the O
most O
toxic O
and O
radioactive O
long O
- O
lived O
human O
- O
made O
radionuclides O
from O
contaminated O
water O
, O
even O
from O
acidic O
solutions O
( O
pH O
< O
2 O
) O
. O

The O
interaction O
of O
GO O
with O
actinides O
including O
Am B
( I
III I
) I
, O
Th B
( I
IV I
) I
, O
Pu B
( I
IV I
) I
, O
Np B
( I
V I
) I
, O
U B
( I
VI I
) I
and O
typical O
fission O
products O
Sr B
( I
II I
) I
, O
Eu B
( I
III I
) I
and O
Tc B
( I
VII I
) I
were O
studied O
, O
along O
with O
their O
sorption O
kinetics O
. O

Cation O
/ O
GO O
coagulation O
occurs O
with O
the O
formation O
of O
nanoparticle O
aggregates O
of O
GO O
sheets O
, O
facilitating O
their O
removal O
. O

GO O
is O
far O
more O
effective O
in O
removal O
of O
transuranium B
elements O
from O
simulated O
nuclear O
waste O
solutions O
than O
other O
routinely O
used O
sorbents O
such O
as O
bentonite B
clays O
and O
activated O
carbon B
. O

These O
results O
point O
toward O
a O
simple O
methodology O
to O
mollify O
the O
severity O
of O
nuclear O
waste O
contamination O
, O
thereby O
leading O
to O
effective O
measures O
for O
environmental O
remediation O
. O

Ebullition O
rates O
and O
mercury B
concentrations O
in O
St O
. O

Lawrence O
river O
sediments O
and O
a O
benthic O
invertebrate O
. O

Ebullition O
, O
the O
release O
of O
gas O
from O
anaerobic O
decomposition O
in O
sediments O
, O
was O
recorded O
in O
a O
mercury B
- O
contaminated O
depositional O
zone O
( O
Zone O
1 O
) O
of O
the O
St O
. O

Lawrence O
River O
Area O
of O
Concern O
in O
Cornwall O
, O
Ontario O
, O
Canada O
. O

The O
aim O
of O
the O
present O
study O
was O
to O
test O
if O
this O
disturbance O
affected O
the O
bioavailability O
of O
total O
mercury B
( O
THg O
) O
and O
methylmercury B
( O
MeHg B
) O
in O
surficial O
sediments O
to O
a O
benthic O
invertebrate O
( O
Echinogammarus O
ischnus O
) O
. O

Ebullition O
rates O
ranged O
from O
< O
1 O
to O
2 O
, O
800 O
ml O
/ O
m O
( O
2 O
) O
daily O
, O
with O
methane B
gas O
comprising O
29 O
to O
84 O
% O
of O
the O
total O
. O

No O
direct O
effects O
of O
ebullition O
were O
found O
on O
either O
abiotic O
( O
sediment O
or O
pore O
water O
THg O
or O
MeHg B
concentrations O
) O
or O
biotic O
( O
amphipod O
THg O
or O
MeHg B
concentrations O
) O
variables O
measured O
. O

Instead O
, O
amphipod O
MeHg B
concentrations O
were O
best O
predicted O
by O
pore O
water O
THg O
and O
MeHg B
concentrations O
, O
organic O
matter O
of O
surficial O
sediments O
, O
and O
water O
depth O
and O
location O
. O

Trend O
surface O
analyses O
demonstrated O
that O
a O
shallow O
, O
southwestern O
part O
of O
Zone O
1 O
was O
most O
contaminated O
with O
pore O
water O
mercury B
, O
which O
decreased O
in O
a O
gradient O
toward O
the O
northeast O
. O

Further O
study O
is O
needed O
to O
determine O
if O
the O
amount O
of O
sediment O
resuspended O
by O
ebullition O
affects O
the O
spatial O
distribution O
of O
mercury B
. O

Ab O
initio O
molecular O
dynamics O
simulation O
on O
the O
formation O
process O
of O
He B
@ O
C O
6 O
0 O
synthesized O
by O
explosion O
. O

The O
applications O
of O
endohedral O
non O
- O
metallic O
fullerenes B
are O
limited O
by O
their O
low O
production O
rate O
. O

Recently O
, O
an O
explosive O
method O
developed O
in O
our O
group O
shows O
promise O
to O
prepare O
He B
@ O
C O
6 O
0 O
at O
fairly O
high O
yield O
, O
but O
the O
mechanism O
of O
He B
inserting O
into O
C O
6 O
0 O
cage O
at O
explosive O
conditions O
was O
not O
clear O
. O

Here O
, O
ab O
initio O
molecular O
dynamics O
analysis O
has O
been O
used O
to O
simulate O
the O
collision O
between O
C B
6 I
0 I
molecules O
at O
high O
- O
temperature O
and O
high O
- O
pressure O
induced O
by O
explosion O
. O

The O
results O
show O
that O
defects O
formed O
on O
the O
fullerene B
cage O
by O
collidsion O
can O
effectively O
decrease O
the O
reaction O
barrier O
for O
the O
insertion O
of O
He B
into O
C B
6 I
0 I
, O
and O
the O
self O
- O
healing O
capability O
of O
the O
defects O
was O
also O
observed O
. O

Biomimetic O
Methodology O
to O
Produce O
Polymeric O
Multilayered O
Particles O
for O
Biotechnological O
and O
Biomedical O
Applications O
. O

The O
production O
of O
multi O
- O
compartmented O
particles O
for O
biomedical O
and O
biotechnological O
applications O
is O
challenging O
and O
the O
existing O
methods O
usually O
involve O
wet O
and O
aggressive O
conditions O
that O
compromise O
the O
encapsulation O
efficiency O
of O
bioactive O
agents O
and O
the O
viability O
of O
cells O
. O

Biomimetic O
superhydrophobic O
surfaces O
allow O
construction O
of O
concentric O
multilayered O
polymeric O
systems O
, O
adding O
sequential O
layers O
where O
molecules O
or O
cells O
may O
be O
separately O
confined O
in O
compartments O
with O
high O
efficiency O
. O

Cynomolgus O
monkey O
as O
a O
potential O
model O
to O
assess O
drug O
interactions O
involving O
hepatic O
organic O
anion O
transporting O
polypeptides O
: O
in O
vitro O
, O
in O
vivo O
, O
and O
in O
vitro O
- O
to O
- O
in O
vivo O
extrapolation O
. O

Organic O
anion O
- O
transporting O
polypeptides O
( O
OATP O
) O
1B1 O
, O
1B3 O
, O
and O
2B1 O
can O
serve O
as O
the O
loci O
of O
drug O
- O
drug O
interactions O
( O
DDIs O
) O
. O

In O
the O
present O
work O
, O
the O
cynomolgus O
monkey O
was O
evaluated O
as O
a O
potential O
model O
for O
studying O
OATP O
- O
mediated O
DDIs O
. O

Three O
cynomolgus O
monkey O
OATPs O
( O
cOATPs O
) O
, O
with O
a O
high O
degree O
of O
amino B
acid I
sequence O
identity O
( O
91 O
. O
9 O
, O
93 O
. O
5 O
, O
and O
96 O
. O
6 O
% O
for O
OATP1B1 O
, O
1B3 O
, O
and O
2B1 O
, O
respectively O
) O
to O
their O
human O
counterparts O
, O
were O
cloned O
, O
expressed O
, O
and O
characterized O
. O

The O
cOATPs O
were O
stably O
transfected O
in O
human O
embryonic O
kidney O
cells O
and O
were O
functionally O
similar O
to O
the O
corresponding O
human O
OATPs O
( O
hOATPs O
) O
, O
as O
evident O
from O
the O
similar O
uptake O
rate O
of O
typical O
substrates O
( O
estradiol B
- I
17 I
beta I
- I
d I
- I
glucuronide I
, O
cholecystokinin O
octapeptide O
, O
and O
estrone B
- I
3 I
- I
sulfate I
) O
. O

Moreover O
, O
six O
known O
hOATP O
inhibitors O
exhibited O
similar O
IC O
( O
50 O
) O
values O
against O
cOATPs O
. O

To O
further O
evaluate O
the O
appropriateness O
of O
the O
cynomolgus O
monkey O
as O
a O
model O
, O
a O
known O
hOATP B
substrate O
[ O
rosuvastatin B
( O
RSV B
) O
] O
- O
inhibitor O
[ O
rifampicin B
( O
RIF B
) O
] O
pair O
was O
examined O
in O
vitro O
; O
the O
monkey O
- O
derived O
parameters O
( O
RSV B
K O
( O
m O
) O
and O
RIF B
IC O
( O
50 O
) O
) O
were O
similar O
( O
within O
3 O
. O
5 O
- O
fold O
) O
to O
those O
obtained O
with O
hOATPs B
and O
human O
primary O
hepatocytes O
. O

In O
vivo O
, O
the O
area O
under O
the O
plasma O
concentration O
- O
time O
curve O
of O
RSV B
( O
3 O
mg O
/ O
kg O
, O
oral O
) O
given O
1 O
hour O
after O
a O
single O
RIF O
dose O
( O
15 O
mg O
/ O
kg O
, O
oral O
) O
was O
increased O
2 O
. O
9 O
- O
fold O
in O
cynomolgus O
monkeys O
, O
consistent O
with O
the O
value O
( O
3 O
. O
0 O
- O
fold O
) O
reported O
in O
humans O
. O

A O
number O
of O
in O
vitro O
- O
in O
vivo O
extrapolation O
approaches O
, O
considering O
the O
fraction O
of O
the O
pathways O
affected O
and O
free O
versus O
total O
inhibitor O
concentrations O
, O
were O
also O
explored O
. O

It O
is O
concluded O
that O
the O
cynomolgus O
monkey O
has O
the O
potential O
to O
serve O
as O
a O
useful O
model O
for O
the O
assessment O
of O
OATP O
- O
mediated O
DDIs O
in O
a O
nonclinical O
setting O
. O

Pesticides O
in O
urban O
streams O
and O
early O
life O
stages O
of O
pacific O
coho O
salmon O
. O

Pesticides O
are O
frequently O
detected O
in O
urban O
streams O
and O
are O
believed O
to O
be O
primarily O
the O
result O
of O
homeowner O
use O
. O

Although O
concentrations O
in O
most O
cases O
are O
low O
( O
< O
1 O
micro O
g O
/ O
L O
) O
, O
there O
is O
concern O
that O
pesticide O
inputs O
threaten O
efforts O
to O
restore O
and O
enhance O
salmon O
habitat O
. O

The O
authors O
exposed O
early O
life O
stages O
of O
coho O
salmon O
( O
Oncorhynchus O
kisutch O
) O
to O
a O
pesticide O
mixture O
( O
" O
cocktail O
" O
) O
representative O
of O
those O
pesticides O
most O
frequently O
reported O
in O
urban O
streams O
in O
western O
Washington O
State O
, O
USA O
. O

Life O
stages O
were O
continuously O
exposed O
to O
pulses O
of O
the O
cocktail O
simulating O
those O
in O
urban O
streams O
in O
fall O
and O
winter O
when O
coho O
salmon O
eggs O
and O
sac O
fry O
are O
present O
. O

Nominal O
concentrations O
of O
eight O
herbicides O
, O
two O
insecticides O
, O
a O
fungicide O
, O
and O
a O
breakdown O
product O
were O
the O
maximum O
detected O
. O

Fertilization O
, O
hatching O
success O
, O
survival O
, O
deformities O
, O
and O
growth O
of O
fry O
were O
not O
significantly O
affected O
. O

A O
reduction O
in O
fertilization O
success O
( O
19 O
- O
25 O
% O
) O
was O
not O
reproducible O
even O
when O
gametes O
were O
exposed O
to O
100 O
times O
the O
maximum O
concentrations O
detected O
. O

Based O
on O
the O
end O
points O
examined O
in O
the O
present O
study O
, O
the O
results O
suggest O
that O
direct O
exposure O
to O
the O
pesticides O
most O
frequently O
detected O
in O
urban O
streams O
in O
western O
Washington O
does O
not O
impair O
early O
life O
stages O
of O
coho O
salmon O
and O
is O
not O
a O
major O
factor O
governing O
the O
recovery O
of O
salmon O
populations O
. O

The O
extent O
to O
which O
pesticide O
exposure O
would O
affect O
smoltification O
, O
outmigration O
, O
and O
ocean O
survival O
needs O
to O
be O
determined O
. O

Resveratrol B
improves O
cardiomyopathy O
in O
dystrophin O
- O
deficient O
mice O
through O
SIRT1 O
protein O
- O
mediated O
modulation O
of O
p300 O
protein O
. O

Cardiomyopathy O
is O
the O
main O
cause O
of O
death O
in O
Duchenne O
muscular O
dystrophy O
. O

Here O
, O
we O
show O
that O
oral O
administration O
of O
resveratrol B
, O
which O
leads O
to O
activation O
of O
an O
NAD B
( I
+ I
) I
- O
dependent O
protein O
deacetylase O
SIRT1 O
, O
suppresses O
cardiac O
hypertrophy O
and O
fibrosis O
and O
restores O
cardiac O
diastolic O
function O
in O
dystrophin O
- O
deficient O
mdx O
mice O
. O

The O
pro O
- O
hypertrophic O
co O
- O
activator O
p300 O
protein O
but O
not O
p300 O
mRNA O
was O
up O
- O
regulated O
in O
the O
mdx O
heart O
, O
and O
resveratrol B
administration O
down O
- O
regulated O
the O
p300 O
protein O
level O
. O

In O
cultured O
cardiomyocytes O
, O
cardiomyocyte O
hypertrophy O
induced O
by O
the O
alpha O
( O
1 O
) O
- O
agonist O
phenylephrine B
was O
inhibited O
by O
the O
overexpression O
of O
SIRT1 O
as O
well O
as O
resveratrol B
, O
both O
of O
which O
down O
- O
regulated O
p300 O
protein O
levels O
but O
not O
p300 O
mRNA O
levels O
. O

In O
addition O
, O
activation O
of O
atrial O
natriuretic O
peptide O
promoter O
by O
p300 O
was O
inhibited O
by O
SIRT1 O
. O

We O
found O
that O
SIRT1 O
induced O
p300 O
down O
- O
regulation O
via O
the O
ubiquitin O
- O
proteasome O
pathway O
by O
deacetylation O
of O
lysine B
residues O
for O
ubiquitination O
. O

These O
findings O
indicate O
the O
pathological O
significance O
of O
p300 O
up O
- O
regulation O
in O
the O
dystrophic O
heart O
and O
indicate O
that O
SIRT1 O
activation O
has O
therapeutic O
potential O
for O
dystrophic O
cardiomyopathy O
. O

The O
dynamics O
of O
dendrimers O
by O
NMR O
relaxation O
: O
interpretation O
pitfalls O
. O

NMR O
is O
a O
powerful O
tool O
to O
study O
the O
dynamics O
of O
dendrimers O
. O

By O
analogy O
to O
linear O
polymers O
, O
shorter O
T O
( O
1 O
) O
relaxation O
times O
have O
been O
traditionally O
associated O
to O
less O
mobile O
nuclei O
and O
hence O
, O
dendrimers O
described O
with O
reduced O
local O
motions O
at O
either O
the O
core O
or O
the O
periphery O
. O

Herein O
we O
report O
a O
NMR O
relaxation O
study O
[ O
( B
1 I
) I
H I
and O
( B
13 I
) I
C I
T O
( O
1 O
) O
, O
T O
( O
2 O
) O
; O
( B
13 I
) I
C I
{ I
( I
1 I
) I
H I
} I
NOE I
; O
various O
fields O
and O
temperatures O
] O
which O
reveals O
profound O
differences O
between O
the O
relaxation O
behavior O
of O
dendrimers O
and O
linear O
polymers O
. O

Dendrimers O
show O
slower O
dynamics O
at O
internal O
layers O
and O
on O
increasing O
generation O
and O
may O
display O
internal O
nuclei O
in O
the O
slow O
motional O
regime O
with O
larger O
T O
( O
1 O
) O
values O
than O
the O
periphery O
. O

In O
contrast O
to O
the O
relaxation O
properties O
of O
linear O
polymers O
, O
these O
T O
( O
1 O
) O
increments O
should O
not O
be O
interpreted O
as O
resulting O
from O
faster O
dynamics O
. O

Only O
the O
recording O
of O
T O
( O
1 O
) O
data O
at O
various O
temperatures O
( O
alternatively O
, O
T O
( O
2 O
) O
or O
NOE O
at O
one O
temperature O
) O
ensures O
the O
correct O
interpretation O
of O
dendrimer O
dynamics O
. O

All B
- I
trans I
retinoic I
acid I
protects O
hepatocellular O
carcinoma O
cells O
against O
serum O
- O
starvation O
- O
induced O
cell O
death O
by O
upregulating O
collagen O
8A2 O
. O

As O
a O
therapeutic O
or O
chemopreventative O
agent O
for O
various O
cancers O
, O
all B
- I
trans I
retinoic I
acid I
( O
atRA B
) O
has O
been O
reported O
to O
inhibit O
growth O
, O
induce O
apoptosis O
or O
cause O
differentiation O
. O

It O
was O
found O
that O
atRA B
could O
protect O
hepatocellular O
carcinoma O
( O
HCC O
) O
cells O
against O
cell O
death O
induced O
by O
serum O
starvation O
. O

Furthermore O
, O
it O
was O
found O
that O
atRA B
could O
enhance O
cell O
adhesion O
, O
but O
had O
no O
effect O
on O
the O
cell O
cycle O
and O
apoptosis O
. O

Using O
an O
Illumina O
Human O
HT O
- O
12 O
v4 O
expression O
microarray O
, O
207 O
upregulated O
and O
173 O
downregulated O
genes O
were O
identified O
in O
HepG2 O
cells O
treated O
with O
atRA B
. O

The O
most O
upregulated O
genes O
are O
cytochrome O
P450 O
family O
26 O
subfamily O
A O
polypeptide O
1 O
( O
CYP26A1 O
) O
, O
histidine B
triad O
nucleotide B
binding O
protein O
3 O
( O
HINT3 O
) O
, O
miR O
- O
1282 O
and O
cytochrome O
P450 O
family O
26 O
subfamily O
B O
polypeptide O
1 O
( O
CYP26B1 O
) O
, O
which O
showed O
more O
than O
fivefold O
greater O
expression O
. O

Using O
Gene O
Ontology O
analysis O
, O
the O
greatest O
significance O
was O
found O
in O
extracellular O
- O
matrix O
- O
related O
molecular O
functions O
and O
the O
cellular O
component O
in O
upregulated O
genes O
. O

The O
upregulation O
of O
collagen O
8A2 O
( O
COL8A2 O
) O
was O
further O
confirmed O
using O
quantitative O
RT O
- O
PCR O
and O
western O
blotting O
. O

Knockdown O
of O
COL8A2 O
blocked O
enhancement O
in O
the O
early O
stage O
of O
cell O
adhesion O
by O
atRA B
treatment O
. O

Re O
- O
expression O
of O
COL8A2 O
in O
COL8A2 O
- O
knocked O
- O
down O
HCC O
cells O
reversed O
the O
effect O
of O
small O
interfering O
RNA O
- O
COL8A2 O
. O

In O
addition O
, O
COL8A2 O
could O
increase O
HCC O
cell O
migration O
and O
invasion O
. O

Thus O
, O
COL8A2 O
was O
identified O
as O
the O
key O
protein O
involved O
in O
the O
enhancement O
of O
cell O
adhesion O
of O
atRA B
under O
serum O
- O
free O
conditions O
. O

In O
conclusion O
, O
atRA B
protects O
HCC O
cells O
against O
serum O
- O
starvation O
- O
induced O
cell O
death O
by O
enhancing O
cell O
adhesion O
, O
and O
COL8A2 O
plays O
an O
important O
role O
in O
HCC O
cell O
migration O
and O
invasion O
. O

Systemic O
leptin O
increases O
the O
electrical O
activity O
of O
supraoptic O
nucleus O
oxytocin B
neurones O
in O
virgin O
and O
late O
pregnant O
rats O
. O

In O
the O
rat O
hypothalamus O
, O
fasting O
attenuates O
the O
expression O
of O
oxytocin B
and O
this O
can O
be O
reversed O
by O
exogenous O
leptin O
administration O
. O

In O
the O
present O
study O
, O
we O
investigated O
the O
effects O
of O
systemically O
administered O
leptin O
on O
the O
electrical O
activity O
of O
magnocellular O
neurones O
in O
the O
supraoptic O
nucleus O
of O
urethane B
- O
anaesthetised O
rats O
. O

In O
virgin O
female O
rats O
, O
systemic O
leptin O
significantly O
excited O
identified O
oxytocin B
neurones O
with O
no O
detected O
effects O
on O
the O
patterning O
of O
activity O
, O
as O
reflected O
by O
hazard O
function O
analyses O
. O

The O
lowest O
dose O
that O
was O
consistently O
effective O
was O
100 O
mu O
g O
/ O
i O
. O
v O
. O
, O
and O
this O
dose O
had O
no O
significant O
effect O
on O
vasopressin O
neurones O
. O

In O
virgin O
rats O
fasted O
overnight O
, O
the O
spontaneous O
firing O
rate O
of O
oxytocin B
neurones O
was O
significantly O
lower O
than O
in O
unfasted O
rats O
, O
although O
leptin O
had O
a O
similar O
excitatory O
effect O
as O
in O
unfasted O
rats O
. O

In O
late O
pregnant O
rats O
( O
days O
19 O
- O
21 O
of O
pregnancy O
) O
, O
spontaneous O
firing O
rates O
of O
oxytocin B
neurones O
were O
higher O
than O
in O
virgins O
, O
and O
the O
initial O
response O
to O
leptin O
was O
similar O
to O
that O
in O
virgin O
rats O
, O
although O
the O
increase O
in O
activity O
was O
more O
persistent O
. O

In O
fasted O
pregnant O
rats O
, O
the O
mean O
spontaneous O
firing O
rate O
of O
oxytocin B
neurones O
was O
again O
lower O
than O
in O
unfasted O
rats O
, O
although O
leptin O
had O
no O
significant O
effect O
even O
at O
the O
higher O
dose O
of O
1 O
mg O
/ O
rat O
. O

Thus O
, O
fasting O
reduced O
the O
spontaneous O
firing O
rates O
of O
oxytocin B
neurones O
in O
nonpregnant O
rats O
, O
and O
this O
effect O
could O
be O
reversed O
by O
the O
excitatory O
effects O
of O
leptin O
. O

Pregnant O
rats O
showed O
some O
evidence O
of O
leptin O
resistance O
but O
only O
after O
an O
overnight O
fast O
. O

Design O
and O
synthesis O
of O
potent O
inhibitor O
of O
apoptosis O
( O
IAP O
) O
proteins O
antagonists O
bearing O
an O
octahydropyrrolo B
[ I
1 I
, I
2 I
- I
a I
] I
pyrazine I
scaffold O
as O
a O
novel O
proline B
mimetic O
. O

To O
develop O
novel O
inhibitor O
of O
apoptosis O
( O
IAP O
) O
proteins O
antagonists O
, O
we O
designed O
a O
bicyclic B
octahydropyrrolo I
[ I
1 I
, I
2 I
- I
a I
] I
pyrazine I
scaffold O
as O
a O
novel O
proline B
bioisostere O
. O

This O
design O
was O
based O
on O
the O
X O
- O
ray O
co O
- O
crystal O
structure O
of O
four O
N B
- O
terminal O
amino B
acid I
residues O
( O
AVPI O
) O
of O
the O
second O
mitochondria O
- O
derived O
activator O
of O
caspase O
( O
Smac O
) O
with O
the O
X O
- O
chromosome O
- O
linked O
IAP O
( O
XIAP O
) O
protein O
. O

Lead O
optimization O
of O
this O
scaffold O
to O
improve O
oral O
absorption O
yielded O
compound O
45 O
, O
which O
showed O
potent O
cellular O
IAP1 O
( O
cIAP1 O
IC O
( O
50 O
) O
: O
1 O
. O
3 O
nM O
) O
and O
XIAP O
( O
IC O
( O
50 O
) O
: O
200 O
nM O
) O
inhibitory O
activity O
, O
in O
addition O
to O
potent O
tumor O
growth O
inhibitory O
activity O
( O
GI O
( O
50 O
) O
: O
1 O
. O
8 O
nM O
) O
in O
MDA O
- O
MB O
- O
231 O
breast O
cancer O
cells O
. O

X O
- O
ray O
crystallographic O
analysis O
of O
compound O
45 O
bound O
to O
XIAP O
and O
to O
cIAP1 O
was O
achieved O
, O
revealing O
the O
various O
key O
interactions O
that O
contribute O
to O
the O
higher O
cIAPI O
affinity O
of O
compound O
45 O
over O
XIAP O
. O

Because O
of O
its O
potent O
IAP O
inhibitory O
activities O
, O
compound O
45 O
( O
T B
- I
3256336 I
) O
caused O
tumor O
regression O
in O
a O
MDA O
- O
MB O
- O
231 O
tumor O
xenograft O
model O
( O
T O
/ O
C O
: O
- O
53 O
% O
at O
30 O
mg O
/ O
kg O
) O
. O

Smart O
mesoporous O
SiO2 B
nanoparticles O
for O
the O
DNAzyme O
- O
induced O
multiplexed O
release O
of O
substrates O
. O

The O
fluorescent O
dyes O
methylene B
blue I
, O
MB B
( I
+ I
) I
, O
and O
thionine B
, O
Th B
( I
+ I
) I
, O
can O
be O
trapped O
in O
the O
pores O
of O
mesoporous O
silica B
, O
MP O
- O
SiO B
( I
2 I
) I
, O
by O
means O
of O
functional O
nanostructures O
consisting O
of O
the O
Mg B
( I
2 I
+ I
) I
- O
or O
Zn B
( I
2 I
+ I
) I
- O
dependent O
DNAzyme O
sequences O
. O

In O
the O
presence O
of O
Mg B
( I
2 I
+ I
) I
or O
Zn B
( I
2 I
+ I
) I
ions O
the O
respective O
DNAzymes O
are O
activated O
, O
leading O
to O
the O
specific O
cleavage O
of O
the O
respective O
caps O
, O
and O
the O
selective O
release O
of O
MB B
( I
+ I
) I
or O
Th B
( I
+ I
) I
. O

The O
enlargement O
of O
the O
conserved O
loop O
domains O
of O
the O
Mg B
( I
2 I
+ I
) I
- O
or O
Zn B
( I
2 I
+ I
) I
- O
dependent O
DNAzyme O
sequences O
with O
foreign O
nucleotides B
prohibits O
the O
formation O
of O
active O
DNAzymes O
and O
eliminates O
the O
release O
of O
the O
respective O
dyes O
. O

This O
is O
due O
to O
the O
flexibility O
of O
the O
loops O
that O
lacks O
affinity O
for O
the O
association O
of O
the O
ions O
. O

The O
insertion O
of O
aptamer O
sequences O
( O
e O
. O
g O
. O
, O
the O
adenosine B
- I
5 I
' I
- I
triphosphate I
( O
ATP B
) O
aptamer O
) O
or O
ion O
- O
binding O
sequences O
( O
e O
. O
g O
. O
, O
T O
- O
rich O
Hg B
( I
2 I
+ I
) I
ion O
- O
binding O
domains O
) O
as O
foreign O
components O
to O
the O
loop O
regions O
allows O
the O
formation O
of O
active O
Mg B
( I
2 I
+ I
) I
- O
or O
Zn B
( I
2 I
+ I
) I
- O
dependent O
DNAzyme O
structures O
through O
the O
cooperative O
formation O
of O
aptamer O
- O
ATP B
complexes O
or O
T O
- O
Hg B
( I
2 I
+ I
) I
- O
T O
bridges O
. O

These O
aptamer O
- O
substrate O
complexes O
or O
T O
- O
Hg B
( I
2 I
+ I
) I
- O
T O
bridges O
allosterically O
stabilize O
and O
activate O
the O
DNAzymes O
, O
thus O
allowing O
the O
selective O
release O
of O
the O
fluorescent O
substrates O
MB B
( I
+ I
) I
or O
Th B
( I
+ I
) I
. O

The O
metal O
ion O
- O
driven O
DNAzyme O
release O
of O
substrates O
from O
the O
pores O
of O
MP O
- O
SiO B
( I
2 I
) I
, O
and O
particularly O
the O
allosteric O
activation O
of O
the O
DNAzymes O
through O
cooperative O
aptamer O
- O
substrate O
complexes O
or O
metal O
- O
ion O
bridges O
, O
has O
important O
future O
nanomedical O
implications O
for O
targeted O
release O
of O
drugs O
. O

This O
is O
demonstrated O
with O
the O
triggered O
release O
of O
the O
anticancer O
drug O
, O
doxorubicin B
, O
by O
the O
Mg B
( I
2 I
+ I
) I
- O
DNAzyme O
- O
locked O
pores O
or O
by O
the O
aptamer O
- O
ATP B
complex O
- O
triggered O
activation O
of O
the O
Mg B
( I
2 I
+ I
) I
- O
dependent O
DNAzyme O
. O

Polymeric O
" O
smart O
" O
coatings O
to O
prevent O
foreign O
body O
response O
to O
implantable O
biosensors O
. O

Application O
of O
implantable O
glucose B
biosensors O
for O
" O
real O
- O
time O
" O
monitoring O
is O
reliant O
on O
controlling O
the O
negative O
tissue O
reaction O
at O
the O
sensor O
tissue O
interphase O
. O

A O
novel O
polymer O
coating O
consisting O
of O
poly B
( I
lactic I
- I
co I
- I
glycolic I
) I
acid I
( O
PLGA B
) O
microsphere O
dispersed O
in O
poly B
( I
vinyl I
alcohol I
) I
( O
PVA B
) O
hydrogels O
was O
evaluated O
in O
combination O
with O
dummy O
sensors O
as O
a O
" O
smart O
" O
drug O
eluting O
biocompatible O
coating O
for O
implantable O
biosensors O
to O
prevent O
the O
foreign O
body O
response O
, O
and O
thus O
enhance O
sensor O
performance O
in O
vivo O
. O

The O
polymeric O
microspheres O
slowly O
release O
tissue O
- O
modifying O
drugs O
at O
the O
implantation O
sites O
to O
control O
the O
inflammation O
and O
fibrous O
encapsulation O
, O
while O
the O
hydrogel O
allows O
rapid O
analyte O
diffusion O
to O
the O
sensing O
elements O
. O

Dummy O
sensors O
with O
identical O
dimensions O
to O
that O
of O
the O
functional O
glucose B
sensors O
( O
0 O
. O
5 O
x O
0 O
. O
5 O
x O
5mm O
) O
were O
coated O
with O
the O
PLGA B
/ O
PVA B
composites O
using O
a O
mold O
fabrication O
process O
. O

Both O
normal O
and O
diabetic O
rats O
were O
used O
in O
the O
current O
study O
to O
investigate O
the O
effect O
of O
the O
diabetic O
state O
on O
tissue O
sensor O
interactions O
. O

It O
was O
evident O
that O
the O
PLGA B
/ O
PVA B
hydrogel O
composite O
was O
able O
to O
form O
a O
uniform O
coating O
around O
the O
dummy O
sensor O
and O
stayed O
intact O
throughout O
the O
course O
of O
the O
study O
( O
one O
month O
) O
. O

Tissue O
samples O
containing O
dummy O
sensors O
that O
were O
coated O
with O
dexamethasone B
free O
composites O
exhibited O
acute O
and O
chronic O
inflammation O
as O
well O
as O
fibrous O
encapsulation O
in O
both O
normal O
and O
diabetic O
rats O
. O

However O
, O
the O
diabetic O
rats O
exhibited O
decreased O
intensity O
and O
delayed O
onset O
of O
the O
foreign O
body O
response O
following O
implantation O
of O
drug O
free O
dummy O
sensors O
in O
comparison O
to O
those O
of O
normal O
rats O
. O

On O
the O
other O
hand O
, O
tissues O
containing O
dummy O
sensors O
that O
were O
coated O
with O
dexamethasone B
containing O
composites O
remained O
normal O
( O
i O
. O
e O
. O
similar O
to O
untreated O
tissues O
) O
, O
with O
no O
inflammatory O
reaction O
or O
fibrous O
encapsulation O
occurring O
over O
the O
one O
- O
month O
period O
in O
both O
the O
normal O
and O
diabetic O
rats O
. O

The O
feasibility O
of O
utilizing O
PLGA B
microsphere O
/ O
PVA B
hydrogel O
composites O
as O
coatings O
for O
implantable O
biosensors O
was O
demonstrated O
. O

This O
polymeric O
composite O
is O
an O
innovative O
approach O
to O
control O
the O
foreign O
body O
reaction O
at O
the O
tissue O
- O
device O
interface O
to O
prolong O
biosensor O
lifetime O
. O

Facile O
sonochemical O
synthesis O
of O
novel O
pyrazolyne B
derivates O
at O
ambient O
conditions O
. O

Claisen O
- O
Schmidt O
condensation O
reaction O
of O
4 B
- I
acetamidoacetophenon I
with O
aromatic B
aldehydes I
under O
ultrasonic O
irradiation O
affords O
acetylaminochalcones B
( O
yields O
: O
71 O
- O
90 O
% O
) O
which O
also O
under O
ultrasonic O
irradiation O
and O
in O
the O
presence O
of O
sodium B
acetate I
and O
acetic B
acid I
aqueous O
undergo O
facile O
and O
clean O
cyclocondensation O
with O
hydrazine B
to O
afford O
3 B
- I
( I
4 I
- I
acetamidophenyl I
) I
- I
5 I
- I
( I
aryl I
) I
- I
1 I
- I
H I
- I
pyrazolines I
. O

The O
pyrazolines B
were O
obtained O
in O
good O
to O
excellent O
yields O
( O
81 O
- O
89 O
% O
) O
, O
and O
were O
characterized O
by O
conventional O
spectral O
data O
. O

The O
work O
- O
up O
is O
simple O
and O
the O
results O
obtained O
indicate O
that O
, O
unlike O
classical O
heating O
, O
ultrasonic O
irradiation O
results O
in O
higher O
yields O
, O
shorter O
reaction O
times O
( O
1 O
. O
5 O
- O
2 O
. O
3 O
h O
) O
and O
milder O
conditions O
. O

Pharmacokinetic O
and O
pharmacodynamic O
modeling O
of O
hedgehog O
inhibitor O
TAK B
- I
441 I
for O
the O
inhibition O
of O
Gli1 O
messenger O
RNA O
expression O
and O
antitumor O
efficacy O
in O
xenografted O
tumor O
model O
mice O
. O

6 B
- I
Ethyl I
- I
N I
- I
[ I
1 I
- I
( I
hydroxyacetyl I
) I
piperidin I
- I
4 I
- I
yl I
] I
- I
1 I
- I
methyl I
- I
4 I
- I
oxo I
- I
5 I
- I
( I
2 I
- I
oxo I
- I
2 I
- I
phenylethyl I
) I
- I
3 I
- I
( I
2 I
, I
2 I
, I
2 I
- I
trifluoroethoxy I
) I
- I
4 I
, I
5 I
- I
dihydro I
- I
1H I
- I
pyrrolo I
[ I
3 I
, I
2 I
- I
c I
] I
pyridine I
- I
2 I
- I
carboxamide I
( O
TAK B
- I
441 I
) O
is O
a O
potent O
, O
selective O
hedgehog O

signaling O
pathway O
inhibitor O
that O
binds O
to O
Smo O
and O
is O
being O
developed O
for O
the O
treatment O
of O
cancer O
. O

The O
objectives O
of O
these O
studies O
were O
to O
explore O
the O
possibility O
of O
establishing O
of O
a O
link O
between O
the O
pharmacokinetics O
of O
TAK O
- O
441 O
and O
the O
responses O
of O
Gli1 O
mRNA O
in O
tumor O
- O
associated O
stromal O
or O
skin O
cells O
and O
the O
antitumor O
effect O
of O
hedgehog O
inhibition O
. O

To O
this O
end O
, O
we O
built O
pharmacokinetic O
and O
pharmacodynamic O
models O
that O
describe O
the O
relationship O
of O
the O
concentrations O
of O
TAK O
- O
441 O
plasma O
to O
the O
responses O
of O
Gli1 O
mRNA O
in O
the O
tumor O
( O
target O
) O
and O
skin O
( O
surrogate O
) O
and O
to O
tumor O
growth O
inhibition O
in O
mice O
bearing O
xenografts O
of O
human O
pancreatic O
tumors O
( O
PAN O
- O
04 O
) O
. O

The O
responses O
of O
Gli1 O
mRNA O
and O
tumor O
growth O
were O
described O
by O
an O
indirect O
response O
model O
and O
an O
exponential O
tumor O
growth O
model O
, O
respectively O
. O

The O
IC50 O
values O
for O
Gli1 O
mRNA O
inhibition O
in O
the O
tumor O
and O
skin O
by O
TAK B
- I
441 I
were O
estimated O
to O
be O
0 O
. O
0457 O
and O
0 O
. O
113 O
mu O
g O
/ O
ml O
, O
respectively O
. O

The O
IC90 O
value O
for O
tumor O
growth O
inhibition O
was O
estimated O
to O
be O
0 O
. O
68 O
mu O
g O
/ O
ml O
. O

These O
results O
suggest O
that O
a O
> O
83 O
% O
inhibition O
of O
Gli1 O
mRNA O
expression O
in O
the O
skin O
or O
a O
> O
94 O
% O
inhibition O
of O
Gli1 O
mRNA O
expression O
in O
the O
tumor O
would O
be O
required O
to O
sufficiently O
inhibit O
( O
> O
90 O
% O
) O
hedgehog O
- O
related O
tumor O
growth O
in O
the O
xenografted O
model O
mice O
. O

We O
conclude O
that O
Gli1 O
mRNA O
expression O
in O
the O
tumor O
and O
skin O
could O
be O
a O
useful O
biomarker O
for O
predicting O
the O
antitumor O
effect O
of O
hedgehog O
inhibitors O
. O

Alternative O
splicing O
in O
the O
aldo O
- O
keto O
reductase O
superfamily O
: O
implications O
for O
protein O
nomenclature O
. O

The O
aldo O
- O
keto O
reductase O
superfamily O
contains O
173 O
proteins O
which O
are O
present O
in O
all O
phyla O
. O

Examination O
of O
the O
human O
and O
mouse O
genomes O
has O
identified O
that O
in O
some O
instances O
a O
single O
AKR O
gene O
can O
give O
rise O
to O
alternatively O
spliced O
mRNA O
variants O
which O
in O
some O
cases O
can O
give O
rise O
to O
more O
than O
one O
protein O
isoform O
. O

This O
is O
currently O
well O
documented O
in O
the O
AKR6A O
subfamily O
which O
contains O
the O
beta O
- O
subunits O
of O
the O
voltage O
- O
gated O
potassium B
ion O
channels O
. O

With O
the O
emergence O
of O
second O
generation O
sequencing O
it O
is O
likely O
that O
the O
occurrence O
of O
transcript O
variants O
and O
protein O
isoforms O
from O
a O
single O
AKR O
gene O
may O
become O
common O
place O
. O

To O
deal O
with O
this O
issue O
we O
recommend O
that O
the O
Ensembl O
data O
- O
base O
nomenclature O
be O
used O
to O
annotate O
the O
transcript O
variants O
from O
a O
single O
AKR O
gene O
. O

However O
, O
since O
multiple O
transcript O
variants O
could O
give O
rise O
to O
either O
the O
same O
or O
multiple O
protein O
isoforms O
from O
the O
same O
AKR O
gene O
we O
also O
propose O
to O
expand O
the O
nomenclature O
of O
the O
AKR O
protein O
superfamily O
, O
so O
that O
when O
a O
protein O
isoform O
is O
shown O
to O
be O
expressed O
and O
is O
functional O
it O
would O
be O
assigned O
the O
standard O
AKR O
name O
followed O
by O
a O
" O
period O
or O
full O
- O
stop O
" O
and O
a O
number O
for O
that O
unique O
isoform O
. O

Numbers O
will O
be O
assigned O
chronologically O
and O
linked O
to O
the O
respective O
transcripts O
annotated O
in O
Ensembl O
e O
. O
g O
. O
AKR6A5 O
. O
1 O
( O
Kv O
beta O
2 O
. O
1 O
) O
( O
AKR6A5 O
- O
001 O
, O
- O
006 O
and O
- O
201 O
) O
, O
followed O
by O
AKR6A5 O
. O
2 O
( O
Kv O
beta O
2 O
. O
2 O
) O
( O
AKR6A5 O
- O
002 O
, O
- O
202 O
) O
. O

This O
nomenclature O
is O
expandable O
and O
it O
enables O
multiple O
protein O
isoforms O
to O
be O
assigned O
to O
their O
respective O
transcripts O
when O
they O
arise O
from O
the O
same O
AKR O
gene O
or O
for O
a O
single O
protein O
isoform O
to O
be O
assigned O
to O
multiple O
transcripts O
when O
the O
transcripts O
encode O
the O
same O
AKR O
protein O
. O

Protective O
effects O
of O
alpha B
lipoic I
acid I
versus O
N B
- I
acetylcysteine I
on O
ifosfamide B
- O
induced O
nephrotoxicity O
. O

Ifosfamide B
( O
IFO B
) O
is O
a O
highly O
effective O
chemotherapeutic O
agent O
for O
treating O
a O
variety O
of O
pediatric O
solid O
tumors O
. O

However O
, O
its O
use O
is O
limited O
due O
to O
its O
serious O
side O
effect O
on O
kidneys O
. O

The O
side O
- O
chain O
oxidation O
of O
IFO O
in O
renal O
tubular O
cells O
produces O
a O
reactive O
toxic O
metabolite O
that O
is O
believed O
to O
be O
responsible O
for O
its O
nephrotoxic O
effect O
. O

Therefore O
, O
this O
study O
was O
carried O
out O
to O
investigate O
the O
possible O
underlying O
mechanisms O
that O
may O
be O
involved O
in O
IFO B
- O
induced O
nephrotoxicity O
, O
including O
free O
radical O
generation O
and O
the O
possible O
role O
of O
alpha B
lipoic I
acid I
( O
ALA B
) O
versus O
N B
- I
acetylcysteine I
( O
NAC B
) O
in O
protection O
against O
this O
toxicity O
. O

Male O
albino O
rats O
were O
injected O
intraperitoneally O
with O
saline O
, O
IFO B
( O
50 O
mg O
/ O
kg O
daily O
for O
5 O
days O
) O
, O
IFO B
+ O
ALA B
( O
100 O
mg O
/ O
kg O
daily O
for O
8 O
days O
) O
and O
IFO B
+ O
NAC B
( O
200 O
mg O
/ O
kg O
daily O
for O
8 O
days O
) O
. O

Kidney O
malondialdehyde B
, O
nitric B
oxide I
and O
glutathione B
contents O
and O
serum O
biochemical O
parameters O
and O
histopathological O
analysis O
were O
determined O
. O

Both O
ALA B
and O
NAC B
markedly O
reduced O
the O
severity O
of O
renal O
dysfunction O
induced O
by O
IFO O
. O

NAC B
was O
more O
nephroprotective O
than O
ALA B
. O

This O
study O
suggests O
that O
oxidative O
stress O
is O
possibly O
involved O
in O
the O
IFO B
- O
induced O
nephrotoxicity O
in O
rats O
. O

The O
study O
also O
suggests O
the O
potential O
therapeutic O
role O
for O
ALA B
and O
NAC B
against O
IFO B
- O
induced O
nephrotoxicity O
. O

Antioxidative O
, O
antiapoptotic O
, O
and O
proliferative O
effect O
of O
curcumin B
on O
liver O
regeneration O
after O
partial O
hepatectomy O
in O
rats O
. O

The O
aim O
of O
the O
present O
study O
was O
to O
assess O
the O
influence O
of O
curcumin B
on O
liver O
regeneration O
after O
partial O
hepatectomy O
( O
PH O
) O
in O
rats O
. O

A O
total O
of O
24 O
male O
Sprague O
Dawley O
rats O
were O
divided O
into O
three O
groups O
: O
sham O
- O
operated O
( O
SH O
) O
, O
PH O
, O
and O
PH O
+ O
curcumin B
; O
each O
group O
contains O
eight O
animals O
. O

The O
rats O
in O
curcumin B
- O
treated O
groups O
were O
given O
curcumin B
( O
in O
a O
dose O
of O
100 O
mg O
/ O
kg O
body O
weight O
) O
once O
a O
day O
orally O
for O
7 O
days O
, O
starting O
3 O
days O
prior O
to O
hepatectomy O
operation O
. O

At O
7 O
days O
after O
resection O
, O
liver O
samples O
were O
collected O
. O

The O
malondialdehyde B
( O
MDA B
) O
, O
superoxide B
dismutase O
( O
SOD O
) O
, O
and O
glutathione B
( O
GSH B
) O
levels O
were O
estimated O
in O
liver O
homogenates O
. O

Moreover O
, O
histopathological O
examination O
, O
mitotic O
index O
( O
MI O
) O
, O
proliferating O
cell O
nuclear O
antigen O
labeling O
, O
proliferation O
index O
( O
PI O
) O
, O
transferase O
- O
mediated O
2 B
' I
- I
deoxyuridine I
, O
5 B
' I
- I
triphosphate I
nick O
end O
- O
labeling O
assay O
, O
and O
apoptotic O
index O
( O
AI O
) O
were O
evaluated O
at O
7 O
days O
after O
hepatectomy O
. O

As O
a O
result O
, O
curcumin B
significantly O
increased O
MI O
and O
PI O
and O
significantly O
decreased O
AI O
in O
PH O
rats O
. O

Additionally O
, O
curcumin B
remarkably O
inhibited O
MDA B
elevation O
, O
restored O
impaired O
antioxidant O
SOD O
activity O
and O
GSH B
level O
and O
also O
attenuated O
hepatic O
vacuolar O
degeneration O
and O
sinusoidal O
congestion O
. O

These O
results O
suggested O
that O
curcumin B
treatment O
had O
a O
beneficial O
effect O
on O
liver O
regenerative O
capacity O
of O
the O
remnant O
liver O
tissue O
after O
hepatectomy O
, O
probably O
due O
to O
its O
antioxidative O
, O
antiapoptotic O
, O
and O
proliferative O
properties O
. O

Structure O
- O
based O
redesign O
of O
proteins O
for O
minimal O
T O
- O
cell O
epitope O
content O
. O

The O
protein O
universe O
displays O
a O
wealth O
of O
therapeutically O
relevant O
activities O
, O
but O
T O
- O
cell O
driven O
immune O
responses O
to O
non O
- O
" O
self O
" O
biological O
agents O
present O
a O
major O
impediment O
to O
harnessing O
the O
full O
diversity O
of O
these O
molecular O
functions O
. O

Mutagenic O
T O
- O
cell O
epitope O
deletion O
seeks O
to O
mitigate O
the O
immune O
response O
, O
but O
can O
typically O
address O
only O
a O
small O
number O
of O
epitopes O
. O

Here O
, O
we O
pursue O
a O
" O
bottom O
- O
up O
" O
approach O
that O
redesigns O
an O
entire O
protein O
to O
remain O
native O
- O
like O
but O
contain O
few O
if O
any O
immunogenic O
epitopes O
. O

We O
do O
so O
by O
extending O
the O
Rosetta O
flexible O
- O
backbone O
protein O
design O
software O
with O
an O
epitope O
scoring O
mechanism O
and O
appropriate O
constraints O
. O

The O
method O
is O
benchmarked O
with O
a O
diverse O
panel O
of O
proteins O
and O
applied O
to O
three O
targets O
of O
therapeutic O
interest O
. O

We O
show O
that O
the O
deimmunized O
designs O
indeed O
have O
minimal O
predicted O
epitope O
content O
and O
are O
native O
- O
like O
in O
terms O
of O
various O
quality O
measures O
, O
and O
moreover O
that O
they O
display O
levels O
of O
native O
sequence O
recovery O
comparable O
to O
those O
of O
non O
- O
deimmunized O
designs O
. O

Long O
- O
range O
corrected O
functionals O
satisfy O
Koopmans O
' O
theorem O
: O
calculation O
of O
correlation O
and O
relaxation O
energies O
. O

In O
this O
article O
, O
we O
show O
that O
the O
long O
- O
range O
- O
corrected O
( O
LC O
) O
density O
functionals O
LC O
- O
BOP O
and O
LCgau O
- O
BOP O
reproduce O
frontier O
orbital O
energies O
and O
highest O
- O
occupied O
molecular O
orbital O
( O
HOMO O
) O
- O
lowest O
- O
unoccupied O
molecular O
orbital O
( O
LUMO O
) O
gaps O
better O
than O
other O
density O
functionals O
. O

The O
negative O
of O
HOMO O
and O
LUMO O
energies O
are O
compared O
with O
the O
vertical O
ionization O
potentials O
( O
IPs O
) O
and O
electron O
affinities O
, O
respectively O
, O
using O
CCSD O
( O
T O
) O
/ O
6 O
- O
311 O
+ O
+ O
G O
( O
3df O
, O
3pd O
) O
for O
113 O
molecules O
, O
and O
we O
found O
LC O
functionals O
to O
satisfy O
Koopmans O
' O
theorem O
. O

We O
also O
report O
that O
the O
frontier O
orbital O
energies O
and O
the O
HOMO O
- O
LUMO O
gaps O
of O
LC O
- O
BOP O
and O
LCgau O
- O
BOP O
are O
better O
than O
those O
of O
recently O
proposed O
omega O
M05 O
- O
D O
( O
Lin O
et O
al O
. O
, O
J O
. O
Chem O
. O
Phys O
. O
2012 O
, O
136 O
, O
154109 O
) O
. O

We O
express O
the O
exact O
IP O
in O
terms O
of O
orbital O
relaxation O
, O
and O
correlation O
energies O
and O
hence O
calculate O
the O
relaxation O
and O
correlation O
energies O
for O
the O
same O
set O
of O
molecules O
. O

It O
is O
found O
that O
the O
LC O
functionals O
, O
in O
general O
, O
includes O
more O
relaxation O
effect O
than O
Hartree O
- O
Fock O
and O
more O
correlation O
effect O
than O
the O
other O
density O
functionals O
without O
LC O
scheme O
. O

Finally O
, O
we O
scan O
mu O
parameter O
in O
LC O
scheme O
from O
0 O
. O
1 O
to O
0 O
. O
6 O
bohr O
( O
- O
1 O
) O
for O
the O
above O
test O
set O
molecules O
with O
LC O
- O
BOP O
functional O
and O
found O
our O
parameter O
value O
, O
0 O
. O
47 O
bohr O
( O
- O
1 O
) O
, O
is O
usefully O
applicable O
to O
our O
tested O
systems O
. O

Simultaneous O
determination O
and O
characterization O
of O
tannins B
and O
triterpene B
saponins I
from O
the O
fruits O
of O
various O
species O
of O
Terminalia O
and O
Phyllantus O
emblica O
using O
a O
UHPLC O
- O
UV O
- O
MS O
method O
: O
application O
to O
triphala O
. O

Terminalia O
species O
are O
a O
rich O
source O
of O
tannins B
. O

Many O
preparations O
of O
these O
species O
are O
used O
in O
traditional O
medicine O
and O
have O
many O
different O
ethnobotanical O
applications O
. O

A O
simple O
UHPLC O
method O
was O
developed O
for O
the O
simultaneous O
analysis O
of O
such O
hydrolysable O
tannins B
and O
triterpene B
saponins I
from O
the O
fruit O
rinds O
of O
different O
species O
of O
Terminalia O
( O
T O
. O
chebula O
, O
T O
. O
arjuna O
, O
T O
. O
bellirica O
) O
and O
Phyllantus O
emblica O
. O

A O
separation O
by O
LC O
was O
achieved O
using O
a O
reversed O
- O
phase O
column O
and O
a O
water O
/ O
acetonitrile B
mobile O
phase O
, O
both O
containing O
formic B
acid I
, O
using O
a O
gradient O
system O
and O
a O
temperature O
of O
40 O
degrees O
C O
. O

Eight O
hydrolysable O
tannins B
( O
gallic B
acid I
, O
gallic B
acid I
methyl I
ester I
, O
corilagin B
, O
chebulagic B
acid I
, O
1 B
, I
2 I
, I
3 I
, I
6 I
- I
tetra I
- I
O I
- I
galloyl I
- I
beta I
- I
D I
- I
glucose I
, O
ellagic B
acid I
, O
chebulinic B
acid I
, O
and O
1 B
, I
2 I
, I
3 I
, I
4 I
, I
6 I
- I
penta I
- I
O I
- I
galloyl I
- I
beta I
- I
D I
- I
glucose I
) O
and O
six O
triterpene B
saponins I
( O
arjunglucoside B
- I
I I
, O
arjunglucoside B
- I
III I
, O

chebuloside B
II I
, O
bellericoside B
, O
arjunetin B
, O
and O
arjunglucoside B
- I
II I
) O
could O
be O
separated O
within O
20 O
minutes O
. O

The O
wavelength O
used O
for O
detection O
with O
the O
diode O
array O
detector O
was O
254 O
and O
275 O
nm O
for O
tannins B
and O
205 O
nm O
for O
triterpene B
saponins I
. O

The O
method O
was O
validated O
for O
linearity O
, O
repeatability O
, O
limits O
of O
detection O
, O
and O
limits O
of O
quantification O
. O

The O
developed O
method O
is O
economical O
, O
fast O
, O
and O
especially O
suitable O
for O
quality O
control O
analysis O
of O
tannins B
and O
triterpene B
saponins I
in O
various O
plant O
samples O
and O
commercial O
products O
of O
Terminalia O
. O

Fetal O
and O
neonatal O
outcomes O
in O
women O
reporting O
ingestion O
of O
licorice O
( O
Glycyrrhiza O
uralensis O
) O
during O
pregnancy O
. O

Maternal O
intake O
of O
licorice O
from O
dietary O
sources O
has O
been O
associated O
with O
adverse O
maternal O
and O
fetal O
outcomes O
. O

We O
prospectively O
studied O
the O
outcome O
of O
185 O
singleton O
pregnancies O
who O
took O
over O
- O
the O
- O
counter O
or O
naturopathic O
formulations O
containing O
licorice O
during O
their O
pregnancy O
, O
and O
370 O
age O
- O
matched O
singleton O
pregnant O
controls O
that O
were O
not O
exposed O
to O
any O
potential O
teratogen O
. O

The O
indication O
in O
56 O
. O
8 O
% O
of O
the O
women O
taking O
licorice O
was O
for O
cough O
and O
cold O
control O
, O
with O
the O
maximum O
dose O
of O
2104 O
mg O
/ O
day O
and O
exposure O
occurring O
between O
the O
4th O
day O
and O
25th O
week O
of O
gestation O
. O

The O
rate O
of O
stillbirths O
was O
marginally O
higher O
among O
women O
who O
took O
licorice O
than O
those O
who O
did O
not O
( O
OR O
= O
7 O
. O
9 O
; O
95 O
% O
CI O
0 O
. O
9 O
- O
71 O
. O
5 O
; O
p O
= O
0 O
. O
048 O
) O
, O
and O
significantly O
higher O
when O
compared O
to O
the O
general O
population O
in O
the O
Republic O
of O
Korea O
( O
OR O
= O
13 O
. O
3 O
; O
95 O
% O
CI O
4 O
. O
9 O
- O
35 O
. O
8 O
; O
p O
< O
0 O
. O
001 O
) O
. O

Other O
fetal O
outcomes O
assessed O
in O
the O
study O
were O
similar O
between O
the O
two O
study O
groups O
, O
e O
. O
g O
. O
, O
the O
OR O
of O
major O
malformations O
was O
3 O
. O
9 O
( O
95 O
% O
CI O
0 O
. O
4 O
- O
43 O
. O
5 O
; O
p O
= O
0 O
. O
27 O
) O
. O

In O
conclusion O
, O
the O
present O
study O
suggests O
that O
licorice O
is O
not O
a O
major O
teratogen O
. O

However O
, O
whether O
licorice O
may O
increase O
the O
risk O
of O
stillbirths O
requires O
careful O
consideration O
in O
further O
studies O
with O
a O
larger O
sample O
size O
. O

Antibodies O
against O
Yariv O
' O
s O
reagent O
for O
immunolocalization O
of O
arabinogalactan O
- O
proteins O
in O
aerial O
parts O
of O
Echinacea O
purpurea O
. O

Arabinogalactan O
- O
proteins O
are O
glycoproteins O
that O
occur O
in O
higher O
plants O
and O
are O
involved O
in O
important O
processes O
like O
cell O
differentiation O
and O
plant O
growth O
. O

In O
the O
medicinal O
plant O
Echinacea O
purpurea O
L O
. O
, O
they O
belong O
to O
the O
putative O
immunomodulating O
compounds O
and O
are O
structurally O
well O
characterized O
. O

For O
microscopic O
localization O
of O
arabinogalactan O
- O
proteins O
, O
synthetic O
( B
beta I
- I
D I
- I
Glc I
) I
3 I
Yariv I
phenylglycoside I
that O
specifically O
binds O
to O
most O
plant O
arabinogalactan O
- O
proteins O
was O
used O
to O
label O
arabinogalactan O
- O
proteins O
in O
fresh O
cut O
sections O
of O
stems O
and O
petioles O
of O
Echinacea O
purpurea O
. O

Polyclonal O
antibodies O
against O
( B
beta I
- I
D I
- I
Glc I
) I
3 I
Yariv I
phenylglycoside I
were O
used O
to O
detect O
the O
arabinogalactan O
- O
protein O
- O
( B
beta I
- I
D I
- I
Glc I
) I
3 I
Yariv I
phenylglycoside I
complex O
. O

After O
addition O
of O
fluorescein B
isothiocyanate I
- O
conjugated O
secondary O
antibodies O
, O
the O
sections O
were O
analyzed O
by O
confocal O
laser O
scanning O
microscopy O
. O

Arabinogalactan O
- O
proteins O
are O
localized O
mainly O
in O
the O
central O
cylinder O
in O
the O
collateral O
vascular O
bundles O
, O
especially O
in O
the O
area O
of O
the O
xylem O
. O

In O
cell O
walls O
of O
fully O
differentiated O
vessels O
and O
tracheids O
, O
arabinogalactan O
- O
proteins O
have O
been O
detected O
mainly O
at O
the O
inner O
area O
of O
the O
wall O
close O
to O
the O
cell O
lumina O
. O

Intense O
labeling O
occurs O
around O
pit O
canals O
connecting O
adjacent O
vessels O
. O

Furthermore O
, O
arabinogalactan O
- O
proteins O
are O
present O
in O
the O
lumina O
of O
cells O
of O
the O
sclerenchyma O
caps O
and O
in O
companion O
cells O
of O
the O
phloem O
. O

An O
in O
vitro O
model O
of O
human O
acute O
ethanol B
exposure O
that O
incorporates O
CXCR3 O
- O
and O
CXCR4 O
- O
dependent O
recruitment O
of O
immune O
cells O
. O

Alcoholic O
liver O
disease O
( O
ALD O
) O
is O
one O
of O
the O
commonest O
causes O
of O
cirrhosis O
and O
liver O
failure O
in O
the O
developed O
world O
. O

Hepatic O
inflammation O
is O
the O
critical O
stage O
in O
progression O
of O
both O
ALD O
and O
non O
- O
ALD O
, O
but O
it O
remains O
difficult O
to O
study O
the O
underlying O
mechanisms O
in O
a O
human O
system O
, O
and O
current O
animal O
models O
do O
not O
fully O
recapitulate O
human O
liver O
disease O
. O

We O
developed O
a O
human O
tissue O
- O
based O
system O
to O
study O
lymphocyte O
recruitment O
in O
response O
to O
ethanol B
challenge O
. O

Precision O
- O
cut O
liver O
slices O
( O
PCLS O
) O
from O
human O
livers O
were O
incubated O
in O
culture O
, O
and O
hepatic O
function O
was O
determined O
by O
albumin O
production O
, O
3 B
- I
( I
4 I
, I
5 I
- I
dimethylthiazol I
) I
- I
2 I
, I
5 I
- I
diphenyl I
tetrazolium I
bromide I
assay O
, O
glucose B
uptake O
responses O
, O
and O
morphometric O
assessment O
. O

Responses O
of O
tissue O
and O
lymphocytes O
to O
ethanol B
exposure O
were O
determined O
by O
PCR O
, O
flow O
cytometry O
, O
histology O
, O
and O
lymphocyte O
infiltration O
assays O
. O

Human O
PCLS O
demonstrated O
appropriate O
upregulation O
of O
CYP2E1 O
, O
ADH1 O
alpha O
, O
and O
ADH3 O
in O
response O
to O
ethanol B
treatment O
. O

Ethanol B
also O
induced O
expression O
of O
endothelial O
VCAM O
- O
1 O
and O
ICAM O
- O
1 O
, O
production O
of O
sICAM O
- O
1 O
and O
CXCL8 O
, O
and O
the O
chemokine O
receptors O
CXCR3 O
and O
CXCR4 O
on O
CD4 O
and O
CD8 O
lymphocytes O
. O

CXCR3 O
- O
and O
CXCR4 O
- O
dependent O
migration O
of O
lymphocytes O
into O
the O
tissue O
increased O
significantly O
in O
response O
to O
treatment O
with O
ethanol B
. O

We O
have O
demonstrated O
that O
ethanol B
increases O
chemokine O
receptor O
expression O
and O
lymphocyte O
recruitment O
into O
human O
liver O
tissue O
, O
suggesting O
that O
it O
may O
operate O
directly O
to O
promote O
hepatitis O
in O
ALD O
. O

The O
physiological O
and O
pathophysiological O
responses O
of O
the O
PCLS O
to O
ethanol B
in O
vitro O
highlight O
the O
potential O
of O
this O
assay O
for O
dissecting O
the O
molecular O
mechanisms O
underlying O
human O
liver O
inflammation O
and O
as O
a O
screening O
tool O
for O
novel O
therapeutics O
. O

Identification O
of O
propofol B
binding O
sites O
in O
a O
nicotinic O
acetylcholine B
receptor O
with O
a O
photoreactive O
propofol B
analog O
. O

Propofol B
, O
a O
widely O
used O
intravenous O
general O
anesthetic O
, O
acts O
at O
anesthetic O
concentrations O
as O
a O
positive O
allosteric O
modulator O
of O
gamma B
- I
aminobutyric I
acid I
type O
A O
receptors O
and O
at O
higher O
concentration O
as O
an O
inhibitor O
of O
nicotinic O
acetylcholine B
receptors O
( O
nAChRs O
) O
. O

Here O
, O
we O
characterize O
propofol B
binding O
sites O
in O
a O
muscle O
- O
type O
nAChR O
by O
use O
of O
a O
photoreactive O
analog O
of O
propofol B
, O
2 B
- I
isopropyl I
- I
5 I
- I
[ I
3 I
- I
( I
trifluoromethyl I
) I
- I
3H I
- I
diazirin I
- I
3 I
- I
yl I
] I
phenol I
( O
AziPm B
) O
. O

Based O
upon O
radioligand O
binding O
assays O
, O
AziPm B
stabilized O
the O
Torpedo O
nAChR O
in O
the O
resting O
state O
, O
whereas O
propofol B
stabilized O
the O
desensitized O
state O
. O

nAChR O
- O
rich O
membranes O
were O
photolabeled O
with O
[ B
( I
3 I
) I
H I
] I
AziPm I
, O
and O
labeled O
amino B
acids I
were O
identified O
by O
Edman O
degradation O
. O

[ B
( I
3 I
) I
H I
] I
AziPm I
binds O
at O
three O
sites O
within O
the O
nAChR O
transmembrane O
domain O
: O
( O
i O
) O
an O
intrasubunit O
site O
in O
the O
delta O
subunit O
helix O
bundle O
, O
photolabeling O
in O
the O
nAChR O
desensitized O
state O
( O
+ O
agonist O
) O
delta O
M2 O
- O
18 O
' O
and O
two O
residues O
in O
delta O
M1 O
( O
delta O
Phe B
- O
232 O
and O
delta O
Cys B
- O
236 O
) O
; O
( O
ii O
) O
in O
the O
ion O
channel O
, O
photolabeling O
in O
the O
nAChR O
resting O
, O
closed O
channel O
state O
( O
- O
agonist O
) O
amino B
acids I
in O
the O
M2 O

helices O
( O
alpha O
M2 O
- O
6 O
' O
, O
beta O
M2 O
- O
6 O
' O
and O
- O
13 O
' O
, O
and O
delta O
M2 O
- O
13 O
' O
) O
that O
line O
the O
channel O
lumen O
( O
with O
photolabeling O
reduced O
by O
> O
90 O
% O
in O
the O
desensitized O
state O
) O
; O
and O
( O
iii O
) O
at O
the O
gamma O
- O
alpha O
interface O
, O
photolabeling O
alpha O
M2 O
- O
10 O
' O
. O

Propofol B
enhanced O
[ B
( I
3 I
) I
H I
] I
AziPm I
photolabeling O
at O
alpha O
M2 O
- O
10 O
' O
. O

Propofol B
inhibited O
[ B
( I
3 I
) I
H I
] I
AziPm I
photolabeling O
within O
the O
delta O
subunit O
helix O
bundle O
at O
lower O
concentrations O
( O
IC50 O
= O
40 O
mu O
m O
) O
than O
it O
inhibited O
ion O
channel O
photolabeling O
( O
IC50 O
= O
125 O
mu O
m O
) O
. O

These O
results O
identify O
for O
the O
first O
time O
a O
single O
intrasubunit O
propofol B
binding O
site O
in O
the O
nAChR O
transmembrane O
domain O
and O
suggest O
that O
this O
is O
the O
functionally O
relevant O
inhibitory O
binding O
site O
. O

BSTA B
promotes O
mTORC2 O
- O
mediated O
phosphorylation O
of O
Akt1 O
to O
suppress O
expression O
of O
FoxC2 O
and O
stimulate O
adipocyte O
differentiation O
. O

Phosphorylation O
and O
activation O
of O
Akt1 O
is O
a O
crucial O
signaling O
event O
that O
promotes O
adipogenesis O
. O

However O
, O
neither O
the O
complex O
multistep O
process O
that O
leads O
to O
activation O
of O
Akt1 O
through O
phosphorylation O
at O
Thr B
( O
3 O
) O
0 O
8 O
and O
Ser B
4 O
7 O
( O
3 O
) O
nor O
the O
mechanism O
by O
which O
Akt1 O
stimulates O
adipogenesis O
is O
fully O
understood O
. O

We O
found O
that O
the O
BSD O
domain O
- O
containing O
signal O
transducer O
and O
Akt O
interactor O
( O
BSTA O
) O
promoted O
phosphorylation O
of O
Akt1 O
at O
Ser B
4 O
7 O
( O
3 O
) O
in O
various O
human O
and O
murine O
cells O
, O
and O
we O
uncovered O
a O
function O
for O
the O
BSD O
domain O
in O
BSTA O
- O
Akt1 O
complex O
formation O
. O

The O
mammalian O
target O
of O
rapamycin B
complex O
2 O
( O
mTORC2 O
) O
facilitated O
the O
phosphorylation O
of O
BSTA B
and O
its O
association O
with O
Akt1 O
, O
and O
the O
BSTA B
- O
Akt1 O
interaction O
promoted O
the O
association O
of O
mTORC2 O
with O
Akt1 O
and O
phosphorylation O
of O
Akt1 O
at O
Ser B
4 O
7 O
( O
3 O
) O
in O
response O
to O
growth O
factor O
stimulation O
. O

Furthermore O
, O
analyses O
of O
bsta O
gene O
- O
trap O
murine O
embryonic O
stem O
cells O
revealed O
an O
essential O
function O
for O
BSTA O
and O
phosphorylation O
of O
Akt1 O
at O
Ser B
4 O
7 O
( O
3 O
) O
in O
promoting O
adipocyte O
differentiation O
, O
which O
required O
suppression O
of O
the O
expression O
of O
the O
gene O
encoding O
the O
transcription O
factor O
FoxC2 O
. O

These O
findings O
indicate O
that O
BSTA B
is O
a O
molecular O
switch O
that O
promotes O
phosphorylation O
of O
Akt1 O
at O
Ser B
4 O
7 O
( O
3 O
) O
and O
reveal O
an O
mTORC2 O
- O
BSTA B
- O
Akt1 O
- O
FoxC2 O
- O
mediated O
signaling O
mechanism O
that O
is O
critical O
for O
adipocyte O
differentiation O
. O

Amino B
acid I
grafted O
chitosan O
for O
high O
performance O
gene O
delivery O
: O
comparison O
of O
amino B
acid I
hydrophobicity O
on O
vector O
and O
polyplex O
characteristics O
. O

To O
develop O
a O
safe O
, O
effective O
, O
and O
biocompatible O
gene O
delivery O
vector O
, O
a O
series O
of O
hydrophobic O
amino B
acid I
grafted O
chitosan O
( O
AGC O
) O
derivatives O
were O
synthesized O
by O
carbodiimide B
mediated O
coupling O
reaction O
. O

Chemical O
characterization O
of O
AGC B
polymers O
was O
performed O
by O
NMR O
and O
elemental O
analysis O
. O

AGC B
polymers O
demonstrated O
excellent O
blood O
compatibility O
and O
cell O
viability O
, O
as O
evaluated O
by O
hemolysis O
and O
MTT B
assay O
, O
respectively O
. O

AGC O
polymers O
could O
effectively O
bind O
and O
condense O
plasmid O
DNA O
( O
pDNA O
) O
to O
form O
polyplexes O
in O
the O
size O
range O
of O
161 O
- O
263 O
nm O
and O
possessed O
net O
cationic O
charge O
. O

The O
resultant O
polyplex B
showed O
3 O
. O
4 O
- O
5 O
. O
4 O
- O
fold O
greater O
cellular O
uptake O
and O
13 O
- O
30 O
- O
fold O
higher O
transfection O
efficiency O
in O
HEK O
293 O
cells O
as O
compared O
to O
unmodified O
chitosan O
. O

Moreover O
, O
both O
cellular O
uptake O
and O
transfection O
efficiency O
improved O
with O
the O
increasing O
amino B
acid I
hydrophobicity O
. O

Hydrophobic O
amino B
acid I
substitution O
contributed O
to O
the O
enhance O
pDNA O
release O
at O
cytosolic O
pH O
. O

These O
data O
demonstrate O
AGC O
polymers O
as O
a O
promising O
novel O
nonviral O
gene O
delivery O
vector O
. O

Improved O
self O
- O
healing O
of O
polyethylene B
/ O
carbon B
black I
nanocomposites O
by O
their O
shape O
memory O
effect O
. O

In O
this O
work O
, O
the O
improved O
self O
- O
healing O
of O
cross O
- O
linked O
polyethylene B
( O
PE O
) O
( O
cPE O
) O
/ O
carbon B
black I
( O
CB O
) O
nanocomposites O
by O
their O
shape O
memory O
effect O
( O
SME O
) O
is O
investigated O
. O

CB O
nanoparticles O
are O
found O
to O
be O
homogeneously O
dispersed O
in O
the O
PE O
matrix O
and O
significantly O
increase O
the O
strength O
of O
the O
materials O
. O

Compared O
with O
the O
breaking O
of O
linear O
PE O
( O
lPE O
) O
at O
the O
melting O
temperature O
( O
T O
( O
m O
) O
) O
, O
the O
cPE O
and O
cPE O
/ O
CB O
nanocomposites O
still O
have O
high O
strength O
above O
T O
( O
m O
) O
due O
to O
the O
formation O
of O
networks O
. O

The O
cPE O
and O
cPE O
/ O
CB O
nanocomposites O
show O
both O
high O
strain O
fixity O
ratio O
( O
R O
( O
f O
) O
) O
and O
high O
strain O
recovery O
ratio O
( O
R O
( O
r O
) O
) O
. O

Crystallization O
- O
induced O
elongation O
is O
observed O
for O
all O
the O
prepared O
shape O
memory O
polymer O
( O
SMP O
) O
materials O
and O
the O
effect O
becomes O
less O
remarkable O
with O
increasing O
volume O
fraction O
of O
CB O
nanoparticles O
( O
v O
( O
CB O
) O
) O
. O

The O
scratch O
self O
- O
healing O
tests O
show O
that O
the O
cross O
- O
linking O
of O
PE O
matrix O
, O
the O
addition O
of O
CB O
nanoparticles O
, O
and O
the O
previous O
stretching O
in O
the O
direction O
perpendicular O
to O
the O
scratch O
favor O
the O
closure O
of O
the O
scratch O
and O
its O
complete O
healing O
. O

This O
SME O
- O
aided O
self O
- O
healing O
could O
have O
potential O
applications O
in O
diverse O
fields O
such O
as O
coating O
and O
structure O
materials O
. O

Formulation O
study O
of O
a O
patch O
containing O
propranolol B
by O
design O
of O
experiments O
. O

Abstract O
Objective O
: O
To O
evaluate O
the O
feasibility O
of O
a O
transdermal O
patch O
containing O
propranolol B
( O
PR O
) O
. O

Method O
: O
Skin O
penetration O
enhancers O
( O
SPEs O
) O
able O
to O
improve O
the O
skin O
permeability O
of O
PR O
were O
selected O
and O
a O
quality O
by O
design O
approach O
was O
applied O
to O
the O
development O
of O
the O
patch O
by O
a O
2 O
( O
4 O
) O
full O
factorial O
design O
. O

The O
permeation O
profile O
of O
PR O
from O
the O
formulations O
was O
assessed O
in O
in O
vitro O
permeation O
studies O
performed O
by O
using O
Franz O
diffusion O
cells O
and O
human O
epidermis O
as O
membrane O
. O

Finally O
, O
skin O
irritation O
was O
evaluated O
by O
the O
Draize O
test O
. O

Results O
: O
N B
- I
methyl I
pyrrolidone I
( O
NMP B
) O
resulted O
as O
the O
best O
SPE O
: O
in O
addition O
, O
the O
critical O
factors O
influencing O
the O
PR O
diffusion O
through O
the O
human O
epidermis O
when O
loaded O
in O
the O
patch O
resulted O
in O
the O
matrix O
thickness O
( O
X O
( O
1 O
) O
, O
p O
= O
0 O
. O
0957 O
) O
and O
PR O
content O
( O
X O
( O
3 O
) O
, O
p O
= O
0 O
. O
0004 O
) O
which O
improved O
the O
flux O
; O
conversely O
, O
NMP B
lacked O
its O
enhancement O
effect O
when O
loaded O
in O
the O
patch O
and O
the O
increase O
in O
its O
concentration O
( O
X O
( O
4 O
) O
, O
p O
= O
0 O
. O
006 O
) O
affected O
the O
drug O

permeation O
through O
human O
epidermis O
. O

The O
flux O
of O
optimal O
formulation O
was O
12 O
. O
7 O
mu O
g O
/ O
cm O
( O
2 O
) O
/ O
h O
. O

On O
the O
basis O
of O
the O
steady O
- O
state O
concentration O
and O
clearance O
of O
PR O
, O
the O
estimated O
patch O
surface O
was O
100 O
- O
120 O
cm O
( O
2 O
) O
, O
since O
the O
activity O
of O
PR O
is O
related O
to O
its O
Senantiomer O
and O
no O
in O
vivo O
bioconversion O
occurs O
. O

Conclusion O
: O
A O
patch O
containing O
( O
S O
) O
- O
PR O
was O
prepared O
and O
the O
( O
S O
) O
- O
PR O
flux O
( O
13 O
. O
3 O
mu O
g O
/ O
cm O
( O
2 O
) O
/ O
h O
) O
permitted O
to O
confirm O
the O
suitability O
of O
a O
transdermal O
administration O
of O
PR O
. O

In O
particular O
, O
the O
use O
of O
a O
50 O
mu O
m O
thick O
methacrylic B
matrix O
containing O
8 O
% O
( B
S I
) I
- I
PR I
and O
15 O
% O
NMP B
can O
allow O
to O
develop O
a O
patch O
non O
- O
irritating O
to O
the O
skin O
, O
in O
order O
to O
ensure O
a O
constant O
permeation O
flux O
of O
PR O
over O
48 O
h O
. O

Nanoscale O
Dynamics O
and O
Protein O
Adhesivity O
of O
Alkylamine B
Self O
- O
Assembled O
Monolayers O
on O
Graphene B
. O

Atomic O
- O
scale O
molecular O
dynamics O
computer O
simulations O
are O
used O
to O
probe O
the O
structure O
, O
dynamics O
, O
and O
energetics O
of O
alkylamine B
self O
- O
assembled O
monolayer O
( O
SAM O
) O
films O
on O
graphene B
and O
to O
model O
the O
formation O
of O
molecular O
bilayers O
and O
protein O
complexes O
on O
the O
films O
. O

Routes O
toward O
the O
development O
and O
exploitation O
of O
functionalized O
graphene B
structures O
are O
detailed O
here O
, O
and O
we O
show O
that O
the O
SAM O
architecture O
can O
be O
tailored O
for O
use O
in O
emerging O
applications O
( O
e O
. O
g O
. O
, O
electrically O
stimulated O
nerve O
fiber O
growth O
via O
the O
targeted O
binding O
of O
specific O
cell O
surface O
peptide O
sequences O
on O
the O
functionalized O
graphene B
scaffold O
) O
. O

The O
simulations O
quantify O
the O
changes O
in O
film O
physisorption O
on O
graphene B
and O
the O
alkyl O
chain O
packing O
efficiency O
as O
the O
film O
surface O
is O
made O
more O
polar O
by O
changing O
the O
terminal O
groups O
from O
methyl B
( O
- O
CH B
( I
3 I
) I
) O
to O
amine B
( O
- O
NH B
( I
2 I
) I
) O
to O
hydroxyl B
( O
- O
OH B
) O
. O

The O
mode O
of O
molecule O
packing O
dictates O
the O
orientation O
and O
spacing O
between O
terminal O
groups O
on O
the O
surface O
of O
the O
SAM O
, O
which O
determines O
the O
way O
in O
which O
successive O
layers O
build O
up O
on O
the O
surface O
, O
whether O
via O
the O
formation O
of O
bilayers O
of O
the O
molecule O
or O
the O
immobilization O
of O
other O
( O
macro O
) O
molecules O
( O
e O
. O
g O
. O
, O
proteins O
) O
on O
the O
SAM O
. O

The O
simulations O
show O
the O
formation O
of O
ordered O
, O
stable O
assemblies O
of O
monolayers O
and O
bilayers O
of O
decylamine B
- O
based O
molecules O
on O
graphene B
. O

These O
films O
can O
serve O
as O
protein O
adsorption O
platforms O
, O
with O
a O
hydrophobin O
protein O
showing O
strong O
and O
selective O
adsorption O
by O
binding O
via O
its O
hydrophobic O
patch O
to O
methyl B
- O
terminated O
films O
and O
binding O
to O
amine B
- O
terminated O
films O
using O
its O
more O
hydrophilic O
surface O
regions O
. O

Design O
rules O
obtained O
from O
modeling O
the O
atomic O
- O
scale O
structure O
of O
the O
films O
and O
interfaces O
may O
provide O
input O
into O
experiments O
for O
the O
rational O
design O
of O
assemblies O
in O
which O
the O
electronic O
, O
physicochemical O
, O
and O
mechanical O
properties O
of O
the O
substrate O
, O
film O
, O
and O
protein O
layer O
can O
be O
tuned O
to O
provide O
the O
desired O
functionality O
. O

Inelastic O
X O
- O
ray O
scattering O
studies O
of O
the O
short O
- O
time O
collective O
vibrational O
motions O
in O
hydrated O
lysozyme O
powders O
and O
their O
possible O
relation O
to O
enzymatic O
function O
. O

High O
- O
resolution O
inelastic O
X O
- O
ray O
scattering O
was O
used O
to O
investigate O
the O
collective O
vibrational O
excitations O
in O
hydrated O
lysozyme O
powders O
as O
a O
function O
of O
hydration O
level O
and O
temperature O
. O

It O
is O
found O
that O
the O
samples O
with O
strong O
enzymatic O
function O
are O
" O
soft O
" O
, O
in O
the O
sense O
that O
they O
exhibit O
low O
frequency O
and O
large O
amplitude O
intraprotein O
collective O
vibrational O
motions O
on O
certain O
length O
scales O
. O

This O
is O
not O
the O
case O
for O
samples O
with O
weak O
or O
no O
enzymatic O
activity O
. O

Thus O
, O
we O
identify O
a O
possible O
correlation O
between O
the O
short O
- O
time O
intraprotein O
collective O
vibrational O
motions O
and O
the O
establishment O
of O
enzymatic O
function O
in O
hydrated O
lysozyme O
powders O
, O
and O
bring O
new O
insight O
to O
notions O
of O
protein O
" O
conformational O
flexibility O
" O
and O
" O
softness O
" O
in O
terms O
of O
these O
motions O
. O

In O
vitro O
evaluation O
of O
( B
99m I
) I
Tc I
- I
EDDA I
/ O
tricine B
- I
HYNIC I
- I
Q I
- I
Litorin I
in O
gastrin O
- O
releasing O
peptide O
receptor O
positive O
tumor O
cell O
lines O
. O

Abstract O
Bombesin B
and O
its O
derivatives O
exhibit O
a O
high O
affinity O
for O
gastrin O
- O
releasing O
peptide O
receptor O
( O
GRPr O
) O
, O
which O
is O
over O
- O
expressed O
in O
a O
variety O
of O
human O
cancers O
( O
prostate O
, O
pancreatic O
, O
lung O
, O
etc O
. O
) O
. O

The O
aim O
of O
this O
study O
was O
to O
investigate O
the O
in O
vitro O
potential O
of O
the O
hydrazinonicotinamid B
( O
HYNIC B
) O
- O
Q B
- O
Litorin B
. O

( B
99m I
) I
Tc I
labeling O
was O
performed O
by O
using O
different O
co O
- O
ligands O
: O
tricine B
and O
ethylenediamine B
diacetic I
acid I
( O
EDDA B
) O
. O

The O
radiochemical O
stability O
of O
radiolabeled O
peptide O
conjugates O
was O
checked O
at O
room O
temperature O
and O
in O
cysteine B
solution O
up O
to O
24 O
h O
. O

The O
in O
vitro O
cell O
uptake O
of O
( B
99m I
) I
Tc I
- I
EDDA I
- I
HYNIC I
- I
Q I
- I
Litorin I
and O
( B
99m I
) I
Tc I
- I
tricine I
- I
HYNIC I
- I
Q I
- I
Litorin I
were O
evaluated O
on O
pancreatic O
tumor O
and O
control O
cell O
lines O
. O

Optimum O
specific O
activity O
and O
incubation O
time O
were O
determined O
for O
all O
the O
cell O
lines O
. O

The O
results O
showed O
that O
the O
cell O
uptake O
of O
the O
radiolabeled O
peptide O
conjugates O
in O
tumor O
cell O
lines O
were O
higher O
than O
in O
the O
control O
cell O
line O
. O

The O
findings O
of O
this O
study O
indicated O
the O
need O
for O
further O
development O
of O
in O
vivo O
study O
as O
a O
radiopharmaceutical O
for O
pancreatic O
tumor O
imaging O
. O

Single O
- O
walled O
carbon B
nanotube O
surface O
control O
of O
complement O
recognition O
and O
activation O
. O

Carbon B
nanotubes O
( O
CNTs O
) O
are O
receiving O
considerable O
attention O
in O
site O
- O
specific O
drug O
and O
nucleic O
acid O
delivery O
, O
photodynamic O
therapy O
, O
and O
photoacoustic O
molecular O
imaging O
. O

Despite O
these O
advances O
, O
nanotubes O
may O
activate O
the O
complement O
system O
( O
an O
integral O
part O
of O
innate O
immunity O
) O
, O
which O
can O
induce O
clinically O
significant O
anaphylaxis O
. O

We O
demonstrate O
that O
single O
- O
walled O
CNTs O
coated O
with O
human O
serum O
albumin O
activate O
the O
complement O
system O
through O
C1q O
- O
mediated O
classical O
and O
the O
alternative O
pathways O
. O

Surface O
coating O
with O
methoxypoly B
( I
ethylene I
glycol I
) I
- O
based O
amphiphiles O
, O
which O
confers O
solubility O
and O
prolongs O
circulation O
profiles O
of O
CNTs O
, O
activates O
the O
complement O
system O
differently O
, O
depending O
on O
the O
amphiphile O
structure O
. O

CNTs O
with O
linear O
poly B
( I
ethylene I
glycol I
) I
amphiphiles O
trigger O
the O
lectin O
pathway O
of O
the O
complement O
through O
both O
L O
- O
ficolin O
and O
mannan O
- O
binding O
lectin O
recognition O
. O

The O
lectin O
pathway O
activation O
, O
however O
, O
did O
not O
trigger O
the O
amplification O
loop O
of O
the O
alternative O
pathway O
. O

An O
amphiphile O
with O
branched O
poly B
( I
ethylene I
glycol I
) I
architecture O
also O
activated O
the O
lectin O
pathway O
but O
only O
through O
L O
- O
ficolin O
recognition O
. O

Importantly O
, O
this O
mode O
of O
activation O
neither O
generated O
anaphylatoxins O
nor O
induced O
triggering O
of O
the O
effector O
arm O
of O
the O
complement O
system O
. O

These O
observations O
provide O
a O
major O
step O
toward O
nanomaterial O
surface O
modification O
with O
polymers O
that O
have O
the O
properties O
to O
significantly O
improve O
innate O
immunocompatibility O
by O
limiting O
the O
formation O
of O
complement O
C3 O
and O
C5 O
convertases O
. O

Synthesis O
of O
novel O
phosphorylated B
guanidine I
derivatives O
from O
cyanamide B
and O
their O
anti O
- O
inflammatory O
activity O
. O

A O
series O
of O
novel O
guanidine B
derivatives O
were O
synthesized O
in O
three O
steps O
and O
their O
anti O
- O
inflammatory O
activities O
in O
vitro O
and O
in O
vivo O
evaluated O
. O

2 B
- I
Aminopyridin I
- I
3 I
- I
ol I
( O
1 O
) O
was O
reacted O
with O
thiophosphoryl B
chloride I
( O
2 O
) O
to O
give O
a O
monochloride B
( O
3 O
) O
. O

It O
was O
further O
reacted O
with O
cyanamide B
to O
afford O
the O
corresponding O
cyanamine B
( O
4 O
) O
, O
which O
was O
subsequently O
reacted O
with O
different O
heterocyclic B
amines I
to O
form O
the O
title O
compounds O
( O
5a O
- O
l O
) O
. O

The O
substituent O
in O
the O
guanidine B
function O
affected O
the O
potency O
of O
anti O
- O
inflammatory O
activity O
. O

The O
compounds O
having O
benzothiazole B
, O
fluorophenyl B
, O
and O
piperazinyl B
moieties O
enhanced O
the O
anti O
- O
inflammatory O
activity O
. O

Discovering O
some O
novel O
7 B
- I
chloroquinolines I
carrying O
a O
biologically O
active O
benzenesulfonamide B
moiety O
as O
a O
new O
class O
of O
anticancer O
agents O
. O

Based O
on O
the O
reported O
anticancer O
activity O
of O
quinolines B
, O
a O
new O
series O
of O
7 B
- I
chloroquinoline I
derivatives O
bearing O
the O
biologically O
active O
benzenesulfonamide B
moiety O
2 O
- O
17 O
and O
19 O
- O
25 O
were O
synthesized O
starting O
with O
4 B
, I
7 I
- I
dichloroquinolne I
1 O
. O

Compound O
17 O
was O
the O
most O
active O
compound O
with O
IC O
( O
50 O
) O
value O
64 O
. O
41 O
, O
75 O
. O
05 O
and O
30 O
. O
71 O
micro O
M O
compared O
with O
Doxorubicin B
as O
reference O
drug O
with O
IC O
( O
50 O
) O
values O
82 O
. O
53 O
, O
88 O
. O
32 O
and O
73 O
. O
72 O
micro O
M O
on O
breast O
cancer O
cells O
, O
skin O
cancer O
cells O
and O
neuroblastoma O
, O
respectively O
. O

All O
the O
synthesized O
compounds O
were O
evaluated O
for O
their O
in O
vitro O
anticancer O
activity O
on O
breast O
cancer O
cells O
, O
skin O
cancer O
cells O
and O
neuroblastoma O
cells O
. O

Most O
of O
the O
synthesized O
compounds O
showed O
moderate O
activity O
. O

In O
order O
to O
suggest O
the O
mechanism O
of O
action O
for O
their O
cytotoxic O
activity O
, O
molecular O
docking O
for O
all O
synthesized O
compounds O
was O
done O
on O
the O
active O
site O
of O
phosphoinositide O
kinase O
( O
PI3K O
) O
and O
good O
results O
were O
obtained O
. O

Syntheses O
of O
2 B
- I
deoxy I
- I
2 I
, I
3 I
- I
didehydro I
- I
N I
- I
acetylneuraminic I
acid I
analogues O
modified O
by O
alpha B
- I
acylaminoamido I
groups O
at O
the O
C O
- O
4 O
position O
using O
isocyanide B
- O
based O
four O
- O
component O
coupling O
and O
biological O
evaluation O
as O
inhibitors O
of O
human O
parainfluenza O
virus O
type O
1 O
. O

Novel O
sialidase O
inhibitors O
11 O
having O
an O
alpha B
- I
acylaminoamido I
group O
at O
the O
C O
- O
4 O
position O
of O
Neu5Ac2en B
1 O
against O
human O
parainfluenza O
virus O
type O
1 O
( O
hPIV O
- O
1 O
) O
were O
synthesized O
using O
one O
- O
pot O
isocyanide B
- O
based O
four O
- O
component O
condensation O
, O
and O
their O
inhibitory O
activities O
against O
hPIV O
- O
1 O
sialidase O
were O
studied O
. O

Compound O
11b O
showed O
inhibitory O
activity O
( O
IC O
( O
50 O
) O
= O
5 O
. O
1 O
mM O
) O
against O
hPIV O
- O
1 O
sialidase O
. O

The O
degree O
of O
inhibition O
of O
11b O
was O
much O
weaker O
than O
that O
of O
1 O
( O
IC O
( O
50 O
) O
= O
0 O
. O
3 O
mM O
) O
. O

Two O
new O
triterpenoid B
saponins I
from O
the O
root O
of O
Platycodon O
grandiflorum O
. O

Two O
new O
triterpenoid B
saponins I
, O
named O
platycodon B
A I
( O
3 B
- I
O I
- I
beta I
- I
D I
- I
glucopyranosyl I
- I
16 I
- I
O I
- I
beta I
- I
D I
- I
glucopyranosyl I
- I
2 I
beta I
, I
3 I
beta I
, I
16 I
beta I
, I
21 I
beta I
- I
tetrahydroxyolean I
- I
12 I
- I
en I
- I
28 I
- I
oic I
acid I
) O
and O
platycodon B
B I
( O
3 B
- I
O I
- I
beta I
- I
D I
- I
glucopyranosyl I
- I
16 I
- I
O I
- I
beta I
- I
D I
- I
xylopyranosyl I
- I
2 I
beta I
, I
3 I
beta I
, I
16 I
beta I

, I
21 I
beta I
- I
tetrahydroxyolean I
- I
12 I
- I
en I
- I
28 I
- I
oic I
acid I
) O
were O
isolated O
from O
the O
roots O
of O
Platycodon O
grandiflorum O
. O

The O
structures O
of O
these O
compounds O
were O
elucidated O
by O
means O
of O
various O
spectroscopic O
analyses O
. O

Compounds O
1 O
and O
2 O
were O
tested O
in O
HepG O
- O
2 O
, O
A549 O
and O
DU145 O
human O
cancer O
cell O
lines O
and O
showed O
remarkable O
cytotoxic O
activities O
against O
HepG O
- O
2 O
and O
A549 O
cancer O
cell O
lines O
with O
IC O
( O
50 O
) O
values O
ranging O
from O
4 O
. O
9 O
to O
9 O
. O
4 O
micro O
M O
, O
but O
they O
displayed O
weak O
cytotoxic O
activities O
against O
DU145 O
cancer O
cell O
line O
with O
IC O
( O
50 O
) O
values O
greater O
than O
10 O
micro O
M O
. O

Comparative O
toxicity O
of O
eight O
metals O
on O
freshwater O
fish O
. O

Two O
freshwater O
fish O
, O
Rasbora O
sumatrana O
( O
Cyprinidae O
) O
and O
Poecilia O
reticulata O
( O
guppy O
; O
Poeciliidae O
) O
, O
were O
exposed O
to O
a O
range O
of O
eight O
heavy O
metals O
( O
copper B
( O
Cu B
) O
, O
cadmium B
( O
Cd B
) O
, O
zinc B
( O
Zn B
) O
, O
lead O
( O
Pb B
) O
, O
nickel B
( O
Ni B
) O
, O
iron B
( O
Fe B
) O
, O
aluminium B
( O
Al B
) O
, O
and O
manganese B
( O
Mn B
) O
) O
at O
varied O
concentrations O
for O
96 O
h O
in O
the O
laboratory O
. O

Mortality O
was O
assessed O
and O
median O
lethal O
concentrations O
( O
LC O
( O
50 O
) O
) O
were O
calculated O
. O

It O
was O
observed O
that O
the O
LC O
( O
50 O
) O
values O
increased O
with O
a O
decrease O
in O
mean O
exposure O
times O
, O
for O
all O
metals O
and O
for O
both O
fish O
types O
. O

The O
96 O
- O
h O
LC O
( O
50 O
) O
values O
for O
Cu B
, O
Cd B
, O
Zn B
, O
Pb B
, O
Ni B
, O
Fe B
, O
Al B
, O
and O
Mn B
were O
0 O
. O
006 O
, O
0 O
. O
10 O
, O
0 O
. O
46 O
, O
0 O
. O
63 O
, O
0 O
. O
83 O
, O
1 O
. O
71 O
, O
1 O
. O
53 O
, O
and O
5 O
. O
71 O
mg O
/ O
L O
for O
R O
. O
sumatrana O
and O
0 O
. O
038 O
, O
0 O
. O
17 O
, O
1 O
. O
06 O
, O
1 O
. O
99 O
, O
15 O
. O
62 O
, O
1 O
. O
46 O
, O
6 O
. O
76 O
, O
and O
23 O
. O
91 O
mg O
/ O
L O
for O
P O
. O
reticulata O
, O
respectively O
. O

The O
metal O
toxicity O
trend O
for O
R O
. O
sumatrana O
and O
P O
. O
reticulata O
from O
most O
to O
least O
toxic O
was O
Cu B
> O
Cd B
> O
Zn B
> O
Pb B
> O
Ni B
> O
Al B
> O
Fe B
> O
Mn B
and O
Cu B
> O
Cd B
> O
Zn B
> O
Fe B
> O
Pb B
> O
Al B
> O
Ni B
> O
Mn B
, O
respectively O
. O

Results O
indicated O
that O
Cu B
was O
the O
most O
toxic O
metal O
on O
both O
fish O
, O
and O
R O
. O
sumatrana O
was O
more O
sensitive O
than O
P O
. O
reticulata O
to O
all O
the O
eight O
metals O
. O

Vertical O
flow O
immunoassay O
( O
VFA O
) O
biosensor O
for O
a O
rapid O
one O
- O
step O
immunoassay O
. O

A O
highly O
rapid O
, O
one O
- O
step O
immunoassay O
of O
high O
sensitivity O
C O
- O
reactive O
protein O
( O
hsCRP O
) O
using O
a O
biosensor O
with O
a O
vertical O
flow O
immunoassay O
( O
VFA O
) O
was O
developed O
. O

The O
VFA O
biosensor O
was O
primarily O
composed O
of O
a O
sample O
pad O
, O
conjugate O
pad O
, O
FTH O
film O
and O
nitrocellulose O
( O
NC O
) O
membrane O
, O
which O
were O
all O
vertically O
stacked O
upon O
one O
another O
. O

Anti O
- O
hsCRP O
and O
secondary O
antibodies O
were O
consecutively O
immobilized O
on O
the O
NC O
membrane O
at O
the O
position O
below O
the O
holes O
. O

Gold O
nanoparticles O
( O
AuNPs O
) O
conjugated O
with O
another O
anti O
- O
hsCRP O
antibody O
were O
encapsulated O
in O
the O
conjugation O
pad O
. O

Various O
assay O
conditions O
, O
including O
the O
size O
of O
the O
hole O
and O
the O
sample O
volume O
, O
were O
optimized O
. O

Under O
optimized O
conditions O
, O
hsCRP O
concentrations O
from O
0 O
. O
01 O
to O
10 O
mu O
g O
mL O
( O
- O
1 O
) O
were O
detected O
within O
2 O
min O
. O

In O
comparison O
with O
a O
lateral O
flow O
assay O
( O
LFA O
) O
system O
, O
the O
VFA O
sensor O
showed O
a O
gradual O
increase O
of O
signal O
in O
a O
concentration O
- O
dependent O
manner O
without O
a O
hook O
effect O
in O
the O
tested O
range O
. O

Synthesis O
and O
characterization O
of O
an O
MRI O
Gd B
- O
based O
probe O
designed O
to O
target O
the O
translocator O
protein O
. O

DPA B
- I
713 I
is O
the O
lead O
compound O
of O
a O
recently O
reported O
pyrazolo B
[ I
1 I
, I
5 I
- I
a I
] I
pyrimidineacetamide I
series O
, O
targeting O
the O
translocator O
protein O
( O
TSPO O
18 O
kDa O
) O
, O
and O
as O
such O
, O
this O
structure O
, O
as O
well O
as O
closely O
related O
derivatives O
, O
have O
been O
already O
successfully O
used O
as O
positron O
emission O
tomography O
radioligands O
. O

On O
the O
basis O
of O
the O
pharmacological O
core O
of O
this O
ligands O
series O
, O
a O
new O
magnetic O
resonance O
imaging O
probe O
, O
coded O
DPA B
- I
C I
( I
6 I
) I
- I
( I
Gd I
) I
DOTAMA I
was O
designed O
and O
successfully O
synthesized O
in O
six O
steps O
and O
13 O
% O
overall O
yield O
from O
DPA B
- I
713 I
. O

The O
Gd B
- I
DOTA I
monoamide I
cage O
( O
DOTA B
= O
1 B
, I
4 I
, I
7 I
, I
10 I
- I
tetraazacyclododecan I
- I
1 I
, I
4 I
, I
7 I
, I
10 I
- I
tetraacetic I
acid I
) O
represents O
the O
magnetic O
resonance O
imaging O
reporter O
, O
which O
is O
spaced O
from O
the O
phenylpyrazolo B
[ I
1 I
, I
5 I
- I
a I
] I
pyrimidineacetamide I
moiety O
( O
DPA B
- I
713 I
motif O
) O
by O
a O
six O
carbon B
- O
atom O
chain O
. O

DPA B
- I
C I
( I
6 I
) I
- I
( I
Gd I
) I
DOTAMA I
relaxometric O
characterization O
showed O
the O
typical O
behavior O
of O
a O
small O
- O
sized O
molecule O
( O
relaxivity O
value O
: O
6 O
. O
02 O
mM O
( O
- O
1 O
) O
s O
( O
- O
1 O
) O
at O
20 O
MHz O
) O
. O

The O
good O
hydrophilicity O
of O
the O
metal O
chelate O
makes O
DPA B
- I
C I
( I
6 I
) I
- I
( I
Gd I
) I
DOTAMA I
soluble O
in O
water O
, O
affecting O
thus O
its O
biodistribution O
with O
respect O
to O
the O
parent O
lipophilic O
DPA B
- I
713 I
molecule O
. O

For O
this O
reason O
, O
it O
was O
deemed O
of O
interest O
to O
load O
the O
probe O
to O
a O
large O
carrier O
in O
order O
to O
increase O
its O
residence O
lifetime O
in O
blood O
. O

Whereas O
DPA B
- I
C I
( I
6 I
) I
- I
( I
Gd I
) I
DOTAMA I
binds O
to O
serum O
albumin O
with O
a O
low O
affinity O
constant O
, O
it O
can O
be O
entrapped O
into O
liposomes O
( O
both O
in O
the O
membrane O
and O
in O
the O
inner O
aqueous O
cavity O
) O
. O

The O
stability O
of O
the O
supramolecular O
adduct O
formed O
by O
the O
Gd B
- O
complex O
and O
liposomes O
was O
assessed O
by O
a O
competition O
test O
with O
albumin O
. O

2 B
- I
Carbaborane I
- I
3 I
- I
phenyl I
- I
1H I
- I
indoles I
- O
- O
synthesis O
via O
McMurry O
reaction O
and O
cyclooxygenase O
( O
COX O
) O
inhibition O
activity O
. O

Cyclooxygenase O
- O
2 O
( O
COX O
- O
2 O
) O
inhibitors O
have O
been O
the O
focus O
of O
medicinal O
chemistry O
efforts O
for O
years O
, O
and O
many O
compounds O
that O
exhibit O
high O
selectivity O
and O
affinity O
have O
been O
developed O
. O

As O
carbaboranes B
represent O
interesting O
pharmacophores O
as O
phenyl B
mimetics O
in O
drug O
development O
, O
this O
paper O
presents O
the O
synthesis O
of O
carbaboranyl B
derivatives O
of O
COX O
- O
2 O
- O
selective O
2 B
, I
3 I
- I
disubstituted I
indoles I
. O

Despite O
the O
lability O
of O
carbaboranes B
under O
reducing O
conditions O
, O
2 B
- I
carbaborane I
- I
3 I
- I
phenyl I
- I
1H I
- I
indoles I
could O
be O
synthesized O
by O
McMurry O
cyclization O
of O
the O
corresponding O
amides B
. O

Whereas O
the O
meta B
- I
carbaboranyl I
- O
substituted O
derivatives O
lacked O
COX O
inhibitory O
activity O
, O
an O
ortho B
- I
carbaboranyl I
analogue O
was O
active O
, O
but O
showed O
a O
selectivity O
shift O
toward O
COX O
- O
1 O
. O

Unwinding O
of O
primer O
- O
templates O
by O
archaeal O
family O
- O
B O
DNA O
polymerases O
in O
response O
to O
template O
- O
strand O
uracil B
. O

Archaeal O
family O
- O
B O
DNA O
polymerases O
bind O
tightly O
to O
deaminated O
bases O
and O
stall O
replication O
on O
encountering O
uracil B
in O
template O
strands O
, O
four O
bases O
ahead O
of O
the O
primer O
- O
template O
junction O
. O

Should O
the O
polymerase O
progress O
further O
towards O
the O
uracil B
, O
for O
example O
, O
to O
position O
uracil B
only O
two O
bases O
in O
front O
of O
the O
junction O
, O
3 O
' O
- O
5 O
' O
proof O
- O
reading O
exonuclease O
activity O
becomes O
stimulated O
, O
trimming O
the O
primer O
and O
re O
- O
setting O
uracil B
to O
the O
+ O
4 O
position O
. O

Uracil B
sensing O
prevents O
copying O
of O
the O
deaminated O
base O
and O
permanent O
mutation O
in O
50 O
% O
of O
the O
progeny O
. O

This O
publication O
uses O
both O
steady O
- O
state O
and O
time O
- O
resolved O
2 B
- I
aminopurine I
fluorescence O
to O
show O
pronounced O
unwinding O
of O
primer O
- O
templates O
with O
Pyrococcus O
furiosus O
( O
Pfu O
) O
polymerase O
- O
DNA O
complexes O
containing O
uracil B
at O
+ O
2 O
; O
much O
less O
strand O
separation O
is O
seen O
with O
uracil B
at O
+ O
4 O
. O

DNA O
unwinding O
has O
long O
been O
recognized O
as O
necessary O
for O
proof O
- O
reading O
exonuclease O
activity O
. O

The O
roles O
of O
M247 O
and O
Y261 O
, O
amino B
acids I
suggested O
by O
structural O
studies O
to O
play O
a O
role O
in O
primer O
- O
template O
unwinding O
, O
have O
been O
probed O
. O

M247 O
appears O
to O
be O
unimportant O
, O
but O
2 B
- I
aminopurine I
fluorescence O
measurements O
show O
that O
Y261 O
plays O
a O
role O
in O
primer O
- O
template O
strand O
separation O
. O

Y261 O
is O
also O
required O
for O
full O
exonuclease O
activity O
and O
contributes O
to O
the O
fidelity O
of O
the O
polymerase O
. O

An O
evolutionarily O
conserved O
signaling O
mechanism O
mediates O
far O
- O
red O
light O
responses O
in O
land O
plants O
. O

Phytochromes O
are O
plant O
photoreceptors O
important O
for O
development O
and O
adaptation O
to O
the O
environment O
. O

Phytochrome O
A O
( O
PHYA O
) O
is O
essential O
for O
the O
far O
- O
red O
( O
FR O
) O
high O
- O
irradiance O
responses O
( O
HIRs O
) O
, O
which O
are O
of O
particular O
ecological O
relevance O
as O
they O
enable O
plants O
to O
establish O
under O
shade O
conditions O
. O

PHYA O
and O
HIRs O
have O
been O
considered O
unique O
to O
seed O
plants O
because O
the O
divergence O
of O
seed O
plants O
and O
cryptogams O
( O
e O
. O
g O
. O
, O
ferns O
and O
mosses O
) O
preceded O
the O
evolution O
of O
PHYA O
. O

Seed O
plant O
phytochromes O
translocate O
into O
the O
nucleus O
and O
regulate O
gene O
expression O
. O

By O
contrast O
, O
there O
has O
been O
little O
evidence O
of O
a O
nuclear O
localization O
and O
function O
of O
cryptogam O
phytochromes O
. O

Here O
, O
we O
identified O
responses O
to O
FR O
light O
in O
cryptogams O
, O
which O
are O
highly O
reminiscent O
of O
PHYA O
signaling O
in O
seed O
plants O
. O

In O
the O
moss O
Physcomitrella O
patens O
and O
the O
fern O
Adiantum O
capillus O
- O
veneris O
, O
phytochromes O
accumulate O
in O
the O
nucleus O
in O
response O
to O
light O
. O

Although O
P O
. O
patens O
phytochromes O
evolved O
independently O
of O
PHYA O
, O
we O
have O
found O
that O
one O
clade O
of O
P O
. O
patens O
phytochromes O
exhibits O
the O
molecular O
properties O
of O
PHYA O
. O

We O
suggest O
that O
HIR O
- O
like O
responses O
had O
evolved O
in O
the O
last O
common O
ancestor O
of O
modern O
seed O
plants O
and O
cryptogams O
and O
that O
HIR O
signaling O
is O
more O
ancient O
than O
PHYA O
. O

Thus O
, O
other O
phytochromes O
in O
seed O
plants O
may O
have O
lost O
the O
capacity O
to O
mediate O
HIRs O
during O
evolution O
, O
rather O
than O
that O
PHYA O
acquired O
it O
. O

Current O
progresses O
of O
novel O
natural O
products O
and O
their O
derivatives O
/ O
analogs O
as O
anti O
- O
Alzheimer O
candidates O
: O
an O
update O
. O

Alzheimer O
' O
s O
disease O
( O
AD O
) O
is O
one O
of O
the O
most O
threatening O
diseases O
affecting O
the O
aged O
with O
high O
incidence O
. O

Though O
AD O
has O
been O
defined O
for O
more O
than O
100 O
years O
, O
it O
is O
still O
incurable O
. O

The O
drugs O
clinically O
used O
for O
the O
treatment O
of O
this O
disease O
, O
such O
as O
acetylcholinesterase O
inhibitors O
( O
AChEIs O
) O
and O
N B
- I
methyl I
- I
D I
- I
aspartate I
( O
NMDA B
) O
receptor O
antagonist O
, O
can O
only O
provide O
a O
limited O
therapeutic O
effect O
. O

The O
need O
of O
effective O
drugs O
has O
stimulated O
the O
search O
for O
new O
compounds O
with O
potential O
clinical O
utility O
. O

Natural O
products O
are O
rich O
and O
unexplored O
sources O
for O
discovering O
novel O
leading O
compounds O
. O

Currently O
, O
a O
great O
number O
of O
natural O
products O
have O
been O
found O
possessing O
anti O
- O
AD O
property O
counteracting O
different O
etiological O
factors O
of O
AD O
. O

This O
review O
will O
give O
an O
update O
demonstration O
on O
the O
novel O
anti O
- O
AD O
natural O
products O
and O
their O
derivatives O
/ O
analogues O
, O
which O
have O
been O
divided O
into O
five O
subgroups O
according O
to O
their O
different O
action O
mechanisms O
: O
AChEIs O
, O
antioxidants O
, O
neuroprotective O
agents O
, O
monoamine B
oxidase O
( O
MAO O
) O
inhibitors O
, O
and O
tau O
hyperphosphorylation O
inhibitors O
. O

We O
put O
special O
emphasis O
on O
the O
findings O
in O
the O
past O
5 O
years O
. O

Besides O
, O
the O
drug O
design O
strategy O
as O
well O
as O
the O
structure O
- O
activity O
relationship O
of O
the O
relevant O
compounds O
is O
also O
discussed O
when O
it O
is O
possible O
. O

Comparison O
of O
antiproliferative O
effects O
of O
metformine B
and O
progesterone B
on O
estrogen B
- O
induced O
endometrial O
hyperplasia O
in O
rats O
. O

Metformin B
has O
been O
shown O
to O
inhibit O
the O
growth O
of O
endometriotic O
implants O
, O
and O
reverse O
endometrial O
hyperplasia O
when O
combined O
with O
oral O
contraceptive O
in O
a O
case O
report O
. O

The O
aim O
of O
this O
study O
is O
to O
compare O
the O
antiproliferative O
effects O
of O
medroxyprogesterone B
acetate I
( O
MPA B
) O
, O
and O
metformin B
in O
oopherectomized O
rat O
endometrium O
. O

Forty O
oopherectomized O
Wistar O
- O
Albino O
rats O
were O
used O
, O
and O
assigned O
to O
receive O
saline O
, O
17 B
beta I
Estradiol I
hemihydrate I
( O
4 O
mg O
/ O
kg O
) O
, O
17 B
beta I
Estradiol I
hemihydrate I
( O
4 O
mg O
/ O
kg O
) O
and O
metformin B
( O
50 O
mg O
/ O
kg O
) O
, O
17 B
beta I
Estradiol I
hemihydrate I
( O
4 O
mg O
/ O
kg O
) O
and O
MPA B
( O
1 O
mg O
/ O
day O
) O
for O
14 O
days O
. O

Histological O
markers O
of O
uterotrophy O
, O
including O
endometrial O
height O
, O
luminal O
ephitelial O
cell O
height O
and O
density O
of O
endometrial O
glands O
on O
hysterectomy O
speciments O
were O
quantified O
for O
each O
specimen O
. O

Rats O
treated O
with O
estradiol B
had O
significantly O
increased O
in O
endometrial O
height O
, O
endomerial O
luminal O
epithelial O
height O
and O
endometrial O
gland O
densitiy O
than O
the O
other O
groups O
. O

Metformin B
and O
MPA B
acetate I
significantly O
reduced O
all O
parameters O
indicating O
endometrial O
hyperplasia O
, O
and O
uterotrophy O
with O
respect O
to O
the O
control O
group O
. O

Antiproliferative O
effects O
of O
metformin B
, O
and O
MPA B
was O
found O
to O
be O
comparable O
for O
all O
three O
parameters O
. O

In O
conclusion O
, O
metformin B
attenuates O
estrogen B
- O
induced O
endometrial O
hyperplasia O
in O
ooferectomized O
rats O
to O
the O
same O
degree O
as O
progesterone B
. O

Photophysical O
and O
electrochemical O
investigations O
of O
the O
fluorescent O
probe O
, O
4 B
, I
4 I
' I
- I
bis I
( I
2 I
- I
benzoxazolyl I
) I
stilbene I
. O

In O
solution O
, O
4 B
, I
4 I
' I
- I
bis I
( I
2 I
- I
benzoxazolyl I
) I
stilbene I
( O
BBS B
) O
was O
found O
to O
exhibit O
consistently O
high O
absolute O
fluorescence O
quantum O
yields O
( O
Phi O
( O
fl O
) O
> O
= O
0 O
. O
88 O
) O
and O
a O
monoexponential O
lifetime O
, O
both O
independent O
of O
BBS B
concentration O
. O

The O
BBS O
steady O
- O
state O
and O
time O
- O
resolved O
photophysics O
were O
investigated O
by O
different O
techniques O
to O
understand O
the O
various O
deactivation O
pathways O
. O

Nonradiative O
deactivation O
of O
BBS B
singlet O
excited O
state O
by O
intersystem O
crossing O
was O
found O
to O
be O
negligible O
. O

Other O
than O
fluorescence O
, O
the O
excited O
state O
of O
BBS B
was O
found O
to O
be O
deactivated O
by O
trans O
- O
cis O
photoisomerization O
. O

At O
low O
concentrations O
( O
= O
~ O
5 O
mu O
g O
/ O
mL O
) O
, O
UV O
spectroscopy O
and O
laser O
flash O
photolysis O
showed O
concordant O
results O
that O
the O
photoinduced O
cis O
isomer O
gradually O
replaced O
the O
original O
absorption O
spectrum O
of O
the O
pure O
trans O
isomer O
. O

However O
, O
at O
high O
concentrations O
( O
= O
~ O
0 O
. O
2 O
mg O
/ O
mL O
) O
, O
( B
1 I
) I
H I
NMR O
and O
DOSY O
measurements O
confirmed O
that O
irradiating O
BBS O
at O
350 O
nm O
induced O
a O
conversion O
from O
the O
trans B
- I
BBS I
into O
its O
cis O
isomer O
by O
photoisomerization O
. O

It O
was O
further O
found O
that O
the O
stilbene B
moiety O
of O
both O
isomers O
was O
photocleaved O
. O

The O
resulting O
photoproduct O
was O
an O
aldehyde B
that O
was O
oxidized O
under O
ambient O
conditions O
to O
its O
corresponding O
carboxylic B
acid I
, O
i O
. O
e O
. O
, O
4 B
- I
( I
1 I
, I
3 I
- I
benzoxazol I
- I
2 I
- I
yl I
) I
benzoic I
acid I
. O

The O
structure O
of O
the O
photoproduct O
was O
unequivocally O
confirmed O
by O
X O
- O
ray O
diffraction O
. O

Spectroscopic O
investigation O
of O
BBS O
showed O
a O
limited O
photoisomerization O
after O
irradiation O
at O
350 O
nm O
of O
a O
trans O
solution O
. O

The O
BBS O
electrochemistry O
showed O
irreversible O
oxidation O
, O
resulting O
in O
an O
unstable O
and O
highly O
reactive O
radical O
cation O
. O

Similarly O
, O
the O
cathodic O
process O
was O
also O
found O
to O
be O
irreversible O
, O
giving O
rise O
to O
a O
radical O
anion O
and O
showing O
its O
n O
- O
doping O
character O
. O

Validating O
a O
faster O
method O
for O
reconstitution O
of O
Crotalidae O
Polyvalent O
Immune O
Fab O
( O
ovine O
) O
. O

BACKGROUND O
: O
Reconstitution O
of O
CroFab O
( O
( O
R O
) O
) O
( O
Crotalidae O
Polyvalent O
Immune O
Fab O
[ O
ovine O
] O
) O
lyophilized O
drug O
product O
was O
previously O
performed O
using O
10 O
mL O
sterile O
water O
for O
injection O
followed O
by O
up O
to O
36 O
min O
of O
gentle O
swirling O
of O
the O
vial O
. O

CroFab O
has O
been O
clinically O
demonstrated O
to O
be O
most O
effective O
when O
administered O
within O
6 O
h O
of O
snake O
envenomation O
, O
and O
improved O
clinical O
outcomes O
are O
correlated O
with O
quicker O
timing O
of O
administration O
. O

An O
alternate O
reconstitution O
method O
was O
devised O
, O
using O
18 O
mL O
0 O
. O
9 O
% O
saline O
with O
manual O
inversion O
, O
with O
the O
goal O
of O
shortening O
reconstitution O
time O
while O
maintaining O
a O
high O
quality O
, O
efficacious O
product O
. O

METHODS O
: O
An O
analytical O
study O
was O
designed O
to O
compare O
the O
physicochemical O
properties O
of O
3 O
separate O
batches O
of O
CroFab O
when O
reconstituted O
using O
the O
standard O
procedure O
( O
10 O
mL O
WFI O
with O
gentle O
swirling O
) O
and O
a O
modified O
rapid O
procedure O
using O
18 O
mL O
0 O
. O
9 O
% O
saline O
and O
manual O
inversion O
. O

The O
physical O
and O
chemical O
characteristics O
of O
the O
same O
3 O
batches O
were O
assessed O
using O
various O
analytic O
methodologies O
associated O
with O
routine O
quality O
control O
release O
testing O
. O

In O
addition O
further O
analytical O
methodologies O
were O
applied O
in O
order O
to O
elucidate O
possible O
structural O
changes O
that O
may O
be O
induced O
by O
the O
changed O
reconstitution O
procedure O
. O

RESULTS O
: O
Batches O
A O
, O
B O
, O
and O
C O
required O
mean O
reconstitution O
times O
of O
25 O
min O
51 O
s O
using O
the O
label O
method O
and O
3 O
min O
07 O
s O
( O
a O
88 O
. O
0 O
% O
mean O
decrease O
) O
using O
the O
modified O
method O
. O

Physicochemical O
characteristics O
( O
color O
and O
clarity O
, O
pH O
, O
purity O
, O
protein O
content O
, O
potency O
) O
were O
found O
to O
be O
highly O
comparable O
. O

Characterization O
assays O
( O
dynamic O
light O
scattering O
, O
analytical O
ultracentrifugation O
, O
LC O
- O
MS O
, O
SDS B
- O
PAGE O
and O
circular O
dichroism O
spectroscopy O
were O
also O
all O
found O
to O
be O
comparable O
between O
methods O
. O

DISCUSSION O
: O
When O
comparing O
CroFab O
batches O
that O
were O
reconstituted O
using O
the O
labeled O
and O
modified O
methods O
, O
the O
physicochemical O
and O
biological O
( O
potency O
) O
characteristics O
of O
CroFab O
were O
not O
significantly O
changed O
when O
challenged O
by O
the O
various O
standard O
analytical O
methodologies O
applied O
in O
routine O
quality O
control O
analysis O
. O

Additionally O
, O
no O
changes O
in O
the O
CroFab B
molecule O
regarding O
degradation O
, O
aggregation O
, O
purity O
, O
structure O
, O
or O
mass O
were O
observed O
. O

CONCLUSION O
: O
The O
analyses O
performed O
validated O
the O
use O
of O
the O
more O
rapid O
reconstitution O
method O
using O
18 O
mL O
0 O
. O
9 O
% O
saline O
in O
order O
to O
allow O
a O
significantly O
reduced O
time O
to O
administration O
of O
CroFab O
to O
patients O
in O
need O
. O

Neuroecology O
: O
a O
fly O
' O
s O
bug O
detector O
. O

Drosophila O
avoid O
food O
contaminated O
by O
pathogenic O
bacteria O
and O
fungi O
using O
an O
olfactory O
pathway O
that O
is O
exquisitely O
tuned O
to O
a O
single O
microbial O
odour O
. O

Synthesis O
and O
dual O
biological O
effects O
of O
hydroxycinnamoyl B
phenylalanyl I
/ I
prolyl I
hydroxamic I
acid I
derivatives O
as O
tyrosinase O
inhibitor O
and O
antioxidant O
. O

We O
previously O
reported O
that O
caffeoyl B
- I
amino I
acidyl I
- I
hydroxamic I
acid I
( O
CA B
- I
Xaa I
- I
NHOH I
) O
acted O
as O
both O
a O
good O
antioxidant O
and O
tyrosinase O
inhibitor O
, O
in O
particular O
when O
caffeic B
acid I
was O
conjugated O
with O
proline B
or O
amino B
acids I
having O
aromatic O
ring O
like O
phenylalanine B
. O

Here O
, O
various O
hydroxycinnamic B
acid I
( O
HCA B
) O
derivatives O
were O
further O
conjugated O
with O
phenylalanyl B
hydroxamic I
acid I
and O
prolyl B
hydroxamic I
acid I
( O
HCA B
- I
Phe I
- I
NHOH I
and O
HCA B
- I
Pro I
- I
NHOH I
) O
to O
study O
the O
structure O
and O
activity O
relationship O
as O
both O
antioxidants O
and O
tyrosinase O
inhibitors O
. O

When O
their O
biological O
activities O
were O
evaluated O
, O
all O
HCA B
- O
Phe B
- I
NHOH I
and O
HCA B
- O
Pro B
- I
NHOH I
exhibited O
enhanced O
antioxidant O
activity O
compared O
to O
HCA B
alone O
. O

Moreover O
, O
derivatives O
of O
caffeic B
acid I
, O
ferulic B
acid I
, O
and O
sinapic B
acid I
inhibited O
lipid O
peroxidation O
more O
efficiently O
than O
vitamin B
E I
analogue O
( O
Trolox B
) O
. O

In O
addition O
, O
derivatives O
of O
caffeic B
acid I
and O
sinapic B
acid I
efficiently O
inhibited O
tyrosinase O
activity O
and O
reduced O
melanin O
content O
in O
melanocytes O
Mel O
- O
Ab O
cell O
. O

Discovery O
of O
a O
small O
- O
molecule O
antiviral O
targeting O
the O
HIV O
- O
1 O
matrix O
protein O
. O

Due O
to O
the O
emergence O
of O
drug O
- O
resistant O
strains O
and O
the O
cumulative O
toxicities O
associated O
with O
current O
therapies O
, O
demand O
remains O
for O
new O
inhibitors O
of O
HIV O
- O
1 O
replication O
. O

The O
HIV O
- O
1 O
matrix O
( O
MA O
) O
protein O
is O
an O
essential O
viral O
component O
with O
established O
roles O
in O
the O
assembly O
of O
the O
virus O
. O

Using O
virtual O
and O
surface O
plasmon O
resonance O
( O
SPR O
) O
- O
based O
screening O
, O
we O
describe O
the O
identification O
of O
the O
first O
small O
molecule O
to O
bind O
to O
the O
HIV O
- O
1 O
MA O
protein O
and O
to O
possess O
broad O
range O
anti O
- O
HIV O
properties O
. O

Two O
distinct O
mechanisms O
of O
Topoisomerase O
1 O
- O
dependent O
mutagenesis O
in O
yeast O
. O

Topoisomerase O
1 O
( O
Top1 O
) O
resolves O
transcription O
- O
associated O
supercoils O
by O
generating O
transient O
single O
- O
strand O
breaks O
in O
DNA O
. O

Top1 O
activity O
in O
yeast O
is O
a O
major O
source O
of O
transcription O
- O
associated O
mutagenesis O
, O
generating O
a O
distinctive O
mutation O
signature O
characterized O
by O
deletions O
in O
short O
, O
tandem O
repeats O
. O

A O
similar O
signature O
is O
associated O
with O
the O
persistence O
of O
ribonucleoside B
monophosphates I
( O
rNMPs B
) O
in O
DNA O
, O
and O
it O
also O
depends O
on O
Top1 O
activity O
. O

There O
is O
only O
partial O
overlap O
, O
however O
, O
between O
Top1 O
- O
dependent O
deletion O
hotspots O
identified O
in O
highly O
transcribed O
DNA O
and O
those O
associated O
with O
rNMPs O
, O
suggesting O
the O
existence O
of O
both O
rNMP O
- O
dependent O
and O
rNMP O
- O
independent O
events O
. O

Here O
, O
we O
present O
genetic O
studies O
confirming O
that O
there O
are O
two O
distinct O
types O
of O
hotspots O
. O

Data O
suggest O
a O
novel O
model O
in O
which O
rNMP O
- O
dependent O
hotspots O
are O
generated O
by O
sequential O
Top1 O
reactions O
and O
are O
consistent O
with O
rNMP O
- O
independent O
hotspots O
reflecting O
processing O
of O
a O
trapped O
Top1 O
cleavage O
complex O
. O

The O
role O
of O
individual O
gastric O
emptying O
of O
pellets O
in O
the O
prediction O
of O
diclofenac B
in O
vivo O
dissolution O
. O

The O
objective O
of O
the O
present O
study O
was O
to O
check O
for O
the O
possibility O
to O
successfully O
predict O
individual O
in O
vivo O
dissolution O
/ O
absorption O
profiles O
resulting O
from O
fasted O
administration O
of O
a O
diclofenac B
extended O
release O
pellet O
formulation O
. O

For O
this O
purpose O
dissolution O
profiles O
were O
generated O
with O
different O
dissolution O
setups O
using O
a O
set O
of O
media O
reflecting O
pH O
- O
conditions O
in O
the O
different O
segments O
of O
the O
gastrointestinal O
tract O
. O

Since O
gastric O
emptying O
of O
pellets O
seemed O
to O
be O
a O
critical O
factor O
for O
in O
vivo O
drug O
release O
, O
a O
set O
of O
different O
gastric O
residence O
times O
was O
screened O
in O
in O
vitro O
studies O
. O

Subsequently O
, O
in O
vitro O
release O
profiles O
were O
first O
directly O
compared O
with O
the O
individual O
in O
vivo O
absorption O
profiles O
and O
in O
a O
second O
step O
a O
mathematical O
model O
, O
which O
had O
been O
developed O
in O
a O
previous O
study O
, O
was O
applied O
to O
calculate O
predicted O
individual O
in O
vivo O
release O
profiles O
based O
on O
in O
vitro O
release O
profiles O
and O
individual O
gastric O
emptying O
. O

The O
comparison O
of O
predicted O
individual O
in O
vivo O
release O
profiles O
and O
individual O
in O
vivo O
absorption O
profiles O
showed O
a O
high O
degree O
of O
similarity O
, O
thus O
confirming O
the O
suitability O
of O
a O
set O
of O
different O
gastric O
residence O
times O
used O
in O
in O
vitro O
drug O
release O
testing O
. O

Additionally O
, O
obtained O
results O
indicated O
that O
a O
substantial O
part O
of O
variability O
of O
diclofenac B
absorption O
profiles O
can O
be O
explained O
by O
the O
variability O
of O
pellet O
gastric O
emptying O
kinetics O
. O

The O
colon O
carcinogen O
2 B
- I
amino I
- I
1 I
- I
methyl I
- I
6 I
- I
phenylimidazo I
[ I
4 I
, I
5 I
- I
b I
] I
pyridine I
( O
PhIP B
) O
is O
actively O
secreted O
in O
the O
distal O
colon O
of O
the O
rat O
: O
an O
integrated O
view O
on O
the O
role O
of O
PhIP B
transport O
and O
metabolism O
in O
PhIP B
- O
induced O
colon O
carcinogenesis O
. O

Epidemiological O
studies O
show O
that O
a O
positive O
correlation O
exists O
between O
the O
consumption O
of O
strongly O
heated O
meat O
and O
fish O
and O
the O
development O
of O
colorectal O
tumours O
. O

In O
this O
context O
, O
it O
has O
been O
postulated O
that O
the O
uptake O
of O
toxic O
substances O
formed O
during O
meat O
and O
fish O
processing O
such O
as O
heterocyclic B
aromatic I
amines I
( O
HCAs B
) O
may O
be O
causally O
related O
to O
colon O
carcinogenesis O
. O

In O
a O
previous O
study O
, O
we O
have O
shown O
that O
2 B
- I
amino I
- I
1 I
- I
methyl I
- I
6 I
- I
phenylimidazo I
[ I
4 I
, I
5 I
- I
b I
] I
pyridine I
( O
PhIP B
) O
, O
the O
most O
abundantly O
formed O
HCA B
in O
the O
above O
- O
mentioned O
food O
items O
, O
is O
mainly O
absorbed O
in O
the O
small O
intestine O
( O
i O
. O
e O
. O
proximal O
jejunum O
) O
of O
the O
rat O
. O

In O
the O
present O
study O
, O
we O
analysed O
whether O
PhIP B
can O
actively O
be O
secreted O
by O
enterocytes O
in O
the O
rat O
proximal O
jejunum O
and O
distal O
colon O
. O

Unidirectional O
PhIP B
flux O
rates O
from O
the O
mucosal O
- O
to O
- O
the O
serosal O
compartment O
( O
J O
ms O
) O
and O
in O
the O
opposite O
direction O
( O
J O
sm O
) O
were O
examined O
in O
Ussing O
chambers O
with O
( B
14 I
) I
C I
- I
PhIP I
as O
radiotracer O
and O
in O
the O
absence O
of O
electrochemical O
gradients O
. O

Under O
these O
experimental O
conditions O
, O
significant O
negative O
net O
flux O
rates O
( O
J O
net O
= O
J O
ms O
- O
J O
sm O
) O
can O
only O
be O
explained O
by O
an O
active O
secretion O
of O
PhIP O
into O
the O
luminal O
compartment O
, O
and O
such O
an O
effect O
was O
observed O
in O
the O
rat O
distal O
colon O
, O
but O
not O
in O
the O
proximal O
jejunum O
. O

Moreover O
, O
the O
data O
obtained O
suggest O
that O
the O
breast O
cancer O
resistance O
protein O
, O
the O
multidrug O
resistance O
protein O
4 O
and O
P O
- O
glycoprotein O
are O
not O
involved O
in O
the O
active O
secretion O
of O
PhIP B
in O
the O
rat O
distal O
colon O
. O

The O
potential O
role O
of O
PhIP B
transport O
in O
colon O
carcinogenesis O
is O
discussed O
. O

Warfarin B
dose O
prediction O
in O
children O
using O
pharmacometric O
bridging O
- O
comparison O
with O
published O
pharmacogenetic O
dosing O
algorithms O
. O

PURPOSE O
: O
Numerous O
studies O
have O
investigated O
causes O
of O
warfarin B
dose O
variability O
in O
adults O
, O
whereas O
studies O
in O
children O
are O
limited O
both O
in O
numbers O
and O
size O
. O

Mechanism O
- O
based O
population O
modelling O
provides O
an O
opportunity O
to O
condense O
and O
propagate O
prior O
knowledge O
from O
one O
population O
to O
another O
. O

The O
main O
objectives O
with O
this O
study O
were O
to O
evaluate O
the O
predictive O
performance O
of O
a O
theoretically O
bridged O
adult O
warfarin B
model O
in O
children O
, O
and O
to O
compare O
accuracy O
in O
dose O
prediction O
relative O
to O
published O
warfarin B
algorithms O
for O
children O
. O

METHOD O
: O
An O
adult O
population O
pharmacokinetic O
/ O
pharmacodynamic O
( O
PK O
/ O
PD O
) O
model O
for O
warfarin B
, O
with O
CYP2C9 O
and O
VKORC1 O
genotype O
, O
age O
and O
target O
international O
normalized O
ratio O
( O
INR O
) O
as O
dose O
predictors O
, O
was O
bridged O
to O
children O
using O
allometric O
scaling O
methods O
. O

Its O
predictive O
properties O
were O
evaluated O
in O
an O
external O
data O
set O
of O
children O
0 O
- O
18 O
years O
old O
, O
including O
comparison O
of O
dose O
prediction O
accuracy O
with O
three O
pharmacogenetics O
- O
based O
algorithms O
for O
children O
. O

RESULTS O
: O
Overall O
, O
the O
bridged O
model O
predicted O
INR O
response O
well O
in O
64 O
warfarin B
- O
treated O
Swedish O
children O
( O
median O
age O
4 O
. O
3 O
years O
) O
, O
but O
with O
a O
tendency O
to O
overpredict O
INR O
in O
children O
< O
= O
2 O
years O
old O
. O

The O
bridged O
model O
predicted O
20 O
of O
49 O
children O
( O
41 O
% O
) O
within O
+ O
/ O
- O
20 O
% O
of O
actual O
maintenance O
dose O
( O
median O
age O
7 O
. O
2 O
years O
) O
. O

In O
comparison O
, O
the O
published O
dosing O
algorithms O
predicted O
33 O
- O
41 O
% O
of O
the O
children O
within O
+ O
/ O
- O
20 O
% O
of O
actual O
dose O
. O

Dose O
optimization O
with O
the O
bridged O
model O
based O
on O
up O
to O
three O
individual O
INR O
observations O
increased O
the O
proportion O
within O
+ O
/ O
- O
20 O
% O
of O
actual O
dose O
to O
70 O
% O
. O

CONCLUSION O
: O
A O
mechanism O
- O
based O
population O
model O
developed O
on O
adult O
data O
provides O
a O
promising O
first O
step O
towards O
more O
individualized O
warfarin B
therapy O
in O
children O
. O

p300 O
- O
mediated O
acetylation O
of O
TRF2 O
is O
required O
for O
maintaining O
functional O
telomeres O
. O

The O
human O
telomeric O
protein O
TRF2 O
is O
required O
to O
protect O
chromosome O
ends O
by O
facilitating O
their O
organization O
into O
the O
protective O
capping O
structure O
. O

Post O
- O
translational O
modifications O
of O
TRF2 O
such O
as O
phosphorylation O
, O
ubiquitination O
, O
SUMOylation O
, O
methylation O
and O
poly B
( I
ADP I
- I
ribosyl I
) I
ation O
have O
been O
shown O
to O
play O
important O
roles O
in O
telomere O
function O
. O

Here O
we O
show O
that O
TRF2 O
specifically O
interacts O
with O
the O
histone O
acetyltransferase O
p300 O
, O
and O
that O
p300 O
acetylates O
the O
lysine B
residue O
at O
position O
293 O
of O
TRF2 O
. O

We O
also O
report O
that O
p300 O
- O
mediated O
acetylation O
stabilizes O
the O
TRF2 O
protein O
by O
inhibiting O
its O
ubiquitin O
- O
dependent O
proteolysis O
and O
is O
required O
for O
efficient O
telomere O
binding O
of O
TRF2 O
. O

Furthermore O
, O
overexpression O
of O
the O
acetylation O
- O
deficient O
mutant O
, O
K293R O
, O
induces O
DNA O
- O
damage O
response O
foci O
at O
telomeres O
, O
thereby O
leading O
to O
induction O
of O
impaired O
cell O
growth O
, O
cellular O
senescence O
and O
altered O
cell O
cycle O
distribution O
. O

A O
small O
but O
significant O
number O
of O
metaphase O
chromosomes O
show O
no O
telomeric O
signals O
at O
chromatid O
ends O
, O
suggesting O
an O
aberrant O
telomere O
structure O
. O

These O
findings O
demonstrate O
that O
acetylation O
of O
TRF2 O
by O
p300 O
plays O
a O
crucial O
role O
in O
the O
maintenance O
of O
functional O
telomeres O
as O
well O
as O
in O
the O
regulation O
of O
the O
telomere O
- O
associated O
DNA O
- O
damage O
response O
, O
thus O
providing O
a O
new O
route O
for O
modulating O
telomere O
protection O
function O
. O

Development O
and O
characterization O
of O
new O
peptidomimetic O
inhibitors O
of O
the O
West O
Nile O
virus O
NS2B O
- O
NS3 O
protease O
. O

A O
series O
of O
new O
substrate O
analogue O
inhibitors O
of O
the O
WNV O
NS2B O
- O
NS3 O
protease O
containing O
decarboxylated B
arginine I
mimetics O
at O
the O
P1 O
position O
was O
developed O
. O

Among O
the O
various O
analogues O
, O
trans B
- I
( I
4 I
- I
guanidino I
) I
cyclohexylmethylamid I
( O
GCMA B
) O
was O
identified O
as O
the O
most O
suitable O
P1 O
residue O
. O

In O
combination O
with O
dichloro B
- I
substituted I
phenylacetyl I
groups O
at O
the O
P4 O
position O
, O
three O
inhibitors O
with O
inhibition O
constants O
of O
< O
0 O
. O
2 O
mu O
M O
were O
obtained O
. O

These O
GCMA O
inhibitors O
have O
a O
better O
selectivity O
profile O
than O
the O
previously O
described O
agmatine B
analogues O
, O
and O
possess O
negligible O
affinity O
for O
the O
trypsin O
- O
like O
serine B
proteases O
thrombin O
, O
factor O
Xa O
, O
and O
matriptase O
. O

A O
crystal O
structure O
in O
complex O
with O
the O
WNV O
protease O
was O
determined O
for O
one O
of O
the O
most O
potent O
inhibitors O
, O
3 B
, I
4 I
- I
dichlorophenylacetyl I
- I
Lys I
- I
Lys I
- I
GCMA I
( O
K O
( O
i O
) O
= O
0 O
. O
13 O
mu O
M O
) O
. O

The O
inhibitor O
adopts O
a O
horseshoe O
- O
like O
conformation O
, O
most O
likely O
due O
to O
a O
hydrophobic O
contact O
between O
the O
P4 O
phenyl B
ring O
and O
the O
P1 O
cyclohexyl B
group O
, O
which O
is O
further O
stabilized O
by O
an O
intramolecular O
hydrogen B
bond O
between O
the O
P1 O
guanidino B
group O
and O
the O
P4 O
carbonyl B
oxygen I
atom O
. O

These O
inhibitors O
are O
stable O
, O
readily O
accessible O
, O
and O
have O
a O
noncovalent O
binding O
mode O
. O

Therefore O
, O
they O
may O
serve O
as O
suitable O
lead O
structures O
for O
further O
development O
. O

Synthesis O
of O
a O
potent O
antimalarial O
agent O
through O
natural O
products O
conjugation O
. O

Au B
naturel O
! O

( B
+ I
) I
- I
Usnic I
acid I
( O
green O
) O
is O
a O
weak O
antimalarial O
agent O
, O
however O
, O
in O
conjugation O
with O
known O
antimalarial O
scaffolds O
and O
drugs O
, O
such O
as O
dihydroartemisinin B
( O
blue O
) O
, O
potent O
activity O
against O
the O
blood O
- O
stage O
parasite O
can O
be O
seen O
both O
in O
vitro O
and O
in O
vivo O
. O

The O
compound O
shown O
exhibits O
an O
IC O
( O
50 O
) O
value O
of O
1 O
. O
4 O
nM O
against O
Plasmodium O
falciparum O
in O
vitro O
and O
proved O
nearly O
as O
efficacious O
as O
artesunate B
in O
a O
mouse O
model O
of O
infection O
. O

Combined O
inhibition O
of O
mTORC1 O
and O
mTORC2 O
signaling O
pathways O
is O
a O
promising O
therapeutic O
option O
in O
inhibiting O
pheochromocytoma O
tumor O
growth O
: O
in O
vitro O
and O
in O
vivo O
studies O
in O
female O
athymic O
nude O
mice O
. O

Several O
lines O
of O
evidence O
, O
including O
the O
recent O
discovery O
of O
novel O
susceptibility O
genes O
, O
point O
out O
an O
important O
role O
for O
the O
mammalian O
target O
of O
rapamycin B
( O
mTOR O
) O
signaling O
pathway O
in O
the O
development O
of O
pheochromocytoma O
. O

Analyzing O
a O
set O
of O
pheochromocytomas O
from O
patients O
with O
different O
genetic O
backgrounds O
, O
we O
observed O
and O
confirmed O
a O
significant O
overexpression O
of O
key O
mTOR O
complex O
( O
mTORC O
) O
signaling O
mediators O
. O

Using O
selective O
ATP B
- O
competitive O
inhibitors O
targeting O
both O
mTORC1 O
and O
mTORC2 O
, O
we O
significantly O
arrested O
the O
in O
vitro O
cell O
proliferation O
and O
blocked O
migration O
of O
pheochromocytoma O
cells O
as O
a O
result O
of O
the O
pharmacological O
suppression O
of O
the O
Akt O
/ O
mTOR O
signaling O
pathway O
. O

Moreover O
, O
AZD8055 B
, O
a O
selective O
ATP B
- O
competitive O
dual O
mTORC1 O
/ O
2 O
small O
molecular O
inhibitor O
, O
significantly O
reduced O
the O
tumor O
burden O
in O
a O
model O
of O
metastatic O
pheochromocytoma O
using O
female O
athymic O
nude O
mice O
. O

This O
study O
suggests O
that O
targeting O
both O
mTORC1 O
and O
mTORC2 O
is O
a O
potentially O
rewarding O
strategy O
and O
supports O
the O
application O
of O
selective O
inhibitors O
in O
combinatorial O
drug O
regimens O
for O
metastatic O
pheochromocytoma O
. O

2 B
, I
3 I
, I
7 I
, I
8 I
- I
Tetrachlorodibenzo I
- I
p I
- I
dioxin I
- O
induced O
hypertension O
: O
The O
beneficial O
effects O
of O
melatonin B
. O

Objective O
: O
The O
purpose O
of O
the O
present O
study O
was O
to O
evaluate O
the O
effects O
of O
melatonin B
on O
biochemical O
and O
cardiovascular O
changes O
resulting O
from O
exposure O
to O
2 B
, I
3 I
, I
7 I
, I
8 I
- I
tetrachlorodibenzo I
- I
p I
- I
dioxin I
( O
TCDD B
) O
, O
a O
polychlorinated B
dibenzo I
- I
para I
- I
dioxin I
. O
Methods O
: O
A O
total O
of O
24 O
Sprague O
- O
Dawley O
rats O
were O
divided O
equally O
into O
the O
following O
four O
groups O
: O
( O
1 O
) O
control O
group O
was O
administered O
with O
0 O
. O
5 O
mL O
corn O
oil O
by O
gavage O
and O
0 O
. O
5 O
cc O
vehicle O
of O

melatonin B
( O
proportionally O
nine O
parts O
physiological O
serum O
+ O
one O
part O
ethyl B
alcohol I
) O
intraperitoneally O
for O
4 O
weeks O
, O
( O
2 O
) O
the O
melatonin B
group O
was O
given O
5 O
mg O
/ O
kg O
/ O
day O
melatonin B
intraperitoneally O
for O
4 O
weeks O
, O
( O
3 O
) O
the O
TCDD B
group O
was O
given O
500 O
ng O
/ O
kg O
/ O
day O
TCDD B
by O
gavage O
for O
4 O
weeks O
and O
( O
4 O
) O
the O
TCDD B
+ O
melatonin B
group O
was O
given O
TCDD B
( O
500 O
ng O
/ O
kg O
/ O
day O
) O
by O
gavage O
and O
melatonin B
( O
5 O
mg O
/ O
kg O

/ O
day O
) O
intraperitoneally O
simultaneously O
for O
4 O
weeks O
. O

Systolic O
blood O
pressure O
was O
evaluated O
by O
the O
tail O
- O
cuff O
method O
. O

Vascular O
responses O
to O
phenylephrine B
and O
acetylcholine B
were O
evaluated O
in O
the O
isolated O
thoracic O
aortas O
. O
Results O
: O
TCDD B
not O
only O
augmented O
the O
systolic O
blood O
pressure O
but O
also O
increased O
the O
contractile O
responses O
to O
phenylephrine B
in O
aorta O
. O

Melatonin B
reversed O
the O
blood O
pressure O
augmented O
by O
TCDD B
and O
decreased O
the O
contractile O
responses O
to O
phenylephrine B
in O
aorta O
. O

TCDD B
induced O
an O
increase O
in O
the O
malondialdehyde B
levels O
in O
kidney O
tissue O
and O
melatonin B
did O
not O
change O
it O
. O

Therefore O
, O
TCDD B
caused O
a O
decrease O
in O
glutathione B
levels O
in O
kidney O
tissues O
and O
melatonin B
reversed O
it O
. O
Conclusion O
: O
Present O
data O
demonstrated O
that O
TCDD B
may O
lead O
to O
an O
increase O
in O
blood O
pressure O
via O
increased O
renal O
oxidative O
stress O
and O
vascular O
reactivity O
. O

However O
, O
melatonin B
might O
ameliorate O
the O
blood O
pressure O
disturbed O
by O
TCDD B
in O
part O
by O
decreasing O
the O
oxidant O
activity O
induced O
by O
TCDD B
. O

Progress O
in O
the O
synthesis O
of O
canthine B
alkaloids I
and O
ring O
- O
truncated O
congeners O
. O

The O
canthines B
represent O
a O
fairly O
large O
subclass O
of O
beta B
- I
carboline I
alkaloids I
, O
with O
the O
first O
members O
described O
75 O
years O
ago O
. O

Over O
the O
last O
60 O
years O
, O
many O
members O
of O
the O
parent O
compound O
, O
canthin B
- I
6 I
- I
one I
( O
1 O
) O
, O
have O
been O
isolated O
from O
various O
plant O
sources O
, O
principally O
the O
Rutaceae O
and O
Simaroubaceae O
families O
, O
and O
recently O
from O
fungi O
. O

Structures O
isolated O
from O
these O
sources O
have O
been O
the O
subject O
of O
total O
synthesis O
, O
which O
continues O
to O
the O
present O
day O
. O

This O
review O
gives O
a O
broad O
overview O
of O
synthetic O
approaches O
to O
canthines B
over O
a O
30 O
- O
year O
period O
from O
1982 O
to O
2012 O
and O
summarizes O
recent O
reports O
on O
the O
synthesis O
of O
less O
well O
known O
ring O
- O
truncated O
congeners O
. O

These O
include O
C O
- O
ring O
- O
truncated O
( O
" O
ABD O
" O
, O
2 O
) O
and O
A O
- O
ring O
- O
truncated O
( O
" O
BCD O
" O
, O
3 O
) O
ring O
systems O
, O
which O
are O
providing O
new O
scaffolds O
for O
potentially O
useful O
therapeutic O
applications O
. O

Diels O
- O
Alder O
mediated O
controlled O
release O
from O
a O
poly B
( I
ethylene I
glycol I
) I
based O
hydrogel O
. O

A O
synthetic O
amino B
acid I
bearing O
a O
furan B
functionality O
was O
developed O
and O
incorporated O
into O
peptide O
sequences O
using O
solid O
phase O
synthesis O
. O

Peptides O
expressing O
the O
furan B
moiety O
were O
attached O
to O
poly B
( I
ethylene I
glycol I
) I
( O
PEG B
) O
hydrogels O
through O
a O
thermally O
reversible O
covalent O
bond O
formed O
by O
a O
Diels O
- O
Alder O
reaction O
. O

Reactions O
of O
thiol B
and O
maleimide B
PEG B
macromers O
in O
an O
off O
- O
stoichiometric O
Michael O
addition O
were O
performed O
, O
such O
that O
the O
maleimide B
moiety O
was O
in O
excess O
, O
to O
create O
hydrogel O
networks O
with O
pendant O
Diels O
- O
Alder O
compatible O
tethering O
sites O
, O
that O
is O
, O
the O
maleimide B
. O

By O
making O
use O
of O
the O
Diels O
- O
Alder O
reaction O
, O
it O
was O
possible O
to O
control O
the O
release O
rate O
of O
reversibly O
bound O
moieties O
from O
the O
hydrogel O
by O
changing O
the O
temperature O
; O
higher O
temperatures O
favor O
a O
faster O
retro O
- O
Diels O
- O
Alder O
reaction O
and O
, O
therefore O
, O
a O
faster O
release O
from O
the O
polymer O
network O
. O

This O
concept O
was O
demonstrated O
by O
incorporating O
a O
fluorescently O
labeled O
furan B
- O
RGDS O
sequence O
into O
a O
hydrogel O
possessing O
excess O
maleimide B
functionalities O
and O
monitoring O
the O
subsequent O
liberation O
of O
RGDS O
at O
various O
temperatures O
, O
illustrating O
a O
Diels O
- O
Alder O
mediated O
release O
mechanism O
. O

The O
release O
profile O
was O
quantified O
at O
temperatures O
ranging O
from O
physiological O
( O
37 O
degrees O
C O
) O
to O
80 O
degrees O
C O
. O

By O
changing O
the O
temperature O
, O
varying O
extents O
of O
release O
were O
attained O
over O
the O
time O
course O
of O
several O
days O
, O
ranging O
from O
40 O
% O
release O
for O
lower O
temperatures O
to O
complete O
release O
for O
the O
highest O
temperature O
considered O
. O

Further O
confirmation O
of O
a O
reaction O
- O
diffusion O
controlled O
release O
mechanism O
was O
obtained O
through O
comparison O
of O
experimental O
release O
data O
to O
a O
reaction O
- O
diffusion O
model O
of O
the O
release O
. O

In O
addition O
to O
thermal O
modulation O
, O
tuning O
of O
the O
release O
rate O
was O
accomplished O
by O
altering O
the O
number O
of O
possible O
Diels O
- O
Alder O
tethering O
sites O
present O
in O
the O
hydrogel O
. O

Increasing O
the O
amount O
of O
free O
maleimide B
and O
, O
therefore O
, O
the O
number O
of O
potential O
Diels O
- O
Alder O
reaction O
sites O
, O
effectively O
slowed O
the O
release O
of O
peptide O
from O
the O
polymer O
. O

For O
instance O
, O
doubling O
the O
amount O
of O
maleimide B
sites O
present O
in O
the O
hydrogel O
system O
decreased O
the O
amount O
of O
peptide O
released O
from O
approximately O
60 O
% O
to O
about O
40 O
% O
in O
the O
same O
span O
of O
time O
. O

Bottom O
- O
up O
approach O
to O
creating O
three O
- O
dimensional O
nanoring O
arrays O
composed O
of O
Au B
nanoparticles O
. O

A O
bottom O
- O
up O
approach O
to O
creating O
3D O
assemblies O
of O
Au B
nanorings O
by O
drying O
aqueous O
dispersions O
of O
PS O
colloidal O
particles O
and O
Au B
NPs O
is O
shown O
. O

The O
evaporation O
of O
water O
from O
the O
dispersion O
allowed O
for O
the O
formation O
of O
hexagonally O
assembled O
colloidal O
crystals O
and O
nanorings O
composed O
of O
Au B
nanoparticles O
among O
the O
PS O
colloidal O
particles O
. O

The O
size O
of O
the O
nanorings O
could O
be O
controlled O
on O
a O
scale O
of O
tens O
to O
hundreds O
of O
nanometers O
. O

After O
sintering O
, O
the O
Au B
NPs O
formed O
Au B
nanorings O
. O

This O
simple O
approach O
supplies O
a O
potentially O
useful O
path O
to O
novel O
plasmonic O
materials O
and O
unique O
metamaterials O
for O
the O
visible O
light O
region O
. O

Covalent O
Layer O
- O
by O
- O
Layer O
Assembly O
of O
Redox O
- O
Active O
Polymer O
Multilayers O
. O

Poly B
( I
ferrocenyl I
( I
3 I
- I
bromopropyl I
) I
methylsilane I
) I
and O
poly B
( I
ethylene I
imine I
) I
are O
employed O
in O
a O
layer O
- O
by O
- O
layer O
deposition O
process O
to O
form O
covalently O
connected O
, O
redox O
- O
active O
multilayer O
thin O
films O
by O
means O
of O
an O
amine B
alkylation O
reaction O
. O

The O
stepwise O
buildup O
of O
these O
multilayers O
on O
silicon B
, O
ITO B
, O
and O
quartz B
substrates O
was O
monitored O
by O
UV O
- O
vis O
absorption O
spectroscopy O
, O
Fourier O
transform O
infrared O
spectroscopy O
( O
FTIR O
) O
, O
static O
contact O
angle O
measurements O
, O
surface O
plasmon O
resonance O
( O
SPR O
) O
, O
atomic O
force O
microscopy O
, O
ellipsometry O
, O
and O
cyclic O
voltammetry O
, O
which O
provide O
evidence O
for O
a O
linear O
increase O
in O
multilayer O
thickness O
with O
the O
number O
of O
deposited O
bilayers O
. O

Upon O
oxidation O
and O
reduction O
, O
these O
covalently O
interconnected O
layers O
do O
not O
disassemble O
, O
in O
contrast O
to O
poly B
( I
ferrocenylsilane I
) I
( O
PFS B
) O
layers O
featuring O
similar O
backbone O
structures O
that O
are O
held O
together O
by O
electrostatic O
forces O
. O

The O
PFS B
/ O
PEI B
multilayers O
are O
effective O
for O
the O
electrochemical O
sensing O
of O
ascorbic B
acid I
and O
hydrogen B
peroxide I
and O
show O
improved O
sensing O
performance O
at O
higher O
bilayer O
numbers O
. O

These O
covalently O
linked O
layers O
are O
readily O
derivatized O
further O
and O
can O
therefore O
be O
regarded O
as O
a O
versatile O
platform O
for O
creating O
robust O
, O
tailorable O
, O
redox O
- O
active O
interfaces O
with O
applications O
in O
sensing O
and O
biofuel O
cells O
. O

Tipping O
the O
energy O
balance O
toward O
longevity O
. O

AMPK O
is O
a O
cellular O
energy O
sensor O
conserved O
across O
eukaryotes O
that O
in O
C O
. O
elegans O
prolongs O
life O
span O
and O
mimics O
dietary O
restriction O
. O

Stenesen O
and O
colleagues O
( O
2012 O
) O
activate O
AMPK O
both O
directly O
and O
indirectly O
by O
altering O
AMP B
biosynthesis O
to O
slow O
aging O
in O
Drosophila O
, O
highlighting O
AMPK O
as O
a O
conserved O
life O
span O
modulator O
that O
links O
energy O
sensing O
to O
longevity O
. O

Quantitative O
photoacoustic O
imaging O
of O
nanoparticles O
in O
cells O
and O
tissues O
. O

Quantitative O
visualization O
of O
nanoparticles O
in O
cells O
and O
tissues O
, O
while O
preserving O
the O
spatial O
information O
, O
is O
very O
challenging O
. O

A O
photoacoustic O
imaging O
technique O
to O
depict O
the O
presence O
and O
quantity O
of O
nanoparticles O
is O
presented O
. O

This O
technique O
is O
based O
on O
the O
dependence O
of O
the O
photoacoustic O
signal O
on O
both O
the O
nanoparticle O
quantity O
and O
the O
laser O
fluence O
. O

Quantitative O
photoacoustic O
imaging O
is O
a O
robust O
technique O
that O
does O
not O
require O
knowledge O
of O
the O
local O
fluence O
, O
but O
a O
relative O
change O
in O
the O
fluence O
. O

This O
eliminates O
the O
need O
for O
sophisticated O
methods O
or O
models O
to O
determine O
the O
energy O
distribution O
of O
light O
in O
turbid O
media O
. O

Quantitative O
photoacoustic O
imaging O
was O
first O
applied O
to O
nanoparticle O
- O
loaded O
cells O
, O
and O
quantitation O
was O
validated O
by O
inductively O
coupled O
plasma O
mass O
spectrometry O
. O

Quantitative O
photoacoustic O
imaging O
was O
then O
extended O
to O
xenograft O
tumor O
tissue O
sections O
, O
and O
excellent O
agreement O
with O
traditional O
histopathological O
analysis O
was O
demonstrated O
. O

Our O
results O
suggest O
that O
quantitative O
photoacoustic O
imaging O
may O
be O
used O
in O
many O
applications O
including O
the O
determination O
of O
the O
efficiency O
and O
effectiveness O
of O
molecular O
targeting O
strategies O
for O
cell O
studies O
and O
animal O
models O
, O
the O
quantitative O
assessment O
of O
photoacoustic O
contrast O
agent O
biodistribution O
, O
and O
the O
validation O
of O
in O
vivo O
photoacoustic O
imaging O
. O

A O
comparative O
protease O
stability O
study O
of O
synthetic O
macrocyclic O
peptides O
that O
mimic O
two O
endocrine O
hormones O
. O

Peptide O
therapeutics O
have O
traditionally O
faced O
many O
challenges O
including O
low O
bioavailability O
, O
poor O
proteolytic O
stability O
and O
difficult O
cellular O
uptake O
. O

Conformationally O
constraining O
the O
backbone O
of O
a O
peptide O
into O
a O
macrocyclic O
ring O
often O
ameliorates O
these O
problems O
and O
allows O
for O
the O
development O
of O
a O
variety O
of O
new O
drugs O
. O

Such O
peptide O
- O
based O
pharmaceuticals O
can O
enhance O
the O
multi O
- O
faceted O
functionality O
of O
peptide O
side O
chains O
, O
permitting O
the O
peptides O
to O
bind O
cellular O
targets O
and O
receptors O
necessary O
to O
impart O
their O
role O
, O
while O
protecting O
them O
from O
degrading O
cellular O
influences O
. O

In O
the O
work O
described O
here O
, O
we O
developed O
three O
cyclic O
peptides O
, O
VP O
mimic1 O
, O
VP O
mimic2 O
and O
OT O
mimic1 O
, O
which O
mimic O
endocrine O
hormones O
vasopressin O
and O
oxytocin B
. O

Making O
notable O
changes O
to O
the O
overall O
structure O
and O
composition O
of O
the O
parent O
hormones O
, O
we O
synthesized O
the O
mimics O
and O
tested O
their O
durability O
against O
treatment O
with O
three O
proteases O
chosen O
for O
their O
specificity O
: O
pepsin O
, O
alpha O
- O
chymotrypsin O
, O
and O
pronase O
. O

Vasopressin O
and O
oxytocin B
contain O
a O
disulfide B
linkage O
leaving O
them O
particularly O
vulnerable O
to O
deactivation O
from O
the O
reducing O
environment O
inside O
the O
cell O
. O

Thus O
, O
we O
increased O
the O
complexity O
of O
our O
assays O
by O
adding O
reducing O
agent O
glutathione B
to O
each O
mixture O
. O

Subsequently O
, O
we O
discovered O
each O
of O
our O
mimics O
withstood O
protease O
treatment O
with O
less O
degradation O
and O
/ O
or O
a O
slower O
rate O
of O
degradation O
as O
compared O
to O
both O
parent O
hormones O
and O
a O
linear O
control O
peptide O
. O

Highly O
selective O
2 B
, I
4 I
- I
diaminopyrimidine I
- I
5 I
- I
carboxamide I
inhibitors O
of O
Sky O
kinase O
. O

We O
report O
the O
SAR O
around O
a O
series O
of O
2 B
, I
4 I
- I
diaminopyrimidine I
- I
5 I
- I
carboxamide I
inhibitors O
of O
Sky O
kinase O
. O

2 B
- I
Aminophenethyl I
analogs O
demonstrate O
excellent O
potency O
but O
moderate O
kinase O
selectivity O
, O
while O
2 B
- I
aminobenzyl I
analogs O
that O
fill O
the O
Ala571 B
subpocket O
exhibit O
good O
inhibition O
activity O
and O
excellent O
kinase O
selectivity O
. O

Synthesis O
and O
antibacterial O
evaluation O
of O
a O
novel O
tricyclic B
oxaborole I
- O
fused O
fluoroquinolone B
. O

We O
have O
designed O
and O
synthesized O
a O
novel O
class O
of O
compounds O
based O
on O
fluoroquinolone B
antibacterial O
prototype O
. O

The O
design O
concept O
involved O
the O
replacement O
of O
the O
3 B
- I
carboxylic I
acid I
in O
ciprofloxacin B
with O
an O
oxaborole B
- O
fused O
ring O
as O
an O
acid O
- O
mimicking O
group O
. O

The O
synthetic O
method O
employed O
in O
this O
work O
provides O
a O
good O
example O
of O
incorporating O
boron B
atom O
in O
complex O
molecules O
with O
multiple O
functional O
groups O
. O

The O
antibacterial O
activity O
of O
the O
newly O
synthesized O
compounds O
has O
been O
evaluated O
. O

Vinclozolin B
- O
- O
no O
transgenerational O
inheritance O
of O
anti O
- O
androgenic O
effects O
after O
maternal O
exposure O
during O
organogenesis O
via O
the O
intraperitoneal O
route O
. O

The O
goal O
of O
this O
study O
was O
to O
examine O
the O
potential O
transgenerational O
inheritance O
of O
anti O
- O
androgenic O
effects O
induced O
by O
Vinclozolin B
administered O
intraperitoneally O
to O
pregnant O
Wistar O
rats O
( O
Crl O
: O
WI O
[ O
Han O
] O
) O
. O

Dams O
were O
dosed O
with O
Vinclozolin B
at O
0 O
, O
4 O
or O
100mg O
/ O
kg O
bw O
/ O
d O
on O
gestation O
days O
6 O
- O
15 O
. O

Male O
offspring O
of O
F1 O
- O
F3 O
generations O
were O
bred O
with O
untreated O
females O
to O
yield O
F2 O
- O
F4 O
offspring O
. O

No O
evident O
anti O
- O
androgenic O
effects O
were O
observed O
at O
4mg O
/ O
kg O
bw O
/ O
d O
, O
but O
a O
case O
of O
hypospadias O
as O
well O
as O
delayed O
sexual O
maturation O
in O
F1 O
male O
offspring O
was O
observed O
as O
a O
sign O
of O
anti O
- O
androgenicity O
at O
100mg O
/ O
kg O
bw O
/ O
d O
. O

However O
, O
F1 O
- O
F3 O
males O
developed O
normally O
to O
sexual O
maturity O
and O
were O
able O
to O
mate O
and O
to O
generate O
healthy O
progeny O
. O

Sperm O
count O
, O
morphology O
and O
motility O
were O
not O
affected O
in O
F1 O
- O
F4 O
generation O
male O
offspring O
. O

In O
conclusion O
, O
transgenerational O
inheritance O
of O
Vinclozolin B
' O
s O
anti O
- O
androgenic O
effects O
was O
not O
evident O
in O
outbred O
Wistar O
rats O
. O

Enhancing O
nicotine B
vaccine O
immunogenicity O
with O
liposomes O
. O

A O
major O
liability O
of O
existing O
nicotine B
vaccine O
candidates O
is O
the O
wide O
variation O
in O
anti O
- O
nicotine B
immune O
responses O
among O
clinical O
trial O
participants O
. O

In O
order O
to O
address O
this O
liability O
, O
significant O
emphasis O
has O
been O
directed O
at O
evaluating O
adjuvants O
and O
delivery O
systems O
that O
confer O
more O
robust O
potentiation O
of O
the O
anti O
- O
nicotine B
immune O
response O
. O

Toward O
that O
end O
, O
we O
have O
initiated O
work O
that O
seeks O
to O
exploit O
the O
adjuvant O
effect O
of O
liposomes O
, O
with O
or O
without O
Toll O
- O
like O
receptor O
agonist O
( O
s O
) O
. O

The O
results O
of O
the O
murine O
immunization O
study O
described O
herein O
support O
the O
hypothesis O
that O
a O
liposomal O
nicotine B
vaccine O
formulation O
may O
provide O
a O
means O
for O
addressing O
the O
immunogenicity O
challenge O
. O

Triglyceride B
accumulation O
inhibitory O
effects O
of O
phenylpropanoid B
glycosides I
from O
Boschniakia O
rossica O
Fedtsch O
et O
Flerov O
. O

Bioassay O
- O
guided O
fractionation O
led O
to O
isolation O
of O
five O
new O
phenylpropanol B
glycosides I
, O
rossicasides B
G I
( I
1 I
) I
, I
H I
( I
2 I
) I
, I
I I
( I
3 I
) I
, I
J I
( I
4 I
) I
, I
and I
K I
( I
5 I
) O
, O
together O
with O
seven O
known O
compounds O
( O
6 O
- O
12 O
) O
from O
Boschniakia O
rossica O
. O

Their O
structures O
were O
elucidated O
by O
chemical O
and O
spectroscopic O
methods O
( O
UV O
, O
IR O
, O
HRESI O
- O
TOF O
- O
MS O
, O
1D O
and O
2D O
NMR O
) O
. O

Activity O
screening O
results O
showed O
that O
some O
isolates O
had O
TG O
accumulation O
inhibitory O
effects O
in O
HepG2 O
cells O
. O

Furthermore O
, O
the O
structure O
- O
activity O
relationship O
was O
partly O
clarified O
. O

Computational O
identification O
and O
quantification O
of O
trabecular O
microarchitecture O
classes O
by O
3 O
- O
D O
texture O
analysis O
- O
based O
clustering O
. O

High O
resolution O
peripheral O
quantitative O
computed O
tomography O
( O
HR O
- O
pQCT O
) O
permits O
the O
non O
- O
invasive O
assessment O
of O
cortical O
and O
trabecular O
bone O
density O
, O
geometry O
, O
and O
microarchitecture O
. O

Although O
researchers O
have O
developed O
various O
post O
- O
processing O
algorithms O
to O
quantify O
HR O
- O
pQCT O
image O
properties O
, O
few O
of O
these O
techniques O
capture O
image O
features O
beyond O
global O
structure O
- O
based O
metrics O
. O

While O
3D O
- O
texture O
analysis O
is O
a O
key O
approach O
in O
computer O
vision O
, O
it O
has O
been O
utilized O
only O
infrequently O
in O
HR O
- O
pQCT O
research O
. O

Motivated O
by O
high O
isotropic O
spatial O
resolution O
and O
the O
information O
density O
provided O
by O
HR O
- O
pQCT O
scans O
, O
we O
have O
developed O
and O
evaluated O
a O
post O
- O
processing O
algorithm O
that O
quantifies O
microarchitecture O
characteristics O
via O
texture O
features O
in O
HR O
- O
pQCT O
scans O
. O

During O
a O
training O
phase O
in O
which O
clustering O
was O
applied O
to O
texture O
features O
extracted O
from O
each O
voxel O
of O
trabecular O
bone O
, O
three O
distinct O
clusters O
, O
or O
trabecular O
microarchitecture O
classes O
( O
TMACs O
) O
were O
identified O
. O

These O
TMACs O
represent O
trabecular O
bone O
regions O
with O
common O
texture O
characteristics O
. O

The O
TMACs O
were O
then O
used O
to O
automatically O
segment O
the O
voxels O
of O
new O
data O
into O
three O
regions O
corresponding O
to O
the O
trained O
cluster O
features O
. O

Regional O
trabecular O
bone O
texture O
was O
described O
by O
the O
histogram O
of O
relative O
trabecular O
bone O
volume O
covered O
by O
each O
cluster O
. O

We O
evaluated O
the O
intra O
- O
scanner O
and O
inter O
- O
scanner O
reproducibility O
by O
assessing O
the O
precision O
errors O
( O
PE O
) O
, O
intra O
class O
correlation O
coefficients O
( O
ICC O
) O
and O
Dice O
coefficients O
( O
DC O
) O
of O
the O
method O
on O
14 O
ultradistal O
radius O
samples O
scanned O
on O
two O
HR O
- O
pQCT O
systems O
. O

DC O
showed O
good O
reproducibility O
in O
intra O
- O
scanner O
set O
- O
up O
with O
a O
mean O
of O
0 O
. O
870 O
+ O
/ O
- O
0 O
. O
027 O
( O
no O
unit O
) O
. O

Even O
in O
the O
inter O
- O
scanner O
set O
- O
up O
the O
ICC O
showed O
high O
reproducibility O
, O
ranging O
from O
0 O
. O
814 O
to O
0 O
. O
964 O
. O

In O
a O
preliminary O
clinical O
test O
application O
, O
the O
TMAC O
histograms O
appear O
to O
be O
a O
good O
indicator O
, O
when O
differentiating O
between O
postmenopausal O
women O
with O
( O
n O
= O
18 O
) O
and O
without O
( O
n O
= O
18 O
) O
prevalent O
fragility O
fractures O
. O

In O
conclusion O
, O
we O
could O
demonstrate O
that O
3D O
- O
texture O
analysis O
and O
feature O
clustering O
seems O
to O
be O
a O
promising O
new O
HR O
- O
pQCT O
post O
- O
processing O
tool O
with O
good O
reproducibility O
, O
even O
between O
two O
different O
scanners O
. O

Anti O
- O
apoptotic O
activity O
of O
hydroxytyrosol B
and O
hydroxytyrosyl B
laurate I
. O

Hydroxytyrosol B
( O
HyT B
) O
is O
a O
polyphenol B
primarily O
released O
in O
olive O
mill O
wastewater O
and O
in O
olive O
oil O
. O

In O
animal O
and O
cell O
model O
studies O
, O
HyT O
and O
its O
metabolites O
have O
strong O
antioxidant O
and O
antimicrobial O
activities O
, O
as O
well O
as O
beneficial O
effects O
on O
the O
cardiovascular O
system O
and O
in O
several O
human O
diseases O
. O

Differently O
, O
many O
researchers O
reported O
that O
HyT O
down O
- O
regulates O
tumor O
cell O
viability O
and O
cell O
cycle O
progression O
, O
and O
induces O
reactive O
oxygen B
species O
( O
ROS O
) O
production O
and O
apoptosis O
. O

In O
this O
study O
we O
have O
investigated O
the O
effects O
of O
HyT O
and O
the O
corresponding O
ester B
hydroxytyrosyl I
laurate I
in O
U937 O
cells O
, O
a O
human O
monocytoid O
cell O
line O
, O
and O
in O
C2C12 O
myoblasts O
, O
a O
murine O
proliferating O
muscle O
cell O
model O
, O
after O
apoptotic O
death O
induction O
. O

Inverted O
, O
light O
and O
transmission O
electron O
microscopy O
have O
been O
utilized O
to O
characterize O
cell O
death O
patterns O
. O

H2O2 B
, O
at O
the O
concentrations O
known O
to O
induce O
apoptosis O
, O
was O
utilized O
as O
cell O
death O
trigger O
. O

The O
results O
obtained O
show O
that O
laur B
- O
HyT O
has O
a O
protective O
antioxidant O
effect O
against O
H2O2 B
treatment O
, O
greater O
than O
HyT B
, O
so O
having O
a O
role O
in O
the O
prevention O
of O
apoptotic O
death O
in O
normal O
and O
tumor O
cells O
. O

These O
data O
suggest O
these O
compounds O
as O
good O
candidate O
for O
novel O
therapeutic O
strategies O
. O

Zinc B
protection O
against O
aluminium B
induced O
altered O
lipid O
profile O
and O
membrane O
integrity O
. O

The O
aim O
of O
the O
present O
study O
was O
to O
investigate O
the O
effects O
of O
Zinc B
( O
Zn B
) O
supplementation O
on O
lipid O
profile O
and O
fluidity O
of O
cerebrum O
and O
cerebellum O
membranes O
of O
rats O
treated O
with O
aluminium B
( O
Al B
) O
. O

Sprague O
dawley O
male O
rats O
were O
divided O
into O
four O
different O
treatment O
groups O
viz O
: O
Control O
, O
aluminium B
treated O
, O
zinc B
treated O
and O
aluminium B
+ O
zinc B
treated O
. O

Aluminium B
( O
AlCl3 B
) O
was O
administered O
orally O
at O
a O
dose O
of O
100mg O
/ O
kgb O
. O
wt O
. O
/ O
day O
( O
dissolved O
in O
drinking O
water O
) O
. O

Zinc B
as O
zinc B
sulphate I
was O
supplemented O
to O
rats O
at O
a O
dose O
of O
227mg O
/ O
l O
in O
drinking O
water O
. O

A O
significant O
decrease O
in O
the O
levels O
of O
total O
lipids O
, O
glycolipids O
, O
phospholipids O
, O
cholesterol B
and O
gangliosides B
contents O
were O
observed O
in O
both O
the O
cerebrum O
and O
cerebellum O
following O
Al B
exposure O
, O
which O
were O
found O
to O
be O
significantly O
increased O
following O
Zn B
supplementation O
. O

On O
the O
contrary O
, O
Al B
treatment O
caused O
a O
significant O
increase O
in O
the O
formation O
of O
conjugated O
dienes B
, O
which O
were O
observed O
to O
be O
reduced O
on O
Zn B
co O
- O
treatment O
. O

Further O
, O
Al B
treatment O
significantly O
elevated O
the O
fluorescence O
polarization O
, O
anisotropy O
and O
order O
parameter O
, O
which O
however O
were O
normalized O
upon O
Zn B
co O
- O
administration O
. O

Hence O
, O
the O
present O
study O
depicts O
the O
potential O
of O
Zn B
in O
moderating O
the O
changes O
caused O
by O
Al B
on O
membrane O
composition O
and O
fluidity O
in O
rat O
brain O
. O

FXR O
- O
dependent O
and O
- O
independent O
interaction O
of O
glucocorticoids O
with O
the O
regulatory O
pathways O
involved O
in O
the O
control O
of O
bile B
acid I
handling O
by O
the O
liver O
. O

Treatment O
with O
glucocorticoids O
( O
GCs O
) O
may O
cause O
adverse O
effects O
, O
including O
cholestasis O
. O

The O
ability O
of O
dexamethasone B
, O
prednisolone B
and O
budesonide B
to O
affect O
the O
liver O
handling O
of O
bile B
acids I
( O
BAs B
) O
has O
been O
investigated O
. O

In O
rats O
treated O
with O
GCs O
for O
4 O
days O
, O
altered O
serum O
and O
bile O
BA O
levels O
, O
changed O
conjugation O
pattern O
, O
and O
delayed O
and O
decreased O
ability O
to O
conjugate O
/ O
secrete O
exogenously O
administered O
deoxycholate B
, O
were O
found O
using O
HPLC O
- O
MS O
/ O
MS O
. O

RT O
- O
QPCR O
analyses O
revealed O
that O
GC O
treatment O
also O
induced O
a O
down O
- O
regulation O
of O
liver O
nuclear O
receptors O
( O
Fxr O
, O
Gr O
and O
Shp O
) O
, O
transporters O
( O
Ntcp O
, O
Mrp4 O
and O
Bcrp O
) O
and O
enzymes O
( O
Cyp7a1 O
and O
Baat O
) O
, O
whereas O
Bsep O
, O
Mrp2 O
and O
Cyp27a1 O
were O
up O
- O
regulated O
. O

Human O
HepG2 O
and O
Alexander O
cell O
lines O
were O
used O
as O
in O
vitro O
models O
of O
liver O
cells O
with O
and O
without O
constitutive O
FXR O
expression O
, O
respectively O
. O

In O
HepG2 O
cells O
, O
GCs O
induced O
a O
decreased O
expression O
of O
FXR O
and O
SHP O
, O
and O
inhibited O
the O
regulatory O
effect O
of O
GW4064 B
on O
FXR O
- O
target O
genes O
. O

In O
Alexander O
cells O
, O
only O
when O
they O
were O
transfected O
with O
FXR O
+ O
RXR O
, O
GW4064 B
caused O
up O
- O
regulation O
of O
SHP O
and O
OST O
beta O
, O
and O
a O
down O
- O
regulation O
of O
CYP27A1 O
. O

GCs O
had O
the O
opposite O
effect O
on O
these O
genes O
, O
both O
in O
the O
absence O
and O
in O
the O
presence O
of O
FXR O
expression O
. O

Co O
- O
transfection O
of O
Alexander O
cells O
with O
IR O
- O
1 O
- O
Luc O
and O
FXR O
+ O
RXR O
revealed O
that O
GCs O
did O
not O
inhibit O
but O
moderately O
enhanced O
FXR O
activity O
. O

Moreover O
, O
GCs O
have O
a O
synergistic O
effect O
on O
GW4064 B
- O
induced O
FXR O
activation O
, O
whereas O
chenodeoxycholate B
and O
GW4064 B
have O
an O
additive O
effect O
. O

In O
conclusion O
, O
GCs O
are O
able O
to O
directly O
or O
indirectly O
activate O
FXR O
but O
they O
also O
antagonize O
, O
through O
FXR O
- O
independent O
mechanisms O
, O
the O
expression O
of O
FXR O
and O
FXR O
target O
genes O
involved O
in O
the O
hepatic O
handling O
of O
BAs B
. O

Toxic O
effects O
of O
dietary O
exposure O
to O
T B
- I
2 I
toxin I
on O
intestinal O
and O
hepatic O
biotransformation O
enzymes O
and O
drug O
transporter O
systems O
in O
broiler O
chickens O
. O

The O
effects O
of O
the O
mycotoxin O
T B
- I
2 I
on O
hepatic O
and O
intestinal O
drug O
- O
metabolizing O
enzymes O
( O
cytochrome O
P450 O
) O
and O
drug O
transporter O
systems O
( O
MDR1 O
and O
MRP2 O
) O
in O
poultry O
were O
investigated O
during O
this O
study O
. O

Broiler O
chickens O
received O
either O
uncontaminated O
feed O
, O
feed O
contaminated O
with O
68 O
mu O
g O
/ O
kg O
or O
752 O
mu O
g O
/ O
kg O
T B
- I
2 I
toxin I
. O

After O
3weeks O
, O
the O
animals O
were O
euthanized O
and O
MDR1 O
, O
MRP2 O
, O
CYP1A4 O
, O
CYP1A5 O
and O
CYP3A37 O
mRNA O
expression O
were O
analyzed O
using O
qRT O
- O
PCR O
. O

Along O
the O
entire O
length O
of O
the O
small O
intestine O
no O
significant O
differences O
were O
observed O
. O

In O
the O
liver O
, O
genes O
coding O
for O
CYP1A4 O
, O
CYP1A5 O
and O
CYP3A37 O
were O
significantly O
down O
- O
regulated O
in O
the O
group O
exposed O
to O
752 O
mu O
g O
/ O
kg O
T O
- O
2 O
. O

For O
CYP1A4 O
, O
even O
a O
contamination O
level O
of O
68 O
mu O
g O
/ O
kg O
T O
- O
2 O
caused O
a O
significant O
decrease O
in O
mRNA O
expression O
. O

Expression O
of O
MDR1 O
was O
not O
significantly O
decreased O
in O
the O
liver O
. O

In O
contrast O
, O
hepatic O
MRP2 O
expression O
was O
significantly O
down O
- O
regulated O
after O
exposure O
to O
752 O
mu O
g O
/ O
kg O
T O
- O
2 O
. O

Hepatic O
and O
intestinal O
microsomes O
were O
prepared O
to O
test O
the O
enzymatic O
activity O
of O
CYP3A O
. O

In O
the O
ileum O
and O
liver O
CYP3A O
activity O
was O
significantly O
increased O
in O
the O
group O
receiving O
752 O
mu O
g O
/ O
kg O
T O
- O
2 O
compared O
to O
the O
control O
group O
. O

The O
results O
of O
this O
study O
show O
that O
drug O
metabolizing O
enzymes O
and O
drug O
transporter O
mechanisms O
can O
be O
influenced O
due O
to O
prolonged O
exposure O
to O
relevant O
doses O
of O
T O
- O
2 O
. O

Enhanced O
chemopreventive O
activity O
of O
hydroxytyrosol B
on O
HL60 O
and O
HL60R O
cells O
by O
chemical O
conversion O
into O
thio O
derivatives O
. O

Thio O
derivatives O
of O
hydroxytyrosol B
containing O
thiol B
, O
thioacetate B
and O
disulfide B
functionalities O
were O
synthesized O
from O
natural O
hydroxytyrosol B
( O
3 B
, I
4 I
- I
DHPEA I
) O
via O
3 B
, I
4 I
- I
dihydroxyphenethyl I
halides I
. O

These O
compounds O
, O
containing O
the O
combination O
of O
catechol B
moiety O
and O
divalent O
sulfur B
functions O
, O
were O
tested O
for O
the O
pro O
- O
apoptotic O
and O
anti O
- O
proliferative O
activities O
on O
both O
parental O
HL60 O
and O
multi O
- O
drug O
resistant O
HL60R O
cells O
. O

It O
was O
found O
that O
all O
synthesized O
compounds O
were O
more O
effective O
than O
3 B
, I
4 I
- I
DHPEA I
in O
inducing O
apoptosis O
on O
HL60R O
cells O
, O
and O
that O
the O
hydroxytyrosol B
disulfide I
was O
the O
most O
active O
pro O
- O
apoptotic O
and O
anti O
- O
proliferative O
compound O
on O
both O
HL60 O
and O
HL60R O
cells O
. O

Different O
from O
3 B
, I
4 I
- I
DHPEA I
, O
all O
thio O
derivatives O
of O
hydroxytyrosol B
induced O
apoptosis O
by O
a O
mechanism O
not O
involving O
the O
release O
of O
H B
( I
2 I
) I
O I
( I
2 I
) I
in O
the O
culture O
medium O
. O

The O
data O
on O
HL60R O
cells O
suggest O
that O
these O
compounds O
could O
be O
able O
to O
reverse O
the O
resistance O
toward O
the O
most O
common O
drugs O
in O
cancer O
therapy O
. O

In O
- O
line O
monitoring O
of O
the O
drug O
content O
of O
powder O
mixtures O
and O
tablets O
by O
near O
- O
infrared O
spectroscopy O
during O
the O
continuous O
direct O
compression O
tableting O
process O
. O

Continuous O
manufacturing O
methods O
offer O
economic O
and O
quality O
advantages O
when O
compared O
with O
batch O
manufacturing O
methods O
. O

In O
continuous O
manufacturing O
, O
one O
requires O
real O
time O
assurance O
of O
quality O
of O
product O
via O
the O
implementation O
of O
PAT O
tools O
. O

This O
study O
focuses O
on O
an O
in O
- O
line O
near O
- O
infrared O
( O
NIR O
) O
spectroscopic O
method O
for O
determining O
the O
drug O
content O
of O
powder O
mixtures O
and O
tablets O
during O
a O
continuous O
tableting O
process O
. O

Tablets O
consisting O
of O
acetaminophen B
( O
20 O
- O
30 O
% O
) O
, O
lactose B
( O
69 O
. O
07 O
- O
78 O
. O
93 O
% O
) O
and O
magnesium B
stearate I
( O
0 O
. O
93 O
- O
1 O
. O
07 O
% O
) O
were O
prepared O
in O
a O
continuous O
direct O
compression O
line O
that O
consisted O
of O
two O
loss O
- O
in O
- O
weight O
feeders O
, O
one O
for O
acetaminophen B
and O
one O
for O
premixed O
lactose B
and O
magnesium B
stearate I
, O
and O
a O
continuous O
mixer O
followed O
by O
a O
rotary O
tablet O
press O
. O

NIR O
spectroscopy O
was O
applied O
to O
the O
continuous O
mixer O
and O
tablet O
press O
to O
perform O
a O
100 O
% O
product O
check O
at O
full O
tableting O
speed O
. O

The O
UV O
- O
spectrophotometric O
method O
was O
used O
as O
an O
off O
- O
line O
reference O
method O
to O
determine O
the O
acetaminophen B
content O
in O
the O
samples O
. O

The O
powder O
mixture O
and O
tablet O
samples O
were O
taken O
during O
the O
process O
for O
the O
calibration O
of O
continuous O
mixer O
and O
tablet O
press O
, O
respectively O
. O

For O
the O
continuous O
mixer O
, O
model O
creation O
with O
the O
PLS O
method O
yielded O
R O
- O
Square O
and O
RMSEC O
( O
root O
mean O
square O
error O
of O
calibration O
) O
values O
of O
0 O
. O
975 O
% O
and O
0 O
. O
56 O
% O
, O
respectively O
. O

For O
the O
tablet O
press O
, O
the O
corresponding O
R O
- O
Square O
and O
RMSEC O
values O
were O
0 O
. O
943 O
% O
and O
0 O
. O
75 O
% O
, O
respectively O
. O

A O
test O
run O
demonstrated O
good O
predictability O
in O
the O
estimation O
of O
the O
API O
content O
in O
the O
powder O
mixtures O
and O
tablets O
during O
the O
continuous O
tableting O
process O
. O

For O
the O
continuous O
mixer O
and O
tablet O
press O
, O
the O
RMSEP O
( O
root O
mean O
square O
error O
of O
prediction O
) O
values O
were O
0 O
. O
96 O
% O
and O
1 O
. O
37 O
% O
, O
respectively O
. O

This O
study O
demonstrates O
that O
an O
NIR O
instrument O
capable O
of O
fast O
spectra O
acquisition O
can O
be O
a O
valuable O
tool O
for O
the O
in O
- O
line O
monitoring O
of O
the O
continuous O
mixing O
and O
tableting O
processes O
. O

OAT1 O
and O
OAT3 O
: O
targets O
of O
drug O
- O
drug O
interaction O
between O
entecavir B
and O
JBP485 B
. O

Entecavir B
and O
JBP485 B
( O
a O
dipeptide B
) O
exhibit O
the O
antihepatitis O
activities O
and O
it O
is O
possible O
for O
the O
two O
drugs O
to O
be O
coadministered O
in O
the O
treatment O
of O
hepatitis O
. O

We O
aimed O
to O
elucidate O
whether O
entecavir B
was O
a O
substrate O
of O
OAT1 O
, O
OAT3 O
, O
OCT O
, O
and O
PEPT1 O
and O
to O
investigate O
the O
targets O
of O
drug O
- O
drug O
interactions O
between O
entecavir B
and O
JBP485 B
. O

Plasma O
and O
urine O
concentrations O
of O
entecavir B
following O
intravenous O
and O
oral O
administration O
in O
vivo O
, O
uptake O
of O
entecavir B
in O
kidney O
slices O
and O
transfected O
cells O
in O
vitro O
, O
were O
determined O
by O
LC O
- O
MS O
/ O
MS O
. O

Following O
intravenous O
co O
- O
administration O
of O
entecavir B
and O
JBP485 B
in O
rats O
, O
entecavir B
AUC O
increased O
1 O
. O
93 O
- O
fold O
, O
t1 O
/ O
2 O
beta O
was O
prolonged O
2 O
. O
08 O
- O
fold O
, O
CLP O
decreased O
49 O
% O
, O
CLR O
decreased O
73 O
% O
, O
and O
accumulated O
urinary O
excretion O
decreased O
54 O
% O
. O

However O
, O
following O
oral O
co O
- O
administration O
, O
the O
entecavir B
Tmax O
and O
Cmax O
were O
not O
affected O
; O
the O
degree O
of O
change O
in O
other O
pharmacokinetic O
parameters O
( O
AUC O
, O
t1 O
/ O
2 O
beta O
, O
CLP O
, O
and O
accumulated O
urinary O
excretion O
) O
was O
similar O
to O
that O
of O
intravenous O
administration O
. O

The O
uptake O
of O
entecavir B
was O
nearly O
identical O
in O
hPEPT1 O
- O
as O
in O
vector O
- O
HELA O
cells O
. O

In O
rat O
kidney O
slices O
, O
uptake O
of O
entecavir B
was O
markedly O
inhibited O
by O
p B
- I
aminohippurate I
, O
benzylpenicillin B
, O
JBP485 B
, O
and O
tetraethyl B
ammonium I
. O

In O
hOAT1 O
- O
and O
hOAT3 O
- O
HEK293 O
cells O
, O
uptake O
of O
entecavir B
was O
significantly O
higher O
compared O
to O
vector O
- O
HEK293 O
cells O
and O
was O
markedly O
inhibited O
by O
p B
- I
aminohippurate I
, O
benzylpenicillin B
, O
and O
JBP485 B
. O

Km O
and O
Vmax O
values O
of O
entecavir B
were O
250 O
mu O
M O
and O
0 O
. O
83 O
nmol O
/ O
mg O
protein O
/ O
30s O
( O
OAT1 O
) O
and O
23 O
mu O
M O
and O
1 O
. O
1 O
nmol O
/ O
mg O
protein O
/ O
30 O
s O
( O
OAT3 O
) O
, O
respectively O
. O

Entecavir B
is O
the O
substrate O
of O
OAT1 O
, O
OAT3 O
, O
and O
OCT O
. O

Moreover O
, O
OAT1 O
and O
OAT3 O
are O
the O
targets O
of O
DDI O
between O
entecavir B
and O
JBP485 B
. O

Bioactive O
barrigenol B
type O
triterpenoids B
from O
the O
leaves O
of O
Xanthoceras O
sorbifolia O
Bunge O
. O

In O
order O
to O
find O
out O
new O
natural O
barrigenol B
type O
triterpenenoids B
as O
antitumor O
agent O
and O
reveal O
the O
difference O
on O
material O
basis O
of O
different O
parts O
of O
Xanthoceras O
sorbifolia O
Bunge O
, O
the O
bioassay O
- O
directed O
separation O
of O
the O
saponin B
fraction O
from O
leaves O
of O
X O
. O
sorbifolia O
Bunge O
was O
carried O
out O
to O
afford O
5 O
new O
barrigenol B
type O
triterpenoids B
( O
1 O
- O
5 O
) O
, O
together O
with O
2 O
known O
ones O
. O

The O
antitumor O
activities O
were O
evaluated O
and O
compounds O
2 O
and O
7 O
showed O
significant O
cytotoxic O
activity O
. O

Furthermore O
, O
the O
SAR O
was O
discussed O
briefly O
. O

On O
the O
basis O
of O
our O
research O
work O
and O
related O
literature O
, O
the O
difference O
of O
chemical O
constituents O
from O
different O
parts O
of O
X O
. O
sorbifolia O
was O
analyzed O
and O
concluded O
. O

The O
result O
can O
be O
a O
useful O
reference O
for O
phytochemistry O
taxology O
and O
safe O
and O
rational O
drug O
use O
of O
X O
. O
sorbifolia O
. O

Synthesis O
of O
quinoline B
derivatives O
: O
discovery O
of O
a O
potent O
and O
selective O
phosphodiesterase O
5 O
inhibitor O
for O
the O
treatment O
of O
Alzheimer O
' O
s O
disease O
. O

Phosphodiesterase O
type O
5 O
( O
PDE5 O
) O
mediates O
the O
degradation O
of O
cGMP B
in O
a O
variety O
of O
tissues O
including O
brain O
. O

Recent O
studies O
have O
demonstrated O
the O
importance O
of O
the O
nitric B
oxide I
/ O
cGMP B
/ O
cAMP B
- O
responsive O
element O
- O
binding O
protein O
( O
CREB O
) O
pathway O
to O
the O
process O
of O
learning O
and O
memory O
. O

Thus O
, O
PDE5 O
inhibitors O
( O
PDE5Is O
) O
are O
thought O
to O
be O
promising O
new O
therapeutic O
agents O
for O
the O
treatment O
of O
Alzheimer O
' O
s O
disease O
( O
AD O
) O
, O
a O
neurodegenerative O
disorder O
characterized O
by O
memory O
loss O
. O

To O
explore O
this O
possibility O
, O
a O
series O
of O
quinoline B
derivatives O
were O
synthesized O
and O
evaluated O
. O

We O
found O
that O
compound O
7a O
selectively O
inhibits O
PDE5 O
with O
an O
IC O
( O
50 O
) O
of O
0 O
. O
27 O
nM O
and O
readily O
crosses O
the O
blood O
brain O
barrier O
. O

In O
an O
in O
vivo O
mouse O
model O
of O
AD O
, O
compound O
7a O
rescues O
synaptic O
and O
memory O
defects O
. O

Quinoline B
- O
based O
, O
CNS O
- O
permeant O
PDE5Is O
have O
potential O
for O
AD O
therapeutic O
development O
. O

Benzo B
[ I
alpha I
] I
pyrene I
repressed O
DNA O
mismatch O
repair O
in O
human O
breast O
cancer O
cells O
. O

DNA O
mismatch O
repair O
( O
MMR O
) O
has O
been O
recently O
implicated O
to O
play O
a O
significant O
role O
in O
breast O
cancer O
progression O
, O
however O
, O
few O
studies O
have O
examined O
how O
various O
carcinogens O
affect O
MMR O
system O
in O
breast O
cancer O
cells O
. O

The O
present O
study O
employs O
an O
in O
vivo O
MMR O
assay O
developed O
in O
our O
laboratory O
to O
assess O
how O
prevalent O
environmental O
carcinogens O
such O
as O
polycyclic B
aromatic I
hydrocarbons I
( O
PAHs B
) O
affect O
MMR O
activity O
in O
human O
breast O
carcinoma O
cells O
. O

Specifically O
, O
we O
quantitatively O
measured O
MMR O
activity O
in O
ZR75 O
- O
1 O
cells O
after O
they O
were O
exposed O
to O
benzo B
[ I
alpha I
] I
pyrene I
( O
BaP B
) O
, O
a O
prototypical O
PAH B
, O
at O
various O
concentrations O
. O

Our O
findings O
revealed O
that O
BaP B
exposure O
at O
high O
concentrations O
of O
1 O
and O
5 O
mu O
M O
induced O
significant O
inhibition O
of O
MMR O
activity O
in O
ZR75 O
- O
1 O
cells O
. O

Further O
, O
we O
also O
identified O
that O
MMR O
repression O
induced O
by O
5 O
mu O
M O
BaP B
was O
mediated O
through O
one O
of O
the O
MMR O
key O
proteins O
MSH6 O
as O
significant O
reduction O
in O
protein O
level O
was O
detected O
by O
western O
blot O
. O

More O
importantly O
, O
ectopic O
expression O
of O
hMSH6 O
restored O
MMR O
activity O
in O
the O
BaP B
treated O
cells O
to O
the O
same O
level O
as O
in O
the O
control O
cells O
. O

Impaired O
MMR O
plays O
an O
important O
role O
in O
carcinogenesis O
. O

Our O
findings O
suggest O
that O
BaP B
induced O
repression O
of O
MMR O
activity O
may O
also O
contribute O
to O
the O
progression O
of O
mutagenesis O
event O
. O

Meanwhile O
, O
the O
present O
study O
also O
for O
the O
first O
demonstrated O
that O
our O
in O
vivo O
DNA O
MMR O
assay O
can O
be O
applied O
in O
the O
field O
of O
environmental O
toxicology O
. O

Detoxification O
of O
aldehydes B
by O
histidine B
- O
containing O
dipeptides B
: O
from O
chemistry O
to O
clinical O
implications O
. O

Aldehydes B
are O
generated O
by O
oxidized O
lipids O
and O
carbohydrates B
at O
increased O
levels O
under O
conditions O
of O
metabolic O
imbalance O
and O
oxidative O
stress O
during O
atherosclerosis O
, O
myocardial O
and O
cerebral O
ischemia O
, O
diabetes O
, O
neurodegenerative O
diseases O
and O
trauma O
. O

In O
most O
tissues O
, O
aldehydes B
are O
detoxified O
by O
oxidoreductases O
that O
catalyze O
the O
oxidation O
or O
the O
reduction O
of O
aldehydes B
or O
enzymatic O
and O
nonenzymatic O
conjugation O
with O
low O
molecular O
weight O
thiols B
and O
amines B
, O
such O
as O
glutathione B
and O
histidine B
dipeptides B
. O

Histidine B
dipeptides I
are O
present O
in O
micromolar O
to O
millimolar O
range O
in O
the O
tissues O
of O
vertebrates O
, O
where O
they O
are O
involved O
in O
a O
variety O
of O
physiological O
functions O
such O
as O
pH O
buffering O
, O
metal O
chelation O
, O
oxidant O
and O
aldehyde B
scavenging O
. O

Histidine B
dipeptides I
such O
as O
carnosine B
form O
Michael O
adducts O
with O
lipid O
- O
derived O
unsaturated B
aldehydes I
, O
and O
react O
with O
carbohydrate B
- O
derived O
oxo B
- I
and I
hydroxy I
- I
aldehydes I
forming O
products O
of O
unknown O
structure O
. O

Although O
these O
peptides O
react O
with O
electrophilic O
molecules O
at O
lower O
rate O
than O
glutathione B
, O
they O
can O
protect O
glutathione B
from O
modification O
by O
oxidant O
and O
they O
may O
be O
important O
for O
aldehyde B
quenching O
in O
glutathione B
- O
depleted O
cells O
or O
extracellular O
space O
where O
glutathione B
is O
scarce O
. O

Consistent O
with O
in O
vitro O
findings O
, O
treatment O
with O
carnosine B
has O
been O
shown O
to O
diminish O
ischemic O
injury O
, O
improve O
glucose B
control O
, O
ameliorate O
the O
development O
of O
complications O
in O
animal O
models O
of O
diabetes O
and O
obesity O
, O
promote O
wound O
healing O
and O
decrease O
atherosclerosis O
. O

The O
protective O
effects O
of O
carnosine B
have O
been O
linked O
to O
its O
anti O
- O
oxidant O
properties O
, O
its O
ability O
to O
promote O
glycolysis O
, O
detoxify O
reactive O
aldehydes B
and O
enhance O
histamine B
levels O
. O

Thus O
, O
treatment O
with O
carnosine B
and O
related O
histidine B
dipeptides I
may O
be O
a O
promising O
strategy O
for O
the O
prevention O
and O
treatment O
of O
diseases O
associated O
with O
high O
carbonyl B
load O
. O

The O
effect O
of O
manganese B
on O
dopamine B
toxicity O
and O
dopamine B
transporter O
( O
DAT O
) O
in O
control O
and O
DAT O
transfected O
HEK O
cells O
. O

Chronic O
exposure O
to O
Mn B
results O
in O
the O
development O
of O
a O
neurological O
disorder O
known O
as O
manganism B
characterized O
by O
neurological O
deficits O
resembling O
that O
seen O
in O
Parkinsonism O
. O

Although O
dopaminergic O
neurons O
within O
the O
nigrostriatal O
pathway O
appear O
intact O
, O
Mn B
- O
induced O
irregularities O
in O
DA O
transmission O
have O
been O
observed O
including O
decreased O
amphetamine B
- O
induced O
DA O
release O
and O
loss O
of O
the O
dopamine B
transporter O
( O
DAT O
) O
. O

Results O
of O
studies O
to O
evaluate O
the O
effect O
of O
Mn B
and O
DA O
on O
cell O
viability O
in O
control O
and O
DAT O
- O
transfected O
HEK O
cells O
reveal O
that O
Mn B
is O
equally O
toxic O
to O
both O
cell O
lines O
whereas O
DA O
was O
only O
toxic O
to O
cells O
containing O
DAT O
. O

DA O
toxicity O
was O
saturable O
suggesting O
that O
transport O
may O
be O
rate O
limiting O
. O

When O
Mn B
and O
DA O
were O
added O
simultaneously O
to O
the O
media O
, O
cell O
toxicity O
was O
similar O
to O
that O
produced O
by O
Mn B
alone O
suggesting O
that O
Mn B
may O
suppress O
DA O
uptake O
in O
the O
DAT O
containing O
cells O
. O

Preincubation O
of O
DA O
prior O
to O
the O
addition O
of O
Mn B
resulted O
in O
cell O
death O
which O
was O
essentially O
additive O
with O
that O
produced O
independently O
by O
the O
two O
agents O
. O

Mn B
was O
also O
shown O
to O
decrease O
DA O
uptake O
and O
amphetamine B
- O
induced O
DA O
efflux O
in O
DAT O
containing O
cells O
. O

Time O
- O
lapsed O
confocal O
microscopy O
indicates O
that O
Mn B
can O
promote O
trafficking O
of O
cell O
surface O
DAT O
into O
intracellular O
compartments O
which O
may O
account O
for O
the O
decrease O
in O
DA O
uptake O
and O
DA O
efflux O
in O
these O
cells O
. O

Mn B
- O
induced O
internalization O
of O
DAT O
may O
provide O
an O
explanation O
for O
disruption O
in O
DA O
transmission O
previously O
reported O
in O
the O
striatum O
. O

Flavonoids B
profiles O
, O
antioxidant O
, O
acetylcholinesterase O
inhibition O
activities O
of O
extract O
from O
Dryoathyrium O
boryanum O
( O
Willd O
. O
) O
Ching O
. O

The O
profiles O
and O
bioactivities O
of O
flavonoids B
extracted O
from O
Dryoathyrium O
boryanum O
( O
Willd O
. O
) O
Ching O
were O
investigated O
. O

The O
total O
flavonoids B
content O
in O
extract O
from O
D O
. O
boryanum O
is O
about O
145 O
. O
8mg O
/ O
g O
. O

By O
means O
of O
HPLC O
- O
DAD O
- O
ESI O
- O
MS O
, O
the O
main O
flavonoids B
in O
D O
. O
boryanum O
were O
tentatively O
identified O
as O
3 B
- I
hydroxyphloretin I
6 I
' I
- I
O I
- I
hexoside I
, O
quercetin B
- I
7 I
- I
hexoside I
, O
apigenin7 B
- I
O I
- I
glucoside I
, O
luteolin B
7 I
- I
O I
- I
glucoside I
, O
apigenin B
7 I
- I
O I
- I
galactoside I
, O
acacetin B
7 I
- I
O I
- I
( I
alpha I
- I
D I
- I
apio I
- I
furanosyl I
) I
( I
1 I
- I
- I
> I
6 I

) I
- I
beta I
- I
d I
- I
glucoside I
, O
3 B
- I
hydroxy I
phloretin I
6 I
- I
O I
- I
hexoside I
, O
luteolin B
- I
6 I
- I
C I
- I
glucoside I
. O

0 O
. O
21mg O
/ O
ml O
flavonoids O
extract O
from O
D O
. O
boryanum O
showed O
very O
strong O
superoxide B
anion O
radical O
scavenging O
potential O
, O
which O
is O
higher O
than O
that O
of O
rutin B
( O
0 O
. O
25mg O
/ O
ml O
) O
. O

The O
extract O
( O
0 O
. O
21mg O
/ O
ml O
of O
flavonoids B
) O
from O
D O
. O
boryanum O
exhibited O
similar O
DPPH B
scavenging O
potential O
with O
that O
of O
rutin B
( O
0 O
. O
25mg O
/ O
ml O
) O
. O

However O
, O
rutin B
( O
0 O
. O
25mg O
/ O
ml O
) O
showed O
a O
significantly O
higher O
reducing O
power O
and O
ABTS B
scavenging O
potential O
than O
that O
of O
0 O
. O
21mg O
/ O
ml O
flavonoids B
extract O
from O
D O
. O
boryanum O
. O

It O
had O
no O
effect O
on O
acetylcholinesterase O
. O

D O
. O
boryanum O
can O
be O
considered O
as O
a O
medicinal O
plant O
and O
the O
flavonoids B
from O
D O
. O
boryanum O
are O
excellent O
antioxidants O
. O

Profiling O
of O
neuraminidase O
inhibitory O
polyphenols B
from O
the O
seeds O
of O
Paeonia O
lactiflora O
. O

Bacterial O
neuraminidase O
( O
NA O
) O
is O
a O
lynch O
pin O
enzyme O
in O
the O
formation O
of O
biofilms O
. O

Thus O
NA O
continues O
to O
be O
one O
of O
the O
key O
enzymes O
targeted O
by O
bacterial O
infection O
. O

The O
purpose O
of O
this O
manuscript O
is O
to O
communicate O
four O
new O
naturally O
derived O
inhibitors O
of O
neuraminidase O
( O
IC50s O
3 O
. O
7 O
- O
24 O
. O
4 O
mu O
M O
) O
. O

All O
these O
active O
species O
( O
1 O
- O
4 O
) O
contained O
a O
resveratrol B
chemotype O
, O
however O
resveratrol B
itself O
was O
inactive O
( O
IC50 O
> O
100 O
mu O
M O
) O
. O

1 O
- O
4 O
were O
isolated O
from O
the O
60 O
% O
aqueous O
ethanol B
extract O
of O
seeds O
of O
Paeonia O
lactiflora O
, O
which O
exhibited O
potent O
neuraminidase O
inhibition O
. O

Purification O
of O
the O
extracts O
yielded O
four O
chiral O
polyphenols B
, O
suffruticosol B
A I
( O
1 O
) O
, O
suffruticosol B
B I
( O
2 O
) O
, O
trans B
- I
epsilon I
- I
viniferin I
( O
3 O
) O
, O
and O
trans B
- I
gnetin I
H I
( O
4 O
) O
. O

Mechanistic O
analysis O
of O
1 O
- O
4 O
' O
s O
inhibition O
showed O
that O
they O
were O
all O
reversible O
, O
noncompetitive O
inhibitors O
. O

Trans B
- I
epsilon I
- I
viniferin I
( O
3 O
) O
underwent O
trans O
- O
cis O
isomerization O
, O
which O
led O
to O
a O
reduction O
in O
inhibition O
potency O
. O

This O
correlates O
with O
the O
fact O
that O
the O
cis O
- O
isomer O
is O
a O
weaker O
inhibitor O
of O
neuraminidase O
than O
the O
trans O
- O
isomer O
. O

Importantly O
, O
significantly O
different O
optical O
rotations O
( O
[ O
alpha O
] O
D O
) O
compared O
to O
previous O
reports O
were O
found O
for O
suffruticosols B
A I
( O
+ O
95 O
vs O
- I
34 I
) I
and I
B I
( O
+ O
136 O
vs O
+ O
13 O
) O
. O

These O
two O
species O
are O
the O
most O
important O
standard O
metabolites O
in O
the O
whole O
paeoniaceae O
family O
and O
therefore O
correction O
of O
this O
error O
is O
important O
. O

Identification O
of O
novel O
antimycobacterial O
chemical O
agents O
through O
the O
in O
silico O
multi O
- O
conformational O
structure O
- O
based O
drug O
screening O
of O
a O
large O
- O
scale O
chemical O
library O
. O

The O
increasing O
prevalence O
of O
drug O
- O
resistant O
tuberculosis O
, O
which O
is O
resistant O
to O
effective O
multiple O
antibiotic O
, O
presents O
a O
major O
global O
health O
threat O
. O

The O
thymidine B
monophosphate I
kinase O
( O
TMPK O
) O
of O
Mycobacterium O
tuberculosis O
( O
M O
. O
tuberculosis O
) O
, O
which O
is O
an O
essential O
enzyme O
for O
the O
maintenance O
of O
the O
thymidine B
triphosphate I
pools O
, O
is O
considered O
an O
attractive O
target O
for O
the O
development O
of O
effective O
antibiotics O
against O
tuberculosis O
. O

In O
this O
study O
, O
we O
attempted O
to O
identify O
novel O
chemical O
compounds O
that O
specifically O
target O
the O
M O
. O
tuberculosis O
TMPK O
( O
mtTMPK O
) O
. O

We O
performed O
in O
silico O
structure O
- O
based O
drug O
screening O
using O
the O
crystal O
structure O
data O
of O
mtTMPK O
and O
a O
large O
- O
scale O
virtual O
compound O
library O
, O
which O
is O
composed O
of O
6 O
, O
192 O
, O
930 O
chemicals O
. O

Through O
a O
three O
- O
step O
screening O
method O
using O
the O
DOCK O
and O
GOLD O
, O
we O
identified O
ten O
chemical O
compounds O
that O
were O
predicted O
to O
have O
high O
binding O
affinity O
to O
the O
active O
site O
cleft O
of O
the O
mtTMPK B
. O

We O
then O
evaluated O
the O
antibiotic O
effects O
of O
these O
chemical O
compounds O
on O
model O
mycobacteria O
strains O
. O

As O
a O
result O
, O
we O
found O
that O
a O
chemical O
compound O
, O
K10 O
, O
completely O
inhibited O
the O
growth O
of O
Mycobacterium O
vanbaalenii O
( O
M O
. O
vanbaalenii O
) O
and O
Mycobacterium O
smegmatis O
( O
M O
. O
smegmatis O
) O
. O

Moreover O
, O
K10 O
does O
not O
exhibit O
any O
toxic O
effects O
on O
the O
growth O
of O
enterobacteria O
and O
mammalian O
cells O
. O

The O
structural O
and O
experimental O
information O
regarding O
this O
novel O
chemical O
compound O
, O
K10 O
, O
is O
likely O
to O
be O
useful O
for O
the O
hit O
- O
to O
- O
lead O
optimization O
of O
new O
antibiotics O
for O
the O
treatment O
of O
tuberculosis O
. O

Monocyclic B
beta I
- I
lactams I
as O
antibacterial O
agents O
: O
facing O
antioxidant O
activity O
of O
N B
- I
methylthio I
- I
azetidinones I
. O

A O
series O
of O
N B
- I
methylthio I
- I
beta I
- I
lactams I
with O
antibacterial O
activity O
were O
thoroughly O
evaluated O
as O
antioxidants O
. O

We O
found O
that O
only O
the O
presence O
of O
a O
polyphenolic B
moiety O
anchored O
to O
the O
beta B
- I
lactam I
ring O
ensured O
an O
adequate O
antioxidant O
potency O
. O

New O
compounds O
, O
efficiently O
combining O
in O
one O
structure O
antioxidant O
and O
antibacterial O
activity O
, O
may O
provide O
a O
promising O
basis O
for O
the O
development O
of O
new O
leads O
useful O
in O
adverse O
clinical O
conditions O
such O
as O
in O
cystic O
fibrosis O
patients O
, O
in O
whom O
colonization O
by O
MRSA O
and O
epithelial O
damage O
by O
chronic O
pulmonary O
oxidative O
stress O
take O
place O
. O

Antimicrobial O
activity O
of O
various O
4 B
- I
and I
5 I
- I
substituted I
1 I
- I
phenylnaphthalenes I
. O

Bacterial O
cell O
division O
occurs O
in O
conjunction O
with O
the O
formation O
of O
a O
cytokinetic O
Z O
- O
ring O
structure O
comprised O
of O
FtsZ O
subunits O
. O

Agents O
that O
can O
disrupt O
Z O
- O
ring O
formation O
have O
the O
potential O
, O
through O
this O
unique O
mechanism O
, O
to O
be O
effective O
against O
several O
of O
the O
newly O
emerging O
multi O
- O
drug O
resistant O
strains O
of O
infectious O
bacteria O
. O

1 B
- I
and I
12 I
- I
Aryl I
substituted I
benzo I
[ I
c I
] I
phenanthridines I
have O
been O
identified O
as O
antibacterial O
agents O
that O
could O
exert O
their O
activity O
by O
disruption O
of O
Z O
- O
ring O
formation O
. O

Substituted O
4 B
- I
and I
5 I
- I
amino I
- I
1 I
- I
phenylnaphthalenes I
represent O
substructures O
within O
the O
pharmacophore O
of O
these O
benzo B
[ I
c I
] I
phenanthridines I
. O

Several O
4 B
- I
and I
5 I
- I
substituted I
1 I
- I
phenylnaphthalenes I
were O
synthesized O
and O
evaluated O
for O
antibacterial O
activity O
against O
Staphylococcus O
aureus O
and O
Enterococcus O
faecalis O
. O

The O
impact O
of O
select O
compounds O
on O
the O
polymerization O
dynamics O
of O
S O
. O
aureus O
FtsZ O
was O
also O
assessed O
. O

Fragment O
- O
based O
design O
, O
synthesis O
, O
and O
biological O
evaluation O
of O
N B
- I
substituted I
- I
5 I
- I
( I
4 I
- I
isopropylthiophenol I
) I
- I
2 I
- I
hydroxynicotinamide I
derivatives O
as O
novel O
Mcl O
- O
1 O
inhibitors O
. O

We O
have O
previously O
reported O
a O
nanomolar O
inhibitor O
of O
antiapoptotic O
Mcl O
- O
1 O
protein O
, O
3 B
- I
thiomorpholin I
- I
8 I
- I
oxo I
- I
8H I
- I
acenaphtho I
[ I
1 I
, I
2 I
- I
b I
] I
pyrrole I
- I
9 I
- I
carbonitrile I
( O
S1 O
) O
. O

S1 O
plays O
its O
function O
by O
binding O
to O
the O
BH3 B
groove O
of O
Mcl O
- O
1 O
. O

Basing O
on O
this O
spacial O
structural O
characteristic O
, O
we O
developed O
a O
novel O
class O
of O
Mcl O
- O
1 O
inhibitor O
using O
fragment O
- O
based O
drug O
discovery O
approach O
. O

By O
dissecting O
S1 O
, O
we O
identified O
the O
compound O
4 O
with O
a O
2 B
- I
hydroxypyridine I
core O
as O
the O
starting O
fragment O
. O

In O
the O
following O
molecular O
growth O
, O
we O
used O
the O
ligand O
efficiency O
evaluation O
and O
fit O
quality O
score O
to O
assess O
the O
fragments O
. O

A O
novel O
potent O
compound O
, O
N B
- I
benzyl I
- I
5 I
- I
( I
4 I
- I
isopropylthiophenol I
) I
- I
2 I
- I
hydroxyl I
nicotinamide I
( O
12c O
) O
, O
which O
binds O
Mcl O
- O
1 O
with O
an O
IC O
( O
50 O
) O
value O
of O
54 O
nM O
was O
obtained O
. O

Compound O
12c O
demonstrated O
a O
better O
aqueous O
solubility O
than O
S1 O
. O

Cellular O
and O
molecular O
mechanisms O
of O
accelerated O
fracture O
healing O
by O
COX2 O
gene O
therapy O
: O
studies O
in O
a O
mouse O
model O
of O
multiple O
fractures O
. O

This O
study O
sought O
to O
determine O
the O
cellular O
and O
molecular O
mechanisms O
of O
cyclooxygenase O
- O
2 O
( O
COX2 O
) O
gene O
therapy O
to O
accelerate O
fracture O
repair O
in O
a O
mouse O
multiple O
tibial O
fractures O
model O
. O

The O
lenti O
- O
COX2 O
( O
or O
lenti O
- O
gfp O
control O
vector O
) O
was O
injected O
into O
fractures O
on O
day O
1 O
post O
- O
fracture O
. O

At O
days O
3 O
- O
7 O
, O
the O
COX2 O
treatment O
increased O
Sdf1 O
- O
, O
Cxcr4 O
- O
, O
Nes O
- O
, O
and O
Podxl O
- O
expressing O
mesenchymal O
stem O
cells O
( O
MSCs O
) O
within O
fracture O
calluses O
, O
suggesting O
an O
enhanced O
MSC O
recruitment O
or O
expansion O
. O

The O
COX2 O
- O
treated O
mice O
formed O
smaller O
cartilaginous O
calluses O
that O
had O
less O
cartilage O
tissues O
than O
control O
mice O
. O

The O
expression O
of O
Sox9 O
mRNA O
was O
7 O
- O
fold O
less O
in O
COX2 O
- O
treated O
than O
in O
control O
calluses O
at O
day O
14 O
, O
implying O
that O
COX2 O
reduces O
chondrocytic O
differentiation O
of O
MSCs O
. O

The O
therapy O
also O
enhanced O
angiogenesis O
as O
reflected O
by O
increased O
immunostaining O
of O
CD31 O
, O
vWF O
, O
and O
alpha O
- O
SMA O
over O
controls O
in O
the O
cartilaginous O
callus O
at O
day O
14 O
- O
21 O
. O

At O
which O
time O
, O
the O
COX2 O
gene O
therapy O
promoted O
bony O
remodeling O
of O
the O
cartilaginous O
callus O
to O
bridge O
the O
fracture O
gap O
that O
was O
accompanied O
by O
2 O
- O
fold O
increase O
in O
osteoclasts O
along O
the O
surface O
of O
the O
woven O
bone O
and O
an O
onset O
of O
osteogenesis O
. O

Blocking O
angiogenesis O
with O
daily O
injection O
of O
endostatin O
from O
day O
4 O
to O
day O
10 O
into O
fracture O
sites O
blocked O
the O
COX2 O
- O
mediated O
reduction O
of O
callus O
size O
that O
was O
associated O
with O
an O
increase O
in O
hypertrophic O
chondrocytes O
and O
concomitant O
reduction O
in O
osteoclasts O
. O

In O
conclusion O
, O
COX2 O
accelerates O
fracture O
healing O
in O
part O
through O
three O
biological O
actions O
: O
1 O
) O
increased O
recruitment O
/ O
expansion O
of O
MSCs O
; O
2 O
) O
decreased O
cartilaginous O
callus O
formation O
; O
and O
3 O
) O
increased O
angiogenesis O
- O
dependent O
cartilage O
remodeling O
. O

These O
effects O
were O
associated O
with O
an O
earlier O
onset O
of O
bony O
bridging O
of O
the O
fracture O
gap O
. O

Singular O
phase O
nano O
- O
optics O
in O
plasmonic O
metamaterials O
for O
label O
- O
free O
single O
- O
molecule O
detection O
. O

The O
non O
- O
trivial O
behaviour O
of O
phase O
is O
crucial O
for O
many O
important O
physical O
phenomena O
, O
such O
as O
, O
for O
example O
, O
the O
Aharonov O
- O
Bohm O
effect O
and O
the O
Berry O
phase O
. O

By O
manipulating O
the O
phase O
of O
light O
one O
can O
create O
' O
twisted O
' O
photons O
, O
vortex O
knots O
and O
dislocations O
which O
has O
led O
to O
the O
emergence O
of O
the O
field O
of O
singular O
optics O
relying O
on O
abrupt O
phase O
changes O
. O

Here O
we O
demonstrate O
the O
feasibility O
of O
singular O
visible O
- O
light O
nano O
- O
optics O
which O
exploits O
the O
benefits O
of O
both O
plasmonic O
field O
enhancement O
and O
the O
peculiarities O
of O
the O
phase O
of O
light O
. O

We O
show O
that O
properly O
designed O
plasmonic O
metamaterials O
exhibit O
topologically O
protected O
zero O
reflection O
yielding O
to O
sharp O
phase O
changes O
nearby O
, O
which O
can O
be O
employed O
to O
radically O
improve O
the O
sensitivity O
of O
detectors O
based O
on O
plasmon O
resonances O
. O

By O
using O
reversible O
hydrogenation O
of O
graphene B
and O
binding O
of O
streptavidin O
- O
biotin B
, O
we O
demonstrate O
an O
areal O
mass O
sensitivity O
at O
a O
level O
of O
fg O
mm O
( O
- O
2 O
) O
and O
detection O
of O
individual O
biomolecules O
, O
respectively O
. O

Our O
proof O
- O
of O
- O
concept O
results O
offer O
a O
route O
towards O
simple O
and O
scalable O
single O
- O
molecule O
label O
- O
free O
biosensing O
technologies O
. O

A O
physiologically O
based O
pharmacokinetic O
model O
for O
the O
oxime B
TMB B
- I
4 I
: O
simulation O
of O
rodent O
and O
human O
data O
. O

Multiple O
oximes B
have O
been O
synthesized O
and O
evaluated O
for O
use O
as O
countermeasures O
against O
chemical O
warfare O
nerve O
agents O
. O

The O
current O
U O
. O
S O
. O
military O
and O
civilian O
oxime B
countermeasure O
, O
2 B
- I
[ I
( I
hydroxyimino I
) I
methyl I
] I
- I
1 I
- I
methylpyridin I
- I
1 I
- I
ium I
chloride I
( O
2 B
- I
PAM I
) O
, O
is O
under O
consideration O
for O
replacement O
with O
a O
more O
effective O
acetylcholinesterase O
reactivator O
, O
1 B
, I
1 I
' I
- I
methylenebis I
{ I
4 I
- I
hydroxyiminomethyl I
} I
pyridinium I
dimethanesulfonate I
( O
MMB B
- I
4 I
) O
. O

Kinetic O
data O
in O
the O
scientific O
literature O
for O
MMB B
- I
4 I
are O
limited O
; O
therefore O
, O
a O
physiologically O
based O
pharmacokinetic O
( O
PBPK O
) O
model O
was O
developed O
for O
a O
structurally O
related O
oxime B
, O
1 B
, I
1 I
' I
- I
trimethylenebis I
{ I
4 I
- I
hydroximinomethyl I
} I
pyridinium I
dibromide I
. O

Based O
on O
a O
previous O
model O
structure O
for O
the O
organophosphate B
diisopropylfluoropho B
, O
the O
model O
includes O
key O
sites O
of O
acetylcholinesterase O
inhibition O
( O
brain O
and O
diaphragm O
) O
, O
as O
well O
as O
fat O
, O
kidney O
, O
liver O
, O
rapidly O
perfused O
tissues O
and O
slowly O
perfused O
tissues O
. O

All O
tissue O
compartments O
are O
diffusion O
limited O
. O

Model O
parameters O
were O
collected O
from O
the O
literature O
, O
predicted O
using O
quantitative O
structure O
- O
property O
relationships O
or O
, O
when O
necessary O
, O
fit O
to O
available O
pharmacokinetic O
data O
from O
the O
literature O
. O

The O
model O
was O
parameterized O
using O
rat O
plasma O
, O
tissue O
and O
urine O
time O
course O
data O
from O
intramuscular O
administration O
, O
as O
well O
as O
human O
blood O
and O
urine O
data O
from O
intravenous O
and O
intramuscular O
administration O
; O
sensitivity O
analyses O
were O
performed O
. O

The O
PBPK O
model O
successfully O
simulates O
rat O
and O
human O
data O
sets O
and O
has O
been O
evaluated O
by O
predicting O
intravenous O
mouse O
and O
intramuscular O
human O
data O
not O
used O
in O
the O
development O
of O
the O
model O
. O

Monte O
Carlo O
analyses O
were O
performed O
to O
quantify O
human O
population O
kinetic O
variability O
in O
the O
human O
evaluation O
data O
set O
. O

The O
model O
identifies O
potential O
pharmacokinetic O
differences O
between O
rodents O
and O
humans O
, O
indicated O
by O
differences O
in O
model O
parameters O
between O
species O
. O

The O
PBPK O
model O
can O
be O
used O
to O
optimize O
the O
dosing O
regimen O
to O
improve O
oxime B
therapeutic O
efficacy O
in O
a O
human O
population O
. O

Improving O
the O
dispersity O
of O
detonation O
nanodiamond O
: O
differential O
scanning O
calorimetry O
as O
a O
new O
method O
of O
controlling O
the O
aggregation O
state O
of O
nanodiamond O
powders O
. O

Detonation O
nanodiamond O
( O
ND O
) O
is O
a O
suitable O
source O
material O
to O
produce O
unique O
samples O
consisting O
of O
almost O
uniform O
diamond B
nanocrystals O
( O
d O
= O
3 O
- O
5 O
nm O
) O
. O

Such O
samples O
exist O
in O
the O
form O
of O
long O
stable O
aqueous O
dispersions O
with O
narrow O
size O
distribution O
of O
diamond B
particles O
. O

The O
material O
is O
finding O
ever O
increasing O
application O
in O
biomedicine O
. O

The O
major O
problem O
in O
producing O
monodispersed O
diamond B
colloids O
lies O
in O
the O
necessity O
of O
deagglomeration O
of O
detonation O
soot O
and O
/ O
or O
removing O
of O
clusters O
formed O
by O
already O
isolated O
core O
particles O
in O
dry O
powders O
. O

To O
do O
this O
one O
must O
have O
an O
effective O
method O
to O
monitor O
the O
aggregation O
state O
or O
dispersity O
of O
powders O
and O
gels O
prior O
to O
the O
preparation O
of O
aqueous O
dispersions O
. O

In O
the O
absence O
of O
dispersity O
control O
at O
various O
stages O
of O
preparation O
the O
reproducibility O
of O
properties O
of O
existing O
ND O
materials O
is O
poor O
. O

In O
this O
paper O
we O
introduce O
differential O
scanning O
calorimetry O
( O
DSC O
) O
as O
a O
new O
tool O
capable O
to O
distinguish O
the O
state O
of O
aggregation O
in O
dry O
and O
wetted O
ND O
materials O
and O
to O
follow O
changes O
in O
this O
state O
under O
different O
types O
of O
treatment O
. O

Samples O
with O
identical O
X O
- O
ray O
diffraction O
patterns O
( O
XRD O
) O
and O
high O
resolution O
transmission O
electron O
microscopy O
( O
HRTEM O
) O
images O
gave O
visibly O
different O
DSC O
traces O
. O

Strong O
correlation O
was O
found O
between O
dynamic O
light O
scattering O
( O
DLS O
) O
data O
for O
colloids O
and O
DSC O
parameters O
for O
gels O
and O
powders O
of O
the O
same O
material O
. O

Based O
on O
DSC O
data O
we O
improved O
dispersity O
of O
existing O
ND O
materials O
and O
isolated O
samples O
with O
the O
best O
possible O
DSC O
parameters O
. O

These O
were O
true O
monodispersed O
easily O
dispersible O
fractions O
of O
ND O
particles O
with O
diameters O
of O
ca O
. O

3 O
nm O
. O

The O
sequence O
of O
the O
enterococcal O
cytolysin O
imparts O
unusual O
lanthionine B
stereochemistry O
. O

The O
enterococcal O
cytolysin O
is O
a O
two O
- O
component O
lantibiotic O
of O
unknown O
structure O
with O
hemolytic O
activity O
that O
is O
important O
for O
virulence O
. O

We O
prepared O
cytolysin O
by O
coexpression O
of O
each O
precursor O
peptide O
with O
the O
synthetase O
CylM O
in O
Escherichia O
coli O
and O
characterized O
its O
structure O
. O

Unexpectedly O
, O
cytolysin O
is O
to O
our O
knowledge O
the O
first O
example O
of O
a O
lantibiotic O
containing O
lanthionine B
and O
methyllanthionine B
structures O
with O
different O
stereochemistries O
in O
the O
same O
peptide O
. O

The O
stereochemistry O
is O
determined O
by O
the O
sequence O
of O
the O
substrate O
peptide O
. O

Fibronectin O
in O
the O
palatine O
tonsil O
as O
a O
susceptibility O
marker O
in O
Egyptian O
rheumatic O
families O
: O
Histological O
and O
immunohistochemical O
studies O
. O

Rheumatic O
fever O
( O
RF O
) O
and O
rheumatic O
heart O
disease O
( O
RHD O
) O
are O
the O
multisystem O
autoimmune O
sequel O
of O
group O
A O
streptococci O
( O
GAS O
) O
infection O
of O
the O
upper O
respiratory O
passages O
, O
mainly O
tonsillopharyngitis O
. O

The O
major O
receptor O
on O
the O
surface O
of O
human O
palatine O
tonsil O
for O
GAS O
is O
fibronectin O
( O
FN O
; O
adhesin O
receptor O
) O
. O

Early O
detection O
of O
RF O
susceptibility O
is O
considered O
as O
an O
important O
aim O
of O
this O
study O
. O

Therefore O
, O
the O
present O
study O
aimed O
to O
use O
FN O
immunoreactivity O
( O
FN O
- O
ir O
) O
as O
a O
marker O
for O
early O
detection O
of O
rheumatic O
susceptible O
children O
with O
palatine O
tonsil O
crypts O
surface O
epithelium O
. O

A O
total O
of O
30 O
palatine O
tonsillar O
specimens O
were O
obtained O
from O
children O
aged O
from O
3 O
to O
15 O
years O
. O

Histological O
studies O
showed O
moderate O
vascular O
changes O
and O
more O
than O
four O
apparent O
epithelial O
disruptions O
in O
the O
crypt O
epithelium O
. O

FN O
- O
ir O
showed O
a O
significant O
increase O
in O
FN O
in O
the O
basal O
layers O
of O
surface O
epithelium O
, O
subepithelial O
connective O
tissue O
and O
interfollicular O
areas O
. O

Tonsils O
of O
children O
in O
rheumatic O
families O
showed O
significant O
increase O
in O
FN O
in O
subepithelial O
connective O
tissue O
areas O
with O
more O
than O
one O
apparent O
crypt O
epithelial O
disruption O
compared O
to O
normal O
children O
. O

We O
can O
conclude O
that O
FN O
plays O
a O
central O
role O
in O
the O
RF O
and O
differentially O
distributed O
in O
the O
functional O
compartments O
of O
the O
palatine O
tonsil O
in O
children O
with O
RHD O
, O
so O
FN O
- O
ir O
can O
be O
used O
as O
a O
marker O
for O
rheumatic O
susceptibility O
. O

Relationship O
between O
oxidative O
stress O
and O
chronic O
daily O
headache O
in O
children O
. O

The O
aim O
of O
this O
study O
was O
to O
investigate O
the O
relationship O
between O
oxidative O
stress O
and O
chronic O
daily O
headache O
( O
CDH O
) O
in O
children O
. O

Although O
there O
are O
reports O
that O
oxidative O
injury O
may O
play O
a O
role O
in O
the O
pathophysiology O
of O
some O
neurologic O
disorders O
, O
such O
as O
migraine O
and O
epilepsy O
, O
by O
disrupting O
or O
destroying O
cell O
membranes O
through O
the O
formation O
of O
free O
radical O
and O
reactive O
oxygen B
species O
, O
the O
pathophysiology O
of O
headache O
is O
not O
clearly O
established O
. O

A O
total O
of O
38 O
children O
( O
16 O
boys O
and O
22 O
girls O
) O
with O
CDH O
, O
aged O
between O
7 O
and O
15 O
years O
, O
were O
enrolled O
in O
the O
study O
. O

The O
control O
group O
consisted O
of O
39 O
healthy O
children O
( O
17 O
boys O
and O
22 O
girls O
) O
, O
aged O
between O
7 O
and O
14 O
years O
. O

The O
mean O
age O
was O
10 O
. O
9 O
+ O
/ O
- O
2 O
. O
2 O
years O
for O
both O
the O
groups O
. O

Activities O
of O
erythrocyte O
superoxide B
dismutase O
( O
SOD O
) O
, O
catalase O
( O
CAT O
) O
, O
and O
glutathione B
peroxidase O
( O
GPx O
) O
as O
well O
as O
malondialdehyde B
( O
MDA B
) O
levels O
in O
all O
the O
children O
of O
both O
the O
groups O
were O
measured O
. O

Mean O
activities O
of O
erythrocyte O
SOD O
, O
CAT O
, O
and O
GPx O
as O
well O
as O
MDA B
levels O
were O
significantly O
higher O
in O
the O
study O
group O
than O
in O
the O
control O
group O
( O
p O
< O
0 O
. O
001 O
) O
. O

The O
findings O
of O
this O
study O
suggest O
that O
oxidative O
stress O
may O
play O
a O
causal O
or O
consequential O
role O
in O
children O
with O
CDH O
. O

Study O
of O
intracellular O
delivery O
of O
doxorubicin B
from O
poly B
( I
lactide I
- I
co I
- I
glycolide I
) I
nanoparticles O
by O
means O
of O
fluorescence O
lifetime O
imaging O
and O
confocal O
Raman O
microscopy O
. O

The O
intracellular O
delivery O
of O
Doxorubicin B
( O
Dox B
) O
from O
poly B
( I
lactide I
- I
co I
- I
glycolide I
) I
( O
PLGA B
) O
nanoparticles O
stabilised O
with O
bovine O
serum O
albumin O
, O
in O
HepG2 O
cells O
, O
is O
studied O
via O
flow O
cytometry O
, O
fluorescence O
lifetime O
imaging O
microscopy O
( O
FLIM O
) O
, O
confocal O
Raman O
microscopy O
( O
CRM O
) O
and O
cell O
viability O
studies O
. O

Flow O
cytometry O
shows O
that O
the O
initial O
uptake O
of O
PLGA B
and O
Dox B
follow O
the O
same O
kinetics O
. O

However O
, O
following O
8 O
h O
of O
incubation O
, O
the O
fluorescence O
intensity O
and O
cellular O
uptake O
of O
Dox B
decreases O
, O
while O
in O
the O
case O
of O
PLGA B
both O
parameters O
remain O
constant O
. O

FLIM O
shows O
the O
presence O
of O
a O
single O
- O
lifetime O
species O
, O
with O
a O
lifetime O
of O
1 O
. O
15 O
ns O
when O
measured O
inside O
the O
cells O
. O

Cell O
viability O
decreases O
by O
approximately O
20 O
% O
when O
incubated O
for O
24 O
h O
with O
PLGA B
loaded O
with O
Dox B
, O
with O
a O
particle O
concentration O
of O
100 O
micro O
g O
. O
mL O
( O
- O
1 O
) O
. O

At O
the O
single O
- O
cell O
level O
, O
CRM O
shows O
changes O
in O
the O
bands O
from O
DNA O
and O
proteins O
in O
the O
cell O
nucleus O
when O
incubated O
with O
PLGA B
loaded O
with O
Dox B
. O

Modern O
subunit O
vaccines O
: O
development O
, O
components O
, O
and O
research O
opportunities O
. O

Traditional O
vaccines O
, O
based O
on O
the O
administration O
of O
killed O
or O
attenuated O
microorganisms O
, O
have O
proven O
to O
be O
among O
the O
most O
effective O
methods O
for O
disease O
prevention O
. O

Safety O
issues O
related O
to O
administering O
these O
complex O
mixtures O
, O
however O
, O
prevent O
their O
universal O
application O
. O

Through O
identification O
of O
the O
microbial O
components O
responsible O
for O
protective O
immunity O
, O
vaccine O
formulations O
can O
be O
simplified O
, O
enabling O
molecular O
- O
level O
vaccine O
characterization O
, O
improved O
safety O
profiles O
, O
prospects O
to O
develop O
new O
high O
- O
priority O
vaccines O
( O
e O
. O
g O
. O
for O
HIV O
, O
tuberculosis O
, O
and O
malaria O
) O
, O
and O
the O
opportunity O
for O
extensive O
vaccine O
component O
optimization O
. O

This O
subunit O
approach O
, O
however O
, O
comes O
at O
the O
expense O
of O
decreased O
immunity O
, O
requiring O
the O
addition O
of O
immunostimulatory O
agents O
( O
adjuvants O
) O
. O

As O
few O
adjuvants O
are O
currently O
used O
in O
licensed O
vaccines O
, O
adjuvant O
development O
represents O
an O
exciting O
area O
for O
medicinal O
chemists O
to O
play O
a O
role O
in O
the O
future O
of O
vaccine O
development O
. O

In O
addition O
, O
immune O
responses O
can O
be O
further O
customized O
though O
optimization O
of O
delivery O
systems O
, O
tuning O
the O
size O
of O
particulate O
vaccines O
, O
targeting O
specific O
cells O
of O
the O
immune O
system O
( O
e O
. O
g O
. O
dendritic O
cells O
) O
, O
and O
adding O
components O
to O
aid O
vaccine O
efficacy O
in O
whole O
immunized O
populations O
( O
e O
. O
g O
. O
promiscuous O
T O
- O
helper O
epitopes O
) O
. O

Herein O
we O
review O
the O
current O
state O
of O
the O
art O
and O
future O
direction O
in O
subunit O
vaccine O
development O
, O
with O
a O
focus O
on O
the O
described O
components O
and O
their O
potential O
to O
steer O
the O
immune O
response O
toward O
a O
desired O
response O
. O

Directed O
motion O
of O
colloidal O
particles O
in O
a O
galvanic O
microreactor O
. O

The O
mechanisms O
leading O
to O
the O
deposition O
of O
colloidal O
particles O
in O
a O
copper B
- O
gold O
galvanic O
microreactor O
are O
investigated O
. O

Using O
in O
situ O
current O
density O
measurements O
and O
particle O
velocimetry O
, O
we O
establish O
correlations O
between O
the O
spatial O
arrangement O
and O
the O
geometry O
of O
the O
electrodes O
, O
current O
density O
distribution O
, O
and O
particle O
aggregation O
behavior O
. O

Ionic O
transport O
phenomena O
are O
responsible O
for O
the O
occurrence O
of O
strongly O
localized O
high O
current O
density O
at O
the O
edges O
and O
corners O
of O
the O
copper B
electrodes O
at O
large O
electrode O
separation O
, O
leading O
to O
a O
preferential O
aggregation O
of O
colloidal O
particles O
at O
the O
electrode O
edges O
. O

Preferential O
aggregation O
appears O
to O
be O
the O
result O
of O
a O
combination O
of O
electrophoretic O
effects O
and O
changes O
in O
bulk O
electrolyte O
flow O
patterns O
. O

We O
demonstrate O
that O
electrolyte O
flow O
is O
most O
likely O
driven O
by O
electrochemical O
potential O
gradients O
of O
reaction O
products O
formed O
during O
the O
inhomogeneous O
copper B
dissolution O
. O

New O
prospects O
for O
vinblastine B
analogues O
as O
anticancer O
agents O
. O

Boger O
et O
al O
. O
synthesized O
a O
series O
of O
C20 B
' I
urea I
derivatives O
of O
vinblastine B
that O
matched O
or O
exceeded O
the O
potency O
of O
vinblastine B
in O
cell O
growth O
inhibition O
assays O
. O

The O
studies O
demonstrated O
the O
importance O
of O
the O
H B
- O
bond O
donor O
on O
the O
C20 O
' O
position O
and O
revealed O
the O
presence O
of O
a O
space O
surrounding O
the O
C20 O
' O
substituent O
that O
tolerates O
a O
wide O
variety O
of O
substituents O
, O
remarkably O
enhancing O
potency O
of O
vinblastine B
analogues O
. O

Rheological O
study O
of O
mutarotation O
of O
fructose B
in O
anhydrous O
state O
. O

Rheological O
measurement O
was O
employed O
to O
study O
the O
mutarotation O
of O
D B
- I
fructose I
in O
anhydrous O
state O
. O

By O
monitoring O
the O
evolution O
of O
shear O
viscosity O
with O
time O
, O
rate O
constants O
for O
mutarotation O
were O
estimated O
, O
and O
two O
different O
stages O
of O
this O
reaction O
were O
identified O
. O

One O
of O
the O
mutarotation O
stages O
is O
rapid O
and O
has O
a O
low O
activation O
energy O
, O
whereas O
the O
other O
is O
much O
slower O
and O
has O
a O
much O
higher O
activation O
energy O
. O

Possible O
conversions O
corresponding O
to O
these O
two O
phases O
are O
discussed O
. O

This O
work O
demonstrates O
that O
, O
in O
addition O
to O
the O
routine O
techniques O
such O
polarimetry O
and O
gas O
- O
liquid O
chromatography O
, O
rheological O
measurement O
can O
be O
used O
as O
an O
alternative O
method O
to O
continuously O
monitor O
the O
mutarotation O
of O
sugars B
. O

One O
- O
pot O
synthesis O
of O
tin B
- O
embedded O
carbon B
/ O
silica B
nanocomposites O
for O
anode O
materials O
in O
lithium B
- O
ion O
batteries O
. O

We O
report O
a O
facile O
" O
one O
- O
pot O
" O
method O
for O
the O
synthesis O
of O
Sn B
- O
embedded O
carbon B
- O
silica B
( O
CS B
) O
mesostructured O
( O
nanostructured O
) O
composites O
through O
the O
selective O
interaction O
of O
resol B
( O
carbon B
precursor O
) O
, O
tetraethylorthosilic B
( O
TEOS B
) O
, O
and O
tributylphenyltin B
( O
Sn B
precursor O
) O
with O
an O
amphiphilic O
diblock O
copolymer O
, O
poly B
( I
ethylene I
oxide I
- I
b O
- I
styrene B
) I
, O
PEO B
- O
b O
- O
PS O
. O

A O
unique O
morphology O
transition O
from O
Sn B
nanowires O
to O
spherical O
Sn B
nanoparticles O
embedded O
in O
CS O
framework O
has O
been O
obtained O
. O

Metallic O
Sn B
species O
are O
homogeneously O
embedded O
in O
a O
rigid O
CS B
framework O
and O
are O
effectively O
confined O
within O
the O
nanostructures O
. O

The O
resulting O
composites O
are O
used O
as O
anode O
materials O
for O
lithium B
- O
ion O
batteries O
and O
exhibit O
high O
specific O
capacities O
( O
600 O
mA O
h O
g O
- O
( O
1 O
) O
at O
a O
current O
density O
of O
45 O
mA O
g O
- O
( O
1 O
) O
, O
and O
440 O
mA O
h O
g O
- O
( O
1 O
) O
at O
a O
current O
density O
of O
300 O
mA O
g O
- O
( O
1 O
) O
) O
and O
an O
excellent O
cyclability O
of O
over O
100 O
cycles O
with O
high O
Coulombic O
efficiency O
. O

Most O
of O
all O
, O
the O
novel O
method O
developed O
in O
this O
work O
for O
synthesizing O
functional O
hybrid O
materials O
can O
be O
extended O
to O
the O
preparation O
of O
various O
functional O
nanocomposites O
owing O
to O
its O
versatility O
and O
facileness O
. O

Enhancement O
of O
angiogenesis O
by O
a O
27 O
kDa O
lectin O
from O
perivitelline O
fluid O
of O
horseshoe O
crab O
embryos O
through O
upregulation O
of O
VEGF O
and O
its O
receptor O
. O

Angiogenesis O
, O
the O
expansion O
of O
a O
capillary O
network O
, O
is O
implicated O
in O
several O
pathological O
conditions O
. O

Drug O
- O
based O
inhibition O
of O
angiogenesis O
is O
being O
explored O
as O
therapy O
. O

Conversely O
, O
therapeutic O
angiogenesis O
contributes O
to O
control O
conditions O
such O
as O
ischemia O
. O

Here O
we O
report O
pro O
- O
angiogenic O
activity O
of O
perivitelline O
fluid O
( O
PVF O
) O
from O
Indian O
horseshoe O
crab O
embryos O
and O
one O
of O
its O
purified O
fractions O
, O
a O
27 O
kDa O
lectin O
, O
using O
the O
chick O
embryonic O
chorioallantoic O
membrane O
assay O
. O

Enhancement O
in O
number O
and O
diameter O
of O
blood O
vessels O
after O
treatment O
with O
PVF O
and O
lectin O
suggested O
their O
pro O
- O
angiogenic O
effect O
. O

Quantitative O
RT O
- O
PCR O
showed O
that O
this O
effect O
is O
mediated O
through O
modulation O
of O
expression O
of O
VEGF O
and O
VEGFR O
- O
2 O
/ O
kinase O
domain O
receptor O
genes O
. O

Novel O
insights O
into O
the O
pervasive O
role O
of O
M O
( O
3 O
) O
muscarinic O
receptor O
in O
cardiac O
diseases O
. O

Cardiac O
diseases O
remain O
the O
leading O
cause O
of O
morbidity O
and O
mortality O
worldwide O
. O

Heart O
functions O
are O
regulated O
by O
autonomic O
nervous O
systems O
through O
their O
transmitters O
and O
modulators O
, O
binding O
to O
cell O
surface O
receptors O
. O

Among O
them O
, O
the O
cardiac O
M O
( O
3 O
) O
muscarinic O
acetylcholine B
receptor O
( O
M O
( O
3 O
) O
- O
mAChR O
) O
has O
been O
studied O
for O
more O
than O
2 O
decades O
since O
its O
first O
discovery O
in O
mammalian O
heart O
in O
1990s O
. O

The O
location O
and O
pathophysiological O
role O
of O
M O
( O
3 O
) O
- O
mAChR O
in O
the O
cardiovascular O
system O
have O
been O
extensively O
studied O
and O
many O
pathways O
involved O
have O
been O
uncovered O
. O

Gain O
- O
and O
loss O
- O
of O
- O
function O
studies O
have O
revealed O
the O
ubiquitous O
roles O
of O
M O
( O
3 O
) O
- O
mAChR O
in O
physiological O
and O
pathological O
conditions O
. O

Recently O
, O
many O
new O
findings O
have O
been O
uncovered O
about O
the O
relationship O
between O
M O
( O
3 O
) O
- O
mAChR O
and O
cardiac O
diseases O
, O
including O
cardiac O
ischemia O
, O
pathological O
cardiac O
hypertrophy O
, O
cardiac O
arrhythmias O
, O
cardiac O
conduction O
and O
heart O
failure O
. O

Furthermore O
, O
the O
novel O
potential O
cardioprotective O
role O
of O
M O
( O
3 O
) O
- O
mAChR O
against O
heart O
injury O
by O
regulation O
of O
microRNAs O
( O
miRNAs O
) O
has O
been O
revealed O
in O
the O
most O
updated O
research O
. O

In O
this O
review O
, O
the O
current O
new O
findings O
on O
the O
role O
of O
M O
( O
3 O
) O
- O
mAChR O
in O
heart O
diseases O
are O
updated O
, O
the O
downstream O
signaling O
pathways O
are O
summarized O
, O
perspectives O
and O
challenges O
of O
M O
( O
3 O
) O
- O
mAChR O
as O
therapeutic O
targets O
are O
discussed O
. O

Growth O
of O
Pt B
nanowires O
by O
atomic O
layer O
deposition O
on O
highly O
ordered O
pyrolytic O
graphite B
. O

The O
formation O
of O
Pt B
nanowires O
( O
NWs O
) O
by O
atomic O
layer O
deposition O
on O
highly O
ordered O
pyrolytic O
graphite B
( O
HOPG O
) O
is O
investigated O
. O

Pt B
is O
deposited O
only O
at O
the O
step O
edges O
of O
HOPG O
and O
not O
on O
the O
basal O
planes O
, O
leading O
to O
the O
formation O
of O
laterally O
aligned O
Pt B
NWs O
. O

A O
growth O
model O
involving O
a O
morphological O
transition O
from O
0 O
- O
D O
to O
1 O
- O
D O
structures O
via O
coalescence O
is O
presented O
. O

The O
width O
of O
the O
NWs O
grows O
at O
a O
rate O
greater O
than O
twice O
the O
vertical O
growth O
rate O
. O

This O
asymmetry O
is O
ascribed O
to O
the O
wetting O
properties O
of O
Pt B
on O
HOPG O
as O
influenced O
by O
the O
formation O
of O
graphene B
oxide I
. O

A O
difference O
in O
Pt B
growth O
kinetics O
based O
on O
crystallographic O
orientation O
may O
also O
contribute O
. O

The O
impact O
of O
oxidative O
stress O
on O
islet O
transplantation O
and O
monitoring O
the O
graft O
survival O
by O
non O
- O
invasive O
imaging O
. O

Islet O
transplantation O
is O
an O
attractive O
strategy O
to O
treat O
severe O
diabetic O
conditions O
in O
patients O
suffering O
from O
autoimmune O
derived O
diabetes O
, O
and O
it O
has O
currently O
been O
considered O
a O
forefront O
research O
arena O
in O
diabetes O
. O

Major O
aim O
of O
islet O
transplantation O
is O
to O
achieve O
successful O
insulin O
independent O
disease O
free O
survival O
. O

The O
key O
challenges O
in O
transplanted O
islets O
are O
the O
generation O
of O
reactive O
oxygen B
species O
( O
ROS O
) O
and O
associated O
oxidative O
stress O
, O
pro O
- O
inflammatory O
cytokine O
- O
( O
TNF O
alpha O
) O
mediated O
apoptotic O
induction O
, O
attack O
by O
immune O
cells O
, O
and O
achieving O
revascularization O
with O
minimal O
hypoxic O
microenvironment O
. O

Free O
radicals O
and O
their O
derivatives O
are O
constantly O
produced O
in O
living O
systems O
, O
but O
at O
relatively O
low O
level O
, O
and O
in O
a O
balanced O
state O
. O

Oxidative O
stress O
, O
which O
occurs O
as O
a O
result O
of O
an O
imbalance O
between O
the O
intracellular O
free O
radicals O
production O
and O
the O
cellular O
antioxidant O
defense O
mechanisms O
in O
the O
transplanted O
islets O
, O
can O
lead O
to O
cell O
death O
. O

The O
balance O
between O
oxidants O
and O
antioxidants O
in O
a O
cell O
can O
be O
easily O
disturbed O
by O
increase O
in O
ROS O
production O
or O
reduction O
in O
the O
level O
of O
cellular O
antioxidant O
defensive O
substances O
, O
which O
can O
cause O
many O
metabolic O
complications O
, O
including O
pancreatic O
beta O
- O
cell O
damage O
. O

Antioxidants O
function O
as O
blockers O
of O
radical O
processes O
by O
eliminating O
harmful O
ROS O
produced O
during O
normal O
cellular O
metabolism O
. O

A O
complex O
antioxidant O
defense O
mechanism O
has O
been O
developed O
by O
nature O
in O
cells O
to O
protect O
the O
cellular O
homeostasis O
. O

This O
system O
mainly O
includes O
antioxidant O
enzymes O
, O
vitamins O
and O
minerals O
. O

As O
transplanted O
islet O
survival O
is O
crucial O
for O
achieving O
successful O
therapy O
, O
most O
of O
these O
antioxidants O
can O
be O
used O
as O
a O
supplement O
to O
scavenge O
the O
local O
ROS O
thereby O
improving O
the O
survival O
of O
transplanted O
islets O
. O

Currently O
, O
very O
few O
techniques O
have O
been O
routinely O
used O
to O
qualitatively O
and O
quantitatively O
assess O
the O
survival O
and O
function O
of O
islet O
grafts O
, O
especially O
to O
confirm O
the O
success O
of O
treatment O
, O
which O
includes O
metabolic O
parameters O
such O
as O
blood O
glucose B
, O
insulin O
and O
C O
- O
peptide O
levels O
. O

These O
biochemical O
measurements O
provide O
markers O
at O
only O
the O
late O
stages O
of O
islet O
rejection O
. O

Use O
of O
molecular O
imaging O
techniques O
has O
the O
potential O
for O
real O
- O
time O
non O
- O
invasive O
monitoring O
of O
the O
functional O
status O
and O
viability O
of O
transplanted O
islet O
grafts O
in O
living O
animals O
. O

This O
review O
mainly O
focuses O
on O
the O
current O
status O
of O
islet O
transplantations O
, O
potential O
preventive O
strategies O
used O
to O
reduce O
oxidative O
stress O
- O
mediated O
toxicity O
in O
islet O
grafts O
, O
and O
use O
of O
molecular O
imaging O
as O
a O
tool O
to O
quantitatively O
evaluate O
the O
functional O
status O
of O
the O
transplanted O
islets O
in O
living O
animals O
. O

Computational O
peptidology O
: O
a O
new O
and O
promising O
approach O
to O
therapeutic O
Peptide O
design O
. O

The O
recent O
focus O
on O
protein O
- O
protein O
interaction O
networks O
has O
increasingly O
been O
shifted O
towards O
the O
disruption O
of O
protein O
complexes O
, O
which O
either O
are O
mediated O
by O
the O
binding O
of O
a O
globular O
domain O
in O
one O
protein O
to O
a O
short O
peptide O
stretch O
in O
another O
, O
or O
involve O
flat O
, O
large O
, O
and O
hydrophobic O
interfaces O
that O
classical O
small O
- O
molecule O
agents O
are O
not O
always O
ideally O
suited O
. O

Rational O
design O
of O
therapeutic O
peptides O
with O
high O
affinity O
targeting O
such O
interactions O
has O
emerged O
as O
a O
new O
and O
promising O
tool O
in O
discovery O
of O
potential O
drug O
candidates O
against O
associated O
diseases O
. O

The O
design O
is O
commonly O
based O
on O
bioinformatics O
methods O
or O
molecular O
modeling O
techniques O
, O
indirectly O
exploiting O
structure O
- O
activity O
relationship O
at O
the O
level O
of O
peptide O
sequence O
or O
directly O
deriving O
lead O
entities O
from O
protein O
complex O
architecture O
. O

Here O
, O
a O
newly O
rising O
subfield O
called O
computational O
peptidology O
that O
focuses O
on O
the O
use O
of O
computational O
and O
theoretical O
approaches O
to O
treat O
peptiderelated O
problems O
is O
comprehensively O
reviewed O
on O
the O
design O
and O
discovery O
of O
peptide O
agents O
targeting O
protein O
- O
protein O
interactions O
. O

We O
address O
a O
systematic O
discussion O
on O
several O
representative O
cases O
in O
which O
the O
computational O
peptidology O
is O
successfully O
employed O
to O
develop O
peptide O
therapeutics O
. O

Besides O
, O
some O
problems O
and O
pitfalls O
accompanied O
with O
the O
current O
use O
of O
computational O
methods O
in O
peptide O
modeling O
and O
design O
are O
also O
present O
. O

Thermal O
sintering O
: O
a O
novel O
technique O
used O
in O
the O
design O
, O
optimization O
and O
biopharmaceutical O
evaluation O
of O
propranolol B
HCl I
gastric O
floating O
tablets O
. O

Abstract O
The O
objective O
of O
the O
present O
investigation O
was O
to O
study O
the O
applicability O
of O
thermal O
sintering O
technique O
for O
the O
development O
of O
gastric O
floating O
tablets O
of O
propranolol B
HCl I
. O

Formulations O
were O
prepared O
using O
four O
independent O
variables O
, O
namely O
( O
i O
) O
polymer O
quantity O
, O
( O
ii O
) O
sodium B
bicarbonate I
concentration O
, O
( O
iii O
) O
sintering O
temperature O
and O
( O
iv O
) O
sintering O
time O
. O

Floating O
lag O
time O
and O
t O
( O
95 O
) O
were O
taken O
as O
dependent O
variables O
. O

Tablets O
were O
prepared O
by O
the O
direct O
compression O
method O
and O
were O
evaluated O
for O
physicochemical O
properties O
, O
in O
vitro O
buoyancy O
and O
dissolution O
studies O
. O

From O
the O
drug O
release O
studies O
, O
it O
was O
observed O
that O
drug O
retarding O
property O
mainly O
depends O
upon O
the O
sintering O
temperature O
and O
time O
of O
exposure O
. O

The O
statistically O
optimized O
formulation O
( O
PTSso O
) O
was O
characterized O
by O
Fourier O
transform O
infrared O
spectroscopy O
and O
differential O
scanning O
calorimetry O
studies O
, O
and O
no O
significant O
chemical O
interaction O
between O
drug O
and O
polymer O
was O
observed O
. O

Optimized O
formulation O
was O
stable O
at O
accelerated O
conditions O
for O
a O
period O
of O
six O
months O
. O

PTSso O
was O
evaluated O
for O
in O
vivo O
buoyancy O
studies O
in O
humans O
for O
both O
fed O
and O
fasted O
states O
and O
found O
that O
gastric O
residence O
time O
of O
the O
floating O
tablets O
were O
enhanced O
by O
fed O
stage O
but O
not O
in O
fasted O
state O
. O

Optimized O
formulation O
PTSso O
and O
commercial O
formulation O
Ciplar B
LA I
80 I
were O
subjected O
to O
bioavailability O
studies O
in O
healthy O
human O
volunteers O
by O
estimating O
pharmacokinetic O
parameters O
such O
as O
C O
( O
max O
) O
, O
T O
( O
max O
) O
, O
area O
under O
curve O
( O
AUC O
) O
( O
, O
) O
elimination O
rate O
constant O
( O
K O
( O
el O
) O
) O
, O
biological O
half O
- O
life O
( O
t O
( O
1 O
/ O
2 O
) O
) O
and O
mean O
residence O
time O
( O
MRT O
) O
. O

There O
was O
a O
significant O
increase O
in O
the O
bioavailability O
of O
the O
propranolol B
HCl I
from O
PTSso O
formulation O
, O
which O
was O
evident O
from O
increased O
AUC O
levels O
and O
larger O
MRT O
values O
than O
Ciplar B
LA O
80 O
. O

Study O
of O
the O
scale O
formation O
mechanism O
on O
gold O
modified O
with O
an O
alkanethiol B
monolayer O
. O

Scaling O
is O
a O
problem O
in O
many O
industrial O
processes O
. O

To O
control O
and O
minimize O
it O
, O
it O
is O
important O
to O
understand O
the O
dynamics O
of O
the O
scale O
formation O
. O

In O
this O
paper O
, O
the O
scale O
formation O
was O
examined O
on O
two O
kinds O
of O
gold O
surfaces O
. O

One O
was O
a O
pure O
metallic O
gold O
surface O
, O
and O
the O
other O
was O
a O
gold O
surface O
modified O
with O
an O
alkanethiol B
self O
- O
assembled O
monolayer O
. O

A O
series O
of O
surface O
characterization O
experiments O
were O
performed O
to O
ensure O
a O
good O
understanding O
of O
the O
gold O
- O
thiol B
bond O
stability O
in O
a O
caustic O
solution O
. O

A O
multivalent O
approach O
towards O
linked O
dual O
- O
pharmacology O
prostaglandin B
F I
receptor O
agonist O
/ O
carbonic O
anhydrase O
- O
II O
inhibitors O
for O
the O
treatment O
of O
glaucoma O
. O

Lowering O
of O
intra O
- O
ocular O
pressure O
is O
the O
primary O
pharmacologic O
approach O
for O
the O
treatment O
of O
glaucoma O
and O
a O
number O
of O
distinct O
mechanisms O
of O
action O
have O
been O
clinically O
validated O
. O

Targeting O
of O
multiple O
mechanisms O
in O
combination O
therapies O
has O
proven O
effective O
both O
clinically O
and O
commercially O
although O
potential O
improvements O
with O
regards O
to O
efficacy O
, O
tolerability O
and O
dosing O
frequency O
remain O
. O

Application O
of O
Theravance O
' O
s O
multivalent O
approach O
to O
drug O
discovery O
towards O
linked O
dual O
- O
pharmacology O
prostaglandin B
F I
receptor O
( O
FP O
) O
agonist O
/ O
carbonic O
anhydrase O
( O
CA O
) O
- O
II O
inhibitor O
compounds O
is O
described O
. O

Compound O
29 O
exhibits O
weak O
potency O
( O
pEC O
( O
50 O
) O
= O
5 O
. O
7 O
, O
IA O
> O
1 O
. O
0 O
) O
as O
an O
FP O
agonist O
with O
high O
binding O
affinity O
( O
pK O
( O
i O
) O
= O
8 O
. O
1 O
) O
to O
the O
CA O
- O
II O
enzyme O
, O
and O
has O
comparable O
corneal O
permeability O
to O
the O
CA O
- O
II O
inhibitor O
dorzolamide B
. O

The O
cancer O
biology O
of O
whole O
- O
chromosome O
instability O
. O

One O
form O
of O
chromosome O
instability O
( O
CIN O
) O
, O
the O
recurrent O
missegregation O
of O
whole O
chromosomes O
during O
cell O
division O
( O
W O
- O
CIN O
) O
, O
leads O
to O
aneuploidy O
. O

Although O
W O
- O
CIN O
is O
a O
hallmark O
of O
most O
cancers O
, O
mutations O
in O
genes O
involved O
in O
chromosome O
segregation O
are O
exceedingly O
rare O
. O

We O
discuss O
an O
oncogene O
- O
induced O
mitotic O
stress O
model O
that O
provides O
a O
mechanistic O
framework O
to O
explain O
this O
paradox O
. O

We O
also O
review O
the O
tumor O
- O
promoting O
and O
tumor O
- O
suppressing O
consequences O
of O
W O
- O
CIN O
. O

Importantly O
, O
we O
do O
this O
in O
the O
context O
of O
cancer O
as O
a O
complex O
systemic O
disease O
, O
rather O
than O
as O
a O
simple O
linearly O
progressing O
disorder O
that O
arises O
from O
a O
single O
abnormal O
cell O
population O
. O

Accordingly O
, O
we O
highlight O
the O
often O
neglected O
effects O
of O
W O
- O
CIN O
on O
key O
non O
- O
cell O
- O
autonomous O
entities O
, O
such O
as O
the O
immune O
system O
and O
the O
tumor O
microenvironment O
. O

Distinct O
tissue O
- O
specific O
susceptibilities O
to O
W O
- O
CIN O
- O
induced O
tumorigenesis O
and O
the O
clinical O
implications O
of O
W O
- O
CIN O
are O
also O
discussed O
. O
Oncogene O
advance O
online O
publication O
, O
14 O
January O
2013 O
; O
doi O
: O
10 O
. O
1038 O
/ O
onc O
. O
2012 O
. O
616 O
. O

Neuroprotective O
efficacy O
and O
pharmacokinetic O
behavior O
of O
novel O
anti O
- O
inflammatory O
para B
- I
phenyl I
substituted I
diindolylmethanes I
in O
a O
mouse O
model O
of O
Parkinson O
' O
s O
disease O
. O

There O
are O
currently O
no O
registered O
drugs O
that O
slow O
the O
progression O
of O
neurodegenerative O
diseases O
, O
in O
part O
because O
translation O
from O
animal O
models O
to O
the O
clinic O
has O
been O
hampered O
by O
poor O
distribution O
to O
the O
brain O
. O

The O
present O
studies O
examined O
a O
selected O
series O
of O
para B
- I
phenyl I
- I
substituted I
diindolylmethane I
( O
C B
- I
DIM I
) O
compounds O
that O
display O
anti O
- O
inflammatory O
and O
neuroprotective O
efficacy O
in O
vitro O
. O

We O
postulated O
that O
the O
pharmacokinetic O
behavior O
of O
C B
- I
DIM I
compounds O
after O
oral O
administration O
would O
correlate O
with O
neuroprotective O
efficacy O
in O
vivo O
in O
a O
mouse O
model O
of O
Parkinson O
' O
s O
disease O
. O

Pharmacokinetics O
and O
metabolism O
of O
1 B
, I
1 I
- I
bis I
( I
3 I
' I
- I
indolyl I
) I
- I
1 I
- I
( I
p I
- I
methoxyphenyl I
) I
methane I
( O
C B
- I
DIM5 I
) O
, O
1 B
, I
1 I
- I
bis I
( I
3 I
' I
- I
indolyl I
) I
- I
1 I
- I
( I
phenyl I
) I
methane I
, O
1 B
, I
1 I
- I
bis I
( I
3 I
' I
- I
indolyl I
) I
- I
1 I
- I
( I
p I
- I
hydroxyphenyl I
) I
methane I
( O
C B
- I
DIM8 I
) O
, O
and O
1 B
, I
1 I
- I
bis I
( I
3 I
' I
- I
indolyl I
) I

- I
1 I
- I
( I
p I
- I
chlorophenyl I
) I
methane I
( O
C B
- I
DIM12 I
) O
were O
determined O
in O
plasma O
and O
brain O
of O
C57Bl O
/ O
6 O
mice O
after O
oral O
and O
intravenous O
administration O
at O
10 O
and O
1 O
mg O
/ O
Kg O
, O
respectively O
. O

Putative O
metabolites O
were O
measured O
in O
plasma O
, O
liver O
, O
and O
urine O
. O

C O
- O
DIM O
compounds O
given O
orally O
displayed O
the O
highest O
area O
under O
the O
curve O
, O
Cmax O
, O
and O
Tmax O
levels O
, O
and O
C O
- O
DIM12 O
exhibited O
the O
most O
favorable O
pharmacokinetics O
of O
the O
compounds O
tested O
. O

Oral O
bioavailability O
of O
each O
compound O
ranged O
from O
6 O
% O
( O
C B
- I
DIM8 I
) O
to O
42 O
% O
( O
C B
- I
DIM12 I
) O
. O

After O
pharmacokinetic O
studies O
, O
the O
neuroprotective O
efficacy O
of O
C B
- I
DIM5 I
, O
C B
- I
DIM8 I
, O
and O
C B
- I
DIM12 I
( O
50 O
mg O
/ O
Kg O
per O
oral O
) O
was O
examined O
in O
mice O
exposed O
to O
1 B
- I
methyl I
- I
4 I
- I
phenyl I
- I
1 I
, I
2 I
, I
3 I
, I
6 I
- I
tetrahydropyridine I
( O
MPTP B
) O
and O
probenecid B
for O
14 O
days O
, O
a O
model O
of O
progressive O
neurodegeneration O
with O
a O
strong O
neuroinflammatory O
component O
. O

C B
- I
DIM5 I
and O
C B
- I
DIM12 I
given O
orally O
once O
daily O
after O
one O
week O
of O
exposure O
to O
MPTP B
and O
probenecid B
prevented O
further O
loss O
of O
dopaminergic O
neurons O
in O
the O
substantia O
nigra O
pars O
compacta O
and O
striatal O
dopamine B
terminals O
, O
indicating O
that O
these O
compounds O
could O
be O
effective O
therapeutic O
agents O
to O
prevent O
neurodegeneration O
. O

Peroxynitrite B
mediates O
testosterone B
- O
induced O
vasodilation O
of O
microvascular O
resistance O
vessels O
. O

Our O
knowledge O
of O
how O
androgens B
influence O
the O
cardiovascular O
system O
is O
far O
from O
complete O
, O
and O
this O
lack O
of O
understanding O
is O
especially O
true O
of O
how O
androgens B
affect O
resistance O
vessels O
. O

Our O
aim O
was O
to O
identify O
the O
signaling O
mechanisms O
stimulated O
by O
testosterone B
( O
TES O
) O
in O
microvascular O
arteries O
and O
to O
understand O
how O
these O
mechanisms O
mediate O
TES O
- O
induced O
vasodilation O
. O

Mesenteric O
microvessels O
were O
isolated O
from O
male O
Sprague O
- O
Dawley O
rats O
. O

Tension O
studies O
demonstrated O
a O
rapid O
, O
concentration O
- O
dependent O
, O
vasodilatory O
response O
to O
TES O
that O
did O
not O
involve O
protein O
synthesis O
or O
aromatization O
to O
17 B
beta I
- I
estradiol I
. O

Dichlorofluorescein B
fluorescence O
and O
nitrotyrosine B
immunoblot O
experiments O
indicated O
that O
TES O
stimulated O
peroxynitrite B
formation O
in O
microvessels O
, O
and O
functional O
studies O
demonstrated O
that O
TES O
- O
induced O
vasodilation O
was O
inhibited O
by O
scavenging O
peroxynitrite B
. O

As O
predicted O
, O
TES O
enhanced O
the O
production O
of O
both O
peroxynitrite B
precursors O
( O
i O
. O
e O
. O
, O
superoxide B
and O
nitic B
oxide I
) O
, O
and O
xanthine B
oxidase O
was O
identified O
as O
the O
likely O
source O
of O
TES O
- O
stimulated O
superoxide B
production O
. O

Functional O
and O
biochemical O
studies O
indicated O
that O
TES O
signaling O
involved O
activity O
of O
the O
phosphoinositide O
3 O
( O
PI3 O
) O
kinase O
- O
protein O
kinase O
B O
( O
Akt O
) O
cascade O
initiated O
by O
activation O
of O
the O
androgen B
receptor O
and O
culminated O
in O
enhanced O
production O
of O
cGMP B
and O
microvascular O
vasodilation O
. O

These O
findings O
, O
derived O
from O
a O
variety O
of O
analytical O
and O
functional O
approaches O
, O
provide O
evidence O
for O
a O
novel O
nongenomic O
signaling O
mechanism O
for O
androgen B
action O
in O
the O
microvasculature O
: O
TES O
- O
stimulated O
vasodilation O
mediated O
primarily O
by O
peroxynitrite B
formed O
from O
xanthine B
oxidase O
- O
generated O
superoxide B
and O
NO B
. O

This O
response O
was O
associated O
with O
activation O
of O
the O
PI3 O
kinase O
- O
Akt O
signaling O
cascade O
initiated O
by O
activation O
of O
the O
androgen B
receptor O
. O

We O
propose O
this O
mechanism O
could O
account O
for O
TES O
- O
stimulated O
cGMP B
production O
in O
microvessels O
and O
, O
ultimately O
, O
vasodilation O
. O

Ordered O
mesoporous O
boron B
- O
doped O
carbons B
as O
metal O
- O
free O
electrocatalysts O
for O
the O
oxygen B
reduction O
reaction O
in O
alkaline O
solution O
. O

Ordered O
mesoporous O
boron B
- I
doped I
carbons I
( O
BOMCs O
) O
were O
prepared O
by O
co O
- O
impregnation O
and O
carbonization O
of O
sucrose B
and O
4 B
- I
hydroxyphenylboronic I
acid I
into O
SBA B
- I
15 I
silica B
template O
. O

Nitrogen B
sorption O
, O
small O
angle O
X O
- O
ray O
diffraction O
( O
XRD O
) O
, O
and O
transmission O
electron O
microscopy O
( O
TEM O
) O
reveals O
that O
BOMCs O
possess O
highly O
ordered O
mesoporous O
structure O
, O
uniform O
pore O
size O
distribution O
, O
and O
high O
surface O
area O
. O

X O
- O
ray O
photoelectron O
spectroscopy O
( O
XPS O
) O
analysis O
demonstrates O
that O
B B
atoms O
can O
be O
successfully O
doped O
into O
the O
framework O
of O
OMCs O
. O

Due O
to O
the O
desirable O
characteristics O
of O
BOMCs O
, O
BOMCs O
are O
highly O
active O
, O
cheap O
, O
and O
selective O
metal O
- O
free O
electrocatalysts O
for O
the O
oxygen B
reduction O
reaction O
( O
ORR O
) O
in O
alkaline O
solution O
. O

Although O
B B
content O
is O
a O
key O
factor O
in O
determining O
ORR O
activity O
, O
the O
ORR O
activity O
of O
BOMCs O
is O
also O
dependent O
on O
the O
surface O
area O
. O

The O
high O
surface O
area O
of O
BOMCs O
facilitates O
the O
exposure O
of O
the O
active O
sites O
for O
ORR O
. O

BOMCs O
may O
be O
further O
exploited O
as O
potentially O
efficient O
and O
inexpensive O
metal O
- O
free O
ORR O
catalysts O
with O
good O
long O
- O
term O
stability O
in O
alkaline O
solution O
. O

Elevated O
vaspin O
and O
leptin O
levels O
are O
associated O
with O
obesity O
in O
prepubertal O
Korean O
children O
. O

Adipokines O
are O
associated O
with O
obesity O
. O

However O
, O
the O
relationships O
between O
adipokines O
, O
specifically O
vaspin O
, O
obesity O
, O
and O
obesity O
- O
related O
variables O
remain O
controversial O
, O
and O
only O
a O
few O
studies O
have O
been O
conducted O
which O
examines O
them O
in O
children O
. O

We O
investigated O
the O
relationships O
between O
obesity O
in O
prepubertal O
Korean O
children O
and O
three O
types O
of O
adipokines O
: O
vaspin O
, O
leptin O
, O
and O
visfatin O
. O

In O
this O
cross O
- O
sectional O
study O
, O
168 O
nine O
- O
year O
- O
old O
boys O
and O
176 O
nine O
- O
year O
- O
old O
girls O
participated O
in O
a O
school O
- O
based O
health O
examination O
program O
. O

Children O
were O
classified O
as O
overweight O
using O
the O
Korean O
Pediatric O
Society O
2007 O
guidelines O
. O

Overweight O
boys O
and O
girls O
had O
higher O
leptin O
and O
vaspin O
levels O
than O
both O
boys O
and O
girls O
of O
normal O
weight O
, O
whereas O
only O
overweight O
boys O
had O
higher O
visfatin O
levels O
than O
normal O
weight O
boys O
. O

Leptin O
, O
visfatin O
and O
vaspin O
concentrations O
were O
correlated O
with O
obesity O
- O
related O
variables O
. O

A O
multiple O
logistic O
regression O
analysis O
showed O
that O
systolic O
blood O
pressure O
( O
SBP O
) O
, O
total O
cholesterol B
( O
TC O
) O
, O
alanine B
aminotransferase O
( O
ALT O
) O
, O
homeostasis O
model O
assessment O
of O
insulin O
resistance O
( O
HOMA O
- O
IR O
) O
, O
leptin O
, O
and O
vaspin O
were O
associated O
with O
an O
increased O
risk O
of O
being O
overweight O
, O
whereas O
high O
- O
density O
lipoprotein O
( O
HDL O
) O
cholesterol B
was O
associated O
with O
a O
decreased O
risk O
of O
being O
overweight O
. O

Elevated O
vaspin O
and O
leptin O
levels O
are O
associated O
with O
obesity O
in O
prepubertal O
Korean O
children O
. O

Peginesatide O
clearance O
, O
distribution O
, O
metabolism O
, O
and O
excretion O
in O
monkeys O
following O
intravenous O
administration O
. O

Peginesatide O
, O
a O
polyethylene B
glycol I
( O
PEG B
) O
ylated O
peptide O
- O
based O
erythropoiesis O
- O
stimulating O
agent O
, O
stimulates O
the O
erythropoietin O
receptor O
dimer O
that O
governs O
erythropoiesis O
. O

Studies O
were O
designed O
to O
determine O
the O
erythropoietic O
response O
, O
pharmacokinetics O
( O
PK O
) O
, O
tissue O
distribution O
, O
metabolism O
, O
and O
excretion O
of O
peginesatide O
in O
nonhuman O
primates O
following O
a O
single O
i O
. O
v O
. O
dose O
. O

The O
PK O
profile O
of O
peginesatide O
( O
0 O
. O
1 O
- O
5 O
mg O
/ O
kg O
) O
is O
characterized O
by O
low O
, O
dose O
- O
dependent O
plasma O
clearance O
; O
small O
volume O
of O
distribution O
; O
and O
long O
half O
- O
life O
. O

The O
peginesatide O
PK O
profile O
following O
a O
single O
i O
. O
v O
. O
dose O
is O
consistent O
with O
the O
sustained O
erythropoiesis O
. O

Biodistribution O
quantitative O
whole O
- O
body O
autoradiography O
demonstrated O
high O
peginesatide O
levels O
in O
bone O
marrow O
( O
i O
. O
e O
. O
, O
primary O
hematopoietic O
site O
) O
as O
well O
as O
other O
known O
hematopoietic O
sites O
persisting O
through O
at O
least O
3 O
weeks O
at O
2 O
. O
1 O
mg O
/ O
kg O
. O

Microautoradiography O
analysis O
at O
48 O
hours O
postdose O
revealed O
uniform O
and O
high O
distribution O
of O
radioactivity O
in O
the O
bone O
marrow O
and O
splenic O
red O
pulp O
with O
less O
extensive O
distribution O
in O
the O
renal O
cortex O
( O
glomeruli O
, O
associated O
ducts O
, O
interstitial O
cells O
) O
. O

Radioactivity O
in O
the O
kidney O
was O
most O
prominent O
in O
the O
outer O
medullary O
and O
papillary O
interstitium O
. O

At O
2 O
weeks O
after O
dosing O
, O
cumulative O
radioactivity O
recovery O
in O
the O
urine O
and O
feces O
was O
60 O
and O
7 O
% O
of O
the O
administered O
dose O
, O
respectively O
, O
with O
most O
of O
the O
radioactivity O
associated O
with O
the O
parent O
molecule O
. O

In O
conclusion O
, O
the O
PK O
characteristics O
are O
consistent O
with O
a O
PEGylated O
peptide O
of O
a O
45 O
- O
kDa O
molecular O
mass O
, O
specifically O
low O
volume O
of O
distribution O
and O
long O
half O
- O
life O
. O

Drug O
was O
localized O
principally O
to O
hematopoietic O
sites O
, O
and O
nonspecific O
tissue O
retention O
was O
not O
observed O
. O

The O
nonhuman O
primate O
data O
indicate O
that O
peginesatide O
is O
metabolically O
stable O
and O
primarily O
excreted O
in O
the O
urine O
. O

Effects O
of O
nicotine B
, O
its O
metabolites O
and O
tobacco O
extracts O
on O
human O
platelet O
function O
in O
vitro O
. O

Cigarette O
smoking O
is O
a O
leading O
cause O
of O
cardiovascular O
disease O
. O

The O
cardiovascular O
effects O
of O
smoking O
are O
probably O
multifactorial O
, O
including O
effects O
on O
platelets O
. O

Previous O
reports O
investigating O
the O
effects O
of O
nicotine B
and O
tobacco O
on O
platelet O
function O
are O
inconsistent O
. O

The O
present O
study O
investigated O
in O
vitro O
effects O
of O
nicotine B
, O
its O
major O
metabolites O
, O
tobacco O
extracts O
and O
extract O
of O
tobacco O
- O
free O
snuff O
on O
human O
platelets O
. O

None O
of O
the O
metabolites O
cotinine B
, O
cotinine B
- I
N I
- I
oxide I
, O
nicotine B
- I
1 I
' I
- I
N I
- I
oxide I
or O
trans B
- I
3 I
' I
- I
hydroxycotinine I
( O
0 O
. O
1 O
- O
10 O
mu O
M O
) O
affected O
platelet O
aggregation O
or O
P O
- O
selectin O
expression O
. O

Nicotine B
( O
10 O
mu O
M O
) O
weakly O
increased O
platelet O
aggregation O
, O
whereas O
trans B
- I
3 I
' I
- I
hydroxycotinine I
( O
0 O
. O
1 O
mu O
M O
) O
and O
nicotine B
- I
1 I
' I
- I
N I
- I
oxide I
( O
1 O
- O
10 O
mu O
M O
) O
weakly O
inhibited O
adhesion O
to O
fibrinogen O
. O

To O
elucidate O
the O
influence O
of O
other O
tobacco O
compounds O
, O
we O
investigated O
the O
impact O
of O
moist O
tobacco O
and O
smoke O
extracts O
on O
platelet O
function O
. O

Filtered O
extracts O
of O
oral O
snuff O
, O
cigarette O
smoke O
and O
tobacco O
free O
snuff O
inhibited O
platelet O
adhesion O
concentration O
- O
dependently O
. O

The O
inhibitory O
effects O
of O
tobacco O
extracts O
on O
platelet O
adhesion O
were O
independent O
of O
nicotine B
content O
and O
the O
nitric B
- I
oxide I
- O
pathway O
and O
not O
mediated O
through O
a O
platelet O
- O
nicotine B
- O
receptor O
. O

Taken O
together O
, O
tobacco O
extracts O
inhibit O
platelet O
activation O
during O
short O
- O
term O
in O
vitro O
challenge O
. O

As O
only O
limited O
effects O
of O
nicotine B
and O
nicotine B
metabolites O
were O
seen O
, O
the O
tobacco O
- O
induced O
platelet O
inhibition O
are O
likely O
induced O
by O
other O
compounds O
present O
in O
tobacco O
and O
tobacco O
free O
snuff O
. O

Re O
- O
print O
of O
" O
Intestinal O
luminal O
nitrogen B
metabolism O
: O
role O
of O
the O
gut O
microbiota O
and O
consequences O
for O
the O
host O
" O
. O

Alimentary O
and O
endogenous O
proteins O
are O
mixed O
in O
the O
small O
intestinal O
lumen O
with O
the O
microbiota O
. O

Although O
experimental O
evidences O
suggest O
that O
the O
intestinal O
microbiota O
is O
able O
to O
incorporate O
and O
degrade O
some O
of O
the O
available O
amino B
acids I
, O
it O
appears O
that O
the O
microbiota O
is O
also O
able O
to O
synthesize O
amino B
acids I
raising O
the O
view O
that O
amino B
acid I
exchange O
between O
the O
microbiota O
and O
host O
can O
proceed O
in O
both O
directions O
. O

Although O
the O
net O
result O
of O
such O
exchanges O
remains O
to O
be O
determined O
, O
it O
is O
likely O
that O
a O
significant O
part O
of O
the O
amino B
acids I
recovered O
from O
the O
alimentary O
proteins O
are O
used O
by O
the O
microbiota O
. O

In O
the O
large O
intestine O
, O
where O
the O
density O
of O
bacteria O
is O
much O
higher O
than O
in O
the O
small O
intestine O
and O
the O
transit O
time O
much O
longer O
, O
the O
residual O
undigested O
luminal O
proteins O
and O
peptides O
can O
be O
degraded O
in O
amino B
acids I
by O
the O
microbiota O
. O

These O
amino B
acids I
cannot O
be O
absorbed O
to O
a O
significant O
extent O
by O
the O
colonic O
epithelium O
, O
but O
are O
precursors O
for O
the O
synthesis O
of O
numerous O
metabolic O
end O
products O
in O
reactions O
made O
by O
the O
microbiota O
. O

Among O
these O
products O
, O
some O
like O
short O
- O
chain O
fatty B
acids I
and O
organic O
acids O
are O
energy O
substrates O
for O
the O
colonic O
mucosa O
and O
several O
peripheral O
tissues O
while O
others O
like O
sulfide B
and O
ammonia B
can O
affect O
the O
energy O
metabolism O
of O
colonic O
epithelial O
cells O
. O

More O
work O
is O
needed O
to O
clarify O
the O
overall O
effects O
of O
the O
intestinal O
microbiota O
on O
nitrogenous O
compound O
metabolism O
and O
consequences O
on O
gut O
and O
more O
generally O
host O
health O
. O

Impaired O
in O
vitro O
erythropoiesis O
following O
deletion O
of O
the O
Scl O
( O
Tal1 O
) O
+ O
40 O
enhancer O
is O
largely O
compensated O
for O
in O
vivo O
despite O
a O
significant O
reduction O
in O
expression O
. O

The O
Scl O
( O
Tal1 O
) O
gene O
encodes O
a O
helix O
- O
loop O
- O
helix O
transcription O
factor O
essential O
for O
hematopoietic O
stem O
cell O
and O
erythroid O
development O
. O

The O
Scl O
+ O
40 O
enhancer O
is O
situated O
downstream O
of O
Map17 O
, O
the O
3 O
' O
flanking O
gene O
of O
Scl O
, O
and O
is O
active O
in O
transgenic O
mice O
during O
primitive O
and O
definitive O
erythropoiesis O
. O

To O
analyze O
the O
in O
vivo O
function O
of O
the O
Scl O
+ O
40 O
enhancer O
within O
the O
Scl O
/ O
Map17 O
transcriptional O
domain O
, O
we O
deleted O
this O
element O
in O
the O
germ O
line O
. O

Scl O
( O
Delta O
40 O
/ O
Delta O
40 O
) O
mice O
were O
viable O
with O
reduced O
numbers O
of O
erythroid O
CFU O
in O
both O
bone O
marrow O
and O
spleen O
yet O
displayed O
a O
normal O
response O
to O
stress O
hematopoiesis O
. O

Analysis O
of O
Scl O
( O
Delta O
40 O
/ O
Delta O
40 O
) O
embryonic O
stem O
( O
ES O
) O
cells O
revealed O
impaired O
erythroid O
differentiation O
, O
which O
was O
accompanied O
by O
a O
failure O
to O
upregulate O
Scl O
when O
erythropoiesis O
was O
initiated O
. O

Map17 O
expression O
was O
also O
reduced O
in O
hematopoietic O
tissues O
and O
differentiating O
ES O
cells O
, O
and O
the O
Scl O
+ O
40 O
element O
was O
able O
to O
enhance O
activity O
of O
the O
Map17 O
promoter O
. O

However O
, O
only O
Scl O
but O
not O
Map17 O
could O
rescue O
the O
Scl O
( O
Delta O
40 O
/ O
Delta O
40 O
) O
ES O
phenotype O
. O

Together O
, O
these O
data O
demonstrate O
that O
the O
Scl O
+ O
40 O
enhancer O
is O
an O
erythroid O
cell O
- O
specific O
enhancer O
that O
regulates O
the O
expression O
of O
both O
Scl O
and O
Map17 O
. O

Moreover O
, O
deletion O
of O
the O
+ O
40 O
enhancer O
causes O
a O
novel O
erythroid O
phenotype O
, O
which O
can O
be O
rescued O
by O
ectopic O
expression O
of O
Scl O
but O
not O
Map17 O
. O

Long O
- O
term O
physicochemical O
and O
immunological O
stability O
of O
a O
liquid O
formulated O
intact O
ovine O
immunoglobulin O
- O
based O
antivenom O
. O

An O
antivenom O
should O
be O
stable O
under O
the O
conditions O
that O
it O
will O
be O
both O
transferred O
and O
stored O
. O

Thus O
instability O
may O
lead O
to O
a O
loss O
of O
efficacy O
and O
an O
increased O
incidence O
and O
severity O
of O
adverse O
effects O
. O

Stability O
is O
a O
particular O
problem O
in O
countries O
where O
the O
temperatures O
and O
humidity O
are O
high O
. O

Here O
we O
investigate O
the O
stability O
of O
a O
liquid O
- O
formulated O
, O
intact O
ovine O
immunoglobulin O
- O
based O
antivenom O
, O
EchiTAbG O
( O
TM O
) O
, O
which O
is O
used O
extensively O
in O
Nigeria O
to O
treat O
envenoming O
by O
the O
West O
African O
saw O
- O
scaled O
viper O
, O
Echis O
ocellatus O
. O

Ampoules O
of O
antivenom O
were O
assessed O
as O
to O
their O
specific O
antibody O
content O
by O
small O
scale O
affinity O
chromatography O
and O
their O
purity O
by O
size O
exclusion O
gel O
filtration O
and O
turbidity O
. O

Three O
different O
batches O
of O
the O
antivenom O
revealed O
no O
significant O
changes O
, O
using O
these O
assessment O
techniques O
, O
during O
42 O
months O
storage O
at O
4 O
degrees O
C O
or O
at O
ambient O
temperature O
, O
followed O
by O
one O
month O
at O
37 O
degrees O
C O
. O

These O
real O
- O
time O
studies O
indicate O
that O
the O
antivenom O
remains O
stable O
for O
a O
minimum O
of O
3 O
. O
5 O
years O
and O
that O
it O
can O
be O
exposed O
to O
tropical O
temperatures O
without O
any O
loss O
in O
immunoglobulin O
binding O
activity O
. O

This O
further O
highlights O
the O
clinical O
utility O
of O
liquid O
formulated O
ovine O
IgG O
antivenoms O
by O
demonstrating O
their O
retention O
of O
potency O
in O
the O
event O
of O
a O
short O
term O
failing O
in O
the O
cold O
chain O
. O

Spontaneous O
and O
experimental O
intoxication O
of O
cattle O
by O
Simarouba O
versicolor O
A O
. O

St O
. O
- O
Hill O
( O
Simaroubaceae O
) O
. O

This O
study O
describes O
an O
outbreak O
of O
Simarouba O
versicolor O
intoxication O
in O
cattle O
from O
Mato O
Grosso O
do O
Sul O
, O
Brazil O
, O
and O
reproduces O
it O
experimentally O
. O

Clinical O
signs O
of O
the O
affected O
animals O
were O
weakness O
, O
tremors O
, O
hind O
limbs O
incoordination O
, O
reluctance O
to O
move O
, O
sternal O
and O
lateral O
recumbency O
and O
death O
. O

The O
main O
necropsy O
findings O
, O
observed O
in O
the O
abomasum O
and O
in O
segments O
of O
the O
small O
and O
large O
intestines O
, O
were O
diffuse O
redness O
and O
mucosal O
and O
serosal O
swelling O
. O

Histological O
examination O
revealed O
necrosis O
of O
lymphoid O
tissues O
and O
necrotizing O
enterocolitis O
. O

One O
experiment O
was O
carried O
out O
using O
3 O
male O
calves O
to O
test O
the O
toxicity O
of O
a O
single O
dose O
of O
S O
. O
versicolor O
leaves O
at O
15 O
g O
/ O
kg O
, O
5 O
g O
/ O
kg O
and O
2 O
. O
5 O
g O
/ O
kg O
. O

Clinical O
signs O
, O
necropsy O
findings O
and O
histological O
examination O
of O
calves O
receiving O
15 O
g O
/ O
kg O
and O
5 O
g O
/ O
kg O
leaves O
were O
similar O
to O
those O
of O
cattle O
from O
the O
intoxication O
outbreak O
. O

The O
calf O
fed O
2 O
. O
5 O
g O
/ O
kg O
leaves O
developed O
clinical O
symptoms O
of O
poisoning O
and O
recovered O
naturally O
. O

In O
a O
second O
experiment O
, O
two O
male O
calves O
received O
daily O
administration O
of O
S O
. O
versicolor O
leaves O
at O
1 O
. O
5 O
g O
/ O
kg O
and O
2 O
. O
5 O
g O
/ O
kg O
for O
10 O
days O
. O

They O
developed O
clinical O
signs O
of O
intoxication O
within O
24 O
h O
and O
recovered O
eight O
to O
nine O
days O
after O
the O
leaves O
were O
administered O
. O

These O
findings O
suggest O
that O
S O
. O
versicolor O
was O
responsible O
for O
the O
outbreak O
studied O
, O
although O
this O
plant O
does O
not O
have O
cumulative O
intoxication O
effects O
on O
cattle O
. O

Effective O
fragment O
potential O
method O
in O
Q O
- O
CHEM O
: O
A O
guide O
for O
users O
and O
developers O
. O

A O
detailed O
description O
of O
the O
implementation O
of O
the O
effective O
fragment O
potential O
( O
EFP O
) O
method O
in O
the O
Q O
- O
CHEM O
electronic O
structure O
package O
is O
presented O
. O

The O
Q O
- O
CHEM O
implementation O
interfaces O
EFP O
with O
standard O
quantum O
mechanical O
( O
QM O
) O
methods O
such O
as O
Hartree O
- O
Fock O
, O
density O
functional O
theory O
, O
perturbation O
theory O
, O
and O
coupled O
- O
cluster O
methods O
, O
as O
well O
as O
with O
methods O
for O
electronically O
excited O
and O
open O
- O
shell O
species O
, O
for O
example O
, O
configuration O
interaction O
, O
time O
- O
dependent O
density O
functional O
theory O
, O
and O
equation O
- O
of O
- O
motion O
coupled O
- O
cluster O
models O
. O

In O
addition O
to O
the O
QM O
/ O
EFP O
functionality O
, O
a O
" O
fragment O
- O
only O
" O
feature O
is O
also O
available O
( O
when O
the O
system O
is O
described O
by O
effective O
fragments O
only O
) O
. O

To O
aid O
further O
developments O
of O
the O
EFP O
methodology O
, O
a O
detailed O
description O
of O
the O
C O
+ O
+ O
classes O
and O
EFP O
module O
' O
s O
workflow O
is O
presented O
. O

The O
EFP O
input O
structure O
and O
EFP O
job O
options O
are O
described O
. O

To O
assist O
setting O
up O
and O
performing O
EFP O
calculations O
, O
a O
collection O
of O
Perl O
service O
scripts O
is O
provided O
. O

The O
precomputed O
EFP O
parameters O
for O
standard O
fragments O
such O
as O
common O
solvents O
are O
stored O
in O
Q O
- O
CHEM O
' O
s O
auxiliary O
library O
; O
they O
can O
be O
easily O
invoked O
, O
similar O
to O
specifying O
standard O
basis O
sets O
. O

The O
instructions O
for O
generating O
user O
- O
defined O
EFP O
parameters O
are O
given O
. O

Fragments O
positions O
can O
be O
specified O
by O
their O
center O
of O
mass O
coordinates O
and O
Euler O
angles O
. O

The O
interface O
with O
the O
IQMOL O
and O
WEBMO O
software O
is O
also O
described O
. O

( O
c O
) O
2013 O
Wiley O
Periodicals O
, O
Inc O
. O

Strategic O
applications O
of O
gene O
expression O
: O
from O
drug O
discovery O
/ O
development O
to O
bedside O
. O

Gene O
expression O
is O
useful O
for O
identifying O
the O
molecular O
signature O
of O
a O
disease O
and O
for O
correlating O
a O
pharmacodynamic O
marker O
with O
the O
dose O
- O
dependent O
cellular O
responses O
to O
exposure O
of O
a O
drug O
. O

Gene O
expression O
offers O
utility O
to O
guide O
drug O
discovery O
by O
illustrating O
engagement O
of O
the O
desired O
cellular O
pathways O
/ O
networks O
, O
as O
well O
as O
avoidance O
of O
acting O
on O
the O
toxicological O
pathways O
. O

Successful O
employment O
of O
gene O
- O
expression O
signatures O
in O
the O
later O
stages O
of O
drug O
development O
depends O
on O
their O
linkage O
to O
clinically O
meaningful O
phenotypic O
characteristics O
and O
requires O
a O
biologically O
meaningful O
mechanism O
combined O
with O
a O
stringent O
statistical O
rigor O
. O

Much O
of O
the O
success O
in O
clinical O
drug O
development O
is O
hinged O
on O
predefining O
the O
signature O
genes O
for O
their O
fitness O
for O
purposes O
of O
application O
. O

Specific O
examples O
are O
highlighted O
to O
illustrate O
the O
breadth O
and O
depth O
of O
the O
potential O
utility O
of O
gene O
- O
expression O
signatures O
in O
drug O
discovery O
and O
clinical O
development O
to O
targeted O
therapeutics O
at O
the O
bedside O
. O

ICA B
- I
105574 I
interacts O
with O
a O
common O
binding O
site O
to O
elicit O
opposite O
effects O
on O
inactivation O
gating O
of O
EAG O
and O
ERG O
potassium B
channels O
. O

Rapid O
and O
voltage O
- O
dependent O
inactivation O
greatly O
attenuates O
outward O
currents O
in O
ether O
- O
a O
- O
go O
- O
go O
- O
related O
gene O
( O
ERG O
) O
K B
( I
+ I
) I
channels O
. O

In O
contrast O
, O
inactivation O
of O
related O
ether O
- O
a O
- O
go O
- O
go O
( O
EAG O
) O
K B
( I
+ I
) I
channels O
is O
very O
slow O
and O
minimally O
reduces O
outward O
currents O
. O

ICA B
- I
105574 I
( O
ICA B
, O
or O
3 B
- I
nitro I
- I
N I
- I
[ I
4 I
- I
phenoxyphenyl I
] I
- I
benzamide I
) O
has O
opposite O
effects O
on O
inactivation O
of O
these O
two O
channel O
types O
. O

Although O
ICA O
greatly O
attenuates O
ERG O
inactivation O
by O
shifting O
its O
voltage O
dependence O
to O
more O
positive O
potentials O
, O
it O
enhances O
the O
rate O
and O
extent O
of O
EAG O
inactivation O
without O
altering O
its O
voltage O
dependence O
. O

Here O
, O
we O
investigate O
whether O
the O
inverse O
functional O
response O
to O
ICA O
in O
EAG O
and O
ERG O
channels O
is O
related O
to O
differences O
in O
ICA O
binding O
site O
or O
to O
intrinsic O
mechanisms O
of O
inactivation O
. O

Molecular O
modeling O
coupled O
with O
site O
- O
directed O
mutagenesis O
suggests O
that O
ICA O
binds O
in O
a O
channel O
- O
specific O
orientation O
to O
a O
hydrophobic O
pocket O
bounded O
by O
the O
S5 O
/ O
pore O
helix O
/ O
S6 O
of O
one O
subunit O
and O
S6 O
of O
an O
adjacent O
subunit O
. O

ICA O
is O
a O
mixed O
agonist O
of O
mutant O
EAG O
and O
EAG O
/ O
ERG O
chimera O
channels O
that O
inactivate O
by O
a O
combination O
of O
slow O
and O
fast O
mechanisms O
. O

With O
the O
exception O
of O
three O
residues O
, O
the O
specific O
amino B
acids I
that O
form O
the O
putative O
binding O
pocket O
for O
ICA O
in O
ERG O
are O
conserved O
in O
EAG O
. O

Mutations O
introduced O
into O
EAG O
to O
replicate O
the O
ICA B
binding O
site O
in O
ERG O
did O
not O
alter O
the O
functional O
response O
to O
ICA B
. O

Together O
these O
findings O
suggest O
that O
ICA O
binds O
to O
the O
same O
site O
in O
EAG O
and O
ERG O
channels O
to O
elicit O
opposite O
functional O
effects O
. O

The O
resultant O
agonist O
or O
antagonist O
activity O
is O
determined O
solely O
by O
channel O
- O
specific O
differences O
in O
the O
mechanisms O
of O
inactivation O
gating O
. O

The O
pharmacology O
of O
L B
- I
DOPA I
- O
induced O
dyskinesia O
in O
Parkinson O
' O
s O
disease O
. O

L B
- I
3 I
, I
4 I
- I
Dihydroxyphenylalani I
( O
L B
- I
DOPA I
) O
remains O
the O
most O
effective O
symptomatic O
treatment O
of O
Parkinson O
' O
s O
disease O
( O
PD O
) O
. O

However O
, O
long O
- O
term O
administration O
of O
L B
- I
DOPA I
is O
marred O
by O
the O
emergence O
of O
abnormal O
involuntary O
movements O
, O
i O
. O
e O
. O
, O
L B
- I
DOPA I
- O
induced O
dyskinesia O
( O
LID O
) O
. O

Years O
of O
intensive O
research O
have O
yielded O
significant O
progress O
in O
the O
quest O
to O
elucidate O
the O
mechanisms O
leading O
to O
the O
development O
and O
expression O
of O
dyskinesia O
and O
maintenance O
of O
the O
dyskinetic O
state O
, O
but O
the O
search O
for O
a O
complete O
understanding O
is O
still O
ongoing O
. O

Herein O
, O
we O
summarize O
the O
current O
knowledge O
of O
the O
pharmacology O
of O
LID O
in O
PD O
. O

Specifically O
, O
we O
review O
evidence O
gathered O
from O
postmortem O
and O
pharmacological O
studies O
, O
both O
preclinical O
and O
clinical O
, O
and O
discuss O
the O
involvement O
of O
dopaminergic O
and O
nondopaminergic O
systems O
, O
including O
glutamatergic O
, O
opioid O
, O
serotonergic O
, O
gamma B
- I
aminobutyric I
acid I
( O
GABA B
) O
- O
ergic O
, O
adenosine B
, O
cannabinoid O
, O
adrenergic O
, O
histaminergic O
, O
and O
cholinergic O
systems O
. O

Moreover O
, O
we O
discuss O
changes O
occurring O
in O
transcription O
factors O
, O
intracellular O
signaling O
, O
and O
gene O
expression O
in O
the O
dyskinetic O
phenotype O
. O

Inasmuch O
as O
a O
multitude O
of O
neurotransmitters O
and O
receptors O
play O
a O
role O
in O
the O
etiology O
of O
dyskinesia O
, O
we O
propose O
that O
to O
optimally O
alleviate O
this O
motor O
complication O
, O
it O
may O
be O
necessary O
to O
develop O
combined O
treatment O
approaches O
that O
will O
target O
simultaneously O
more O
than O
one O
neurotransmitter O
system O
. O

This O
could O
be O
achieved O
via O
three O
ways O
as O
follows O
: O
1 O
) O
by O
developing O
compounds O
that O
will O
interact O
simultaneously O
to O
a O
multitude O
of O
receptors O
with O
the O
required O
agonist O
/ O
antagonist O
effect O
at O
each O
target O
, O
2 O
) O
by O
targeting O
intracellular O
signaling O
cascades O
where O
the O
signals O
mediated O
by O
multiple O
receptors O
converge O
, O
and O
/ O
or O
3 O
) O
to O
regulate O
gene O
expression O
in O
a O
manner O
that O
has O
effects O
on O
signaling O
by O
multiple O
pathways O
. O

It O
is O
the O
outside O
that O
counts O
: O
chemical O
and O
physical O
control O
of O
dynamic O
surfaces O
. O

Materials O
capable O
of O
dynamically O
controlling O
surface O
chemistry O
and O
topography O
are O
highly O
desirable O
. O

We O
have O
designed O
a O
system O
that O
is O
uniquely O
able O
to O
remotely O
control O
the O
presented O
functionality O
and O
geometry O
at O
a O
given O
time O
by O
using O
a O
functionalizable O
shape O
memory O
material O
. O

This O
was O
accomplished O
by O
incorporating O
controlled O
amounts O
of O
an O
azide B
- O
containing O
monomer O
into O
a O
shape O
memory O
polymeric O
material O
. O

These O
materials O
are O
capable O
of O
physically O
changing O
surface O
geometry O
over O
a O
broad O
range O
of O
length O
scales O
from O
> O
1 O
mm O
to O
100 O
nm O
. O

Using O
copper B
- O
assisted O
click O
chemistry O
, O
they O
can O
be O
functionalized O
with O
a O
variety O
of O
molecules O
to O
yield O
different O
surfaces O
. O

Combining O
these O
features O
gave O
materials O
that O
can O
change O
both O
the O
presented O
geometry O
and O
functionality O
at O
tunable O
transition O
temperatures O
. O

Development O
of O
a O
novel O
bioerodible O
dexamethasone B
implant O
for O
uveitis O
and O
postoperative O
cataract O
inflammation O
. O

Delivery O
of O
anti O
- O
inflammatory O
steroids O
concurrently O
to O
both O
anterior O
and O
posterior O
segments O
of O
the O
eye O
is O
a O
challenge O
. O

The O
anterior O
ocular O
structures O
limit O
topical O
delivery O
. O

Injection O
can O
be O
disproportionately O
and O
repeatedly O
invasive O
and O
selective O
for O
only O
one O
ocular O
hemisphere O
. O

We O
developed O
a O
novel O
implant O
that O
can O
compensate O
for O
the O
limited O
conveyance O
of O
topical O
medicine O
and O
reduce O
the O
repetitive O
invasiveness O
of O
injection O
from O
the O
capsular O
bag O
allowing O
dexamethasone B
( O
DXM B
) O
delivery O
to O
both O
the O
anterior O
and O
posterior O
chambers O
. O

To O
establish O
proof O
of O
concept O
, O
microparticles O
were O
prepared O
with O
PLGA B
[ O
poly B
( I
d I
, I
l I
- I
lactide I
- I
co I
- I
glycolide I
) I
, O
50 O
: O
50 O
, O
MW O
. O
7000 O
- O
17000 O
] O
, O
hydroxypropyl B
methyl I
cellulose O
( O
HPMC O
) O
, O
and O
DXM B
by O
oil O
- O
in O
- O
water O
emulsion O
/ O
solvent O
evaporation O
technique O
. O

Zeatsizer O
Nano O
and O
SEM O
( O
scanning O
electron O
microscopy O
) O
results O
showed O
microspheres O
in O
the O
range O
of O
8 O
+ O
/ O
- O
1 O
micro O
m O
. O

The O
target O
load O
of O
DXM B
in O
the O
microparticles O
was O
~ O
20 O
. O
0 O
% O
with O
a O
% O
recovery O
of O
99 O
. O
9 O
% O
( O
w O
/ O
w O
) O
. O

Dose O
related O
pharmacokinetics O
with O
near O
zero O
order O
kinetics O
was O
observed O
for O
up O
to O
6 O
weeks O
in O
rabbits O
with O
intracapsular O
bag O
implants O
. O

DXM B
flow O
was O
bidirectional O
from O
the O
endocapsular O
space O
and O
significant O
concentrations O
were O
found O
in O
the O
anterior O
and O
posterior O
chambers O
after O
up O
to O
6 O
weeks O
. O

Whereas O
, O
with O
topical O
drops O
the O
exposure O
was O
minimal O
in O
all O
the O
ocular O
tissues O
with O
greater O
systemic O
exposure O
. O

Intraocular O
pressure O
was O
normal O
in O
all O
of O
the O
study O
groups O
; O
slit O
lamp O
biomicroscopy O
examinations O
revealed O
that O
no O
cells O
or O
fibrin O
formation O
in O
the O
anterior O
and O
posterior O
chamber O
with O
implants O
but O
flare O
, O
cells O
and O
fibrin O
was O
present O
in O
the O
topical O
drops O
group O
. O

Histological O
examination O
revealed O
normal O
tissues O
and O
no O
signs O
of O
inflammation O
in O
all O
the O
groups O
. O

The O
implant O
did O
not O
migrate O
to O
the O
center O
of O
the O
eye O
or O
obstruct O
the O
visual O
axis O
. O

We O
believe O
these O
findings O
demonstrate O
the O
feasibility O
of O
drug O
delivery O
from O
the O
capsular O
bag O
to O
the O
anterior O
and O
posterior O
segments O
effectively O
compared O
to O
topical O
alternatives O
. O

Meta O
- O
analysis O
of O
telomere O
length O
in O
19 O
713 O
subjects O
reveals O
high O
heritability O
, O
stronger O
maternal O
inheritance O
and O
a O
paternal O
age O
effect O
. O

Telomere O
length O
( O
TL O
) O
has O
been O
associated O
with O
aging O
and O
mortality O
, O
but O
individual O
differences O
are O
also O
influenced O
by O
genetic O
factors O
, O
with O
previous O
studies O
reporting O
heritability O
estimates O
ranging O
from O
34 O
to O
82 O
% O
. O

Here O
we O
investigate O
the O
heritability O
, O
mode O
of O
inheritance O
and O
the O
influence O
of O
parental O
age O
at O
birth O
on O
TL O
in O
six O
large O
, O
independent O
cohort O
studies O
with O
a O
total O
of O
19 O
713 O
participants O
. O

The O
meta O
- O
analysis O
estimate O
of O
TL O
heritability O
was O
0 O
. O
70 O
( O
95 O
% O
CI O
0 O
. O
64 O
- O
0 O
. O
76 O
) O
and O
is O
based O
on O
a O
pattern O
of O
results O
that O
is O
highly O
similar O
for O
twins O
and O
other O
family O
members O
. O

We O
observed O
a O
stronger O
mother O
- O
offspring O
( O
r O
= O
0 O
. O
42 O
; O
P O
- O
value O
= O
3 O
. O
60 O
x O
10 O
( O
- O
61 O
) O
) O
than O
father O
- O
offspring O
correlation O
( O
r O
= O
0 O
. O
33 O
; O
P O
- O
value O
= O
7 O
. O
01 O
x O
10 O
( O
- O
5 O
) O
) O
, O
and O
a O
significant O
positive O
association O
with O
paternal O
age O
at O
offspring O
birth O
( O
beta O
= O
0 O
. O
005 O
; O
P O
- O
value O
= O
7 O
. O
01 O
x O
10 O
( O
- O
5 O
) O
) O
. O

Interestingly O
, O
a O
significant O
and O
quite O
substantial O
correlation O
in O
TL O
between O
spouses O
( O
r O
= O
0 O
. O
25 O
; O
P O
- O
value O
= O
2 O
. O
82 O
x O
10 O
( O
- O
30 O
) O
) O
was O
seen O
, O
which O
appeared O
stronger O
in O
older O
spouse O
pairs O
( O
mean O
age O
> O
= O
55 O
years O
; O
r O
= O
0 O
. O
31 O
; O
P O
- O
value O
= O
4 O
. O
27 O
x O
10 O
( O
- O
23 O
) O
) O
than O
in O
younger O
pairs O
( O
mean O
age O
< O
55 O
years O
; O
r O
= O
0 O
. O
20 O
; O
P O
- O
value O
= O
3 O
. O
24 O
x O
10 O
( O
- O
10 O
) O
) O
. O

In O
summary O
, O
we O
find O
a O
high O
and O
very O
consistent O
heritability O
estimate O
for O
TL O
, O
evidence O
for O
a O
maternal O
inheritance O
component O
and O
a O
positive O
association O
with O
paternal O
age O
. O
European O
Journal O
of O
Human O
Genetics O
advance O
online O
publication O
, O
16 O
January O
2013 O
; O
doi O
: O
10 O
. O
1038 O
/ O
ejhg O
. O
2012 O
. O
303 O
. O

Caffeine B
has O
greater O
potency O
and O
efficacy O
than O
theophylline B
to O
reverse O
the O
motor O
impairment O
caused O
by O
chronic O
but O
not O
acute O
interruption O
of O
striatal O
dopaminergic O
transmission O
in O
rats O
. O

In O
order O
to O
assess O
whether O
caffeine B
and O
theophylline B
have O
the O
same O
potency O
and O
efficacy O
to O
reverse O
the O
impairment O
of O
motor O
function O
caused O
by O
acute O
or O
chronic O
interruption O
of O
striatal O
dopamine B
transmission O
, O
a O
comparison O
of O
their O
dose O
- O
response O
relationship O
was O
made O
in O
the O
acute O
model O
of O
haloperidol B
- O
induced O
catalepsy O
, O
and O
the O
chronic O
model O
of O
unilateral O
lesion O
of O
the O
dopamine B
nigrostriatal O
pathway O
with O
6 B
- I
hydroxydopamine I
. O

At O
equimolar O
doses O
, O
both O
drugs O
reduced O
catalepsy O
intensity O
and O
increased O
its O
onset O
latency O
in O
a O
dose O
- O
dependent O
fashion O
, O
showing O
comparable O
potencies O
and O
attaining O
the O
maximal O
effect O
at O
similar O
doses O
. O

Catalepsy O
intensity O
: O
caffeine B
ED50 O
= O
24 O
. O
1 O
mu O
mol O
/ O
kg O
[ O
95 O
% O
CI O
, O
18 O
. O
4 O
- O
31 O
. O
5 O
] O
; O
theophylline B
ED50 O
= O
22 O
. O
0 O
mu O
mol O
/ O
kg O
[ O
95 O
% O
CI O
, O
17 O
. O
0 O
- O
28 O
. O
4 O
] O
. O

Catalepsy O
latency O
: O
caffeine B
ED50 O
= O
27 O
. O
0 O
mu O
mol O
/ O
kg O
[ O
95 O
% O
CI O
, O
21 O
. O
1 O
- O
34 O
. O
6 O
] O
; O
theophylline B
ED50 O
= O
28 O
. O
8 O
mu O
mol O
/ O
kg O
[ O
95 O
% O
CI O
, O
22 O
. O
5 O
- O
36 O
. O
7 O
] O
. O

In O
one O
group O
of O
hemiparkinsonian O
rats O
( O
n O
= O
5 O
) O
, O
caffeine B
caused O
a O
dose O
- O
dependent O
recovery O
of O
the O
contralateral O
forepaw O
stepping O
: O
ED50 O
= O
2 O
. O
4 O
mu O
mol O
/ O
kg O
/ O
day O
[ O
95 O
% O
CI O
, O
1 O
. O
9 O
- O
3 O
. O
1 O
] O
) O
, O
reaching O
its O
maximum O
at O
the O
dose O
of O
5 O
. O
15 O
mu O
mol O
/ O
kg O
/ O
day O
. O

When O
the O
treatment O
of O
these O
same O
rats O
was O
switched O
to O
5 O
. O
15 O
mu O
mol O
/ O
kg O
/ O
day O
of O
theophylline B
, O
the O
stepping O
recovery O
was O
only O
51 O
+ O
/ O
- O
12 O
% O
of O
that O
induced O
by O
caffeine B
. O

Assessing O
the O
dose O
- O
response O
relationship O
of O
theophylline B
in O
another O
group O
of O
hemiparkinsonian O
rats O
( O
n O
= O
7 O
) O
revealed O
that O
it O
caused O
stepping O
recovery O
in O
an O
all O
- O
or O
- O
none O
fashion O
. O

Thus O
, O
the O
three O
lower O
doses O
had O
no O
effect O
, O
but O
at O
the O
dose O
of O
5 O
. O
15 O
mu O
mol O
/ O
kg O
/ O
day O
theophylline B
suddenly O
increased O
the O
stepping O
to O
56 O
+ O
/ O
- O
5 O
% O
of O
the O
maximal O
effect O
observed O
when O
the O
treatment O
of O
these O
same O
rats O
was O
switched O
to O
an O
equimolar O
dose O
of O
caffeine B
. O

Increasing O
the O
dose O
of O
theophylline B
up O
to O
15 O
. O
45 O
mu O
mol O
/ O
kg O
/ O
day O
caused O
no O
further O
stepping O
improvement O
since O
it O
was O
only O
41 O
+ O
/ O
- O
6 O
% O
of O
the O
maximal O
effect O
produced O
by O
caffeine B
at O
the O
dose O
of O
5 O
. O
15 O
mu O
mol O
/ O
kg O
/ O
day O
. O

Given O
that O
theophylline B
showed O
less O
potency O
and O
efficacy O
than O
caffeine B
to O
reverse O
the O
motor O
impairment O
caused O
by O
chronic O
, O
but O
not O
acute O
, O
interruption O
of O
striatal O
dopaminergic O
transmission O
in O
rats O
, O
it O
is O
suggested O
that O
caffeine B
would O
provide O
more O
benefits O
than O
theophylline B
to O
improve O
the O
motor O
function O
in O
patients O
with O
Parkinson O
' O
s O
disease O
. O

Arsenic B
present O
in O
the O
soil O
- O
vine O
- O
wine O
chain O
in O
vineyards O
situated O
in O
an O
old O
mining O
area O
in O
Trentino O
, O
Italy O
. O

The O
present O
study O
follows O
arsenic B
( O
As B
) O
transfer O
through O
the O
chain O
of O
soil O
- O
vine O
- O
leaves O
- O
grapes O
- O
wine O
to O
assess O
the O
possible O
risk O
of O
arsenic B
intake O
related O
to O
consuming O
grapes O
and O
wines O
produced O
in O
10 O
vineyards O
located O
in O
a O
mining O
area O
rich O
in O
this O
element O
. O

The O
results O
are O
compared O
with O
date O
from O
18 O
uncontaminated O
areas O
. O

In O
the O
soil O
, O
the O
content O
of O
As B
extracted O
with O
acqua O
regia O
and O
that O
extracted O
with O
ammonium B
acetate I
, O
were O
analyzed O
. O

Leaves O
and O
berries O
were O
analyzed O
after O
washing O
with O
acidified O
aqueous O
solution O
and O
acid O
mineralization O
in O
a O
closed O
vessel O
, O
whereas O
wines O
were O
simply O
diluted O
before O
analysis O
. O

All O
analyses O
were O
performed O
using O
an O
inductively O
coupled O
plasma O
mass O
- O
spectrometer O
. O

The O
aqua O
regia O
extractable O
As B
concentration O
in O
soil O
ranged O
from O
3 O
. O
7 O
to O
283 O
mg O
/ O
kg O
, O
whereas O
available O
As B
varied O
from O
18 O
to O
639 O
micro O
g O
/ O
kg O
, O
and O
As B
total O
concentration O
ranged O
from O
16 O
. O
3 O
to O
579 O
micro O
g O
/ O
kg O
dry O
weight O
in O
leaves O
and O
from O
< O
0 O
. O
1 O
to O
36 O
. O
8 O
micro O
g O
/ O
kg O
dry O
weight O
in O
grapes O
. O

Arsenic B
levels O
in O
wines O
were O
always O
below O
1 O
. O
62 O
micro O
g O
/ O
L O
, O
with O
higher O
concentration O
in O
red O
wines O
than O
in O
white O
wines O
. O

Significant O
and O
positive O
correlations O
between O
the O
As B
concentrations O
in O
soils O
, O
leaves O
, O
and O
berries O
are O
highlighted O
, O
with O
the O
samples O
collected O
near O
the O
mining O
area O
having O
significantly O
higher O
values O
. O

Nevertheless O
, O
As B
levels O
in O
wines O
were O
always O
well O
below O
the O
limit O
( O
200 O
micro O
g O
/ O
L O
) O
suggested O
by O
the O
International O
Organization O
of O
Vine O
and O
Wine O
. O

Reduced O
Blood O
Leukocyte O
and O
Neutrophil O
Numbers O
in O
the O
Pathogenesis O
of O
Type O
1 O
Diabetes O
. O

Very O
little O
is O
known O
about O
the O
role O
of O
the O
innate O
immune O
system O
in O
the O
course O
of O
human O
type O
1 O
diabetes O
. O

Here O
we O
investigated O
neutrophil O
numbers O
along O
with O
other O
leukocyte O
populations O
in O
patients O
at O
diagnosis O
of O
type O
1 O
diabetes O
and O
during O
prediabetes O
. O

Complete O
and O
differential O
blood O
counts O
were O
analyzed O
from O
107 O
adult O
patients O
with O
newly O
diagnosed O
type O
1 O
diabetes O
, O
21 O
children O
with O
persistent O
islet O
autoantibodies O
and O
a O
family O
history O
of O
type O
1 O
diabetes O
, O
and O
1 O
238 O
age O
and O
gender O
matched O
control O
subjects O
, O
all O
individuals O
without O
any O
signs O
of O
acute O
infection O
. O
Adult O
patients O
with O
newly O
diagnosed O
type O
1 O
diabetes O
had O
significantly O
lower O
total O
WBC O
( O
p O
< O
1 O
x O
10 O
- O
6 O
) O
, O
neutrophil O
( O
p O
< O
1 O
x O
10 O
- O
6 O
) O
, O
basophil O
( O
p O
< O
1 O
x O
10 O
- O
6 O
) O
, O
monocyte O
( O
p O
= O
4 O
x O
10 O
- O
6 O
) O
and O
lymphocyte O
( O

p O
< O
1 O
x O
10 O
- O
6 O
) O
counts O
compared O
to O
control O
subjects O
. O

Erythrocyte O
, O
eosinophil O
and O
platelet O
counts O
did O
not O
differ O
between O
groups O
. O

Similarly O
, O
children O
with O
persistent O
islet O
autoantibodies O
had O
decreased O
WBC O
( O
p O
= O
0 O
. O
001 O
) O
, O
neutrophils O
( O
p O
= O
0 O
. O
003 O
) O
, O
and O
lymphocytes O
( O
p O
= O
0 O
. O
006 O
) O
in O
comparison O
to O
control O
children O
. O

Our O
findings O
demonstrate O
a O
perturbation O
of O
leukocyte O
homeostasis O
at O
and O
prior O
to O
onset O
of O
type O
1 O
diabetes O
suggesting O
a O
general O
involvement O
of O
the O
innate O
immune O
system O
in O
the O
pathogenesis O
of O
type O
1 O
diabetes O
. O

A O
genome O
- O
wide O
siRNA O
screen O
reveals O
positive O
and O
negative O
regulators O
of O
the O
NOD2 O
and O
NF O
- O
kappa O
B O
signaling O
pathways O
. O

The O
cytoplasmic O
receptor O
NOD2 O
( O
nucleotide B
- O
binding O
oligomerization O
domain O
2 O
) O
senses O
peptidoglycan O
fragments O
and O
triggers O
host O
defense O
pathways O
, O
including O
activation O
of O
nuclear O
factor O
kappa O
B O
( O
NF O
- O
kappa O
B O
) O
signaling O
, O
which O
lead O
to O
inflammatory O
immune O
responses O
. O

Dysregulation O
of O
NOD2 O
signaling O
is O
associated O
with O
inflammatory O
diseases O
, O
such O
as O
Crohn O
' O
s O
disease O
and O
Blau O
syndrome O
. O

We O
used O
a O
genome O
- O
wide O
small O
interfering O
RNA O
screen O
to O
identify O
regulators O
of O
the O
NOD2 O
signaling O
pathway O
. O

Several O
genes O
associated O
with O
Crohn O
' O
s O
disease O
risk O
were O
identified O
in O
the O
screen O
. O

A O
comparison O
of O
candidates O
from O
this O
screen O
with O
other O
" O
omics O
" O
data O
sets O
revealed O
interconnected O
networks O
of O
genes O
implicated O
in O
NF O
- O
kappa O
B O
signaling O
, O
thus O
supporting O
a O
role O
for O
NOD2 O
and O
NF O
- O
kappa O
B O
pathways O
in O
the O
pathogenesis O
of O
Crohn O
' O
s O
disease O
. O

Many O
of O
these O
regulators O
were O
validated O
in O
secondary O
assays O
, O
such O
as O
measurement O
of O
interleukin O
- O
8 O
secretion O
, O
which O
is O
partially O
dependent O
on O
NF O
- O
kappa O
B O
. O

Knockdown O
of O
putative O
regulators O
in O
human O
embryonic O
kidney O
293 O
cells O
followed O
by O
stimulation O
with O
tumor O
necrosis O
factor O
- O
alpha O
revealed O
that O
most O
of O
the O
genes O
identified O
were O
general O
regulators O
of O
NF O
- O
kappa O
B O
signaling O
. O

Overall O
, O
the O
genes O
identified O
here O
provide O
a O
resource O
to O
facilitate O
the O
elucidation O
of O
the O
molecular O
mechanisms O
that O
regulate O
NOD2 O
- O
and O
NF O
- O
kappa O
B O
- O
mediated O
inflammation O
. O

Cloning O
and O
functional O
characterization O
of O
the O
pig O
( O
Sus O
scrofa O
) O
organic O
anion O
transporting O
polypeptide O
1a2 O
. O

Abstract O
1 O
. O

Organic O
anion O
transporting O
polypeptides O
( O
OATPs O
) O
are O
a O
family O
of O
transporter O
proteins O
that O
have O
been O
extensively O
recognized O
as O
key O
determinants O
of O
absorption O
, O
distribution O
, O
metabolism O
and O
excretion O
of O
various O
drugs O
. O

Human O
OATP1A2 O
has O
been O
demonstrated O
to O
transport O
wide O
spectrum O
of O
endogenous O
and O
exogenous O
compounds O
. O

Study O
on O
OATP1A2 O
orthologues O
of O
other O
species O
, O
however O
, O
is O
still O
limited O
. O

2 O
. O

Here O
, O
we O
described O
the O
cloning O
and O
functional O
characterization O
of O
a O
member O
of O
the O
OATP O
/ O
Oatp O
family O
member O
obtained O
from O
pig O
( O
Sus O
scrofa O
) O
liver O
. O

Sequence O
analysis O
suggested O
that O
it O
has O
a O
high O
homology O
with O
human O
OATP1A2 O
and O
bovine O
Oatp1a2 O
. O

Prototypic O
substrates O
estrone B
- I
3 I
- I
sulfate I
( O
E B
- I
3 O
- O
S O
) O
and O
taurocholic B
acid I
were O
transported O
by O
the O
protein O
. O

The O
transport O
of O
these O
two O
substrates O
is O
pH O
- O
dependent O
, O
with O
lower O
pH O
showing O
higher O
uptake O
function O
. O

Kinetic O
study O
showed O
the O
transport O
of O
these O
two O
substrates O
have O
a O
K O
( O
m O
) O
of O
42 O
. O
5 O
+ O
/ O
- O
12 O
. O
1 O
and O
33 O
. O
1 O
+ O
/ O
- O
8 O
. O
7 O
micro O
M O
, O
respectively O
. O

Pig O
Slco1a2 O
has O
the O
highest O
expression O
level O
in O
the O
liver O
, O
and O
to O
a O
less O
extend O
in O
the O
brain O
and O
small O
intestine O
. O

3 O
. O

In O
conclusion O
, O
an O
OATP O
member O
was O
cloned O
from O
pig O
liver O
. O

Sequence O
analysis O
and O
phylogenic O
study O
revealed O
it O
as O
an O
orthologue O
of O
human O
OATP1A2 O
. O

Its O
kinetic O
characteristic O
for O
prototypic O
substrates O
and O
organ O
distribution O
are O
similar O
with O
that O
of O
OATP1A2 O
. O

Folic B
acid I
modified O
cationic O
gamma B
- I
cyclodextrin I
- O
oligoethylenimine B
star O
polymer O
with O
bioreducible O
disulfide B
linker O
for O
efficient O
targeted O
gene O
delivery O
. O

For O
an O
efficient O
folate B
- O
targeted O
delivery O
, O
while O
the O
interaction O
between O
the O
folate B
on O
the O
carriers O
and O
the O
folate B
receptor O
( O
FR O
) O
on O
the O
cells O
is O
necessary O
, O
the O
recovering O
and O
recycling O
of O
FR O
to O
maintain O
a O
high O
density O
level O
of O
FR O
on O
the O
cellular O
membrane O
is O
also O
important O
. O

Herein O
, O
we O
demonstrate O
a O
design O
and O
synthesis O
of O
a O
new O
star O
- O
shaped O
cationic O
polymer O
containing O
a O
gamma B
- I
cyclodextrin I
( O
gamma B
- I
CD I
) O
core O
and O
multiple O
oligoethylenimine B
( O
OEI B
) O
arms O
with O
folic B
acid I
( O
FA O
) O
linked O
by O
a O
bioreducible O
disulfide B
bond O
for O
efficient O
targeted O
gene O
delivery O
. O

The O
newly O
synthesized O
cationic O
polymer O
, O
named O
gamma B
- I
CD I
- I
OEI I
- I
SS I
- I
FA I
, O
could O
be O
cleaved O
efficiently O
, O
and O
FA O
was O
readily O
released O
under O
reductive O
condition O
similar O
to O
intracellular O
environment O
. O

The O
gamma B
- I
CD I
- I
OEI I
- I
SS I
- I
FA I
polymer O
was O
well O
- O
characterized O
and O
studied O
in O
terms O
of O
its O
gene O
delivery O
properties O
in O
FR O
- O
positive O
KB O
cells O
and O
FR O
- O
negative O
A549 O
cells O
under O
various O
conditions O
, O
in O
comparison O
with O
cationic O
polymers O
such O
as O
high O
molecular O
weight O
branched O
polyethylenimine B
( O
PEI B
) O
, O
gamma B
- I
CD I
- I
OEI I
star O
- O
shaped O
cationic O
polymer O
, O
gamma B
- I
CD I
- I
OEI I
- I
FA I
polymer O
where O
FA O
was O
directed O
linked O
to O
the O
star O
polymer O
without O
disulfide B
linker O
. O

Our O
data O
have O
demonstrated O
that O
the O
new O
gamma B
- I
CD I
- O
OEI O
- O
SS O
- O
FA O
gene O
carrier O
had O
low O
cytotoxicity O
and O
possessed O
capacity O
to O
target O
and O
deliver O
DNA O
to O
specific O
tumor O
cells O
that O
overexpress O
FRs O
, O
as O
well O
as O
functions O
to O
recover O
and O
recycle O
FRs O
onto O
cellular O
membranes O
to O
facilitate O
continuous O
FR O
- O
mediated O
endocytosis O
to O
achieve O
very O
high O
levels O
of O
gene O
expression O
. O

This O
study O
has O
expanded O
the O
strategy O
of O
FA O
- O
targeted O
delivery O
by O
combining O
the O
smart O
FR O
- O
recycling O
function O
to O
achieve O
the O
significant O
enhancement O
of O
gene O
expression O
. O

The O
new O
FA O
- O
targeted O
and O
bioreducible O
carrier O
may O
be O
a O
promising O
efficient O
gene O
delivery O
system O
for O
potential O
cancer O
gene O
therapy O
. O

Diterpenoid B
alkaloids I
from O
Aconitum O
kirinense O
. O

A O
new O
C B
( I
18 I
) I
- I
diterpenoid I
alkaloid I
, O
kirinenine B
A I
( O
1 O
) O
, O
was O
isolated O
from O
the O
root O
of O
Aconitum O
kirinense O
, O
along O
with O
eight O
known O
diterpenoid B
alkaloids I
. O

The O
structures O
of O
all O
compounds O
were O
characterized O
on O
the O
basis O
of O
extensive O
NMR O
and O
MS O
analyses O
and O
by O
comparison O
with O
literature O
values O
, O
and O
the O
new O
one O
was O
further O
confirmed O
by O
X O
- O
ray O
crystallographic O
diffraction O
. O

All O
the O
compounds O
were O
isolated O
from O
the O
title O
plant O
for O
the O
first O
time O
. O

A O
new O
compound O
from O
liquid O
fermentation O
broth O
of O
Armillaria O
mellea O
and O
the O
determination O
of O
its O
absolute O
configuration O
. O

A O
new O
2 B
, I
5 I
- I
diketopiperazine I
, O
( B
R I
) I
- I
2 I
- I
( I
2 I
- I
( I
furan I
- I
2 I
- I
yl I
) I
- I
oxoethyl I
) I
- I
octahydropyrrolo I
[ I
1 I
, I
2 I
- I
a I
] I
pyrazine I
- I
1 I
, I
4 I
- I
dione I
, O
and O
seven O
known O
compounds O
were O
isolated O
from O
the O
ethyl B
acetate I
extract O
of O
liquid O
fermentation O
broth O
of O
Armillaria O
mellea O
. O

The O
structures O
of O
the O
isolated O
compounds O
were O
established O
from O
NMR O
and O
HR O
- O
MS O
data O
. O

The O
absolute O
configuration O
of O
the O
new O
compound O
was O
established O
by O
comparing O
the O
experimental O
electronic O
circular O
dichroism O
( O
ECD O
) O
spectrum O
with O
the O
calculated O
ECD O
data O
. O

Dissecting O
single O
- O
molecule O
signal O
transduction O
in O
carbon B
nanotube O
circuits O
with O
protein O
engineering O
. O

Single O
- O
molecule O
experimental O
methods O
have O
provided O
new O
insights O
into O
biomolecular O
function O
, O
dynamic O
disorder O
, O
and O
transient O
states O
that O
are O
all O
invisible O
to O
conventional O
measurements O
. O

A O
novel O
, O
nonfluorescent O
single O
- O
molecule O
technique O
involves O
attaching O
single O
molecules O
to O
single O
- O
walled O
carbon B
nanotube O
field O
- O
effective O
transistors O
( O
SWNT O
FETs O
) O
. O

These O
ultrasensitive O
electronic O
devices O
provide O
long O
- O
duration O
, O
label O
- O
free O
monitoring O
of O
biomolecules O
and O
their O
dynamic O
motions O
. O

However O
, O
generalization O
of O
the O
SWNT O
FET O
technique O
first O
requires O
design O
rules O
that O
can O
predict O
the O
success O
and O
applicability O
of O
these O
devices O
. O

Here O
, O
we O
report O
on O
the O
transduction O
mechanism O
linking O
enzymatic O
processivity O
to O
electrical O
signal O
generation O
by O
a O
SWNT O
FET O
. O

The O
interaction O
between O
SWNT O
FETs O
and O
the O
enzyme O
lysozyme O
was O
systematically O
dissected O
using O
eight O
different O
lysozyme O
variants O
synthesized O
by O
protein O
engineering O
. O

The O
data O
prove O
that O
effective O
signal O
generation O
can O
be O
accomplished O
using O
a O
single O
charged O
amino B
acid I
, O
when O
appropriately O
located O
, O
providing O
a O
foundation O
to O
widely O
apply O
SWNT O
FET O
sensitivity O
to O
other O
biomolecular O
systems O
. O

A O
new O
di B
- I
O I
- I
prenylated I
flavone I
from O
an O
actinomycete O
Streptomyces O
sp O
. O

MA O
- O
12 O
. O

A O
new O
di B
- I
O I
- I
prenylated I
flavone I
, O
named O
7 B
, I
3 I
' I
- I
di I
- I
( I
gamma I
, I
gamma I
- I
dimethylallyloxy I
) I
- I
5 I
- I
hydroxy I
- I
4 I
' I
- I
methoxyflavone I
( O
1 O
) O
, O
was O
isolated O
from O
the O
culture O
broth O
of O
the O
endophytic O
actinomycete O
Streptomyces O
sp O
. O

MA O
- O
12 O
isolated O
from O
the O
root O
of O
the O
semi O
- O
mangrove O
plant O
Myoporum O
bontioides O
A O
. O

Gray O
. O

The O
structure O
of O
1 O
was O
determined O
by O
comprehensive O
spectroscopic O
methods O
, O
including O
1D O
and O
2D O
NMR O
experiments O
( O
COSY O
, O
HMQC O
, O
and O
HMBC O
) O
. O

Primary O
bioassays O
showed O
that O
1 O
at O
concentration O
of O
0 O
. O
25 O
mM O
had O
moderate O
inhibitory O
activity O
against O
three O
plant O
pathogenic O
fungi O
including O
Colletotrichum O
musae O
, O
Gibberella O
zeae O
( O
Schweinitz O
) O
Petch O
, O
and O
Penicillium O
citrinum O
Thom O
. O

New O
tetraterpene B
glycosides I
from O
the O
fruits O
of O
Lycium O
chinense O
. O

Two O
new O
compounds O
lyciumtetraterpenic B
hexaarabinoside I
( O
1 O
) O
and O
tetraterpenyl B
hexaarabinoside I
( O
2 O
) O
, O
along O
with O
two O
known O
compounds O
, O
were O
isolated O
from O
the O
methanol B
extract O
of O
the O
fruits O
of O
Lycium O
chinense O
Miller O
( O
Solanaceae O
) O
, O
and O
their O
structures O
have O
been O
elucidated O
as O
6 B
- I
( I
1 I
, I
1 I
, I
5 I
- I
trimethyl I
- I
5 I
alpha I
- I
hydroxycyclohexanyl I
) I
- I
6 I
' I
- I
( I
1 I
' I
, I
1 I
' I
, I
5 I
' I
- I
trimethyl I
- I
2 I
' I
beta I
- I

hydroxycyclohexanyl I
) I
- I
9 I
, I
13 I
, I
9 I
' I
, I
13 I
' I
- I
tetramethyloctadec I
- I
7 I
, I
9 I
, I
11 I
, I
13 I
, I
15 I
, I
7 I
' I
, I
9 I
' I
, I
11 I
' I
, I
13 I
' I
- I
nonene I
- I
5 I
alpha I
- I
D I
- I
arabinopyranosyl I
( I
2a I
- I
- I
> I
1b I
) I
- I
beta I
- I
D I
- I
arabinopyranosyl I
- I
( I
2b I
- I
- I
> I
1c I
) I
- I
beta I
- I
D I
- I
arabinopyranosyl I
- I
2 I
' I
- I
beta I
- I
D I
- I
arabinopyranosyl I
- I

( I
2d I
- I
- I
> I
1e I
) I
- I
alpha I
- I
D I
- I
arabinopyranosyl I
- I
( I
2e I
- I
- I
> I
1f I
) I
- I
alpha I
- I
D I
- I
arabinopyranoside I
( O
1 O
) O
and O
1 B
( I
6 I
) I
, I
11 I
( I
12 I
) I
, I
13 I
( I
14 I
) I
, I
1 I
' I
( I
6 I
' I
) I
, I
11 I
' I
( I
12 I
' I
) I
, I
13 I
' I
( I
14 I
' I
) I
- I
dodecahydro I
- I
beta I
- I
caroten I
- I
4 I
beta I
, I
4 I
' I
beta I
- I
diol I
- I
4 I
beta I
- I
L I
- I
arabinopyranosyl I
- I
( I
2a I
- I
- I
> I
1b I
) I

- I
beta I
- I
L I
- I
arabinopyranosyl I
- I
( I
2b I
- I
- I
> I
1c I
) I
- I
beta I
- I
D I
- I
arabinopyranosido I
- I
4 I
' I
beta I
- I
L I
- I
arabinopyranosyl I
- I
( I
2d I
- I
- I
> I
1e I
) I
- I
beta I
- I
L I
- I
arabinopyranosyl I
- I
( I
2e I
- I
- I
> I
1f I
) I
- I
beta I
- I
D I
- I
arabinopyranoside I
( O
2 O
) O
on O
the O
basis O
of O
spectral O
data O
analysis O
and O
chemical O
reactions O
. O

Evolution O
of O
novel O
tricyclic B
CRTh2 O
receptor O
antagonists O
from O
a O
( B
E I
) I
- I
2 I
- I
cyano I
- I
3 I
- I
( I
1H I
- I
indol I
- I
3 I
- I
yl I
) I
acrylamide I
scaffold O
. O

( B
E I
) I
- I
2 I
- I
( I
3 I
- I
( I
3 I
- I
( I
( I
3 I
- I
Bromophenyl I
) I
amino I
) I
- I
2 I
- I
cyano I
- I
3 I
- I
oxoprop I
- I
1 I
- I
en I
- I
1 I
- I
yl I
) I
- I
1H I
- I
indol I
- I
1 I
- I
yl I
) I
acetic I
acid I
( O
1 O
) O
was O
discovered O
in O
a O
HTS O
campaign O
for O
CRTh2 O
receptor O
antagonists O
. O

An O
SAR O
around O
this O
hit O
could O
be O
established O
and O
representatives O
with O
interesting O
activity O
profiles O
were O
obtained O
. O

Ring O
closing O
tactics O
to O
convert O
this O
hit O
series O
into O
a O
novel O
2 B
, I
3 I
, I
4 I
, I
5 I
- I
tetrahydro I
- I
1H I
- I
pyrido I
[ I
4 I
, I
3 I
- I
b I
] I
indole I
based O
CRTh2 O
receptor O
antagonist O
series O
is O
presented O
. O

Genetic O
association O
study O
of O
WNT10B O
polymorphisms O
with O
BMD O
and O
adiposity O
parameters O
in O
Danish O
and O
Belgian O
males O
. O

Because O
of O
the O
importance O
of O
the O
Wnt O
pathway O
in O
the O
development O
and O
maintenance O
of O
both O
adipose O
and O
bone O
tissue O
, O
we O
wanted O
to O
evaluate O
the O
involvement O
of O
WNT10B O
, O
a O
Wnt O
pathway O
activator O
, O
in O
adipogenesis O
and O
osteoblastogenesis O
in O
humans O
. O

Genetic O
association O
between O
WNT10B O
polymorphisms O
and O
adiposity O
parameters O
as O
well O
as O
bone O
mineral O
density O
( O
BMD O
) O
measurements O
was O
analysed O
in O
two O
independent O
populations O
. O

The O
first O
is O
a O
population O
of O
1 O
, O
228 O
Danish O
men O
( O
702 O
aged O
20 O
- O
29 O
years O
; O
532 O
aged O
60 O
- O
74 O
years O
) O
from O
the O
Odense O
Androgen B
Study O
( O
OAS O
) O
, O
which O
was O
designed O
as O
a O
cross O
- O
sectional O
, O
population O
- O
based O
study O
. O

The O
second O
population O
, O
called O
SIBLOS O
, O
includes O
922 O
Belgian O
men O
( O
34 O
+ O
/ O
- O
5 O
years O
old O
) O
and O
contains O
siblings O
selected O
from O
over O
500 O
families O
. O

Four O
tagSNPs O
( O
rs833840 O
, O
rs833841 O
, O
rs10875902 O
and O
rs4018511 O
) O
that O
capture O
variation O
of O
ten O
SNPs O
( O
MAF O
> O
5 O
% O
) O
in O
a O
15 O
. O
2 O
kb O
region O
spanning O
the O
WNT10B O
gene O
and O
its O
flanking O
regions O
were O
genotyped O
. O

Although O
no O
association O
with O
body O
mass O
index O
was O
found O
, O
we O
found O
all O
tagSNPs O
to O
be O
associated O
with O
BMD O
parameters O
( O
BMD O
whole O
body O
, O
total O
hip O
and O
femoral O
neck O
) O
and O
height O
in O
the O
OAS O
population O
. O

The O
association O
of O
rs10875902 O
was O
most O
prominent O
( O
nominal O
p O
= O
0 O
. O
012 O
) O
and O
confirmed O
a O
previously O
shown O
negative O
effect O
on O
BMD O
. O

No O
significant O
associations O
were O
observed O
in O
the O
SIBLOS O
population O
. O

In O
the O
present O
study O
, O
no O
association O
between O
WNT10B O
polymorphisms O
and O
adiposity O
parameters O
was O
found O
. O

However O
, O
our O
results O
clearly O
illustrate O
a O
role O
for O
WNT10B O
variants O
in O
determining O
human O
BMD O
. O

The O
effect O
of O
WNT10B O
polymorphisms O
on O
height O
should O
be O
evaluated O
in O
additional O
populations O
. O

The O
5 O
- O
HT1D O
/ O
1B O
receptor O
agonist O
sumatriptan B
enhances O
fear O
of O
simulated O
speaking O
and O
reduces O
plasma O
levels O
of O
prolactin O
. O

This O
study O
measured O
the O
effects O
of O
the O
preferential O
5 O
- O
HT1D O
/ O
1B O
receptor O
agonist O
sumatriptan B
in O
healthy O
volunteers O
who O
performed O
the O
Simulated O
Public O
Speaking O
Test O
( O
SPST O
) O
, O
which O
recruits O
the O
neural O
network O
involved O
in O
panic O
disorder O
and O
social O
anxiety O
disorder O
. O

In O
a O
double O
- O
blind O
, O
randomised O
experiment O
, O
36 O
males O
received O
placebo O
( O
12 O
) O
, O
50 O
mg O
( O
12 O
) O
or O
100 O
mg O
( O
12 O
) O
of O
sumatriptan B
2 O
h O
before O
the O
SPST O
. O

Subjective O
, O
physiological O
and O
hormonal O
measures O
were O
taken O
before O
, O
during O
and O
after O
the O
test O
. O

The O
dose O
of O
100 O
mg O
of O
sumatriptan B
increased O
speech O
- O
induced O
fear O
more O
than O
either O
a O
50mg O
dose O
of O
the O
drug O
or O
placebo O
. O

The O
largest O
dose O
of O
sumatriptan B
also O
enhanced O
vigilance O
more O
than O
placebo O
, O
without O
any O
change O
in O
blood O
pressure O
, O
heart O
rate O
or O
electrical O
skin O
conductance O
. O

Sumatriptan B
decreased O
plasma O
levels O
of O
prolactin O
. O

A O
significant O
but O
moderate O
increase O
in O
plasma O
cortisol B
after O
SPST O
occurred O
, O
independent O
of O
treatment O
. O

Because O
sumatriptan B
decreases O
5 B
- I
HT I
release O
into O
the O
extracellular O
space O
, O
the O
potentiation O
of O
SPST O
- O
induced O
fear O
caused O
by O
the O
drug O
supports O
the O
hypothesis O
that O
5 B
- I
HT I
attenuates O
this O
emotional O
state O
. O

As O
acute O
administration O
of O
antidepressants O
has O
also O
been O
shown O
to O
enhance O
speaking O
fear O
and O
increase O
plasma O
prolactin O
, O
in O
contrast O
to O
sumatriptan B
, O
the O
5 B
- I
HT I
regulation O
of O
stress O
- O
hormone O
release O
is O
likely O
to O
be O
different O
from O
that O
of O
emotion O
. O

Increases O
in O
triglyceride B
levels O
are O
associated O
with O
clinical O
response O
to O
clozapine B
treatment O
. O

Increases O
in O
serum O
triglyceride B
( O
TG O
) O
levels O
are O
associated O
with O
clinical O
response O
to O
clozapine B
treatment O
. O

Clozapine B
is O
the O
most O
efficacious O
therapy O
for O
treatment O
of O
refractory O
schizophrenia O
, O
although O
its O
use O
is O
well O
recognised O
to O
be O
associated O
with O
substantial O
metabolic O
dysfunction O
. O

Interestingly O
, O
there O
is O
some O
evidence O
that O
the O
therapeutic O
benefit O
of O
clozapine B
is O
associated O
with O
treatment O
- O
emergent O
weight O
gain O
and O
dyslipidaemia O
, O
specifically O
hypertriglyceridaemi O
. O

In O
this O
prospective O
observational O
study O
, O
we O
examine O
associations O
between O
therapeutic O
response O
to O
clozapine B
in O
49 O
patients O
with O
treatment O
- O
resistant O
schizophrenia O
and O
lipid O
dysregulation O
. O

An O
increase O
in O
TG O
levels O
was O
strongly O
predictive O
of O
clinical O
improvement O
( O
B O
= O
9 O
. O
33 O
, O
t O
= O
3 O
. O
56 O
, O
df O
= O
4 O
, O
p O
< O
0 O
. O
001 O
) O
and O
of O
improvement O
in O
positive O
PANSS O
scores O
( O
B O
= O
2 O
. O
85 O
, O
t O
= O
3 O
. O
61 O
, O
df O
= O
4 O
, O
p O
= O
0 O
. O
001 O
) O
as O
well O
as O
negative O
PANSS O
scores O
( O
B O
= O
1 O
. O
93 O
, O
t O
= O
2 O
. O
36 O
, O
df O
= O
4 O
, O
p O
= O
0 O
. O
02 O
) O
, O
when O
controlling O
for O
potential O
confounds O
of O
weight O
gain O
, O
change O
in O
waist O
circumference O
, O
baseline O

antipsychotic O
polypharmacy O
and O
serum O
clozapine B
levels O
. O

This O
finding O
suggests O
that O
clozapine B
' O
s O
therapeutic O
efficacy O
is O
linked O
to O
serum O
lipid O
changes O
. O

Hypertriglyceridaemi O
as O
a O
predictor O
of O
clinical O
response O
in O
patients O
treated O
with O
clozapine B
merits O
further O
investigation O
in O
order O
to O
better O
elucidate O
its O
effect O
on O
the O
pharmacological O
activity O
of O
clozapine B
. O

Design O
and O
synthesis O
of O
some O
new O
quinazolin B
- I
4 I
- I
( I
3H I
) I
- I
ones I
as O
anticonvulsant O
and O
antidepressant O
agents O
. O

A O
series O
of O
3 B
- I
[ I
( I
4 I
- I
substituted I
- I
benzylidene I
) I
- I
amino I
] I
- I
2 I
- I
phenyl I
- I
3H I
- I
quinazolin I
- I
4 I
- I
ones I
( O
5a O
- O
k O
) O
were O
synthesized O
by O
reacting O
3 B
- I
amino I
- I
2 I
- I
phenyl I
- I
1H I
- I
quinazolin I
- I
4 I
- I
one I
with O
p B
- I
hydroxybenzaldehyde I
, O
and O
then O
further O
with O
various O
alkyl B
/ I
benzyl I
halides I
or O
substituted O
phenacyl B
bromides I
. O

The O
structures O
of O
the O
compounds O
were O
confirmed O
on O
the O
basis O
of O
IR O
, O
NMR O
, O
MS O
and O
elemental O
analysis O
. O

Anticonvulsant O
activities O
were O
evaluated O
using O
the O
MES O
and O
scPTZ O
tests O
. O

Some O
of O
the O
selected O
compounds O
were O
evaluated O
for O
antidepressant O
activity O
by O
forced O
swim O
pool O
test O
. O

Compound O
3 B
- I
[ I
( I
4 I
- I
butoxy I
- I
benzylidene I
) I
- I
amino I
] I
- I
2 I
- I
phenyl I
- I
3H I
- I
quinazolin I
- I
4 I
- I
one I
was O
emerged O
as O
the O
most O
promising O
anticonvulsant O
agent O
without O
any O
motor O
impairment O
effect O
. O

The O
whole O
brain O
GABA B
estimation O
of O
brain O
homogenate O
indicated O
that O
the O
anticonvulsant O
activity O
of O
above O
mentioned O
quinazolinone B
derivatives O
might O
be O
due O
to O
an O
increased O
GABA B
concentration O
. O

An O
autonomous O
chromatin O
/ O
DNA O
- O
PK O
mechanism O
for O
localized O
DNA O
damage O
signaling O
in O
mammalian O
cells O
. O

Rapid O
phosphorylation O
of O
histone O
variant O
H2AX O
proximal O
to O
DNA O
breaks O
is O
an O
initiating O
event O
and O
a O
hallmark O
of O
eukaryotic O
DNA O
damage O
responses O
. O

Three O
mammalian O
kinases O
are O
known O
to O
phosphorylate O
H2AX O
in O
response O
to O
DNA O
damage O
. O

However O
, O
the O
mechanism O
( O
s O
) O
for O
damage O
- O
localized O
phosphorylation O
remains O
incompletely O
understood O
. O

The O
DNA O
- O
dependent O
protein O
kinase O
( O
DNA O
- O
PK O
) O
is O
the O
most O
abundant O
H2AX O
- O
modifying O
kinases O
and O
uniquely O
activated O
by O
binding O
DNA O
termini O
. O

Here O
, O
we O
have O
developed O
a O
novel O
approach O
to O
examine O
enzyme O
activity O
and O
substrate O
properties O
by O
executing O
biochemical O
assays O
on O
intact O
cellular O
structures O
. O

We O
apply O
this O
approach O
to O
examine O
the O
mechanisms O
of O
localized O
protein O
modification O
in O
chromatin O
within O
fixed O
cells O
. O

DNA O
- O
PK O
retains O
substrate O
specificity O
and O
independently O
generates O
break O
- O
localized O
gamma O
H2AX O
foci O
in O
chromatin O
. O

In O
situ O
DNA O
- O
PK O
activity O
recapitulates O
localization O
and O
intensity O
of O
in O
vivo O
H2AX O
phosphorylation O
and O
requires O
no O
active O
cellular O
processes O
. O

Nuclease O
treatments O
or O
addition O
of O
exogenous O
DNA O
resulted O
in O
genome O
- O
wide O
H2AX O
phosphorylation O
, O
showing O
that O
DNA O
termini O
dictated O
the O
locality O
of O
H2AX O
phosphorylation O
in O
situ O
. O

DNA O
- O
PK O
also O
reconstituted O
focal O
phosphorylation O
of O
structural O
maintenance O
of O
chromatin O
protein O
1 O
, O
but O
not O
activating O
transcription O
factor O
2 O
. O

Allosteric O
regulation O
of O
DNA O
- O
PK O
by O
DNA O
termini O
protruding O
from O
chromatin O
constitutes O
an O
autonomous O
mechanism O
for O
break O
- O
localized O
protein O
phosphorylation O
that O
generates O
sub O
- O
nuclear O
foci O
. O

We O
discuss O
generalized O
implications O
of O
this O
mechanism O
in O
localizing O
mammalian O
DNA O
damage O
responses O
. O

Use O
of O
a O
Routh O
- O
Russel O
deformation O
map O
to O
achieve O
film O
formation O
of O
a O
latex O
with O
a O
high O
glass O
transition O
temperature O
. O

In O
the O
film O
formation O
of O
latex O
, O
particle O
deformation O
can O
occur O
by O
processes O
of O
wet O
sintering O
, O
dry O
sintering O
, O
or O
capillary O
action O
. O

When O
latex O
films O
dry O
nonuniformly O
and O
when O
particles O
deform O
and O
coalesce O
while O
the O
film O
is O
still O
wet O
, O
a O
detrimental O
skin O
layer O
will O
develop O
at O
the O
film O
surface O
. O

In O
their O
process O
model O
, O
Routh O
and O
Russel O
proposed O
that O
the O
operative O
particle O
deformation O
mechanism O
can O
be O
determined O
by O
the O
values O
of O
control O
parameters O
on O
a O
deformation O
map O
. O

Here O
, O
the O
film O
formation O
processes O
of O
three O
methyl B
methacrylate I
/ O
butyl B
acrylate I
copolymer O
latexes O
with O
high O
glass O
transition O
temperatures O
( O
T O
( O
g O
) O
) O
, O
ranging O
from O
45 O
to O
64 O
degrees O
C O
, O
have O
been O
studied O
when O
heated O
by O
infrared O
radiation O
. O

Adjusting O
the O
infrared O
( O
IR O
) O
power O
density O
enables O
the O
film O
temperature O
, O
polymer O
viscosity O
, O
and O
evaporation O
rate O
during O
latex O
film O
formation O
to O
be O
controlled O
precisely O
. O

Different O
polymer O
particle O
deformation O
mechanisms O
have O
been O
demonstrated O
for O
the O
same O
latex O
under O
a O
variety O
of O
film O
formation O
process O
conditions O
. O

When O
the O
temperature O
is O
too O
high O
, O
a O
skin O
layer O
develops O
. O

On O
the O
other O
hand O
, O
when O
the O
temperature O
is O
too O
low O
, O
particles O
deform O
by O
dry O
sintering O
, O
and O
the O
process O
requires O
extended O
time O
periods O
. O

The O
deduced O
mechanisms O
can O
be O
interpreted O
and O
explained O
by O
the O
Routh O
- O
Russel O
deformation O
maps O
. O

Film O
formation O
of O
hard O
( O
high O
T O
( O
g O
) O
) O
coatings O
is O
achieved O
without O
using O
coalescing O
aids O
that O
emit O
volatile O
organic O
compounds O
( O
VOCs O
) O
, O
which O
is O
a O
significant O
technical O
achievement O
. O

Dynamic O
Domains O
in O
Polymersomes O
: O
Mixtures O
of O
Polyanionic O
and O
Neutral O
Diblocks O
Respond O
More O
Rapidly O
to O
Changes O
in O
Calcium B
than O
to O
pH O
. O

Chemical O
triggering O
of O
membrane O
domain O
dynamics O
is O
of O
broad O
relevance O
to O
cell O
signaling O
through O
lipid O
bilayers O
and O
might O
also O
be O
exploited O
in O
application O
of O
phase O
- O
separated O
vesicles O
. O

Here O
we O
describe O
the O
morphodynamics O
and O
remixing O
kinetics O
of O
spotted O
polymersomes O
made O
with O
mixtures O
of O
polyanionic O
and O
neutral O
amphiphiles O
plus O
calcium B
. O

Addition O
of O
the O
calcium B
chelator O
EDTA B
to O
vesicle O
dispersions O
produced O
a O
decrease O
in O
domain O
size O
within O
minutes O
, O
whereas O
increasing O
the O
pH O
with O
NaOH B
led O
to O
the O
viscous O
fingering O
of O
domains O
and O
decreased O
domain O
size O
over O
hours O
. O

Although O
the O
latter O
suggests O
that O
the O
charge O
of O
the O
polyanion O
contributes O
to O
domain O
formation O
, O
the O
remixing O
of O
more O
negative O
chains O
at O
high O
pH O
is O
surprising O
. O

Domain O
roughening O
at O
high O
pH O
is O
also O
accelerated O
by O
EDTA B
, O
which O
highlights O
the O
dominance O
of O
cross O
- O
bridging O
. O

Importantly O
, O
even O
though O
vesicles O
were O
perturbed O
only O
externally O
, O
the O
inner O
and O
outer O
leaflets O
remain O
coupled O
throughout O
, O
consistent O
with O
molecular O
dynamics O
simulations O
and O
suggestive O
of O
an O
order O
- O
disorder O
transition O
that O
underlies O
the O
remixing O
kinetics O
. O

Quasiclassical O
Trajectory O
Study O
of O
CH B
( I
3 I
) I
NO I
( I
2 I
) I
Decomposition O
via O
Roaming O
Mediated O
Isomerization O
Using O
a O
Global O
Potential O
Energy O
Surface O
. O

We O
report O
a O
global O
potential O
energy O
surface O
( O
PES O
) O
for O
CH B
( I
3 I
) I
NO I
( I
2 I
) I
based O
on O
fitting O
roughly O
114 O
000 O
density O
functional O
theory O
( O
UB3LYP O
/ O
6 O
- O
311 O
+ O
g O
( O
d O
, O
p O
) O
) O
electronic O
energies O
. O

The O
PES O
is O
a O
precise O
, O
permutationally O
invariant O
fit O
to O
these O
energies O
. O

Properties O
of O
the O
PES O
are O
described O
, O
as O
are O
some O
preliminary O
quasiclassical O
trajectory O
calculations O
. O

An O
isomerization O
- O
roaming O
pathway O
to O
the O
CH B
( I
3 I
) I
ONO B
isomer O
and O
then O
to O
the O
CH B
( I
3 I
) I
O I
+ O
NO B
products O
is O
found O
. O

Although O
the O
pathway O
occurs O
at O
larger O
distances O
than O
a O
related O
loose O
saddle O
- O
point O
on O
the O
PES O
, O
the O
pathway O
supports O
the O
supposition O
of O
such O
a O
pathway O
based O
on O
locating O
a O
loose O
first O
- O
order O
saddle O
point O
and O
associated O
IRC O
, O
reported O
previously O
by O
Zhu O
and O
Lin O
[ O
Zhu O
, O
R O
. O
S O
. O
and O
Lin O
, O
M O
. O
C O
. O
Chem O
. O
Phys O
. O
Lett O
. O
2009 O
, O
478 O
, O
11 O
] O
. O

Selective O
inhibition O
of O
extracellular O
thioredoxin O
by O
asymmetric O
disulfides B
. O

Whereas O
the O
role O
of O
mammalian O
thioredoxin O
( O
Trx O
) O
as O
an O
intracellular O
protein O
cofactor O
is O
widely O
appreciated O
, O
its O
function O
in O
the O
extracellular O
environment O
is O
not O
well O
- O
understood O
. O

Only O
few O
extracellular O
targets O
of O
Trx O
- O
mediated O
thiol B
- O
disulfide B
exchange O
are O
known O
. O

For O
example O
, O
Trx O
activates O
extracellular O
transglutaminase O
2 O
( O
TG2 O
) O
via O
reduction O
of O
an O
intramolecular O
disulfide B
bond O
. O

Because O
hyperactive O
TG2 O
is O
thought O
to O
play O
a O
role O
in O
various O
diseases O
, O
understanding O
the O
biological O
role O
of O
extracellular O
Trx O
may O
provide O
critical O
insight O
into O
the O
pathogenesis O
of O
these O
disorders O
. O

Starting O
from O
a O
clinical O
- O
stage O
asymmetric O
disulfide B
lead O
, O
we O
have O
identified O
analogs O
with O
> O
100 O
- O
fold O
specificity O
for O
Trx O
. O

Structure O
- O
activity O
relationship O
and O
computational O
docking O
model O
analyses O
have O
provided O
insights O
into O
the O
features O
important O
for O
enhancing O
potency O
and O
specificity O
. O

The O
most O
active O
compound O
identified O
had O
an O
IC O
( O
50 O
) O
below O
0 O
. O
1 O
mu O
M O
in O
cell O
culture O
and O
may O
be O
appropriate O
for O
in O
vivo O
use O
to O
interrogate O
the O
role O
of O
extracellular O
Trx O
in O
health O
and O
disease O
. O

Invasive O
lobular O
carcinoma O
stable O
for O
4 O
. O
5 O
years O
in O
a O
postmenopausal O
woman O
user O
of O
hormone O
therapy O
for O
25 O
years O
. O

We O
present O
a O
case O
of O
a O
72 O
- O
year O
- O
old O
woman O
referred O
to O
the O
breast O
disorder O
service O
due O
to O
abnormalities O
on O
mammography O
and O
breast O
ultrasound O
. O

The O
patient O
reported O
using O
different O
hormone O
therapy O
( O
HT O
) O
formulations O
during O
25 O
years O
and O
had O
stopped O
taking O
HT O
for O
4 O
years O
. O

Physical O
examination O
showed O
no O
alterations O
in O
the O
breasts O
or O
axilla O
. O

Mammography O
from O
2012 O
detected O
asymmetry O
at O
the O
3 O
o O
' O
clock O
position O
in O
the O
anterior O
right O
breast O
. O

Ultrasound O
revealed O
an O
irregular O
, O
hypoechoic O
mass O
with O
indistinct O
margins O
, O
and O
posterior O
acoustic O
shadowing O
. O

A O
retrospective O
analysis O
of O
mammographies O
from O
2007 O
, O
2009 O
and O
2010 O
showed O
that O
a O
very O
subtle O
asymmetry O
had O
existed O
since O
2007 O
. O

Follow O
- O
up O
imaging O
demonstrated O
no O
change O
in O
asymmetry O
during O
4 O
. O
5 O
years O
. O

The O
patient O
underwent O
breast O
- O
conserving O
therapy O
and O
sentinel O
lymph O
node O
biopsy O
. O

Histopathologic O
examination O
demonstrated O
classic O
invasive O
lobular O
carcinoma O
. O

There O
were O
no O
sentinel O
node O
metastases O
. O

The O
patient O
received O
radiotherapy O
and O
endrocrine B
therapy O
. O

This O
case O
demonstrates O
that O
breast O
cancer O
may O
remain O
stable O
and O
not O
grow O
for O
many O
years O
. O

This O
aspect O
should O
be O
kept O
in O
mind O
by O
all O
professionals O
dealing O
with O
women O
' O
s O
healthcare O
, O
in O
particular O
HT O
users O
who O
may O
develop O
breast O
cancer O
with O
a O
less O
aggressive O
behavior O
. O

Any O
suspicious O
finding O
on O
mammography O
, O
despite O
being O
unchanged O
for O
a O
number O
of O
years O
, O
must O
be O
investigated O
. O

Dibenzocyclooctadien B
lignans I
and O
norlignans B
from O
fruits O
of O
Schisandra O
wilsoniana O
. O

Seven O
new O
dibenzocyclooctadien B
lignans I
, O
marlignans B
M I
- I
S I
( O
1 O
- O
7 O
) O
, O
four O
new O
norlignans B
, O
marphenols B
C I
- I
F I
( O
8 O
- O
11 O
) O
, O
and O
21 O
known O
compounds O
( O
12 O
- O
32 O
) O
were O
isolated O
from O
the O
fruits O
of O
Schisandra O
wilsoniana O
. O

The O
structures O
of O
1 O
- O
11 O
were O
elucidated O
by O
spectroscopic O
methods O
including O
1D O
- O
and O
2D O
- O
NMR O
techniques O
and O
CD O
experiments O
. O

Compounds O
1 O
- O
11 O
were O
evaluated O
for O
their O
anti O
- O
HIV O
activities O
and O
showed O
EC O
( O
50 O
) O
values O
in O
the O
range O
2 O
. O
97 O
- O
6 O
. O
18 O
mu O
g O
/ O
mL O
and O
therapeutic O
index O
values O
of O
5 O
. O
33 O
- O
29 O
. O
13 O
. O

Acutely O
administered O
antipsychotic O
drugs O
are O
highly O
selective O
for O
dopamine B
D2 O
over O
D3 O
receptors O
. O

We O
showed O
previously O
, O
using O
[ B
( I
3 I
) I
H I
] I
- I
( I
+ I
) I
- I
4 I
- I
propyl I
- I
9 I
- I
hydroxynaphthoxazine I
( O
[ B
( I
3 I
) I
H I
] I
- I
( I
+ I
) I
- I
PHNO I
) O
autoradiography O
, O
that O
several O
antipsychotic O
drugs O
do O
not O
occupy O
dopamine B
D3 O
receptors O
at O
clinically O
- O
relevant O
doses O
in O
rat O
. O

This O
is O
an O
unexpected O
finding O
considering O
the O
near O
- O
equivalent O
in O
vitro O
affinity O
of O
these O
drugs O
for O
D2 O
and O
D3 O
receptors O
. O

The O
purpose O
of O
the O
current O
study O
was O
to O
address O
two O
possible O
methodological O
limitations O
of O
our O
previous O
report O
, O
namely O
that O
( O
1 O
) O
[ B
( I
3 I
) I
H I
] I
- I
( I
+ I
) I
- I
PHNO I
may O
have O
been O
administered O
at O
non O
- O
tracer O
dose O
, O
potentially O
causing O
underestimate O
of O
D3 O
receptor O
occupancy O
, O
and O
( O
2 O
) O
antipsychotic O
drugs O
were O
administered O
chronically O
, O
potentially O
causing O
increased O
D3 O
receptor O
expression O
not O
accounted O
for O
in O
the O
vehicle O
- O
treated O
control O
group O
. O

We O
found O
that O
decreasing O
[ B
( I
3 I
) I
H I
] I
- I
( I
+ I
) I
- I
PHNO I
dose O
from O
5 O
. O
6nmol O
/ O
kg O
( O
our O
previous O
dose O
) O
to O
0 O
. O
6nmol O
/ O
kg O
caused O
a O
> O
60 O
% O
increase O
in O
[ B
( I
3 I
) I
H I
] I
- I
( I
+ I
) I
- I
PHNO I
binding O
to O
D3 O
receptors O
in O
cerebellar O
lobes O
9 O
and O
10 O
, O
indicating O
that O
our O
previous O
study O
was O
indeed O
conducted O
under O
non O
- O
tracer O
dose O
conditions O
. O

However O
, O
neither O
reducing O
[ B
( I
3 I
) I
H I
] I
- I
( I
+ I
) I
- I
PHNO I
dose O
further O
to O
0 O
. O
3nmol O
/ O
kg O
( O
a O
tracer O
dose O
) O
, O
nor O
administering O
antipsychotics O
acutely O
affected O
antipsychotic O
receptor O
occupancy O
. O

At O
clinically O
- O
relevant O
levels O
of O
D2 O
occupancy O
( O
57 O
- O
82 O
% O
inhibition O
of O
striatal O
binding O
) O
, O
neither O
olanzapine B
nor O
haloperidol B
occupied O
D3 O
receptors O
, O
while O
clozapine B
occupied O
D3 O
receptors O
at O
levels O
similar O
to O
our O
previous O
report O
( O
33 O
% O
) O
. O

Risperidone B
moderately O
occupied O
D3 O
receptors O
( O
40 O
% O
) O
, O
but O
at O
a O
dose O
occupying O
> O
90 O
% O
of O
D2 O
receptors O
and O
therefore O
of O
questionable O
clinical O
relevance O
. O

These O
findings O
demonstrate O
that O
the O
lack O
of O
antipsychotic O
occupancy O
of O
D3 O
receptors O
is O
not O
attributable O
to O
limitations O
of O
our O
previous O
study O
. O

These O
results O
suggest O
that O
D3 O
receptor O
blockade O
is O
not O
necessary O
for O
the O
therapeutic O
effects O
of O
the O
antipsychotic O
drugs O
examined O
. O

Lifestyle O
and O
osteoporosis O
in O
middle O
- O
aged O
and O
elderly O
women O
: O
Chiba O
bone O
survey O
. O

Osteoporosis O
causes O
an O
enormous O
health O
and O
economic O
impact O
in O
Japan O
. O

We O
investigated O
the O
relation O
between O
lifestyle O
and O
bone O
fracture O
in O
middle O
- O
aged O
and O
elderly O
women O
. O

This O
was O
a O
population O
- O
based O
, O
multicenter O
, O
cross O
- O
sectional O
survey O
for O
postmenopausal O
osteoporosis O
in O
Chiba O
City O
, O
Japan O
( O
Chiba O
bone O
survey O
) O
. O

This O
survey O
included O
64 O
, O
809 O
Japanese O
women O
aged O
> O
40 O
years O
. O

All O
participants O
underwent O
anthropometric O
measurements O
including O
bone O
mineral O
density O
( O
BMD O
) O
and O
completed O
a O
structured O
, O
nurse O
- O
assisted O
, O
self O
- O
administered O
questionnaire O
also O
including O
patient O
lifestyle O
. O

Bone O
fracture O
during O
the O
recent O
5 O
years O
was O
observed O
in O
5 O
. O
3 O
% O
, O
and O
the O
fracture O
group O
had O
significantly O
higher O
age O
, O
BMI O
, O
and O
number O
of O
births O
, O
family O
histories O
of O
kyphosis O
and O
hip O
fracture O
, O
diabetes O
mellitus O
( O
DM O
) O
, O
dyslipidemia O
, O
kidney O
disease O
, O
exercise O
, O
fall O
, O
and O
osteoporosis O
, O
and O
had O
significantly O
lower O
BMD O
and O
proportion O
of O
menstruating O
participants O
. O

Logistic O
regression O
analysis O
revealed O
that O
bone O
fracture O
was O
closely O
associated O
with O
not O
only O
low O
bone O
mass O
but O
also O
age O
, O
fall O
, O
family O
histories O
of O
kyphosis O
and O
hip O
fracture O
, O
DM O
, O
kidney O
disease O
, O
menopause O
, O
and O
lifestyle O
factors O
of O
dieting O
, O
exercise O
, O
and O
alcohol O
. O

Women O
' O
s O
health O
care O
focusing O
on O
lifestyle O
- O
related O
fracture O
risks O
such O
as O
dieting O
, O
exercise O
, O
and O
alcohol O
appears O
necessary O
to O
prevent O
bone O
fracture O
in O
postmenopausal O
osteoporosis O
. O

Transport O
by O
OATP1B1 O
and O
OATP1B3 O
enhances O
the O
cytotoxicity O
of O
epigallocatechin B
3 I
- I
O I
- I
gallate I
and O
several O
quercetin B
derivatives O
. O

Organic O
anion O
transporting O
polypeptides O
( O
OATPs O
) O
1B1 O
and O
1B3 O
are O
transporters O
that O
are O
expressed O
selectively O
in O
human O
hepatocytes O
under O
normal O
conditions O
. O

OATP1B3 O
is O
also O
expressed O
in O
certain O
cancers O
. O

Flavonoids B
such O
as O
green O
tea O
catechins B
and O
quercetin B
glycosides I
have O
been O
shown O
to O
modulate O
the O
function O
of O
some O
OATPs O
. O

In O
the O
present O
study O
, O
the O
extent O
to O
which O
six O
substituted O
quercetin B
derivatives O
( O
1 O
- O
6 O
) O
affected O
the O
function O
of O
OATP1B1 O
and O
OATP1B3 O
was O
investigated O
. O

Uptake O
of O
the O
radiolabeled O
model O
substrates O
estradiol B
17 I
beta I
- I
glucuronide I
, O
estrone B
3 I
- I
sulfate I
, O
and O
dehydroepiandrostero B
sulfate I
( O
DHEAS B
) O
was O
determined O
in O
the O
absence O
and O
presence O
of O
compounds O
1 O
- O
6 O
using O
Chinese O
hamster O
ovary O
( O
CHO O
) O
cells O
stably O
expressing O
either O
OATP1B1 O
or O
OATP1B3 O
. O

Several O
of O
compounds O
1 O
- O
6 O
inhibited O
OATP O
- O
mediated O
uptake O
of O
all O
three O
model O
substrates O
, O
suggesting O
that O
they O
could O
also O
be O
potential O
substrates O
. O

Compound O
6 O
stimulated O
OATP1B3 O
- O
mediated O
estradiol B
17 I
beta I
- I
glucuronide I
uptake O
by O
increasing O
the O
apparent O
affinity O
of O
OATP1B3 O
for O
its O
substrate O
. O

Cytotoxicity O
assays O
demonstrated O
that O
epigallocatechin B
3 I
- I
O I
- I
gallate I
( O
EGCG B
) O
and O
most O
of O
compounds O
1 O
- O
6 O
killed O
preferentially O
OATP O
- O
expressing O
CHO O
cells O
. O

EGCG B
, O
1 O
, O
and O
3 O
were O
the O
most O
potent O
cytotoxic O
compounds O
, O
with O
EGCG B
and O
3 O
selectively O
killing O
OATP1B3 O
- O
expressing O
cells O
. O

Given O
that O
OATP1B3 O
is O
expressed O
in O
several O
cancers O
, O
EGCG B
and O
some O
of O
the O
quercetin B
derivatives O
studied O
might O
be O
promising O
lead O
compounds O
for O
the O
development O
of O
novel O
anticancer O
drugs O
. O

Labdane B
- O
type O
diterpenoids B
from O
the O
fruits O
of O
Vitex O
trifolia O
. O

Seven O
new O
labdane B
- O
type O
diterpenoids B
, O
vitextrifolins B
A I
- I
G I
( O
1 O
- O
7 O
) O
, O
along O
with O
eight O
previously O
reported O
analogues O
, O
were O
isolated O
from O
the O
fruits O
of O
Vitex O
trifolia O
. O

The O
structures O
of O
1 O
- O
7 O
were O
elucidated O
by O
spectroscopic O
data O
interpretation O
. O

The O
isolates O
were O
evaluated O
for O
their O
cytotoxicity O
against O
four O
human O
cancer O
cell O
lines O
( O
A549 O
, O
HCT116 O
, O
HL O
- O
60 O
, O
and O
ZR O
- O
75 O
- O
30 O
) O
, O
but O
all O
were O
inactive O
( O
IC O
( O
50 O
) O
< O
5 O
mu O
g O
/ O
mL O
) O
. O

Injectable O
hyaluronic O
acid O
- O
tyramine B
hydrogels O
incorporating O
interferon O
- O
alpha O
2a O
for O
liver O
cancer O
therapy O
. O

We O
report O
an O
injectable O
hydrogel O
system O
that O
incorporates O
interferon O
- O
alpha O
2a O
( O
IFN O
- O
alpha O
2a O
) O
for O
liver O
cancer O
therapy O
. O

IFN O
- O
alpha O
2a O
was O
incorporated O
in O
hydrogels O
composed O
of O
hyaluronic O
acid O
- O
tyramine B
( O
HA O
- O
Tyr B
) O
conjugates O
through O
the O
oxidative O
coupling O
of O
Tyr B
moieties O
with O
hydrogen B
peroxide I
( O
H2O2 B
) O
and O
horseradish O
peroxidase O
( O
HRP O
) O
. O

IFN O
- O
alpha O
2a O
- O
incorporated O
HA O
- O
Tyr B
hydrogels O
of O
varying O
stiffness O
were O
formed O
by O
changing O
the O
H2O2 B
concentration O
. O

The O
incorporation O
of O
IFN O
- O
alpha O
2a O
did O
not O
affect O
the O
rheological O
properties O
of O
the O
hydrogels O
. O

The O
activity O
of O
IFN O
- O
alpha O
2a O
was O
furthermore O
well O
- O
maintained O
in O
the O
hydrogels O
with O
lower O
stiffness O
. O

Through O
the O
caspase O
- O
3 O
/ O
7 O
pathway O
in O
vitro O
, O
IFN O
- O
alpha O
2a O
released O
from O
HA O
- O
Tyr B
hydrogels O
inhibited O
the O
proliferation O
of O
liver O
cancer O
cells O
and O
induced O
apoptosis O
. O

In O
the O
study O
of O
the O
pharmacokinetics O
, O
a O
higher O
concentration O
of O
IFN O
- O
alpha O
2a O
was O
shown O
in O
the O
plasma O
of O
mice O
treated O
with O
IFN O
- O
alpha O
2a O
- O
incorporated O
hydrogels O
after O
4h O
post O
injection O
, O
with O
a O
much O
higher O
amount O
of O
IFN O
- O
alpha O
2a O
delivered O
at O
the O
tumor O
tissue O
comparing O
to O
that O
of O
injecting O
an O
IFN O
- O
alpha O
2a O
solution O
. O

The O
tumor O
regression O
study O
revealed O
that O
IFN O
- O
alpha O
2a O
- O
incorporated O
HA O
- O
Tyr B
hydrogels O
effectively O
inhibited O
tumor O
growth O
, O
while O
the O
injection O
of O
an O
IFN O
- O
alpha O
2a O
solution O
did O
not O
demonstrate O
antitumor O
efficacy O
. O

Histological O
studies O
confirmed O
that O
tumor O
tissues O
in O
mice O
treated O
with O
IFN O
- O
alpha O
2a O
- O
incorporated O
HA O
- O
Tyr B
hydrogels O
showed O
lower O
cell O
density O
, O
with O
more O
apoptotic O
and O
less O
proliferating O
cells O
compared O
with O
tissues O
treated O
with O
an O
IFN O
- O
alpha O
2a O
solution O
. O

In O
addition O
, O
the O
IFN O
- O
alpha O
2a O
- O
incorporated O
hydrogel O
treatment O
greatly O
inhibited O
the O
angiogenesis O
of O
tumor O
tissues O
. O

Nonalcoholic O
fatty O
liver O
disease O
: O
current O
issues O
and O
novel O
treatment O
approaches O
. O

Nonalcoholic O
fatty O
liver O
disease O
( O
NAFLD O
) O
is O
considered O
the O
most O
common O
liver O
disorder O
in O
the O
Western O
world O
. O

It O
is O
commonly O
associated O
with O
insulin O
resistance O
, O
obesity O
, O
dyslipidaemia O
, O
type O
2 O
diabetes O
mellitus O
( O
T2DM O
) O
and O
cardiovascular O
disease O
. O

Nonalcoholic O
steatohepatitis O
( O
NASH O
) O
is O
characterized O
by O
steatosis O
with O
necroinflammation O
and O
eventual O
fibrosis O
, O
which O
can O
lead O
to O
end O
- O
stage O
liver O
disease O
and O
hepatocellular O
carcinoma O
. O

Its O
pathogenesis O
is O
complex O
, O
and O
involves O
a O
state O
of O
' O
lipotoxicity O
' O
in O
which O
insulin O
resistance O
, O
with O
increased O
free O
fatty B
acid I
release O
from O
adipose O
tissue O
to O
the O
liver O
, O
play O
a O
key O
role O
in O
the O
onset O
of O
a O
' O
lipotoxic O
liver O
disease O
' O
and O
its O
progression O
to O
NASH O
. O

The O
diagnosis O
of O
NASH O
is O
challenging O
, O
as O
most O
affected O
patients O
are O
symptom O
free O
and O
the O
role O
of O
routine O
screening O
is O
not O
clearly O
established O
. O

A O
complete O
medical O
history O
is O
important O
to O
rule O
out O
other O
causes O
of O
fatty O
liver O
disease O
( O
alcohol B
abuse O
, O
medications O
, O
other O
) O
. O

Plasma O
aminotransferase O
levels O
and O
liver O
ultrasound O
are O
helpful O
in O
the O
diagnosis O
of O
NAFLD O
/ O
NASH O
, O
but O
a O
liver O
biopsy O
is O
often O
required O
for O
a O
definitive O
diagnosis O
. O

However O
, O
there O
is O
an O
active O
search O
for O
plasma O
biomarkers O
and O
imaging O
techniques O
that O
may O
non O
- O
invasively O
aid O
in O
the O
diagnosis O
. O

The O
treatment O
of O
NASH O
requires O
a O
multifaceted O
approach O
. O

The O
goal O
is O
to O
reverse O
obesity O
- O
associated O
lipotoxicity O
and O
insulin O
resistance O
via O
lifestyle O
intervention O
. O

Although O
there O
is O
no O
pharmacological O
agent O
approved O
for O
the O
treatment O
of O
NAFLD O
, O
vitamin B
E I
( O
in O
patients O
without O
T2DM O
) O
and O
the O
thiazolidinedione B
pioglitazone B
( O
in O
patients O
with O
and O
without O
T2DM O
) O
have O
shown O
the O
most O
consistent O
results O
in O
randomized O
controlled O
trials O
. O

This O
review O
concentrates O
on O
our O
current O
understanding O
of O
the O
disease O
, O
with O
a O
focus O
on O
the O
existing O
therapeutic O
approaches O
and O
potential O
future O
pharmacological O
developments O
for O
NAFLD O
and O
NASH O
. O

Ranolazine B
: O
a O
review O
of O
its O
use O
as O
add O
- O
on O
therapy O
in O
patients O
with O
chronic O
stable O
angina O
pectoris O
. O

Extended O
- O
release O
ranolazine B
( O
ranolazine B
ER O
) O
[ O
Ranexa O
( O
( O
R O
) O
) O
] O
is O
an O
antianginal O
agent O
that O
achieves O
its O
effects O
via O
a O
novel O
mechanism O
of O
action O
( O
inhibition O
of O
the O
late O
phase O
of O
the O
inward O
sodium B
current O
) O
, O
without O
affecting O
heart O
rate O
or O
blood O
pressure O
( O
BP O
) O
. O

This O
article O
reviews O
the O
efficacy O
, O
safety O
and O
tolerability O
of O
ranolazine B
ER I
as O
add O
- O
on O
therapy O
in O
patients O
with O
chronic O
stable O
angina O
pectoris O
, O
as O
well O
as O
summarizing O
its O
pharmacological O
properties O
and O
its O
use O
in O
non O
- O
ST O
- O
elevation O
acute O
coronary O
syndromes O
. O

In O
the O
CARISA O
and O
ERICA O
trials O
, O
add O
- O
on O
therapy O
with O
ranolazine B
ER O
improved O
exercise O
tolerance O
and O
/ O
or O
reduced O
angina O
frequency O
and O
nitroglycerin B
use O
in O
patients O
with O
chronic O
stable O
angina O
; O
benefits O
were O
seen O
across O
a O
variety O
of O
patient O
subgroups O
. O

Although O
results O
of O
the O
MERLIN O
- O
TIMI O
36 O
trial O
do O
not O
support O
the O
use O
of O
ranolazine B
ER I
in O
the O
acute O
management O
of O
non O
- O
ST O
- O
elevation O
acute O
coronary O
syndromes O
, O
they O
do O
support O
its O
use O
as O
an O
antianginal O
therapy O
. O

Ranolazine B
ER O
was O
generally O
well O
tolerated O
, O
with O
the O
most O
commonly O
reported O
adverse O
events O
including O
dizziness O
, O
nausea O
, O
asthenia O
and O
constipation O
. O

Despite O
being O
associated O
with O
modest O
increases O
in O
the O
corrected O
QT O
interval O
, O
ranolazine B
ER O
demonstrated O
antiarrhythmic O
effects O
in O
the O
MERLIN O
- O
TIMI O
36 O
trial O
. O

In O
conclusion O
, O
ranolazine B
ER I
provides O
an O
important O
option O
for O
use O
as O
add O
- O
on O
therapy O
to O
reduce O
symptoms O
in O
patients O
with O
chronic O
stable O
angina O
. O

Recognition O
of O
viral O
RNA O
stem O
- O
loops O
by O
the O
tandem O
double O
- O
stranded O
RNA O
binding O
domains O
of O
PKR O
. O

In O
humans O
, O
the O
double O
- O
stranded O
RNA O
( O
dsRNA O
) O
- O
activated O
protein O
kinase O
( O
PKR O
) O
is O
expressed O
in O
late O
stages O
of O
the O
innate O
immune O
response O
to O
viral O
infection O
by O
the O
interferon O
pathway O
. O

PKR O
consists O
of O
tandem O
dsRNA O
binding O
motifs O
( O
dsRBMs O
) O
connected O
via O
a O
flexible O
linker O
to O
a O
Ser B
/ O
Thr B
kinase O
domain O
. O

Upon O
interaction O
with O
viral O
dsRNA O
, O
PKR O
is O
converted O
into O
a O
catalytically O
active O
enzyme O
capable O
of O
phosphorylating O
a O
number O
of O
target O
proteins O
that O
often O
results O
in O
host O
cell O
translational O
repression O
. O

A O
number O
of O
high O
- O
resolution O
structural O
studies O
involving O
individual O
dsRBMs O
from O
proteins O
other O
than O
PKR O
have O
highlighted O
the O
key O
features O
required O
for O
interaction O
with O
perfectly O
duplexed O
RNA O
substrates O
. O

However O
, O
viral O
dsRNA O
molecules O
are O
highly O
structured O
and O
often O
contain O
deviations O
from O
perfect O
A O
- O
form O
RNA O
helices O
. O

By O
use O
of O
small O
- O
angle O
X O
- O
ray O
scattering O
( O
SAXS O
) O
, O
we O
present O
solution O
conformations O
of O
the O
tandem O
dsRBMs O
of O
PKR O
in O
complex O
with O
two O
imperfectly O
base O
- O
paired O
viral O
dsRNA O
stem O
- O
loops O
; O
HIV O
- O
1 O
TAR O
and O
adenovirus O
VA O
( O
I O
) O
- O
AS O
. O

Both O
individual O
components O
and O
complexes O
were O
purified O
by O
size O
exclusion O
chromatography O
and O
characterized O
by O
dynamic O
light O
scattering O
at O
multiple O
concentrations O
to O
ensure O
monodispersity O
. O

SAXS O
ab O
initio O
solution O
conformations O
of O
the O
individual O
components O
and O
RNA O
- O
protein O
complexes O
were O
determined O
and O
highlight O
the O
potential O
of O
PKR O
to O
interact O
with O
both O
stem O
and O
loop O
regions O
of O
the O
RNA O
. O

Excellent O
agreement O
between O
experimental O
and O
model O
- O
based O
hydrodynamic O
parameter O
determination O
heightens O
our O
confidence O
in O
the O
obtained O
models O
. O

Taken O
together O
, O
these O
data O
support O
and O
provide O
a O
framework O
for O
the O
existing O
biochemical O
data O
regarding O
the O
tolerance O
of O
imperfectly O
base O
- O
paired O
viral O
dsRNA O
by O
PKR O
. O

Nuclear O
receptors O
in O
bile B
acid I
metabolism O
. O

Bile B
acids I
are O
signaling O
molecules O
that O
activate O
nuclear O
receptors O
, O
such O
as O
farnesoid O
X O
receptor O
, O
pregnane B
X O
receptor O
, O
constitutive O
androstane B
receptor O
, O
and O
vitamin B
D I
receptor O
, O
and O
play O
a O
critical O
role O
in O
the O
regulation O
of O
lipid O
, O
glucose B
, O
energy O
, O
and O
drug O
metabolism O
. O

These O
xenobiotic O
/ O
endobiotic O
- O
sensing O
nuclear O
receptors O
regulate O
phase O
I O
oxidation O
, O
phase O
II O
conjugation O
, O
and O
phase O
III O
transport O
in O
bile B
acid I
and O
drug O
metabolism O
in O
the O
digestive O
system O
. O

Integration O
of O
bile B
acid I
metabolism O
with O
drug O
metabolism O
controls O
absorption O
, O
transport O
, O
and O
metabolism O
of O
nutrients O
and O
drugs O
to O
maintain O
metabolic O
homeostasis O
and O
also O
protects O
against O
liver O
injury O
, O
inflammation O
, O
and O
related O
metabolic O
diseases O
, O
such O
as O
nonalcoholic O
fatty O
liver O
disease O
, O
diabetes O
, O
and O
obesity O
. O

Bile B
- I
acid I
- O
based O
drugs O
targeting O
nuclear O
receptors O
are O
in O
clinical O
trials O
for O
treating O
cholestatic O
liver O
diseases O
and O
fatty O
liver O
disease O
. O

Bioanalytical O
assay O
strategies O
for O
the O
development O
of O
antibody O
- O
drug O
conjugate O
biotherapeutics O
. O

Antibody O
- O
drug O
conjugates O
( O
ADCs O
) O
are O
monoclonal O
antibodies O
with O
covalently O
bound O
cytotoxic O
drugs O
. O

They O
are O
designed O
to O
target O
tumor O
antigens O
selectively O
and O
offer O
the O
hope O
of O
cancer O
treatment O
without O
the O
debilitating O
side O
- O
effects O
of O
conventional O
therapies O
. O

The O
concept O
of O
ADCs O
is O
not O
new O
; O
however O
, O
development O
of O
these O
therapeutics O
is O
challenging O
and O
only O
recently O
are O
promising O
clinical O
data O
emerging O
. O

These O
challenges O
include O
ADC O
bioanalysis O
, O
such O
as O
quantifying O
in O
serum O
/ O
plasma O
for O
PK O
studies O
and O
strategies O
for O
assessing O
immunogenicity O
. O

ADCs O
have O
complex O
molecular O
structures O
incorporating O
large O
- O
and O
small O
- O
molecule O
characteristics O
and O
require O
diverse O
analytical O
methods O
, O
including O
ligand O
- O
binding O
assays O
and O
MS O
- O
based O
methods O
. O

ADCs O
are O
typically O
mixtures O
with O
a O
range O
of O
drug O
- O
to O
- O
antibody O
ratios O
. O

Biotransformations O
in O
vivo O
can O
lead O
to O
additional O
changes O
in O
drug O
- O
to O
- O
antibody O
ratios O
resulting O
in O
dynamically O
changing O
mixtures O
. O

Thus O
, O
a O
standard O
calibration O
curve O
consisting O
of O
the O
reference O
standard O
may O
not O
be O
appropriate O
for O
quantification O
of O
analytes O
in O
vivo O
and O
represents O
a O
unique O
challenge O
. O

This O
paper O
will O
share O
our O
perspective O
on O
why O
ADC O
bioanalysis O
is O
so O
complex O
and O
describe O
the O
strategies O
and O
rationale O
that O
we O
have O
used O
for O
ADCs O
, O
with O
highlights O
of O
original O
data O
from O
a O
variety O
of O
nonclinical O
and O
clinical O
case O
studies O
. O

Our O
strategy O
has O
involved O
novel O
protein O
structural O
characterization O
tools O
to O
help O
understand O
ADC O
biotransformations O
in O
vivo O
and O
use O
of O
the O
analyte O
knowledge O
gained O
to O
guide O
the O
development O
of O
quantitative O
bioanalytical O
assays O
. O

Electrokinetic O
charging O
and O
evidence O
for O
charge O
evaporation O
in O
liquid O
microjets O
of O
aqueous O
salt O
solution O
. O

Electrokinetic O
charging O
of O
aqueous O
microjets O
was O
characterized O
by O
measuring O
streaming O
currents O
as O
a O
function O
of O
sodium B
iodide I
salt O
concentration O
. O

Measured O
streaming O
currents O
at O
high O
salt O
concentrations O
( O
up O
to O
0 O
. O
5 O
M O
) O
varied O
nonmonotonically O
with O
the O
jet O
velocity O
and O
can O
be O
explained O
by O
a O
multipolar O
charge O
distribution O
at O
the O
nozzle O
- O
water O
interface O
. O

In O
the O
case O
of O
potassium B
fluoride I
no O
multipolar O
charge O
distribution O
is O
observed O
. O

Electrokinetic O
potentials O
were O
estimated O
from O
the O
streaming O
currents O
, O
under O
the O
assumption O
that O
all O
excess O
charges O
are O
confined O
within O
the O
liquid O
jet O
. O

Measured O
photoelectron O
spectra O
indicate O
much O
smaller O
streaming O
potentials O
. O

To O
resolve O
the O
apparent O
discrepancy O
, O
we O
propose O
that O
a O
significant O
fraction O
of O
excess O
charges O
evaporates O
in O
the O
form O
of O
ion O
- O
water O
clusters O
. O

Multilayered O
hierarchical O
capsules O
providing O
cell O
adhesion O
sites O
. O

Liquified O
capsules O
featuring O
( O
i O
) O
an O
external O
shell O
by O
layer O
- O
by O
- O
layer O
assembly O
of O
poly B
( I
l I
- I
lysine I
) I
, O
alginate O
, O
and O
chitosan O
, O
and O
encapsulating O
( O
ii O
) O
surface O
functionalized O
poly B
( I
l I
- I
lactic I
acid I
) I
( O
PLLA B
) O
microparticles O
were O
developed O
. O

We O
hypothesize O
that O
, O
while O
the O
liquified O
environment O
enhances O
the O
diffusion O
of O
essential O
molecules O
for O
cell O
survival O
, O
microparticles O
dispersed O
in O
the O
liquified O
core O
of O
capsules O
provide O
the O
physical O
support O
required O
for O
cellular O
functions O
of O
anchorage O
- O
dependent O
cells O
. O

The O
influence O
of O
the O
incorporation O
of O
PLL B
on O
the O
regime O
growth O
, O
thickness O
, O
and O
stability O
was O
analyzed O
. O

Results O
show O
a O
more O
resistant O
and O
thicker O
film O
with O
an O
exponential O
build O
- O
up O
growth O
regime O
. O

Moreover O
, O
capsules O
ability O
to O
support O
cell O
survival O
was O
assessed O
. O

Capsules O
containing O
microparticles O
revealed O
an O
enhanced O
biological O
outcome O
in O
cell O
metabolic O
activity O
and O
proliferation O
, O
suggesting O
their O
potential O
to O
boost O
the O
development O
of O
innovative O
biomaterial O
designs O
for O
bioencapsulation O
systems O
and O
tissue O
engineering O
products O
. O

Interaction O
between O
group O
IIb O
divalent O
transition B
- I
metal I
cations O
and O
3 B
- I
mercaptopropionic I
acid I
: O
a O
computational O
and O
topological O
perspective O
. O

Density O
functional O
theory O
was O
applied O
to O
study O
the O
interaction O
of O
group O
IIb O
transition B
- I
metal I
cations O
( O
Zn B
( I
2 I
+ I
) I
, O
Cd B
( I
2 I
+ I
) I
, O
and O
Hg B
( I
2 I
+ I
) I
) O
with O
one O
and O
two O
fully O
or O
partially O
deprotonated O
3 B
- I
mercaptopropionic I
acid I
ligands O
. O

In O
this O
investigation O
, O
we O
determined O
the O
geometries O
of O
all O
possible O
complexes O
resulting O
from O
the O
coordination O
of O
the O
metal O
ions O
with O
the O
ligands O
at O
different O
binding O
sites O
selected O
on O
each O
ligand O
. O

The O
relative O
energies O
of O
the O
complexes O
, O
metal O
- O
ion O
affinities O
, O
free O
energies O
, O
and O
entropies O
were O
also O
determined O
. O

The O
natures O
of O
the O
bonds O
were O
critically O
analyzed O
by O
natural O
bond O
orbital O
( O
NBO O
) O
analysis O
and O
clarified O
further O
using O
the O
atoms O
- O
in O
- O
molecules O
( O
AIM O
) O
approach O
. O

The O
substantial O
influence O
of O
the O
solvent O
( O
water O
) O
polarization O
on O
the O
energetics O
, O
geometries O
, O
and O
bonding O
of O
the O
molecular O
complexes O
was O
also O
investigated O
by O
the O
conductor O
- O
like O
screening O
solvation O
model O
( O
COSMO O
) O
. O

In O
an O
attempt O
to O
simulate O
the O
complexes O
in O
an O
aqueous O
environment O
, O
water O
molecules O
were O
added O
explicitly O
to O
complete O
the O
coordination O
sphere O
of O
the O
metal O
cations O
, O
and O
the O
corresponding O
metal O
- O
ion O
affinities O
were O
calculated O
to O
study O
the O
effect O
of O
microhydration O
. O

Planar O
to O
3D O
transition O
in O
the O
B6H B
( I
y I
) I
anions O
. O

Potential O
energy O
surfaces O
of O
anionic O
B B
( I
6 I
) I
H I
( I
y I
) I
clusters O
were O
sampled O
using O
the O
coalescence O
kick O
method O
. O

We O
found O
that O
the O
planar O
to O
three O
- O
dimensional O
transition O
occurs O
in O
this O
system O
when O
y O
= O
4 O
. O

This O
is O
an O
important O
discovery O
because O
this O
transition O
suggests O
a O
major O
structural O
change O
as O
a O
function O
of O
dehydrogenation O
for O
the O
stoichiometric O
B B
( I
n I
) I
H I
( I
n I
) I
( I
- I
) I
polyhedral B
boranes I
. O

We O
also O
found O
that O
the O
B B
( I
6 I
) I
H I
( I
3 I
) I
( I
- I
) I
global O
minimum O
structure O
has O
an O
optical O
isomer O
. O

The O
chemical O
bonding O
patterns O
revealed O
by O
the O
adaptive O
natural O
density O
partitioning O
( O
AdNDP O
) O
analysis O
explain O
the O
geometric O
structure O
of O
all O
clusters O
presented O
here O
. O

From O
our O
chemical O
bonding O
analysis O
, O
we O
concluded O
that O
the O
2D O
- O
3D O
transition O
occurs O
at O
B B
( I
6 I
) I
H I
( I
4 I
) I
( I
- I
) I
because O
the O
addition O
of O
one O
extra O
hydrogen B
atom O
further O
destroys O
the O
network O
of O
the O
peripheral O
2c O
- O
2e O
B B
- I
B I
sigma O
- O
bonding O
, O
making O
planar O
structures O
less O
stable O
, O
and O
because O
the O
distorted O
octahedral O
structure O
provides O
some O
occupation O
of O
all O
s O
- O
and O
p O
- O
AOs O
of O
boron B
, O
avoiding O
the O
presence O
of O
any O
empty O
atomic O
orbitals O
. O

Theoretical O
vertical O
electron O
detachment O
energies O
( O
VDEs O
) O
were O
calculated O
for O
comparison O
with O
future O
experimental O
work O
. O

The O
transcription O
factor O
Pitx3 O
is O
expressed O
selectively O
in O
midbrain O
dopaminergic O
neurons O
susceptible O
to O
neurodegenerative O
stress O
. O

The O
homeodomain O
transcription O
factor O
Pitx3 O
is O
critical O
for O
the O
survival O
of O
midbrain O
dopaminergic O
( O
mDA O
) O
neurons O
. O

Pitx3 O
- O
deficient O
mice O
exhibit O
severe O
but O
selective O
developmental O
loss O
of O
mDA O
neurons O
, O
with O
accompanying O
locomotor O
deficits O
resembling O
those O
seen O
in O
Parkinson O
' O
s O
disease O
( O
PD O
) O
models O
. O

Here O
, O
we O
identify O
specific O
mDA O
cell O
subpopulations O
that O
are O
consistently O
spared O
in O
adult O
Pitx3 O
- O
hypomorphic O
( O
aphakia O
) O
mice O
, O
demonstrating O
that O
Pitx3 O
is O
not O
indiscriminately O
required O
by O
all O
mDA O
neurons O
for O
their O
survival O
. O

In O
aphakia O
mice O
, O
virtually O
all O
surviving O
mDA O
neurons O
in O
the O
substantia O
nigra O
( O
SN O
) O
and O
the O
majority O
of O
neurons O
in O
the O
adjacent O
ventral O
tegmental O
area O
( O
VTA O
) O
also O
express O
calbindin O
- O
D28k O
, O
a O
calcium B
- O
binding O
protein O
previously O
associated O
with O
resistance O
to O
injury O
in O
PD O
and O
in O
animal O
models O
. O

Cell O
- O
mapping O
studies O
in O
wild O
- O
type O
mice O
revealed O
that O
Pitx3 O
is O
primarily O
expressed O
in O
the O
ventral O
SN O
, O
a O
region O
particularly O
susceptible O
to O
MPTP B
and O
other O
dopaminergic O
neurotoxins O
. O

Furthermore O
, O
Pitx3 O
- O
expressing O
SN O
cells O
are O
preferentially O
lost O
following O
MPTP B
treatment O
. O

Finally O
, O
SN O
mDA O
neurons O
in O
Pitx3 O
hemizygous O
mice O
show O
increased O
sensitivity O
when O
exposed O
to O
MPTP B
. O

Thus O
, O
SN O
mDA O
neurons O
are O
represented O
by O
at O
least O
two O
distinct O
subpopulations O
including O
MPTP B
- O
resistant O
Pitx3 O
- O
autonomous O
, O
calbindin O
- O
positive O
neurons O
, O
and O
calbindin O
- O
negative O
Pitx O
- O
3 O
- O
dependent O
cells O
that O
display O
elevated O
vulnerability O
to O
toxic O
injury O
, O
and O
probably O
correspond O
to O
the O
subpopulation O
that O
degenerates O
in O
PD O
. O

Impairment O
of O
Pitx3 O
- O
dependent O
pathways O
therefore O
increases O
vulnerability O
of O
mDA O
neurons O
to O
toxic O
injury O
. O

Together O
, O
these O
data O
suggest O
a O
novel O
link O
between O
Pitx3 O
function O
and O
the O
selective O
pattern O
of O
mDA O
cell O
loss O
observed O
in O
PD O
. O

Fundamental O
studies O
of O
electrochemically O
controlled O
surface O
oxidation O
and O
hydrophobicity O
of O
natural O
enargite B
. O

The O
surface O
oxidation O
and O
hydrophobicity O
of O
natural O
enargite B
( O
Cu B
( I
3 I
) I
AsS I
( I
4 I
) I
) O
and O
the O
formation O
of O
oxidation O
species O
at O
the O
mineral O
surface O
have O
been O
examined O
by O
a O
novel O
experimental O
approach O
that O
combines O
electrochemical O
techniques O
and O
atomic O
force O
microscopy O
( O
AFM O
) O
. O

This O
approach O
allows O
for O
in O
- O
situ O
, O
synchronized O
electrochemical O
control O
and O
examination O
of O
the O
oxidative O
surface O
morphology O
of O
enargite B
. O

Combined O
with O
ex O
- O
situ O
cryo O
X O
- O
ray O
photoelectron O
spectroscopy O
surface O
analysis O
, O
the O
surface O
speciation O
of O
enargite B
surface O
oxidation O
has O
been O
obtained O
, O
comparing O
the O
newly O
fractured O
natural O
enargite B
surface O
with O
those O
that O
have O
been O
electrochemically O
oxidized O
at O
pHs O
4 O
and O
10 O
. O

At O
pH O
4 O
, O
surface O
layer O
formations O
consisting O
of O
metal O
- O
deficient O
sulfide B
and O
elemental O
sulfur B
were O
identified O
, O
associated O
with O
a O
limited O
increase O
in O
root O
- O
mean O
- O
square O
( O
rms O
) O
roughness O
( O
1 O
. O
228 O
to O
3 O
. O
143 O
nm O
) O
and O
apparent O
heterogeneous O
distribution O
of O
surface O
products O
as O
demonstrated O
by O
AFM O
imaging O
. O

A O
mechanism O
of O
initial O
rapid O
dissolution O
of O
Cu B
followed O
by O
diffusion O
- O
limited O
surface O
layer O
deposition O
was O
identified O
. O

At O
pH O
10 O
, O
a O
similar O
mechanism O
was O
identified O
although O
the O
differences O
between O
the O
initial O
and O
diffusion O
- O
limited O
phases O
were O
less O
definitive O
. O

Surface O
species O
were O
identified O
as O
copper B
sulfate I
and O
copper B
hydroxide I
. O

A O
significant O
increase O
in O
surface O
roughness O
was O
found O
as O
rms O
roughness O
increased O
from O
0 O
. O
795 O
to O
9 O
. O
723 O
nm O
. O

Dynamic O
( O
receding O
) O
contact O
angle O
measurements O
were O
obtained O
by O
a O
droplet O
evaporation O
method O
. O

No O
significant O
difference O
in O
the O
contact O
angle O
on O
a O
surface O
oxidized O
at O
pH O
10 O
and O
the O
freshly O
polished O
surface O
was O
found O
. O

A O
significant O
difference O
was O
found O
between O
the O
polished O
surface O
and O
that O
oxidized O
at O
pH O
4 O
, O
with O
an O
increase O
in O
contact O
angle O
of O
about O
13 O
degrees O
( O
46 O
degrees O
to O
59 O
degrees O
) O
after O
oxidation O
. O

Competing O
effects O
of O
hydrophilic O
( O
copper B
oxides I
and I
hydroxides I
) O
and O
hydrophobic O
( O
elemental O
sulfur I
) O
species O
on O
the O
mineral O
surface O
under O
oxidizing O
conditions O
at O
pH O
4 O
and O
the O
change O
in O
surface O
roughness O
at O
pH O
10 O
may O
contribute O
to O
the O
observed O
effects O
of O
electrochemically O
controlled O
oxidation O
on O
enargite B
hydrophobicity O
. O

Crystal O
and O
magnetic O
structures O
and O
physical O
properties O
of O
a O
new O
pyroxene B
NaMnGe2O6 B
synthesized O
under O
high O
pressure O
. O

A O
new O
pyroxene B
compound O
, O
NaMnGe B
( I
2 I
) I
O I
( I
6 I
) I
, O
has O
been O
synthesized O
at O
3 O
GPa O
and O
800 O
degrees O
C O
and O
fully O
characterized O
by O
X O
- O
ray O
single O
- O
crystal O
diffraction O
, O
neutron O
powder O
diffraction O
, O
and O
measurements O
of O
magnetization O
and O
specific O
heat O
. O

NaMnGe B
( I
2 I
) I
O I
( I
6 I
) I
crystallizes O
into O
a O
monoclinic O
C2 O
/ O
c O
structure O
with O
unit O
- O
cell O
parameters O
a O
= O
9 O
. O
859 O
( O
2 O
) O
A O
, O
b O
= O
8 O
. O
7507 O
( O
18 O
) O
A O
, O
c O
= O
5 O
. O
5724 O
( O
11 O
) O
A O
, O
and O
beta O
= O
105 O
. O
64 O
( O
3 O
) O
degrees O
at O
153 O
K O
. O

A O
cooperative O
Jahn O
- O
Teller O
distortion O
is O
formed O
by O
an O
ordering O
of O
the O
longest O
Mn B
- I
O I
bonds O
between O
two O
neighboring O
octahedra O
along O
the O
chain O
direction O
. O

This O
feature O
distinguishes O
NaMnGe B
( I
2 I
) I
O I
( I
6 I
) I
from O
other O
pyroxene B
compounds O
without O
Jahn O
- O
Teller O
active O
cations O
and O
suggests O
that O
the O
Jahn O
- O
Teller O
distortion O
competes O
with O
the O
intrinsic O
local O
distortion O
in O
the O
pyroxene B
structure O
. O

No O
orbital O
order O
- O
disorder O
transition O
has O
been O
found O
up O
to O
750 O
K O
. O

Like O
other O
alkali B
- I
metal I
pyroxenes I
with O
S O
> O
( O
1 O
) O
/ O
( O
2 O
) O
, O
NaMnGe B
( I
2 I
) I
O I
( I
6 I
) I
( O
S O
= O
2 O
) O
was O
found O
to O
undergo O
a O
long O
- O
range O
antiferromagnetic O
( O
AF O
) O
ordering O
at O
T O
( O
N O
) O
= O
7 O
K O
due O
to O
intrachain O
and O
interchain O
exchange O
interactions O
. O

Due O
to O
the O
peculiar O
structural O
features O
and O
the O
corresponding O
magnetic O
coupling O
, O
the O
weak O
AF O
spin O
ordering O
gives O
way O
to O
a O
ferromagnetic O
- O
like O
state O
at O
a O
sufficiently O
high O
magnetic O
field O
. O

Specific O
- O
heat O
measurements O
demonstrated O
that O
a O
large O
portion O
of O
the O
magnetic O
entropy O
, O
> O
60 O
% O
, O
has O
been O
removed O
above O
T O
( O
N O
) O
as O
a O
result O
of O
strong O
spin O
correlations O
within O
the O
quasi O
- O
one O
- O
dimensional O
Mn B
( I
3 I
+ I
) I
- O
spin O
chains O
. O

The O
Reitveld O
refinement O
of O
neutron O
powder O
diffraction O
data O
gives O
a O
commensurate O
magnetic O
structure O
defined O
by O
k O
= O
[ O
0 O
0 O
0 O
. O
5 O
] O
with O
Mn B
moments O
aligned O
mainly O
along O
the O
c O
- O
axis O
with O
a O
small O
component O
along O
both O
a O
- O
and O
b O
- O
axes O
. O

Sequence O
- O
specific O
transcription O
factor O
NF O
- O
Y O
displays O
histone O
- O
like O
DNA O
binding O
and O
H2B O
- O
like O
ubiquitination O
. O

The O
sequence O
- O
specific O
transcription O
factor O
NF O
- O
Y O
binds O
the O
CCAAT O
box O
, O
one O
of O
the O
sequence O
elements O
most O
frequently O
found O
in O
eukaryotic O
promoters O
. O

NF O
- O
Y O
is O
composed O
of O
the O
NF O
- O
YA O
and O
NF O
- O
YB O
/ O
NF O
- O
YC O
subunits O
, O
the O
latter O
two O
hosting O
histone O
- O
fold O
domains O
( O
HFDs O
) O
. O

The O
crystal O
structure O
of O
NF O
- O
Y O
bound O
to O
a O
25 O
bp O
CCAAT O
oligonucleotide O
shows O
that O
the O
HFD O
dimer O
binds O
to O
the O
DNA O
sugar B
- O
phosphate B
backbone O
, O
mimicking O
the O
nucleosome O
H2A O
/ O
H2B O
- O
DNA O
assembly O
. O

NF O
- O
YA O
both O
binds O
to O
NF O
- O
YB O
/ O
NF O
- O
YC O
and O
inserts O
an O
alpha O
helix O
deeply O
into O
the O
DNA O
minor O
groove O
, O
providing O
sequence O
- O
specific O
contacts O
to O
the O
CCAAT O
box O
. O

Structural O
considerations O
and O
mutational O
data O
indicate O
that O
NF O
- O
YB O
ubiquitination O
at O
Lys138 B
precedes O
and O
is O
equivalent O
to O
H2B O
Lys120 B
monoubiquitination O
, O
important O
in O
transcriptional O
activation O
. O

Thus O
, O
NF O
- O
Y O
is O
a O
sequence O
- O
specific O
transcription O
factor O
with O
nucleosome O
- O
like O
properties O
of O
nonspecific O
DNA O
binding O
and O
helps O
establish O
permissive O
chromatin O
modifications O
at O
CCAAT O
promoters O
. O

Our O
findings O
suggest O
that O
other O
HFD O
- O
containing O
proteins O
may O
function O
in O
similar O
ways O
. O

Physical O
exercise O
and O
its O
effects O
on O
coronary O
artery O
disease O
. O

The O
beneficial O
effects O
of O
physical O
exercise O
on O
stable O
coronary O
artery O
disease O
( O
CAD O
) O
have O
been O
shown O
by O
an O
increasing O
number O
of O
studies O
. O

Exercise O
training O
leads O
to O
an O
improved O
bioavailability O
of O
the O
endothelial O
nitric B
oxide I
and O
partially O
attenuates O
endothelial O
dysfunction O
. O

Further O
effects O
are O
an O
economization O
of O
ventricular O
function O
and O
a O
reduction O
of O
cardiovascular O
risk O
factors O
. O

In O
clinical O
studies O
exercise O
training O
was O
associated O
with O
a O
decreased O
total O
and O
cardiovascular O
mortality O
and O
a O
reduced O
angina O
pectoris O
threshold O
. O

Thus O
exercise O
training O
has O
developed O
to O
an O
evidence O
- O
based O
therapeutic O
option O
of O
stable O
CAD O
with O
a O
Class O
Ia O
recommendation O
in O
the O
guidelines O
. O

Composition O
and O
anti O
- O
oxidant O
, O
anti O
- O
cancer O
and O
anti O
- O
inflammatory O
activities O
of O
Artemisia O
herba O
- O
alba O
, O
Ruta O
chalpensis O
L O
. O
and O
Peganum O
harmala O
L O
. O

In O
this O
study O
, O
biological O
activities O
of O
methanolic O
extracts O
from O
Artemisia O
herba O
- O
alba O
, O
Ruta O
chalpensis O
L O
. O
and O
Peganum O
harmala O
L O
. O
plants O
, O
collected O
in O
Centre O
of O
Tunisia O
, O
were O
investigated O
. O

Results O
showed O
an O
important O
phenolic O
composition O
of O
Artemisia O
herba O
- O
alba O
( O
123 O
. O
95 O
+ O
/ O
- O
4 O
. O
3g O
GAE O
/ O
kg O
of O
dry O
mass O
) O
. O

The O
extract O
of O
this O
plant O
showed O
, O
using O
different O
antioxidant O
assays O
( O
DPPH B
, O
ABTS B
and O
AAPH B
/ O
linoleic B
acid I
methods O
) O
and O
an O
IFN O
- O
gamma O
/ O
LPS O
induced O
RAW O
264 O
. O
7 O
murine O
macrophages O
' O
assay O
, O
the O
highest O
antioxidant O
( O
IC50 O
( O
DPPH B
assay O
) O
20 O
. O
64 O
+ O
/ O
- O
0 O
. O
84mg O
/ O
L O
) O
and O
anti O
- O
inflammatory O
( O
72 O
% O
inhibition O
at O
150mg O
/ O
L O
) O
activities O
, O
respectively O
. O

Excepting O
Peganum O
harmala O
L O
. O
extract O
, O
the O
two O
other O
extracts O
showed O
a O
high O
anticancer O
activity O
against O
several O
cell O
lines O
( O
human O
bladder O
carcinoma O
RT112 O
, O
human O
laryngeal O
carcinoma O
Hep2 O
and O
human O
myelogenous O
leukemia O
K562 O
) O
, O
for O
A O
. O
herba O
- O
laba O
IC50 O
= O
81 O
. O
59 O
+ O
/ O
- O
4 O
. O
4 O
, O
59 O
. O
05 O
+ O
/ O
- O
3 O
. O
66 O
and O
90 O
. O
96mg O
/ O
L O
respectively O
, O
but O
not O
on O
normal O
peripheral O
blood O
mononuclear O
cells O
. O

All O
these O
biological O
activities O
are O
well O
correlated O
with O
the O
phenolic O
contents O
of O
these O
extracts O
. O

These O
findings O
demonstrate O
the O
remarkable O
potential O
of O
these O
plants O
as O
valuable O
source O
of O
antioxidants O
with O
exhibit O
original O
and O
interesting O
anti O
- O
inflammatory O
and O
anticancer O
capacities O
. O

Areca O
nut O
procyanidins B
ameliorate O
streptozocin B
- O
induced O
hyperglycemia O
by O
regulating O
gluconeogenesis O
. O

Hepatic O
gluconeogenesis O
is O
a O
major O
contributor O
to O
blood O
glucose B
in O
diabetes O
mellitus O
. O

Our O
previous O
study O
indicated O
that O
areca O
nut O
extract O
enriched O
with O
catechin B
- O
based O
procyanidins B
from O
oligomers O
to O
polymers O
gave O
rise O
to O
anti O
- O
inflammatory O
effects O
in O
vitro O
and O
in O
vivo O
. O

Here O
we O
have O
surveyed O
the O
molecular O
features O
of O
areca O
nut O
procyanidins B
( O
ANPs O
) O
using O
quadrupole O
time O
- O
of O
- O
flight O
liquid O
chromatography O
/ O
mass O
spectrometry O
( O
Q O
- O
TOF O
LC O
/ O
MS O
) O
and O
the O
resulting O
mass O
spectrum O
accurately O
described O
ANP O
from O
monomer O
to O
hexadecamer O
. O

Furthermore O
, O
the O
potential O
of O
ANP O
in O
terms O
of O
blood O
glucose B
homeostasis O
was O
explored O
using O
cyclic B
adenosine I
monophosphate I
( O
cAMP B
) O
/ O
dexamethasone B
stimulated O
primary O
mouse O
hepatocytes O
and O
multiple O
low O
dose O
streptozocin B
( O
MLD O
- O
STZ B
) O
treated O
mice O
. O

With O
the O
primary O
hepatocytes O
, O
ANP O
dose O
- O
dependently O
inhibited O
gluconeogenesis O
and O
reduced O
the O
mRNA O
expression O
of O
two O
gluconeogenic O
key O
enzymes O
, O
phosphoenol B
- I
pyruvate I
carboxykinase O
( O
PEPCK O
) O
and O
glucose B
- O
6 O
- O
phosphatase O
( O
G6Pase O
) O
. O

Intragastrically O
feeding O
of O
10mg O
/ O
kg O
ANP O
for O
4weeks O
reduced O
the O
levels O
of O
fasting O
blood O
glucose B
, O
PEPCK O
and O
G6Pase O
in O
MLD O
- O
STZ B
mice O
. O

In O
additional O
, O
the O
level O
of O
5 B
' I
- I
AMP I
- O
activated O
protein O
kinase O
( O
AMPK O
) O
expression O
showed O
a O
trend O
towards O
being O
restored O
in O
the O
ANP O
treated O
MLD O
- O
STZ B
- O
mice O
. O

This O
study O
indicated O
that O
ANP O
has O
the O
potential O
to O
improve O
hyperglycemia O
by O
regulating O
gluconeogenic O
related O
kinases O
in O
MLD O
- O
STZ B
- O
mice O
. O

Suppression O
of O
Src O
/ O
ERK O
and O
GSK O
- O
3 O
/ O
beta O
- O
catenin O
signaling O
by O
pinosylvin B
inhibits O
the O
growth O
of O
human O
colorectal O
cancer O
cells O
. O

Pinosylvin B
, O
a O
naturally O
occurring O
trans B
- I
stilbenoid I
mainly O
found O
in O
Pinus O
species O
, O
has O
exhibited O
a O
potential O
cancer O
chemopreventive O
activity O
. O

However O
, O
the O
growth O
inhibitory O
activity O
against O
cancer O
cells O
and O
the O
underlying O
molecular O
mechanisms O
remain O
to O
be O
elucidated O
. O

Therefore O
, O
the O
anti O
- O
proliferative O
activity O
of O
pinosylvin B
was O
investigated O
in O
human O
colorectal O
HCT O
116 O
cancer O
cells O
. O

Pinosylvin B
inhibited O
the O
proliferation O
of O
HCT O
116 O
cells O
by O
arresting O
transition O
of O
cell O
cycle O
from O
G1 O
to O
S O
phase O
along O
with O
the O
downregulation O
of O
cyclin O
D1 O
, O
cyclin O
E O
, O
cyclin O
A O
, O
cyclin O
dependent O
kinase O
2 O
( O
CDK2 O
) O
, O
CDK4 O
, O
c O
- O
Myc O
, O
and O
retinoblastoma O
protein O
( O
pRb O
) O
, O
and O
the O
upregulation O
of O
p21 O
( O
WAF1 O
/ O
CIP1 O
) O
and O
p53 O
. O

Pinosylvin B
was O
also O
found O
to O
attenuate O
the O
activation O
of O
proteins O
involved O
in O
focal O
adhesion O
kinase O
( O
FAK O
) O
/ O
c O
- O
Src O
/ O
extracellular O
signal O
- O
regulated O
kinase O
( O
ERK O
) O
signaling O
, O
and O
phosphoinositide O
3 O
- O
kinase O
( O
PI3K O
) O
/ O
Akt O
/ O
glycogen O
synthase O
kinase O
3 O
beta O
( O
GSK O
- O
3 O
beta O
) O
signaling O
pathway O
. O

Subsequently O
, O
pinosylvin B
suppressed O
the O
nuclear O
translocation O
of O
beta O
- O
catenin O
, O
one O
of O
downstream O
molecules O
of O
PI3K O
/ O
Akt O
/ O
GSK O
- O
3 O
beta O
signaling O
, O
and O
these O
events O
led O
to O
the O
sequential O
downregulation O
of O
beta O
- O
catenin O
- O
mediated O
transcription O
of O
target O
genes O
including O
BMP4 O
, O
ID2 O
, O
survivin O
, O
cyclin O
D1 O
, O
MMP7 O
, O
and O
c O
- O
Myc O
. O

These O
findings O
demonstrate O
that O
the O
anti O
- O
proliferative O
activity O
of O
pinosylvin B
might O
be O
associated O
with O
the O
cell O
cycle O
arrest O
and O
downregulation O
of O
cell O
proliferation O
regulating O
signaling O
pathways O
in O
human O
colorectal O
cancer O
cells O
. O

Comparative O
pharmacokinetic O
profiles O
of O
picrosides B
I I
and I
II I
from O
kutkin O
, O
Picrorhiza O
kurroa O
extract O
and O
its O
formulation O
in O
rats O
. O

Picrosides B
I I
and I
II I
are O
the O
active O
chemical O
constituents O
, O
present O
in O
the O
roots O
and O
rhizomes O
of O
Picrorhiza O
kurroa O
Royle O
( O
family O
: O
Scrophulariaceae O
) O
. O

The O
plant O
is O
ethnomedically O
claimed O
for O
the O
treatment O
of O
liver O
and O
upper O
respiratory O
tract O
infection O
, O
fever O
, O
dyspepsia O
and O
scorpion O
sting O
. O

This O
study O
attempts O
to O
determine O
the O
in O
vivo O
pharmacokinetic O
profile O
of O
picrosides B
I I
and I
II I
in O
rats O
after O
oral O
administration O
of O
three O
different O
preparations O
namely O
, O
kutkin O
( O
a O
mixture O
of O
picrosides B
I I
and I
II I
) O
, O
P O
. O
kurroa O
extract O
and O
Picrolax O
( O
R O
) O
capsule O
( O
marketed O
formulation O
) O
. O

A O
simple O
, O
precise O
, O
specific O
and O
sensitive O
method O
was O
developed O
for O
simultaneous O
quantification O
of O
picrosides B
I I
and I
II I
in O
rat O
plasma O
and O
was O
applied O
for O
the O
pharmacokinetic O
study O
. O

Pharmacokinetic O
parameters O
were O
calculated O
from O
the O
observed O
plasma O
concentration O
of O
picrosides B
I I
and I
II I
. O

The O
results O
showed O
a O
significant O
difference O
( O
p O
< O
= O
0 O
. O
05 O
) O
in O
oral O
bioavailability O
of O
picrosides B
I I
and I
II I
from O
different O
preparations O
. O

Both O
the O
compounds O
were O
found O
to O
be O
more O
bioavailable O
from O
P O
. O
kurroa O
extract O
followed O
by O
Picrolax B
( O
R O
) O
capsule O
and O
kutkin O
. O

Moreover O
, O
we O
also O
developed O
a O
novel O
method O
for O
isolation O
of O
kutkin O
from O
roots O
of O
P O
. O
kurroa O
with O
a O
high O
yield O
of O
2 O
. O
4 O
% O
w O
/ O
w O
. O

The O
information O
gained O
from O
this O
study O
provides O
a O
meaningful O
basis O
for O
clinical O
application O
and O
mechanistic O
study O
of O
such O
phytochemicals O
. O

Correlation O
between O
the O
antibacterial O
activity O
and O
the O
composition O
of O
extracts O
derived O
from O
various O
Spanish O
Cistus O
species O
. O

Cistaceae O
is O
a O
large O
family O
of O
shrubs O
commonly O
distributed O
in O
the O
Mediterranean O
ecosystem O
. O

The O
aim O
of O
this O
study O
was O
to O
explore O
the O
potential O
antimicrobial O
properties O
against O
Escherichia O
coli O
and O
/ O
or O
Staphylococcus O
aureus O
of O
different O
extracts O
obtained O
from O
four O
Cistaceae O
species O
that O
are O
especially O
abundant O
in O
Spanish O
semi O
- O
arid O
regions O
. O

MIC50 O
values O
of O
the O
extracts O
of O
C O
. O
salviifolius O
exhibited O
potent O
bacteriostatic O
effects O
against O
S O
. O
aureus O
compared O
with O
the O
other O
Cistus O
species O
tested O
. O

Spray O
- O
drying O
had O
less O
impact O
on O
the O
antimicrobial O
activities O
and O
polyphenolic B
contents O
than O
did O
evaporation O
followed O
by O
freeze O
- O
drying O
. O

When O
C O
. O
salviifolius O
extract O
was O
concentrated O
and O
the O
polar O
fraction O
was O
removed O
, O
its O
bacteriostatic O
and O
bactericidal O
activities O
against O
both O
strains O
were O
significantly O
enhanced O
. O

Seasonal O
influences O
on O
the O
composition O
have O
also O
been O
found O
. O

Up O
to O
48 O
compounds O
were O
found O
in O
the O
aqueous O
extract O
of O
C O
. O
salviifolius O
using O
RRLC O
- O
ESI O
- O
TOF O
- O
MS O
. O

The O
analysis O
of O
the O
composition O
of O
the O
extracts O
revealed O
that O
the O
inhibitory O
activity O
against O
E O
. O
coli O
may O
be O
related O
to O
the O
presence O
of O
galloylated B
flavanols I
and O
specific O
flavonols B
, O
whereas O
the O
inhibitory O
capacity O
against O
S O
. O
aureus O
may O
be O
related O
primarily O
to O
polar O
compounds O
and O
to O
other O
flavonols B
. O

Potential O
synergistic O
effects O
among O
polyphenols B
may O
deserve O
further O
studies O
. O

These O
extracts O
may O
serve O
as O
an O
alternative O
source O
of O
antimicrobial O
ingredients O
focused O
on O
medical O
devices O
or O
cosmetics O
. O

I O
kappa O
B O
kinase O
epsilon O
( O
IKK O
epsilon O
) O
: O
a O
therapeutic O
target O
in O
inflammation O
and O
cancer O
. O

The O
innate O
immune O
system O
forms O
our O
first O
line O
of O
defense O
against O
invading O
pathogens O
and O
relies O
for O
a O
major O
part O
on O
the O
activation O
of O
two O
transcription O
factors O
, O
NF O
- O
kappa O
B O
and O
IRF3 O
. O

Signaling O
pathways O
that O
activate O
these O
transcription O
factors O
are O
intertwined O
at O
the O
level O
of O
the O
canonical O
I O
kappa O
B O
kinases O
( O
IKK O
alpha O
, O
IKK O
beta O
) O
and O
non O
- O
canonical O
IKK O
- O
related O
kinases O
( O
IKK O
epsilon O
, O
TBK1 O
) O
. O

Recently O
, O
significant O
progress O
has O
been O
made O
in O
understanding O
the O
function O
and O
mechanism O
of O
action O
of O
IKK O
epsilon O
in O
immune O
signaling O
. O

In O
addition O
, O
IKK O
epsilon O
impacts O
on O
cell O
proliferation O
and O
transformation O
, O
and O
is O
thereby O
also O
classified O
as O
an O
oncogene O
. O

Studies O
with O
IKK O
epsilon O
knockout O
mice O
have O
illustrated O
a O
key O
role O
for O
IKK O
epsilon O
in O
inflammatory O
and O
metabolic O
diseases O
. O

In O
this O
review O
we O
will O
highlight O
the O
mechanisms O
by O
which O
IKK O
epsilon O
impacts O
on O
signaling O
pathways O
involved O
in O
disease O
development O
and O
discuss O
its O
potential O
as O
a O
novel O
therapeutic O
target O
. O

Genotoxic O
and O
inflammatory O
effects O
of O
organic O
extracts O
from O
traffic O
- O
related O
particulate O
matter O
in O
human O
lung O
epithelial O
A549 O
cells O
: O
the O
role O
of O
quinones B
. O

Traffic O
- O
related O
particulate O
matter O
( O
PM O
) O
is O
associated O
with O
adverse O
health O
effects O
. O

Quinones B
present O
in O
the O
traffic O
- O
related O
PM O
are O
hypothesized O
to O
contribute O
to O
these O
harmful O
effects O
through O
reactive O
oxygen B
species O
( O
ROS O
) O
generation O
. O

However O
, O
the O
impacts O
of O
the O
traffic O
- O
related O
PM O
and O
quinones B
on O
inflammatory O
processes O
and O
genotoxic O
damages O
are O
less O
well O
known O
. O

In O
present O
study O
we O
aimed O
to O
examine O
the O
genotoxic O
and O
inflammatory O
impacts O
of O
organic O
extracts O
from O
traffic O
- O
related O
PM O
( O
oTRP O
) O
in O
human O
lung O
epithelial O
A549 O
cells O
, O
and O
reveal O
the O
contributions O
from O
quinones B
. O

Significant O
cytotoxicity O
and O
DNA O
damage O
were O
caused O
by O
oTRP B
. O

The O
pro O
- O
inflammatory O
genes O
, O
interleukin O
- O
6 O
( O
Il O
- O
6 O
) O
, O
interleukin O
- O
8 O
( O
Il O
- O
8 O
) O
and O
tumor O
necrosis O
factor O
( O
Tnf O
) O
, O
and O
two O
aromatic B
hydrocarbon I
receptor O
- O
regulated O
genes O
, O
Cyp1a1 O
and O
1b1 O
, O
were O
significantly O
up O
- O
regulated O
by O
oTRP B
. O

A O
concomitant O
increase O
in O
ROS O
was O
observed O
, O
suggesting O
that O
oTRP B
may O
mediate O
genotoxic O
and O
inflammatory O
effects O
through O
oxidative O
stress O
pathway O
. O

Second O
, O
the O
effects O
from O
two O
typical O
airborne O
quinones B
, O
9 B
, I
10 I
- I
anthraquinone I
( O
AQ O
) O
and O
1 B
, I
4 I
- I
naphthroquinone I
( O
NQ O
) O
were O
compared O
. O

NQ O
, O
but O
not O
AQ O
, O
induced O
significant O
DNA O
damage O
in O
A549 O
cells O
. O

NQ O
up O
- O
regulated O
Il O
- O
8 O
, O
Tnf O
, O
and O
Mcp O
- O
1 O
genes O
, O
while O
AQ O
induced O
the O
expression O
of O
Rantes O
gene O
. O

These O
results O
suggest O
that O
the O
NQ O
and O
AQ O
may O
participate O
in O
the O
pro O
- O
inflammatory O
responses O
through O
releasing O
different O
types O
of O
cytokines O
/ O
chemokines O
. O

Activation O
of O
Rac1 O
GTPase O
by O
nanoparticulate O
structures O
in O
human O
macrophages O
. O

Inflammatory O
activation O
of O
alveolar O
macrophages O
by O
ambient O
particles O
can O
be O
facilitated O
via O
Toll O
- O
like O
receptors O
( O
TLR O
) O
. O

The O
action O
of O
TLR O
agonists O
and O
antagonists O
has O
been O
reported O
to O
depend O
on O
the O
formation O
of O
nanoparticulate O
structures O
. O

Aim O
of O
the O
present O
study O
was O
to O
identify O
the O
signaling O
pathways O
induced O
by O
nanoparticulate O
structures O
in O
human O
macrophages O
, O
which O
might O
be O
critical O
for O
inflammatory O
cell O
activation O
. O

METHODS O
: O
Studies O
were O
performed O
in O
primary O
human O
alveolar O
macrophages O
or O
in O
differentiated O
THP O
- O
1 O
macrophages O
. O

Silica B
nanoparticles O
were O
prepared O
by O
St O
o O
ber O
synthesis O
and O
characterized O
by O
dynamic O
light O
scattering O
and O
scanning O
electron O
microscopy O
. O

Mycobacterial O
DNA O
was O
isolated O
from O
Mycobacterium O
bovis O
BCG O
, O
and O
nanoparticle O
formation O
was O
assessed O
by O
atomic O
force O
microscopy O
and O
dynamic O
light O
scattering O
. O

Actin O
polymerization O
was O
measured O
by O
phalloidin B
- O
TRITC O
staining O
, O
and O
cell O
activation O
was O
determined O
by O
reverse O
transcription O
quantitative O
PCR O
analysis O
, O
L929 O
cytotoxicity O
assay O
( O
cytokine O
induction O
) O
, O
and O
pull O
- O
down O
assays O
( O
Rho O
GTPases O
) O
. O

RESULTS O
: O
In O
contrast O
to O
immune O
stimulatory O
sequence O
ISS O
1018 O
, O
BCG O
DNA O
spontaneously O
formed O
nanoparticulate O
structures O
and O
induced O
actin O
polymerization O
as O
did O
synthetic O
silica B
nanoparticles O
. O

Co O
- O
incubation O
with O
silica B
nanoparticles O
amplified O
the O
responsiveness O
of O
macrophages O
toward O
the O
TLR9 O
ligand O
ISS O
1018 O
. O

The O
activation O
of O
Rac1 O
was O
induced O
by O
silica B
nanoparticles O
as O
well O
as O
BCG O
DNA O
and O
is O
suggested O
as O
the O
critical O
signaling O
event O
inducing O
both O
cytoskeleton O
changes O
as O
well O
as O
inflammatory O
cell O
activation O
. O

CONCLUSION O
: O
Nanoparticles O
can O
induce O
signaling O
pathways O
, O
which O
amplify O
an O
inflammatory O
response O
in O
macrophages O
. O

Administration O
of O
the O
optimized O
beta B
- I
Lapachone I
- O
poloxamer B
- I
cyclodextrin I
ternary O
system O
induces O
apoptosis O
, O
DNA O
damage O
and O
reduces O
tumor O
growth O
in O
a O
human O
breast O
adenocarcinoma O
xenograft O
mouse O
model O
. O

beta B
- I
Lapachone I
( O
beta B
- I
Lap I
) O
is O
a O
1 B
, I
2 I
- I
orthonaphthoquinone I
that O
selectively O
induces O
cell O
death O
in O
human O
cancer O
cells O
through O
NAD B
( I
P I
) I
H I
: O
quinone B
oxidoreductase O
- O
1 O
( O
NQO1 O
) O
. O

NQO1 O
is O
overexpressed O
in O
a O
variety O
of O
tumors O
, O
as O
compared O
to O
normal O
adjacent O
tissue O
. O

However O
, O
the O
low O
solubility O
and O
non O
- O
specific O
distribution O
of O
beta O
- O
Lap O
limit O
its O
suitability O
for O
clinical O
assays O
. O

We O
formulated O
beta B
- I
Lap I
in O
an O
optimal O
random O
methylated B
- I
beta I
- I
cyclodextrin I
/ O
poloxamer B
407 I
mixture O
( O
i O
. O
e O
. O
, O
beta B
- I
Lap I
ternary O
system O
) O
and O
, O
using O
human O
breast O
adenocarcinoma O
MCF O
- O
7 O
cells O
and O
immunodeficient O
mice O
, O
performed O
in O
vitro O
and O
in O
vivo O
evaluation O
of O
its O
anti O
- O
tumor O
effects O
on O
proliferation O
, O
cell O
cycle O
, O
apoptosis O
, O
DNA O
damage O
, O
and O
tumor O
growth O
. O

This O
ternary O
system O
is O
fluid O
at O
room O
temperature O
, O
gels O
over O
29 O
degrees O
C O
, O
and O
provides O
a O
significant O
amount O
of O
drug O
, O
thus O
facilitating O
intratumoral O
delivery O
, O
in O
situ O
gelation O
, O
and O
the O
formation O
of O
a O
depot O
for O
time O
- O
release O
. O

Administration O
of O
beta O
- O
Lap O
ternary O
system O
to O
MCF O
- O
7 O
cells O
induces O
an O
increase O
in O
apoptosis O
and O
DNA O
damage O
, O
while O
producing O
no O
changes O
in O
cell O
cycle O
. O

Moreover O
, O
in O
a O
mouse O
xenograft O
tumor O
model O
, O
intratumoral O
injection O
of O
the O
system O
significantly O
reduces O
tumor O
volume O
, O
while O
increasing O
apoptosis O
and O
DNA O
damage O
without O
visible O
toxicity O
to O
liver O
or O
kidney O
. O

These O
anti O
- O
tumoral O
effects O
and O
lack O
of O
visible O
toxicity O
make O
this O
system O
a O
promising O
new O
therapeutic O
agent O
for O
breast O
cancer O
treatment O
. O

Hydrophobicity O
of O
rare B
- I
earth I
oxide I
ceramics O
. O

Hydrophobic O
materials O
that O
are O
robust O
to O
harsh O
environments O
are O
needed O
in O
a O
broad O
range O
of O
applications O
. O

Although O
durable O
materials O
such O
as O
metals O
and O
ceramics O
, O
which O
are O
generally O
hydrophilic O
, O
can O
be O
rendered O
hydrophobic O
by O
polymeric O
modifiers O
, O
these O
deteriorate O
in O
harsh O
environments O
. O

Here O
we O
show O
that O
a O
class O
of O
ceramics O
comprising O
the O
entire O
lanthanide B
oxide I
series O
, O
ranging O
from O
ceria B
to O
lutecia B
, O
is O
intrinsically O
hydrophobic O
. O

We O
attribute O
their O
hydrophobicity O
to O
their O
unique O
electronic O
structure O
, O
which O
inhibits O
hydrogen B
bonding O
with O
interfacial O
water O
molecules O
. O

We O
also O
show O
with O
surface O
- O
energy O
measurements O
that O
polar O
interactions O
are O
minimized O
at O
these O
surfaces O
and O
with O
Fourier O
transform O
infrared O
/ O
grazing O
- O
angle O
attenuated O
total O
reflection O
that O
interfacial O
water O
molecules O
are O
oriented O
in O
the O
hydrophobic O
hydration O
structure O
. O

Moreover O
, O
we O
demonstrate O
that O
these O
ceramic O
materials O
promote O
dropwise O
condensation O
, O
repel O
impinging O
water O
droplets O
, O
and O
sustain O
hydrophobicity O
even O
after O
exposure O
to O
harsh O
environments O
. O

Rare B
- I
earth I
oxide I
ceramics O
should O
find O
widespread O
applicability O
as O
robust O
hydrophobic O
surfaces O
. O

Microcalcifications O
in O
breast O
cancer O
: O
Lessons O
from O
physiological O
mineralization O
. O

Mammographic O
mammary O
microcalcifications O
are O
routinely O
used O
for O
the O
early O
detection O
of O
breast O
cancer O
, O
however O
the O
mechanisms O
by O
which O
they O
form O
remain O
unclear O
. O

Two O
species O
of O
mammary O
microcalcifications O
have O
been O
identified O
; O
calcium B
oxalate I
and O
hydroxyapatite B
. O

Calcium B
oxalate I
is O
mostly O
associated O
with O
benign O
lesions O
of O
the O
breast O
, O
whereas O
hydroxyapatite B
is O
associated O
with O
both O
benign O
and O
malignant O
tumors O
. O

The O
way O
in O
which O
hydroxyapatite B
forms O
within O
mammary O
tissue O
remains O
largely O
unexplored O
, O
however O
lessons O
can O
be O
learned O
from O
the O
process O
of O
physiological O
mineralization O
. O

Normal O
physiological O
mineralization O
by O
osteoblasts O
results O
in O
hydroxyapatite B
deposition O
in O
bone O
. O

This O
review O
brings O
together O
existing O
knowledge O
from O
the O
field O
of O
physiological O
mineralization O
and O
juxtaposes O
it O
with O
our O
current O
understanding O
of O
the O
genesis O
of O
mammary O
microcalcifications O
. O

As O
an O
increasing O
number O
of O
breast O
cancers O
are O
being O
detected O
in O
their O
non O
- O
palpable O
stage O
through O
mammographic O
microcalcifications O
, O
it O
is O
important O
that O
future O
studies O
investigate O
the O
underlying O
mechanisms O
of O
their O
formation O
in O
order O
to O
fully O
understand O
the O
significance O
of O
this O
unique O
early O
marker O
of O
breast O
cancer O
. O

Self O
- O
assembly O
of O
double O
helical O
nanostructures O
inside O
carbon B
nanotubes O
. O

We O
use O
molecular O
dynamics O
( O
MD O
) O
simulations O
to O
show O
that O
a O
DNA O
- O
like O
double O
helix O
of O
two O
poly B
( I
acetylene I
) I
( O
PA O
) O
chains O
can O
form O
inside O
single O
- O
walled O
carbon B
nanotubes O
( O
SWNTs O
) O
. O

The O
computational O
results O
indicate O
that O
SWNTs O
can O
activate O
and O
guide O
the O
self O
- O
assembly O
of O
polymer O
chains O
, O
allowing O
them O
to O
adopt O
a O
helical O
configuration O
in O
a O
SWNT O
through O
the O
combined O
action O
of O
the O
van O
der O
Waals O
potential O
well O
and O
the O
pi O
- O
pi O
stacking O
interaction O
between O
the O
polymer O
and O
the O
inner O
surface O
of O
SWNTs O
. O

Meanwhile O
both O
the O
SWNT O
size O
and O
polymer O
chain O
stiffness O
determine O
the O
outcome O
of O
the O
nanostructure O
. O

Furthermore O
, O
we O
also O
found O
that O
water O
clusters O
encourage O
the O
self O
- O
assembly O
of O
PA O
helical O
structures O
in O
the O
tube O
. O

This O
molecular O
model O
may O
lead O
to O
a O
better O
understanding O
of O
the O
formation O
of O
a O
double O
helix O
biological O
molecule O
inside O
SWNTs O
. O

Alternatively O
, O
it O
could O
form O
the O
basis O
of O
a O
novel O
nanoscale O
material O
by O
utilizing O
the O
' O
empty O
' O
spaces O
of O
SWNTs O
. O

Human O
skin O
neural O
crest O
progenitor O
cells O
are O
susceptible O
to O
BRAF O
( O
V600E O
) O
- O
induced O
transformation O
. O

Adult O
stem O
cells O
are O
multipotent O
and O
persist O
in O
small O
numbers O
in O
adult O
tissues O
throughout O
the O
lifespan O
of O
an O
organism O
. O

Unlike O
differentiated O
cells O
, O
adult O
stem O
cells O
are O
intrinsically O
resistant O
to O
senescence O
. O

It O
is O
unclear O
how O
adult O
stem O
cells O
in O
solid O
organs O
respond O
to O
oncogenic O
stimulation O
and O
whether O
these O
cells O
have O
a O
role O
in O
tumor O
initiation O
. O

We O
report O
here O
that O
expression O
of O
BRAF O
( O
V600E O
) O
in O
human O
neural O
crest O
progenitor O
cells O
( O
hNCPCs O
) O
did O
not O
induce O
growth O
arrest O
as O
seen O
in O
human O
melanocytes O
, O
but O
instead O
, O
increased O
their O
cell O
proliferation O
capacity O
. O

These O
cells O
( O
hNCPCs O
( O
V600E O
) O
) O
acquired O
anchorage O
- O
independent O
growth O
ability O
and O
were O
weakly O
tumorigenic O
in O
vivo O
. O

Unlike O
in O
human O
melanocytes O
, O
BRAF O
( O
V600E O
) O
expression O
in O
hNCPCs O
did O
not O
induce O
p16 O
( O
INK4a O
) O
expression O
. O

BRAF O
( O
V600E O
) O
induced O
elevated O
expression O
of O
CDK2 O
, O
CDK4 O
, O
MITF O
and O
EST1 O
/ O
2 O
protein O
in O
hNCPCs O
, O
and O
also O
induced O
melanocytic O
differentiation O
of O
these O
cells O
. O

Furthermore O
, O
overexpression O
of O
MITF O
in O
hNCPCs O
( O
V600E O
) O
dramatically O
increased O
their O
tumorigenicity O
and O
resulted O
in O
fully O
transformed O
tumor O
cells O
. O

These O
findings O
indicate O
that O
hNCPCs O
are O
susceptible O
to O
BRAF O
( O
V600E O
) O
- O
induced O
transformation O
, O
and O
MITF B
potentiates O
the O
oncogenic O
effect O
of O
BRAF O
( O
V600E O
) O
in O
these O
progenitor O
cells O
. O

These O
results O
suggest O
that O
the O
hNCPCs O
are O
potential O
targets O
for O
BRAF O
( O
V600E O
) O
- O
induced O
melanocytic O
tumor O
formation O
. O
Oncogene O
advance O
online O
publication O
, O
21 O
January O
2013 O
; O
doi O
: O
10 O
. O
1038 O
/ O
onc O
. O
2012 O
. O
642 O
. O

Almorexant B
effects O
on O
CYP3A4 O
activity O
studied O
by O
its O
simultaneous O
and O
time O
- O
separated O
administration O
with O
simvastatin B
and O
atorvastatin B
. O

PURPOSE O
: O
To O
characterise O
further O
the O
previously O
observed O
cytochrome O
P450 O
3A4 O
( O
CYP3A4 O
) O
interaction O
of O
the O
dual O
orexin O
receptor O
antagonist O
almorexant B
. O

METHODS O
: O
Pharmacokinetic O
interactions O
were O
investigated O
( O
n O
= O
14 O
healthy O
male O
subjects O
in O
two O
treatment O
groups O
) O
between O
almorexant B
at O
steady O
- O
state O
when O
administered O
either O
concomitantly O
or O
2 O
h O
after O
administration O
of O
single O
doses O
of O
simvastatin B
( O
40 O
mg O
) O
or O
atorvastatin B
( O
40 O
mg O
) O
. O

RESULTS O
: O
Almorexant B
dose O
- O
dependently O
increased O
simvastatin B
exposure O
( O
AUC O
( O
0 O
- O
infinity O
) O
) O
when O
administered O
concomitantly O
[ O
geometric O
mean O
ratios O
( O
90 O
% O
CI O
) O
: O
2 O
. O
5 O
( O
2 O
. O
1 O
, O
2 O
. O
9 O
) O
( O
100 O
mg O
) O
, O
3 O
. O
9 O
( O
3 O
. O
3 O
, O
4 O
. O
6 O
) O
( O
200 O
mg O
) O
] O
, O
but O
not O
C O
( O
max O
) O
[ O
3 O
. O
7 O
( O
3 O
. O
0 O
, O
4 O
. O
5 O
) O
for O
both O
doses O
] O
. O

Time O
- O
separated O
administration O
resulted O
in O
relevant O
reductions O
of O
the O
interaction O
[ O
AUC O
( O
0 O
- O
infinity O
) O
: O
1 O
. O
4 O
( O
1 O
. O
2 O
, O
1 O
. O
7 O
) O
( O
100 O
mg O
) O
, O
1 O
. O
7 O
( O
1 O
. O
5 O
, O
2 O
. O
0 O
) O
( O
200 O
mg O
) O
; O
C O
( O
max O
) O
: O
1 O
. O
5 O
( O
1 O
. O
3 O
, O
1 O
. O
9 O
) O
( O
100 O
mg O
) O
, O
1 O
. O
9 O
( O
1 O
. O
6 O
, O
2 O
. O
4 O
) O
( O
200 O
mg O
) O
] O
. O

Similar O
results O
were O
obtained O
for O
hydroxyacid B
simvastatin I
. O

Independent O
of O
almorexant B
dose O
and O
relative O
time O
of O
administration O
, O
AUC O
( O
0 O
- O
infinity O
) O
and O
C O
( O
max O
) O
of O
atorvastatin B
increased O
( O
ratios O
ranged O
from O
1 O
. O
1 O
to O
1 O
. O
5 O
) O
. O

AUC O
( O
0 O
- O
infinity O
) O
and O
C O
( O
max O
) O
of O
o B
- I
hydroxy I
atorvastatin I
decreased O
dose O
- O
independently O
[ O
AUC O
( O
0 O
- O
infinity O
) O
: O
0 O
. O
8 O
( O
0 O
. O
8 O
, O
0 O
. O
9 O
) O
( O
100 O
mg O
) O
, O
0 O
. O
6 O
( O
0 O
. O
5 O
, O
0 O
. O
6 O
) O
( O
200 O
mg O
) O
; O
C O
( O
max O
) O
: O
0 O
. O
3 O
( O
0 O
. O
3 O
, O
0 O
. O
4 O
) O
( O
100 O
mg O
) O
, O
0 O
. O
2 O
( O
0 O
. O
2 O
, O
0 O
. O
3 O
) O
( O
200 O
mg O
) O
] O
when O
atorvastatin B
was O
concomitantly O
administered O
. O

C O
( O
max O
) O
of O
o B
- I
hydroxy I
atorvastatin I
slightly O
decreased O
( O
0 O
. O
8 O
for O
both O
doses O
) O
following O
time O
- O
separated O
administration O
; O
AUC O
( O
0 O
- O
infinity O
) O
was O
unchanged O
. O

CONCLUSIONS O
: O
Whereas O
almorexant B
increased O
simvastatin B
exposure O
dose O
- O
and O
relative O
time O
of O
administration O
- O
dependently O
, O
atorvastatin B
exposure O
increased O
to O
a O
smaller O
extent O
and O
irrespective O
of O
dose O
and O
time O
. O

This O
suggests O
that O
the O
observed O
interaction O
of O
almorexant B
with O
simvastatin B
is O
mainly O
caused O
by O
intestinal O
CYP3A4 O
inhibition O
, O
whereas O
the O
interaction O
with O
atorvastatin B
is O
more O
due O
to O
hepatic O
CYP3A4 O
inhibition O
. O

Designing O
high O
- O
performance O
electrochemical O
energy O
- O
storage O
nanoarchitectures O
to O
balance O
rate O
and O
capacity O
. O

The O
impressive O
specific O
capacitance O
and O
high O
- O
rate O
performance O
reported O
for O
many O
nanometric O
charge O
- O
storing O
films O
on O
planar O
substrates O
cannot O
impact O
a O
technology O
space O
beyond O
microdevices O
unless O
such O
performance O
translates O
into O
a O
macroscale O
form O
factor O
. O

In O
this O
report O
, O
we O
explore O
how O
the O
nanoscale O
- O
to O
- O
macroscale O
properties O
of O
the O
electrode O
architecture O
( O
pore O
size O
/ O
distribution O
, O
void O
volume O
, O
thickness O
) O
define O
energy O
and O
power O
performance O
when O
scaled O
to O
technologically O
relevant O
dimensions O
. O

Our O
test O
bed O
is O
a O
device O
- O
ready O
electrode O
architecture O
in O
which O
scalable O
, O
manufacturable O
carbon B
nanofoam O
papers O
with O
tunable O
pore O
sizes O
( O
5 O
- O
200 O
nm O
) O
and O
thickness O
( O
100 O
- O
300 O
mu O
m O
) O
are O
painted O
with O
~ O
10 O
nm O
coatings O
of O
manganese B
oxide I
( O
MnOx B
) O
. O

The O
quantity O
of O
capacitance O
and O
the O
rate O
at O
which O
it O
is O
delivered O
for O
four O
different O
MnOx B
- O
C O
variants O
was O
assessed O
by O
fabricating O
symmetric O
electrochemical O
capacitors O
using O
a O
concentrated O
aqueous O
electrolyte O
. O

Carbon B
nanofoam O
papers O
containing O
primarily O
10 O
- O
20 O
nm O
mesopores O
support O
high O
MnOx B
loadings O
( O
60 O
wt O
% O
) O
and O
device O
- O
level O
capacitance O
( O
30 O
F O
g O
( O
- O
1 O
) O
) O
, O
but O
the O
small O
mesoporous O
network O
hinders O
electrolyte O
transport O
and O
the O
low O
void O
volume O
restricts O
the O
quantity O
of O
charge O
- O
compensating O
ions O
within O
the O
electrode O
, O
making O
the O
full O
capacitance O
only O
accessible O
at O
slow O
rates O
( O
5 O
mV O
s O
( O
- O
1 O
) O
) O
. O

Carbon B
nanofoam O
papers O
with O
macropores O
( O
100 O
- O
200 O
nm O
) O
facilitate O
high O
rate O
operation O
( O
50 O
mV O
s O
( O
- O
1 O
) O
) O
, O
but O
deliver O
significantly O
lower O
device O
capacitance O
( O
13 O
F O
g O
( O
- O
1 O
) O
) O
as O
a O
result O
of O
lower O
MnOx B
loadings O
( O
41 O
wt O
% O
) O
. O

Devices O
comprising O
MnOx B
- O
carbon B
nanofoams O
with O
interconnecting O
networks O
of O
meso O
- O
and O
macropores O
balance O
capacitance O
and O
rate O
performance O
, O
delivering O
33 O
F O
g O
( O
- O
1 O
) O
at O
5 O
mV O
s O
( O
- O
1 O
) O
and O
23 O
F O
g O
( O
- O
1 O
) O
at O
50 O
mV O
s O
( O
- O
1 O
) O
. O

The O
use O
of O
carbon B
nanofoam O
papers O
with O
size O
- O
tunable O
pore O
structures O
and O
thickness O
provides O
the O
opportunity O
to O
engineer O
the O
electrode O
architecture O
to O
deliver O
scalable O
quantities O
of O
capacitance O
( O
F O
cm O
( O
- O
2 O
) O
) O
in O
tens O
of O
seconds O
with O
a O
single O
device O
. O

Microfluidic O
chemostat O
for O
measuring O
single O
cell O
dynamics O
in O
bacteria O
. O

We O
designed O
a O
microfluidic O
chemostat O
consisting O
of O
600 O
sub O
- O
micron O
trapping O
/ O
growth O
channels O
connected O
to O
two O
feeding O
channels O
. O

The O
microchemostat O
traps O
E O
. O
coli O
cells O
and O
forces O
them O
to O
grow O
in O
lines O
for O
over O
50 O
generations O
. O

Excess O
cells O
, O
including O
the O
mother O
cells O
captured O
at O
the O
start O
of O
the O
process O
, O
are O
removed O
from O
both O
ends O
of O
the O
growth O
channels O
by O
the O
media O
flow O
. O

With O
the O
aid O
of O
time O
- O
lapse O
microscopy O
, O
we O
have O
monitored O
dynamic O
properties O
such O
as O
growth O
rate O
and O
GFP O
expression O
at O
the O
single O
- O
cell O
level O
for O
many O
generations O
while O
maintaining O
a O
population O
of O
bacteria O
of O
similar O
age O
. O

We O
also O
use O
the O
microchemostat O
to O
show O
how O
the O
population O
responds O
to O
dynamic O
changes O
in O
the O
environment O
. O

Since O
more O
than O
100 O
individual O
bacterial O
cells O
are O
aligned O
and O
immobilized O
in O
a O
single O
field O
of O
view O
, O
the O
microchemostat O
is O
an O
ideal O
platform O
for O
high O
- O
throughput O
intracellular O
measurements O
. O

We O
demonstrate O
this O
capability O
by O
tracking O
with O
sub O
- O
diffraction O
resolution O
the O
movements O
of O
fluorescently O
tagged O
loci O
in O
more O
than O
one O
thousand O
cells O
on O
a O
single O
device O
. O

The O
device O
yields O
results O
comparable O
to O
conventional O
agar O
microscopy O
experiments O
with O
substantial O
increases O
in O
throughput O
and O
ease O
of O
analysis O
. O

High O
- O
grade O
prostate O
cancer O
and O
biochemical O
recurrence O
after O
radical O
prostatectomy O
among O
men O
using O
5 O
alpha O
- O
reductase O
inhibitors O
and O
alpha O
- O
blockers O
. O

BACKGROUND O
: O
Two O
clinical O
trials O
have O
shown O
that O
users O
of O
5 O
alpha O
- O
reductase O
inhibitors O
finasteride B
and O
dutasteride B
( O
5 O
- O
ARIs O
) O
have O
reduced O
overall O
prostate O
cancer O
risk O
, O
while O
the O
proportion O
of O
high O
- O
grade O
tumors O
is O
increased O
. O

We O
studied O
tumor O
characteristics O
, O
risk O
of O
biochemical O
recurrence O
and O
mortality O
after O
radical O
prostatectomy O
in O
5 O
- O
ARI O
and O
alpha O
- O
blocker O
users O
. O

METHODS O
: O
The O
study O
cohort O
consisted O
of O
1 O
, O
315 O
men O
who O
underwent O
radical O
prostatectomy O
at O
the O
Tampere O
University O
Hospital O
during O
1995 O
- O
2009 O
. O

Biochemical O
relapse O
was O
defined O
as O
serum O
PSA O
> O
= O
0 O
. O
2 O
ng O
/ O
ml O
after O
the O
operation O
. O

Information O
on O
mortality O
and O
medication O
purchases O
was O
obtained O
from O
national O
registries O
. O

Cox O
proportional O
regression O
was O
used O
to O
analyze O
hazard O
ratios O
( O
HRs O
) O
and O
95 O
% O
confidence O
intervals O
( O
95 O
% O
CI O
) O
of O
biochemical O
relapse O
and O
death O
. O

RESULTS O
: O
The O
proportion O
of O
high O
- O
grade O
( O
Gleason O
7 O
- O
10 O
) O
tumors O
was O
significantly O
elevated O
among O
men O
who O
had O
used O
5 B
- I
ARIs I
for O
4 O
years O
or O
longer O
compared O
to O
the O
non O
- O
users O
( O
83 O
. O
3 O
% O
vs O
. O
53 O
. O
3 O
% O
, O
respectively O
) O
. O

Survival O
curves O
for O
biochemical O
relapse O
- O
free O
survival O
differed O
between O
long O
- O
term O
and O
short O
- O
term O
5 B
- I
ARI I
users O
, O
but O
the O
hazard O
ratio O
remained O
statistically O
non O
- O
significant O
. O

Risk O
of O
biochemical O
recurrence O
was O
elevated O
among O
alpha B
- O
blocker O
users O
( O
HR O
1 O
. O
68 O
, O
95 O
% O
CI O
1 O
. O
37 O
- O
2 O
. O
06 O
) O
, O
but O
in O
sensitivity O
analyses O
this O
was O
evident O
only O
in O
men O
using O
alpha O
- O
blockers O
after O
prostatectomy O
. O

Mortality O
was O
not O
associated O
with O
medication O
usage O
. O

CONCLUSIONS O
: O
Long O
- O
term O
users O
of O
finasteride B
or O
dutasteride B
had O
more O
often O
high O
- O
grade O
prostate O
cancer O
. O

Our O
results O
suggest O
also O
worse O
progression O
- O
free O
survival O
. O

The O
association O
between O
risk O
of O
biochemical O
recurrence O
and O
post O
- O
operative O
alpha O
- O
blocker O
usage O
suggests O
that O
voiding O
or O
storage O
symptoms O
after O
prostatectomy O
may O
predict O
biochemical O
relapse O
. O

Prostate O
( O
c O
) O
2013 O
Wiley O
Periodicals O
, O
Inc O
. O

Fluocinolone B
acetonide I
intravitreal O
implant O
( O
Iluvien O
( O
R O
) O
) O
: O
in O
diabetic O
macular O
oedema O
. O

Fluocinolone B
acetonide I
intravitreal O
implant O
( O
Iluvien O
( O
R O
) O
) O
is O
an O
injectable O
, O
non O
- O
erodible O
, O
corticosteroid B
implant O
that O
is O
approved O
in O
several O
European O
countries O
for O
the O
treatment O
of O
chronic O
diabetic O
macular O
oedema O
( O
DMO O
) O
. O

In O
analyses O
of O
two O
multinational O
trials O
in O
patients O
with O
DMO O
previously O
treated O
with O
macular O
laser O
photocoagulation O
, O
fluocinolone B
acetonide I
intravitreal O
implant O
0 O
. O
2 O
mu O
g O
/ O
day O
was O
significantly O
more O
efficacious O
than O
sham O
injection O
in O
improving O
visual O
acuity O
. O

At O
24 O
months O
post O
injection O
, O
29 O
% O
of O
fluocinolone B
acetonide I
intravitreal O
implant O
0 O
. O
2 O
mu O
g O
/ O
day O
recipients O
had O
an O
improvement O
in O
the O
best O
- O
corrected O
visual O
acuity O
( O
BCVA O
) O
letter O
score O
of O
> O
= O
15 O
compared O
with O
16 O
% O
in O
the O
sham O
injection O
group O
( O
p O
= O
0 O
. O
002 O
) O
[ O
primary O
endpoint O
] O
. O

Treatment O
benefit O
was O
most O
evident O
in O
the O
subgroup O
of O
patients O
whose O
duration O
of O
DMO O
was O
> O
= O
3 O
years O
. O

In O
this O
subgroup O
at O
36 O
months O
, O
34 O
% O
of O
fluocinolone B
acetonide I
intravitreal O
implant O
0 O
. O
2 O
mu O
g O
/ O
day O
recipients O
had O
an O
increase O
in O
the O
BCVA O
score O
of O
> O
= O
15 O
, O
compared O
with O
13 O
% O
of O
sham O
injection O
recipients O
( O
p O
< O
0 O
. O
001 O
) O
. O

Fluocinolone B
acetonide I
intravitreal O
implant O
recipients O
also O
had O
generally O
greater O
benefits O
than O
sham O
injection O
recipients O
on O
secondary O
endpoints O
. O

In O
patients O
who O
were O
phakic O
in O
the O
study O
eye O
at O
baseline O
, O
cataracts O
occurred O
in O
82 O
% O
of O
fluocinolone B
acetonide I
intravitreal O
implant O
0 O
. O
2 O
mu O
g O
/ O
day O
recipients O
and O
51 O
% O
of O
sham O
injection O
recipients O
. O

Overall O
, O
37 O
% O
and O
12 O
% O
of O
patients O
in O
the O
fluocinolone B
acetonide I
intravitreal O
implant O
and O
sham O
injection O
groups O
developed O
raised O
intraocular O
pressure O
( O
IOP O
) O
, O
which O
was O
generally O
controlled O
with O
IOP O
- O
lowering O
drugs O
. O

Group O
I O
mGluRs O
evoke O
K B
- O
ATP B
current O
by O
intracellular O
Ca2 B
+ I
mobilization O
in O
rat O
subthalamus O
neurons O
. O

We O
reported O
previously O
that O
Ca B
( I
2 I
+ I
) I
influx O
through O
N B
- I
methly I
- I
d I
- I
aspartate I
- O
gated O
channels O
evokes O
ATP B
- O
sensitive O
K B
( I
+ I
) I
( O
K B
- O
ATP B
) O
currents O
in O
rat O
subthalamic O
nucleus O
( O
STN O
) O
neurons O
. O

By O
using O
whole O
- O
cell O
patch O
clamp O
recordings O
in O
brain O
slices O
, O
we O
investigated O
the O
ability O
of O
( B
RS I
) I
- I
3 I
, I
5 I
- I
dihydroxyphenylglyci I
( O
DHPG B
) O
, O
a O
group O
I O
metabotropic O
glutamate B
receptor O
( O
mGluR O
) O
agonist O
, O
to O
evoke O
K B
- O
ATP B
currents O
. O

DHPG B
( O
20 O
micro O
M O
) O
evoked O
outward O
current O
at O
- O
70 O
mV O
and O
was O
associated O
with O
a O
positive O
slope O
conductance O
of O
2 O
. O
7 O
nS O
. O

The O
sulfonylurea B
agent O
tolbutamide B
( O
100 O
micro O
M O
) O
converted O
the O
positive O
slope O
to O
negative O
slope O
conductance O
, O
indicating O
mediation O
by O
K B
- O
ATP B
channels O
( O
ATP B
- O
sensitive O
K B
+ I
channels O
) O
. O

Currents O
evoked O
by O
DHPG B
were O
significantly O
reduced O
by O
a O
combination O
of O
mGluR1 O
and O
mGluR5 O
negative O
allosteric O
modulators O
. O

DHPG B
- O
evoked O
outward O
current O
was O
blocked O
by O
cyclopiazonic B
acid I
and O
thapsigargin B
and O
mimicked O
by O
caffeine B
, O
suggesting O
mediation O
by O
release O
of O
intracellular O
Ca B
( I
2 I
+ I
) I
. O

DHPG B
outward O
current O
was O
also O
blocked O
by O
ryanodine B
and O
2 B
- I
aminoethoxydiphenylb I
, O
suggesting O
mediation O
by O
ryanodine B
- O
and O
inositol B
1 I
, I
4 I
, I
5 I
- I
triphosphate I
- O
sensitive O
Ca B
( I
2 I
+ I
) I
release O
. O

The O
nitric B
oxide I
synthase O
inhibitor O
N B
( I
G I
) I
- I
nitro I
- I
l I
- I
arginine I
methyl I
ester I
and O
inhibitors O
of O
protein O
kinase O
G O
activity O
also O
suppressed O
DHPG B
- O
induced O
outward O
current O
. O

Voltage O
recordings O
showed O
that O
tolbutamide B
prolonged O
depolarizing O
plateau O
potentials O
and O
increased O
the O
spontaneous O
firing O
rate O
of O
STN O
neurons O
recorded O
in O
the O
presence O
of O
DHPG B
. O

These O
results O
show O
that O
group O
I O
mGluR O
stimulation O
generates O
K B
- O
ATP B
current O
by O
a O
nitric B
oxide I
- O
and O
protein O
kinase O
G O
- O
dependent O
process O
that O
is O
mediated O
by O
release O
of O
Ca B
( I
2 I
+ I
) I
from O
intracellular O
stores O
. O

Because O
burst O
firing O
is O
linked O
to O
symptoms O
of O
Parkinson O
' O
s O
disease O
, O
we O
suggest O
that O
K B
- O
ATP B
channels O
might O
provide O
a O
physiologically O
important O
inhibitory O
influence O
on O
STN O
neuronal O
activity O
. O

Internalization O
Pathways O
of O
Anisotropic O
Disc O
- O
Shaped O
Zeolite B
L I
Nanocrystals O
with O
Different O
Surface O
Properties O
in O
HeLa O
Cancer O
Cells O
. O

Information O
about O
the O
mechanisms O
underlying O
the O
interactions O
of O
nanoparticles O
with O
living O
cells O
is O
crucial O
for O
their O
medical O
application O
and O
also O
provides O
indications O
of O
the O
putative O
toxicity O
of O
such O
materials O
. O

Here O
the O
uptake O
and O
intracellular O
delivery O
of O
disc O
- O
shaped O
zeolite B
L I
nanocrystals O
as O
porous O
aminosilicates B
with O
well O
- O
defined O
crystal O
structure O
, O
uncoated O
as O
well O
as O
with O
COOH B
- O
, O
NH B
( I
2 I
) I
- O
, O
polyethyleneglycol B
( O
PEG B
) O
- O
and O
polyallylamine B
hydrochloride I
( O
PAH B
) O
surface O
coatings O
are O
reported O
. O

HeLa O
cells O
are O
used O
as O
a O
model O
system O
to O
demonstrate O
the O
relation O
between O
these O
particles O
and O
cancer O
cells O
. O

Interactions O
are O
studied O
in O
terms O
of O
their O
fates O
under O
diverse O
in O
vitro O
cell O
culture O
conditions O
. O

Differently O
charged O
coatings O
demonstrated O
dissimilar O
behavior O
in O
terms O
of O
agglomeration O
in O
media O
, O
serum O
protein O
adsorption O
, O
nanoparticle O
cytotoxicity O
and O
cell O
internalization O
. O

It O
is O
also O
found O
that O
functionalized O
disc O
- O
shaped O
zeolite B
L I
particles O
enter O
the O
cancer O
cells O
via O
different O
, O
partly O
not O
yet O
characterized O
, O
pathways O
. O

These O
in O
vitro O
results O
provide O
additional O
insight O
about O
low O
- O
aspect O
ratio O
anisotropic O
nanoparticle O
interactions O
with O
cancer O
cells O
and O
demonstrate O
the O
possibility O
to O
manipulate O
the O
interactions O
of O
nanoparticles O
and O
cells O
by O
surface O
coating O
for O
the O
use O
of O
nanoparticles O
in O
medical O
applications O
. O

Nanostructural O
anisotropy O
underlies O
anisotropic O
electrical O
bistability O
. O

Regular O
arrays O
of O
nanorods O
having O
asymmetric O
cross O
- O
sections O
are O
fabricated O
by O
a O
combination O
of O
electrodeposition O
and O
glancing O
- O
angle O
deposition O
( O
GLAD O
) O
. O

When O
these O
nanorods O
are O
embedded O
in O
a O
polymer O
matrix O
, O
they O
give O
rise O
to O
composite O
materials O
in O
which O
the O
structural O
anisotropy O
at O
the O
nanoscale O
translates O
into O
functional O
anisotropy O
in O
the O
form O
of O
direction O
- O
dependent O
electrical O
bistability O
. O

The O
degree O
of O
this O
directional O
bistability O
depends O
on O
and O
can O
be O
controlled O
by O
the O
spacing O
between O
the O
nearby O
nanorods O
. O

Comparative O
toxicological O
study O
of O
the O
novel O
protein O
phosphatase O
inhibitor O
19 B
- I
Epi I
- I
okadaic I
acid I
in O
primary O
cultures O
of O
rat O
cerebellar O
cells O
. O

Okadaic B
acid I
( O
OKA B
) O
and O
analogues O
are O
frequent O
contaminants O
of O
coastal O
waters O
and O
seafood O
. O

Structure O
analysis O
of O
the O
isolated O
OKA B
analogue O
19 B
- I
epi I
- I
OKA I
showed O
important O
conformation O
differences O
expected O
to O
result O
in O
lower O
protein O
phosphatase O
( O
PP O
) O
inhibitory O
potencies O
than O
OKA B
. O

However O
, O
19 B
- I
epi I
- I
OKA I
and O
OKA B
inhibitory O
activities O
versus O
PP2A O
were O
unexpectedly O
found O
to O
be O
virtually O
equipotent O
. O

To O
investigate O
the O
toxicological O
relevance O
of O
these O
findings O
, O
we O
tested O
the O
effects O
of O
19 B
- I
epi I
- I
OKA I
on O
cultured O
cerebellar O
cells O
and O
compared O
them O
with O
those O
of O
OKA B
and O
its O
isomer O
dinophysistoxin B
- I
2 I
. O

19 B
- I
epi I
- I
OKA I
caused O
degeneration O
of O
neurites O
and O
neuronal O
death O
with O
much O
lower O
potency O
than O
its O
congeners O
. O

The O
concentration O
of O
19 B
- I
epi I
- I
OKA I
that O
reduced O
after O
24h O
the O
maximum O
neuronal O
survival O
( O
EC5024 O
) O
by O
50 O
% O
was O
~ O
300nM O
compared O
with O
~ O
2nM O
and O
~ O
8nM O
for O
OKA B
and O
dinophysistoxin B
- I
2 I
, O
respectively O
. O

Exposure O
to O
19 B
- I
epi I
- I
OKA I
resulted O
also O
in O
less O
toxicity O
for O
cultured O
glial O
cells O
( O
EC5024 O
, O
19 B
- I
epi I
- I
OKA I
~ O
600nM O
; O
EC5024 O
, O
OKA B
~ O
20nM O
) O
. O

19 B
- I
epi I
- I
OKA I
induced O
apoptotic O
condensation O
and O
fragmentation O
of O
chromatin O
, O
activation O
of O
caspases O
, O
and O
activation O
of O
ERK1 O
/ O
2 O
MAP O
kinases O
, O
features O
previously O
reported O
for O
OKA B
and O
dinophysistoxin B
- I
2 I
. O

Also O
, O
differential O
sensitivity O
to O
19 B
- I
epi I
- I
OKA I
was O
observed O
between O
neuronal O
and O
glial O
cells O
, O
a O
specific O
characteristic O
shared O
by O
OKA B
and O
dinophysistoxin B
- I
2 I
but O
not O
by O
other O
toxins O
. O

Our O
results O
are O
consistent O
with O
19 B
- I
epi I
- I
OKA I
being O
included O
among O
the O
group O
of O
toxins O
of O
OKA B
and O
derivatives O
and O
support O
the O
suitability O
of O
cellular O
bioassays O
for O
the O
detection O
of O
these O
compounds O
. O

Hypoxia O
stress O
test O
reveals O
exaggerated O
cardiovascular O
effects O
in O
hypertensive O
rats O
after O
exposure O
to O
the O
air O
pollutant O
acrolein B
. O

Exposure O
to O
air O
pollution O
increases O
the O
risk O
of O
cardiovascular O
morbidity O
and O
mortality O
, O
especially O
in O
susceptible O
populations O
. O

Despite O
increased O
risk O
, O
adverse O
responses O
are O
often O
delayed O
and O
require O
additional O
stress O
tests O
to O
reveal O
latent O
effects O
of O
exposure O
. O

The O
goal O
of O
this O
study O
was O
to O
use O
an O
episode O
of O
" O
transient O
hypoxia O
" O
as O
an O
extrinsic O
stressor O
to O
uncover O
latent O
susceptibility O
to O
environmental O
pollutants O
in O
a O
rodent O
model O
of O
hypertension O
. O

We O
hypothesized O
that O
exposure O
to O
acrolein B
, O
an O
unsaturated B
aldehyde I
and O
mucosal O
irritant O
found O
in O
cigarette O
smoke O
, O
diesel O
exhaust O
, O
and O
power O
plant O
emissions O
, O
would O
increase O
cardiopulmonary O
sensitivity O
to O
hypoxia O
, O
particularly O
in O
hypertensive O
rats O
. O

Spontaneously O
hypertensive O
and O
Wistar O
Kyoto O
( O
normotensive O
) O
rats O
, O
implanted O
with O
radiotelemeters O
, O
were O
exposed O
once O
for O
3h O
to O
3 O
ppm O
acrolein B
gas O
or O
filtered O
air O
in O
whole O
- O
body O
plethysmograph O
chambers O
and O
challenged O
with O
a O
10 O
% O
oxygen B
atmosphere O
( O
10min O
) O
24h O
later O
. O

Acrolein B
exposure O
increased O
heart O
rate O
, O
blood O
pressure O
, O
breathing O
frequency O
, O
and O
minute O
volume O
in O
hypertensive O
rats O
and O
also O
increased O
the O
heart O
rate O
variability O
parameter O
LF O
, O
suggesting O
a O
potential O
role O
for O
increased O
sympathetic O
tone O
. O

Normotensive O
rats O
only O
had O
increased O
blood O
pressure O
during O
acrolein B
exposure O
. O

The O
hypoxia O
stress O
test O
after O
acrolein B
exposure O
revealed O
increased O
diastolic O
blood O
pressure O
only O
in O
hypertensive O
rats O
and O
increased O
minute O
volume O
and O
expiratory O
time O
only O
in O
normotensive O
rats O
. O

These O
results O
suggest O
that O
hypertension O
confers O
exaggerated O
sensitivity O
to O
air O
pollution O
and O
that O
the O
hypoxia O
stress O
test O
is O
a O
novel O
tool O
to O
reveal O
the O
potential O
latent O
effects O
of O
air O
pollution O
exposure O
. O

Gobichelin B
A I
and I
B I
: O
Mixed O
- O
Ligand O
Siderophores O
Discovered O
Using O
Proteomics O
. O

" O
Omic O
" O
strategies O
have O
been O
increasingly O
applied O
to O
natural O
product O
discovery O
processes O
, O
with O
( O
meta O
- O
) O
genome O
sequencing O
and O
mining O
implemented O
in O
many O
laboratories O
to O
date O
. O

Using O
the O
proteomics O
- O
based O
discovery O
platform O
called O
PrISM O
( O
Proteomic O
Investigation O
of O
Secondary O
Metabolism O
) O
, O
we O
discovered O
two O
new O
siderophores O
gobichelin B
A I
and I
B I
from O
Streptomyces O
sp O
. O

NRRL O
F O
- O
4415 O
, O
a O
strain O
without O
a O
sequenced O
genome O
. O

Using O
the O
proteomics O
information O
as O
a O
guide O
, O
the O
37 O
kb O
gene O
cluster O
responsible O
for O
production O
of O
gobichelins B
was O
sequenced O
and O
its O
20 O
open O
reading O
frames O
interpreted O
into O
a O
biosynthetic O
scheme O
. O

This O
led O
to O
the O
targeted O
detection O
and O
structure O
elucidation O
of O
the O
new O
compounds O
produced O
by O
nonribosomal O
peptide O
( O
NRP O
) O
synthesis O
. O

Mechanistic O
insight O
into O
inhibition O
of O
two O
- O
component O
system O
signaling O
. O

Two O
- O
component O
signal O
transduction O
systems O
( O
TCSs O
) O
are O
commonly O
used O
by O
bacteria O
to O
couple O
environmental O
stimuli O
to O
adaptive O
responses O
. O

Targeting O
the O
highly O
conserved O
kinase O
domain O
in O
these O
systems O
represents O
a O
promising O
strategy O
for O
the O
design O
of O
a O
broad O
- O
spectrum O
antibiotic O
; O
however O
, O
development O
of O
such O
compounds O
has O
been O
marred O
by O
an O
incomplete O
understanding O
of O
the O
conserved O
binding O
features O
within O
the O
active O
site O
that O
could O
be O
exploited O
in O
molecule O
design O
. O

Consequently O
, O
a O
large O
percentage O
of O
the O
available O
TCS O
inhibitors O
demonstrate O
poor O
target O
specificity O
and O
act O
via O
multiple O
mechanisms O
, O
with O
aggregation O
of O
the O
kinase O
being O
the O
most O
notable O
. O

In O
order O
to O
elucidate O
the O
mode O
of O
action O
of O
some O
of O
these O
compounds O
, O
molecular O
modeling O
was O
employed O
to O
dock O
a O
suite O
of O
molecules O
into O
the O
ATP B
- O
binding O
domain O
of O
several O
histidine B
kinases O
. O

This O
effort O
revealed O
a O
key O
structural O
feature O
of O
the O
domain O
that O
is O
likely O
interacting O
with O
several O
known O
inhibitors O
and O
is O
also O
highly O
conserved O
. O

Furthermore O
, O
generation O
of O
several O
simplified O
scaffolds O
derived O
from O
a O
reported O
inhibitor O
and O
characterization O
of O
these O
compounds O
using O
activity O
assays O
, O
protein O
aggregation O
studies O
and O
saturation O
transfer O
differential O
( O
STD O
) O
NMR O
suggests O
that O
targeting O
of O
this O
protein O
feature O
may O
provide O
a O
basis O
for O
the O
design O
of O
ATP B
- O
competitive O
compounds O
. O

5 B
- I
Hydroxytryptamine I
type O
7 O
receptor O
neuroprotection O
against O
NMDA B
- O
induced O
excitotoxicity O
is O
PDGF O
beta O
receptor O
dependent O
. O

The O
serotonin B
( O
5 B
- I
HT I
) O
type O
7 O
receptor O
is O
expressed O
throughout O
the O
CNS O
including O
the O
hippocampus O
. O

Long O
- O
term O
( O
2 O
- O
24 O
h O
) O
activation O
of O
5 O
- O
HT7 O
receptors O
regulates O
growth O
factor O
receptor O
expression O
, O
including O
the O
expression O
of O
platelet O
- O
derived O
growth O
factor O
( O
PDGF O
) O
beta O
receptors O
. O

Direct O
activation O
of O
PDGF O
beta O
receptors O
in O
primary O
hippocampal O
and O
cortical O
neurons O
inhibits O
NMDA B
receptor O
activity O
and O
attenuates O
NMDA B
receptor O
- O
induced O
neurotoxicity O
. O

Our O
objective O
was O
to O
investigate O
whether O
the O
5 O
- O
HT7 O
receptor O
- O
induced O
increase O
in O
PDGF O
beta O
receptor O
expression O
would O
be O
similarly O
neuroprotective O
. O

We O
demonstrate O
that O
5 O
- O
HT7 O
receptor O
agonist O
treatment O
in O
primary O
hippocampal O
neurons O
also O
increases O
the O
expression O
of O
phospholipase O
C O
( O
PLC O
) O
gamma O
, O
a O
downstream O
effector O
of O
PDGF O
beta O
receptors O
associated O
with O
the O
inhibition O
of O
NMDA B
receptor O
activity O
. O

To O
determine O
if O
the O
up O
- O
regulation O
of O
PDGF O
beta O
receptors O
is O
neuroprotective O
, O
primary O
hippocampal O
neurons O
were O
incubated O
with O
the O
5 O
- O
HT7 O
receptor O
agonist O
, O
LP B
12 I
, O
for O
24 O
h O
. O

Indeed O
, O
LP O
12 O
treatment O
prevented O
NMDA B
- O
induced O
neurotoxicity O
and O
this O
effect O
was O
dependent O
on O
PDGF O
beta O
receptor O
kinase O
activity O
. O

Treatment O
of O
primary O
neurons O
with O
LP O
12 O
also O
differentially O
altered O
NMDA B
receptor O
subunit O
expression O
, O
reducing O
the O
expression O
of O
NR1 O
and O
NR2B O
, O
but O
not O
NR2A O
. O

These O
findings O
demonstrate O
the O
potential O
for O
providing O
growth O
factor O
receptor O
- O
dependent O
neuroprotective O
effects O
using O
small O
- O
molecule O
ligands O
of O
G O
protein O
- O
coupled O
receptors O
. O

Mixed O
valency O
in O
hydrogen B
bonded O
' O
dimers O
of O
dimers O
' O
. O

Dimolybdenum B
quadruply O
bonded O
compounds O
containing O
a O
pendant O
lactam B
functional O
group O
form O
self O
- O
complementary O
hydrogen B
bonded O
' O
dimers O
of O
dimers O
' O
in O
the O
solid O
- O
state O
and O
CH B
( I
2 I
) I
Cl I
( I
2 I
) I
solutions O
. O

Electrochemical O
studies O
in O
CH B
( I
2 I
) I
Cl I
( I
2 I
) I
show O
two O
consecutive O
one O
- O
electron O
redox O
processes O
corresponding O
to O
oxidation O
of O
the O
Mo B
( I
2 I
) I
( I
4 I
+ I
) I
cores O
. O

Spectroelectrochemic O
studies O
on O
the O
' O
dimers O
of O
dimers O
' O
show O
no O
evidence O
of O
intervalence O
charge O
transfer O
bands O
in O
the O
mixed O
valence O
radical O
cations O
formed O
by O
one O
- O
electron O
oxidation O
, O
indicating O
that O
they O
are O
examples O
of O
proton O
- O
coupled O
mixed O
valency O
. O

Lower O
physical O
activity O
is O
a O
risk O
factor O
for O
a O
clustering O
of O
metabolic O
risk O
factors O
in O
non O
- O
obese O
and O
obese O
Japanese O
subjects O
: O
The O
Takahata O
study O
. O

In O
several O
countries O
including O
Japan O
, O
people O
without O
obesity O
but O
with O
a O
clustering O
of O
metabolic O
risk O
factors O
( O
MetRFs O
) O
were O
not O
considered O
to O
have O
the O
metabolic O
syndrome O
( O
MetS O
) O
. O

Here O
, O
we O
examined O
whether O
lifestyle O
characteristics O
differed O
between O
non O
- O
obese O
and O
obese O
subjects O
with O
or O
without O
a O
clustering O
of O
MetRFs O
. O

From O
a O
population O
- O
based O
cross O
- O
sectional O
study O
of O
Japanese O
subjects O
aged O
> O
= O
40 O
years O
, O
1 O
, O
601 O
subjects O
( O
age O
: O
61 O
. O
9 O
+ O
/ O
- O
10 O
. O
3 O
years O
; O
710 O
/ O
891 O
men O
/ O
women O
) O
were O
recruited O
. O

Physical O
activity O
status O
and O
daily O
nutritional O
intake O
were O
estimated O
using O
questionnaires O
. O

A O
clustering O
of O
MetRFs O
was O
defined O
based O
on O
the O
presence O
of O
at O
least O
two O
non O
- O
essential O
risk O
factors O
for O
the O
diagnosis O
of O
the O
MetS O
in O
Japan O
. O

Energy O
intake O
was O
not O
higher O
in O
subjects O
with O
a O
clustering O
of O
MetRFs O
compared O
with O
those O
without O
. O

Among O
men O
, O
energy O
expenditure O
at O
work O
was O
significantly O
lower O
in O
non O
- O
obese O
( O
9 O
. O
0 O
+ O
/ O
- O
8 O
. O
2 O
vs O
. O
11 O
. O
3 O
+ O
/ O
- O
9 O
. O
3 O
METs O
( O
metabolic O
equivalents O
) O
, O
P O
= O
. O
025 O
) O
and O
obese O
( O
9 O
. O
0 O
+ O
/ O
- O
7 O
. O
9 O
vs O
. O
11 O
. O
6 O
+ O
/ O
- O
9 O
. O
4 O
METs O
, O
P O
= O
. O
017 O
) O
subjects O
with O
a O
clustering O
of O
MetRFs O
than O
in O
those O
without O
. O

Multiple O
logistic O
regression O
analysis O
showed O
that O
energy O
expenditure O
at O
work O
was O
significantly O
associated O
with O
a O
clustering O
of O
MetRFs O
after O
adjusting O
for O
possible O
confounding O
factors O
including O
total O
energy O
intake O
. O

The O
ORs O
( O
per O
1 O
MET O
( O
metabolic O
equivalent O
) O
) O
were O
0 O
. O
970 O
( O
95 O
% O
CI O
, O
0 O
. O
944 O
- O
0 O
. O
997 O
; O
P O
= O
. O
032 O
) O
in O
non O
- O
obese O
men O
and O
0 O
. O
962 O
( O
0 O
. O
926 O
- O
0 O
. O
999 O
; O
P O
= O
. O
043 O
) O
in O
obese O
men O
. O

Similar O
associations O
were O
not O
observed O
in O
women O
. O

In O
Japanese O
males O
, O
lower O
physical O
activity O
, O
but O
not O
excessive O
energy O
intake O
, O
is O
a O
risk O
factor O
for O
a O
clustering O
of O
MetRFs O
independent O
of O
their O
obesity O
status O
. O

Drug O
shortages O
in O
the O
United O
States O
: O
a O
critical O
evaluation O
of O
root O
causes O
and O
the O
need O
for O
action O
. O

Every O
day O
it O
is O
easy O
to O
find O
news O
articles O
detailing O
the O
impact O
of O
drug O
shortages O
on O
patients O
. O

Where O
this O
was O
once O
only O
a O
concern O
of O
patients O
with O
rare O
, O
orphan O
diseases O
, O
it O
is O
now O
the O
concern O
of O
patients O
receiving O
even O
the O
most O
common O
chemotherapeutic O
regimens O
, O
the O
most O
efficacious O
antimicrobial O
therapy O
, O
or O
even O
the O
most O
rapid O
- O
acting O
analgesics O
, O
largely O
as O
a O
result O
of O
manufacturing O
quality O
problems O
. O

Unfortunately O
for O
many O
of O
these O
patients O
, O
there O
are O
no O
efficacious O
alternatives O
. O

Call O
to O
action O
: O
finding O
solutions O
for O
the O
drug O
shortage O
crisis O
in O
the O
United O
States O
. O

In O
their O
article O
in O
this O
issue O
of O
CPT O
, O
Woodcock O
and O
Wosinska O
are O
the O
first O
to O
clearly O
outline O
the O
quality O
and O
manufacturing O
problems O
causing O
drug O
shortages O
of O
generic O
injectables O
. O

These O
authors O
have O
focused O
on O
the O
main O
issue O
, O
namely O
, O
that O
manufacturing O
problems O
and O
the O
lack O
of O
incentives O
for O
quality O
products O
are O
the O
primary O
reasons O
for O
most O
recent O
shortages O
of O
generic O
injectable O
drugs O
. O

Anagliptin B
, O
a O
DPP O
- O
4 O
inhibitor O
, O
suppresses O
proliferation O
of O
vascular O
smooth O
muscles O
and O
monocyte O
inflammatory O
reaction O
and O
attenuates O
atherosclerosis O
in O
male O
apo O
E O
- O
deficient O
mice O
. O

Dipeptyl O
peptidase O
- O
4 O
( O
DPP O
- O
4 O
) O
inhibitors O
modulate O
the O
progression O
of O
atherosclerosis O
. O

To O
gain O
insights O
into O
their O
mechanism O
of O
action O
, O
9 O
- O
wk O
- O
old O
male O
apolipoprotein O
E O
( O
apoE O
) O
- O
deficient O
mice O
were O
fed O
a O
DPP O
- O
4 O
inhibitor O
, O
anagliptin B
- O
containing O
diet O
. O

The O
effects O
of O
anagliptin B
were O
investigated O
in O
, O
a O
monocyte O
cell O
line O
, O
human O
THP O
- O
1 O
cells O
, O
and O
rat O
smooth O
muscle O
cells O
( O
SMCs O
) O
. O

Treatment O
with O
anagliptin B
for O
16 O
wk O
significantly O
reduced O
accumulation O
of O
monocytes O
and O
macrophages O
in O
the O
vascular O
wall O
, O
SMC O
content O
in O
plaque O
areas O
, O
and O
oil O
red I
O O
- O
stained O
area O
around O
the O
aortic O
valve O
without O
affecting O
glucose B
tolerance O
or O
body O
weight O
. O

Serum O
DPP O
- O
4 O
concentrations O
were O
significantly O
higher O
in O
apoE O
- O
deficient O
mice O
than O
control O
mice O
, O
and O
the O
levels O
increased O
with O
aging O
, O
suggesting O
the O
involvement O
of O
DPP O
- O
4 O
in O
the O
progression O
of O
atherosclerosis O
. O

Indeed O
, O
soluble O
DPP O
- O
4 O
augmented O
cultured O
SMC O
proliferation O
, O
and O
anagliptin B
suppressed O
the O
proliferation O
by O
inhibiting O
ERK O
phosphorylation O
. O

In O
THP O
- O
1 O
cells O
, O
anagliptin B
reduced O
lipopolysaccharide O
- O
induced O
TNF O
- O
alpha O
production O
with O
inhibiting O
ERK O
phosphorylation O
and O
nuclear O
translocation O
of O
nuclear O
factor O
- O
kappa O
B O
. O

Quantitative O
analysis O
also O
showed O
that O
anagliptin B
reduced O
the O
area O
of O
atherosclerotic O
lesion O
in O
apoE O
- O
deficient O
mice O
. O

These O
results O
indicated O
that O
the O
anti O
- O
atherosclerotic O
effect O
of O
anagliptin B
is O
mediated O
, O
at O
least O
in O
part O
, O
through O
its O
direct O
inhibition O
of O
SMC O
proliferation O
and O
inflammatory O
reaction O
of O
monocytes O
. O

Prenatal O
exposure O
to O
bisphenol B
A I
impacts O
midbrain O
dopamine B
neurons O
and O
hippocampal O
spine O
synapses O
in O
non O
- O
human O
primates O
. O

Prevalent O
use O
of O
bisphenol B
- I
A I
( O
BPA B
) O
in O
the O
manufacture O
of O
resins O
, O
plastics O
and O
paper O
products O
has O
led O
to O
frequent O
exposure O
of O
most O
people O
to O
this O
endocrine O
disruptor O
. O

Some O
rodent O
studies O
have O
suggested O
that O
BPA B
can O
exert O
detrimental O
effects O
on O
brain O
development O
. O

However O
as O
rodent O
models O
cannot O
be O
relied O
on O
to O
predict O
consequences O
of O
human O
exposure O
to O
BPA B
during O
development O
, O
it O
is O
important O
to O
investigate O
the O
effects O
of O
BPA B
on O
non O
- O
human O
primate O
brain O
development O
. O

Previous O
research O
suggests O
that O
BPA B
preferentially O
targets O
dopamine B
neurons O
in O
ventral O
mesencephalon O
and O
glutamatergic O
neurons O
in O
hippocampus O
, O
so O
the O
present O
work O
examined O
the O
susceptibility O
of O
these O
systems O
to O
low O
dose O
BPA B
exposure O
at O
the O
fetal O
and O
juvenile O
stages O
of O
development O
in O
non O
- O
human O
primates O
. O

Exposure O
of O
pregnant O
rhesus O
monkeys O
to O
relatively O
low O
levels O
of O
BPA B
during O
the O
final O
2 O
months O
of O
gestation O
, O
induced O
abnormalities O
in O
fetal O
ventral O
mesencephalon O
and O
hippocampus O
. O

Specifically O
, O
light O
microscopy O
revealed O
a O
decrease O
in O
tyrosine B
hydroxylase O
- O
expressing O
( O
dopamine B
) O
neurons O
in O
the O
midbrain O
of O
BPA B
- O
exposed O
fetuses O
and O
electron O
microscopy O
identified O
a O
reduction O
in O
spine O
synapses O
in O
the O
CA1 O
region O
of O
hippocampus O
. O

In O
contrast O
, O
administration O
of O
BPA B
to O
juvenile O
vervet O
monkeys O
( O
14 O
- O
18 O
months O
of O
age O
) O
was O
without O
effect O
on O
these O
indices O
, O
or O
on O
dopamine B
and O
serotonin B
concentrations O
in O
striatum O
and O
prefrontal O
cortex O
, O
or O
on O
performance O
of O
a O
cognitive O
task O
that O
tests O
working O
memory O
capacity O
. O

These O
data O
indicate O
that O
BPA B
exerts O
an O
age O
- O
dependent O
detrimental O
impact O
on O
primate O
brain O
development O
, O
at O
blood O
levels O
within O
the O
range O
measured O
in O
humans O
having O
only O
environmental O
contact O
with O
BPA B
. O

Assessment O
of O
emerging O
biomarkers O
of O
liver O
injury O
in O
human O
subjects O
. O

Hepatotoxicity O
remains O
a O
major O
challenge O
in O
drug O
development O
. O

Although O
alanine B
aminotransferase O
( O
ALT O
) O
remains O
the O
gold O
standard O
biomarker O
of O
liver O
injury O
, O
alternative O
biomarker O
strategies O
to O
better O
predict O
the O
potential O
for O
severe O
drug O
- O
induced O
liver O
injury O
( O
DILI O
) O
are O
essential O
. O

In O
this O
study O
, O
we O
evaluated O
the O
utility O
of O
glutamate B
dehydrogenase O
( O
GLDH O
) O
, O
purine B
nucleoside I
phosphorylase O
( O
PNP O
) O
, O
malate B
dehydrogenase O
( O
MDH O
) O
, O
and O
paraxonase O
1 O
( O
PON1 O
) O
as O
indicators O
of O
liver O
injury O
in O
cohorts O
of O
human O
subjects O
, O
including O
healthy O
subjects O
across O
age O
and O
gender O
, O
subjects O
with O
a O
variety O
of O
liver O
impairments O
, O
and O
several O
cases O
of O
acetaminophen B
poisoning O
. O

In O
the O
healthy O
subjects O
, O
levels O
of O
GLDH O
and O
MDH O
were O
not O
affected O
by O
age O
or O
gender O
. O

Reference O
ranges O
for O
GLDH O
and O
MDH O
in O
healthy O
subjects O
were O
1 O
- O
10 O
and O
79 O
- O
176U O
/ O
L O
, O
respectively O
. O

In O
contrast O
, O
the O
levels O
of O
PON1 O
and O
PNP O
were O
not O
consistent O
across O
cohorts O
of O
healthy O
subjects O
. O

Furthermore O
, O
GLDH O
and O
MDH O
had O
a O
strong O
correlation O
with O
elevated O
ALT O
levels O
and O
possessed O
a O
high O
predictive O
power O
for O
liver O
injury O
, O
as O
determined O
by O
ROC O
analysis O
. O

In O
contrast O
, O
PON1 O
and O
PNP O
did O
not O
detect O
liver O
injury O
in O
our O
study O
. O

Finally O
, O
evaluation O
of O
patients O
with O
acetaminophen B
- O
induced O
liver O
injury O
provided O
evidence O
that O
both O
GLDH O
and O
MDH O
might O
have O
utility O
as O
biomarkers O
of O
DILI O
in O
humans O
. O

This O
study O
is O
the O
first O
to O
evaluate O
GLDH O
, O
MDH O
, O
PON1 O
, O
and O
PNP O
in O
a O
large O
number O
of O
human O
subjects O
and O
, O
and O
it O
provides O
an O
impetus O
for O
prospective O
clinical O
studies O
to O
fully O
evaluate O
the O
diagnostic O
value O
of O
GLDH O
and O
MDH O
for O
detection O
of O
liver O
injury O
. O

Graphene B
nanoribbons O
as O
an O
advanced O
precursor O
for O
making O
carbon B
fiber O
. O

Graphene B
oxide I
nanoribbons O
( O
GONRs O
) O
and O
chemically O
reduced O
graphene B
nanoribbons O
( O
crGNRs O
) O
were O
dispersed O
at O
high O
concentrations O
in O
chlorosulfonic B
acid I
to O
form O
anisotropic O
liquid O
crystal O
phases O
. O

The O
liquid O
crystal O
solutions O
were O
spun O
directly O
into O
hundreds O
of O
meters O
of O
continuous O
macroscopic O
fibers O
. O

The O
relationship O
of O
fiber O
morphology O
to O
coagulation O
bath O
conditions O
was O
studied O
. O

The O
effects O
of O
colloid O
concentration O
, O
annealing O
temperature O
, O
spinning O
air O
gap O
, O
and O
pretension O
during O
annealing O
on O
the O
fibers O
' O
performance O
were O
also O
investigated O
. O

Heat O
treatment O
of O
the O
as O
- O
spun O
GONR O
fibers O
at O
1500 O
degrees O
C O
produced O
thermally O
reduced O
graphene B
nanoribbon O
( O
trGNR O
) O
fibers O
with O
a O
tensile O
strength O
of O
378 O
MPa O
, O
Young O
' O
s O
modulus O
of O
36 O
. O
2 O
GPa O
, O
and O
electrical O
conductivity O
of O
285 O
S O
/ O
cm O
, O
which O
is O
considerably O
higher O
than O
that O
in O
other O
reported O
graphene B
- O
derived O
fibers O
. O

This O
better O
trGNR O
fiber O
performance O
was O
due O
to O
the O
air O
gap O
spinning O
and O
annealing O
with O
pretension O
that O
produced O
higher O
molecular O
alignment O
within O
the O
fibers O
, O
as O
determined O
by O
X O
- O
ray O
diffraction O
and O
scanning O
electron O
microscopy O
. O

The O
specific O
modulus O
of O
trGNR O
fibers O
is O
higher O
than O
that O
of O
the O
commercial O
general O
purpose O
carbon B
fibers O
and O
commonly O
used O
metals O
such O
as O
Al B
, O
Cu B
, O
and O
steel B
. O

The O
properties O
of O
trGNR O
fibers O
can O
be O
further O
improved O
by O
optimizing O
the O
spinning O
conditions O
with O
higher O
draw O
ratio O
, O
annealing O
conditions O
with O
higher O
pretensions O
, O
and O
using O
longer O
flake O
GONRs O
. O

This O
technique O
is O
a O
new O
high O
- O
carbon B
- O
yield O
approach O
to O
make O
the O
next O
generation O
carbon B
fibers O
based O
on O
solution O
- O
based O
liquid O
crystal O
phase O
spinning O
. O

Time O
- O
dependent O
changes O
in O
hepatic O
and O
intestinal O
induction O
of O
cytochrome O
P450 O
3A O
after O
administration O
of O
dexamethasone B
to O
rats O
. O

Abstract O
1 O
. O
We O
investigated O
the O
effects O
of O
the O
dose O
of O
and O
the O
number O
of O
times O
an O
inducer O
was O
administered O
and O
the O
duration O
of O
induction O
of O
hepatic O
and O
intestinal O
cytochrome O
P450 O
3A O
( O
CYP3A O
) O
in O
rats O
using O
dexamethasone B
21 I
- I
phosphate I
( O
DEX B
- I
P I
) O
and O
midazolam B
( O
MDZ B
) O
as O
an O
inducer O
and O
a O
substrate O
to O
CYP3A O
, O
respectively O
. O

2 O
. O
The O
number O
of O
times O
DEX B
- I
P I
was O
administered O
was O
not O
a O
significant O
factor O
in O
the O
induction O
of O
either O
hepatic O
or O
intestinal O
CYP3A O
; O
however O
, O
administration O
of O
DEX B
- I
P I
multiple O
times O
markedly O
decreased O
the O
bioavailability O
of O
DEX B
- I
P I
by O
self O
- O
induction O
of O
CYP3A O
. O

3 O
. O
CYP3A O
induction O
in O
the O
liver O
increased O
depending O
on O
the O
dose O
of O
DEX B
- I
P I
, O
whereas O
that O
in O
intestine O
showed O
a O
mild O
increase O
, O
but O
the O
induction O
level O
was O
almost O
constant O
regardless O
of O
the O
dose O
of O
DEX B
- I
P I
. O

4 O
. O
Administration O
of O
a O
single O
dose O
of O
DEX B
- I
P I
showed O
a O
temporal O
increase O
in O
CYP3A O
activity O
in O
both O
tissues O
and O
the O
induction O
ratios O
reached O
maximum O
values O
at O
12 O
h O
after O
DEX B
- I
P I
administration O
. O

On O
the O
other O
hand O
, O
a O
mild O
increase O
of O
CYP3A O
activity O
, O
which O
lasted O
for O
at O
least O
48 O
h O
, O
was O
observed O
in O
both O
tissues O
after O
administration O
of O
multiple O
doses O
. O

5 O
. O
Some O
physiological O
compounds O
such O
as O
cytokines O
might O
be O
involved O
in O
decreasing O
the O
CYP3A O
activity O
to O
maintain O
homeostasis O
of O
the O
body O
. O

Photoinduced O
formation O
mechanism O
of O
the O
thymine B
- O
thymine B
( O
6 O
- O
4 O
) O
adduct O
. O

The O
photoinduced O
mechanism O
leading O
to O
the O
formation O
of O
the O
thymine B
- O
thymine B
( O
6 O
- O
4 O
) O
photolesion O
has O
been O
studied O
by O
using O
the O
CASPT2 O
/ O
/ O
CASSCF O
approach O
over O
a O
dinucleotide B
model O
in O
vacuo O
. O

Following O
light O
absorption O
, O
localization O
of O
the O
excitation O
on O
a O
single O
thymine B
leads O
to O
fast O
singlet O
- O
triplet O
crossing O
that O
populates O
the O
triplet O
( O
3 O
) O
( O
n O
pi O
* O
) O
state O
of O
thymine B
. O

This O
state O
, O
displaying O
an O
elongated O
C B
( I
4 I
) I
= I
O I
bond O
, O
triggers O
( O
6 O
- O
4 O
) O
dimer O
formation O
by O
reaction O
with O
the O
C B
( I
5 I
) I
= I
C I
( I
6 I
) I
double O
bond O
of O
the O
adjacent O
thymine B
, O
followed O
by O
a O
second O
intersystem O
crossing O
, O
which O
acts O
as O
a O
gate O
between O
the O
excited O
state O
of O
the O
reactant O
and O
the O
ground O
state O
of O
the O
photoproduct O
. O

The O
requirement O
of O
localized O
excitation O
on O
just O
one O
thymine B
, O
whose O
main O
decay O
channel O
( O
by O
radiationless O
repopulation O
of O
its O
ground O
state O
) O
is O
nonphotochemical O
, O
can O
rationalize O
the O
experimentally O
observed O
low O
quantum O
yield O
of O
formation O
for O
the O
thymine B
- O
thymine B
( O
6 O
- O
4 O
) O
adduct O
. O

Assessment O
of O
effects O
of O
IR O
and O
IPC O
on O
activities O
of O
cytochrome O
P450 O
isozymes O
in O
rats O
by O
a O
five O
- O
drug O
cocktail O
approach O
. O

Abstract O
Background O
and O
objective O
: O
To O
evaluate O
the O
effects O
of O
ischemia O
and O
reperfusion O
( O
IR O
) O
and O
ischemic O
preconditioning O
( O
IPC O
) O
on O
the O
metabolic O
activities O
of O
cytochrome O
P450 O
( O
CYP O
) O
isozymes O
in O
rats O
by O
a O
five O
- O
drug O
cocktail O
approach O
. O

Methods O
: O
Cocktail O
approach O
was O
used O
to O
evaluate O
the O
influence O
of O
IR O
and O
IPC O
on O
the O
activities O
of O
CYP1A2 O
, O
CYP2C9 O
, O
CYP2E1 O
, O
CYP2D6 O
and O
CYP3A4 O
, O
which O
were O
reflected O
by O
the O
changes O
of O
pharmacokinetic O
parameters O
of O
five O
specific O
probe O
drugs O
: O
caffeine B
, O
chlorzoxazone B
, O
tolbutamide B
, O
metoprolol B
and O
midazolam B
, O
respectively O
. O

Rats O
were O
randomly O
divided O
into O
IR O
, O
IPC O
and O
sham O
groups O
, O
and O
then O
injected O
the O
mixture O
of O
five O
probe O
drugs O
. O

Blood O
samples O
were O
collected O
at O
a O
series O
of O
time O
- O
points O
and O
the O
concentrations O
of O
probe O
drugs O
in O
plasma O
were O
determined O
by O
a O
HPLC O
method O
with O
UV O
detection O
. O

The O
pharmacokinetic O
parameters O
were O
calculated O
by O
the O
software O
of O
DAS O
2 O
. O
0 O
. O

Results O
: O
The O
parameters O
including O
t O
( O
1 O
/ O
2 O
beta O
) O
, O
CLs O
, O
AUC O
, O
MRT O
and O
K O
( O
10 O
) O
exhibited O
a O
similar O
tendency O
for O
both O
IR O
and O
IPC O
groups O
. O

Compared O
with O
sham O
group O
, O
CLs O
and O
K O
( O
10 O
) O
of O
five O
probe O
drugs O
were O
significantly O
lower O
( O
p O
< O
0 O
. O
05 O
) O
, O
AUC O
and O
t O
( O
1 O
/ O
2 O
beta O
) O
of O
five O
or O
some O
probe O
drugs O
were O
significantly O
increased O
in O
IR O
and O
IPC O
groups O
( O
p O
< O
0 O
. O
05 O
) O
. O

Compared O
with O
IPC O
group O
, O
CLs O
of O
five O
probe O
drugs O
were O
decreased O
and O
AUC O
were O
significantly O
increased O
in O
the O
IR O
group O
( O
p O
< O
0 O
. O
05 O
) O
. O

Conclusion O
: O
IR O
can O
variably O
decrease O
the O
activities O
of O
CYP O
isozymes O
in O
rats O
and O
this O
decrease O
can O
be O
attenuated O
by O
IPC O
. O

In O
vitro O
toxicity O
of O
camalexin B
derivatives O
in O
human O
cancer O
and O
non O
- O
cancer O
cells O
. O

The O
aim O
of O
the O
study O
was O
to O
investigate O
the O
cytotoxic O
activity O
of O
camalexin B
and O
its O
five O
synthetic O
derivatives O
in O
cancer O
and O
non O
- O
cancer O
cells O
. O

In O
cancer O
cells O
the O
benzocamalexin B
( O
BC O
) O
displayed O
the O
most O
potent O
activity O
with O
an O
IC O
value O
of O
23 O
. O
3 O
- O
30 O
. O
1 O
mu O
mol O
/ O
L O
. O

On O
the O
other O
hand O
, O
minimal O
toxicity O
( O
IC O
> O
100 O
. O
0 O
mu O
mol O
/ O
L O
) O
in O
non O
- O
cancer O
cells O
was O
observed O
. O

Based O
on O
these O
results O
, O
BC O
was O
selected O
for O
further O
studies O
. O

Flow O
cytometric O
analysis O
revealed O
a O
BC O
- O
induced O
arrest O
of O
the O
cell O
cycle O
in O
the O
G2 O
phase O
associated O
with O
downregulation O
of O
alpha O
- O
tubulin O
, O
alpha O
1 O
- O
tubulin O
, O
beta O
5 O
- O
tubulin O
expression O
. O

These O
findings O
suggest O
that O
the O
inhibitory O
effect O
of O
BC O
is O
mediated O
via O
inhibition O
of O
microtubule O
formation O
. O

Moreover O
, O
BC O
downregulated O
the O
expression O
of O
microtubule O
- O
related O
protein O
indicating O
the O
effect O
of O
this O
compound O
on O
microtubule O
assembly O
. O

After O
treatment O
with O
BC O
increase O
of O
the O
sub O
- O
G O
DNA O
content O
fraction O
was O
noted O
which O
is O
considered O
to O
be O
a O
marker O
of O
apoptotic O
cell O
death O
. O

Apoptosis O
was O
also O
confirmed O
by O
DNA O
fragmentation O
assay O
. O

Moreover O
, O
quantitative O
real O
- O
time O
PCR O
showed O
that O
BC O
downregulated O
the O
expression O
of O
antiapoptotic O
genes O
Bcl O
- O
2 O
and O
Bcl O
- O
xL O
and O
upregulated O
the O
expression O
of O
proapoptotic O
Bax O
. O

Taken O
together O
, O
our O
study O
suggests O
that O
the O
blockade O
of O
cell O
cycle O
progression O
and O
initiation O
of O
apoptosis O
may O
play O
an O
important O
role O
in O
the O
antiproliferative O
activity O
of O
BC O
in O
human O
cancer O
cells O
. O

Antivenom O
therapy O
of O
carpet O
viper O
( O
Echis O
ocellatus O
) O
envenoming O
: O
Effectiveness O
and O
strategies O
for O
delivery O
in O
West O
Africa O
. O

In O
West O
Africa O
, O
response O
to O
specific O
, O
geographically O
appropriate O
, O
antivenom O
is O
often O
dramatic O
following O
carpet O
viper O
( O
Echis O
ocellatus O
) O
envenoming O
with O
rapid O
restoration O
of O
blood O
coagulability O
and O
resolution O
of O
spontaneous O
haemorrhage O
. O

Envenoming O
from O
Australasian O
snakes O
causing O
similar O
coagulopathies O
may O
respond O
less O
dramatically O
and O
the O
effectiveness O
of O
antivenom O
is O
being O
questioned O
. O

Here O
we O
have O
reviewed O
and O
re O
- O
analysed O
all O
published O
preclinical O
and O
clinical O
studies O
on O
envenoming O
and O
antivenom O
therapy O
conducted O
in O
West O
Africa O
to O
determine O
the O
effectiveness O
of O
antivenom O
. O

22 O
studies O
provided O
relevant O
information O
: O
12 O
observational O
studies O
, O
4 O
RCTs O
and O
6 O
preclinical O
studies O
. O

Four O
comparative O
studies O
confirmed O
statistically O
significant O
protection O
against O
mortality O
ranging O
from O
57 O
to O
87 O
% O
using O
specific O
antivenoms O
compared O
to O
non O
- O
specific O
or O
no O
antivenoms O
. O

Meta O
- O
analysis O
estimated O
combined O
Odds O
Ratio O
( O
95 O
% O
CI O
) O
of O
0 O
. O
25 O
( O
0 O
. O
14 O
- O
0 O
. O
45 O
) O
of O
dying O
among O
those O
treated O
with O
specific O
antivenom O
or O
75 O
% O
( O
95 O
% O
CI O
: O
55 O
- O
86 O
% O
) O
protection O
against O
death O
. O

Mortality O
more O
than O
doubled O
during O
times O
when O
stocks O
of O
reliable O
antivenoms O
ran O
out O
, O
with O
Relative O
Risk O
( O
95 O
% O
CI O
) O
] O
of O
2 O
. O
33 O
( O
1 O
. O
26 O
- O
4 O
. O
06 O
) O
. O

Serum O
kinetics O
of O
venom O
antigen O
/ O
antivenom O
levels O
also O
confirmed O
that O
decline O
of O
venom O
antigen O
levels O
coincided O
with O
resolution O
of O
coagulopathy O
while O
decline O
of O
antivenom O
levels O
was O
associated O
with O
venom O
antigen O
reappearance O
and O
recurrence O
of O
coagulopathy O
. O

Preclinical O
and O
antivenomics O
analysis O
confirmed O
efficacy O
of O
regionally O
appropriate O
antivenoms O
against O
E O
. O
ocellatus O
and O
related O
species O
' O
venoms O
in O
Sub O
- O
Saharan O
Africa O
but O
not O
against O
Asian O
Echis O
carinatus O
venom O
. O

Antivenoms O
raised O
against O
E O
. O
carinatus O
were O
ineffective O
in O
human O
studies O
. O

In O
West O
Africa O
, O
specific O
antivenom O
is O
effective O
in O
managing O
carpet O
viper O
envenoming O
. O

A O
centralized O
hub O
- O
and O
- O
spoke O
strategy O
is O
suggested O
for O
broadening O
antivenom O
access O
to O
endemic O
rural O
areas O
together O
with O
instituting O
quality O
assurance O
, O
standardization O
and O
manpower O
training O
. O

Benefits O
, O
risks O
, O
cost O
- O
effectiveness O
and O
feasibility O
of O
the O
approach O
should O
be O
formally O
assessed O
. O

Medical O
aspects O
of O
bio O
- O
terrorism O
. O

INTRODUCTION O
: O
Bioterrorism O
is O
a O
terrorist O
action O
involving O
the O
intentional O
release O
or O
dissemination O
of O
a O
biological O
warfare O
agent O
( O
BWA O
) O
, O
which O
includes O
some O
bacteria O
, O
viruses O
, O
rickettsiae O
, O
fungi O
or O
biological O
toxins O
. O

BWA O
is O
a O
naturally O
occurring O
or O
human O
- O
modified O
form O
that O
may O
kill O
or O
incapacitate O
humans O
, O
animals O
or O
plants O
as O
an O
act O
of O
war O
or O
terrorism O
. O

BWA O
is O
a O
weapon O
of O
choice O
for O
mass O
destruction O
and O
terrorism O
, O
because O
of O
the O
incubation O
period O
, O
less O
effective O
amount O
than O
chemical O
warfare O
agents O
, O
easily O
distribution O
, O
odorless O
, O
colorless O
, O
difficult O
to O
detect O
, O
no O
need O
of O
specialized O
equipment O
for O
production O
and O
naturally O
distribution O
which O
can O
easily O
be O
obtained O
. O

BWA O
may O
be O
disseminating O
as O
an O
aerosol O
, O
spray O
, O
explosive O
device O
, O
and O
by O
food O
or O
water O
. O

CLASSIFICATION O
: O
Based O
on O
the O
risk O
for O
human O
health O
, O
BWAs O
have O
been O
prioritized O
into O
three O
categories O
of O
A O
, O
B O
and O
C O
. O

Category O
A O
includes O
microorganisms O
or O
toxins O
that O
easily O
spread O
, O
leading O
to O
intoxication O
with O
high O
death O
rates O
such O
as O
Anthrax O
, O
Botulism O
, O
Plague O
, O
Smallpox O
, O
Tularemia O
and O
Viral O
hemorrhagic O
fevers O
. O

Category O
B O
has O
lower O
toxicity O
with O
wider O
range O
, O
including O
Staphylococcal O
Entrotoxin O
type O
B O
( O
SEB O
) O
, O
Epsilon O
toxin O
of O
Clostridium O
perfringens O
, O
Ricin O
, O
Saxotoxins O
, O
Abrin O
and O
Trichothecene B
mycotoxins O
. O

The O
C O
category O
includes O
emerging O
pathogens O
that O
could O
also O
be O
engineered O
for O
mass O
spread O
such O
as O
Hanta O
viruses O
, O
multidrug O
- O
resistant O
tuberculosis O
, O
Nipah O
virus O
, O
the O
tick O
- O
borne O
encephalitis O
viruses O
, O
hemorrhagic O
fever O
viruses O
and O
yellow O
fever O
. O

CLINICAL O
MANIFESTATIONS O
OF O
BIOTOXINS O
IN O
HUMAN O
: O
Clinical O
features O
and O
severity O
of O
intoxication O
depend O
on O
the O
agent O
and O
exposed O
dose O
, O
route O
of O
entry O
, O
individual O
variation O
and O
environmental O
factors O
. O

Onset O
of O
symptoms O
varies O
from O
2 O
- O
24 O
h O
in O
Ricin O
to O
24 O
- O
96 O
h O
in O
Botulism O
. O

Clinical O
manifestations O
also O
vary O
from O
irritation O
of O
the O
eyes O
, O
skin O
and O
mucus O
membranes O
in O
T O
( O
2 O
) O
toxin O
to O
an O
acute O
flaccid O
paralysis O
of O
bilateral O
cranial O
nerve O
impairment O
of O
descending O
manner O
in O
botulism O
. O

Most O
of O
the O
pyrogenic O
toxins O
such O
as O
SEB O
produce O
the O
same O
signs O
and O
symptoms O
as O
toxic O
shock O
syndrome O
including O
a O
rapid O
drop O
in O
blood O
pressure O
, O
elevated O
temperature O
, O
and O
multiple O
organ O
failure O
. O

MANAGEMENT O
: O
There O
is O
no O
specific O
antidote O
or O
effective O
treatment O
for O
most O
of O
the O
biotoxins O
. O

The O
clinical O
management O
is O
thus O
more O
supportive O
and O
symptomatic O
. O

Fortunately O
vaccines O
are O
now O
available O
for O
most O
of O
BWA O
. O

Therefore O
, O
immunization O
of O
personnel O
at O
risk O
of O
exposure O
is O
recommended O
. O

CONCLUSION O
: O
Biotoxins O
are O
very O
wide O
and O
bioterrorism O
is O
a O
heath O
and O
security O
threat O
that O
may O
induce O
national O
and O
international O
problems O
. O

Therefore O
, O
the O
security O
authorities O
, O
health O
professional O
and O
even O
public O
should O
be O
aware O
of O
bioterrorism O
. O

Sonochemical O
effects O
on O
free O
phenolic B
acids I
under O
ultrasound O
treatment O
in O
a O
model O
system O
. O

Sonochemical O
effects O
on O
seven O
free O
phenolic B
acids I
under O
ultrasound O
treatment O
in O
a O
model O
system O
have O
been O
investigated O
. O

The O
degradation O
products O
have O
also O
been O
tentatively O
identified O
by O
FTIR O
and O
HPLC O
- O
UV O
- O
ESIMS O
. O

Five O
phenolic B
acids I
( O
protocatechuic B
acid I
, O
p B
- I
hydroxybenzoic I
acid I
, O
vanillic B
acid I
, O
p B
- I
coumaric I
acid I
, O
and O
ferulic B
acid I
) O
proved O
to O
be O
stable O
, O
while O
two O
others O
( O
caffeic B
acid I
and O
sinapic B
acid I
) O
were O
degraded O
under O
ultrasound O
treatment O
. O

The O
nature O
of O
the O
solvent O
and O
the O
temperature O
has O
been O
identified O
as O
important O
factors O
in O
determining O
the O
degradation O
reaction O
. O

Liquid O
height O
, O
ultrasonic O
intensity O
, O
and O
duty O
cycle O
of O
the O
ultrasound O
exposure O
affected O
only O
the O
degradation O
rate O
and O
did O
not O
change O
the O
nature O
of O
the O
degradation O
. O

The O
degradation O
rates O
of O
caffeic B
acid I
and O
sinapic B
acid I
decreased O
with O
increasing O
temperature O
. O

The O
degradation O
kinetics O
of O
these O
two O
acids O
under O
ultrasound O
conformed O
to O
zeroth O
- O
order O
reactions O
at O
- O
5 O
to O
25 O
degrees O
C O
. O

Both O
decomposition O
and O
polymerization O
reactions O
occurred O
when O
caffeic B
acid I
and O
sinapic B
acid I
were O
subjected O
to O
ultrasound O
. O

Degradation O
products O
, O
such O
as O
the O
corresponding O
decarboxylation O
products O
and O
their O
dimers O
, O
have O
been O
tentatively O
identified O
. O

Characterization O
of O
a O
key O
aminoglycoside B
phosphotransferase O
in O
gentamicin B
biosynthesis O
. O

Gentamicin B
is O
an O
aminoglycoside B
antibiotic O
obtained O
from O
cultures O
of O
Micromonospora O
as O
the O
important O
anti O
- O
infective O
agents O
. O

Gentamicin B
which O
lacks O
3 B
' I
- I
hydroxyl I
group O
can O
avoid O
the O
attack O
from O
the O
modification O
enzymes O
of O
antibiotic O
- O
resistant O
bacteria O
in O
clinic O
. O

Consequently O
, O
C O
- O
3 O
' O
dehydroxylation O
is O
the O
key O
step O
in O
gentamicins B
biosynthesis O
. O

We O
suppose O
that O
there O
are O
some O
enzymes O
responsible O
for O
converting O
intermediate O
JI B
- I
20A I
to O
3 O
' O
, O
4 O
' O
- O
bisdehydroxylated O
final O
product O
gentamicin B
C I
( O
1a O
) O
, O
while O
phosphorylation O
of O
3 B
' I
- I
OH I
is O
possibly O
the O
first O
step O
for O
C O
- O
3 O
' O
dehydroxylation O
. O

The O
gentamicin B
biosynthetic O
gene O
gntI O
, O
encoding O
an O
aminoglycoside B
phosphotransferase O
, O
was O
cloned O
from O
Micromonospora O
echinospora O
ATCC15835 O
and O
overexpressed O
in O
Escherichia O
coli O
. O

The O
resulting O
phosphotransferase O
was O
purified O
, O
and O
the O
kinetic O
parameters O
for O
Kanamycin B
A I
, O
Kanamycin B
B I
, O
Neomycin B
B I
and O
Amikacin B
were O
determined O
. O

Elucidation O
of O
NMR O
data O
of O
phosphorylated B
kanamycin I
B I
has O
unambiguously O
demonstrated O
a O
regiospecific O
phosphorylation O
of O
3 B
' I
- I
hydroxyl I
of O
the O
6 B
- I
aminohexose I
ring O
. O

The O
results O
described O
here O
partly O
confirm O
that O
the O
3 O
' O
- O
dehydroxylation O
step O
is O
preceded O
by O
a O
3 O
' O
phosphorylation O
step O
. O

It O
is O
predicted O
that O
GntI O
belongs O
to O
a O
new O
aminoglycoside B
phosphotransferase O
group O
involved O
with O
aminoglycoside B
antibiotics O
biosynthesis O
pathway O
. O

Relationship O
of O
cellular O
topoisomerase O
II O
alpha O
inhibition O
to O
cytotoxicity O
and O
published O
genotoxicity O
of O
fluoroquinolone B
antibiotics O
in O
V79 O
cells O
. O

Fluoroquinolone B
( O
FQ O
) O
antibiotics O
are O
bacteriocidal O
through O
inhibition O
of O
the O
bacterial O
gyrase O
and O
at O
sufficient O
concentrations O
in O
vitro O
, O
they O
can O
inhibit O
the O
homologous O
eukaryotic O
topoisomerase O
( O
TOPO O
) O
II O
enzyme O
. O

FQ O
exert O
a O
variety O
of O
genotoxic O
effects O
in O
mammalian O
systems O
through O
mechanisms O
not O
yet O
established O
, O
but O
which O
are O
postulated O
to O
involve O
inhibition O
of O
TOPO O
II O
enzymes O
. O

To O
assess O
the O
relationship O
of O
inhibition O
of O
cell O
nuclear O
TOPO O
II O
to O
cytotoxicity O
and O
reported O
genotoxicity O
, O
two O
FQ O
, O
clinafloxacin B
( O
CLFX B
) O
and O
lomefloxacin B
( O
LOFX B
) O
, O
having O
available O
genotoxicity O
data O
showing O
substantial O
differences O
with O
CLFX B
being O
more O
potent O
than O
LOFX B
, O
were O
selected O
for O
study O
. O

The O
relative O
inhibitory O
activities O
of O
these O
FQ O
on O
nuclear O
TOPO O
II O
alpha O
in O
cultured O
Chinese O
hamster O
lung O
fibroblasts O
( O
V79 O
cells O
) O
over O
dose O
ranges O
and O
at O
equimolar O
concentrations O
were O
assessed O
by O
measuring O
nuclear O
stabilized O
cleavage O
complexes O
of O
TOPO O
II O
alpha O
- O
DNA O
. O

Cytotoxicity O
was O
measured O
by O
relative O
cell O
counts O
. O

Both O
FQ O
inhibited O
V79 O
cell O
nuclear O
TOPO O
II O
alpha O
. O

The O
lowest O
- O
observed O
- O
adverse O
- O
effect O
levels O
for O
TOPO O
II O
alpha O
inhibition O
were O
55 O
mu O
M O
for O
CLFX O
, O
and O
516 O
mu O
M O
for O
LOFX O
. O

The O
no O
- O
observed O
- O
adverse O
- O
effect O
- O
levels O
were O
41 O
mu O
M O
for O
CLFX O
, O
and O
258 O
mu O
M O
for O
LOFX O
. O

At O
equimolar O
concentrations O
( O
175 O
mu O
M O
) O
, O
CLFX O
was O
more O
potent O
than O
LOFX O
. O

Likewise O
, O
CLFX O
was O
more O
cytotoxic O
than O
LOFX O
. O

Thus O
, O
the O
two O
FQ O
, O
inhibited O
TOPO O
II O
alpha O
in O
intact O
V79 O
cells O
, O
differed O
in O
their O
potencies O
and O
exhibited O
no O
- O
observed O
- O
adverse O
- O
effect O
levels O
. O

These O
findings O
are O
in O
concordance O
with O
published O
genotoxicity O
data O
and O
observed O
cytotoxicity O
. O

IGF O
- O
I O
signaling O
is O
essential O
for O
FSH O
stimulation O
of O
AKT O
and O
steroidogenic O
genes O
in O
granulosa O
cells O
. O

FSH O
and O
IGF O
- O
I O
synergistically O
stimulate O
gonadal O
steroid B
production O
; O
conversely O
, O
silencing O
the O
FSH O
or O
the O
IGF O
- O
I O
genes O
leads O
to O
infertility O
and O
hypogonadism O
. O

To O
determine O
the O
molecular O
link O
between O
these O
hormones O
, O
we O
examined O
the O
signaling O
cross O
talk O
downstream O
of O
their O
receptors O
. O

In O
human O
and O
rodent O
granulosa O
cells O
( O
GCs O
) O
, O
IGF O
- O
I O
potentiated O
the O
stimulatory O
effects O
of O
FSH O
and O
cAMP B
on O
the O
expression O
of O
steroidogenic O
genes O
. O

In O
contrast O
, O
inhibition O
of O
IGF O
- O
I O
receptor O
( O
IGF O
- O
IR O
) O
activity O
or O
expression O
using O
pharmacological O
, O
genetic O
, O
or O
biochemical O
approaches O
prevented O
the O
FSH O
- O
and O
cAMP B
- O
induced O
expression O
of O
steroidogenic O
genes O
and O
estradiol B
production O
. O

In O
vivo O
experiments O
demonstrated O
that O
IGF O
- O
IR O
inactivation O
reduces O
the O
stimulation O
of O
steroidogenic O
genes O
and O
follicle O
growth O
by O
gonadotropins O
. O

FSH O
or O
IGF O
- O
I O
alone O
stimulated O
protein O
kinase O
B O
( O
PKB O
) O
, O
which O
is O
also O
known O
as O
AKT O
and O
in O
combination O
synergistically O
increased O
AKT O
phosphorylation O
. O

Remarkably O
, O
blocking O
IGF O
- O
IR O
expression O
or O
activity O
decreased O
AKT O
basal O
activity O
and O
abolished O
AKT O
activation O
by O
FSH O
. O

In O
GCs O
lacking O
IGF O
- O
IR O
activity O
, O
FSH O
stimulation O
of O
Cyp19 O
expression O
was O
rescued O
by O
overexpression O
of O
constitutively O
active O
AKT O
. O

Our O
findings O
demonstrate O
, O
for O
the O
first O
time O
, O
that O
in O
human O
, O
mouse O
, O
and O
rat O
GCs O
, O
the O
well O
- O
known O
stimulatory O
effect O
of O
FSH O
on O
Cyp19 O
and O
AKT O
depends O
on O
IGF O
- O
I O
and O
on O
the O
expression O
and O
activation O
of O
the O
IGF O
- O
IR O
. O

Palladium B
nanoparticles O
supported O
on O
nitrogen B
- O
doped O
HOPG O
: O
a O
surface O
science O
and O
electrochemical O
study O
. O

We O
have O
investigated O
by O
photoemission O
spectroscopy O
and O
scanning O
tunnelling O
microscopy O
what O
are O
the O
chemical O
and O
structural O
changes O
induced O
by O
nitrogen B
ion O
implantation O
( O
500 O
eV O
) O
on O
highly O
oriented O
pyrolytic O
graphite B
and O
how O
the O
defects O
induced O
by O
this O
process O
modify O
the O
growth O
and O
thermal O
stability O
of O
palladium B
nanoparticles O
, O
deposited O
in O
situ O
by O
physical O
vapour O
deposition O
. O

Since O
nitrogen B
derived O
defects O
are O
mostly O
buried O
below O
the O
surface O
, O
they O
are O
not O
accessible O
for O
a O
chemical O
interaction O
with O
metal O
nanoparticles O
; O
however O
, O
the O
amorphization O
induced O
by O
the O
ion O
beam O
in O
the O
outermost O
layers O
of O
the O
substrate O
beneficially O
affects O
the O
metal O
morphology O
, O
limiting O
the O
size O
of O
the O
nanoparticles O
and O
improving O
their O
thermal O
stability O
. O

The O
supported O
nanoparticles O
have O
been O
tested O
towards O
the O
oxygen B
reduction O
reaction O
indicating O
that O
the O
electrochemical O
activity O
does O
not O
depend O
significantly O
on O
the O
ion O
implantation O
, O
but O
mostly O
on O
the O
amount O
of O
palladium B
. O

Metabolic O
profiles O
of O
brain O
metastases O
. O

Metastasis O
to O
the O
brain O
is O
a O
feared O
complication O
of O
systemic O
cancer O
, O
associated O
with O
significant O
morbidity O
and O
poor O
prognosis O
. O

A O
better O
understanding O
of O
the O
tumor O
metabolism O
might O
help O
us O
meet O
the O
challenges O
in O
controlling O
brain O
metastases O
. O

The O
study O
aims O
to O
characterize O
the O
metabolic O
profile O
of O
brain O
metastases O
of O
different O
origin O
using O
high O
resolution O
magic O
angle O
spinning O
( O
HR O
- O
MAS O
) O
magnetic O
resonance O
spectroscopy O
( O
MRS O
) O
to O
correlate O
the O
metabolic O
profiles O
to O
clinical O
and O
pathological O
information O
. O

Biopsy O
samples O
of O
human O
brain O
metastases O
( O
n O
= O
49 O
) O
were O
investigated O
. O

A O
significant O
correlation O
between O
lipid O
signals O
and O
necrosis O
in O
brain O
metastases O
was O
observed O
( O
p O
< O
0 O
. O
01 O
) O
, O
irrespective O
of O
their O
primary O
origin O
. O

The O
principal O
component O
analysis O
( O
PCA O
) O
showed O
that O
brain O
metastases O
from O
malignant O
melanomas O
cluster O
together O
, O
while O
lung O
carcinomas O
were O
metabolically O
heterogeneous O
and O
overlap O
with O
other O
subtypes O
. O

Metastatic O
melanomas O
have O
higher O
amounts O
of O
glycerophosphocholin B
than O
other O
brain O
metastases O
. O

A O
significant O
correlation O
between O
microscopically O
visible O
lipid O
droplets O
estimated O
by O
Nile B
Red I
staining O
and O
MR O
visible O
lipid O
signals O
was O
observed O
in O
metastatic O
lung O
carcinomas O
( O
p O
= O
0 O
. O
01 O
) O
, O
indicating O
that O
the O
proton O
MR O
visible O
lipid O
signals O
arise O
from O
cytoplasmic O
lipid O
droplets O
. O

MRS O
- O
based O
metabolomic O
profiling O
is O
a O
useful O
tool O
for O
exploring O
the O
metabolic O
profiles O
of O
metastatic O
brain O
tumors O
. O

Low O
oxygen B
tension O
maintains O
multipotency O
, O
whereas O
normoxia O
increases O
differentiation O
of O
mouse O
bone O
marrow O
stromal O
cells O
. O

Optimization O
of O
mesenchymal O
stem O
cells O
( O
MSC O
) O
culture O
conditions O
is O
of O
great O
importance O
for O
their O
more O
successful O
application O
in O
regenerative O
medicine O
. O

O B
( I
2 I
) I
regulates O
various O
aspects O
of O
cellular O
biology O
and O
, O
in O
vivo O
, O
MSC O
are O
exposed O
to O
different O
O B
( I
2 I
) I
concentrations O
spanning O
from O
very O
low O
tension O
in O
the O
bone O
marrow O
niche O
, O
to O
higher O
amounts O
in O
wounds O
. O

In O
our O
present O
work O
, O
we O
isolated O
mouse O
bone O
marrow O
stromal O
cells O
( O
BMSC O
) O
and O
showed O
that O
they O
contained O
a O
population O
meeting O
requirements O
for O
MSC O
definition O
. O

In O
order O
to O
establish O
the O
effect O
of O
low O
O B
( I
2 I
) I
on O
cellular O
properties O
, O
we O
examined O
BSMC O
cultured O
under O
hypoxic O
( O
3 O
% O
O B
( I
2 I
) I
) O
conditions O
. O

Our O
results O
demonstrate O
that O
3 O
% O
O B
( I
2 I
) I
augmented O
proliferation O
of O
BMSC O
, O
as O
well O
as O
the O
formation O
of O
colonies O
in O
the O
colony O
- O
forming O
unit O
assay O
( O
CFU O
- O
A O
) O
, O
the O
percentage O
of O
quiescent O
cells O
, O
and O
the O
expression O
of O
stemness O
markers O
Rex O
- O
1 O
and O
Oct O
- O
4 O
, O
thereby O
suggesting O
an O
increase O
in O
the O
stemness O
of O
culture O
when O
exposed O
to O
hypoxia O
. O

In O
contrast O
, O
intrinsic O
differentiation O
processes O
were O
inhibited O
by O
3 O
% O
O B
( I
2 I
) I
. O

Overall O
yield O
of O
differentiation O
was O
dependent O
on O
the O
adjustment O
of O
O B
( I
2 I
) I
tension O
to O
the O
specific O
stage O
of O
BMSC O
culture O
. O

Thus O
, O
we O
established O
a O
strategy O
for O
efficient O
BMSC O
in O
vitro O
differentiation O
using O
an O
initial O
phase O
of O
cell O
propagation O
at O
3 O
% O
O B
( I
2 I
) I
, O
followed O
by O
differentiation O
stage O
at O
21 O
% O
O B
( I
2 I
) I
. O

We O
also O
demonstrated O
that O
3 O
% O
O B
( I
2 I
) I
affected O
BMSC O
differentiation O
in O
p53 O
and O
reactive O
oxygen B
species O
( O
ROS O
) O
independent O
pathways O
. O

Our O
findings O
can O
significantly O
contribute O
to O
the O
obtaining O
of O
high O
- O
quality O
MSC O
for O
effective O
cell O
therapy O
. O

The O
first O
dehydration O
and O
the O
competing O
reaction O
pathways O
of O
glucose B
homogeneously O
and O
heterogeneously O
catalyzed O
by O
acids O
. O

The O
dehydration O
mechanisms O
for O
glucose B
in O
beta B
- I
pyranose I
( O
BP O
) O
and O
in O
open O
- O
chain O
( O
OC O
) O
forms O
, O
catalyzed O
by O
acids O
homogeneously O
and O
heterogeneously O
, O
were O
investigated O
using O
density O
functional O
and O
two O
- O
layer O
ONIOM O
calculations O
. O

The O
first O
dehydration O
reaction O
and O
competing O
reaction O
pathways O
are O
the O
main O
focus O
of O
the O
present O
study O
. O

The O
energetics O
of O
five O
dehydration O
and O
two O
isomerization O
pathways O
were O
examined O
for O
the O
protonated O
form O
of O
BP O
in O
acidic O
aqueous O
solutions O
and O
the O
most O
favorable O
pathway O
of O
these O
was O
found O
to O
be O
the O
dehydration O
at O
the O
anomeric O
site O
. O

No O
dehydration O
pathway O
of O
OC O
glucose B
is O
favored O
over O
its O
isomerization O
to O
BP O
or O
to O
fructose B
. O

The O
relative O
ease O
of O
dehydration O
over O
isomerization O
depends O
on O
the O
selection O
of O
the O
reaction O
media O
for O
the O
protonated O
form O
of O
BP O
. O

These O
two O
reaction O
pathways O
catalyzed O
by O
a O
surface O
Br B
o O
nsted I
acid O
site O
were O
then O
examined O
and O
the O
isomerization O
pathway O
was O
found O
to O
be O
more O
favorable O
than O
dehydration O
at O
the O
anomeric O
site O
on O
a O
surface O
acid O
site O
. O

These O
mechanistic O
insights O
provide O
an O
important O
guide O
for O
the O
catalyst O
design O
/ O
selection O
of O
the O
reaction O
media O
for O
glucose B
dehydration O
. O

Early O
- O
Adulthood O
Cardiovascular O
Disease O
Risk O
Factor O
Profiles O
Among O
Individuals O
With O
and O
Without O
Diabetes O
in O
the O
Framingham O
Heart O
Study O
. O

OBJECTIVEMany O
studies O
of O
diabetes O
have O
examined O
risk O
factors O
at O
the O
time O
of O
diabetes O
diagnosis O
instead O
of O
considering O
the O
lifetime O
burden O
of O
adverse O
risk O
factor O
levels O
. O

We O
examined O
the O
30 O
- O
year O
cardiovascular O
disease O
( O
CVD O
) O
risk O
factor O
burden O
that O
participants O
have O
up O
to O
the O
time O
of O
diabetes O
diagnosis O
. O
RESEARCH O
DESIGN O
AND O
METHODSAmong O
participants O
free O
of O
CVD O
, O
incident O
diabetes O
cases O
( O
fasting O
plasma O
glucose B
> O
= O
126 O
mg O
/ O
dL O
or O
treatment O
) O
occurring O
at O
examinations O
2 O
through O
8 O
( O
1979 O
- O
2008 O
) O
of O
the O
Framingham O
Heart O
Study O
Offspring O
cohort O
were O
age O
- O
and O
sex O
- O
matched O
1 O
: O
2 O
to O
controls O
. O

CVD O
risk O
factors O
( O
hypertension O
, O
high O
LDL O
cholesterol B
, O
low O
HDL O
cholesterol B
, O
high O
triglycerides B
, O
obesity O
) O
were O
measured O
at O
the O
time O
of O
diabetes O
diagnosis O
and O
at O
time O
points O
10 O
, O
20 O
, O
and O
30 O
years O
prior O
. O

Conditional O
logistic O
regression O
was O
used O
to O
compare O
risk O
factor O
levels O
at O
each O
time O
point O
between O
diabetes O
cases O
and O
controls O
. O
RESULTSWe O
identified O
525 O
participants O
with O
new O
- O
onset O
diabetes O
who O
were O
matched O
to O
1 O
, O
049 O
controls O
( O
mean O
age O
, O
60 O
years O
; O
40 O
% O
women O
) O
. O

Compared O
with O
those O
without O
diabetes O
, O
individuals O
who O
eventually O
developed O
diabetes O
had O
higher O
levels O
of O
hypertension O
( O
odds O
ratio O
[ O
OR O
] O
, O
2 O
. O
2 O
; O
P O
= O
0 O
. O
003 O
) O
, O
high O
LDL O
( O
OR O
, O
1 O
. O
5 O
; O
P O
= O
0 O
. O
04 O
) O
, O
low O
HDL O
( O
OR O
, O
2 O
. O
1 O
; O
P O
= O
0 O
. O
0001 O
) O
, O
high O
triglycerides B
( O
OR O
, O
1 O
. O
7 O
; O
P O
= O
0 O
. O
04 O
) O
, O
and O
obesity O
( O
OR O
, O
3 O
. O
3 O
; O
P O
< O
0 O
. O
0001 O
) O
at O
time O
points O
30 O
years O
before O
diabetes O
diagnosis O
. O

After O
further O
adjustment O
for O
BMI O
, O
the O
ORs O
for O
hypertension O
( O
OR O
, O
1 O
. O
9 O
; O
P O
= O
0 O
. O
02 O
) O
and O
low O
HDL O
( O
OR O
, O
1 O
. O
7 O
; O
P O
= O
0 O
. O
01 O
) O
remained O
statistically O
significant O
. O
CONCLUSIONSCVD O
risk O
factors O
are O
increased O
up O
to O
30 O
years O
before O
diagnosis O
of O
diabetes O
. O

These O
findings O
highlight O
the O
importance O
of O
a O
life O
course O
approach O
to O
CVD O
risk O
factor O
identification O
among O
individuals O
at O
risk O
for O
diabetes O
. O

Television O
Viewing O
and O
Low O
Leisure O
- O
Time O
Physical O
Activity O
in O
Adolescence O
Independently O
Predict O
the O
Metabolic O
Syndrome O
in O
Mid O
- O
Adulthood O
. O

OBJECTIVEWe O
investigated O
whether O
television O
( O
TV O
) O
viewing O
and O
low O
leisure O
- O
time O
physical O
activity O
in O
adolescence O
predict O
the O
metabolic O
syndrome O
in O
mid O
- O
adulthood O
. O
RESEARCH O
DESIGN O
AND O
METHODSTV O
viewing O
habits O
and O
participation O
in O
leisure O
- O
time O
physical O
activity O
at O
age O
16 O
years O
were O
assessed O
by O
self O
- O
administered O
questionnaires O
in O
a O
population O
- O
based O
cohort O
in O
Northern O
Sweden O
. O

The O
presence O
of O
the O
metabolic O
syndrome O
at O
age O
43 O
years O
was O
ascertained O
in O
888 O
participants O
( O
82 O
% O
of O
the O
baseline O
sample O
) O
using O
the O
International O
Diabetes O
Federation O
criteria O
. O

Odds O
ratios O
( O
ORs O
) O
and O
CIs O
were O
calculated O
using O
logistic O
regression O
. O
RESULTSThe O
overall O
prevalence O
of O
the O
metabolic O
syndrome O
at O
age O
43 O
years O
was O
26 O
. O
9 O
% O
. O

Adjusted O
OR O
for O
the O
metabolic O
syndrome O
at O
age O
43 O
years O
was O
2 O
. O
14 O
( O
95 O
% O
CI O
1 O
. O
24 O
- O
3 O
. O
71 O
) O
for O
those O
who O
reported O
" O
watching O
several O
shows O
a O
day O
" O
versus O
" O
one O
show O
/ O
week O
" O
or O
less O
and O
2 O
. O
31 O
( O
1 O
. O
13 O
- O
4 O
. O
69 O
) O
for O
leisure O
- O
time O
physical O
activity O
" O
several O
times O
/ O
month O
" O
or O
less O
compared O
with O
" O
daily O
" O
leisure O
- O
time O
physical O
activity O
at O
age O
16 O
years O
. O

TV O
viewing O
at O
age O
16 O
years O
was O
associated O
with O
central O
obesity O
, O
low O
HDL O
cholesterol B
, O
and O
hypertension O
at O
age O
43 O
years O
, O
whereas O
low O
leisure O
- O
time O
physical O
activity O
at O
age O
16 O
years O
was O
associated O
with O
central O
obesity O
and O
triglycerides B
at O
age O
43 O
years O
. O
CONCLUSIONSBoth O
TV O
viewing O
and O
low O
leisure O
- O
time O
physical O
activity O
in O
adolescence O
independently O
predicted O
the O
metabolic O
syndrome O
and O
several O
of O
the O
metabolic O
syndrome O
components O
in O
mid O
- O
adulthood O
. O

These O
findings O
suggest O
that O
reduced O
TV O
viewing O
in O
adolescence O
, O
in O
addition O
to O
regular O
physical O
activity O
, O
may O
contribute O
to O
cardiometabolic O
health O
later O
in O
life O
. O

25 B
- I
Hydroxyvitamin I
D I
in O
Obese O
Youth O
Across O
the O
Spectrum O
of O
Glucose B
Tolerance O
From O
Normal O
to O
Prediabetes O
to O
Type O
2 O
Diabetes O
. O

OBJECTIVETo O
1 O
) O
determine O
if O
plasma O
25 B
- I
hydroxyvitamin I
D I
( O
25 B
[ I
OH I
] I
D I
) O
concentrations O
differ O
among O
obese O
youth O
with O
normal O
glucose B
tolerance O
( O
NGT O
) O
versus O
prediabetes O
versus O
type O
2 O
diabetes O
, O
and O
2 O
) O
assess O
the O
relationships O
between O
25 B
( I
OH I
) I
D I
and O
in O
vivo O
insulin O
sensitivity O
and O
beta O
- O
cell O
function O
in O
this O
cohort O
. O
RESEARCH O
DESIGN O
AND O
METHODSPlasma O
25 B
( I
OH I
) I
D I
concentrations O
were O
examined O
in O
banked O
specimens O
in O
9 O
- O
to O
20 O
- O
year O
- O
old O
obese O
youth O
( O

n O
= O
175 O
; O
male O
42 O
. O
3 O
% O
, O
black O
46 O
. O
3 O
% O
) O
( O
NGT O
, O
n O
= O
105 O
; O
impaired O
glucose B
tolerance O
[ O
IGT O
] O
, O
n O
= O
43 O
; O
type O
2 O
diabetes O
, O
n O
= O
27 O
) O
who O
had O
in O
vivo O
insulin O
sensitivity O
and O
secretion O
measured O
by O
hyperinsulinemic O
- O
euglycemic O
and O
hyperglycemic O
clamp O
techniques O
and O
had O
an O
assessment O
of O
total O
body O
composition O
and O
abdominal O
adiposity O
. O
RESULTSThe O
mean O
age O
and O
BMI O
of O
the O
subjects O
were O
14 O
. O
3 O
+ O
/ O
- O
2 O
. O
1 O
years O
and O
35 O
. O
7 O
+ O
/ O
- O

5 O
. O
6 O
kg O
/ O
m O
( O
2 O
) O
, O
respectively O
. O

BMI O
, O
plasma O
25 B
( I
OH I
) I
D I
, O
and O
the O
proportion O
of O
vitamin B
D I
- O
deficient O
and O
- O
insufficient O
children O
did O
not O
differ O
across O
the O
three O
groups O
. O

Furthermore O
, O
there O
was O
no O
association O
between O
25 B
( I
OH I
) I
D I
and O
in O
vivo O
insulin O
sensitivity O
or O
beta O
- O
cell O
function O
relative O
to O
insulin O
sensitivity O
( O
disposition O
index O
) O
in O
all O
groups O
combined O
or O
in O
each O
group O
separately O
. O
CONCLUSIONSOur O
data O
in O
obese O
youth O
show O
1 O
) O
no O
differences O
in O
plasma O
25 B
( I
OH I
) I
D I
concentrations O
across O
the O
glucose B
tolerance O
groups O
, O
and O
2 O
) O
no O
relationship O
between O
25 B
( I
OH I
) I
D I
and O
in O
vivo O
insulin O
sensitivity O
and O
beta O
- O
cell O
function O
relative O
to O
insulin O
sensitivity O
in O
any O
of O
the O
groups O
. O

It O
remains O
uncertain O
if O
enhancement O
of O
the O
vitamin B
D I
status O
could O
improve O
pathophysiological O
mechanisms O
of O
prediabetes O
and O
type O
2 O
diabetes O
in O
obese O
youth O
. O

Serum O
25 B
- I
hydroxyvitamin I
D I
, O
parathyroid O
hormone O
, O
and O
their O
association O
with O
metabolic O
syndrome O
in O
Chinese O
. O

Increasing O
evidence O
suggests O
that O
25 B
- I
hydroxyvitamin I
D I
[ O
25 B
( I
OH I
) I
D I
] O
and O
parathyroid O
hormone O
( O
PTH O
) O
levels O
are O
associated O
with O
metabolic O
syndrome O
( O
MetS O
) O
. O

In O
2010 O
, O
we O
explored O
the O
association O
of O
serum O
25 B
( I
OH I
) I
D I
and O
PTH O
levels O
with O
MetS O
in O
1 O
, O
390 O
Chinese O
participants O
, O
aged O
20 O
- O
83 O
years O
. O

Anthropometric O
phenotypes O
, O
blood O
pressure O
, O
and O
the O
incidence O
of O
MetS O
were O
evaluated O
. O

In O
addition O
, O
serum O
lipids O
, O
25 B
( I
OH I
) I
D I
, O
and O
PTH O
were O
measured O
. O

The O
median O
concentration O
of O
25 B
( I
OH I
) I
D I
and O
PTH O
were O
55 O
. O
3 O
nmol O
/ O
l O
and O
2 O
. O
8 O
pmol O
/ O
l O
, O
respectively O
. O

The O
prevalence O
of O
vitamin B
D I
deficiency O
( O
< O
50 O
nmol O
/ O
l O
) O
was O
39 O
. O
9 O
% O
, O
with O
34 O
. O
5 O
% O
in O
men O
and O
47 O
. O
8 O
% O
in O
women O
. O

After O
accounting O
for O
confounding O
factors O
and O
serum O
PTH O
, O
a O
10 O
nmol O
/ O
l O
higher O
serum O
25 B
( I
OH I
) I
D I
level O
was O
associated O
with O
a O
10 O
% O
lower O
risk O
of O
MetS O
( O
OR O
= O
0 O
. O
90 O
, O
95 O
% O
CI O
0 O
. O
84 O
- O
0 O
. O
96 O
, O
P O
= O
0 O
. O
0007 O
) O
. O

Furthermore O
, O
participants O
with O
vitamin B
D I
sufficiency O
had O
a O
35 O
% O
lower O
risk O
of O
MetS O
than O
those O
with O
vitamin B
D I
deficiency O
( O
OR O
= O
0 O
. O
65 O
, O
95 O
% O
CI O
0 O
. O
51 O
- O
0 O
. O
84 O
, O
P O
= O
0 O
. O
0009 O
) O
. O

PTH O
was O
not O
associated O
with O
the O
risk O
of O
MetS O
after O
adjustment O
for O
confounding O
factors O
. O

These O
results O
were O
confirmed O
in O
both O
men O
and O
women O
. O

Thus O
in O
this O
cohort O
of O
Chinese O
individuals O
, O
vitamin B
D I
deficiency O
is O
common O
and O
optimal O
vitamin B
D I
level O
is O
inversely O
associated O
with O
MetS O
, O
independent O
of O
several O
confounders O
and O
PTH O
level O
. O

The O
clinical O
significance O
of O
these O
findings O
warrants O
further O
study O
. O

Novel O
type O
II O
fatty B
acid I
biosynthesis O
( O
FAS O
II O
) O
inhibitors O
as O
multistage O
antimalarial O
agents O
. O

Malaria O
is O
a O
potentially O
fatal O
disease O
caused O
by O
Plasmodium O
parasites O
and O
poses O
a O
major O
medical O
risk O
in O
large O
parts O
of O
the O
world O
. O

The O
development O
of O
new O
, O
affordable O
antimalarial O
drugs O
is O
of O
vital O
importance O
as O
there O
are O
increasing O
reports O
of O
resistance O
to O
the O
currently O
available O
therapeutics O
. O

In O
addition O
, O
most O
of O
the O
current O
drugs O
used O
for O
chemoprophylaxis O
merely O
act O
on O
parasites O
already O
replicating O
in O
the O
blood O
. O

At O
this O
point O
, O
a O
patient O
might O
already O
be O
suffering O
from O
the O
symptoms O
associated O
with O
the O
disease O
and O
could O
additionally O
be O
infectious O
to O
an O
Anopheles O
mosquito O
. O

These O
insects O
act O
as O
a O
vector O
, O
subsequently O
spreading O
the O
disease O
to O
other O
humans O
. O

In O
order O
to O
cure O
not O
only O
malaria O
but O
prevent O
transmission O
as O
well O
, O
a O
drug O
must O
target O
both O
the O
blood O
- O
and O
pre O
- O
erythrocytic O
liver O
stages O
of O
the O
parasite O
. O

P O
. O
falciparum O
( O
Pf O
) O
enoyl B
acyl I
carrier O
protein O
( O
ACP O
) O
reductase O
( O
ENR O
) O
is O
a O
key O
enzyme O
of O
plasmodial O
type O
II O
fatty B
acid I
biosynthesis O
( O
FAS O
II O
) O
. O

It O
has O
been O
shown O
to O
be O
essential O
for O
liver O
- O
stage O
development O
of O
Plasmodium O
berghei O
and O
is O
therefore O
qualified O
as O
a O
target O
for O
true O
causal O
chemoprophylaxis O
. O

Using O
virtual O
screening O
based O
on O
two O
crystal O
structures O
of O
PfENR O
, O
we O
identified O
a O
structurally O
novel O
class O
of O
FAS O
inhibitors O
. O

Subsequent O
chemical O
optimization O
yielded O
two O
compounds O
that O
are O
effective O
against O
multiple O
stages O
of O
the O
malaria O
parasite O
. O

These O
two O
most O
promising O
derivatives O
were O
found O
to O
inhibit O
blood O
- O
stage O
parasite O
growth O
with O
IC O
( O
50 O
) O
values O
of O
1 O
. O
7 O
and O
3 O
. O
0 O
mu O
M O
and O
lead O
to O
a O
more O
prominent O
developmental O
attenuation O
of O
liver O
- O
stage O
parasites O
than O
the O
gold O
- O
standard O
drug O
, O
primaquine B
. O

A O
Robust O
Route O
to O
Enzymatically O
Functional O
, O
Hierarchically O
Self O
- O
Assembled O
Peptide O
Frameworks O
. O

The O
addition O
of O
enzyme O
biofunctionality O
to O
self O
- O
assembling O
peptide O
nanofibers O
is O
challenging O
since O
such O
additions O
can O
inhibit O
functionality O
or O
self O
- O
assembly O
. O

We O
introduce O
a O
method O
for O
peptide O
nanofiber O
enzyme O
functionalization O
, O
demonstrated O
by O
the O
attachment O
of O
a O
polymerization O
synthase O
to O
peptide O
nanofibers O
. O

The O
enzyme O
generates O
a O
biocompatible O
, O
biodegradable O
biopolyester O
coat O
on O
the O
fibers O
with O
applicablity O
in O
medical O
engineering O
. O

This O
approach O
provides O
a O
template O
for O
generation O
of O
functional O
bionanomaterials O
. O

Solid O
- O
state O
NMR O
study O
reveals O
collagen O
I O
structural O
modifications O
of O
amino B
acid I
side O
chains O
upon O
fibrillogenesis O
. O

In O
vivo O
, O
collagen O
I O
, O
the O
major O
structural O
protein O
in O
human O
body O
, O
is O
found O
assembled O
into O
fibrils O
. O

In O
the O
present O
work O
, O
we O
study O
a O
high O
concentrated O
collagen O
sample O
in O
its O
soluble O
, O
fibrillar O
, O
and O
denatured O
states O
using O
one O
and O
two O
dimensional O
{ B
( I
1 I
) I
H I
} I
- O
( B
13 I
) I
C I
solid O
- O
state O
NMR O
spectroscopy O
. O

We O
interpret O
( B
13 I
) I
C I
chemical O
shift O
variations O
in O
terms O
of O
dihedral O
angle O
conformation O
changes O
. O

Our O
data O
show O
that O
fibrillogenesis O
increases O
the O
side O
chain O
and O
backbone O
structural O
complexity O
. O

Nevertheless O
, O
only O
three O
to O
five O
rotameric O
equilibria O
are O
found O
for O
each O
amino B
acid I
residue O
, O
indicating O
a O
relatively O
low O
structural O
heterogeneity O
of O
collagen O
upon O
fibrillogenesis O
. O

Using O
side O
chain O
statistical O
data O
, O
we O
calculate O
equilibrium O
constants O
for O
a O
great O
number O
of O
amino B
acid I
residues O
. O

Moreover O
, O
based O
on O
a O
( B
13 I
) I
C I
quantitative O
spectrum O
, O
we O
estimate O
the O
percentage O
of O
residues O
implicated O
in O
each O
equilibrium O
. O

Our O
data O
indicate O
that O
fibril O
formation O
greatly O
affects O
hydroxyproline B
and O
proline B
prolyl B
pucker O
ring O
conformation O
. O

Finally O
, O
we O
discuss O
the O
implication O
of O
these O
structural O
data O
and O
propose O
a O
model O
in O
which O
the O
attractive O
force O
of O
fibrillogenesis O
comes O
from O
a O
structural O
reorganization O
of O
10 O
to O
15 O
% O
of O
the O
amino B
acids I
. O

These O
results O
allow O
us O
to O
further O
understand O
the O
self O
- O
assembling O
process O
and O
fibrillar O
structure O
of O
collagen O
. O

Detecting O
Allosteric O
Sites O
of O
HIV O
- O
1 O
Reverse O
Transcriptase O
by O
X O
- O
ray O
Crystallographic O
Fragment O
Screening O
. O

HIV O
- O
1 O
reverse O
transcriptase O
( O
RT O
) O
undergoes O
a O
series O
of O
conformational O
changes O
during O
viral O
replication O
and O
is O
a O
central O
target O
for O
antiretroviral O
therapy O
. O

The O
intrinsic O
flexibility O
of O
RT O
can O
provide O
novel O
allosteric O
sites O
for O
inhibition O
. O

Crystals O
of O
RT O
that O
diffract O
X O
- O
rays O
to O
better O
than O
2 O
A O
resolution O
facilitated O
the O
probing O
of O
RT O
for O
new O
druggable O
sites O
using O
fragment O
screening O
by O
X O
- O
ray O
crystallography O
. O

A O
total O
of O
775 O
fragments O
were O
grouped O
into O
143 O
cocktails O
, O
which O
were O
soaked O
into O
crystals O
of O
RT O
in O
complex O
with O
the O
non O
- O
nucleoside B
drug O
rilpivirine B
( O
TMC278 B
) O
. O

Seven O
new O
sites O
were O
discovered O
, O
including O
the O
Incoming O
Nucleotide B
Binding O
, O
Knuckles O
, O
NNRTI O
Adjacent O
, O
and O
399 O
sites O
, O
located O
in O
the O
polymerase O
region O
of O
RT O
, O
and O
the O
428 O
, O
RNase O
H O
Primer O
Grip O
Adjacent O
, O
and O
507 O
sites O
, O
located O
in O
the O
RNase O
H O
region O
. O

Three O
of O
these O
sites O
( O
Knuckles O
, O
NNRTI O
Adjacent O
, O
and O
Incoming O
Nucleotide B
Binding O
) O
are O
inhibitory O
and O
provide O
opportunities O
for O
discovery O
of O
new O
anti O
- O
AIDS O
drugs O
. O

Cluster O
phases O
of O
decorated O
micellar O
solutions O
with O
macrocyclic O
ligands O
. O

An O
aqueous O
self O
- O
assembled O
micellar O
system O
( O
sodium B
dodecyl I
sulfate I
, O
SDS B
, O
decorated O
with O
various O
adhesive O
sites O
, O
cryptand B
Kryptofix I
222 I
and O
crown B
ether I
18 B
- I
Crown I
- I
6 I
molecules O
) O
has O
been O
investigated O
by O
dynamic O
light O
scattering O
( O
DLS O
) O
and O
small O
angle O
x O
- O
ray O
scattering O
( O
SAXS O
) O
to O
have O
insights O
into O
the O
micellar O
structure O
, O
the O
micellar O
interactions O
, O
and O
the O
aggregation O
properties O
of O
the O
system O
. O

DLS O
demonstrates O
the O
existence O
of O
populations O
of O
aggregates O
in O
the O
submicrometer O
/ O
micrometer O
range O
, O
while O
the O
Guinier O
analysis O
of O
the O
SAXS O
curves O
helps O
in O
detailing O
objects O
smaller O
than O
30 O
nm O
. O

The O
aggregates O
of O
micelles O
are O
here O
named O
cluster O
phases O
of O
micelles O
( O
CPMs O
) O
. O

Considering O
that O
SDS B
micelles O
in O
water O
do O
not O
aggregate O
at O
low O
concentration O
, O
it O
is O
shown O
that O
macrocyclic O
ligands O
induce O
the O
SDS B
micelle O
aggregation O
as O
a O
function O
of O
the O
concentration O
( O
i O
. O
e O
. O
, O
investigated O
ligand O
/ O
SDS B
molar O
ratios O
are O
5 O
. O
0 O
, O
1 O
. O
5 O
, O
1 O
. O
0 O
, O
and O
0 O
. O
5 O
) O
and O
hydrophobicity O
of O
the O
adhesive O
sites O
. O

The O
sizes O
and O
the O
percentages O
of O
the O
micelles O
and O
the O
CPMs O
have O
been O
monitored O
to O
test O
the O
stability O
and O
reversibility O
of O
the O
system O
. O

DLS O
results O
clearly O
show O
that O
the O
aggregation O
processes O
of O
the O
decorated O
micelles O
are O
reproducible O
at O
time O
intervals O
of O
the O
order O
of O
1 O
month O
, O
while O
the O
stability O
may O
not O
be O
entirely O
maintained O
after O
a O
year O
. O

As O
an O
issue O
of O
particular O
relevance O
, O
the O
higher O
the O
ligand O
/ O
surfactant O
molar O
ratio O
, O
the O
larger O
are O
the O
CPMs O
induced O
. O

The O
K222 O
ligand O
results O
in O
being O
more O
effective O
in O
promoting O
the O
micellar O
aggregation O
than O
18C6 O
as O
a O
consequence O
of O
the O
different O
hydrophobicity O
. O

Personality O
and O
the O
acute O
subjective O
effects O
of O
d B
- I
amphetamine I
in O
humans O
. O

There O
is O
evidence O
that O
subjective O
responses O
to O
psychoactive O
drugs O
are O
related O
to O
personality O
traits O
. O

Here O
, O
we O
extend O
previous O
findings O
by O
examining O
personality O
measures O
in O
relation O
to O
acute O
responses O
to O
d B
- I
amphetamine I
( O
AMPH B
) O
in O
a O
large O
sample O
of O
healthy O
volunteers O
. O

Healthy O
adults O
( O
n O
= O
286 O
) O
completed O
the O
Multidimensional O
Personality O
Questionnaire O
Brief O
Form O
( O
MPQ O
- O
BF O
) O
and O
participated O
in O
four O
sessions O
during O
which O
they O
received O
oral O
AMPH B
( O
0 O
, O
5 O
, O
10 O
, O
20 O
mg O
) O
, O
under O
double O
- O
blind O
conditions O
. O

Subjective O
responses O
to O
the O
drug O
were O
measured O
using O
the O
Profile O
of O
Mood O
States O
, O
Addiction O
Research O
Center O
Inventory O
, O
and O
Drug O
Effects O
Questionnaire O
. O

Drug O
responses O
were O
reduced O
via O
principal O
components O
analysis O
to O
three O
higher O
- O
order O
factors O
( O
' O
Euphoria O
' O
, O
' O
Arousal O
' O
, O
' O
Dysphoria O
' O
) O
. O

Participants O
were O
rank O
ordered O
on O
selected O
MPQ O
- O
BF O
scales O
; O
the O
top O
and O
bottom O
third O
on O
each O
trait O
were O
compared O
on O
the O
drug O
response O
factors O
. O

High O
trait O
physical O
fearlessness O
was O
significantly O
associated O
with O
greater O
amphetamine B
- O
related O
Arousal O
, O
and O
high O
trait O
reward O
sensitivity O
was O
significantly O
associated O
with O
greater O
Euphoria O
. O

In O
addition O
, O
high O
trait O
impulsivity O
was O
significantly O
associated O
with O
greater O
Arousal O
and O
Euphoria O
. O

These O
results O
provide O
further O
evidence O
that O
individual O
differences O
in O
the O
subjective O
effects O
of O
AMPH B
are O
partially O
explained O
by O
differences O
in O
personality O
, O
and O
are O
consistent O
with O
the O
idea O
that O
both O
personality O
and O
responses O
to O
stimulants O
depend O
upon O
shared O
neurochemical O
systems O
. O

In O
- O
plane O
coassembly O
route O
to O
atomically O
thick O
inorganic O
- O
organic O
hybrid O
nanosheets O
. O

Control O
over O
the O
anisotropic O
assembly O
of O
small O
building O
blocks O
into O
organized O
structures O
is O
considered O
an O
effective O
way O
to O
design O
organic O
nanosheets O
and O
atomically O
thick O
inorganic O
nanosheets O
with O
nonlayered O
structure O
. O

However O
, O
there O
is O
still O
no O
available O
route O
so O
far O
to O
control O
the O
assembly O
of O
inorganic O
and O
organic O
building O
blocks O
into O
a O
flattened O
hybrid O
nanosheet O
with O
atomic O
thickness O
. O

Herein O
, O
we O
highlight O
for O
the O
first O
time O
a O
universal O
in O
- O
plane O
coassembly O
process O
for O
the O
design O
and O
synthesis O
of O
transition B
- I
metal I
chalcogenide I
- O
alkylamine B
inorganic O
- O
organic O
hybrid O
nanosheets O
with O
atomic O
thickness O
. O

The O
structure O
, O
formation O
mechanism O
, O
and O
stability O
of O
the O
hybrid O
nanosheets O
were O
investigated O
in O
detail O
by O
taking O
the O
Co B
9 I
S I
8 I
- I
oleylamine I
( O
Co B
9 I
S I
8 I
- I
OA I
) O
hybrid O
nanosheets O
as O
an O
example O
. O

Both O
experimental O
data O
and O
theoretical O
simulations O
demonstrate O
that O
the O
hybrid O
nanosheets O
were O
formed O
by O
in O
- O
plane O
connection O
of O
small O
two O
- O
dimensional O
( O
2D O
) O
Co B
9 I
S I
8 I
nanoplates O
via O
oleylamine B
molecules O
adsorbed O
at O
the O
side O
surface O
and O
corner O
sites O
of O
the O
nanoplates O
. O

X O
- O
ray O
absorption O
fine O
structure O
spectroscopy O
study O
reveals O
the O
structure O
distortion O
of O
the O
small O
2D O
Co B
9 I
S I
8 I
nanoplates O
that O
endows O
structural O
stability O
of O
the O
atomically O
thick O
Co B
9 I
S I
8 I
- O
OA O
hybrid O
nanosheets O
. O

The O
brand O
new O
atomically O
thick O
nanosheets O
with O
inorganic O
- O
organic O
hybrid O
network O
nanostructure O
will O
not O
only O
enrich O
the O
family O
of O
atomically O
thick O
2D O
nanosheets O
but O
also O
inspire O
more O
interest O
in O
their O
potential O
applications O
. O

Targeted O
drug O
delivery O
to O
treat O
pain O
and O
cerebral O
hypoxia O
. O

Limited O
drug O
penetration O
is O
an O
obstacle O
that O
is O
often O
encountered O
in O
treatment O
of O
central O
nervous O
system O
( O
CNS O
) O
diseases O
including O
pain O
and O
cerebral O
hypoxia O
. O

Over O
the O
past O
several O
years O
, O
biochemical O
characteristics O
of O
the O
brain O
( O
i O
. O
e O
. O
, O
tight O
junction O
protein O
complexes O
at O
brain O
barrier O
sites O
, O
expression O
of O
influx O
and O
efflux O
transporters O
) O
have O
been O
shown O
to O
be O
directly O
involved O
in O
determining O
CNS O
permeation O
of O
therapeutic O
agents O
; O
however O
, O
the O
vast O
majority O
of O
these O
studies O
have O
focused O
on O
understanding O
those O
mechanisms O
that O
prevent O
drugs O
from O
entering O
the O
CNS O
. O

Recently O
, O
this O
paradigm O
has O
shifted O
toward O
identifying O
and O
characterizing O
brain O
targets O
that O
facilitate O
CNS O
drug O
delivery O
. O

Such O
targets O
include O
the O
organic O
anion O
- O
transporting O
polypeptides O
( O
OATPs O
in O
humans O
; O
Oatps O
in O
rodents O
) O
, O
a O
family O
of O
sodium B
- O
independent O
transporters O
that O
are O
endogenously O
expressed O
in O
the O
brain O
and O
are O
involved O
in O
drug O
uptake O
. O

OATP O
/ O
Oatp B
substrates O
include O
drugs O
that O
are O
efficacious O
in O
treatment O
of O
pain O
and O
/ O
or O
cerebral O
hypoxia O
( O
i O
. O
e O
. O
, O
opioid O
analgesic O
peptides O
, O
3 B
- I
hydroxy I
- I
3 I
- I
methylglutaryl I
coenzyme I
A O
reductase O
inhibitors O
) O
. O

This O
clearly O
suggests O
that O
OATP O
/ O
Oatp O
isoforms O
are O
viable O
transporter O
targets O
that O
can O
be O
exploited O
for O
optimization O
of O
drug O
delivery O
to O
the O
brain O
and O
, O
therefore O
, O
improved O
treatment O
of O
CNS O
diseases O
. O

This O
review O
summarizes O
recent O
knowledge O
in O
this O
area O
and O
emphasizes O
the O
potential O
that O
therapeutic O
targeting O
of O
OATP O
/ O
Oatp O
isoforms O
may O
have O
in O
facilitating O
CNS O
drug O
delivery O
and O
distribution O
. O

Additionally O
, O
information O
presented O
in O
this O
review O
will O
point O
to O
novel O
strategies O
that O
can O
be O
used O
for O
treatment O
of O
pain O
and O
cerebral O
hypoxia O
. O

A O
Molecular O
- O
Modeling O
Toolbox O
Aimed O
at O
Bridging O
the O
Gap O
between O
Medicinal O
Chemistry O
and O
Computational O
Sciences O
. O

In O
the O
current O
era O
of O
high O
- O
throughput O
drug O
discovery O
and O
development O
, O
molecular O
modeling O
has O
become O
an O
indispensable O
tool O
for O
identifying O
, O
optimizing O
and O
prioritizing O
small O
- O
molecule O
drug O
candidates O
. O

The O
required O
background O
in O
computational O
chemistry O
and O
the O
knowledge O
of O
how O
to O
handle O
the O
complex O
underlying O
protocols O
, O
however O
, O
might O
keep O
medicinal O
chemists O
from O
routinely O
using O
in O
silico O
technologies O
. O

Our O
objective O
is O
to O
encourage O
those O
researchers O
to O
exploit O
existing O
modeling O
technologies O
more O
frequently O
through O
easy O
- O
to O
- O
use O
graphical O
user O
interfaces O
. O

In O
this O
account O
, O
we O
present O
two O
innovative O
tools O
( O
which O
we O
are O
prepared O
to O
share O
with O
academic O
institutions O
) O
facilitating O
computational O
tasks O
commonly O
utilized O
in O
drug O
discovery O
and O
development O
: O
( O
1 O
) O
the O
VirtualDesignLab O
estimates O
the O
binding O
affinity O
of O
small O
molecules O
by O
simulating O
and O
quantifying O
their O
binding O
to O
the O
three O
- O
dimensional O
structure O
of O
a O
target O
protein O
; O
and O
( O
2 O
) O
the O
MD O
Client O
launches O
molecular O
dynamics O
simulations O
aimed O
at O
exploring O
the O
time O
- O
dependent O
stability O
of O
ligand O
- O
protein O
complexes O
and O
provides O
residue O
- O
based O
interaction O
energies O
. O

This O
allows O
medicinal O
chemists O
to O
identify O
sites O
of O
potential O
improvement O
in O
their O
candidate O
molecule O
. O

As O
a O
case O
study O
, O
we O
present O
the O
application O
of O
our O
tools O
towards O
the O
design O
of O
novel O
antagonists O
for O
the O
FimH O
adhesin O
. O

Bioactivity O
and O
applications O
of O
sulphated O
polysaccharides O
from O
marine O
microalgae O
. O

Marine O
microalgae O
have O
been O
used O
for O
a O
long O
time O
as O
food O
for O
humans O
, O
such O
as O
Arthrospira O
( O
formerly O
, O
Spirulina O
) O
, O
and O
for O
animals O
in O
aquaculture O
. O

The O
biomass O
of O
these O
microalgae O
and O
the O
compounds O
they O
produce O
have O
been O
shown O
to O
possess O
several O
biological O
applications O
with O
numerous O
health O
benefits O
. O

The O
present O
review O
puts O
up O
- O
to O
- O
date O
the O
research O
on O
the O
biological O
activities O
and O
applications O
of O
polysaccharides O
, O
active O
biocompounds O
synthesized O
by O
marine O
unicellular O
algae O
, O
which O
are O
, O
most O
of O
the O
times O
, O
released O
into O
the O
surrounding O
medium O
( O
exo O
- O
or O
extracellular O
polysaccharides O
, O
EPS O
) O
. O

It O
goes O
through O
the O
most O
studied O
activities O
of O
sulphated O
polysaccharides O
( O
sPS O
) O
or O
their O
derivatives O
, O
but O
also O
highlights O
lesser O
known O
applications O
as O
hypolipidaemic O
or O
hypoglycaemic O
, O
or O
as O
biolubricant O
agents O
and O
drag O
- O
reducers O
. O

Therefore O
, O
the O
great O
potentials O
of O
sPS O
from O
marine O
microalgae O
to O
be O
used O
as O
nutraceuticals O
, O
therapeutic O
agents O
, O
cosmetics O
, O
or O
in O
other O
areas O
, O
such O
as O
engineering O
, O
are O
approached O
in O
this O
review O
. O

Catalytic O
transformation O
of O
alcohols B
to O
carboxylic B
acid I
salts O
and O
H2 B
using O
water O
as O
the O
oxygen B
atom O
source O
. O

The O
oxidation O
of O
alcohols B
to O
carboxylic B
acids I
is O
an O
important O
industrial O
reaction O
used O
in O
the O
synthesis O
of O
bulk O
and O
fine O
chemicals O
. O

Most O
current O
processes O
are O
performed O
by O
making O
use O
of O
either O
stoichiometric O
amounts O
of O
toxic O
oxidizing O
agents O
or O
the O
use O
of O
pressurized O
dioxygen B
. O

Here O
, O
we O
describe O
an O
alternative O
dehydrogenative O
pathway O
effected O
by O
water O
and O
base O
with O
the O
concomitant O
generation O
of O
hydrogen B
gas O
. O

A O
homogeneous O
ruthenium B
complex O
catalyses O
the O
transformation O
of O
primary B
alcohols I
to O
carboxylic B
acid I
salts O
at O
low O
catalyst O
loadings O
( O
0 O
. O
2 O
mol O
% O
) O
in O
basic O
aqueous O
solution O
. O

A O
consequence O
of O
this O
finding O
could O
be O
a O
safer O
and O
cleaner O
process O
for O
the O
synthesis O
of O
carboxylic B
acids I
and O
their O
derivatives O
at O
both O
laboratory O
and O
industrial O
scales O
. O

Increased O
impulsive O
choice O
for O
saccharin B
during O
PCP B
withdrawal O
in O
female O
monkeys O
: O
influence O
of O
menstrual O
cycle O
phase O
. O

BACKGROUND O
: O
In O
previous O
studies O
with O
male O
and O
female O
rhesus O
monkeys O
, O
withdrawal O
of O
access O
to O
oral O
phencyclidine B
( O
PCP B
) O
self O
- O
administration O
reduced O
responding O
for O
food O
under O
a O
high O
fixed O
- O
ratio O
( O
FR O
) O
schedule O
more O
in O
males O
than O
females O
, O
and O
with O
a O
delay O
discounting O
( O
DD O
) O
task O
with O
saccharin B
( O
SACC B
) O
as O
the O
reinforcer O
impulsive O
choice O
for O
SACC O
increased O
during O
PCP B
withdrawal O
more O
in O
males O
than O
females O
. O

OBJECTIVES O
: O
The O
goal O
of O
the O
present O
study O
was O
to O
examine O
the O
effect O
of O
PCP B
( O
0 O
. O
25 O
or O
0 O
. O
5 O
mg O
/ O
ml O
) O
withdrawal O
on O
impulsive O
choice O
for O
SACC O
in O
females O
during O
the O
follicular O
and O
luteal O
phases O
of O
the O
menstrual O
cycle O
. O

MATERIALS O
AND O
METHODS O
: O
In O
component O
1 O
, O
PCP B
and O
water O
were O
available O
from O
two O
drinking O
spouts O
for O
1 O
. O
5 O
h O
sessions O
under O
concurrent O
FR O
16 O
schedules O
. O

In O
component O
2 O
, O
a O
SACC O
solution O
was O
available O
for O
45 O
min O
under O
a O
DD O
schedule O
. O

Monkeys O
had O
a O
choice O
of O
one O
immediate O
SACC O
delivery O
( O
0 O
. O
6 O
ml O
) O
or O
six O
delayed O
SACC B
deliveries O
, O
and O
the O
delay O
was O
increased O
by O
1 O
s O
after O
a O
response O
on O
the O
delayed O
lever O
and O
decreased O
by O
1 O
s O
after O
a O
response O
on O
the O
immediate O
lever O
. O

There O
was O
then O
a O
10 O
- O
day O
water O
substitution O
phase O
, O
or O
PCP B
withdrawal O
, O
that O
occurred O
during O
the O
mid O
- O
follicular O
phase O
( O
days O
7 O
- O
11 O
) O
or O
the O
late O
luteal O
phase O
( O
days O
24 O
- O
28 O
) O
of O
the O
menstrual O
cycle O
. O

Access O
to O
PCP B
and O
concurrent O
water O
was O
then O
restored O
, O
and O
the O
PCP B
withdrawal O
procedure O
was O
repeated O
over O
several O
follicular O
and O
luteal O
menstrual O
phases O
. O

RESULTS O
: O
PCP B
deliveries O
were O
higher O
during O
the O
luteal O
( O
vs O
follicular O
) O
phase O
. O

Impulsive O
choice O
was O
greater O
during O
the O
luteal O
( O
vs O
follicular O
) O
phase O
during O
withdrawal O
of O
the O
higher O
PCP B
concentration O
. O

CONCLUSIONS O
: O
PCP B
withdrawal O
was O
associated O
with O
elevated O
impulsive O
choice O
for O
SACC O
, O
especially O
in O
the O
luteal O
( O
vs O
follicular O
) O
phase O
of O
the O
menstrual O
cycle O
in O
female O
monkeys O
. O

A O
donor O
- O
acceptor O
type O
organic O
dye O
connected O
with O
a O
quinoidal B
thiophene I
for O
dye O
- O
sensitized O
solar O
cells O
. O

A O
donor O
- O
acceptor O
type O
organic O
dye O
connected O
with O
a O
quinoidal B
thiophene I
as O
a O
pi O
- O
conjugated O
chain O
, O
cyano B
- I
[ I
5 I
' I
- I
( I
4 I
' I
' I
- I
( I
N I
, I
N I
- I
dimethylamino I
) I
benzylidene I
) I
- I
5H I
- I
thiophen I
- I
2 I
' I
- I
ylidene I
] I
acetic I
acid I
, O
was O
synthesized O
and O
applied O
to O
dye O
- O
sensitized O
solar O
cells O
( O
DSSCs O
) O
. O

The O
absorption O
band O
of O
this O
quinoidal B
thiophene I
dye O
appeared O
at O
longer O
wavelengths O
than O
those O
of O
dyes O
with O
similar O
pi O
- O
conjugation O
length O
, O
indicating O
the O
effective O
pi O
- O
conjugation O
through O
the O
quinoidal B
structure O
. O

Although O
the O
excited O
state O
of O
the O
quinoidal B
thiophene I
dye O
is O
deactivated O
within O
several O
picoseconds O
even O
in O
solution O
, O
the O
DSSCs O
using O
the O
quinoidal B
thiophene I
dye O
showed O
incident O
photon O
to O
current O
conversion O
efficiency O
( O
IPCE O
) O
values O
of O
more O
than O
90 O
% O
, O
demonstrating O
the O
fast O
and O
efficient O
electron O
injection O
from O
the O
excited O
dye O
to O
TiO B
( I
2 I
) I
. O

By O
optimizing O
the O
fabrication O
conditions O
, O
the O
DSSC O
using O
this O
dye O
afforded O
a O
photoelectric O
conversion O
efficiency O
of O
5 O
. O
2 O
% O
, O
without O
enlarging O
the O
molecular O
size O
. O

Oxidative O
stress O
and O
alteration O
of O
biochemical O
markers O
in O
liver O
and O
kidney O
by O
malathion B
in O
rat O
pups O
. O

The O
present O
study O
was O
undertaken O
to O
determine O
the O
effects O
of O
malathion B
exposure O
through O
maternal O
milk O
on O
oxidative O
stress O
, O
functional O
an O
metabolic O
parameters O
in O
kidney O
and O
liver O
of O
rat O
pups O
. O

We O
found O
that O
lactational O
exposure O
to O
malation B
( O
200 O
mg O
/ O
kg O
, O
body O
weight O
( O
bw O
) O
) O
induced O
an O
oxidative O
stress O
status O
assessed O
by O
an O
increase O
in O
malondialdhyde B
( O
MDA B
) O
content O
, O
reflecting O
lipoperoxidation O
, O
a O
decrease O
in O
thiol O
groups O
' O
content O
as O
well O
as O
depletion O
of O
enzyme O
activities O
as O
a O
superoxide B
dismutase O
( O
SOD O
) O
and O
catalase O
( O
CAT O
) O
on O
postnatal O
days O
( O
Pnds O
) O
21 O
and O
51 O
. O

Moreover O
, O
the O
current O
study O
showed O
that O
malathion B
induced O
liver O
and O
kidney O
dysfunctions O
demonstrated O
by O
considerable O
increase O
in O
phosphatase O
alkaline O
( O
PAL O
) O
, O
aspartate B
aminotransferase O
( O
AST O
) O
and O
alanine B
aminotransferase O
( O
ALT O
) O
activities O
as O
well O
as O
total O
and O
direct O
bilirubin B
, O
creatinine B
urea I
and O
acid B
uric I
contents O
. O

We O
also O
observed O
an O
increase O
in O
triglyceride B
( O
TG O
) O
, O
total O
cholesterol B
( O
TC O
) O
, O
low O
- O
density O
lipoprotein O
cholesterol B
( O
LDL O
- O
C O
) O
and O
a O
decrease O
in O
high O
- O
density O
lipoprotein O
cholesterol B
( O
HDL O
- O
C O
) O
in O
the O
plasma O
of O
treated O
rat O
pups O
. O

These O
findings O
evidenced O
that O
malathion B
exposure O
during O
lactation O
through O
maternal O
milk O
of O
rats O
pups O
induced O
kidney O
and O
liver O
oxidative O
stress O
as O
well O
as O
functional O
and O
metabolic O
disorders O
that O
play O
a O
role O
in O
the O
development O
of O
others O
pathologies O
as O
cardiovascular O
diseases O
and O
cancers O
. O

Interleukin O
- O
10 O
involvement O
in O
exposure O
to O
low O
dose O
of O
benzene B
. O

OBJECTIVE O
: O
To O
establish O
if O
serum O
levels O
of O
interleukin O
- O
10 O
( O
IL O
- O
10 O
) O
in O
subjects O
exposed O
to O
benzene B
are O
connected O
with O
age O
, O
working O
years O
, O
and O
employment O
age O
. O

METHODS O
: O
We O
evaluated O
serum O
levels O
of O
IL O
- O
10 O
in O
51 O
employees O
working O
in O
oil O
refinery O
( O
group O
A O
) O
and O
in O
16 O
office O
workers O
who O
resided O
in O
the O
same O
area O
( O
group O
B O
) O
. O

RESULTS O
: O
There O
was O
no O
statistically O
significant O
difference O
between O
serum O
concentrations O
of O
IL O
- O
10 O
in O
groups O
A O
and O
B O
. O

There O
was O
a O
statistically O
significant O
dependent O
relationship O
in O
group O
A O
between O
age O
, O
working O
years O
, O
and O
serum O
concentration O
of O
IL O
- O
10 O
. O

There O
was O
a O
statistically O
significant O
and O
positive O
dependent O
relationship O
in O
group O
A O
between O
serum O
concentration O
of O
IL O
- O
10 O
and O
employment O
age O
. O

CONCLUSIONS O
: O
The O
role O
played O
by O
IL O
- O
10 O
in O
benzene B
immune O
suppression O
may O
be O
relevant O
and O
attention O
should O
be O
directed O
toward O
assessment O
of O
age O
, O
working O
years O
, O
and O
employment O
age O
in O
benzene B
- O
exposed O
populations O
. O

Regulation O
of O
sodium B
and O
calcium B
in O
Daphnia O
magna O
exposed O
to O
silver B
nanoparticles O
. O

The O
toxicity O
of O
manufactured O
silver B
nanoparticles O
( O
AgNPs O
) O
has O
been O
widely O
studied O
, O
but O
the O
influence O
of O
AgNPs O
on O
the O
major O
ions O
( O
such O
as O
sodium B
[ O
Na B
] O
and O
calcium B
[ O
Ca B
] O
) O
regulations O
are O
unknown O
. O

In O
the O
present O
study O
, O
a O
freshwater O
cladoceran O
Daphnia O
magna O
was O
exposed O
to O
commercial O
AgNPs O
coated O
with O
polyvinylpyrrolidone B
. O

After O
48 O
h O
, O
the O
Na B
body O
content O
was O
significantly O
reduced O
by O
AgNO3 B
exposure O
, O
but O
the O
Ca B
body O
content O
was O
significantly O
increased O
under O
AgNO3 B
and O
AgNP O
exposures O
, O
respectively O
. O

No O
effect O
was O
observed O
on O
the O
body O
concentrations O
of O
Na B
and O
Ca B
at O
50 O
to O
500 O
micro O
g O
/ O
L O
AgNPs O
with O
1 O
- O
micro O
M O
cysteine B
addition O
. O

Exposure O
of O
AgNO3 B
and O
AgNPs O
inhibited O
the O
Na B
influx O
and O
elevated O
the O
Na B
efflux O
. O

In O
contrast O
, O
their O
exposure O
increased O
the O
Ca B
influx O
, O
but O
did O
not O
affect O
the O
Ca B
efflux O
. O

The O
results O
of O
the O
present O
study O
demonstrated O
the O
significant O
influences O
of O
AgNO3 B
and O
AgNPs O
( O
without O
cysteine B
) O
on O
Na B
and O
Ca B
regulations O
. O

Such O
effect O
of O
AgNPs O
on O
Na B
and O
Ca B
regulation O
disappeared O
after O
cysteine B
addition O
, O
indicating O
that O
the O
soluble O
Ag B
released O
from O
AgNPs O
played O
a O
major O
role O
in O
the O
ionoregulatory O
dysfunction O
. O

Depletion O
of O
molecular O
chaperones O
from O
the O
endoplasmic O
reticulum O
and O
fragmentation O
of O
the O
Golgi O
apparatus O
associated O
with O
pathogenesis O
in O
Pelizaeus O
- O
Merzbacher O
disease O
. O

Missense O
mutations O
in O
the O
proteolipid O
protein O
1 O
( O
PLP1 O
) O
gene O
cause O
a O
wide O
spectrum O
of O
hypomyelinating O
disorders O
, O
from O
mild O
spastic O
paraplegia O
type O
2 O
to O
severe O
Pelizaeus O
- O
Merzbacher O
disease O
( O
PMD O
) O
. O

Mutant O
PLP1 O
accumulates O
in O
the O
endoplasmic O
reticulum O
( O
ER O
) O
and O
induces O
ER O
stress O
. O

However O
, O
the O
link O
between O
the O
clinical O
severity O
of O
PMD O
and O
the O
cellular O
response O
induced O
by O
mutant O
PLP1 O
remains O
largely O
unknown O
. O

Accumulation O
of O
misfolded O
proteins O
in O
the O
ER O
generally O
leads O
to O
up O
- O
regulation O
of O
ER O
chaperones O
to O
alleviate O
ER O
stress O
. O

Here O
, O
we O
found O
that O
expression O
of O
the O
PLP1 O
- O
A243V O
mutant O
, O
which O
causes O
severe O
disease O
, O
depletes O
some O
ER O
chaperones O
with O
a O
KDEL O
( O
Lys B
- I
Asp I
- I
Glu I
- I
Leu I
) O
motif O
, O
in O
HeLa O
cells O
, O
MO3 O
. O
13 O
oligodendrocytic O
cells O
, O
and O
primary O
oligodendrocytes O
. O

The O
same O
PLP1 O
mutant O
also O
induces O
fragmentation O
of O
the O
Golgi O
apparatus O
( O
GA O
) O
. O

These O
organelle O
changes O
are O
less O
prominent O
in O
cells O
with O
milder O
disease O
- O
associated O
PLP1 O
mutants O
. O

Similar O
changes O
are O
also O
observed O
in O
cells O
expressing O
another O
disease O
- O
causing O
gene O
that O
triggers O
ER O
stress O
, O
as O
well O
as O
in O
cells O
treated O
with O
brefeldin B
A I
, O
which O
induces O
ER O
stress O
and O
GA O
fragmentation O
by O
inhibiting O
GA O
to O
ER O
trafficking O
. O

We O
also O
found O
that O
mutant O
PLP1 O
disturbs O
localization O
of O
the O
KDEL O
receptor O
, O
which O
transports O
the O
chaperones O
with O
the O
KDEL O
motif O
from O
the O
GA O
to O
the O
ER O
. O

These O
data O
show O
that O
PLP1 O
mutants O
inhibit O
GA O
to O
ER O
trafficking O
, O
which O
reduces O
the O
supply O
of O
ER O
chaperones O
and O
induces O
GA O
fragmentation O
. O

We O
propose O
that O
depletion O
of O
ER O
chaperones O
and O
GA O
fragmentation O
induced O
by O
mutant O
misfolded O
proteins O
contribute O
to O
the O
pathogenesis O
of O
inherited O
ER O
stress O
- O
related O
diseases O
and O
affect O
the O
disease O
severity O
. O

Topoisomerase O
II O
beta O
deficiency O
enhances O
camptothecin B
- O
induced O
apoptosis O
. O

Camptothecin B
( O
CPT B
) O
, O
a O
topoisomerase O
( O
Top O
) O
I O
- O
targeting O
drug O
that O
stabilizes O
Top1 O
- O
DNA O
covalent O
adducts O
, O
can O
induce O
S O
- O
phase O
- O
specific O
cytotoxicity O
due O
to O
the O
arrest O
of O
progressing O
replication O
forks O
. O

However O
, O
CPT B
- O
induced O
non O
- O
S O
- O
phase O
cytotoxicity O
is O
less O
well O
characterized O
. O

In O
this O
study O
, O
we O
have O
identified O
topoisomerase O
II O
beta O
( O
Top2 O
beta O
) O
as O
a O
specific O
determinant O
for O
CPT B
sensitivity O
, O
but O
not O
for O
many O
other O
cytotoxic O
agents O
, O
in O
non O
- O
S O
- O
phase O
cells O
. O

First O
, O
quiescent O
mouse O
embryonic O
fibroblasts O
( O
MEFs O
) O
lacking O
Top2 O
beta O
were O
shown O
to O
be O
hypersensitive O
to O
CPT B
with O
prominent O
induction O
of O
apoptosis O
. O

Second O
, O
ICRF B
- I
187 I
, O
a O
Top2 O
catalytic O
inhibitor O
known O
to O
deplete O
Top2 O
beta O
, O
specifically O
sensitized O
MEFs O
to O
CPT B
. O

To O
explore O
the O
molecular O
basis O
for O
CPT B
hypersensitivity O
in O
Top2 O
beta O
- O
deficient O
cells O
, O
we O
found O
that O
upon O
CPT B
exposure O
, O
the O
RNA O
polymerase O
II O
large O
subunit O
( O
RNAP O
LS O
) O
became O
progressively O
depleted O
, O
followed O
by O
recovery O
to O
nearly O
the O
original O
level O
in O
wild O
- O
type O
MEFs O
, O
whereas O
RNAP O
LS O
remained O
depleted O
without O
recovery O
in O
Top2 O
beta O
- O
deficient O
cells O
. O

Concomitant O
with O
the O
reduction O
of O
the O
RNAP O
LS O
level O
, O
the O
p53 O
protein O
level O
was O
greatly O
induced O
. O

Interestingly O
, O
RNAP O
LS O
depletion O
has O
been O
well O
documented O
to O
lead O
to O
p53 O
- O
dependent O
apoptosis O
. O

Altogether O
, O
our O
findings O
support O
a O
model O
in O
which O
Top2 O
beta O
deficiency O
promotes O
CPT B
- O
induced O
apoptosis O
in O
quiescent O
non O
- O
S O
- O
phase O
cells O
, O
possibly O
due O
to O
RNAP O
LS O
depletion O
and O
p53 O
accumulation O
. O

Two O
novel O
mutations O
in O
CYP11B1 O
and O
modeling O
the O
consequent O
alterations O
of O
the O
translated O
protein O
in O
classic O
congenital O
adrenal O
hyperplasia O
patients O
. O

Mutations O
in O
the O
11 O
beta O
- O
hydroxylase O
( O
CYP11B1 O
) O
gene O
are O
the O
second O
leading O
cause O
of O
congenital O
adrenal O
hyperplasia O
( O
CAH O
) O
, O
an O
autosomal O
recessive O
disorder O
characterized O
by O
adrenal O
insufficiency O
, O
virilization O
of O
female O
external O
genitalia O
, O
and O
hypertension O
with O
or O
without O
hypokalemic O
alkalosis O
. O

Molecular O
analysis O
of O
CYP11B1 O
gene O
in O
CAH O
patients O
with O
11 O
beta O
- O
hydroxylase O
deficiency O
was O
performed O
in O
this O
study O
. O

Cycle O
sequencing O
of O
9 O
exons O
in O
CYP11B1 O
was O
performed O
in O
5 O
unrelated O
families O
with O
11 O
beta O
- O
hydroxylase O
deficient O
children O
. O

Three O
- O
dimensional O
models O
for O
the O
normal O
and O
mutant O
proteins O
and O
their O
affinity O
to O
their O
known O
substrates O
were O
examined O
. O

Analysis O
of O
the O
CYP11B1 O
gene O
revealed O
two O
novel O
mutations O
, O
a O
small O
insertion O
in O
exon O
7 O
( O
InsAG393 O
) O
and O
a O
small O
deletion O
in O
exon O
2 O
( O
DelG766 O
) O
, O
and O
three O
previously O
known O
missense O
mutations O
( O
T318M O
, O
Q356X O
, O
and O
R427H O
) O
. O

According O
to O
docking O
results O
, O
the O
affinity O
of O
the O
protein O
to O
its O
substrates O
is O
highly O
reduced O
by O
these O
novel O
mutations O
. O

DelG766 O
has O
more O
negative O
impact O
on O
the O
protein O
in O
comparison O
to O
InsAG393 O
. O

The O
novel O
mutations O
, O
InsAG393 O
and O
DelG766 O
, O
change O
the O
folding O
of O
the O
protein O
and O
disrupt O
the O
enzyme O
' O
s O
active O
site O
as O
it O
was O
measured O
in O
the O
protein O
modeling O
and O
substrate O
binding O
analysis O
. O

Molecular O
modeling O
and O
sequence O
conservation O
were O
predictive O
of O
clinical O
severity O
of O
the O
disease O
and O
correlated O
with O
the O
clinical O
diagnosis O
of O
the O
patients O
. O

Isolation O
and O
synthesis O
of O
melodamide B
A I
, O
a O
new O
anti O
- O
inflammatory O
phenolic B
amide I
from O
the O
leaves O
of O
Melodorum O
fruticosum O
. O

Together O
with O
twelve O
known O
compounds O
( O
2 O
- O
13 O
) O
, O
melodamide B
A I
( O
1 O
) O
, O
a O
new O
phenolic B
amide I
possessing O
p B
- I
quinol I
moiety O
, O
was O
purified O
and O
characterized O
from O
the O
methanolic O
extracts O
of O
the O
leaves O
of O
Melodorum O
fruticosum O
. O

The O
structure O
of O
melodamide B
A I
( O
1 O
) O
was O
established O
with O
a O
combination O
of O
2D O
NMR O
experiments O
, O
HR O
- O
ESI O
- O
MS O
and O
X O
- O
ray O
analyses O
. O

The O
other O
known O
compounds O
were O
identified O
by O
comparison O
of O
their O
spectroscopic O
and O
physical O
data O
with O
those O
reported O
in O
the O
literature O
. O

Moreover O
, O
some O
isolated O
compounds O
were O
examined O
for O
their O
inhibitory O
activity O
towards O
superoxide B
anion O
generation O
and O
elastase O
release O
in O
human O
neutrophils O
. O

Among O
the O
tested O
compounds O
, O
1 O
, O
3 O
, O
and O
5 O
exhibited O
strong O
inhibition O
of O
superoxide B
anion O
generation O
with O
IC50 O
values O
ranging O
from O
5 O
. O
25 O
to O
8 O
. O
65 O
micro O
M O
. O

Furthermore O
, O
synthesis O
and O
biological O
evaluation O
of O
melodamide B
A I
( O
1 O
) O
and O
its O
analogs O
( O
14a O
- O
p O
) O
were O
described O
. O

Blocking O
the O
proliferation O
of O
human O
tumor O
cell O
lines O
by O
peptidase O
inhibitors O
from O
Bauhinia O
seeds O
. O

In O
cancer O
tumors O
, O
growth O
, O
invasion O
, O
and O
formation O
of O
metastasis O
at O
a O
secondary O
site O
play O
a O
pivotal O
role O
, O
participating O
in O
diverse O
processes O
in O
the O
development O
of O
the O
pathology O
, O
such O
as O
degradation O
of O
extracellular O
matrix O
. O

Bauhinia O
seeds O
contain O
relatively O
large O
quantities O
of O
peptidase O
inhibitors O
, O
and O
two O
Bauhinia O
inhibitors O
were O
obtained O
in O
a O
recombinant O
form O
from O
the O
Bauhinia O
bauhinioides O
species O
, O
B O
. O
bauhinoides O
cruzipain O
inhibitor O
, O
which O
is O
a O
cysteine B
and O
serine B
peptidase O
inhibitor O
, O
and O
B O
. O
bauhinioides O
kallikrein O
inhibitor O
, O
which O
is O
a O
serine B
peptidase O
inhibitor O
. O

While O
recombinant O
B O
. O
bauhinoides O
cruzipain O
inhibitor O
inhibits O
human O
neutrophil O
elastase O
cathepsin O
G O
and O
the O
cysteine O
proteinase O
cathepsin O
L O
, O
recombinant O
B O
. O
bauhinioides O
kallikrein O
inhibitor O
inhibits O
plasma O
kallikrein O
and O
plasmin O
. O

The O
effects O
of O
recombinant O
B O
. O
bauhinoides O
cruzipain O
inhibitor O
and O
recombinant O
B O
. O
bauhinioides O
kallikrein O
inhibitor O
on O
the O
viability O
of O
tumor O
cell O
lines O
with O
a O
distinct O
potential O
of O
growth O
from O
the O
same O
tissue O
were O
compared O
to O
those O
of O
the O
clinical O
cytotoxic O
drug O
5 B
- I
fluorouracil I
. O

At O
12 O
. O
5 O
micro O
M O
concentration O
, O
recombinant O
B O
. O
bauhinoides O
cruzipain O
inhibitor O
and O
recombinant O
B O
. O
bauhinioides O
kallikrein O
inhibitor O
were O
more O
efficient O
than O
5 B
- I
fluorouracil I
in O
inhibiting O
MKN O
- O
28 O
and O
Hs746T O
( O
gastric O
) O
, O
HCT116 O
and O
HT29 O
( O
colorectal O
) O
, O
SkBr O
- O
3 O
and O
MCF O
- O
7 O
( O
breast O
) O
, O
and O
THP O
- O
1 O
and O
K562 O
( O
leukemia O
) O
cell O
lines O
. O

Additionally O
, O
recombinant O
B O
. O
bauhinoides O
cruzipain O
inhibitor O
inhibited O
40 O
% O
of O
the O
migration O
of O
Hs746T O
, O
the O
most O
invasive O
gastric O
cell O
line O
, O
while O
recombinant O
B O
. O
bauhinioides O
kallikrein O
inhibitor O
did O
not O
affect O
cell O
migration O
. O

Recombinant O
B O
. O
bauhinioides O
kallikrein O
inhibitor O
and O
recombinant O
B O
. O
bauhinoides O
cruzipain O
inhibitor O
, O
even O
at O
high O
doses O
, O
did O
not O
affect O
hMSC O
proliferation O
while O
5 B
- I
fluorouracil I
greatly O
reduced O
the O
proliferation O
rates O
of O
hMSCs O
. O

Therefore O
, O
both O
recombinant O
B O
. O
bauhinoides O
cruzipain O
inhibitor O
and O
recombinant O
B O
. O
bauhinioides O
kallikrein O
inhibitor O
might O
be O
considered O
for O
further O
studies O
to O
block O
peptidase O
activities O
in O
order O
to O
target O
specific O
peptidase O
- O
mediated O
growth O
and O
invasion O
characteristics O
of O
individual O
tumors O
, O
mainly O
in O
patients O
resistant O
to O
5 B
- I
fluorouracil I
chemotherapy O
. O

Mass O
spectrometry O
method O
to O
identify O
aging O
pathways O
of O
Sp O
- O
and O
Rp O
- O
tabun B
adducts O
on O
human O
butyrylcholinesteras O
based O
on O
the O
acid O
labile O
P B
- I
N I
bond O
. O

The O
phosphoramidate B
nerve O
agent O
tabun O
inhibits O
butyrylcholinesteras O
( O
BChE O
) O
and O
acetylcholinesterase O
by O
making O
a O
covalent O
bond O
on O
the O
active O
site O
serine B
. O

The O
adduct O
loses O
an O
alkyl B
group O
in O
a O
process O
called O
aging O
. O

The O
mechanism O
of O
aging O
of O
the O
tabun B
adduct O
is O
controversial O
. O

Some O
studies O
claim O
that O
aging O
proceeds O
through O
deamination O
, O
whereas O
crystal O
structure O
studies O
show O
aging O
by O
O B
- O
dealkylation O
. O

Our O
goal O
was O
to O
develop O
a O
method O
that O
clearly O
distinguishes O
between O
deamination O
and O
O B
- O
dealkylation O
. O

We O
began O
by O
studying O
the O
tetraisopropyl B
pyrophosphoramide I
adduct O
of O
BChE O
because O
this O
adduct O
has O
two O
P B
- I
N I
bonds O
. O

Mass O
spectra O
showed O
that O
the O
P B
- I
N I
bonds O
were O
stable O
during O
trypsin O
digestion O
at O
pH O
8 O
but O
were O
cleaved O
during O
pepsin O
digestion O
at O
pH O
2 O
. O

The O
P B
- I
N I
bond O
in O
tabun O
was O
also O
acid O
labile O
, O
whereas O
the O
P B
- I
O I
bond O
was O
stable O
. O

A O
scheme O
to O
distinguish O
aging O
by O
deamination O
from O
aging O
by O
O B
- O
dealkylation O
was O
based O
on O
the O
acid O
labile O
P B
- I
N I
bond O
. O

BChE O
was O
inhibited O
with O
Sp O
- I
and I
Rp I
- I
tabun I
thiocholine B
nerve O
agent O
model O
compounds O
to O
make O
adducts O
identical O
to O
those O
of O
tabun B
with O
known O
stereochemistry O
. O

After O
aging O
and O
digestion O
with O
pepsin O
at O
pH O
2 O
, O
peptide O
FGES198AGAAS O
from O
Sp O
- O
tabun O
thiocholine O
had O
a O
mass O
of O
902 O
. O
2 O
m O
/ O
z O
in O
negative O
mode O
, O
indicating O
that O
it O
had O
aged O
by O
deamination O
, O
whereas O
peptide O
FGES198AGAAS O
from O
Rp O
- O
tabun O
thiocholine O
had O
a O
mass O
of O
874 O
. O
2 O
m O
/ O
z O
in O
negative O
mode O
, O
indicating O
that O
it O
had O
aged O
by O
O B
- O
dealkylation O
. O

BChE O
inhibited O
by O
authentic O
, O
racemic O
tabun B
yielded O
both O
902 O
. O
2 O
and O
874 O
. O
2 O
m O
/ O
z O
peptides O
, O
indicating O
that O
both O
stereoisomers O
reacted O
with O
BChE O
and O
aged O
either O
by O
deamination O
or O
dealkylation O
. O

Synthesis O
of O
antioxidants O
for O
prevention O
of O
age O
- O
related O
macular O
degeneration O
. O

Photooxidation O
of O
A2E O
may O
be O
involved O
in O
diseases O
of O
the O
macula O
, O
and O
antioxidants O
could O
serve O
as O
therapeutic O
agents O
for O
these O
diseases O
. O

Inhibitors O
of O
A2E O
photooxidation O
were O
prepared O
by O
Mannich O
reaction O
of O
the O
antioxidant O
quercetin B
. O

These O
compounds O
contain O
water O
- O
solubilizing O
amine B
groups O
, O
and O
several O
were O
more O
potent O
inhibitors O
of O
A2E O
photooxidation O
than O
quercetin B
. O

The O
mannose B
6 I
- I
phosphate I
- O
binding O
sites O
of O
M6P O
/ O
IGF2R O
determine O
its O
capacity O
to O
suppress O
matrix O
invasion O
by O
squamous O
cell O
carcinoma O
cells O
. O

The O
M6P O
( O
mannose B
6 I
- I
phosphate I
) O
/ O
IGF2R O
( O
insulin O
- O
like O
growth O
factor O
II O
receptor O
) O
interacts O
with O
a O
variety O
of O
factors O
that O
impinge O
on O
tumour O
invasion O
and O
metastasis O
. O

It O
has O
been O
shown O
that O
expression O
of O
wild O
- O
type O
M6P O
/ O
IGF2R O
reduces O
the O
tumorigenic O
and O
invasive O
properties O
of O
receptor O
- O
deficient O
SCC O
- O
VII O
squamous O
cell O
carcinoma O
cells O
. O

We O
have O
now O
used O
mutant O
forms O
of O
M6P O
/ O
IGF2R O
to O
assess O
the O
relevance O
of O
the O
different O
ligand O
- O
binding O
sites O
of O
the O
receptor O
for O
its O
biological O
activities O
in O
this O
cellular O
system O
. O

The O
results O
of O
the O
present O
study O
demonstrate O
that O
M6P O
/ O
IGF2R O
does O
not O
require O
a O
functional O
binding O
site O
for O
insulin O
- O
like O
growth O
factor O
II O
for O
inhibition O
of O
anchorage O
- O
independent O
growth O
and O
matrix O
invasion O
by O
SCC O
- O
VII O
cells O
. O

In O
contrast O
, O
the O
simultaneous O
mutation O
of O
both O
M6P O
- O
binding O
sites O
is O
sufficient O
to O
impair O
all O
cellular O
functions O
of O
the O
receptor O
tested O
. O

These O
findings O
highlight O
that O
the O
interaction O
between O
M6P O
/ O
IGF2R O
and O
M6P O
- O
modified O
ligands O
is O
not O
only O
important O
for O
intracellular O
accumulation O
of O
lysosomal O
enzymes O
and O
formation O
of O
dense O
lysosomes O
, O
but O
is O
also O
crucial O
for O
the O
ability O
of O
the O
receptor O
to O
suppress O
SCC O
- O
VII O
growth O
and O
invasion O
. O

The O
present O
study O
also O
shows O
that O
some O
of O
the O
biological O
activities O
of O
M6P O
/ O
IGF2R O
in O
SCC O
- O
VII O
cells O
strongly O
depend O
on O
a O
functional O
M6P O
- O
binding O
site O
within O
domain O
3 O
, O
thus O
providing O
further O
evidence O
for O
the O
non O
- O
redundant O
cellular O
functions O
of O
the O
individual O
carbohydrate B
- O
binding O
domains O
of O
the O
receptor O
. O

Recombinant O
Luteinizing O
Hormone O
supplementation O
in O
poor O
responders O
undergoing O
IVF O
: O
a O
systematic O
review O
and O
meta O
- O
analysis O
. O

The O
results O
of O
several O
studies O
about O
the O
effectiveness O
of O
recombinant O
luteinizing O
hormone O
( O
rLH O
) O
supplementation O
in O
poor O
responder O
in O
vitro O
fertilization O
( O
IVF O
) O
patients O
were O
conflicting O
. O

To O
evaluate O
the O
current O
available O
data O
regarding O
the O
efficacy O
of O
rLH O
supplementation O
in O
poor O
responders O
, O
a O
meta O
- O
analysis O
was O
performed O
. O

A O
systemic O
search O
was O
performed O
without O
language O
limitation O
but O
restricted O
to O
randomized O
controlled O
trial O
( O
RCT O
) O
. O

We O
mainly O
explored O
MEDLINE O
, O
EMBASE O
, O
CNKI O
and O
Cochrane O
Library O
for O
the O
relevant O
studies O
. O

Three O
studies O
were O
considered O
eligible O
for O
inclusion O
. O

The O
meta O
- O
analysis O
indicated O
that O
rLH O
supplementation O
did O
not O
increase O
the O
ongoing O
pregnancy O
rate O
in O
poor O
responders O
( O
OR O
1 O
. O
30 O
, O
95 O
% O
CI O
: O
0 O
. O
80 O
, O
2 O
. O
11 O
) O
. O

Furthermore O
, O
there O
was O
no O
significant O
difference O
in O
the O
number O
of O
oocytes O
retrieved O
, O
total O
dose O
of O
rFSH O
used O
, O
total O
duration O
of O
stimulation O
, O
number O
of O
retrieved O
metaphase O
II O
oocytes O
and O
cycle O
cancellation O
rate O
between O
the O
study O
and O
control O
groups O
. O

In O
conclusions O
, O
the O
available O
evidence O
does O
not O
support O
the O
addition O
of O
rLH O
in O
poor O
responders O
treated O
with O
rFSH O
and O
GnRHa O
for O
IVF O
. O

It O
was O
inconclusive O
. O

Future O
research O
should O
be O
based O
on O
strict O
criteria O
to O
define O
poor O
responders O
, O
and O
large O
, O
well O
- O
designed O
RCTs O
are O
necessary O
to O
definitively O
answer O
the O
important O
question O
of O
whether O
there O
was O
need O
to O
use O
rLH O
in O
poor O
responders O
undergoing O
IVF O
. O

Catalytic O
DNAs O
that O
harness O
violet O
light O
to O
repair O
thymine B
dimers O
in O
a O
DNA O
substrate O
. O

UV1C O
is O
an O
in O
vitro O
selected O
catalytic O
DNA O
that O
shows O
efficient O
photolyase O
activity O
, O
using O
light O
of O
< O
310 O
nm O
wavelength O
to O
photo O
- O
reactivate O
CPD B
thymine B
dimers I
within O
a O
substrate O
DNA O
. O

We O
show O
here O
that O
a O
minimal O
mutational O
strategy O
of O
substituting O
a O
guanine B
analogue O
, O
6MI O
, O
for O
single O
guanine B
residues O
within O
UV1C O
extends O
the O
DNAzyme O
' O
s O
activity O
into O
the O
violet O
region O
of O
the O
spectrum O
. O

These O
6MI O
point O
mutant O
DNAzymes O
fall O
into O
three O
distinct O
functional O
classes O
, O
which O
photo O
- O
reactivate O
the O
thymine B
dimer O
along O
different O
pathways O
. O

Cumulatively O
, O
they O
reveal O
the O
modus O
operandi O
of O
the O
original O
UV1C O
DNAzyme O
to O
be O
a O
surprisingly O
versatile O
one O
. O

The O
interchangeable O
properties O
of O
no O
less O
than O
six O
of O
the O
G O
- O
- O
> O
6MI O
point O
mutants O
highlight O
UV1C O
' O
s O
built O
- O
in O
functional O
flexibility O
, O
which O
may O
serve O
as O
a O
starting O
point O
for O
the O
creation O
of O
efficient O
, O
visible O
light O
- O
harnessing O
, O
photolyase O
DNAzymes O
for O
either O
the O
prophylaxis O
or O
therapy O
of O
UV O
damage O
to O
human O
skin O
. O

Supramolecular O
hydrogels O
from O
in O
situ O
host O
- O
guest O
inclusion O
between O
chemically O
modified O
cellulose O
nanocrystals O
and O
cyclodextrin O
. O

When O
grafted O
beta B
- I
cyclodextrin I
is O
used O
as O
targeting O
sites O
, O
Pluronic B
polymers O
have O
been O
introduced O
on O
the O
surface O
of O
cellulose O
nanocrystals O
by O
means O
of O
inclusion O
interaction O
between O
beta B
- I
cyclodextrin I
and O
hydrophobic O
segment O
of O
the O
polymer O
. O

Because O
of O
the O
steric O
stabilization O
effect O
, O
surface O
poly B
( I
ethylene I
glycol I
) I
chains O
facilitate O
the O
dispersion O
and O
compatibility O
of O
nanocrystals O
, O
which O
also O
enhance O
the O
loading O
levels O
of O
nanocrystals O
in O
the O
hydrogel O
system O
. O

Meanwhile O
, O
uncovered O
poly B
( I
ethylene I
glycol I
) I
segments O
render O
the O
participating O
inclusion O
of O
alpha B
- I
cyclodextrin I
for O
the O
architecture O
of O
in O
situ O
hydrogels O
. O

Surface O
grafting O
and O
inclusion O
reactions O
were O
proved O
by O
solid O
( B
13 I
) I
C I
NMR O
and O
FTIR O
. O

Grafting O
efficiency O
of O
beta B
- I
cyclodextrin I
and O
inclusion O
efficiency O
of O
Pluronic B
on O
the O
surface O
of O
nanocrystals O
were O
confirmed O
by O
UV O
spectroscopy O
and O
elemental O
analysis O
. O

A O
significant O
enhancement O
of O
the O
structural O
and O
thermal O
stability O
of O
in O
situ O
hydrogels O
with O
high O
loading O
levels O
of O
modified O
nanocrystals O
( O
> O
5 O
. O
77 O
wt O
% O
) O
was O
observed O
by O
rheological O
analysis O
. O

Further O
study O
reveals O
the O
performance O
and O
behavior O
of O
hydrogels O
under O
a O
different O
pH O
environment O
. O

Finally O
, O
in O
situ O
hydrogels O
were O
used O
as O
drug O
carrier O
for O
in O
vitro O
release O
of O
doxorubicin B
and O
exhibit O
the O
behavior O
of O
prolonged O
drug O
release O
with O
special O
release O
kinetics O
. O

Structure O
of O
polyelectrolyte O
brushes O
subject O
to O
normal O
electric O
fields O
. O

Molecular O
dynamic O
simulations O
of O
salt O
- O
free O
polyelectrolyte O
brushes O
subject O
to O
external O
fields O
applied O
normal O
to O
the O
grafting O
substrate O
reveal O
the O
three O
- O
dimensional O
monomer O
and O
counterion O
distributions O
. O

It O
is O
found O
that O
below O
a O
critical O
electric O
field O
, O
local O
electroneutrality O
holds O
for O
densely O
grafted O
brushes O
and O
the O
brush O
height O
remains O
independent O
of O
field O
intensity O
. O

Above O
this O
critical O
field O
( O
which O
scales O
as O
1 O
/ O
3 O
with O
grafting O
density O
) O
brush O
height O
increases O
smoothly O
, O
and O
the O
fraction O
of O
condensed O
counterions O
decreases O
. O

The O
brush O
bifurcates O
into O
two O
subpopulations O
of O
stretched O
and O
collapsed O
chains O
when O
the O
grafting O
density O
is O
not O
low O
. O

At O
intermediate O
grafting O
densities O
, O
the O
majority O
of O
chains O
are O
stretched O
and O
the O
minority O
are O
nonstretched O
. O

At O
high O
grafting O
densities O
bifurcation O
and O
brush O
height O
growth O
occur O
consecutively O
. O

The O
majority O
of O
the O
chains O
are O
nonstretched O
at O
high O
grafting O
densities O
. O

Although O
not O
observed O
prior O
to O
overstretching O
of O
the O
chain O
model O
, O
it O
is O
predicted O
that O
the O
two O
subpopulations O
will O
re O
- O
merge O
to O
a O
single O
highly O
stretched O
phase O
when O
field O
intensity O
reaches O
a O
third O
critical O
value O
. O

The O
ability O
to O
control O
subpopulations O
of O
chains O
suggests O
that O
utilizing O
electric O
fields O
normal O
to O
polyelectrolyte O
brushes O
holds O
potential O
as O
controllable O
gates O
in O
microfluidic O
devices O
. O

Nanocomposites O
derived O
from O
montmorillonite B
and O
metallosupramolecula O
polyelectrolytes O
: O
modular O
compounds O
for O
electrorheological O
fluids O
. O

Nanocomposites O
made O
from O
Na B
- O
montmorillonite B
and O
metallo O
- O
supramolecular O
polyelectrolytes O
( O
MEPE O
) O
based O
on O
nickel B
and O
ditopic B
bis I
- I
terpyridine I
ligands O
are O
prepared O
by O
an O
aqueous O
synthesis O
. O

Intercalation O
is O
confirmed O
by O
IR O
- O
spectroscopy O
, O
thermogravimetric O
analysis O
, O
and O
X O
- O
ray O
powder O
diffraction O
. O

The O
rheological O
response O
in O
the O
presence O
of O
an O
electric O
field O
of O
the O
dispersed O
nanocomposites O
in O
silicone O
oil O
is O
measured O
with O
a O
rheometer O
. O

The O
nanocomposites O
show O
a O
distinct O
electrorheological O
effect O
depending O
on O
the O
concentration O
and O
the O
kind O
of O
intercalated O
species O
. O

The O
effect O
occurs O
with O
a O
low O
content O
of O
active O
material O
while O
only O
very O
small O
currents O
are O
observed O
. O

Adsorption O
and O
dilational O
rheology O
of O
mixed O
beta O
- O
casein O
/ O
DoTAB B
layers O
formed O
by O
sequential O
and O
simultaneous O
adsorption O
at O
the O
water O
/ O
hexane B
interface O
. O

The O
interfacial O
behavior O
of O
beta O
- O
casein O
( O
beta O
CS O
) O
has O
been O
investigated O
in O
presence O
of O
the O
cationic O
surfactant O
dodecyl B
trimethyl I
ammonium I
bromide I
( O
DoTAB B
) O
at O
the O
water O
/ O
hexane B
interface O
and O
compared O
to O
that O
obtained O
for O
the O
water O
/ O
air O
interface O
. O

The O
used O
experimental O
technique O
is O
a O
drop O
profile O
analysis O
tensiometer O
specially O
equipped O
with O
a O
coaxial O
double O
capillary O
, O
which O
allows O
investigation O
of O
sequential O
adsorption O
of O
individual O
components O
besides O
the O
traditional O
simultaneous O
adsorption O
of O
two O
species O
. O

This O
method O
also O
provides O
the O
dilational O
rheological O
measurements O
based O
on O
low O
frequency O
harmonic O
drop O
oscillations O
. O

The O
tensiometric O
results O
show O
that O
the O
equilibrium O
states O
of O
the O
mixed O
beta O
CS B
/ O
DoTAB B
layers O
built O
up O
on O
the O
two O
different O
routes O
do O
not O
differ O
significantly O
, O
that O
is O
, O
the O
general O
compositions O
of O
the O
mixed O
layers O
are O
similar O
. O

However O
, O
the O
results O
of O
dilational O
rheology O
for O
the O
two O
adsorption O
strategies O
are O
remarkably O
different O
indicating O
different O
dynamic O
characteristics O
of O
the O
adsorbed O
layers O
. O

These O
findings O
suggest O
that O
the O
respective O
mixed O
layers O
are O
more O
proteinlike O
if O
they O
are O
formed O
via O
sequential O
adsorption O
and O
more O
surfactant O
- O
like O
after O
simultaneous O
adsorption O
. O

In O
contrast O
to O
the O
W O
/ O
A O
interface O
, O
at O
the O
W O
/ O
H O
interface O
proteins O
remain O
at O
the O
interface O
once O
adsorbed O
and O
cannot O
be O
displaced O
just O
by O
competitive O
adsorption O
of O
surfactants O
. O

5 B
- I
Iodo I
- I
2 I
- I
aminoindan I
( O
5 B
- I
IAI I
) O
: O
chemistry O
, O
pharmacology O
, O
and O
toxicology O
of O
a O
research O
chemical O
producing O
MDMA B
- O
like O
effects O
. O

In O
2010 O
, O
an O
internet O
snapshot O
of O
EMCDDA O
anticipated O
the O
presence O
of O
5 B
- I
iodo I
- I
2 I
- I
aminoindan I
( O
5 B
- I
IAI I
) O
within O
the O
recreational O
drug O
market O
. O

In O
2011 O
, O
this O
compound O
, O
a O
psychoactive O
derivative O
of O
2 B
- I
aminoindane I
, O
was O
identified O
in O
recreational O
products O
sold O
in O
the O
United O
Kingdom O
. O

5 B
- I
IAI I
is O
a O
rigid O
analogue O
of O
p B
- I
iodoamphetamine I
producing O
MDMA B
- O
like O
effects O
. O

The O
aim O
of O
this O
paper O
is O
to O
summarize O
the O
clinical O
, O
pharmacological O
, O
and O
toxicological O
information O
about O
this O
new O
potential O
drug O
of O
abuse O
. O

Morphine B
withdrawal O
produces O
ERK O
- O
dependent O
and O
ERK O
- O
independent O
epigenetic O
marks O
in O
neurons O
of O
the O
nucleus O
accumbens O
and O
lateral O
septum O
. O

Epigenetic O
changes O
such O
as O
covalent O
modifications O
of O
histone O
proteins O
represent O
complex O
molecular O
signatures O
that O
provide O
a O
cellular O
memory O
of O
previously O
experienced O
stimuli O
without O
irreversible O
changes O
of O
the O
genetic O
code O
. O

In O
this O
study O
we O
show O
that O
new O
gene O
expression O
induced O
in O
vivo O
by O
morphine B
withdrawal O
occurs O
with O
concomitant O
epigenetic O
modifications O
in O
brain O
regions O
critically O
involved O
in O
drug O
- O
dependent O
behaviors O
. O

We O
found O
that O
naloxone B
- O
precipitated O
withdrawal O
, O
but O
not O
chronic O
morphine B
administration O
, O
caused O
a O
strong O
induction O
of O
phospho O
- O
histone O
H3 O
immunoreactivity O
in O
the O
nucleus O
accumbens O
( O
NAc O
) O
shell O
/ O
core O
and O
in O
the O
lateral O
septum O
( O
LS O
) O
, O
a O
change O
that O
was O
accompanied O
by O
augmented O
H3 O
acetylation O
( O
lys14 O
) O
in O
neurons O
of O
the O
NAc O
shell O
. O

Morphine B
withdrawal O
induced O
the O
phosphorylation O
of O
the O
epigenetic O
factor O
methyl B
- O
CpG O
- O
binding O
protein O
2 O
( O
MeCP2 O
) O
in O
Ser421 B
both O
in O
the O
LS O
and O
the O
NAc O
shell O
. O

These O
epigenetic O
changes O
were O
accompanied O
by O
the O
activation O
of O
members O
of O
the O
ERK O
pathway O
as O
well O
as O
increased O
expression O
of O
the O
immediate O
early O
genes O
( O
IEG O
) O
c O
- O
fos O
and O
activity O
- O
regulated O
cytoskeleton O
- O
associated O
protein O
( O
Arc O
/ O
Arg3 O
. O
1 O
) O
. O

Using O
a O
pharmacological O
approach O
, O
we O
found O
that O
H3 O
phosphorylation O
and O
IEG O
expression O
were O
partially O
dependent O
on O
ERK O
activation O
, O
while O
MeCP2 O
phosphorylation O
was O
fully O
ERK O
- O
independent O
. O

These O
findings O
provide O
new O
important O
information O
on O
the O
role O
of O
the O
ERK O
pathway O
in O
the O
regulation O
of O
epigenetic O
marks O
and O
gene O
expression O
that O
may O
concur O
to O
regulate O
in O
vivo O
the O
cellular O
changes O
underlying O
the O
onset O
of O
the O
opioid O
withdrawal O
syndrome O
. O

Motivational O
properties O
of O
D2 O
and O
D3 O
dopamine B
receptors O
agonists O
and O
cocaine B
, O
but O
not O
with O
D1 O
dopamine B
receptors O
agonist O
and O
l B
- I
dopa I
, O
in O
bilateral O
6 B
- I
OHDA I
- O
lesioned O
rat O
. O

Dopamine B
dysregulation O
syndrome O
in O
Parkinson O
' O
s O
disease O
( O
PD O
) O
has O
been O
attributed O
to O
dopamine B
replacement O
therapy O
( O
DRT O
) O
. O

We O
hypothesize O
that O
DRT O
can O
induce O
a O
potential O
rewarding O
effect O
in O
an O
animal O
model O
of O
PD O
. O

Using O
the O
conditioned O
place O
preference O
( O
CPP O
) O
paradigm O
, O
we O
investigated O
the O
motivational O
effects O
of O
l B
- I
dopa I
, O
dopamine B
receptor O
agonists O
( O
DRAs O
) O
, O
and O
cocaine B
in O
rat O
with O
a O
bilateral O
6 B
- I
OHDA I
lesion O
of O
the O
nigrostriatal O
dopaminergic O
pathway O
. O

In O
6 B
- I
OHDA I
animals O
, O
D1 O
receptors O
agonist O
( O
SKF81297 B
) O
revealed O
significantly O
a O
conditioned O
place O
aversion O
( O
CPA O
) O
at O
3 O
mg O
/ O
kg O
and O
9 O
mg O
/ O
kg O
doses O
. O

D2 O
receptors O
agonist O
( O
bromocriptine B
) O
induced O
both O
CPP O
and O
CPA O
at O
1 O
mg O
/ O
kg O
and O
10 O
mg O
/ O
kg O
doses O
respectively O
. O

D3 O
receptors O
agonist O
( O
PD128907 B
) O
induced O
a O
CPP O
only O
at O
1 O
mg O
/ O
kg O
, O
comparable O
to O
that O
of O
cocaine B
. O

Sham O
animals O
revealed O
biphasic O
CPP O
curves O
, O
with O
significant O
dose O
effect O
, O
for O
the O
intermediate O
dose O
of O
the O
3 O
DRAs O
. O

However O
, O
l B
- I
dopa I
induced O
no O
significant O
effect O
while O
cocaine B
induced O
CPP O
in O
both O
lesioned O
and O
sham O
animals O
. O

In O
conclusion O
, O
this O
study O
confirms O
the O
predominant O
roles O
of O
D2R O
class O
, O
and O
most O
specifically O
D3R O
subtypes O
, O
in O
rewarding O
properties O
of O
DRT O
. O

New O
insight O
into O
the O
discharge O
mechanism O
of O
silicon B
- O
air O
batteries O
using O
electrochemical O
impedance O
spectroscopy O
. O

The O
mechanism O
of O
discharge O
termination O
in O
silicon B
- O
air O
batteries O
, O
employing O
a O
silicon B
wafer O
anode O
, O
a O
room O
- O
temperature O
fluorohydrogenate B
ionic O
liquid O
electrolyte O
and O
an O
air O
cathode O
membrane O
, O
is O
investigated O
using O
a O
wide O
range O
of O
tools O
. O

EIS O
studies O
indicate O
that O
the O
interfacial O
impedance O
between O
the O
electrolyte O
and O
the O
silicon B
wafer O
increases O
upon O
continuous O
discharge O
. O

In O
addition O
, O
it O
is O
shown O
that O
the O
impedance O
of O
the O
air O
cathode O
- O
electrolyte O
interface O
is O
several O
orders O
of O
magnitude O
lower O
than O
that O
of O
the O
anode O
. O

Equivalent O
circuit O
fitting O
parameters O
indicate O
the O
difference O
in O
the O
anode O
- O
electrolyte O
interface O
characteristics O
for O
different O
types O
of O
silicon B
wafers O
. O

Evolution O
of O
porous O
silicon B
surfaces O
at O
the O
anode O
and O
their O
properties O
, O
by O
means O
of O
estimated O
circuit O
parameters O
, O
is O
also O
presented O
. O

Moreover O
, O
it O
is O
found O
that O
the O
silicon B
anode O
potential O
has O
the O
highest O
negative O
impact O
on O
the O
battery O
discharge O
voltage O
, O
while O
the O
air O
cathode O
potential O
is O
actually O
stable O
and O
invariable O
along O
the O
whole O
discharge O
period O
. O

The O
discharge O
capacity O
of O
the O
battery O
can O
be O
increased O
significantly O
by O
mechanically O
replacing O
the O
silicon B
anode O
. O

The O
effect O
of O
apricots O
on O
the O
experimental O
cataract O
model O
formed O
by O
sodium B
selenite I
. O

This O
study O
was O
designed O
in O
order O
to O
investigate O
whether O
sun O
dried O
apricots O
have O
a O
preventive O
effect O
on O
the O
experimental O
cataract O
model O
formed O
by O
sodium B
selenite I
in O
rats O
. O

Fifty O
- O
nine O
Spraque O
- O
Dawley O
rat O
pups O
were O
divided O
into O
three O
groups O
. O

Group O
1 O
( O
control O
group O
) O
consisted O
of O
twenty O
rat O
pups O
, O
born O
from O
the O
rats O
nourished O
ad O
libitum O
. O

Group O
2 O
consisted O
of O
18 O
newborn O
rats O
, O
born O
from O
the O
rats O
nourished O
ad O
libitum O
with O
10 O
% O
sun O
dried O
natural O
apricots O
. O

Group O
3 O
consisted O
of O
21 O
newborn O
rats O
, O
born O
from O
the O
rats O
nourished O
ad O
libitum O
. O

Subcutaneous O
( O
30nmol O
/ O
gr O
) O
sodium B
selenite I
injection O
was O
applied O
to O
all O
the O
newborn O
rats O
except O
the O
control O
group O
( O
Group O
1 O
) O
on O
postpartum O
day O
10 O
. O

Cataract O
development O
was O
graded O
by O
slit O
- O
lamp O
examination O
and O
photography O
. O

Encapsulated O
lenses O
were O
analyzed O
for O
reduced B
glutathione I
( O
GSH B
) O
and O
malondialdehyde B
( O
MDA B
) O
, O
a O
marker O
of O
lipid O
per O
oxidation O
. O

Lenses O
were O
also O
analyzed O
for O
total O
nitrite B
( O
TN O
) O
. O

The O
presence O
of O
oxidative O
stress O
in O
selenite B
cataract O
development O
and O
its O
prevention O
by O
sun O
dried O
apricots O
. O

Anti O
- O
inflammatory O
activity O
of O
patchouli B
alcohol I
in O
RAW264 O
. O
7 O
and O
HT O
- O
29 O
cells O
. O

Patchouli B
alcohol I
( O
PA O
) O
is O
a O
chemical O
compound O
extracted O
from O
patchouli O
which O
belongs O
to O
the O
genus O
Pogostemon O
, O
herb O
of O
mint O
family O
. O

Recently O
, O
it O
has O
been O
reported O
that O
PA O
inhibits O
the O
production O
of O
inflammatory O
mediators O
. O

However O
, O
the O
biological O
mechanisms O
of O
PA O
for O
anti O
- O
inflammatory O
activities O
have O
not O
been O
studied O
. O

In O
this O
study O
, O
we O
investigated O
whether O
PA O
decreases O
the O
production O
of O
inflammatory O
mediators O
through O
downregulation O
of O
the O
NF O
- O
kappa O
B O
and O
ERK O
pathway O
. O

Our O
data O
indicated O
that O
PA O
inhibits O
the O
over O
- O
expression O
of O
iNOS O
and O
IL O
- O
6 O
in O
protein O
and O
mRNA O
levels O
in O
LPS O
- O
stimulated O
RAW264 O
. O
7 O
and O
TNF O
- O
alpha O
stimulated O
HT O
- O
29 O
cells O
. O

PA O
inhibited O
I O
kappa O
B O
- O
alpha O
degradation O
and O
p65 O
nuclear O
translocation O
, O
and O
subsequently O
suppressed O
transcriptional O
activity O
of O
NF O
- O
kappa O
B O
in O
LPS O
- O
stimulated O
RAW264 O
. O
7 O
and O
TNF O
- O
alpha O
- O
stimulated O
HT O
- O
29 O
cells O
. O

In O
addition O
, O
PA O
inhibited O
LPS O
- O
or O
TNF O
- O
alpha O
- O
stimulated O
ERK1 O
/ O
2 O
activation O
by O
decreasing O
phosphorylation O
of O
ERK1 O
/ O
2 O
. O

These O
findings O
suggest O
that O
PA O
shows O
anti O
- O
inflammatory O
activities O
through O
suppressing O
ERK O
- O
mediated O
NF O
- O
kappa O
B O
pathway O
in O
mouse O
macrophage O
and O
human O
colorectal O
cancer O
cells O
. O

ALDH16A1 O
is O
a O
novel O
non O
- O
catalytic O
enzyme O
that O
may O
be O
involved O
in O
the O
etiology O
of O
gout O
via O
protein O
- O
protein O
interactions O
with O
HPRT1 O
. O

Gout O
, O
a O
common O
form O
of O
inflammatory O
arthritis O
, O
is O
strongly O
associated O
with O
elevated O
uric B
acid I
concentrations O
in O
the O
blood O
( O
hyperuricemia O
) O
. O

A O
recent O
study O
in O
Icelanders O
identified O
a O
rare O
missense O
single O
nucleotide O
polymorphism O
( O
SNP O
) O
in O
the O
ALDH16A1 O
gene O
, O
ALDH16A1 O
* O
2 O
, O
to O
be O
associated O
with O
gout O
and O
serum O
uric B
acid I
levels O
. O

ALDH16A1 O
is O
a O
novel O
and O
rather O
unique O
member O
of O
the O
ALDH O
superfamily O
in O
relation O
to O
its O
gene O
and O
protein O
structures O
. O

ALDH16 O
genes O
are O
present O
in O
fish O
, O
amphibians O
, O
protista O
, O
bacteria O
but O
absent O
from O
archaea O
, O
fungi O
and O
plants O
. O

In O
most O
mammalian O
species O
, O
two O
ALDH16A1 O
spliced O
variants O
( O
ALDH16A1 O
, O
long O
form O
and O
ALDH16A1 O
_ O
v2 O
, O
short O
form O
) O
have O
been O
identified O
and O
both O
are O
expressed O
in O
HepG O
- O
2 O
, O
HK O
- O
2 O
and O
HK O
- O
293 O
human O
cell O
lines O
. O

The O
ALDH16 O
proteins O
contain O
two O
ALDH O
domains O
( O
as O
opposed O
to O
one O
in O
the O
other O
members O
of O
the O
superfamily O
) O
, O
four O
transmembrane O
and O
one O
coiled O
- O
coil O
domains O
. O

The O
active O
site O
of O
ALDH16 O
proteins O
from O
bacterial O
, O
frog O
and O
lower O
animals O
contain O
the O
catalytically O
important O
cysteine B
residue O
( O
Cys B
- O
302 O
) O
; O
this O
residue O
is O
absent O
from O
the O
mammalian O
and O
fish O
orthologs O
. O

Molecular O
modeling O
predicts O
that O
both O
the O
short O
and O
long O
forms O
of O
human O
ALDH16A1 O
protein O
would O
lack O
catalytic O
activity O
but O
may O
interact O
with O
the O
hypoxanthine B
- O
guanine B
phosphoribosyltransf O
( O
HPRT1 O
) O
protein O
, O
a O
key O
enzyme O
involved O
in O
uric B
acid I
metabolism O
and O
gout O
. O

Interestingly O
, O
such O
protein O
- O
protein O
interactions O
with O
HPRT1 O
are O
predicted O
to O
be O
impaired O
for O
the O
long O
or O
short O
forms O
of O
ALDH16A1 O
* O
2 O
. O

These O
results O
lead O
to O
the O
intriguing O
possibility O
that O
association O
between O
ALDH16A1 O
and O
HPRT1 O
may O
be O
required O
for O
optimal O
HPRT O
activity O
with O
disruption O
of O
this O
interaction O
possibly O
contributing O
to O
the O
hyperuricemia O
seen O
in O
ALDH16A1 O
* O
2 O
carriers O
. O

Kava O
for O
the O
Treatment O
of O
Generalized O
Anxiety O
Disorder O
RCT O
: O
Analysis O
of O
Adverse O
Reactions O
, O
Liver O
Function O
, O
Addiction O
, O
and O
Sexual O
Effects O
. O

Presently O
, O
little O
is O
known O
about O
a O
number O
issues O
concerning O
kava O
( O
Piper O
methysticum O
) O
, O
including O
( O
i O
) O
whether O
kava B
has O
any O
withdrawal O
or O
addictive O
effects O
; O
( O
ii O
) O
if O
genetic O
polymorphisms O
of O
the O
cytochrome O
( O
CYP O
) O
P450 O
2D6 O
liver O
enzyme O
moderates O
any O
potential O
adverse O
effects O
; O
and O
( O
iii O
) O
if O
medicinal O
application O
of O
kava O
has O
any O
negative O
or O
beneficial O
effect O
on O
sexual O
function O
and O
experience O
. O

The O
study O
design O
was O
a O
6 O
- O
week O
, O
double O
- O
blind O
, O
randomized O
controlled O
trial O
( O
n O
= O
75 O
) O
involving O
chronic O
administration O
of O
kava B
( O
one O
tablet O
of O
kava B
twice O
per O
day O
; O
120 O
mg O
of O
kavalactones B
per O
day O
, O
titrated O
in O
non O
- O
response O
to O
two O
tablets O
of O
kava B
twice O
per O
day O
; O
240 O
mg O
of O
kavalactones B
) O
or O
placebo O
for O
participants O
with O
generalized O
anxiety O
disorder O
. O

Results O
showed O
no O
significant O
differences O
across O
groups O
for O
liver O
function O
tests O
, O
nor O
were O
there O
any O
significant O
adverse O
reactions O
that O
could O
be O
attributed O
to O
kava B
. O

No O
differences O
in O
withdrawal O
or O
addiction O
were O
found O
between O
groups O
. O

Interesting O
, O
kava O
significantly O
increased O
female O
' O
s O
sexual O
drive O
compared O
to O
placebo O
( O
p O
= O
0 O
. O
040 O
) O
on O
a O
sub O
- O
domain O
of O
the O
Arizona O
Sexual O
Experience O
Scale O
( O
ASEX O
) O
, O
with O
no O
negative O
effects O
seen O
in O
males O
. O

Further O
, O
it O
was O
found O
that O
there O
was O
a O
highly O
significant O
correlation O
between O
ASEX O
reduction O
( O
improved O
sexual O
function O
and O
performance O
) O
and O
anxiety O
reduction O
in O
the O
whole O
sample O
. O

Copyright O
( O
c O
) O
2013 O
John O
Wiley O
& O
Sons O
, O
Ltd O
. O

Evaluation O
of O
suppressive O
and O
pro O
- O
resolving O
effects O
of O
EPA B
and O
DHA B
in O
human O
primary O
monocytes O
and O
T O
- O
helper O
cells O
. O

Despite O
their O
beneficial O
anti O
- O
inflammatory O
properties O
, O
eicosapentaenoic B
acid I
( O
EPA B
) O
and O
docosahexaenoic B
acid I
( O
DHA B
) O
may O
increase O
the O
infection O
risk O
at O
high O
doses O
, O
likely O
by O
generating O
an O
immune O
- O
depressed O
state O
. O

To O
assess O
the O
contribution O
of O
different O
immune O
cell O
populations O
to O
the O
immunomodulatory O
fatty B
acid I
effect O
, O
we O
comparatively O
investigated O
several O
aspects O
of O
inflammation O
in O
human O
T O
- O
helper O
( O
Th O
) O
cells O
and O
monocytes O
. O

Both O
fatty B
acids I
, O
but O
DHA B
to O
a O
lesser O
extent O
compared O
with O
EPA B
, O
selectively O
and O
dose O
- O
dependently O
reduced O
the O
percentage O
of O
cytokine O
- O
expressing O
Th O
cells O
in O
a O
peroxisome O
proliferator O
- O
activated O
receptor O
( O
PPAR O
) O
gamma O
- O
dependent O
fashion O
, O
whereas O
the O
expression O
of O
the O
cell O
surface O
marker O
CD69 O
was O
unaltered O
on O
activated O
T O
cells O
. O

In O
monocytes O
, O
both O
EPA B
and O
DHA B
increased O
interleukin O
( O
IL O
) O
- O
10 O
without O
affecting O
tumor O
necrosis O
factor O
( O
TNF O
) O
- O
alpha O
and O
IL O
- O
6 O
. O

Cellular O
incorporation O
of O
EPA B
and O
DHA B
occurred O
mainly O
at O
the O
expense O
of O
arachidonic B
acid I
. O

Concomitantly O
, O
thromboxane B
B I
( O
TXB B
) O
2 I
and O
leukotriene B
B I
( O
LTB B
) O
4 I
in O
supernatants O
decreased O
, O
while O
levels O
of O
TXB3 B
and O
LTB5 B
increased O
. O

This O
increase O
was O
independent O
of O
activation O
and O
in O
accordance O
with O
cyclooxygenase O
expression O
patterns O
in O
monocytes O
. O

Moreover O
, O
EPA B
and O
DHA B
gave O
rise O
to O
a O
variety O
of O
mono B
- I
and I
trihydroxy I
derivatives O
of O
highly O
anti O
- O
inflammatory O
potential O
, O
such O
as O
resolvins B
and O
their O
precursors O
. O

Our O
results O
suggest O
that O
EPA B
and O
DHA B
do O
not O
generally O
affect O
immune O
cell O
functions O
in O
an O
inhibitory O
manner O
but O
rather O
promote O
pro O
- O
resolving O
responses O
. O

Activation O
of O
islet O
autoreactive O
naive O
T O
cells O
in O
infants O
is O
influenced O
by O
homeostatic O
mechanisms O
and O
antigen O
presenting O
capacity O
. O

Islet O
autoimmunity O
precedes O
type O
1 O
diabetes O
onset O
. O

We O
previously O
found O
that O
islet O
autoimmunity O
rarely O
starts O
before O
age O
six O
months O
but O
reaches O
its O
highest O
incidence O
already O
at O
around O
1 O
year O
of O
age O
. O

We O
now O
examine O
whether O
homeostatic O
expansion O
and O
immune O
competence O
changes O
seen O
in O
a O
maturating O
immune O
system O
may O
account O
for O
this O
marked O
variation O
in O
islet O
autoimmunity O
risk O
in O
the O
first O
year O
of O
life O
. O

We O
found O
na O
i O
ve O
proinsulin O
- O
and O
GAD65 O
- O
responsive O
T O
cells O
in O
cord O
blood O
of O
healthy O
newborns O
, O
with O
highest O
responses O
observed O
in O
children O
with O
type O
1 O
diabetes O
susceptible O
HLA O
- O
DRB1 O
/ O
DQB1 O
genotypes O
. O

Homeostatic O
expansion O
characteristics O
with O
increased O
IL O
- O
7 O
concentrations O
and O
enhanced O
T O
cell O
responsiveness O
to O
IL O
- O
7 O
were O
observed O
throughout O
the O
first O
year O
of O
life O
. O

However O
, O
the O
ability O
of O
antigen O
- O
presenting O
cells O
to O
activate O
na O
i O
ve O
T O
cells O
was O
compromised O
at O
birth O
, O
and O
cord O
blood O
monocytes O
had O
low O
surface O
expression O
of O
CD40 O
and O
HLA O
class O
II O
. O

In O
contrast O
, O
antigen O
presentation O
and O
expression O
of O
these O
molecules O
had O
reached O
competent O
adult O
levels O
by O
the O
high O
incidence O
age O
of O
8 O
months O
. O

We O
propose O
that O
temporal O
changes O
in O
islet O
autoimmunity O
seroconversion O
in O
infants O
are O
a O
consequence O
of O
the O
changing O
balance O
between O
homeostatic O
drive O
and O
antigen O
presentation O
competence O
. O

These O
findings O
are O
relevant O
for O
early O
prevention O
of O
type O
1 O
diabetes O
. O

Reduction O
of O
reactive O
oxygen B
species O
ameliorates O
metabolism O
- O
secretion O
coupling O
in O
islets O
of O
diabetic O
GK O
rats O
by O
suppressing O
lactate B
overproduction O
. O

We O
previously O
demonstrated O
that O
impaired O
glucose B
- O
induced O
insulin O
secretion O
( O
IS O
) O
and O
ATP B
elevation O
in O
islets O
of O
Goto O
- O
Kakizaki O
( O
GK O
) O
rats O
, O
a O
non O
- O
obese O
model O
of O
diabetes O
, O
were O
significantly O
restored O
by O
30 O
~ O
60 O
min O
suppression O
of O
endogenous O
reactive O
oxygen B
species O
( O
ROS O
) O
overproduction O
. O

In O
this O
study O
, O
we O
investigated O
the O
effect O
of O
longer O
( O
12 O
h O
) O
suppression O
of O
ROS O
on O
metabolism O
- O
secretion O
coupling O
in O
beta O
- O
cells O
by O
exposure O
to O
tempol B
, O
a O
superoxide B
dismutase O
mimic O
, O
plus O
ebselen B
, O
a O
glutathione B
peroxidase O
mimic O
( O
TE O
- O
treatment O
) O
. O

In O
GK O
islets O
, O
both O
H B
( I
2 I
) I
O I
( I
2 I
) I
and O
superoxide B
were O
sufficiently O
reduced O
and O
glucose B
- O
induced O
IS O
and O
ATP B
elevation O
were O
improved O
by O
TE O
- O
treatment O
. O

Glucose B
oxidation O
, O
an O
indicator O
of O
Krebs O
cycle O
velocity O
, O
also O
was O
improved O
by O
TE O
- O
treatment O
at O
high O
glucose B
, O
whereas O
glucokinase O
activity O
, O
which O
determines O
glycolytic O
velocity O
, O
was O
not O
affected O
. O

Lactate B
production O
was O
markedly O
increased O
in O
GK O
islets O
and O
TE O
- O
treatment O
reduced O
lactate B
production O
and O
protein O
expression O
of O
lactate B
dehydrogenase O
and O
hypoxia O
- O
inducible O
factor O
1 O
alpha O
( O
HIF1 O
alpha O
) O
. O

These O
results O
indicate O
that O
the O
Warburg O
- O
like O
effect O
, O
which O
is O
characteristic O
of O
aerobic O
metabolism O
in O
cancer O
cells O
by O
which O
lactate B
is O
overproduced O
with O
reduced O
linking O
to O
mitochondria O
metabolism O
, O
plays O
an O
important O
role O
in O
impaired O
metabolism O
- O
secretion O
coupling O
in O
diabetic O
beta O
- O
cells O
and O
suggest O
that O
ROS O
reduction O
can O
improve O
mitochondrial O
metabolism O
by O
suppressinglactate O
overproduction O
through O
inhibition O
of O
HIF1 O
alpha O
stabilization O
. O

The O
type O
2 O
diabetes O
associated O
gene O
Ide O
is O
required O
for O
insulin O
secretion O
and O
suppression O
of O
alpha O
- O
synuclein O
levels O
in O
beta O
- O
cells O
. O

Genome O
wide O
association O
studies O
have O
identified O
several O
type O
2 O
diabetes O
( O
T2D O
) O
risk O
loci O
linked O
to O
impaired O
beta O
- O
cell O
function O
. O

The O
identity O
and O
function O
of O
the O
causal O
genes O
in O
these O
susceptibility O
loci O
remain O
, O
however O
, O
elusive O
. O

The O
HHEX O
/ O
IDE O
T2D O
locus O
is O
associated O
with O
decreased O
insulin O
secretion O
in O
response O
to O
oral O
glucose B
stimulation O
in O
humans O
. O

Here O
we O
have O
assessed O
beta O
- O
cell O
function O
in O
Ide O
knock O
- O
out O
( O
KO O
) O
mice O
. O

We O
find O
that O
glucose B
stimulated O
insulin O
secretion O
( O
GSIS O
) O
is O
decreased O
in O
Ide O
KO O
mice O
due O
to O
impaired O
replenishment O
of O
the O
releasable O
pool O
of O
granules O
and O
that O
the O
Ide O
gene O
is O
haploinsufficient O
. O

We O
also O
show O
that O
autophagic O
flux O
and O
microtubule O
content O
is O
reduced O
in O
beta O
- O
cells O
of O
Ide O
KO O
mice O
. O

One O
important O
cellular O
role O
for O
IDE O
involves O
the O
neutralization O
of O
amyloidogenic O
proteins O
and O
we O
find O
that O
alpha O
- O
synuclein O
and O
IDE O
levels O
are O
inversely O
correlated O
in O
beta O
- O
cells O
of O
Ide O
KO O
mice O
and O
T2D O
patients O
. O

Moreover O
, O
we O
provide O
evidence O
that O
both O
gain O
- O
and O
loss O
- O
of O
- O
function O
of O
alpha O
- O
synuclein O
in O
beta O
- O
cells O
in O
vivo O
not O
only O
impair O
GSIS O
but O
also O
autophagy O
. O

Together O
, O
these O
data O
identify O
the O
Ide O
gene O
as O
a O
regulator O
of O
GSIS O
, O
suggest O
a O
molecular O
mechanism O
for O
beta O
- O
cell O
degeneration O
as O
a O
consequence O
of O
Ide O
deficiency O
, O
and O
additionally O
corroborates O
and O
extends O
a O
previously O
established O
important O
role O
for O
alpha O
- O
synuclein O
in O
beta O
- O
cell O
function O
. O

Enhanced O
NF O
kappa O
B O
Activity O
Impairs O
Vascular O
Function O
through O
PARP O
- O
1 O
, O
SP O
- O
1 O
and O
COX2 O
- O
Dependent O
Mechanisms O
in O
Type O
2 O
Diabetes O
. O

Type O
2 O
diabetes O
( O
T2D O
) O
is O
associated O
with O
vascular O
dysfunction O
. O

We O
hypothesized O
that O
increased O
nuclear O
factor O
kappa O
B O
( O
NF O
kappa O
B O
) O
signaling O
contributes O
to O
vascular O
dysfunction O
in O
T2D O
. O

We O
have O
treated O
type O
2 O
diabetic O
( O
db O
( O
- O
) O
/ O
db O
( O
- O
) O
) O
and O
control O
( O
db O
( O
- O
) O
/ O
db O
( O
+ O
) O
) O
mice O
with O
two O
NF O
kappa O
B O
inhibitors O
( O
DHMEQ O
, O
6mg O
/ O
kg O
, O
twice O
a O
week O
and O
IKK O
- O
NBD O
peptide O
, O
500 O
mu O
g O
/ O
kg O
/ O
day O
) O
for O
four O
weeks O
. O

Pressure O
- O
induced O
myogenic O
tone O
( O
MT O
) O
was O
significantly O
potentiated O
, O
while O
endothelium O
dependent O
relaxation O
( O
EDR O
) O
was O
impaired O
in O
small O
coronary O
arterioles O
( O
CA O
) O
and O
mesenteric O
resistance O
artery O
( O
MRA O
) O
from O
diabetic O
mice O
compared O
to O
control O
. O

Interestingly O
, O
diabetic O
mice O
treated O
with O
NF O
kappa O
B O
inhibitors O
significantly O
reduced O
MT O
potentiation O
and O
improved O
EDR O
. O

Importantly O
, O
vascular O
function O
was O
also O
rescued O
in O
db B
( I
- I
) I
/ O
db O
( O
- O
p50NF O
kappa O
B O
- O
/ O
- O
) O
and O
db B
( I
- O
) I
/ O
db O
( O
- O
PARP O
- O
1 O
- O
/ O
- O
) O
double O
knockout O
mice O
compared O
to O
db B
( I
- I
) I
/ O
db O
( O
- O
) I
mice O
. O

Additionally O
, O
the O
acute O
in O
vitro O
down O
regulation O
of O
NF O
kappa O
B O
- O
p65 O
using O
p65NF O
kappa O
B O
shRNA O
lentivirus O
in O
arteries O
from O
db O
( O
- O
) O
/ O
db O
( O
- O
) O
mice O
also O
improved O
vascular O
function O
. O

The O
NF O
kappa O
B O
inhibition O
did O
not O
affect O
blood O
glucose B
level O
and O
body O
weight O
. O

The O
RNA O
levels O
for O
Sp O
- O
1 O
and O
eNOS O
phosphorylation O
were O
decreased O
, O
while O
p65NF O
kappa O
B O
phosphorylation O
, O
cleaved O
PARP O
- O
1 O
and O
COX O
- O
2 O
expression O
were O
increased O
in O
arteries O
from O
diabetic O
mice O
, O
which O
were O
restored O
after O
NF O
kappa O
B O
inhibition O
and O
in O
db O
( O
- O
) O
/ O
db O
( O
- O
p50NF O
kappa O
B O
- O
/ O
- O
) O
and O
db O
( O
- O
) O
/ O
db O
( O
- O
PARP O
- O
1 O
- O
/ O
- O
) O
mice O
. O
In O
the O
present O
study O
, O
we O
provided O
evidence O
that O
enhanced O
NF O
kappa O
B O

activity O
impairs O
vascular O
function O
by O
PARP O
- O
1 O
, O
Sp O
- O
1 O
and O
COX O
- O
2 O
- O
dependent O
mechanisms O
in O
male O
type O
2 O
diabetic O
mice O
. O

Therefore O
, O
NF O
kappa O
B O
could O
be O
a O
potential O
target O
to O
overcome O
diabetes O
- O
induced O
vascular O
dysfunction O
. O

Intracellular O
drug O
release O
from O
curcumin B
- O
loaded O
PLGA B
nanoparticles O
induces O
G2 O
/ O
M O
block O
in O
breast O
cancer O
cells O
. O

PLGA B
nanoparticles O
are O
among O
the O
most O
studied O
polymer O
nanoformulations O
for O
several O
drugs O
against O
different O
kinds O
of O
malignant O
diseases O
, O
thanks O
to O
their O
in O
vivo O
stability O
and O
tumor O
localization O
exploiting O
the O
well O
- O
documented O
" O
enhanced O
permeation O
and O
retention O
" O
( O
EPR O
) O
effect O
. O

In O
this O
paper O
, O
we O
have O
developed O
uniform O
curcumin B
- O
bearing O
PLGA B
nanoparticles O
by O
a O
single O
- O
emulsion O
process O
, O
which O
exhibited O
a O
curcumin B
release O
following O
a O
Fickian O
- O
law O
diffusion O
over O
10 O
days O
in O
vitro O
. O

PLGA B
nanoparticles O
were O
about O
120 O
nm O
in O
size O
, O
as O
determined O
by O
dynamic O
light O
scattering O
, O
with O
a O
surface O
negative O
charge O
of O
- O
30 O
mV O
. O

The O
loading O
ratio O
of O
encapsulated O
drug O
in O
our O
PLGA B
nanoformulation O
was O
8 O
wt O
% O
. O

PLGA B
encapsulation O
provided O
efficient O
protection O
of O
curcumin B
from O
environment O
, O
as O
determined O
by O
fluorescence O
emission O
experiments O
. O

Next O
, O
we O
have O
investigated O
the O
possibility O
to O
study O
the O
intracellular O
degradation O
of O
nanoparticles O
associated O
with O
a O
specific O
G2 O
/ O
M O
blocking O
effect O
on O
MCF7 O
breast O
cancer O
cells O
caused O
by O
curcumin B
release O
in O
the O
cytoplasm O
, O
which O
provided O
direct O
evidence O
on O
the O
mechanism O
of O
action O
of O
our O
nanocomplex O
. O

This O
study O
was O
carried O
out O
using O
Annexin O
V O
- O
based O
cell O
death O
analysis O
, O
MTT B
assessment O
of O
proliferation O
, O
flow O
cytometry O
, O
and O
confocal O
laser O
scanning O
microscopy O
. O

PLGA B
nanoparticles O
proved O
to O
be O
completely O
safe O
, O
suggesting O
a O
potential O
utilization O
of O
this O
nanocomplex O
to O
improve O
the O
intrinsically O
poor O
bioavailability O
of O
curcumin B
for O
the O
treatment O
of O
severe O
malignant O
breast O
cancer O
. O

Molecular O
reorganization O
in O
organic O
field O
- O
effect O
transistors O
and O
its O
effect O
on O
two O
- O
dimensional O
charge O
transport O
pathways O
. O

Charge O
transport O
in O
organic O
thin O
film O
transistors O
takes O
place O
in O
the O
first O
few O
molecular O
layers O
in O
contact O
with O
the O
gate O
dielectric O
. O

Here O
we O
demonstrate O
that O
the O
charge O
transport O
pathways O
in O
these O
devices O
are O
extremely O
sensitive O
to O
the O
orientational O
defects O
of O
the O
first O
monolayers O
, O
which O
arise O
from O
specific O
growth O
conditions O
. O

Although O
these O
defects O
partially O
heal O
during O
the O
growth O
, O
they O
cause O
depletion O
of O
charge O
carriers O
in O
the O
first O
monolayer O
, O
and O
drive O
the O
current O
to O
flow O
in O
the O
monolayers O
above O
the O
first O
one O
. O

Moreover O
, O
the O
residual O
defects O
induce O
lower O
crystalline O
order O
and O
charge O
mobility O
. O

These O
results O
, O
which O
are O
not O
intuitively O
explained O
by O
electrostatics O
arguments O
, O
have O
been O
obtained O
by O
combining O
in O
situ O
real O
time O
structural O
and O
electrical O
characterization O
together O
with O
ex O
situ O
AFM O
measurements O
, O
on O
thin O
films O
of O
a O
relevant O
n O
- O
type O
organic O
semiconductor O
, O
N B
, I
N I
' I
- I
bis I
( I
n I
- I
octyl I
) I
- I
dicyanoperylene I
- I
3 I
, I
4 I
: I
9 I
, I
10 I
- I
bis I
dicarboximide I
grown O
by O
sublimation O
in O
a O
quasi O
- O
layer O
- O
by O
- O
layer O
mode O
at O
different O
substrate O
temperatures O
. O

Sulfated O
Small O
Molecules O
Targeting O
EBV O
in O
Burkitt O
Lymphoma O
: O
From O
In O
Silico O
Screening O
to O
the O
Evidence O
of O
In O
Vitro O
Effect O
on O
Viral O
Episomal O
DNA O
. O

Epstein O
- O
Barr O
virus O
( O
EBV O
) O
infects O
more O
than O
90 O
% O
of O
the O
world O
population O
. O

Following O
primary O
infection O
, O
Epstein O
- O
Barr O
virus O
persists O
in O
an O
asymptomatic O
latent O
state O
. O

Occasionally O
, O
it O
may O
switch O
to O
lytic O
infection O
. O

Latent O
EBV O
infection O
has O
been O
associated O
with O
several O
diseases O
, O
such O
as O
Burkitt O
lymphoma O
( O
BL O
) O
. O

To O
date O
, O
there O
are O
no O
available O
drugs O
to O
target O
latent O
EBV O
, O
and O
the O
existing O
broad O
- O
spectrum O
antiviral O
drugs O
are O
mainly O
active O
against O
lytic O
viral O
infection O
. O

Thus O
, O
using O
computational O
molecular O
docking O
, O
a O
virtual O
screen O
of O
a O
library O
of O
small O
molecules O
, O
including O
xanthones B
and O
flavonoids B
( O
described O
with O
potential O
for O
antiviral O
activity O
against O
EBV O
) O
, O
was O
carried O
out O
targeting O
EBV O
proteins O
. O

The O
more O
interesting O
molecules O
were O
selected O
for O
further O
computational O
analysis O
, O
and O
sub O
- O
sequently O
, O
the O
compounds O
were O
tested O
in O
the O
Raji O
( O
BL O
) O
cell O
line O
, O
to O
evaluate O
their O
activity O
against O
latent O
EBV O
. O

This O
work O
identified O
three O
novel O
sulfated O
small O
molecules O
capable O
of O
decreasing O
EBV O
levels O
in O
a O
BL O
. O

Therefore O
, O
the O
in O
silico O
screening O
presents O
a O
good O
approach O
for O
the O
development O
of O
new O
anti O
- O
EBV O
agents O
. O

Genome O
wide O
association O
studies O
for O
diabetes O
: O
perspective O
on O
results O
and O
challenges O
. O

Recent O
results O
of O
genome O
wide O
association O
study O
( O
GWAS O
) O
for O
diabetes O
genes O
, O
while O
reaching O
impressive O
technical O
milestones O
and O
implicating O
new O
findings O
for O
research O
, O
have O
been O
uniformly O
disappointing O
in O
terms O
of O
immediate O
clinical O
utility O
. O

The O
relative O
risk O
associated O
with O
any O
of O
the O
newly O
reported O
genetic O
loci O
, O
or O
even O
considering O
all O
of O
them O
together O
, O
is O
far O
less O
than O
simply O
that O
which O
can O
be O
obtained O
by O
taking O
a O
history O
and O
a O
physical O
exam O
. O

For O
type O
2 O
diabetes O
( O
T2D O
) O
, O
GWAS O
have O
implicated O
novel O
pathways O
, O
supported O
previously O
known O
associations O
, O
and O
highlighted O
the O
importance O
of O
the O
beta O
cell O
and O
insulin O
secretion O
. O

Monogenic O
forms O
of O
diabetes O
, O
on O
the O
other O
hand O
, O
continue O
to O
yield O
interesting O
insights O
into O
genes O
controlling O
human O
beta O
cell O
function O
but O
most O
cases O
of O
monogenic O
diabetes O
are O
simply O
not O
diagnosed O
. O

Here O
, O
we O
briefly O
review O
recent O
results O
related O
to O
type O
1 O
, O
type O
2 O
and O
maturity O
onset O
diabetes O
of O
youth O
( O
MODY O
) O
diabetes O
and O
suggest O
that O
future O
studies O
emphasizing O
quantitative O
traits O
are O
likely O
to O
yield O
even O
more O
insights O
. O

Chiral O
bicyclic B
tetramates I
as O
non O
- O
planar O
templates O
for O
chemical O
library O
synthesis O
. O

Chemoselective O
Dieckmann O
cyclization O
reactions O
may O
be O
used O
on O
oxazolidine B
and O
thiazolidine B
templates O
derived O
from O
various O
aldehydes B
to O
access O
bicyclic B
tetramates I
, O
which O
have O
potential O
as O
templates O
for O
chemical O
library O
construction O
. O

Bioassay O
against O
Staphylococcus O
aureus O
and O
Escherichia O
coli O
showed O
that O
these O
systems O
have O
little O
or O
no O
intrinsic O
antibacterial O
bioactivity O
. O

Pyrrolopyrazines B
as O
Selective O
Spleen O
Tyrosine B
Kinase O
Inhibitors O
. O

We O
describe O
the O
discovery O
of O
several O
pyrrolopyrazines B
as O
potent O
and O
selective O
Syk O
inhibitors O
and O
the O
efforts O
that O
eventually O
led O
to O
the O
desired O
improvements O
in O
physicochemical O
properties O
and O
human O
whole O
blood O
potencies O
. O

Ultimately O
, O
our O
mouse O
model O
revealed O
unexpected O
toxicity O
that O
precluded O
us O
from O
further O
advancing O
this O
series O
. O

Termini O
of O
bottom O
- O
up O
fabricated O
graphene B
nanoribbons O
. O

Atomically O
precise O
graphene B
nanoribbons O
( O
GNRs O
) O
can O
be O
obtained O
via O
thermally O
induced O
polymerization O
of O
suitable O
precursor O
molecules O
on O
a O
metal O
surface O
. O

This O
communication O
discusses O
the O
atomic O
structure O
found O
at O
the O
termini O
of O
armchair O
GNRs O
obtained O
via O
this O
bottom O
- O
up O
approach O
. O

The O
short O
zigzag O
edge O
at O
the O
termini O
of O
the O
GNRs O
under O
study O
gives O
rise O
to O
a O
localized O
midgap O
state O
with O
a O
characteristic O
signature O
in O
scanning O
tunneling O
microscopy O
( O
STM O
) O
. O

By O
combining O
STM O
experiments O
with O
large O
- O
scale O
density O
functional O
theory O
calculations O
, O
we O
demonstrate O
that O
the O
termini O
are O
passivated O
by O
hydrogen B
. O

Our O
results O
suggest O
that O
the O
length O
of O
nanoribbons O
grown O
by O
this O
protocol O
may O
be O
limited O
by O
hydrogen B
passivation O
during O
the O
polymerization O
step O
. O

Copper B
( I
I I
) I
- O
catalyzed O
borylative O
exo O
- O
cyclization O
of O
alkenyl B
halides I
containing O
unactivated O
double O
bond O
. O

A O
borylative O
exo O
- O
cyclization O
of O
alkenyl B
halides I
has O
been O
reported O
. O

The O
reaction O
includes O
the O
regioselective O
addition O
of O
a O
borylcopper B
( I
I I
) I
intermediate O
to O
unactivated O
terminal O
alkenes B
, O
followed O
by O
the O
intramolecular O
substitution O
of O
the O
resulting O
alkylcopper B
( I
I I
) I
moiety O
for O
the O
halide B
leaving O
groups O
. O

Experimental O
and O
theoretical O
investigations O
of O
the O
reaction O
mechanism O
have O
also O
been O
described O
. O

This O
reaction O
provides O
a O
new O
method O
for O
the O
synthesis O
of O
alkylboronates B
containing O
strained O
cycloalkyl B
structures O
from O
simple O
starting O
materials O
. O

Chemogenomics O
Approaches O
to O
Rationalizing O
the O
Mode O
- O
of O
- O
Action O
of O
Traditional O
Chinese O
and O
Ayurvedic O
Medicines O
. O

Traditional O
Chinese O
medicine O
( O
TCM O
) O
and O
Ayurveda O
have O
been O
used O
in O
humans O
for O
thousands O
of O
years O
. O

While O
the O
link O
to O
a O
particular O
indication O
has O
been O
established O
in O
man O
, O
the O
mode O
- O
of O
- O
action O
( O
MOA O
) O
of O
the O
formulations O
often O
remains O
unknown O
. O

In O
this O
study O
, O
we O
aim O
to O
understand O
the O
MOA O
of O
formulations O
used O
in O
traditional O
medicine O
using O
an O
in O
silico O
target O
prediction O
algorithm O
, O
which O
aims O
to O
predict O
protein O
targets O
( O
and O
hence O
MOAs O
) O
, O
given O
the O
chemical O
structure O
of O
a O
compound O
. O

Following O
this O
approach O
we O
were O
able O
to O
establish O
several O
links O
between O
suggested O
MOAs O
and O
experimental O
evidence O
. O

In O
particular O
, O
compounds O
from O
the O
' O
tonifying O
and O
replenishing O
medicinal O
' O
class O
from O
TCM O
exhibit O
a O
hypoglycemic O
effect O
which O
can O
be O
related O
to O
activity O
of O
the O
ingredients O
against O
the O
Sodium B
- O
Glucose B
Transporters O
( O
SGLT O
) O
1 O
and O
2 O
as O
well O
as O
Protein O
Tyrosine B
Phosphatase O
( O
PTP O
) O
. O

Similar O
results O
were O
obtained O
for O
Ayurvedic O
anticancer O
drugs O
. O

Here O
, O
both O
primary O
anticancer O
targets O
( O
those O
directly O
involved O
in O
cancer O
pathogenesis O
) O
such O
as O
steroid B
- O
5 O
- O
alpha O
- O
reductase O
1 O
and O
2 O
were O
predicted O
as O
well O
as O
targets O
which O
act O
synergistically O
with O
the O
primary O
target O
, O
such O
as O
the O
efflux O
pump O
P O
- O
glycoprotein O
( O
P O
- O
gp O
) O
. O

In O
addition O
, O
we O
were O
able O
to O
elucidate O
some O
targets O
which O
may O
point O
us O
to O
novel O
MOAs O
as O
well O
as O
explain O
side O
effects O
. O

Most O
notably O
, O
GPBAR1 O
, O
which O
was O
predicted O
as O
a O
target O
for O
both O
' O
tonifying O
and O
replenishing O
medicinal O
' O
and O
anticancer O
classes O
, O
suggests O
an O
influence O
of O
the O
compounds O
on O
metabolism O
. O

Understanding O
the O
MOA O
of O
these O
compounds O
is O
beneficial O
as O
it O
provides O
a O
resource O
for O
NMEs O
with O
possibly O
higher O
efficacy O
in O
the O
clinic O
than O
those O
identified O
by O
single O
- O
target O
biochemical O
assays O
. O

Pharmacokinetics O
, O
tissue O
distribution O
and O
excretion O
study O
of O
resveratrol B
and O
its O
prodrug O
3 B
, I
5 I
, I
4 I
' I
- I
tri I
- I
O I
- I
acetylresveratrol I
in O
rats O
. O

3 B
, I
5 I
, I
4 I
' I
- I
Tri I
- I
O I
- I
acetylresveratrol I
( O
TARES B
) O
synthesized O
by O
acetylating O
three O
hydroxyl B
groups O
of O
resveratrol B
( O
RES B
) O
is O
a O
prodrug O
of O
RES B
. O

The O
aim O
of O
this O
study O
was O
to O
investigate O
and O
compare O
the O
pharmacokinetics O
, O
tissue O
distribution O
and O
excretion O
of O
TARES B
and O
RES B
in O
rats O
following O
a O
single O
intragastric O
gavage O
( O
i O
. O
g O
. O
) O
administration O
. O

After O
RES B
is O
transformed O
into O
TARES B
, O
its O
pharmacokinetic O
properties O
are O
improved O
, O
such O
as O
the O
t1 O
/ O
2 O
has O
been O
prolonged O
and O
the O
AUC O
has O
been O
enhanced O
. O

And O
TARES B
follows O
linear O
plasma O
pharmacokinetics O
across O
the O
investigated O
dosage O
range O
in O
rats O
( O
77 O
. O
5 O
- O
310mg O
/ O
kg O
) O
. O

The O
major O
distribution O
tissues O
of O
TARES B
or O
RES B
in O
rats O
were O
liver O
, O
spleen O
, O
heart O
and O
lung O
. O

TARES O
can O
increase O
the O
content O
of O
RES B
in O
lung O
significantly O
. O

There O
was O
no O
long O
- O
term O
accumulation O
of O
RES B
in O
rat O
tissues O
. O

Whether O
we O
administrated O
to O
rats O
of O
equimolar O
TARES B
or O
RES B
, O
total O
recoveries O
of O
RES B
in O
urine O
and O
feces O
within O
36h O
were O
low O
( O
0 O
. O
99 O
% O
or O
0 O
. O
07 O
% O
in O
urine O
and O
1 O
. O
69 O
% O
or O
0 O
. O
15 O
% O
in O
feces O
) O
. O

Biofilm O
inhibitors O
that O
target O
amyloid O
proteins O
. O

Bacteria O
establish O
stable O
communities O
, O
known O
as O
biofilms O
, O
that O
are O
resistant O
to O
antimicrobials O
. O

Biofilm O
robustness O
is O
due O
to O
the O
presence O
of O
an O
extracellular O
matrix O
, O
which O
for O
several O
species O
- O
among O
them O
Bacillus O
subtilis O
- O
includes O
amyloid O
- O
like O
protein O
fibers O
. O

In O
this O
work O
, O
we O
show O
that O
B O
. O
subtilis O
biofilms O
can O
be O
a O
simple O
and O
reliable O
tool O
for O
screening O
of O
molecules O
with O
antiamyloid O
activity O
. O

We O
identified O
two O
molecules O
, O
AA B
- I
861 I
and O
parthenolide B
, O
which O
efficiently O
inhibited O
biofilms O
by O
preventing O
the O
formation O
of O
amyloid O
- O
like O
fibers O
. O

Parthenolide B
also O
disrupted O
pre O
- O
established O
biofilms O
. O

These O
molecules O
also O
impeded O
the O
formation O
of O
biofilms O
of O
other O
bacterial O
species O
that O
secrete O
amyloid O
proteins O
, O
such O
as O
Bacillus O
cereus O
and O
Escherichia O
coli O
. O

Furthermore O
, O
the O
identified O
molecules O
decreased O
the O
conversion O
of O
the O
yeast O
protein O
New1 O
to O
the O
prion O
state O
in O
a O
heterologous O
host O
, O
indicating O
the O
broad O
range O
of O
activity O
of O
the O
molecules O
. O

Development O
of O
amino B
- I
pyrimidine I
inhibitors O
of O
c O
- O
Jun O
N B
- O
terminal O
kinase O
( O
JNK O
) O
: O
kinase O
profiling O
guided O
optimization O
of O
a O
1 B
, I
2 I
, I
3 I
- I
benzotriazole I
lead O
. O

A O
series O
of O
amino B
- I
pyrimidines I
was O
developed O
based O
upon O
an O
initial O
kinase O
cross O
- O
screening O
hit O
from O
a O
CDK2 O
program O
. O

Kinase O
profiling O
and O
structure O
- O
based O
drug O
design O
guided O
the O
optimization O
from O
the O
initial O
1 B
, I
2 I
, I
3 I
- I
benzotriazole I
hit O
to O
a O
potent O
and O
selective O
JNK O
inhibitor O
, O
compound O
24f O
( O
JNK1 O
and O
2 O
IC O
( O
50 O
) O
= O
16 O
and O
66 O
nM O
, O
respectively O
) O
, O
with O
bioavailability O
in O
rats O
and O
suitable O
for O
further O
in O
vivo O
pharmacological O
evaluation O
. O

Comparative O
properties O
of O
A O
beta O
1 O
- O
42 O
, O
A O
beta O
11 O
- O
42 O
, O
and O
[ O
Pyr I
( I
1 I
) I
( I
1 O
) O
] O
A O
beta O
11 O
- O
42 O
generated O
from O
O B
- I
acyl I
isopeptides I
. O

The O
use O
of O
water O
- O
soluble O
O B
- I
acyl I
isopeptides I
enabled O
us O
to O
investigate O
the O
biochemical O
properties O
of O
A O
beta O
11 O
- O
42 O
species O
, O
by O
preparing O
highly O
concentrated O
stock O
solutions O
after O
a O
pretreatment O
. O

A O
beta O
11 O
- O
42 O
and O
[ O
Pyr B
( O
11 O
) O
] O
A O
beta O
11 O
- O
42 O
showed O
comparable O
aggregation O
capability O
and O
cytotoxicity O
, O
suggesting O
that O
the O
pyroglutamate B
modification O
at O
Glu B
( O
11 O
) O
does O
not O
have O
a O
crucial O
role O
in O
these O
events O
. O

However O
, O
given O
that O
A O
beta O
11 O
- O
42 O
is O
converted O
to O
[ B
Pyr I
( I
11 I
) I
] O
A O
beta O
11 O
- O
42 O
by O
a O
glutamyl B
cyclase O
in O
vivo O
, O
the O
potential O
aggregative O
and O
cytotoxic O
nature O
of O
[ B
Pyr I
( I
11 I
) I
] I
A O
beta O
11 O
- O
42 O
that O
was O
observed O
in O
the O
present O
study O
provides O
valuable O
insights O
into O
the O
pathological O
functions O
of O
pyroglutamate B
- O
modified O
A O
beta O
species O
in O
Alzheimer O
' O
s O
disease O
. O

Menopause O
, O
atherosclerosis O
, O
and O
coronary O
artery O
disease O
. O

Women O
have O
coronary O
heart O
disease O
( O
CHD O
) O
later O
than O
men O
. O

This O
review O
describes O
studies O
of O
CHD O
risk O
factors O
or O
outcomes O
based O
on O
studies O
of O
premenopausal O
women O
followed O
through O
the O
menopause O
transition O
, O
and O
prospective O
cohort O
studies O
of O
younger O
or O
older O
women O
with O
CHD O
risk O
markers O
or O
disease O
outcomes O
in O
the O
context O
of O
their O
menopause O
history O
. O

Major O
early O
reports O
from O
both O
types O
of O
studies O
are O
included O
in O
order O
to O
put O
more O
recent O
work O
in O
context O
. O

Most O
attention O
has O
been O
paid O
to O
the O
Healthy O
Women O
Study O
( O
HWS O
) O
, O
Study O
of O
Women O
' O
s O
Health O
across O
the O
Nation O
( O
SWAN O
) O
, O
the O
Nurses O
' O
Health O
Study O
( O
NHS O
) O
, O
and O
the O
Rancho O
Bernardo O
Study O
( O
RBS O
) O
because O
they O
continue O
to O
produce O
recent O
publications O
designed O
to O
distinguish O
the O
effect O
of O
age O
from O
the O
effect O
of O
menopause O
. O

Understanding O
these O
differences O
has O
important O
implications O
for O
women O
' O
s O
cardiovascular O
health O
, O
but O
remains O
incomplete O
. O

Transition O
studies O
have O
relatively O
short O
( O
< O
10 O
years O
) O
follow O
- O
up O
and O
exclude O
women O
with O
surgical O
menopause O
. O

Cohort O
studies O
suggest O
that O
women O
with O
oophorectomy O
are O
at O
greater O
risk O
for O
CHD O
than O
intact O
women O
, O
pointing O
to O
a O
greater O
risk O
from O
testosterone B
deficiency O
than O
from O
estradiol B
levels O
. O

Perfluorocarbon B
- O
loaded O
lipid O
nanocapsules O
as O
oxygen B
sensors O
for O
tumor O
tissue O
pO B
( I
2 I
) I
assessment O
. O

The O
assessment O
of O
tumor O
oxygenation O
is O
a O
crucial O
factor O
in O
cancer O
therapy O
and O
may O
be O
carried O
out O
using O
fluorine B
MRI O
once O
fluorine B
probes O
have O
been O
distributed O
within O
the O
tumor O
. O

However O
, O
the O
deposit O
of O
those O
highly O
fluorinated O
compounds O
often O
jeopardizes O
anatomical O
image O
quality O
and O
requires O
emulsification O
of O
the O
probes O
. O

Due O
to O
the O
high O
density O
and O
the O
high O
lipophilicity O
of O
perfluorocarbons B
, O
nanoemulsion O
of O
these O
molecules O
usually O
requires O
high O
- O
energy O
processes O
. O

In O
the O
present O
work O
, O
we O
discuss O
the O
synthesis O
and O
the O
physico O
- O
chemical O
characterization O
of O
perfluorocarbon B
nanocapsules O
using O
a O
low O
- O
energy O
phase O
- O
inversion O
process O
. O

The O
nanocapsules O
were O
tested O
on O
a O
mouse O
tumor O
brain O
model O
to O
assess O
oxygenation O
. O

Ultrasonic O
gene O
and O
drug O
delivery O
using O
eLiposomes O
. O

eLiposomes O
are O
liposomes O
encapsulating O
emulsions O
and O
therapeutics O
for O
targeted O
delivery O
. O

By O
applying O
ultrasound O
to O
eLiposomes O
, O
emulsion O
droplets O
can O
transform O
from O
liquid O
to O
gas O
and O
rupture O
the O
lipid O
bilayer O
of O
the O
eLiposome O
to O
release O
a O
drug O
or O
plasmid O
. O

In O
this O
study O
, O
perfluoropentane B
( O
PFC5 B
) O
emulsions O
were O
encapsulated O
inside O
folated O
eLiposomes O
carrying O
a O
model O
drug O
( O
calcein B
) O
or O
a O
model O
GFP O
plasmid O
to O
examine O
the O
effects O
of O
a O
folate B
ligand O
, O
PFC5 B
emulsion O
and O
various O
ultrasonic O
acoustic O
parameters O
in O
drug O
delivery O
and O
gene O
transfection O
into O
HeLa O
cells O
. O

Confocal O
microscopy O
was O
used O
to O
quantify O
drug O
delivery O
and O
the O
level O
of O
plasmid O
transfection O
into O
HeLa O
cells O
. O

The O
results O
showed O
that O
drug O
delivery O
or O
transfection O
was O
minimal O
without O
incorporation O
of O
internal O
PFC5 B
emulsions O
and O
folate B
ligand O
on O
the O
eLiposome O
surface O
. O

It O
was O
also O
shown O
that O
application O
of O
ultrasound O
greatly O
enhanced O
the O
drug O
delivery O
and O
plasmid O
transfection O
. O

Delivery O
of O
these O
therapeutics O
appears O
to O
be O
to O
the O
cytosol O
, O
indicating O
that O
the O
expansion O
of O
the O
emulsion O
droplets O
disrupted O
both O
the O
eLiposomes O
and O
the O
endosomes O
. O

Models O
of O
drug O
- O
induced O
liver O
injury O
for O
evaluation O
of O
phytotherapeutics O
and O
other O
natural O
products O
. O

Extracts O
from O
medicinal O
plants O
, O
many O
of O
which O
have O
been O
used O
for O
centuries O
, O
are O
increasingly O
tested O
in O
models O
of O
hepatotoxicity O
. O

One O
of O
the O
most O
popular O
models O
to O
evaluate O
the O
hepatoprotective O
potential O
of O
natural O
products O
is O
acetaminophen B
( O
APAP B
) O
- O
induced O
liver O
injury O
, O
although O
other O
hepatotoxicity O
models O
such O
as O
carbon B
tetrachloride I
, O
thioacetamide B
, O
ethanol B
and O
endotoxin O
are O
occasionally O
used O
. O

APAP B
overdose O
is O
a O
clinically O
relevant O
model O
of O
drug O
- O
induced O
liver O
injury O
. O

Critical O
mechanisms O
and O
signaling O
pathways O
, O
which O
trigger O
necrotic O
cell O
death O
and O
sterile O
inflammation O
, O
are O
discussed O
. O

Although O
there O
is O
increasing O
understanding O
of O
the O
pathophysiology O
of O
APAP B
- O
induced O
liver O
injury O
, O
the O
mechanism O
is O
complex O
and O
prone O
to O
misinterpretation O
, O
especially O
when O
unknown O
chemicals O
such O
as O
plant O
extracts O
are O
tested O
. O

This O
review O
discusses O
the O
fundamental O
aspects O
that O
need O
to O
be O
considered O
when O
using O
this O
model O
, O
such O
as O
selection O
of O
the O
animal O
species O
or O
in O
vitro O
system O
, O
timing O
and O
dose O
- O
responses O
of O
signaling O
events O
, O
metabolic O
activation O
and O
protein O
adduct O
formation O
, O
the O
role O
of O
lipid O
peroxidation O
and O
apoptotic O
versus O
necrotic O
cell O
death O
, O
and O
the O
impact O
of O
the O
ensuing O
sterile O
inflammatory O
response O
. O

The O
goal O
is O
to O
enable O
researchers O
to O
select O
the O
appropriate O
model O
and O
experimental O
conditions O
for O
testing O
of O
natural O
products O
that O
will O
yield O
clinically O
relevant O
results O
and O
allow O
valid O
interpretations O
of O
the O
pharmacological O
mechanisms O
. O

Feasibility O
of O
spray O
drying O
bacteriophages O
into O
respirable O
powders O
to O
combat O
pulmonary O
bacterial O
infections O
. O

The O
use O
of O
bacterial O
viruses O
for O
antibacterial O
treatment O
( O
bacteriophage O
therapy O
) O
is O
currently O
being O
reevaluated O
. O

In O
this O
study O
, O
we O
analyze O
the O
potential O
of O
processing O
bacteriophages O
in O
a O
dry O
powder O
formulation O
, O
using O
a O
laboratory O
spray O
dryer O
. O

The O
phages O
were O
dried O
in O
the O
presence O
of O
lactose B
, O
trehalose B
or O
dextran O
35 O
, O
serving O
as O
an O
excipient O
to O
give O
the O
resulting O
powder O
the O
necessary O
bulk O
mass O
and O
offer O
protection O
to O
the O
delicate O
phage O
structure O
. O

Out O
of O
the O
three O
excipients O
tested O
, O
trehalose B
was O
found O
to O
be O
the O
most O
efficient O
in O
protecting O
the O
phages O
from O
temperature O
and O
shear O
stress O
throughout O
the O
spray O
drying O
process O
. O

A O
low O
inlet O
air O
temperature O
and O
atomizing O
force O
appeared O
to O
be O
the O
best O
parameter O
conditions O
for O
phage O
survival O
. O

Pseudomonas O
podovirus O
LUZ19 O
was O
remarkably O
stable O
, O
suffering O
less O
than O
1 O
logarithmic O
unit O
reduction O
in O
phage O
titer O
. O

The O
phage O
titer O
of O
Staphyloccus O
phage O
Romulus O
- O
containing O
powders O
, O
a O
member O
of O
the O
Myoviridae O
family O
, O
showed O
more O
than O
2 O
. O
5 O
logarithmic O
units O
reduction O
. O

On O
the O
other O
hand O
, O
Romulus O
- O
containing O
powders O
showed O
more O
favorable O
characteristics O
for O
pulmonary O
delivery O
, O
with O
a O
high O
percentage O
of O
dry O
powder O
particles O
in O
the O
pulmonary O
deposition O
fraction O
( O
1 O
- O
5 O
mu O
m O
particle O
diameter O
) O
. O

Even O
though O
the O
parameters O
for O
spray O
drying O
all O
phages O
were O
not O
optimized O
, O
it O
was O
demonstrated O
that O
spray O
drying O
phages O
with O
this O
industrial O
relevant O
and O
scalable O
set O
up O
was O
possible O
. O

The O
resulting O
powders O
had O
desirable O
size O
ranges O
for O
pulmonary O
delivery O
of O
phages O
with O
dry O
powder O
inhalers O
( O
DPIs O
) O
. O

Sonhafouonic B
acid I
, O
a O
new O
cytotoxic O
and O
antifungal O
hopene B
- O
triterpenoid B
from O
Zehneria O
scabra O
camerunensis O
. O

A O
new O
hopene B
- O
type O
triterpenoid B
, O
namely O
sonhafouonic B
acid I
1a O
was O
isolated O
from O
Zehneria O
scabra O
camerunensis O
, O
together O
with O
eight O
known O
compounds O
. O

The O
structure O
of O
1a O
was O
established O
by O
extensive O
NMR O
and O
high O
resolution O
MS O
techniques O
and O
confirmed O
by O
single O
- O
crystal O
X O
- O
ray O
crystallographic O
analysis O
. O

Compound O
1a O
exhibited O
inhibitory O
activity O
against O
mycelial O
growth O
of O
two O
peronosporomycete O
phytopathogens O
Pythium O
ultimum O
and O
Aphanomyces O
cochliodes O
and O
cytotoxicity O
towards O
brine O
shrimp O
larvae O
( O
Artemia O
salina O
) O
at O
10 O
mu O
g O
/ O
mL O
. O

Pestaloficiols B
Q I
- I
S I
from O
the O
plant O
endophytic O
fungus O
Pestalotiopsis O
fici O
. O

Two O
new O
isoprenylated B
chromone I
derivatives O
, O
pestaloficiols B
Q I
( I
1 I
) I
and I
R I
( O
2 O
) O
, O
and O
one O
new O
benzofuran B
derivative O
, O
pestaloficiol B
S I
( O
3 O
) O
, O
along O
with O
three O
known O
metabolites O
, O
anofinic B
acid I
( O
4 O
) O
, O
siccayne B
( O
5 O
) O
, O
and O
pyrenophorol B
( O
6 O
) O
were O
isolated O
from O
solid O
cultures O
of O
the O
plant O
endophytic O
fungus O
Pestalotiopsis O
fici O
. O

Their O
structures O
were O
elucidated O
primarily O
by O
NMR O
spectroscopy O
, O
and O
the O
absolute O
of O
the O
C O
- O
6 O
secondary B
alcohol I
in O
1 O
was O
deduced O
on O
the O
basis O
of O
circular O
dichroism O
( O
CD O
) O
data O
. O

Compound O
5 O
showed O
cytotoxic O
activity O
against O
the O
human O
cancer O
cell O
lines O
, O
HeLa O
and O
HT29 O
, O
with O
IC50 O
values O
of O
48 O
. O
2 O
and O
33 O
. O
9 O
mu O
M O
, O
respectively O
. O

Syntheses O
and O
anti O
- O
allergic O
activity O
of O
2 B
- I
( I
( I
bis I
( I
trimethylsilyl I
) I
methylthio I
/ I
methylsulfonyl I
) I
methyl I
) I
- I
5 I
- I
aryl I
- I
1 I
, I
3 I
, I
4 I
- I
oxadiazoles I
. O

A O
new O
class O
of O
sila B
- I
substituted I
1 I
, I
3 I
, I
4 I
- I
oxadiazoles I
was O
synthesized O
by O
a O
convenient O
synthetic O
method O
. O

Both O
silathio B
/ I
silasulfonyl I
acetic I
acids I
were O
efficiently O
condensed O
with O
benzohydrazides B
in O
the O
presence O
of O
phosphorus B
oxychloride I
to O
give O
sila B
- I
substituted I
1 I
, I
3 I
, I
4 I
- I
oxadiazoles I
in O
high O
yields O
. O

The O
compounds O
displayed O
variable O
extent O
of O
anti O
- O
allergic O
activity O
on O
IgE O
/ O
Ag O
- O
stimulated O
RBL O
- O
2H3 O
cells O
at O
50 O
and O
100 O
mu O
M O
concentrations O
. O

Compounds O
having O
sulfonyl B
moiety O
with O
bis B
( I
trimethylsilyl I
) I
- I
1 I
, I
3 I
, I
4 I
- I
oxadiazoles I
( O
5a O
- O
c O
) O
, O
exhibited O
better O
anti O
- O
allergic O
activities O
than O
those O
of O
compounds O
having O
sulphur B
moiety O
with O
bis B
( I
trimethylsilyl I
) I
- I
1 I
, I
3 I
, I
4 I
- I
oxadiazoles I
( O
4a O
- O
c O
) O
. O

Anti O
- O
hepatitis O
B O
virus O
and O
anti O
- O
cancer O
activities O
of O
novel O
isoflavone B
analogs O
. O

We O
have O
synthesized O
a O
series O
of O
novel O
isoflavone B
analogs O
and O
evaluated O
their O
anti O
- O
HBV O
and O
anti O
- O
cancer O
activities O
in O
vitro O
. O

The O
bioassays O
showed O
that O
the O
majority O
of O
the O
resultant O
compounds O
exerted O
inhibitory O
effects O
on O
HBsAg O
and O
HBeAg O
levels O
, O
HBV O
DNA O
replication O
, O
as O
well O
as O
the O
growth O
of O
four O
human O
cancer O
cell O
lines O
to O
various O
extents O
, O
which O
supported O
the O
rationale O
of O
the O
design O
. O

In O
particular O
, O
compound O
8f O
showed O
the O
highest O
activity O
against O
HBV O
infection O
and O
HBV O
- O
related O
liver O
cancer O
. O

Compound O
7l O
( O
IC50 O
= O
0 O
. O
47 O
mu O
M O
) O
also O
exerted O
remarkable O
inhibitory O
effect O
on O
the O
growth O
lung O
cancer O
cell O
line O
A O
- O
549 O
. O

Design O
, O
synthesis O
and O
SAR O
of O
piperidyl B
- I
oxadiazoles I
as O
11 B
beta I
- I
hydroxysteroid I
dehydrogenase O
1 O
inhibitors O
. O

The O
potential O
roles O
of O
11 O
beta O
- O
HSD1 O
inhibitors O
in O
metabolic O
syndrome O
, O
T2D O
and O
obesity O
were O
well O
established O
and O
currently O
several O
classes O
of O
11 O
beta O
- O
HSD1 O
inhibitors O
have O
been O
developed O
as O
promising O
agents O
against O
metabolic O
diseases O
. O

To O
find O
potent O
compounds O
with O
good O
pharmacokinetics O
, O
we O
used O
the O
bioisosterism O
approach O
, O
and O
designed O
the O
compound O
2 O
and O
3 O
bearing O
an O
1 B
, I
2 I
, I
4 I
- I
oxadiazole I
ring O
to O
replace O
the O
amide B
group O
in O
compound O
1 O
. O

Guided O
by O
docking O
study O
, O
we O
then O
transformed O
compound O
3 O
into O
a O
potent O
lead O
compound O
4a O
by O
changing O
sulfonamide B
group O
to O
amide B
. O

To O
elaborate O
this O
series O
of O
piperidyl B
- I
oxadiazole I
derivatives O
as O
human O
11 O
beta O
- O
HSD1 O
inhibitors O
, O
we O
explored O
the O
structure O
- O
activity O
relationship O
of O
several O
parts O
of O
the O
lead O
compound O
. O

Based O
on O
their O
potency O
toward O
human O
11 O
beta O
- O
HSD1 O
two O
compounds O
4h O
and O
4q O
were O
advanced O
to O
pharmacokinetic O
study O
. O

It O
was O
found O
that O
4h O
and O
4q O
are O
potent O
and O
selective O
human O
11 O
beta O
- O
HSD1 O
inhibitors O
with O
better O
pharmacokinetic O
properties O
than O
those O
of O
the O
original O
piperidine B
- I
3 I
- I
carboxamide I
compound O
1 O
, O
and O
suitable O
for O
further O
in O
vivo O
preclinical O
study O
in O
primate O
model O
. O

( B
E I
) I
- I
4 I
- I
Aryl I
- I
4 I
- I
oxo I
- I
2 I
- I
butenoic I
acid I
amides I
, O
chalcone B
- O
aroylacrylic B
acid I
chimeras O
: O
Design O
, O
antiproliferative O
activity O
and O
inhibition O
of O
tubulin O
polymerization O
. O

Antiproliferative O
activity O
of O
twenty O
- O
nine O
( B
E I
) I
- I
4 I
- I
aryl I
- I
4 I
- I
oxo I
- I
2 I
- I
butenoic I
acid I
amides I
against O
three O
human O
tumor O
cell O
lines O
( O
HeLa O
, O
FemX O
, O
and O
K562 O
) O
is O
reported O
. O

Compounds O
showed O
antiproliferative O
activity O
in O
one O
- O
digit O
micromolar O
to O
submicromolar O
concentrations O
. O

The O
most O
active O
derivatives O
toward O
all O
the O
cell O
lines O
tested O
bear O
alkyl O
substituents O
on O
the O
aroyl B
moiety O
of O
the O
molecules O
. O

Fourteen O
compounds O
showed O
tubulin O
assembly O
inhibition O
at O
concentrations O
< O
20 O
mu O
M O
. O

The O
most O
potent O
inhibitor O
of O
tubulin O
assembly O
was O
unsubstituted O
compound O
1 O
, O
with O
IC50 O
= O
2 O
. O
9 O
mu O
M O
. O

Compound O
23 O
had O
an O
oral O
LD50in O
vivo O
of O
45 O
mg O
/ O
kg O
in O
mice O
. O

Cell O
cycle O
analysis O
on O
K562 O
cells O
showed O
that O
compounds O
1 O
, O
2 O
and O
23 O
caused O
accumulation O
of O
cells O
in O
the O
G2 O
/ O
M O
phase O
, O
but O
inhibition O
of O
microtubule O
polymerization O
is O
not O
the O
principal O
mode O
of O
action O
of O
the O
compounds O
. O

Nevertheless O
, O
they O
may O
be O
useful O
leads O
for O
the O
design O
of O
a O
new O
class O
of O
antitubulin O
agents O
. O

Design O
, O
synthesis O
and O
biological O
evaluation O
of O
novel O
hybrid O
compounds O
of O
imidazole B
scaffold O
- O
based O
2 B
- I
benzylbenzofuran I
as O
potent O
anticancer O
agents O
. O

A O
series O
of O
novel O
hybrid O
compounds O
between O
2 B
- I
benzylbenzofuran I
and O
imidazole B
has O
been O
prepared O
and O
evaluated O
in O
vitro O
against O
a O
panel O
of O
human O
tumor O
cell O
lines O
. O

The O
results O
suggest O
that O
the O
existence O
of O
benzimidazole B
ring O
and O
substitution O
of O
the O
imidazolyl B
- O
3 O
- O
position O
with O
a O
naphthylacyl B
or O
4 B
- I
methoxyphenacyl I
group O
were O
vital O
for O
modulating O
cytotoxic O
activity O
. O

In O
particular O
, O
hybrid O
compounds O
46 O
and O
47 O
were O
found O
to O
be O
the O
most O
potent O
derivatives O
against O
5 O
strains O
human O
tumor O
cell O
lines O
and O
more O
active O
than O
cisplatin B
( O
DDP B
) O
, O
and O
exhibited O
cytotoxic O
activities O
selectively O
against O
breast O
carcinoma O
( O
MCF O
- O
7 O
) O
and O
myeloid O
liver O
carcinoma O
( O
SMMC O
- O
7721 O
) O
, O
respectively O
. O

Inhibition O
of O
enterovirus O
71 O
infections O
and O
viral O
IRES O
activity O
by O
Fructus O
gardeniae O
and O
geniposide B
. O

Fructus O
gardeniae O
has O
long O
been O
used O
by O
traditional O
Chinese O
medical O
practitioners O
for O
its O
anti O
- O
inflammatory O
, O
anti O
- O
oxidant O
, O
anti O
- O
tumor O
and O
anti O
- O
hyperlipidemic O
characteristics O
. O

Here O
we O
describe O
our O
finding O
that O
F O
. O
gardeniae O
greatly O
reduces O
anti O
- O
enterovirus O
71 O
( O
EV71 O
) O
activity O
, O
resulting O
in O
significant O
decreases O
in O
EV71 O
virus O
yields O
, O
EV71 O
infections O
, O
and O
internal O
ribosome O
entry O
site O
activity O
. O

We O
also O
found O
that O
geniposide B
, O
a O
primary O
F O
. O
gardeniae O
component O
, O
inhibited O
both O
EV71 O
replication O
and O
viral O
IRES O
activity O
. O

Our O
data O
suggest O
the O
presence O
of O
a O
mechanism O
that O
blocks O
viral O
protein O
translation O
. O

According O
to O
our O
findings O
, O
F O
. O
gardeniae O
and O
geniposide B
deserve O
a O
closer O
look O
as O
potential O
chemopreventive O
agents O
against O
EV71 O
infections O
. O

Multifunctional O
terpolymeric O
MRI O
contrast O
agent O
with O
superior O
signal O
enhancement O
in O
blood O
and O
tumor O
. O

A O
new O
multifunctional O
terpolymeric O
system O
for O
simultaneous O
imaging O
and O
drug O
delivery O
has O
been O
recently O
developed O
in O
our O
laboratory O
. O

Herein O
we O
report O
the O
investigation O
of O
terpolymeric O
contrast O
agent O
for O
magnetic O
resonance O
imaging O
and O
doxorubicin B
( O
Dox B
) O
delivery O
. O

The O
polymer O
was O
synthesized O
by O
graft O
polymerization O
of O
methacrylic B
acid I
( O
MAA B
) O
and O
polysorbate B
80 I
( O
PS B
80 I
) O
onto O
starch O
with O
multiple O
, O
chemically O
bound O
diethylenetriaminepe B
acetic I
acid I
( O
DTPA B
) O
groups O
for O
gadolinium B
chelating O
. O

The O
terpolymer O
self O
- O
assembled O
to O
form O
nanoparticles O
upon O
addition O
of O
doxorubicin B
which O
binds O
with O
the O
PMAA B
chain O
. O

The O
physicochemical O
, O
biological O
and O
pharmacokinetic O
properties O
of O
the O
polymeric O
system O
were O
characterized O
and O
their O
contrast O
enhancement O
capability O
was O
evaluated O
in O
vitro O
and O
in O
vivo O
. O

The O
polymer O
was O
able O
to O
load O
gadolinium B
with O
high O
thermodynamic O
stability O
and O
exhibited O
low O
cytotoxicity O
. O

The O
Gd B
- O
loaded O
polymer O
( O
PolyGd B
) O
, O
and O
Gd B
- O
Dox B
co O
- O
loaded O
nanoparticles O
( O
PolyGd B
- O
Dox B
) O
significantly O
enhanced O
MR O
signals O
, O
with O
ionic O
T1 O
relaxivities O
3 O
- O
5 O
times O
higher O
than O
those O
from O
Omniscan O
( O
R O
) O
, O
a O
small O
molecule O
contrast O
agent O
. O

In O
vivo O
studies O
showed O
superior O
and O
prolonged O
contrast O
enhancement O
compared O
to O
Omniscan B
( O
R O
) O
at O
one O
fourth O
the O
equivalent O
dose O
, O
without O
adverse O
effects O
. O

The O
PolyGd O
and O
PolyGd O
- O
Dox B
accumulated O
in O
the O
tumor O
and O
painted O
the O
tumor O
boundaries O
clearly O
for O
at O
least O
48h O
. O

The O
PolyGd O
also O
enhanced O
angiogram O
contrast O
with O
contrast O
to O
noise O
ratio O
values O
of O
up O
to O
55 O
- O
fold O
and O
a O
blood O
half O
- O
life O
time O
of O
200min O
. O

Seven O
days O
after O
intravenous O
administration O
, O
only O
relatively O
small O
amounts O
of O
gadolinium B
could O
be O
detected O
in O
the O
major O
organs O
of O
the O
mice O
( O
supplementary O
materials O
) O
. O

These O
results O
suggest O
that O
the O
new O
terpolymeric O
system O
is O
useful O
as O
a O
theranostic O
platform O
for O
contrast O
enhanced O
MR O
imaging O
of O
vasculature O
and O
tumor O
as O
well O
as O
Dox B
delivery O
. O

Silica B
- O
lipid O
hybrid O
( O
SLH O
) O
formulations O
enhance O
the O
oral O
bioavailability O
and O
efficacy O
of O
celecoxib B
: O
An O
in O
vivo O
evaluation O
. O

This O
study O
is O
the O
first O
to O
demonstrate O
in O
canines O
the O
ability O
of O
silica B
- O
lipid O
hybrid O
( O
SLH O
) O
microparticles O
to O
enhance O
the O
bioavailability O
and O
efficacy O
of O
a O
poorly O
water O
- O
soluble O
drug O
after O
oral O
administration O
. O

Spray O
- O
dried O
SLH O
microparticles O
comprising O
Capmul B
MCM I
( O
mono B
- I
diglycerides I
of O
C8 B
/ I
C12 I
fatty B
acids I
) O
and O
silica B
nanoparticles O
( O
Aerosil B
( O
R O
) O
380 O
) O
were O
shown O
to O
significantly O
enhance O
the O
fasted O
state O
oral O
bioavailability O
of O
celecoxib B
( O
CEL B
) O
( O
6 O
. O
5 O
fold O
, O
relative O
to O
an O
aqueous O
suspension O
and O
more O
than O
2 O
- O
fold O
higher O
relative O
to O
the O
fed O
state O
) O
after O
oral O
administration O
to O
beagle O
dogs O
. O

Comparable O
bioavailability O
was O
observed O
between O
the O
SLH O
microparticle O
formulation O
and O
a O
conventional O
Capmul B
lipid O
solution O
, O
however O
, O
plasma O
concentrations O
were O
observed O
to O
be O
higher O
( O
Cmax O
, O
1 O
. O
1 O
+ O
/ O
- O
0 O
. O
06 O
vs O
. O
0 O
. O
8 O
+ O
/ O
- O
0 O
. O
03 O
mu O
g O
/ O
mL O
) O
( O
p O
< O
= O
0 O
. O
05 O
) O
with O
the O
SLH O
microparticle O
system O
. O

The O
enhanced O
bioavailability O
of O
CEL O
observed O
with O
the O
SLH O
microparticles O
was O
reflected O
in O
a O
subsequent O
efficacy O
study O
conducted O
in O
an O
adjuvant O
- O
induced O
arthritis O
model O
in O
the O
rat O
. O

Reduced O
clinical O
and O
histological O
severity O
was O
observed O
at O
a O
dose O
of O
3mg O
/ O
kg O
/ O
day O
, O
with O
the O
progression O
of O
arthritic O
symptoms O
and O
tissue O
damage O
reduced O
to O
a O
similar O
degree O
to O
that O
of O
a O
higher O
dose O
administered O
at O
5mg O
/ O
kg O
/ O
day O
and O
prepared O
in O
an O
aqueous O
suspension O
. O
, O
The O
enhanced O
bioavailability O
and O
improved O
efficacy O
observed O
with O
the O
SLH O
microparticles O
were O
attributed O
to O
the O
maintenance O
of O
CEL O
in O
a O
solubilised O
form O
during O
digestion O
of O
the O
lipid O
vehicle O
. O

We O
hypothesise O
that O
the O
presence O
of O
silica B
in O
the O
formulation O
may O
have O
contributed O
to O
the O
prevention O
of O
drug O
precipitation O
in O
the O
intestinal O
lumen O
by O
providing O
an O
alternative O
binding O
site O
for O
CEL O
to O
adsorb O
to O
prior O
to O
re O
- O
solubilisation O
and O
absorption O
. O

The O
study O
highlights O
the O
potential O
utility O
of O
novel O
SLH O
microparticle O
formulations O
as O
stable O
dry O
powders O
that O
possess O
the O
properties O
of O
a O
lipid O
- O
based O
formulation O
for O
the O
enhanced O
delivery O
and O
efficacy O
of O
poorly O
water O
- O
soluble O
drugs O
. O

Gender O
- O
specific O
effects O
of O
fluoxetine B
on O
hippocampal O
glucocorticoid O
receptor O
phosphorylation O
and O
behavior O
in O
chronically O
stressed O
rats O
. O

Chronic O
psychosocial O
isolation O
stress O
( O
CPSI O
) O
modulates O
glucocorticoid O
receptor O
( O
GR O
) O
functioning O
in O
Wistar O
male O
rat O
hippocampus O
( O
HIPPO O
) O
through O
alteration O
of O
nuclear O
GR O
phosphorylation O
and O
its O
upstream O
kinases O
signaling O
, O
which O
parallels O
animal O
depressive O
- O
like O
behavior O
. O

The O
current O
study O
investigated O
potential O
gender O
specificities O
regarding O
the O
effect O
of O
chronic O
therapy O
by O
an O
antidepressant O
fluoxetine B
( O
FLU B
) O
on O
GR O
signaling O
in O
HIPPO O
and O
depressive O
- O
like O
behavior O
in O
CPSI O
animals O
. O

FLU B
was O
administrated O
to O
female O
and O
male O
na O
i O
ve O
or O
CPSI O
rats O
for O
21 O
days O
and O
GR O
protein O
, O
its O
phosphorylation O
status O
and O
upstream O
kinases O
, O
as O
well O
as O
GR O
and O
BDNF O
mRNA O
were O
followed O
in O
HIPPO O
together O
with O
animal O
serum O
corticosterone B
( O
CORT B
) O
and O
depressive O
- O
like O
behavior O
. O

The O
results O
showed O
that O
CPSI O
increased O
immobility O
in O
males O
versus O
hyperactivity O
in O
females O
and O
disrupted O
nuclear O
pGR232 O
- O
Cdk5 O
pathway O
and O
JNK O
signaling O
in O
a O
gender O
- O
specific O
way O
. O

In O
contrast O
, O
in O
both O
genders O
CPSI O
increased O
the O
nuclear O
levels O
of O
GR O
and O
pGR246 O
but O
decreased O
CORT B
and O
mRNA O
levels O
of O
GR O
and O
BDNF O
. O

Concomitant O
FLU B
normalized O
the O
depressive O
- O
like O
behavior O
and O
altered O
the O
nuclear O
pGR232 O
- O
Cdk5 O
signaling O
in O
a O
gender O
- O
specific O
manner O
. O

In O
both O
females O
and O
males O
, O
FLU B
reversed O
the O
nuclear O
levels O
of O
GR O
and O
pGR246 O
without O
affecting O
CORT B
and O
GR O
mRNA O
levels O
. O

In O
contrast O
, O
FLU B
exhibited O
gender O
- O
specific O
effect O
on O
BDNF O
mRNA O
in O
CPSI O
animals O
, O
by O
increasing O
it O
in O
females O
, O
but O
not O
in O
males O
. O

In O
spite O
of O
normalization O
the O
total O
nuclear O
GR O
level O
upon O
FLU B
treatment O
in O
both O
gender O
, O
down O
- O
regulation O
of O
GR O
mRNA O
is O
possibly O
maintained O
through O
prevalence O
of O
pGR232 O
isoform O
only O
in O
males O
. O

The O
gender O
- O
specific O
alterations O
of O
pGR232 O
- O
Cdk5 O
signaling O
and O
BDNF O
gene O
expression O
in O
HIPPO O
and O
normalization O
of O
depressive O
- O
like O
behavior O
upon O
FLU B
treatment O
distinguishes O
this O
signaling O
pathway O
as O
potential O
future O
antidepressant O
target O
for O
gender O
- O
specific O
therapy O
of O
stress O
related O
mood O
disorders O
. O

Improved O
pharmaceutical O
stability O
of O
a O
boronphenylalanine B
mannitol B
formulation O
for O
boron B
neutron O
capture O
therapy O
. O

Boron B
neutron O
capture O
therapy O
( O
BNCT O
) O
is O
a O
radiotherapy O
based O
cancer O
treatment O
requiring O
the O
availability O
of O
a O
low O
energy O
thermal O
neutron O
beam O
and O
a O
boron B
containing O
drug O
. O

These O
requirements O
limit O
BNCT O
availability O
with O
the O
latter O
pharmaceutical O
issue O
related O
to O
the O
extremely O
short O
shelf O
- O
life O
and O
clinical O
acceptability O
of O
the O
current O
fructose B
based O
L B
- I
boronphenylalanine I
( O
BPA B
) O
formulation O
. O

Resolution O
of O
the O
formulation O
issues O
would O
remove O
this O
factor O
and O
therefore O
the O
stability O
of O
an O
alternative O
mannitol B
BPA B
formulation O
has O
been O
investigated O
. O

A O
mannitol B
BPA B
solution O
formulation O
was O
prepared O
and O
either O
lyophilised O
or O
stored O
as O
a O
solution O
at O
varying O
temperatures O
. O

After O
suitable O
periods O
the O
formulation O
was O
analysed O
by O
HPLC O
for O
BPA B
and O
degradation O
products O
. O

Lyophilised O
and O
solution O
mannitol B
BPA I
formulations O
exhibited O
a O
temperature O
and O
time O
dependent O
loss O
of O
BPA B
with O
concomitant O
increases O
in O
degradation O
products O
. O

Autoclaving O
the O
solution O
induced O
and O
accelerated O
degradation O
. O

A O
solution O
or O
lyophilised O
mannitol B
BPA I
formulation O
has O
a O
shelf O
- O
life O
of O
between O
1 O
and O
4 O
years O
respectively O
, O
a O
marked O
improvement O
over O
the O
current O
fructose B
formulation O
. O

Due O
to O
temperature O
dependent O
degradation O
the O
formulation O
cannot O
be O
terminally O
sterilised O
by O
autoclaving O
. O

The O
enhanced O
stability O
of O
the O
mannitol B
formulation O
removes O
the O
requirement O
for O
extemporaneous O
aseptic O
preparation O
of O
BPA B
just O
prior O
to O
treatment O
and O
eliminates O
one O
of O
the O
issues O
complicating O
the O
delivery O
of O
BNCT O
. O

Methods O
for O
analysis O
of O
citrinin B
in O
human O
blood O
and O
urine O
. O

Citrinin B
( O
CIT B
) O
, O
produced O
by O
several O
Penicillium O
, O
Aspergillus O
, O
and O
Monascus O
species O
, O
has O
been O
detected O
as O
contaminant O
in O
feeds O
, O
grains O
, O
and O
other O
food O
commodities O
. O

CIT B
can O
co O
- O
occur O
with O
ochratoxin B
A I
( O
OTA B
) O
, O
a O
mycotoxin O
also O
known O
for O
its O
nephrotoxicity O
, O
and O
this O
raises O
concern O
regarding O
possible O
combined O
effects O
. O

But O
, O
in O
contrast O
to O
OTA B
, O
data O
on O
CIT B
contamination O
in O
foods O
for O
human O
consumption O
are O
scarce O
, O
and O
CIT B
biomonitoring O
has O
not O
been O
conducted O
so O
far O
due O
a O
lack O
of O
suitable O
methods O
for O
human O
specimen O
. O

Thus O
, O
it O
was O
the O
aim O
of O
the O
present O
study O
to O
develop O
sensitive O
methods O
for O
the O
analysis O
of O
CIT B
in O
human O
blood O
and O
urine O
to O
investigate O
human O
exposure O
. O

To O
this O
end O
, O
we O
assessed O
different O
methods O
of O
sample O
preparation O
and O
instrumental O
analysis O
for O
these O
matrices O
. O

Clean O
- O
up O
of O
blood O
plasma O
by O
protein O
precipitation O
followed O
by O
LC O
- O
MS O
/ O
MS O
- O
based O
analysis O
allowed O
robust O
detection O
of O
CIT B
( O
LOD O
0 O
. O
07 O
ng O
/ O
mL O
, O
LOQ O
0 O
. O
15 O
ng O
/ O
mL O
) O
. O

For O
urine O
, O
sample O
clean O
- O
up O
by O
an O
immunoaffinity O
column O
( O
CitriTest B
( O
( O
R O
) O
) O
) O
proved O
to O
be O
clearly O
superior O
to O
SPE O
with O
RP O
( O
18 O
) O
material O
for O
subsequent O
analysis O
by O
LC O
- O
MS O
/ O
MS O
. O

For O
CIT B
and O
its O
metabolite O
dihydrocitrinone B
( O
HO B
- I
CIT I
) O
, O
the O
LOD O
and O
LOQ O
determined O
by O
external O
calibration O
curves O
in O
matrix O
were O
0 O
. O
02 O
and O
0 O
. O
05 O
ng O
/ O
mL O
for O
CIT B
, O
and O
those O
for O
HO B
- I
CIT I
were O
0 O
. O
05 O
and O
0 O
. O
1 O
ng O
/ O
mL O
urine O
. O

The O
newly O
developed O
method O
was O
applied O
in O
a O
small O
pilot O
study O
: O
CIT B
was O
present O
in O
all O
plasma O
samples O
from O
8 O
German O
adults O
, O
at O
concentrations O
ranging O
from O
0 O
. O
11 O
to O
0 O
. O
26 O
ng O
/ O
mL O
. O

The O
molar O
( O
nM O
) O
concentrations O
of O
CIT B
are O
similar O
to O
those O
measured O
for O
OTA B
in O
these O
samples O
as O
a O
result O
of O
dietary O
mycotoxin O
intake O
. O

CIT B
was O
detected O
in O
8 O
/ O
10 O
urines O
( O
from O
4 O
adults O
and O
6 O
infants O
) O
in O
a O
range O
of O
0 O
. O
16 O
- O
0 O
. O
79 O
ng O
/ O
mL O
, O
and O
HO O
- O
CIT B
was O
present O
in O
5 O
/ O
10 O
samples O
at O
similar O
concentrations O
. O

Thus O
, O
CIT B
is O
excreted O
in O
urine O
as O
parent O
compound O
and O
also O
as O
metabolite O
. O

These O
first O
results O
in O
humans O
point O
to O
the O
need O
for O
further O
studies O
on O
CIT B
exposure O
. O

Bioactive O
microconstituents O
and O
antioxidant O
properties O
of O
wild O
edible O
mushrooms O
from O
the O
island O
of O
Lesvos O
, O
Greece O
. O

Crude O
composition O
, O
fatty B
acids I
, O
sterols B
, O
total O
phenolic O
content O
( O
TPC O
) O
, O
individual O
polyphenols B
and O
terpenic B
acids I
were O
determined O
in O
five O
wild O
edible O
mushrooms O
species O
( O
Lactarius O
deliciosus O
, O
Lactarius O
sanguifluus O
, O
Lactarius O
semisanguifluus O
, O
Russula O
delica O
, O
Suillus O
bellinii O
) O
from O
Lesvos O
Island O
, O
Greece O
. O

In O
addition O
, O
the O
DPPH B
scavenging O
capacity O
, O
the O
ferric B
ion O
reducing O
power O
( O
FRAP O
) O
and O
the O
ferrous B
ion O
chelating O
activity O
of O
mushroom O
methanolic O
extracts O
were O
assessed O
. O

Among O
sterols B
, O
ergosterol B
predominated O
at O
concentrations O
9 O
. O
2 O
- O
18 O
. O
0mg O
/ O
100g O
fw O
. O

Total O
phenolic O
content O
of O
mushroom O
extracts O
ranged O
from O
6 O
. O
0 O
to O
20 O
. O
8mg O
GAE O
/ O
100g O
fw O
. O

Up O
to O
19 O
simple O
polyphenols B
were O
determined O
in O
mushrooms O
extracts O
, O
the O
more O
abundant O
being O
p B
- I
OH I
- I
benzoic I
acid I
, O
p B
- I
OH I
- I
phenylacetic I
acid I
, O
o B
- I
coumaric I
acid I
, O
ferulic B
acid I
and O
chrysin B
. O

In O
addition O
, O
the O
triterpenic B
acids I
oleanolic B
and I
ursolic I
were O
detected O
for O
the O
first O
time O
in O
mushrooms O
. O

All O
species O
exerted O
antioxidant O
activity O
and O
ferrous B
ion O
chelating O
capacity O
. O

Principal O
component O
analysis O
revealed O
good O
correlations O
between O
TPC O
, O
DPPH B
and O
FRAP O
but O
not O
with O
metal O
chelating O
activity O
. O

It O
seems O
that O
mushrooms O
polyphenols B
exert O
antiradical O
and O
reducing O
activities O
, O
but O
they O
are O
not O
strong O
metal O
chelators O
, O
the O
observed O
chelating O
ability O
being O
probably O
due O
to O
other O
classes O
of O
compounds O
. O

To O
our O
knowledge O
, O
this O
is O
the O
first O
report O
on O
the O
bioactive O
microconstituents O
and O
antioxidant O
activity O
of O
wild O
Greek O
edible O
mushrooms O
. O

Subchronic O
memantine B
induced O
concurrent O
functional O
disconnectivity O
and O
altered O
ultra O
- O
structural O
tissue O
integrity O
in O
the O
rodent O
brain O
: O
revealed O
by O
multimodal O
MRI O
. O

BACKGROUND O
: O
An O
effective O
NMDA B
antagonist O
imaging O
model O
may O
find O
key O
utility O
in O
advancing O
schizophrenia O
drug O
discovery O
research O
. O

We O
investigated O
effects O
of O
subchronic O
treatment O
with O
the O
NMDA B
antagonist O
memantine B
by O
using O
behavioural O
observation O
and O
multimodal O
MRI O
. O

METHODS O
: O
Pharmacological O
MRI O
( O
phMRI O
) O
was O
used O
to O
map O
the O
neuroanatomical O
binding O
sites O
of O
memantine B
after O
acute O
and O
subchronic O
treatment O
. O

Resting O
state O
fMRI O
( O
rs O
- O
fMRI O
) O
and O
diffusion O
MRI O
were O
used O
to O
study O
the O
changes O
in O
functional O
connectivity O
( O
FC O
) O
and O
ultra O
- O
structural O
tissue O
integrity O
before O
and O
after O
subchronic O
memantine B
treatment O
. O

Further O
corroborating O
behavioural O
evidences O
were O
documented O
. O

RESULTS O
: O
Dose O
- O
dependent O
phMRI O
activation O
was O
observed O
in O
the O
prelimbic O
cortex O
following O
acute O
doses O
of O
memantine B
. O

Subchronic O
treatment O
revealed O
significant O
effects O
in O
the O
hippocampus O
, O
cingulate O
, O
prelimbic O
and O
retrosplenial O
cortices O
. O

Decreases O
in O
FC O
amongst O
the O
hippocampal O
and O
frontal O
cortical O
structures O
( O
prelimbic O
, O
cingulate O
) O
were O
apparent O
through O
rs O
- O
fMRI O
investigation O
, O
indicating O
a O
loss O
of O
connectivity O
. O

Diffusion O
kurtosis O
MRI O
showed O
decreases O
in O
fractional O
anisotropy O
and O
mean O
diffusivity O
changes O
, O
suggesting O
ultra O
- O
structural O
changes O
in O
the O
hippocampus O
and O
cingulate O
cortex O
. O

Limited O
behavioural O
assessment O
suggested O
that O
memantine B
induced O
behavioural O
effects O
comparable O
to O
other O
NMDA B
antagonists O
as O
measured O
by O
locomotor O
hyperactivity O
and O
that O
the O
effects O
could O
be O
reversed O
by O
antipsychotic O
drugs O
. O

CONCLUSION O
: O
Our O
findings O
substantiate O
the O
hypothesis O
that O
repeated O
NMDA B
receptor O
blockade O
with O
nonspecific O
, O
noncompetitive O
NMDA B
antagonists O
may O
lead O
to O
functional O
and O
ultra O
- O
structural O
alterations O
, O
particularly O
in O
the O
hippocampus O
and O
cingulate O
cortex O
. O

These O
changes O
may O
underlie O
the O
behavioural O
effects O
. O

Furthermore O
, O
the O
present O
findings O
underscore O
the O
utility O
and O
the O
translational O
potential O
of O
multimodal O
MR O
imaging O
and O
acute O
/ O
subchronic O
memantine B
model O
in O
the O
search O
for O
novel O
disease O
- O
modifying O
treatments O
for O
schizophrenia O
. O

A O
prospective O
study O
of O
selenium B
concentration O
and O
risk O
of O
preeclampsia O
in O
pregnant O
Iranian O
women O
: O
a O
nested O
case O
- O
control O
study O
. O

Preeclampsia O
remains O
a O
leading O
cause O
of O
maternal O
and O
perinatal O
mortality O
and O
morbidity O
worldwide O
; O
however O
, O
its O
specific O
etiology O
still O
remains O
obscure O
. O

Some O
studies O
implicate O
poor O
maternal O
selenium B
status O
predisposing O
the O
mother O
to O
preeclampsia O
. O

This O
study O
was O
designed O
to O
determine O
changes O
in O
plasma O
selenium B
levels O
in O
women O
having O
preeclampsia O
as O
compared O
with O
those O
with O
normal O
pregnancy O
. O

In O
a O
nested O
case O
- O
control O
study O
, O
650 O
normal O
primigravida O
in O
their O
first O
24 O
- O
28 O
weeks O
participated O
in O
the O
study O
. O

After O
3 O
months O
of O
follow O
- O
up O
of O
all O
subjects O
, O
blood O
selenium B
levels O
were O
measured O
in O
38 O
women O
presenting O
consecutively O
with O
preeclampsia O
and O
in O
38 O
women O
having O
a O
normal O
pregnancy O
by O
atomic O
absorption O
spectrophotometry O
. O

Birth O
outcomes O
were O
recorded O
, O
such O
as O
gestational O
age O
at O
delivery O
, O
height O
, O
weight O
, O
birth O
head O
circumflex O
and O
1 O
- O
min O
Apgar O
score O
. O

Preeclampsia O
affects O
about O
5 O
. O
84 O
% O
of O
pregnancies O
, O
and O
in O
our O
study O
, O
there O
were O
no O
significant O
differences O
in O
age O
, O
anthropometric O
indices O
, O
and O
family O
history O
of O
preeclampsia O
between O
the O
preeclamptic O
and O
control O
groups O
. O

The O
selenium B
concentrations O
in O
plasma O
in O
women O
with O
preeclampsia O
were O
significantly O
lower O
as O
compared O
with O
those O
in O
women O
with O
normal O
pregnancy O
( O
70 O
. O
63 O
+ O
/ O
- O
21 O
. O
41 O
versus O
82 O
. O
03 O
+ O
/ O
- O
15 O
. O
54 O
mu O
g O
/ O
L O
, O
p O
< O
0 O
. O
05 O
) O
. O

Being O
in O
the O
bottom O
tertile O
of O
selenium B
concentration O
( O
less O
than O
62 O
. O
2 O
mu O
g O
/ O
L O
) O
was O
associated O
with O
greater O
risk O
of O
preeclampsia O
in O
pregnant O
women O
. O

The O
reduced O
selenium B
in O
the O
maternal O
circulations O
observed O
in O
the O
preeclamptic O
mothers O
support O
the O
hypothesis O
that O
insufficient O
selenium B
concentration O
may O
be O
a O
contributing O
factor O
to O
the O
pathophysiological O
mechanisms O
associated O
with O
preeclampsia O
, O
and O
optimizing O
the O
dietary O
selenium B
intake O
through O
supplementation O
could O
produce O
demonstrable O
clinical O
benefits O
. O

Environmental O
concentrations O
and O
bioaccumulations O
of O
cadmium B
and O
zinc B
in O
coastal O
watersheds O
along O
the O
Chinese O
Northern O
Bohai O
and O
Yellow O
Seas O
. O

Cadmium B
( O
Cd B
) O
and O
zinc B
( O
Zn B
) O
in O
surface O
water O
, O
sediment O
, O
carp O
, O
and O
crab O
samples O
collected O
from O
upstream O
and O
downstream O
regions O
of O
coastal O
watersheds O
along O
the O
Chinese O
Northern O
Bohai O
and O
Yellow O
Seas O
were O
analyzed O
to O
provide O
a O
comprehensive O
understanding O
and O
assessment O
of O
their O
environmental O
concentrations O
and O
bioaccumulations O
. O

The O
results O
showed O
that O
downstream O
waters O
contaminated O
with O
Zn B
would O
have O
adverse O
effects O
on O
aquatic O
organisms O
. O

Although O
nearly O
all O
sediments O
were O
contaminated O
with O
Cd B
due O
to O
human O
activities O
, O
little O
potential O
existed O
for O
Cd B
toxicity O
in O
sediment O
- O
dwelling O
fauna O
. O

Concentrations O
of O
Cd B
and O
Zn B
in O
most O
water O
, O
sediment O
, O
carp O
, O
and O
crab O
were O
less O
than O
published O
values O
. O

The O
downstream O
carp O
and O
crabs O
had O
higher O
mean O
bioaccumulation O
factors O
and O
biota O
- O
sediment O
accumulation O
factors O
for O
Cd B
but O
lower O
mean O
biota O
- O
sediment O
accumulation O
factors O
for O
Zn B
than O
the O
upstream O
carp O
and O
crabs O
. O

Based O
on O
the O
relationships O
among O
Cd B
and O
Zn B
concentrations O
in O
water O
, O
sediment O
, O
and O
biota O
, O
the O
authors O
conclude O
that O
Cd B
and O
Zn B
in O
crabs O
primarily O
derived O
from O
sediment O
exposure O
. O

Although O
Cd B
and O
Zn B
in O
water O
and O
sediment O
originated O
from O
some O
of O
the O
same O
sources O
, O
the O
sources O
of O
Cd B
or O
Zn B
in O
water O
were O
likely O
different O
from O
those O
in O
sediment O
. O

The O
reversal O
of O
inhibitors O
in O
congenital O
hemophilia O
. O

Hemophilias O
A O
and O
B O
are O
heritable O
bleeding O
disorders O
characterized O
by O
deficient O
baseline O
levels O
of O
factor O
VIII O
( O
fVIII O
) O
and O
factor O
IX O
( O
fIX O
) O
, O
respectively O
. O

Standard O
treatment O
for O
acute O
bleeding O
events O
and O
for O
prophylaxis O
in O
patients O
with O
severe O
disease O
consists O
of O
recombinant O
fVIII O
and O
fIX O
infusions O
. O

The O
development O
of O
alloantibodies O
, O
or O
inhibitors O
, O
is O
a O
serious O
complication O
of O
congenital O
hemophilia O
that O
may O
impair O
the O
effectiveness O
of O
fVIII O
and O
fIX O
, O
leading O
to O
increased O
morbidity O
and O
cost O
of O
therapy O
. O

When O
inhibitors O
are O
present O
, O
bypassing O
agents O
such O
as O
recombinant O
activated O
factor O
VII O
and O
factor O
eight O
inhibitor O
bypass O
agent O
are O
available O
for O
treatment O
of O
bleeding O
events O
. O

Although O
usually O
effective O
, O
they O
are O
costly O
treatments O
. O

Immune O
- O
modulatory O
therapy O
may O
reverse O
inhibitors O
, O
allowing O
fVIII O
and O
fIX O
to O
be O
used O
again O
. O

Immune O
tolerance O
induction O
is O
the O
chief O
treatment O
option O
to O
decrease O
inhibitor O
levels O
, O
but O
about O
20 O
- O
30 O
% O
of O
patients O
fail O
this O
treatment O
. O

Alternatively O
, O
multiple O
immune O
- O
modulating O
agents O
have O
been O
tried O
with O
limited O
success O
. O

Rituximab O
, O
an O
anti O
- O
CD20 O
monoclonal O
antibody O
, O
is O
one O
therapy O
that O
has O
been O
successful O
in O
reducing O
inhibitor O
titers O
in O
multiple O
case O
reports O
. O

Although O
current O
evidence O
is O
limited O
and O
questions O
regarding O
its O
use O
and O
place O
in O
therapy O
still O
exist O
, O
this O
agent O
shows O
promise O
for O
the O
future O
. O

3 B
- I
Methylglutaconic I
aciduria O
- O
lessons O
from O
50 O
genes O
and O
977 O
patients O
. O

Elevated O
urinary O
excretion O
of O
3 B
- I
methylglutaconic I
acid I
is O
considered O
rare O
in O
patients O
suspected O
of O
a O
metabolic O
disorder O
. O

In O
3 B
- I
methylglutaconyl I
- I
CoA I
hydratase O
deficiency O
( O
mutations O
in O
AUH O
) O
, O
it O
derives O
from O
leucine B
degradation O
. O

In O
all O
other O
disorders O
with O
3 B
- I
methylglutaconic I
aciduria O
the O
origin O
is O
unknown O
, O
yet O
mitochondrial O
dysfunction O
is O
thought O
to O
be O
the O
common O
denominator O
. O

We O
investigate O
the O
biochemical O
, O
clinical O
and O
genetic O
data O
of O
388 O
patients O
referred O
to O
our O
centre O
under O
suspicion O
of O
a O
metabolic O
disorder O
showing O
3 B
- I
methylglutaconic I
aciduria O
in O
routine O
metabolic O
screening O
. O

Furthermore O
, O
we O
investigate O
591 O
patients O
with O
50 O
different O
, O
genetically O
proven O
, O
mitochondrial O
disorders O
for O
the O
presence O
of O
3 B
- I
methylglutaconic I
aciduria O
. O

Three O
percent O
of O
all O
urine O
samples O
of O
the O
patients O
referred O
showed O
3 B
- I
methylglutaconic I
aciduria O
, O
often O
in O
correlation O
with O
disorders O
not O
reported O
earlier O
in O
association O
with O
3 B
- I
methylglutaconic I
aciduria O
( O
e O
. O
g O
. O
organic O
acidurias O
, O
urea B
cycle O
disorders O
, O
haematological O
and O
neuromuscular O
disorders O
) O
. O

In O
the O
patient O
cohort O
with O
genetically O
proven O
mitochondrial O
disorders O
11 O
% O
presented O
3 B
- I
methylglutaconic I
aciduria O
. O

It O
was O
more O
frequently O
seen O
in O
ATPase O
related O
disorders O
, O
with O
mitochondrial O
DNA O
depletion O
or O
deletion O
, O
but O
not O
in O
patients O
with O
single O
respiratory O
chain O
complex O
deficiencies O
. O

Besides O
, O
it O
was O
a O
consistent O
feature O
of O
patients O
with O
mutations O
in O
TAZ O
, O
SERAC1 O
, O
OPA3 O
, O
DNAJC19 O
and O
TMEM70 O
accounting O
for O
mitochondrial O
membrane O
related O
pathology O
. O

3 B
- I
methylglutaconic I
aciduria O
is O
found O
quite O
frequently O
in O
patients O
suspected O
of O
a O
metabolic O
disorder O
, O
and O
mitochondrial O
dysfunction O
is O
indeed O
a O
common O
denominator O
. O

It O
is O
only O
a O
discriminative O
feature O
of O
patients O
with O
mutations O
in O
AUH O
, O
TAZ O
, O
SERAC1 O
, O
OPA3 O
, O
DNAJC19 O
TMEM70 O
. O

These O
conditions O
should O
therefore O
be O
referred O
to O
as O
inborn O
errors O
of O
metabolism O
with O
3 B
- I
methylglutaconic I
aciduria O
as O
discriminative O
feature O
. O

Gas O
Dielectric O
Transistor O
of O
CuPc O
Single O
Crystalline O
Nanowire O
for O
SO2 B
Detection O
Down O
to O
Sub O
- O
ppm O
Levels O
at O
Room O
Temperature O
. O

A O
room O
- O
temperature O
highly O
- O
sensitive O
SO2 B
sensor O
with O
fast O
response O
and O
complete O
recovery O
is O
constructed O
based O
on O
gas O
dielectric O
field O
- O
effect O
transistor O
( O
FET O
) O
of O
CuPc B
single O
crystalline O
nanowire O
. O

The O
exposed O
conductive O
channel O
by O
gas O
dielectric O
is O
responsible O
for O
the O
high O
sensitivity O
to O
SO2 B
and O
the O
adsorption O
of O
the O
SO2 B
molecules O
dramatically O
enhances O
the O
field O
- O
effect O
mobility O
. O

These O
results O
not O
only O
open O
up O
new O
opportunities O
to O
develop O
new O
SO2 B
sensors O
, O
but O
also O
provide O
an O
efficient O
way O
to O
improve O
the O
performance O
of O
organic O
FETs O
. O

Efficient O
stacking O
on O
protein O
amide B
fragments O
. O

The O
less O
polar O
pi O
- O
surface O
of O
protein O
amide B
groups O
is O
exposed O
in O
many O
receptor O
binding O
sites O
, O
either O
as O
part O
of O
the O
backbone O
or O
in O
Gln B
/ O
Asn B
side O
chains O
. O

Using O
quantum O
chemical O
calculations O
and O
Protein O
Data O
Bank O
( O
PDB O
) O
searches O
on O
model O
systems O
, O
we O
investigate O
the O
energetics O
and O
geometric O
preferences O
for O
the O
stacking O
on O
amide B
groups O
of O
a O
large O
number O
of O
heteroarenes B
that O
are O
relevant O
to O
medicinal O
chemistry O
. O

From O
this O
study O
, O
we O
discern O
that O
the O
stacking O
energy O
of O
an O
aromatic O
ligand O
substituent O
can O
be O
improved O
by O
: O
1 O
) O
orienting O
the O
fragment O
dipole O
vector O
such O
that O
it O
is O
aligned O
in O
an O
antiparallel O
fashion O
with O
the O
dipole O
of O
the O
interacting O
protein O
amide B
group O
, O
2 O
) O
increasing O
its O
dipole O
moment O
, O
and O
3 O
) O
decreasing O
its O
pi O
- O
electron O
density O
. O

These O
guidelines O
should O
be O
helpful O
to O
more O
rationally O
exploit O
this O
interaction O
type O
in O
future O
structure O
- O
based O
drug O
design O
. O

Relation O
between O
respiratory O
function O
tests O
and O
life O
habits O
of O
the O
university O
students O
. O

Among O
the O
university O
students O
especially O
in O
adolescence O
period O
, O
smoking O
habits O
and O
unhealthy O
lifestyles O
are O
major O
problems O
in O
social O
life O
. O

In O
this O
study O
, O
it O
is O
intended O
to O
reveal O
smoking O
habits O
and O
lifestyles O
of O
the O
students O
from O
Suleyman O
Demirel O
University O
and O
to O
determine O
the O
effects O
of O
smoking O
and O
lifestyles O
on O
pulmonary O
functions O
. O

Materials O
and O
methods O
: O
Participants O
were O
94 O
university O
students O
who O
were O
getting O
formal O
education O
in O
the O
Suleyman O
Demirel O
University O
central O
campus O
. O

Data O
were O
analysed O
by O
analysis O
of O
variance O
and O
chi O
- O
square O
tests O
. O

For O
all O
analysis O
, O
p O
value O
of O
< O
0 O
. O
05 O
was O
considered O
significant O
. O

Results O
: O
Students O
' O
mean O
age O
was O
19 O
. O
9 O
+ O
/ O
- O
0 O
. O
9 O
years O
, O
and O
of O
all O
the O
students O
74 O
( O
78 O
. O
7 O
% O
) O
were O
undergraduate O
students O
; O
remaining O
20 O
( O
21 O
. O
3 O
% O
) O
were O
graduate O
students O
. O

Of O
all O
the O
students O
, O
27 O
( O
28 O
. O
7 O
% O
) O
, O
which O
comprised O
the O
largest O
group O
of O
the O
students O
, O
were O
living O
in O
state O
dormitory O
. O

Body O
mass O
index O
( O
BMI O
) O
was O
examined O
for O
the O
study O
group O
; O
according O
to O
BMI O
, O
body O
weight O
was O
generally O
within O
normal O
limits O
but O
17 O
. O
39 O
% O
of O
girls O
' O
were O
found O
to O
be O
underweight O
. O

Conclusions O
: O
Respiratory O
parameters O
can O
be O
affected O
by O
many O
factors O
. O

Smoking O
habit O
of O
university O
students O
can O
be O
prevented O
, O
and O
it O
is O
an O
important O
point O
that O
they O
have O
a O
healthy O
lifestyle O
both O
for O
their O
own O
health O
and O
for O
future O
generations O
. O

Lapatinib B
- O
mediated O
cyclooxygenase O
- O
2 O
expression O
via O
epidermal O
growth O
factor O
receptor O
/ O
HuR O
interaction O
enhances O
the O
aggressiveness O
of O
triple O
- O
negative O
breast O
cancer O
cells O
. O

Lapatinib B
, O
a O
dual O
epidermal O
growth O
factor O
receptor O
( O
EGFR O
) O
/ O
human O
epidermal O
growth O
factor O
receptor O
2 O
( O
HER2 O
) O
kinase O
inhibitor O
, O
showed O
clinical O
benefits O
in O
advanced O
HER2 O
- O
positive O
breast O
cancer O
patients O
. O

Because O
some O
triple O
- O
negative O
breast O
cancers O
( O
TNBCs O
) O
frequently O
overexpress O
EGFR O
, O
the O
antitumor O
activity O
of O
lapatinib B
in O
such O
diseases O
was O
also O
tested O
. O

However O
, O
the O
results O
showed O
a O
worse O
event O
- O
free O
survival O
rate O
. O

It O
remains O
unknown O
whether O
and O
how O
lapatinib B
elicits O
the O
aggressiveness O
of O
such O
cancer O
cells O
. O

In O
this O
study O
, O
our O
results O
demonstrated O
that O
lapatinib B
facilitated O
axillary O
and O
lung O
metastases O
of O
triple O
- O
negative O
MDA O
- O
MB O
- O
231 O
breast O
cancer O
cells O
without O
affecting O
their O
viability O
, O
leading O
to O
worse O
survival O
in O
orthotopic O
xenograft O
mice O
. O

The O
lapatinib B
- O
increased O
motility O
was O
attributed O
by O
the O
elevation O
of O
EGFR O
through O
the O
downregulation O
of O
microRNA O
- O
7 O
and O
by O
the O
subsequent O
overexpression O
of O
cyclooxygenase O
- O
2 O
( O
COX O
- O
2 O
) O
. O

Strikingly O
, O
independent O
of O
its O
kinase O
activity O
, O
the O
elevated O
EGFR O
at O
least O
partly O
stabilized O
COX O
- O
2 O
expression O
by O
enhancing O
the O
binding O
of O
HuR O
to O
COX O
- O
2 O
mRNA O
. O

Our O
results O
suggest O
that O
lapatinib B
may O
increase O
the O
migration O
and O
invasion O
of O
MDA O
- O
MB O
- O
231 O
cells O
by O
upregulating O
EGFR O
and O
COX O
- O
2 O
through O
the O
downregulation O
of O
microRNA O
- O
7 O
, O
providing O
a O
potential O
explanation O
for O
the O
worse O
clinical O
outcome O
of O
TNBC O
patients O
who O
receive O
lapatinib B
- O
based O
treatment O
. O

These O
findings O
also O
shed O
new O
light O
on O
the O
molecular O
mechanism O
of O
COX O
- O
2 O
mRNA O
stabilization O
by O
EGFR O
in O
a O
kinase O
- O
independent O
manner O
. O

Dispersion O
and O
Filtration O
of O
Carbon B
Nanotubes O
( O
CNTs O
) O
and O
Measurement O
of O
Nanoparticle O
Agglomerates O
in O
Diesel O
Exhaust O
. O

Carbon B
nanotubes O
( O
CNTs O
) O
tend O
to O
form O
bundles O
due O
to O
their O
geometry O
and O
van O
der O
Walls O
forces O
, O
which O
usually O
complicates O
studies O
of O
the O
CNT O
properties O
. O

Dispersion O
plays O
a O
significant O
role O
in O
CNT O
studies O
and O
we O
summarize O
dispersion O
techniques O
to O
generate O
airborne O
CNTs O
from O
suspensions O
or O
powders O
. O

We O
describe O
in O
detail O
our O
technique O
of O
CNT O
aerosolization O
with O
controlled O
degree O
of O
agglomeration O
using O
an O
electrospray O
system O
. O

The O
results O
of O
animal O
inhalation O
studies O
using O
the O
electrosprayed O
CNTs O
are O
presented O
. O

We O
have O
performed O
filtration O
experiments O
for O
CNTs O
through O
a O
screen O
filter O
. O

A O
numerical O
model O
has O
been O
established O
to O
simulate O
the O
CNT O
filtration O
experiments O
. O

Both O
the O
modeling O
and O
experimental O
results O
show O
that O
the O
CNT O
penetration O
is O
less O
than O
the O
penetration O
for O
a O
sphere O
with O
the O
same O
mobility O
diameter O
, O
which O
is O
mainly O
due O
to O
the O
larger O
interception O
length O
of O
the O
CNTs O
. O

There O
is O
a O
need O
for O
instruments O
capable O
of O
fast O
and O
online O
measurement O
of O
gas O
- O
borne O
nanoparticle O
agglomerates O
. O

We O
developed O
an O
instrument O
Universal O
NanoParticle O
Analyzer O
( O
UNPA O
) O
and O
the O
measurement O
results O
for O
diesel O
exhaust O
particulates O
are O
presented O
. O

The O
results O
presented O
here O
are O
pertinent O
to O
non O
- O
spherical O
aerosol O
particles O
, O
and O
illustrate O
the O
effects O
of O
particle O
morphology O
on O
aerosol O
behaviors O
. O

Design O
and O
synthesis O
of O
cyclopropylamide B
analogues O
of O
combretastatin B
- I
A4 I
as O
novel O
microtubule O
- O
stabilizing O
agents O
. O

A O
series O
of O
novel O
cyclopropylamide B
analogues O
of O
combretastatin B
- I
A4 I
( O
CA B
- I
4 I
) O
were O
designed O
and O
synthesized O
. O

Most O
of O
them O
had O
significant O
in O
vitro O
antiproliferative O
activities O
, O
particularly O
for O
compounds O
7i4 O
, O
7c4 O
, O
8a4 O
, O
and O
8c4 O
. O

Moreover O
, O
compound O
8c4 O
was O
also O
equally O
potent O
against O
paclitaxel B
resistant O
cancer O
cells O
. O

Interestingly O
, O
the O
novel O
cyclopropylamide B
analogues O
had O
different O
binding O
mechanisms O
from O
CA B
- I
4 I
. O

Instead O
of O
inhibiting O
tubulin O
polymerization O
, O
these O
CA B
- I
4 I
derivatives O
were O
able O
to O
stimulate O
tubulin O
polymerization O
. O

Flow O
cytometry O
revealed O
that O
compound O
8c4 O
arrested O
A549 O
cancer O
cells O
in O
the O
G2 O
/ O
M O
phase O
and O
resulted O
in O
cellular O
apoptosis O
. O

Further O
immunofluorescence O
assays O
revealed O
that O
compound O
8c4 O
induced O
mitotic O
arrest O
in O
A549 O
cells O
through O
disrupting O
microtubule O
dynamics O
. O

In O
addition O
, O
compound O
8c4 O
also O
effectively O
inhibited O
the O
tumor O
growth O
in O
the O
A549 O
xenograft O
model O
without O
causing O
significant O
loss O
of O
body O
weight O
. O

Compound O
8c4 O
represents O
a O
novel O
class O
of O
microtubule O
- O
stabilizing O
agent O
and O
can O
be O
used O
as O
a O
promising O
lead O
for O
the O
development O
of O
new O
antitumor O
agents O
. O

A O
new O
iridoid B
glycoside I
and O
potential O
MRB O
inhibitory O
activity O
of O
isolated O
compounds O
from O
the O
rhizomes O
of O
Cyperus O
rotundus O
L O
. O

A O
new O
iridoid B
glycoside I
, O
rotunduside B
( O
1 O
) O
, O
along O
with O
four O
known O
iridoid B
glycosides I
, O
10 B
- I
O I
- I
p I
- I
hydroxybenzoylthevir I
( O
2 O
) O
, O
10 B
- I
O I
- I
vanilloyltheviridosi I
( O
3 O
) O
, O
6 B
' I
' I
- I
O I
- I
( I
trans I
- I
p I
- I
coumaroyl I
) I
- I
procumbide I
( O
4 O
) O
and O
loganic B
acid I
( O
5 O
) O
, O
was O
isolated O
from O
the O
rhizomes O
of O
Cyperus O
rotundus O
L O
. O

Their O
chemical O
structures O
were O
elucidated O
on O
the O
basis O
of O
UV O
, O
IR O
, O
MS O
and O
NMR O
spectroscopic O
analyses O
. O

In O
addition O
, O
the O
macrophages O
respiratory O
burst O
( O
MRB O
) O
inhibitory O
activity O
of O
the O
isolated O
compounds O
was O
reported O
. O

Compound O
2 O
exhibited O
considerable O
MRB O
inhibitory O
activity O
in O
the O
test O
with O
IC O
( O
50 O
) O
value O
of O
~ O
37 O
mu O
M O
. O

Two O
new O
glycosides O
from O
Vitex O
negundo O
. O

Two O
new O
glycosides O
, O
2 B
- I
methyl I
pyromeconic I
acid I
3 I
- I
O I
- I
beta I
- I
d I
- I
glucopyranoside I
- I
6 I
' I
- I
( I
O I
- I
4 I
' I
' I
- I
hydroxybenzoate I
) I
( O
1 O
) O
, O
6 B
' I
- I
O I
- I
p I
- I
hydroxybenzoyl I
- I
gardoside I
( O
2 O
) O
and O
four O
known O
iridoid B
glycosides I
( O
3 O
- O
6 O
) O
were O
isolated O
from O
the O
whole O
plant O
of O
Vitex O
negundo O
. O

Their O
structures O
were O
elucidated O
on O
the O
basis O
of O
spectroscopic O
methods O
including O
HR O
- O
ESI O
- O
MS O
, O
1D O
and O
2D O
NMR O
. O

Identification O
of O
alpha B
- I
tocopherol I
and O
alpha B
- I
tocopheryl I
acetate I
from O
the O
cuticle O
of O
soybean O
pods O
armyworm O
( O
Spodoptera O
cosmioides O
) O
. O

The O
chemical O
composition O
of O
the O
soybean O
pods O
armyworm O
Spodoptera O
cosmioides O
( O
Walker O
, O
1858 O
) O
( O
Lepidoptera O
: O
Noctuidae O
) O
and O
Anticarsia O
gemmatalis O
H O
u O
bner O
, O
1818 O
( O
Lepidoptera O
: O
Erebidae O
) O
larval O
cuticles O
was O
evaluated O
using O
gas O
chromatography O
coupled O
to O
a O
mass O
detector O
( O
GC O
- O
MS O
) O
. O

Among O
the O
usual O
lipids O
found O
in O
the O
insect O
cuticle O
, O
alpha B
- I
tocopherol I
and O
alpha B
- I
tocopheryl I
acetate I
were O
also O
isolated O
from O
S O
. O
cosmioides O
. O

On O
the O
other O
hand O
, O
no O
vitamin B
E I
derivative O
was O
found O
in O
A O
. O
gemmatalis O
exuvia O
. O

This O
is O
the O
first O
report O
of O
vitamin B
E I
occurrence O
in O
the O
insect O
' O
s O
cuticle O
. O

Bioactives O
and O
nutraceutical O
phytochemicals O
naturally O
occurring O
in O
virgin O
olive O
oil O
. O

The O
case O
study O
of O
the O
Nocellara O
del O
Belice O
Italian O
olive O
cultivar O
. O

This O
work O
reports O
on O
the O
composition O
and O
bionutritional O
value O
of O
organic O
virgin O
olive O
oil O
from O
the O
Nocellara O
del O
Belice O
variety O
, O
one O
cultivated O
in O
the O
olive O
areas O
of O
the O
Sicily O
region O
, O
Italy O
. O

Destoned O
oils O
obtained O
by O
processing O
olives O
with O
a O
destoning O
- O
based O
procedure O
were O
compared O
with O
conventional O
oils O
. O

This O
innovative O
technique O
, O
consisting O
in O
removing O
the O
stone O
from O
fruits O
prior O
to O
processing O
, O
strongly O
enhanced O
the O
already O
high O
- O
quality O
level O
of O
the O
conventional O
product O
. O

An O
in O
- O
depth O
analytical O
investigation O
from O
2008 O
to O
2010 O
showed O
how O
this O
innovative O
olive O
extraction O
process O
led O
to O
an O
excellent O
peculiar O
final O
product O
, O
mainly O
attributable O
to O
the O
improved O
biophenol O
and O
volatile O
composition O
, O
as O
well O
as O
higher O
concentrations O
of O
the O
lipophilic O
and O
vitamin O
antioxidants O
( O
tocopherols B
and O
tocotrienols B
) O
. O

It O
had O
higher O
levels O
of O
oleocanthal B
( O
p B
- I
HPEA I
- I
EDA I
) O
, O
a O
nutraceutical O
compound O
exerting O
actions O
against O
COX1 O
and O
COX2 O
( O
cycloxygenases O
) O
. O

Its O
head O
- O
space O
aroma O
displayed O
new O
volatile O
phytomolecules O
and O
also O
had O
higher O
levels O
of O
green O
volatiles O
from O
the O
lipoxygenase O
( O
LOX O
) O
- O
pathway O
( O
one O
having O
as O
precursors O
the O
polyunsaturated B
fatty I
acids I
containing O
a O
cis B
- I
cis I
- I
1 I
, I
4 I
- I
pentadiene I
system O
) O
. O

Among O
the O
other O
bioactives O
, O
we O
highlight O
its O
significant O
levels O
of O
trans B
- I
beta I
- I
carotene I
and O
xanthophylls O
( O
lutein B
, O
violaxanthin B
, O
neoxanthin B
and O
other O
carotenoids O
) O
. O

Its O
enhanced O
nutritional O
value O
was O
also O
attributable O
to O
the O
increased O
intensity O
of O
valuable O
tasting O
notes O
. O

Revealing O
the O
excited O
- O
state O
dynamics O
of O
the O
fluorescent O
protein O
Dendra2 O
. O

Green O
- O
to O
- O
red O
photoconversion O
is O
a O
reaction O
that O
occurs O
in O
a O
limited O
number O
of O
fluorescent O
proteins O
and O
that O
is O
currently O
mechanistically O
debated O
. O

In O
this O
contribution O
, O
we O
report O
on O
our O
investigation O
of O
the O
photoconvertible O
fluorescent O
protein O
Dendra2 O
by O
employing O
a O
combination O
of O
pump O
- O
probe O
, O
up O
- O
conversion O
and O
single O
photon O
timing O
spectroscopic O
techniques O
. O

Our O
findings O
indicate O
that O
upon O
excitation O
of O
the O
neutral O
green O
state O
an O
excited O
state O
proton O
transfer O
proceeds O
with O
a O
time O
constant O
of O
3 O
. O
4 O
ps O
between O
the O
neutral O
green O
and O
the O
anionic O
green O
states O
. O

In O
concentrated O
solution O
we O
detected O
resonance O
energy O
transfer O
( O
25 O
ps O
time O
constant O
) O
between O
green O
and O
red O
monomers O
. O

The O
time O
- O
resolved O
emission O
spectra O
suggest O
also O
the O
formation O
of O
a O
super O
- O
red O
species O
, O
first O
observed O
for O
DsRed O
( O
a O
red O
fluorescent O
protein O
from O
the O
corallimorph O
species O
Discosoma O
) O
and O
consistent O
with O
peculiar O
structural O
details O
present O
in O
both O
proteins O
. O

Improvement O
of O
p B
- I
cymene I
antinociceptive O
and O
anti O
- O
inflammatory O
effects O
by O
inclusion O
in O
beta B
- I
cyclodextrin I
. O

Previously O
, O
we O
have O
demonstrated O
the O
analgesic O
- O
like O
property O
of O
p B
- I
cymene I
in O
rodents O
. O

Short O
half O
- O
life O
is O
a O
limitation O
for O
p B
- I
cymene I
application O
and O
several O
approaches O
have O
been O
used O
to O
improve O
pharmaceutical O
properties O
of O
monoterpenes B
, O
including O
the O
employment O
of O
drug O
- O
delivery O
systems O
. O

Here O
, O
we O
used O
p B
- I
cymene I
/ O
beta B
- I
cyclodextrin I
( O
beta B
- I
CD I
) O
complex O
and O
p B
- I
cymene I
( O
PC O
) O
isolated O
to O
evaluated O
whether O
the O
complex O
formulation O
is O
able O
to O
improve O
the O
antinociceptive O
activity O
of O
this O
monoterpene B
. O

Male O
mice O
( O
26 O
- O
30g O
) O
were O
pretreated O
with O
PC O
/ O
beta B
- I
CD I
( O
20 O
or O
40mg O
/ O
kg O
, O
p O
. O
o O
. O
) O
, O
PC O
( O
20 O
or O
40mg O
/ O
kg O
, O
p O
. O
o O
. O
) O
or O
vehicle O
( O
distilled O
water O
) O
, O
0 O
. O
5h O
before O
painful O
tests O
and O
antinociceptive O
effect O
was O
evaluated O
at O
times O
: O
0 O
. O
5 O
, O
1 O
, O
2 O
, O
4 O
, O
8 O
, O
and O
16h O
after O
treatment O
. O

We O
evaluated O
the O
analgesic O
- O
like O
effect O
of O
PC O
/ O
beta B
- I
CD I
and O
PC O
in O
acetic B
acid I
- O
induced O
abdominal O
writhes O
, O
hot O
- O
plate O
, O
carrageenan O
- O
induced O
paw O
edema O
and O
in O
rota O
- O
rod O
apparatus O
. O

Our O
results O
demonstrated O
that O
acute O
treatment O
with O
complex O
PC O
/ O
beta B
- I
CD I
produced O
an O
antinocicepitve O
effect O
( O
p O
< O
0 O
. O
01 O
or O
p O
< O
0 O
. O
001 O
) O
for O
8h O
followed O
whereas O
isolated O
PC O
produced O
the O
same O
effect O
for O
2h O
. O

Similar O
results O
were O
obtained O
in O
hot O
- O
plate O
test O
, O
PC O
/ O
beta B
- I
CD I
, O
in O
all O
doses O
, O
significantly O
reduces O
( O
p O
< O
0 O
. O
01 O
or O
p O
< O
0 O
. O
001 O
) O
nociceptive O
behavior O
for O
8h O
while O
isolated O
PC O
for O
1h O
, O
did O
so O
only O
in O
higher O
dose O
. O

Such O
results O
were O
unlikely O
to O
be O
caused O
by O
motor O
abnormality O
. O

Systemic O
pretreatment O
with O
PC O
/ O
beta B
- I
CD I
and O
PC O
inhibited O
the O
development O
paw O
edema O
by O
carrageenan O
1 O
% O
, O
but O
PC O
/ O
beta B
- I
CD I
did O
so O
during O
a O
longer O
period O
when O
compared O
with O
isolated O
monoterpene B
alone O
. O

Our O
results O
provide O
evidence O
to O
propose O
that O
the O
complex O
with O
beta B
- I
CD I
improved O
analgesic O
and O
anti O
- O
inflammatory O
effects O
of O
p B
- I
cymene I
. O

Towards O
the O
validation O
of O
a O
lung O
tumorigenesis O
model O
with O
mainstream O
cigarette O
smoke O
inhalation O
using O
the O
A O
/ O
J O
mouse O
. O

A O
generally O
accepted O
and O
validated O
laboratory O
model O
for O
smoking O
- O
associated O
pulmonary O
tumorigenesis O
would O
be O
useful O
for O
both O
basic O
and O
applied O
research O
applications O
, O
such O
as O
the O
development O
of O
early O
diagnostic O
endpoints O
or O
the O
evaluation O
of O
modified O
risk O
tobacco O
products O
, O
respectively O
. O

The O
A O
/ O
J O
mouse O
is O
susceptible O
for O
developing O
both O
spontaneous O
and O
induced O
lung O
adenomas O
and O
adenocarcinomas O
, O
and O
increased O
lung O
tumor O
multiplicities O
were O
also O
observed O
in O
previous O
cigarette O
smoke O
inhalation O
studies O
. O

The O
present O
study O
was O
designed O
to O
collect O
data O
useful O
towards O
the O
validation O
of O
an O
18 O
- O
month O
mainstream O
smoke O
( O
MS O
) O
inhalation O
model O
. O

Male O
and O
female O
A O
/ O
J O
mice O
were O
exposed O
whole O
- O
body O
at O
three O
MS O
concentration O
levels O
for O
6h O
/ O
day O
, O
and O
the O
results O
were O
compared O
to O
a O
previous O
study O
in O
the O
same O
laboratory O
and O
with O
a O
similar O
design O
. O

A O
linear O
MS O
concentration O
- O
dependent O
increase O
in O
lung O
tumorigenesis O
was O
observed O
with O
similar O
slopes O
for O
both O
sexes O
and O
both O
studies O
and O
a O
maximal O
5 O
- O
fold O
increase O
in O
multiplicity O
beyond O
sham O
control O
. O

The O
minimal O
detectable O
difference O
in O
lung O
tumor O
multiplicity O
for O
the O
current O
study O
was O
37 O
% O
. O

In O
the O
larynx O
, O
papillomas O
were O
detectable O
in O
all O
MS O
- O
exposed O
groups O
in O
a O
non O
- O
concentration O
dependent O
manner O
. O

No O
other O
extra O
- O
pulmonary O
MS O
- O
dependent O
neoplastic O
lesions O
were O
found O
. O

Gene O
expression O
signatures O
of O
lung O
tumor O
tissues O
allowed O
a O
clear O
differentiation O
of O
sham O
- O
and O
high O
dose O
MS O
- O
exposed O
mice O
. O

In O
combination O
with O
data O
from O
previous O
smoke O
inhalation O
studies O
with O
A O
/ O
J O
mice O
, O
the O
current O
data O
suggest O
that O
this O
model O
for O
MS O
inhalation O
- O
induced O
pulmonary O
tumorigenesis O
is O
reliable O
and O
relevant O
, O
two O
crucial O
requirements O
towards O
validation O
of O
such O
a O
model O
. O

Dichloro B
- I
dihydro I
- I
fluorescein I
diacetate I
( O
DCFH B
- I
DA I
) O
assay O
: O
a O
quantitative O
method O
for O
oxidative O
stress O
assessment O
of O
nanoparticle O
- O
treated O
cells O
. O

No O
consensus O
exists O
on O
how O
to O
address O
possible O
toxicity O
of O
nanomaterials O
as O
they O
interfere O
with O
most O
in O
vitro O
screening O
tests O
based O
on O
colorimetric O
and O
fluorimetric O
probes O
such O
as O
the O
dichloro B
- I
dihydro I
- I
fluorescein I
diacetate I
( O
DCFH B
- I
DA I
) O
assay O
for O
detection O
of O
oxidative O
species O
. O

In O
the O
present O
research O
, O
nanomaterial O
interaction O
with O
DCFH B
- I
DA I
was O
studied O
in O
relation O
to O
its O
nature O
and O
/ O
or O
assay O
conditions O
( O
cell O
- O
based O
and O
time O
exposure O
) O
by O
incubating O
Rhodamine O
( O
Rhd O
) O
- O
labeled O
25nm O
and O
50nm O
silica B
( O
SiO2 B
) O
, O
naked O
and O
oleic B
acid I
coated O
magnetite B
, O
( O
Fe3O4 B
) O
and O
maghemite B
( O
Fe2O3 B
) O
iron B
oxide I
, O
titanium B
dioxide I
( O
TiO2 B
) O
and O
poly B
( I
ethylene I
oxide I
) I
- O
poly B
( I
lactide I
/ O

glycolide I
) I
acid I
( O
PLGA B
- I
PEO I
) O
nanoparticles O
( O
NPs O
) O
with O
metabolically O
active O
rat O
hepatocytes O
for O
4 O
and O
24 O
- O
h O
periods O
. O

Data O
indicated O
that O
nanoparticle O
uptake O
correlated O
with O
quenching O
of O
dye O
fluorescence O
emission O
. O

In O
spite O
of O
their O
masking O
effect O
, O
the O
oxidative O
potential O
of O
NPs O
could O
be O
detected O
at O
a O
limited O
threshold O
concentration O
when O
exposed O
for O
periods O
of O
time O
longer O
than O
those O
frequently O
used O
for O
this O
test O
. O

However O
, O
changes O
in O
the O
experimental O
conditions O
did O
not O
systematically O
result O
in O
free O
radical O
formation O
for O
all O
nanomaterials O
tested O
. O

Overall O
data O
indicate O
that O
despite O
the O
quenching O
effect O
of O
nanoparticles O
on O
DCFH B
- I
DA I
assay O
, O
it O
can O
be O
considered O
as O
a O
useful O
tool O
for O
quantitative O
measurement O
of O
NPs O
- O
induced O
oxidative O
stress O
by O
minor O
modifications O
of O
standardized O
protocols O
. O

Formation O
of O
mainstream O
cigarette O
smoke O
constituents O
prioritized O
by O
the O
World O
Health O
Organization O
- O
- O
yield O
patterns O
observed O
in O
market O
surveys O
, O
clustering O
and O
inverse O
correlations O
. O

The O
WHO O
TobReg O
proposed O
mandating O
ceilings O
on O
selected O
smoke O
constituents O
determined O
from O
the O
market O
- O
specific O
median O
of O
nicotine B
- O
normalized O
yield O
distributions O
. O

Data O
validating O
this O
regulatory O
concept O
were O
obtained O
from O
essentially O
single O
- O
blend O
surveys O
. O

This O
process O
is O
strongly O
impacted O
by O
inverse O
correlations O
among O
yields O
. O

In O
the O
present O
study O
, O
18 O
priority O
WHO O
smoke O
constituent O
yields O
( O
nicotine B
- O
normalized O
) O
were O
determined O
( O
using O
two O
smoking O
regimens O
) O
from O
262 O
commercial O
brands O
including O
American O
, O
Virginia O
and O
local O
blends O
from O
13 O
countries O
. O

Principal O
Component O
Analysis O
was O
used O
to O
identify O
yields O
patterns O
, O
clustering O
of O
blend O
types O
and O
the O
inverse O
correlations O
causing O
these O
clusters O
. O

Three O
principal O
components O
explain O
about O
75 O
% O
of O
total O
data O
variability O
. O

PC1 O
was O
sensitive O
to O
the O
relative O
levels O
of O
gas O
- O
and O
particle O
- O
phase O
compounds O
. O

PC2 B
and O
PC3 B
cluster O
American O
- O
and O
Virginia O
- O
blends O
, O
revealing O
inverse O
correlations O
: O
Nitrogen B
oxides I
and O
amino B
- O
or O
nitroso I
- O
aromatic O
compounds O
inversely O
correlate O
to O
either O
formaldehyde B
and O
acrolein B
, O
or O
benzo B
( I
a I
) I
pyrene I
and O
di B
- I
hydroxybenzenes I
. O

These O
results O
can O
be O
explained O
by O
reviewing O
the O
processes O
determining O
each O
components O
smoke O
delivery O
. O

Regulatory O
initiatives O
simultaneously O
targeting O
selected O
smoke O
constituents O
in O
markets O
with O
mixed O
blend O
styles O
will O
be O
strongly O
impacted O
by O
the O
inverse O
correlations O
described O
. O

It O
is O
difficult O
to O
predict O
the O
ultimate O
impact O
of O
such O
regulations O
on O
public O
health O
, O
considering O
the O
complex O
chemistry O
of O
cigarette O
smoke O
formation O
. O

The O
association O
between O
daily O
calcium B
intake O
and O
sarcopenia O
in O
older O
, O
non O
- O
obese O
Korean O
adults O
: O
the O
fourth O
Korea O
national O
health O
and O
nutrition O
examination O
survey O
( O
KNHANES O
IV O
) O
2009 O
. O

Recent O
data O
suggest O
that O
variations O
in O
calcium B
intake O
may O
influence O
body O
weight O
and O
composition O
; O
however O
, O
the O
relationship O
between O
daily O
calcium B
intake O
and O
muscle O
mass O
has O
not O
been O
well O
established O
. O

The O
objective O
of O
this O
study O
was O
to O
assess O
the O
relationship O
between O
daily O
calcium B
intake O
and O
sarcopenia O
. O

We O
analyzed O
data O
for O
older O
adults O
( O
over O
60 O
years O
) O
from O
the O
fourth O
Korea O
National O
Health O
and O
Nutrition O
Examination O
Survey O
( O
KNHANES O
) O
conducted O
in O
2009 O
. O

A O
total O
of O
1339 O
Non O
- O
Obese O
( O
BMI O
between O
18 O
. O
5 O
and O
25 O
kg O
/ O
m O
( O
2 O
) O
) O
, O
older O
adults O
( O
592 O
men O
and O
707 O
women O
) O
were O
enrolled O
. O

Dietary O
variables O
were O
assessed O
using O
a O
nutrition O
survey O
that O
used O
a O
24 O
- O
hour O
recall O
method O
. O

Daily O
calcium B
intake O
based O
on O
the O
consumption O
of O
each O
food O
item O
was O
calculated O
. O

Sarcopenia O
was O
defined O
as O
an O
appendicular O
skeletal O
muscle O
mass O
divided O
by O
body O
weight O
less O
than O
2 O
SD O
below O
the O
sex O
- O
specific O
mean O
for O
young O
adults O
. O

We O
found O
that O
daily O
calcium B
intake O
was O
negatively O
correlated O
with O
total O
body O
fat O
percentage O
and O
positively O
correlated O
with O
appendicular O
skeletal O
mass O
( O
p O
< O
0 O
. O
001 O
) O
. O

Participants O
with O
sarcopenia O
appear O
to O
have O
significantly O
lower O
daily O
calcium B
intakes O
than O
participants O
without O
sarcopenia O
( O
p O
< O
0 O
. O
001 O
) O
. O

The O
unadjusted O
prevalence O
of O
sarcopenia O
according O
to O
daily O
calcium B
intake O
tertiles O
were O
6 O
. O
3 O
% O
, O
4 O
. O
3 O
% O
, O
and O
2 O
. O
7 O
% O
in O
tertiles O
1 O
, O
2 O
, O
and O
3 O
, O
respectively O
. O

After O
adjustment O
for O
age O
, O
sex O
, O
BMI O
, O
total O
energy O
intake O
, O
and O
lifestyle O
factors O
, O
compared O
with O
those O
in O
the O
lowest O
tertile O
of O
daily O
calcium B
intake O
, O
participants O
in O
the O
highest O
tertile O
had O
an O
odds O
ratio O
for O
sarcopenia O
of O
0 O
. O
295 O
( O
95 O
% O
confidence O
interval O
, O
0 O
. O
087 O
- O
0 O
. O
768 O
; O
p O
for O
trend O
= O
0 O
. O
014 O
) O
. O

We O
found O
that O
daily O
calcium B
intake O
, O
corrected O
for O
total O
energy O
intake O
and O
serum O
25 B
( I
OH I
) I
D I
status O
, O
was O
significantly O
lower O
in O
subjects O
with O
sarcopenia O
than O
in O
those O
without O
. O

Our O
results O
suggest O
a O
strong O
inverse O
association O
between O
daily O
calcium B
intake O
and O
sarcopenia O
in O
non O
- O
obese O
, O
older O
Korean O
adults O
. O

Functional O
profiling O
discovers O
the O
dieldrin B
organochlorinated O
pesticide O
affects O
leucine B
availability O
in O
yeast O
. O

Exposure O
to O
organochlorinated B
pesticides O
such O
as O
dieldrin B
has O
been O
linked O
to O
Parkinson O
' O
s O
and O
Alzheimer O
' O
s O
diseases O
, O
endocrine O
disruption O
, O
and O
cancer O
, O
but O
the O
cellular O
and O
molecular O
mechanisms O
of O
toxicity O
behind O
these O
effects O
remain O
largely O
unknown O
. O

Here O
we O
demonstrate O
, O
using O
a O
functional O
genomics O
approach O
in O
the O
model O
eukaryote O
Saccharomyces O
cerevisiae O
, O
that O
dieldrin B
alters O
leucine B
availability O
. O

This O
model O
is O
supported O
by O
multiple O
lines O
of O
congruent O
evidence O
: O
( O
1 O
) O
mutants O
defective O
in O
amino B
acid I
signaling O
or O
transport O
are O
sensitive O
to O
dieldrin B
, O
which O
is O
reversed O
by O
the O
addition O
of O
exogenous O
leucine B
; O
( O
2 O
) O
dieldrin B
sensitivity O
of O
wild O
- O
type O
or O
mutant O
strains O
is O
dependent O
upon O
leucine B
concentration O
in O
the O
media O
; O
( O
3 O
) O
overexpression O
of O
proteins O
that O
increase O
intracellular O
leucine B
confer O
resistance O
to O
dieldrin B
; O
( O
4 O
) O
leucine B
uptake O
is O
inhibited O
in O
the O
presence O
of O
dieldrin B
; O
and O
( O
5 O
) O
dieldrin B

induces O
the O
amino B
acid I
starvation O
response O
. O

Additionally O
, O
we O
demonstrate O
that O
appropriate O
negative O
regulation O
of O
the O
Ras O
/ O
protein O
kinase O
A O
pathway O
, O
along O
with O
an O
intact O
pyruvate B
dehydrogenase O
complex O
, O
is O
required O
for O
dieldrin B
tolerance O
. O

Many O
yeast O
genes O
described O
in O
this O
study O
have O
human O
orthologs O
that O
may O
modulate O
dieldrin B
toxicity O
in O
humans O
. O

Brain O
hemispheric O
differences O
in O
the O
neurochemical O
effects O
of O
lead O
, O
prenatal O
stress O
, O
and O
the O
combination O
and O
their O
amelioration O
by O
behavioral O
experience O
. O

Brain O
lateralization O
, O
critical O
to O
mediation O
of O
cognitive O
functions O
and O
to O
" O
multitasking O
, O
" O
is O
disrupted O
in O
conditions O
such O
as O
attention O
deficit O
disorder O
and O
schizophrenia O
. O

Both O
low O
- O
level O
lead O
( O
Pb B
) O
exposure O
and O
prenatal O
stress O
( O
PS O
) O
have O
been O
associated O
with O
mesocorticolimbic O
system O
- O
mediated O
executive O
- O
function O
cognitive O
and O
attention O
deficits O
. O

Mesocorticolimbic O
systems O
demonstrate O
significant O
laterality O
. O

Thus O
, O
altered O
brain O
lateralization O
could O
play O
a O
role O
in O
this O
behavioral O
toxicity O
. O

This O
study O
examined O
laterality O
of O
mesocorticolimbic O
monoamines B
( O
frontal O
cortex O
, O
nucleus O
accumbens O
, O
striatum O
, O
midbrain O
) O
and O
amino B
acids I
( O
frontal O
cortex O
) O
in O
male O
and O
female O
rats O
subjected O
to O
lifetime O
Pb B
exposure O
( O
0 O
or O
50 O
ppm O
in O
drinking O
water O
) O
, O
PS O
( O
restraint O
stress O
on O
gestational O
days O
16 O
- O
17 O
) O
, O
or O
the O
combination O
with O
and O
without O
repeated O
learning O
behavioral O
experience O
. O

Control O
males O
exhibited O
prominent O
laterality O
, O
particularly O
in O
midbrain O
and O
also O
in O
frontal O
cortex O
and O
striatum O
; O
females O
exhibited O
less O
laterality O
, O
and O
this O
was O
primarily O
striatal O
. O

Lateralized O
Pb B
+ O
/ O
- O
PS O
induced O
neurotransmitter O
changes O
were O
assessed O
only O
in O
males O
because O
of O
limited O
sample O
sizes O
of O
Pb B
+ O
PS O
females O
. O

In O
males O
, O
Pb B
+ O
/ O
- O
PS O
changes O
occurred O
in O
left O
hemisphere O
of O
frontal O
cortex O
and O
right O
hemisphere O
of O
midbrain O
. O

Behavioral O
experience O
modified O
the O
laterality O
of O
Pb B
+ O
/ O
- O
PS O
- O
induced O
neurotransmitter O
changes O
in O
a O
region O
- O
dependent O
manner O
. O

Notably O
, O
behavioral O
experience O
eliminated O
Pb B
+ O
/ O
- O
PS O
neurotransmitter O
changes O
in O
males O
. O

These O
findings O
underscore O
the O
critical O
need O
to O
evaluate O
both O
sexes O
and O
brain O
hemispheres O
for O
the O
mechanistic O
understanding O
of O
sex O
- O
dependent O
differences O
in O
neuro O
- O
and O
behavioral O
toxicity O
. O

Furthermore O
, O
assessment O
of O
central O
nervous O
system O
mechanisms O
in O
the O
absence O
of O
behavioral O
experience O
, O
shown O
here O
for O
males O
, O
may O
constitute O
less O
relevant O
models O
of O
human O
health O
effects O
. O

Transcriptome O
alterations O
following O
developmental O
atrazine B
exposure O
in O
zebrafish O
are O
associated O
with O
disruption O
of O
neuroendocrine O
and O
reproductive O
system O
function O
, O
cell O
cycle O
, O
and O
carcinogenesis O
. O

Atrazine B
, O
a O
herbicide O
commonly O
applied O
to O
agricultural O
areas O
and O
a O
common O
contaminant O
of O
potable O
water O
supplies O
, O
is O
implicated O
as O
an O
endocrine O
- O
disrupting O
chemical O
( O
EDC O
) O
and O
potential O
carcinogen O
. O

Studies O
show O
that O
EDCs O
can O
cause O
irreversible O
changes O
in O
tissue O
formation O
, O
decreased O
reproductive O
potential O
, O
obesity O
, O
and O
cancer O
. O

The O
U O
. O
S O
. O

Environmental O
Protection O
Agency O
considers O
an O
atrazine B
concentration O
of O
< O
= O
3 O
ppb O
in O
drinking O
water O
safe O
for O
consumption O
. O

The O
specific O
adverse O
human O
health O
effects O
associated O
with O
a O
developmental O
atrazine B
exposure O
and O
the O
underlying O
genetic O
mechanisms O
of O
these O
effects O
are O
not O
well O
defined O
. O

In O
this O
study O
, O
zebrafish O
embryos O
were O
exposed O
to O
a O
range O
of O
atrazine B
concentrations O
to O
establish O
toxicity O
. O

Morphological O
, O
transcriptomic O
, O
and O
protein O
alterations O
were O
then O
assessed O
at O
72h O
postfertilization O
following O
developmental O
atrazine B
exposure O
at O
0 O
, O
0 O
. O
3 O
, O
3 O
, O
or O
30 O
ppb O
. O

A O
significant O
increase O
in O
head O
length O
was O
observed O
in O
all O
three O
atrazine B
treatments O
. O

Transcriptomic O
profiles O
revealed O
21 O
, O
62 O
, O
and O
64 O
genes O
with O
altered O
expression O
in O
the O
0 O
. O
3 O
, O
3 O
, O
and O
30 O
ppb O
atrazine B
treatments O
, O
respectively O
. O

Altered O
genes O
were O
associated O
with O
neuroendocrine O
and O
reproductive O
system O
development O
, O
function O
, O
and O
disease O
; O
cell O
cycle O
control O
; O
and O
carcinogenesis O
. O

There O
was O
a O
significant O
overlap O
( O
42 O
genes O
) O
between O
the O
3 O
and O
30 O
ppb O
differentially O
expressed O
gene O
lists O
, O
with O
two O
of O
these O
genes O
( O
CYP17A1 O
and O
SAMHD1 O
) O
present O
in O
all O
three O
atrazine B
treatments O
. O

Increased O
transcript O
levels O
were O
translated O
to O
significant O
upregulation O
in O
protein O
expression O
. O

Overall O
, O
this O
study O
identifies O
genetic O
and O
molecular O
targets O
altered O
in O
response O
to O
a O
developmental O
atrazine B
exposure O
to O
further O
define O
the O
biological O
pathways O
and O
mechanisms O
of O
toxicity O
. O

Integrative O
Analysis O
of O
miRNA O
and O
inflammatory O
gene O
expression O
after O
acute O
particulate O
matter O
exposure O
. O

MicroRNAs O
( O
miRNAs O
) O
are O
environmentally O
sensitive O
inhibitors O
of O
gene O
expression O
that O
may O
mediate O
the O
effects O
of O
metal O
- O
rich O
particulate O
matter O
( O
PM O
) O
and O
toxic O
metals O
on O
human O
individuals O
. O

Previous O
environmental O
miRNA O
studies O
have O
investigated O
a O
limited O
number O
of O
candidate O
miRNAs O
and O
have O
not O
yet O
evaluated O
the O
functional O
effects O
on O
gene O
expression O
. O

In O
this O
study O
, O
we O
wanted O
to O
identify O
PM O
- O
sensitive O
miRNAs O
using O
microarray O
profiling O
on O
matched O
baseline O
and O
postexposure O
RNA O
from O
foundry O
workers O
with O
well O
- O
characterized O
exposure O
to O
metal O
- O
rich O
PM O
and O
to O
characterize O
miRNA O
relations O
with O
expression O
of O
candidate O
inflammatory O
genes O
. O

We O
applied O
microarray O
analysis O
of O
847 O
human O
miRNAs O
and O
real O
- O
time O
PCR O
analysis O
of O
18 O
candidate O
inflammatory O
genes O
on O
matched O
blood O
samples O
collected O
from O
foundry O
workers O
at O
baseline O
and O
after O
3 O
days O
of O
work O
( O
postexposure O
) O
. O

We O
identified O
differentially O
expressed O
miRNAs O
( O
fold O
change O
[ O
FC O
] O
> O
2 O
and O
p O
< O
0 O
. O
05 O
) O
and O
correlated O
their O
expression O
with O
the O
inflammatory O
associated O
genes O
. O

We O
performed O
in O
silico O
network O
analysis O
in O
MetaCore O
v6 O
. O
9 O
to O
characterize O
the O
biological O
pathways O
connecting O
miRNA O
- O
mRNA O
pairs O
. O

Microarray O
analysis O
identified O
four O
miRNAs O
that O
were O
differentially O
expressed O
in O
postexposure O
compared O
with O
baseline O
samples O
, O
including O
miR O
- O
421 O
( O
FC O
= O
2 O
. O
81 O
, O
p O
< O
0 O
. O
001 O
) O
, O
miR O
- O
146a O
( O
FC O
= O
2 O
. O
62 O
, O
p O
= O
0 O
. O
007 O
) O
, O
miR O
- O
29a O
( O
FC O
= O
2 O
. O
91 O
, O
p O
< O
0 O
. O
001 O
) O
, O
and O
let O
- O
7g O
( O
FC O
= O
2 O
. O
73 O
, O
p O
= O
0 O
. O
019 O
) O
. O

Using O
false O
discovery O
date O
adjustment O
for O
multiple O
comparisons O
, O
we O
found O
11 O
miRNA O
- O
mRNA O
correlated O
pairs O
involving O
the O
4 O
differentially O
expressed O
miRNAs O
and O
candidate O
inflammatory O
genes O
. O

In O
silico O
network O
analysis O
with O
MetaCore O
database O
identified O
biological O
interactions O
for O
all O
the O
11 O
miRNA O
- O
mRNA O
pairs O
, O
which O
ranged O
from O
direct O
mRNA O
targeting O
to O
complex O
interactions O
with O
multiple O
intermediates O
. O

Acute O
PM O
exposure O
may O
affect O
gene O
regulation O
through O
PM O
- O
responsive O
miRNAs O
that O
directly O
or O
indirectly O
control O
inflammatory O
gene O
expression O
. O

Molecular O
mechanisms O
of O
central O
leptin O
resistance O
in O
obesity O
. O

The O
rapidly O
increasing O
prevalence O
of O
obesity O
confers O
a O
huge O
health O
burden O
globally O
. O

The O
hypothalamus O
plays O
a O
central O
role O
in O
the O
regulation O
of O
energy O
homeostasis O
by O
integrating O
multiple O
metabolic O
signals O
from O
peripheral O
organs O
and O
modulating O
feeding O
behavior O
and O
energy O
metabolism O
. O

Leptin O
, O
a O
key O
appetite O
- O
regulating O
hormone O
derived O
from O
the O
white O
adipose O
tissue O
, O
primarily O
acts O
on O
hypothalamic O
neurons O
to O
activate O
catabolic O
pathway O
and O
inhibit O
anabolic O
pathway O
, O
which O
can O
result O
in O
anorexia O
and O
weight O
reduction O
. O

Despite O
striking O
obesity O
resulting O
from O
leptin O
deficiency O
, O
treatment O
with O
this O
hormone O
in O
human O
obesity O
has O
been O
unsuccessful O
due O
to O
leptin O
resistance O
. O

In O
this O
review O
, O
we O
describe O
recent O
researches O
extending O
our O
understanding O
of O
obesity O
- O
associated O
hypothalamic O
leptin O
resistance O
. O

Evaluation O
of O
Current O
Eligibility O
Criteria O
for O
Bariatric O
Surgery O
: O
Diabetes O
prevention O
and O
risk O
factor O
changes O
in O
the O
Swedish O
Obese O
Subjects O
( O
SOS O
) O
study O
. O

OBJECTIVE O
Patients O
with O
a O
BMI O
< O
35 O
kg O
/ O
m O
( O
2 O
) O
and O
patients O
with O
a O
BMI O
between O
35 O
and O
40 O
kg O
/ O
m O
( O
2 O
) O
without O
comorbidities O
are O
noneligible O
by O
current O
eligibility O
criteria O
for O
bariatric O
surgery O
. O

We O
used O
Swedish O
obese O
subjects O
( O
SOS O
) O
to O
explore O
long O
- O
term O
outcomes O
in O
noneligible O
versus O
eligible O
patients O
. O

RESEARCH O
DESIGN O
AND O
METHODS O
The O
SOS O
study O
involved O
2 O
, O
010 O
obese O
patients O
who O
underwent O
bariatric O
surgery O
( O
68 O
% O
vertical O
- O
banded O
gastroplasty O
, O
19 O
% O
banding O
, O
and O
13 O
% O
gastric O
bypass O
) O
and O
2 O
, O
037 O
contemporaneously O
matched O
obese O
controls O
receiving O
usual O
care O
. O

At O
inclusion O
, O
the O
participant O
age O
was O
37 O
- O
60 O
years O
and O
BMI O
was O
> O
= O
34 O
kg O
/ O
m O
( O
2 O
) O
in O
men O
and O
> O
= O
38 O
kg O
/ O
m O
( O
2 O
) O
in O
women O
. O

The O
effect O
of O
surgery O
was O
assessed O
in O
patients O
that O
do O
( O
n O
= O
3 O
, O
814 O
) O
and O
do O
not O
( O
n O
= O
233 O
) O
meet O
current O
eligibility O
criteria O
. O

The O
date O
of O
analysis O
was O
1 O
January O
2012 O
. O

The O
follow O
- O
up O
time O
was O
up O
to O
20 O
years O
, O
with O
a O
median O
of O
10 O
years O
. O

RESULTS O
Cardiovascular O
risk O
factors O
were O
significantly O
improved O
both O
in O
noneligible O
and O
eligible O
individuals O
after O
10 O
years O
of O
follow O
- O
up O
. O

Surgery O
reduced O
the O
diabetes O
incidence O
in O
both O
the O
noneligible O
( O
adjusted O
hazard O
ratio O
0 O
. O
33 O
[ O
95 O
% O
CI O
0 O
. O
13 O
- O
0 O
. O
82 O
] O
, O
P O
= O
0 O
. O
017 O
) O
and O
eligible O
( O
0 O
. O
27 O
[ O
0 O
. O
22 O
- O
0 O
. O
33 O
] O
, O
P O
< O
0 O
. O
001 O
) O
groups O
. O

We O
could O
not O
detect O
a O
difference O
in O
the O
effect O
of O
surgery O
between O
the O
groups O
( O
adjusted O
interaction O
P O
value O
= O
0 O
. O
713 O
) O
. O

CONCLUSIONS O
Bariatric O
surgery O
drastically O
reduced O
the O
incidence O
of O
type O
2 O
diabetes O
both O
in O
noneligible O
and O
eligible O
patients O
and O
improved O
cardiovascular O
risk O
factors O
in O
both O
groups O
. O

Our O
results O
show O
that O
strict O
BMI O
cutoffs O
are O
of O
limited O
use O
for O
bariatric O
surgery O
prioritization O
if O
the O
aim O
is O
to O
prevent O
diabetes O
and O
improve O
cardiovascular O
risk O
factors O
. O

GLP O
- O
1 O
Action O
and O
Glucose B
Tolerance O
in O
Subjects O
With O
Remission O
of O
Type O
2 O
Diabetes O
Mellitus O
After O
Gastric O
Bypass O
Surgery O
. O

OBJECTIVEGlucagon O
like O
peptide O
- O
1 O
( O
GLP O
- O
1 O
) O
has O
been O
suggested O
as O
a O
major O
factor O
for O
the O
improved O
glucose B
tolerance O
ensuing O
after O
Roux O
- O
en O
- O
Y O
Gastric O
Bypass O
( O
RYGBP O
) O
surgery O
. O

We O
examined O
the O
effect O
of O
blocking O
endogenous O
GLP O
- O
1 O
action O
on O
glucose B
tolerance O
in O
subjects O
with O
sustained O
remission O
of O
type O
2 O
diabetes O
( O
T2DM O
) O
present O
before O
RYGBP O
. O
RESEARCH O
DESIGN O
AND O
METHODSBlood O
glucose B
, O
insulin O
, O
C O
- O
peptide O
, O
glucagon O
, O
GLP O
- O
1 O
, O
and O
glucose B
- O
dependent O
insulinotropic O
peptide O
levels O
were O
measured O
after O
a O
meal O
challenge O
with O
either O
exendin O
- O
( O
9 O
- O
39 O
) O
( O
a O
GLP O
- O
1r O
antagonist O
) O
or O
saline O
infusion O
in O
eight O
subjects O
with O
sustained O
remission O
of O
T2DM O

after O
RYGBP O
and O
seven O
healthy O
controls O
. O
RESULTSInfusion O
of O
exendin O
- O
( O
9 O
- O
39 O
) O
resulted O
in O
marginal O
deterioration O
of O
the O
2 O
- O
h O
plasma O
glucose B
after O
meal O
intake O
in O
RYGBP O
subjects O
( O
saline O
78 O
. O
4 O
+ O
/ O
- O
15 O
. O
1 O
mg O
/ O
dL O
compared O
with O
exendin O
- O
( O
9 O
- O
39 O
) O
116 O
. O
5 O
+ O
/ O
- O
22 O
. O
3 O
mg O
/ O
dL O
; O
P O
< O
0 O
. O
001 O
) O
. O

Furthermore O
, O
glucose B
response O
to O
meal O
intake O
was O
similarly O
enlarged O
in O
the O
two O
study O
groups O
( O
percent O
change O
in O
the O
area O
under O
the O
curve O
of O
glucose B
exendin O
- O
( O
9 O
- O
39 O
) O
- O
infusion O
versus O
saline O
- O
infusion O
: O
controls O
10 O
. O
84 O
+ O
/ O
- O
8 O
. O
8 O
% O
versus O
RYGBP O
9 O
. O
94 O
+ O
/ O
- O
8 O
. O
4 O
% O
; O
P O
= O
0 O
. O
884 O
) O
. O

In O
the O
RYGBP O
group O
, O
the O
blockade O
of O
the O
enlarged O
GLP O
- O
1 O
response O
to O
meal O
intake O
resulted O
in O
reduced O
insulin O
( O
P O
= O
0 O
. O
001 O
) O
and O
C O
- O
peptide O
( O
P O
< O
0 O
. O
001 O
) O
, O
but O
no O
change O
in O
glucagon O
( O
P O
= O
0 O
. O
258 O
) O
responses O
. O
CONCLUSIONThe O
limited O
deterioration O
of O
glucose B
tolerance O
on O
blockade O
of O
GLP O
- O
1 O
action O
in O
our O
study O
suggests O
the O
resolution O
of O
T2DM O
after O
RYGBP O
may O
be O
explained O
by O
mechanisms O
beyond O
enhancement O
of O
GLP O
- O
1 O
action O
. O

Case O
study O
of O
the O
Swiss O
flora O
for O
prior O
phytochemical O
and O
biological O
investigations O
. O

Estimates O
in O
the O
literature O
as O
to O
what O
extent O
the O
world O
' O
s O
higher O
plant O
species O
have O
been O
studied O
chemically O
or O
for O
bioactivity O
are O
contradictory O
and O
range O
from O
0 O
. O
5 O
% O
to O
> O
12 O
% O
. O

In O
this O
survey O
, O
a O
model O
to O
make O
credible O
estimates O
of O
the O
extent O
of O
their O
study O
is O
proposed O
and O
is O
exemplified O
by O
applying O
it O
in O
a O
case O
study O
of O
plants O
native O
to O
Switzerland O
. O

Using O
a O
widely O
available O
database O
( O
SciFinder O
Scholar O
) O
, O
454 O
535 O
literature O
references O
for O
the O
2677 O
native O
Swiss O
plant O
species O
were O
retrieved O
. O

It O
was O
determined O
that O
55 O
% O
of O
these O
species O
have O
been O
investigated O
phytochemically O
and O
28 O
% O
for O
biological O
activity O
. O

The O
influence O
of O
factors O
such O
as O
commonness O
, O
growth O
form O
, O
habitat O
, O
medicinal O
use O
, O
and O
reported O
toxicity O
on O
the O
extent O
to O
which O
different O
plant O
groups O
have O
been O
studied O
is O
analyzed O
. O

The O
predictive O
value O
of O
random O
sampling O
of O
subsets O
of O
plants O
is O
compared O
to O
the O
study O
of O
the O
entire O
Swiss O
flora O
, O
to O
show O
that O
a O
credible O
estimate O
of O
the O
extent O
of O
prior O
studies O
can O
be O
achieved O
with O
just O
5 O
% O
of O
these O
species O
. O

Bioactive O
sesterterpenoids B
from O
a O
Korean O
sponge O
Monanchora O
sp O
. O

Chemical O
investigation O
of O
a O
Korean O
marine O
sponge O
, O
Monanchora O
sp O
. O
, O
yielded O
nine O
new O
sesterterpenoids B
( O
1 O
- O
9 O
) O
along O
with O
phorbaketals B
A I
- I
C I
( O
10 O
- O
12 O
) O
. O

The O
planar O
structures O
were O
established O
on O
the O
basis O
of O
NMR O
and O
MS O
analysis O
, O
and O
the O
absolute O
configurations O
of O
1 O
- O
9 O
were O
defined O
using O
the O
modified O
Mosher O
' O
s O
method O
and O
CD O
spectroscopic O
data O
analysis O
. O

Compounds O
1 O
- O
8 O
, O
designated O
as O
phorbaketals B
D I
- I
K I
, O
possess O
a O
spiroketal B
- O
modified O
benzopyran B
moiety O
such O
as O
phorbaketal B
A I
, O
and O
their O
structural O
variations O
are O
due O
to O
oxidation O
and O
/ O
or O
reduction O
of O
the O
tricyclic O
core O
or O
the O
side O
chain O
. O

Compound O
9 O
, O
designated O
as O
phorbin B
A I
, O
has O
a O
monocyclic O
structure O
and O
is O
proposed O
to O
be O
a O
possible O
biogenetic O
precursor O
of O
the O
phorbaketals B
. O

Compounds O
1 O
- O
9 O
were O
evaluated O
for O
cytotoxicity O
against O
four O
human O
cancer O
cell O
lines O
( O
A498 O
, O
ACHN O
, O
MIA O
- O
paca O
, O
and O
PANC O
- O
1 O
) O
, O
and O
a O
few O
of O
them O
were O
found O
to O
exhibit O
cytotoxic O
activity O
. O

Modulation O
of O
cytochrome O
P450 O
enzymes O
in O
response O
to O
continuous O
or O
intermittent O
high O
- O
fat O
diet O
in O
pigs O
. O

Abstract O
1 O
. O

To O
date O
, O
no O
information O
has O
been O
available O
on O
the O
modulation O
of O
cytochrome O
P450 O
enzymes O
( O
CYPs O
) O
following O
the O
administration O
of O
a O
hyperlipidemic O
diet O
in O
pigs O
. O

2 O
. O

We O
investigated O
the O
potential O
modulation O
of O
xenobiotic O
- O
metabolizing O
CYPs O
in O
liver O
, O
heart O
and O
duodenum O
of O
pigs O
subjected O
to O
a O
high O
- O
fat O
/ O
high O
- O
cholesterol B
diet O
for O
2 O
months O
continuously O
( O
C O
- O
HFD O
) O
or O
on O
alternate O
weeks O
( O
A O
- O
HFD O
) O
. O

3 O
. O

The O
administration O
of O
the O
high O
- O
fat O
diet O
resulted O
in O
considerably O
increased O
plasma O
cholesterol B
levels O
although O
the O
animals O
were O
still O
able O
to O
manage O
the O
lipid O
overload O
efficiently O
, O
and O
no O
sign O
of O
effective O
tissue O
inflammation O
occurred O
in O
livers O
. O

Plasma O
lipid O
profile O
and O
liver O
histology O
indicated O
a O
better O
adaptive O
response O
of O
the O
A O
- O
HFD O
pigs O
compared O
to O
the O
C O
- O
HFD O
group O
. O

We O
showed O
a O
post O
- O
transcriptional O
induction O
of O
hepatic O
CYP2E1 O
activity O
in O
C O
- O
HFD O
pigs O
and O
a O
transcriptional O
induction O
of O
hepatic O
CYP3As O
- O
especially O
in O
the O
A O
- O
HFD O
group O
. O

No O
further O
CYP O
modulation O
was O
observed O
in O
either O
liver O
or O
extra O
- O
hepatic O
tissues O
. O

4 O
. O

In O
conclusion O
, O
the O
administration O
of O
a O
high O
- O
fat O
diet O
in O
pigs O
resulted O
in O
limited O
effects O
on O
the O
drug O
metabolism O
system O
. O

The O
better O
adaptive O
response O
of O
A O
- O
HFD O
pigs O
compared O
to O
C O
- O
HFD O
pigs O
is O
a O
very O
interesting O
observation O
since O
the O
intermittent O
administration O
of O
the O
diet O
reflects O
the O
mode O
of O
human O
behavior O
more O
closely O
. O

Therapeutic O
potential O
of O
targeting O
lipid O
aldehydes B
and O
lipoxidation O
end O
- O
products O
in O
the O
treatment O
of O
ocular O
disease O
. O

Lipoxidation O
reactions O
and O
the O
subsequent O
accumulation O
of O
advanced O
lipoxidation O
end O
products O
( O
ALEs O
) O
have O
been O
implicated O
in O
the O
pathogenesis O
of O
many O
of O
the O
leading O
causes O
of O
visual O
impairment O
. O

Here O
, O
we O
begin O
by O
outlining O
some O
of O
the O
major O
lipid O
aldehydes B
produced O
through O
lipoxidation O
reactions O
, O
the O
ALEs O
formed O
upon O
their O
reaction O
with O
proteins O
, O
and O
the O
endogenous O
aldehyde B
metabolizing O
enzymes O
involved O
in O
protecting O
cells O
against O
lipoxidation O
mediated O
damage O
. O

Discussions O
are O
subsequently O
focused O
on O
the O
clinical O
and O
experimental O
evidence O
supporting O
the O
contribution O
of O
lipid O
aldehydes B
and O
ALEs O
in O
the O
development O
of O
ocular O
diseases O
. O

From O
these O
discussions O
, O
it O
is O
clear O
that O
inhibition O
of O
lipoxidation O
reactions O
and O
ALE O
formation O
could O
represent O
a O
new O
therapeutic O
avenue O
for O
the O
treatment O
of O
a O
broad O
range O
of O
ocular O
disorders O
. O

Current O
and O
emerging O
pharmacological O
strategies O
to O
prevent O
or O
neutralize O
the O
effects O
of O
lipid O
aldehydes B
and O
ALEs O
are O
therefore O
considered O
, O
with O
particular O
emphasis O
on O
the O
potential O
of O
these O
drugs O
for O
treatment O
of O
diseases O
of O
the O
eye O
. O

Exploring O
a O
new O
frontier O
in O
cancer O
treatment O
: O
targeting O
the O
ubiquitin O
and O
ubiquitin O
- O
like O
activating O
enzymes O
. O

The O
labeling O
of O
proteins O
with O
small O
ubiquitin O
( O
Ub O
) O
and O
ubiquitin O
- O
like O
( O
Ubl O
) O
modifiers O
regulates O
a O
plethora O
of O
activities O
within O
the O
cell O
, O
such O
as O
protein O
recycling O
, O
cell O
cycle O
modifications O
, O
and O
protein O
translocation O
. O

These O
processes O
are O
often O
overactive O
in O
diseased O
cells O
, O
leading O
to O
unregulated O
cell O
growth O
and O
disease O
progression O
. O

Therefore O
, O
in O
systems O
where O
Ub O
/ O
Ubl O
protein O
labeling O
is O
dysregulated O
, O
the O
development O
of O
drugs O
to O
selectively O
and O
potently O
disrupt O
Ub O
/ O
Ubl O
protein O
labeling O
offers O
a O
targeted O
molecular O
approach O
for O
sensitizing O
these O
diseased O
cells O
. O

This O
Perspective O
outlines O
the O
progress O
that O
has O
been O
made O
in O
the O
context O
of O
inhibitor O
development O
for O
targeting O
Ub O
/ O
Ubl O
pathways O
. O

Parallel O
nanometric O
3D O
tracking O
of O
intracellular O
gold O
nanorods O
using O
multifocal O
two O
- O
photon O
microscopy O
. O

We O
report O
a O
novel O
technique O
for O
long O
- O
term O
parallel O
three O
dimensional O
( O
3D O
) O
- O
tracking O
of O
gold O
nanorods O
in O
live O
cells O
with O
nanometer O
resolution O
. O

Gold O
nanorods O
feature O
a O
strong O
plasmon O
- O
enhanced O
two O
- O
photon O
luminescence O
, O
can O
be O
easily O
functionalized O
, O
and O
have O
been O
shown O
to O
be O
nontoxic O
. O

These O
properties O
make O
gold O
nanorods O
very O
suitable O
for O
in O
vivo O
two O
- O
photon O
luminescence O
microscopy O
. O

By O
rapid O
multifocal O
scanning O
, O
we O
combine O
the O
advantages O
of O
3D O
molecular O
tracking O
methods O
using O
wide O
- O
field O
imaging O
with O
the O
advantages O
of O
two O
- O
photon O
microscopy O
. O

Isolated O
gold O
nanorods O
can O
be O
localized O
with O
a O
resolution O
of O
4 O
nm O
in O
the O
xy O
- O
plane O
and O
8 O
nm O
in O
the O
z O
- O
direction O
. O

The O
polarization O
- O
dependence O
of O
the O
two O
- O
photon O
luminescence O
signal O
can O
be O
used O
to O
resolve O
the O
angular O
orientation O
, O
even O
when O
two O
gold O
nanorods O
are O
separated O
by O
less O
than O
the O
diffraction O
limit O
. O

Individual O
nanorods O
in O
live O
U2OS O
cells O
could O
be O
followed O
in O
3 O
dimensions O
for O
over O
30 O
min O
, O
with O
a O
photon O
noise O
limited O
accuracy O
, O
and O
a O
time O
resolution O
of O
50 O
ms O
in O
2D O
and O
500 O
ms O
in O
3D O
. O

Discovery O
of O
a O
potent O
and O
isoform O
- O
selective O
targeted O
covalent O
inhibitor O
of O
the O
lipid O
kinase O
PI3K O
alpha O
. O

PI3K O
alpha O
has O
been O
identified O
as O
an O
oncogene O
in O
human O
tumors O
. O

By O
use O
of O
rational O
drug O
design O
, O
a O
targeted O
covalent O
inhibitor O
3 O
( O
CNX B
- I
1351 I
) O
was O
created O
that O
potently O
and O
specifically O
inhibits O
PI3K O
alpha O
. O

We O
demonstrate O
, O
using O
mass O
spectrometry O
and O
X O
- O
ray O
crystallography O
, O
that O
the O
selective O
inhibitor O
covalently O
modifies O
PI3K O
alpha O
on O
cysteine B
862 O
( O
C862 O
) O
, O
an O
amino B
acid I
unique O
to O
the O
alpha O
isoform O
, O
and O
that O
PI3K O
beta O
, O
- O
gamma O
, O
and O
- O
delta O
are O
not O
covalently O
modified O
. O

3 O
is O
able O
to O
potently O
( O
EC O
( O
50 O
) O
< O
100 O
nM O
) O
and O
specifically O
inhibit O
signaling O
in O
PI3K O
alpha O
- O
dependent O
cancer O
cell O
lines O
, O
and O
this O
leads O
to O
a O
potent O
antiproliferative O
effect O
( O
GI O
( O
50 O
) O
< O
100 O
nM O
) O
. O

A O
covalent O
probe O
, O
8 O
( O
CNX B
- I
1220 I
) O
, O
which O
selectively O
bonds O
to O
PI3K O
alpha O
, O
was O
used O
to O
investigate O
the O
duration O
of O
occupancy O
of O
3 O
with O
PI3K O
alpha O
in O
vivo O
. O

This O
is O
the O
first O
report O
of O
a O
PI3K O
alpha O
- O
selective O
inhibitor O
, O
and O
these O
data O
demonstrate O
the O
biological O
impact O
of O
selectively O
targeting O
PI3K O
alpha O
. O

Synthesis O
and O
Structure O
- O
Activity O
Relationships O
of O
N B
- I
Methyl I
- I
5 I
, I
6 I
, I
7 I
- I
trimethoxylindoles I
as O
Novel O
Antimitotic O
and O
Vascular O
Disrupting O
Agents O
. O

Several O
new O
series O
of O
5 B
, I
6 I
, I
7 I
- I
trimethoxyindole I
derivatives O
were O
synthesized O
and O
their O
structure O
- O
activity O
relationships O
( O
SARs O
) O
were O
studied O
. O

Some O
of O
these O
compounds O
exhibited O
strong O
antiproliferative O
activities O
in O
the O
submicromolar O
range O
. O

N B
- I
Methyl I
- I
5 I
, I
6 I
, I
7 I
- I
trimethoxylindoles I
21 O
and O
31 O
displayed O
the O
highest O
antiproliferative O
activities O
, O
with O
IC O
( O
50 O
) O
values O
ranging O
from O
22 O
to O
125 O
nM O
in O
four O
human O
cancer O
cell O
lines O
and O
activated O
human O
umbilical O
vein O
endothelial O
cells O
( O
HUVECs O
) O
. O

In O
addition O
to O
vascular O
disrupting O
activity O
verified O
by O
in O
vitro O
assays O
, O
compounds O
21 O
and O
31 O
displayed O
much O
higher O
selectivity O
for O
activated O
HUVECs O
versus O
quiescent O
HUVECs O
than O
those O
of O
colchicine B
and O
combretastatinA B
- I
4 I
. O

The O
polymerization O
of O
cancer O
cell O
tubulin O
was O
inhibited O
and O
the O
cell O
cycle O
was O
arrested O
in O
the O
G2 O
/ O
M O
phase O
after O
treatment O
with O
21 O
and O
31 O
. O

It O
was O
showed O
that O
21 O
disrupted O
tumor O
vasculature O
by O
use O
of O
in O
vivo O
assay O
. O

Our O
results O
suggest O
that O
these O
two O
new O
compounds O
we O
synthesized O
may O
become O
the O
promising O
leads O
for O
the O
development O
of O
vascular O
disrupting O
agents O
. O

Bisphenol B
A I
activates O
the O
Nrf1 O
/ O
2 O
- O
antioxidant O
response O
element O
pathway O
in O
HEK O
293 O
cells O
. O

Bisphenol B
A I
( O
BPA B
) O
is O
used O
in O
the O
production O
of O
polycarbonate B
plastics O
and O
epoxy B
resins O
for O
baby O
bottles O
, O
liners O
of O
canned O
food O
, O
and O
many O
other O
consumer O
products O
. O

Previously O
, O
BPA B
has O
been O
shown O
to O
reduce O
the O
activity O
of O
several O
antioxidant O
enzymes O
, O
which O
may O
contribute O
to O
oxidative O
stress O
. O

However O
, O
the O
underlying O
mechanism O
of O
the O
BPA B
- O
mediated O
effect O
upon O
antioxidant O
enzyme O
activity O
is O
unknown O
. O

Antioxidant O
and O
phase O
II O
metabolizing O
enzymes O
protect O
cells O
from O
oxidative O
stress O
and O
are O
transcriptionally O
activated O
by O
Nrf1 O
and O
Nrf2 O
factors O
through O
their O
cis O
- O
regulatory O
antioxidant O
response O
elements O
( O
AREs O
) O
. O

In O
this O
work O
, O
we O
have O
assessed O
the O
effect O
of O
BPA B
on O
the O
Nrf1 O
/ O
2 O
- O
ARE O
pathway O
in O
cultured O
human O
embryonic O
kidney O
( O
HEK O
) O
293 O
cells O
. O

Surprisingly O
, O
glutathione B
and O
reactive O
oxygen B
species O
( O
ROS O
) O
assays O
revealed O
that O
BPA B
application O
created O
a O
more O
reduced O
intracellular O
environment O
in O
cultured O
HEK O
293 O
cells O
. O

Furthermore O
, O
BPA B
increased O
the O
transactivation O
activity O
of O
ectopic O
Nrf1 O
and O
Nrf2 O
and O
increased O
the O
expression O
of O
ARE O
- O
target O
genes O
ho O
- O
1 O
and O
nqo1 O
at O
high O
( O
100 O
- O
200 O
mu O
M O
) O
BPA B
concentrations O
only O
. O

Our O
study O
suggests O
that O
BPA B
activates O
the O
Nrf1 O
/ O
2 O
- O
ARE O
pathway O
at O
high O
( O
> O
10 O
mu O
M O
) O
micromolar O
concentrations O
. O

Organoselenium B
compounds O
modulate O
extracellular O
redox O
by O
induction O
of O
extracellular O
cysteine B
and O
cell O
surface O
thioredoxin O
reductase O
. O

The O
effect O
of O
selenium B
compounds O
on O
extracellular O
redox O
modulating O
capacity O
was O
studied O
in O
murine O
macrophage O
RAW O
264 O
. O
7 O
cells O
and O
differentiated O
human O
THP O
- O
1 O
monocytes O
. O

The O
arylselenium B
compounds O
benzeneselenol B
( O
PhSeH B
) O
, O
dibenzyl B
diselenide I
( O
DBDSe B
) O
, O
diphenyl B
diselenide I
( O
DPDSe B
) O
, O
and O
ebselen B
were O
capable O
of O
inducing O
extracellular O
cysteine B
accumulation O
via O
a O
cystine B
- O
and O
glucose B
- O
dependent O
process O
. O

Extracellular O
cysteine B
production O
was O
dose O
- O
dependently O
inhibited O
by O
glutamate B
, O
an O
inhibitor O
of O
cystine B
/ O
glutamate B
antiporter O
( O
Xc O
( O
- O
) O
transporter O
) O
, O
supporting O
the O
involvement O
of O
Xc O
( O
- O
) O
transporter O
for O
cystine B
uptake O
in O
the O
above O
process O
. O

These O
arylselenium B
compounds O
also O
induced O
cellular O
thioredoxin O
reductase O
( O
TrxR O
) O
expression O
, O
particularly O
at O
the O
exofacial O
surface O
of O
cells O
. O

TrxR1 O
knockdown O
using O
small O
interfering O
RNA O
attenuated O
TrxR O
increases O
and O
cysteine B
efflux O
induced O
in O
cells O
by O
DPDSe O
. O

Sodium B
selenite I
( O
Na2SeO3 B
) O
, O
selenomethionine B
( O
SeMet B
) O
, O
seleno B
- I
l I
- I
cystine I
( O
SeCySS B
) O
, O
and O
Se B
- I
methylselenocysteine I
( O
MeSeCys B
) O
did O
not O
have O
these O
effects O
on O
macrophages O
under O
the O
same O
treatment O
conditions O
. O

The O
effects O
of O
organoselenium B
compounds O
on O
extracellular O
redox O
may O
contribute O
to O
the O
known O
, O
but O
inadequately O
understood O
, O
biological O
effects O
of O
selenium B
compounds O
. O

A O
nonribosomal O
peptide O
synthetase O
- O
derived O
iron B
( I
III I
) I
complex O
from O
the O
pathogenic O
fungus O
Aspergillus O
fumigatus O
. O

Small O
molecules O
( O
SMs O
) O
play O
central O
roles O
as O
virulence O
factors O
of O
pathogenic O
fungi O
and O
bacteria O
; O
however O
, O
genomic O
analyses O
suggest O
that O
the O
majority O
of O
microbial O
SMs O
have O
remained O
uncharacterized O
. O

Based O
on O
microarray O
analysis O
followed O
by O
comparative O
metabolomics O
of O
overexpression O
/ O
knockout O
mutants O
, O
we O
identified O
a O
tryptophan B
- O
derived O
iron B
( I
III I
) I
- O
complex O
, O
hexadehydro B
- I
astechrome I
( O
HAS B
) O
, O
as O
the O
major O
product O
of O
the O
cryptic O
has O
nonribosomal O
peptide O
synthetase O
( O
NRPS O
) O
gene O
cluster O
in O
the O
human O
pathogen O
Aspergillus O
fumigatus O
. O

Activation O
of O
the O
has O
cluster O
created O
a O
highly O
virulent O
A O
. O
fumigatus O
strain O
that O
increased O
mortality O
of O
infected O
mice O
. O

Comparative O
metabolomics O
of O
different O
mutant O
strains O
allowed O
to O
propose O
a O
pathway O
for O
HAS O
biosynthesis O
and O
further O
revealed O
cross O
- O
talk O
with O
another O
NRPS O
pathway O
producing O
the O
anticancer O
fumitremorgins B
. O

Intracellular O
drug O
concentrations O
. O

Many O
drug O
targets O
are O
intracellular O
. O

To O
access O
them O
, O
a O
drug O
molecule O
must O
pass O
through O
the O
cell O
membrane O
, O
a O
process O
often O
facilitated O
or O
impeded O
by O
transporters O
. O

Once O
in O
the O
cytoplasm O
, O
basic O
molecules O
may O
become O
concentrated O
in O
organelles O
. O

To O
predict O
the O
pharmacologic O
effect O
accurately O
, O
there O
must O
be O
data O
concerning O
the O
concentration O
at O
the O
target O
, O
which O
is O
difficult O
to O
measure O
. O

Techniques O
that O
combine O
mass O
spectrometry O
and O
imaging O
techniques O
( O
matrix O
- O
assisted O
laser O
desorption O
/ O
ionization O
, O
secondary O
ion O
mass O
spectrometry O
( O
SIMS O
) O
, O
and O
nanoSIMS O
) O
have O
promise O
in O
addressing O
this O
problem O
. O

Emerging O
lymphae O
for O
the O
fountain O
of O
life O
. O

The O
lymphatic O
system O
is O
indispensable O
for O
the O
collection O
and O
cycling O
of O
tissue O
- O
extravasated O
fluids O
, O
macromolecules O
and O
immune O
cells O
into O
the O
bloodstream O
. O

Different O
mechanisms O
, O
including O
sprouting O
, O
ballooning O
and O
budding O
of O
lymphatic O
endothelial O
cells O
from O
the O
cardinal O
vein O
, O
have O
been O
proposed O
for O
lymphatic O
vessel O
formation O
during O
mammalial O
embryogenesis O
. O

H O
a O
gerling O
et O
al O
( O
2013 O
) O
now O
provide O
a O
cell O
- O
scale O
model O
of O
lymphoangiogenesis O
by O
applying O
selective O
plane O
illumination O
- O
based O
ultramicroscopy O
( O
Becker O
et O
al O
, O
2008 O
) O
to O
wholemount O
- O
immunostained O
mouse O
embryos O
. O

They O
describe O
VEGFR O
- O
3 O
, O
VEGF O
- O
C O
and O
CCBE1 O
as O
key O
regulators O
of O
lymphatic O
endothelial O
cell O
budding O
and O
migration O
at O
the O
early O
emergence O
of O
lymphatics O
from O
venous O
endothelium O
. O

Narrow O
bandgap O
colloidal O
metal B
chalcogenide I
quantum O
dots O
: O
synthetic O
methods O
, O
heterostructures O
, O
assemblies O
, O
electronic O
and O
infrared O
optical O
properties O
. O

The O
chemistry O
, O
material O
processing O
and O
fundamental O
understanding O
of O
colloidal O
semiconductor O
nanocrystals O
( O
quantum O
dots O
) O
are O
advancing O
at O
an O
astounding O
rate O
, O
bringing O
the O
prospects O
of O
widespread O
commercialization O
of O
these O
novel O
and O
exciting O
materials O
ever O
closer O
. O

Interest O
in O
narrow O
bandgap O
nanocrystals O
in O
particular O
has O
intensified O
in O
recent O
years O
, O
and O
the O
results O
of O
research O
worldwide O
point O
to O
the O
realistic O
prospects O
of O
applications O
for O
these O
materials O
in O
solar O
cells O
, O
infrared O
optoelectronics O
( O
e O
. O
g O
. O
lasers O
, O
optical O
modulators O
, O
photodetectors O
and O
photoimaging O
devices O
) O
, O
low O
cost O
/ O
large O
format O
microelectronics O
, O
and O
in O
biological O
imaging O
and O
biosensor O
systems O
to O
name O
only O
some O
technologies O
. O

Improvements O
in O
fundamental O
understanding O
and O
material O
quality O
are O
built O
on O
a O
vast O
body O
of O
experience O
spread O
over O
many O
different O
methods O
of O
colloidal O
synthetic O
growth O
, O
each O
with O
their O
own O
strengths O
and O
weaknesses O
for O
different O
materials O
and O
sometimes O
with O
regard O
to O
particular O
applications O
. O

The O
nanocrystal O
growth O
expertise O
is O
matched O
by O
a O
rapidly O
expanding O
, O
and O
highly O
interdisciplinary O
, O
understanding O
of O
how O
best O
to O
assemble O
these O
materials O
into O
films O
or O
hybrid O
composites O
and O
thereby O
into O
useful O
devices O
, O
and O
again O
there O
are O
many O
different O
strategies O
that O
can O
be O
adopted O
. O

In O
this O
review O
we O
have O
attempted O
to O
survey O
and O
compare O
the O
recent O
work O
on O
colloidal O
synthesis O
, O
film O
and O
nanocrystal O
composite O
material O
fabrication O
, O
concentrating O
on O
narrow O
bandgap O
chalcogenide O
materials O
and O
some O
of O
their O
topical O
applications O
in O
the O
solar O
energy O
and O
biological O
fields O
. O

Since O
these O
applications O
are O
attracting O
rising O
interest O
across O
a O
wide O
range O
of O
disciplines O
, O
from O
the O
biological O
sciences O
, O
device O
engineering O
, O
and O
materials O
processing O
fields O
as O
well O
as O
the O
physics O
and O
synthetic O
chemistry O
communities O
, O
we O
have O
endeavoured O
to O
make O
the O
review O
of O
these O
narrow O
bandgap O
nanomaterials O
both O
comprehensive O
and O
accessible O
to O
newcomers O
to O
the O
area O
. O

Identification O
of O
a O
small O
- O
molecule O
inhibitor O
of O
HIV O
- O
1 O
assembly O
that O
targets O
the O
phosphatidylinositol B
( I
4 I
, I
5 I
) I
- I
bisphosphate I
binding O
site O
of O
the O
HIV O
- O
1 O
matrix O
protein O
. O

The O
development O
of O
drug O
resistance O
remains O
a O
critical O
problem O
for O
current O
HIV O
- O
1 O
antiviral O
therapies O
, O
creating O
a O
need O
for O
new O
inhibitors O
of O
HIV O
- O
1 O
replication O
. O

We O
previously O
reported O
on O
a O
novel O
anti O
- O
HIV O
- O
1 O
compound O
, O
N B
( I
2 I
) I
- I
( I
phenoxyacetyl I
) I
- I
N I
- I
[ I
4 I
- I
( I
1 I
- I
piperidinylcarbonyl I
) I
benzyl I
] I
glycinamide I
( O
14 O
) O
, O
that O
binds O
to O
the O
highly O
conserved O
phosphatidylinositol B
( I
4 I
, I
5 I
) I
- I
bisphosphate I
( O
PI B
( I
4 I
, I
5 I
) I
P I
( I
2 I
) I
) O
binding O
pocket O
of O
the O
HIV O
- O
1 O
matrix O
( O
MA O
) O
protein O
. O

In O
this O
study O
, O
we O
re O
- O
evaluate O
the O
hits O
from O
the O
virtual O
screen O
used O
to O
identify O
compound O
14 O
and O
test O
them O
directly O
in O
an O
HIV O
- O
1 O
replication O
assay O
using O
primary O
human O
peripheral O
blood O
mononuclear O
cells O
. O

This O
study O
resulted O
in O
the O
identification O
of O
three O
new O
compounds O
with O
antiviral O
activity O
; O
2 B
- I
( I
4 I
- I
{ I
[ I
3 I
- I
( I
4 I
- I
fluorophenyl I
) I
- I
1 I
, I
2 I
, I
4 I
- I
oxadiazol I
- I
5 I
- I
yl I
] I
methyl I
} I
) I
- I
1 I
- I
piperazinyl I
) I
- I
N I
- I
( I
4 I
- I
methylphenyl I
) I
acetamide I
( O
7 O
) O
, O
3 B
- I
( I
2 I
- I
ethoxyphenyl I
) I
- I
5 I
- I
[ I
[ I
4 I
- I
( I
4 I
- I
nitrophenyl I
) I
piperazin I
- I
1 I
- I
yl I
] I
methyl I
] I
- I
1 I
, I

2 I
, I
4 I
- I
oxadiazole I
( O
17 O
) O
, O
and O
N B
- I
[ I
4 I
- I
ethoxy I
- I
3 I
- I
( I
1 I
- I
piperidinylsulfonyl I
) I
phenyl I
] I
- I
2 I
- I
( I
imidazo I
[ I
2 I
, I
1 I
- I
b I
] I
[ I
1 I
, I
3 I
] I
thiazol I
- I
6 I
- I
yl I
) I
acetamide I
( O
18 O
) O
, O
with O
compound O
7 O
being O
the O
most O
potent O
of O
these O
hits O
. O

Mechanistic O
studies O
on O
7 O
demonstrated O
that O
it O
directly O
interacts O
with O
and O
functions O
through O
HIV O
- O
1 O
MA O
. O

In O
accordance O
with O
our O
drug O
target O
, O
compound O
7 O
competes O
with O
PI B
( I
4 I
, I
5 I
) I
P I
( I
2 I
) I
for O
MA O
binding O
and O
, O
as O
a O
result O
, O
diminishes O
the O
production O
of O
new O
virus O
. O

Mutation O
of O
residues O
within O
the O
PI B
( I
4 I
, I
5 I
) I
P I
( I
2 I
) I
binding O
site O
of O
MA O
decreased O
the O
antiviral O
effect O
of O
compound O
7 O
. O

Additionally O
, O
compound O
7 O
displays O
a O
broadly O
neutralizing O
anti O
- O
HIV O
activity O
, O
with O
IC O
( O
50 O
) O
values O
of O
7 O
. O
5 O
- O
15 O
. O
6 O
mu O
M O
for O
the O
group O
M O
isolates O
tested O
. O

Taken O
together O
, O
these O
results O
point O
towards O
a O
novel O
chemical O
probe O
that O
can O
be O
used O
to O
more O
closely O
study O
the O
biological O
role O
of O
MA O
and O
could O
, O
through O
further O
optimization O
, O
lead O
to O
a O
new O
class O
of O
anti O
- O
HIV O
- O
1 O
therapeutics O
. O

CrbpI O
regulates O
mammary O
retinoic B
acid I
homeostasis O
and O
the O
mammary O
microenvironment O
. O

Cellular O
retinol B
- O
binding O
protein O
, O
type O
I O
( O
CrbpI O
) O
, O
encoded O
by O
retinol B
- O
binding O
protein O
, O
type O
1 O
( O
Rbp1 O
) O
, O
is O
a O
chaperone O
of O
vitamin B
A I
( O
retinol B
) O
that O
is O
epigenetically O
silenced O
in O
~ O
25 O
% O
of O
human O
breast O
cancers O
. O

CrbpI O
delivers O
vitamin B
A I
to O
enzymes O
for O
metabolism O
into O
an O
active O
metabolite O
, O
all B
- I
trans I
retinoic I
acid I
( O
atRA B
) O
, O
where O
atRA B
is O
essential O
to O
cell O
proliferation O
, O
apoptosis O
, O
differentiation O
, O
and O
migration O
. O

Here O
, O
we O
show O
the O
effect O
of O
CrbpI O
loss O
on O
mammary O
atRA B
homeostasis O
using O
the O
Rbp1 O
( O
- O
/ O
- O
) O
mouse O
model O
. O

Rbp1 O
( O
- O
/ O
- O
) O
mouse O
mammary O
tissue O
has O
disrupted O
retinoid B
homeostasis O
that O
results O
in O
40 O
% O
depleted O
endogenous O
atRA B
. O

CrbpI O
loss O
and O
atRA B
depletion O
precede O
defects O
in O
atRA B
biosynthesis O
enzyme O
expression O
. O

Compensation O
by O
CrbpIII O
as O
a O
retinoid B
chaperone O
does O
not O
functionally O
replace O
CrbpI O
. O

Mammary O
subcellular O
fractions O
isolated O
from O
Rbp1 O
( O
- O
/ O
- O
) O
mice O
have O
altered O
retinol B
dehydrogenase O
/ O
reductase O
( O
Rdh O
) O
enzyme O
activity O
that O
results O
in O
24 O
- O
42 O
% O
less O
atRA B
production O
. O

Rbp1 O
( O
- O
/ O
- O
) O
mammary O
tissue O
has O
epithelial O
hyperplasia O
, O
stromal O
hypercellularity O
, O
increased O
collagen O
, O
and O
increased O
oxidative O
stress O
characteristic O
of O
atRA B
deficiency O
and O
early O
tissue O
dysfunction O
that O
precedes O
tumor O
formation O
. O

Consistent O
with O
the O
findings O
from O
the O
Rbp1 O
( O
- O
/ O
- O
) O
mouse O
, O
tumorigenic O
epithelial O
cells O
lacking O
CrbpI O
expression O
produce O
51 O
% O
less O
atRA B
. O

Together O
, O
these O
data O
show O
that O
CrbpI O
loss O
disrupts O
atRA B
homeostasis O
in O
mammary O
tissue O
, O
resulting O
in O
microenvironmental O
defects O
similar O
to O
those O
observed O
at O
the O
early O
stages O
of O
tumorigenesis O
. O
- O
Pierzchalski O
, O
K O
. O
, O
Yu O
, O
J O
. O
, O
Norman O
, O
V O
. O
, O
Kane O
, O
M O
. O

A O
. O

CrbpI O
regulates O
mammary O
retinoic B
acid I
homeostasis O
and O
the O
mammary O
microenvironment O
. O

Small O
- O
molecule O
- O
mediated O
axonal O
branching O
in O
Caenorhabditis O
elegans O
. O

An O
in O
vivo O
system O
for O
monitoring O
small O
- O
molecule O
- O
mediated O
neuronal O
branching O
has O
been O
developed O
by O
using O
C O
. O
elegans O
. O

Growth O
- O
promoting O
compounds O
can O
be O
detected O
by O
visual O
inspection O
of O
GFPlabeled O
cholinergic O
neurons O
, O
as O
axonal O
branching O
occurs O
following O
treatment O
with O
neurotrophic O
agents O
. O

Investigation O
of O
the O
structure O
- O
activity O
relationship O
of O
the O
neurotrophic O
natural O
product O
clovanemagnolol B
( O
1 O
) O
led O
us O
to O
a O
comparable O
chemically O
edited O
derivative O
. O

Multifarious O
roles O
of O
intrinsic O
disorder O
in O
proteins O
illustrate O
its O
broad O
impact O
on O
plant O
biology O
. O

Intrinsically O
disordered O
proteins O
( O
IDPs O
) O
are O
highly O
abundant O
in O
eukaryotic O
proteomes O
. O

Plant O
IDPs O
play O
critical O
roles O
in O
plant O
biology O
and O
often O
act O
as O
integrators O
of O
signals O
from O
multiple O
plant O
regulatory O
and O
environmental O
inputs O
. O

Binding O
promiscuity O
and O
plasticity O
allow O
IDPs O
to O
interact O
with O
multiple O
partners O
in O
protein O
interaction O
networks O
and O
provide O
important O
functional O
advantages O
in O
molecular O
recognition O
through O
transient O
protein O
- O
protein O
interactions O
. O

Short O
interaction O
- O
prone O
segments O
within O
IDPs O
, O
termed O
molecular O
recognition O
features O
, O
represent O
potential O
binding O
sites O
that O
can O
undergo O
disorder O
- O
to O
- O
order O
transition O
upon O
binding O
to O
their O
partners O
. O

In O
this O
review O
, O
we O
summarize O
the O
evidence O
for O
the O
importance O
of O
IDPs O
in O
plant O
biology O
and O
evaluate O
the O
functions O
associated O
with O
intrinsic O
disorder O
in O
five O
different O
types O
of O
plant O
protein O
families O
experimentally O
confirmed O
as O
IDPs O
. O

Functional O
studies O
of O
these O
proteins O
illustrate O
the O
broad O
impact O
of O
disorder O
on O
many O
areas O
of O
plant O
biology O
, O
including O
abiotic O
stress O
, O
transcriptional O
regulation O
, O
light O
perception O
, O
and O
development O
. O

Based O
on O
the O
roles O
of O
disorder O
in O
the O
protein O
- O
protein O
interactions O
, O
we O
propose O
various O
modes O
of O
action O
for O
plant O
IDPs O
that O
may O
provide O
insight O
for O
future O
experimental O
approaches O
aimed O
at O
understanding O
the O
molecular O
basis O
of O
protein O
function O
within O
important O
plant O
pathways O
. O

Mutations O
in O
the O
putative O
dimer O
- O
dimer O
interfaces O
of O
the O
measles O
virus O
hemagglutinin O
head O
domain O
affect O
membrane O
fusion O
triggering O
. O

Measles O
virus O
( O
MV O
) O
, O
an O
enveloped O
RNA O
virus O
belonging O
to O
the O
Paramyxoviridae O
family O
, O
enters O
the O
cell O
through O
membrane O
fusion O
mediated O
by O
two O
viral O
envelope O
proteins O
, O
an O
attachment O
protein O
hemagglutinin O
( O
H O
) O
and O
a O
fusion O
( O
F O
) O
protein O
. O

The O
crystal O
structure O
of O
the O
receptor O
- O
binding O
head O
domain O
of O
MV O
- O
H O
bound O
to O
its O
cellular O
receptor O
revealed O
that O
the O
MV O
- O
H O
head O
domain O
forms O
a O
tetrameric O
assembly O
( O
dimer O
of O
dimers O
) O
, O
which O
occurs O
in O
two O
forms O
( O
forms O
I O
and O
II O
) O
. O

In O
this O
study O
, O
we O
show O
that O
mutations O
in O
the O
putative O
dimer O
- O
dimer O
interface O
of O
the O
head O
domain O
in O
either O
form O
inhibit O
the O
ability O
of O
MV O
- O
H O
to O
support O
membrane O
fusion O
, O
without O
greatly O
affecting O
its O
cell O
surface O
expression O
, O
receptor O
binding O
, O
and O
interaction O
with O
the O
F O
protein O
. O

Notably O
, O
some O
anti O
- O
MV O
- O
H O
neutralizing O
monoclonal O
antibodies O
are O
directed O
to O
the O
region O
around O
the O
dimer O
- O
dimer O
interface O
in O
form O
I O
rather O
than O
receptor O
- O
binding O
sites O
. O

These O
observations O
suggest O
that O
the O
dimer O
- O
dimer O
interactions O
of O
the O
MV O
- O
H O
head O
domain O
, O
especially O
that O
in O
form O
I O
, O
contribute O
to O
triggering O
membrane O
fusion O
, O
and O
that O
conformational O
shift O
of O
head O
domain O
tetramers O
plays O
a O
role O
in O
the O
process O
. O

Furthermore O
, O
our O
results O
indicate O
that O
although O
the O
stalk O
and O
transmembrane O
regions O
may O
be O
mainly O
responsible O
for O
the O
tetramer O
formation O
of O
MV O
- O
H O
, O
the O
head O
domain O
alone O
can O
form O
tetramers O
, O
albeit O
at O
a O
low O
efficiency O
. O

Sialylneolacto B
- I
N I
- I
tetraose I
c I
( O
LSTc B
) O
- O
bearing O
liposomal O
decoys O
capture O
influenza O
A O
virus O
. O

Influenza O
is O
a O
severe O
disease O
in O
humans O
and O
animals O
with O
few O
effective O
therapies O
available O
. O

All O
strains O
of O
influenza O
virus O
are O
prone O
to O
developing O
drug O
resistance O
due O
to O
the O
high O
mutation O
rate O
in O
the O
viral O
genome O
. O

A O
therapeutic O
agent O
that O
targets O
a O
highly O
conserved O
region O
of O
the O
virus O
could O
bypass O
resistance O
and O
also O
be O
effective O
against O
multiple O
strains O
of O
influenza O
. O

Influenza O
uses O
many O
individually O
weak O
ligand O
binding O
interactions O
for O
a O
high O
avidity O
multivalent O
attachment O
to O
sialic B
acid I
- O
bearing O
cells O
. O

Polymerized O
sialic B
acid I
analogs O
can O
form O
multivalent O
interactions O
with O
influenza O
but O
are O
not O
ideal O
therapeutics O
due O
to O
solubility O
and O
toxicity O
issues O
. O

We O
used O
liposomes O
as O
a O
novel O
means O
for O
delivery O
of O
the O
glycan O
sialylneolacto B
- I
N I
- I
tetraose I
c I
( O
LSTc B
) O
. O

LSTc B
- O
bearing O
decoy O
liposomes O
form O
multivalent O
, O
polymer O
- O
like O
interactions O
with O
influenza O
virus O
. O

Decoy O
liposomes O
competitively O
bind O
influenza O
virus O
in O
hemagglutination O
inhibition O
assays O
and O
inhibit O
infection O
of O
target O
cells O
in O
a O
dose O
- O
dependent O
manner O
. O

Inhibition O
is O
specific O
for O
influenza O
virus O
, O
as O
inhibition O
of O
Sendai O
virus O
and O
respiratory O
syncytial O
virus O
is O
not O
observed O
. O

In O
contrast O
, O
monovalent O
LSTc O
does O
not O
bind O
influenza O
virus O
or O
inhibit O
infectivity O
. O

LSTc O
decoy O
liposomes O
prevent O
the O
spread O
of O
influenza O
virus O
during O
multiple O
rounds O
of O
replication O
in O
vitro O
and O
extend O
survival O
of O
mice O
challenged O
with O
a O
lethal O
dose O
of O
virus O
. O

LSTc O
decoy O
liposomes O
co O
- O
localize O
with O
fluorescently O
tagged O
influenza O
virus O
, O
whereas O
control O
liposomes O
do O
not O
. O

Considering O
the O
conservation O
of O
the O
hemagglutinin O
binding O
pocket O
and O
the O
ability O
of O
decoy O
liposomes O
to O
form O
high O
avidity O
interactions O
with O
influenza O
hemagglutinin O
, O
our O
decoy O
liposomes O
have O
potential O
as O
a O
new O
therapeutic O
agent O
against O
emerging O
influenza O
strains O
. O

Evidence O
for O
metal O
- O
surface O
interactions O
and O
their O
role O
in O
stabilizing O
well O
- O
defined O
immobilized O
Ru B
- O
NHC B
alkene O
metathesis O
catalysts O
. O

Secondary O
interactions O
are O
demonstrated O
to O
direct O
the O
stability O
of O
well O
- O
defined O
Ru B
- O
NHC B
- O
based O
heterogeneous O
alkene O
metathesis O
catalysts O
. O

By O
providing O
key O
stabilization O
of O
the O
active O
sites O
, O
higher O
catalytic O
performance O
is O
achieved O
. O

Specifically O
, O
they O
can O
be O
described O
as O
interactions O
between O
the O
metal O
center O
( O
active O
site O
) O
and O
the O
surface O
functionality O
of O
the O
support O
, O
and O
they O
have O
been O
detected O
by O
surface O
- O
enhanced O
( B
1 I
) I
H I
- O
( B
29 I
) I
Si I
NMR O
spectroscopy O
of O
the O
ligand O
and O
( B
31 I
) I
P I
solid O
- O
state O
NMR O
of O
the O
catalyst O
precursor O
. O

They O
are O
present O
only O
when O
the O
metal O
center O
is O
attached O
to O
the O
surface O
via O
a O
flexible O
linker O
( O
a O
propyl B
group O
) O
, O
which O
allows O
the O
active O
site O
to O
either O
react O
with O
the O
substrate O
or O
relax O
, O
reversibly O
, O
to O
the O
surface O
, O
thus O
providing O
stability O
. O

In O
contrast O
, O
the O
use O
of O
a O
rigid O
linker O
( O
here O
mesitylphenyl B
) O
leads O
to O
a O
well O
- O
defined O
active O
site O
far O
away O
from O
the O
surface O
, O
stabilized O
only O
by O
a O
phosphine B
ligand O
which O
under O
reaction O
conditions O
leaves O
probably O
irreversibly O
, O
leading O
to O
faster O
decomposition O
and O
deactivation O
of O
the O
catalysts O
. O

Intercalation O
pathway O
in O
many O
- O
particle O
LiFePO4 B
electrode O
revealed O
by O
nanoscale O
state O
- O
of O
- O
charge O
mapping O
. O

The O
intercalation O
pathway O
of O
lithium B
iron I
phosphate I
( O
LFP B
) O
in O
the O
positive O
electrode O
of O
a O
lithium B
- O
ion O
battery O
was O
probed O
at O
the O
~ O
40 O
nm O
length O
scale O
using O
oxidation O
- O
state O
- O
sensitive O
X O
- O
ray O
microscopy O
. O

Combined O
with O
morphological O
observations O
of O
the O
same O
exact O
locations O
using O
transmission O
electron O
microscopy O
, O
we O
quantified O
the O
local O
state O
- O
of O
- O
charge O
of O
approximately O
450 O
individual O
LFP O
particles O
over O
nearly O
the O
entire O
thickness O
of O
the O
porous O
electrode O
. O

With O
the O
electrode O
charged O
to O
50 O
% O
state O
- O
of O
- O
charge O
in O
0 O
. O
5 O
h O
, O
we O
observed O
that O
the O
overwhelming O
majority O
of O
particles O
were O
either O
almost O
completely O
delithiated O
or O
lithiated O
. O

Specifically O
, O
only O
~ O
2 O
% O
of O
individual O
particles O
were O
at O
an O
intermediate O
state O
- O
of O
- O
charge O
. O

From O
this O
small O
fraction O
of O
particles O
that O
were O
actively O
undergoing O
delithiation O
, O
we O
conclude O
that O
the O
time O
needed O
to O
charge O
a O
particle O
is O
~ O
1 O
/ O
50 O
the O
time O
needed O
to O
charge O
the O
entire O
particle O
ensemble O
. O

Surprisingly O
, O
we O
observed O
a O
very O
weak O
correlation O
between O
the O
sequence O
of O
delithiation O
and O
the O
particle O
size O
, O
contrary O
to O
the O
common O
expectation O
that O
smaller O
particles O
delithiate O
before O
larger O
ones O
. O

Our O
quantitative O
results O
unambiguously O
confirm O
the O
mosaic O
( O
particle O
- O
by O
- O
particle O
) O
pathway O
of O
intercalation O
and O
suggest O
that O
the O
rate O
- O
limiting O
process O
of O
charging O
is O
initiating O
the O
phase O
transformation O
by O
, O
for O
example O
, O
a O
nucleation O
- O
like O
event O
. O

Therefore O
, O
strategies O
for O
further O
enhancing O
the O
performance O
of O
LFP O
electrodes O
should O
not O
focus O
on O
increasing O
the O
phase O
- O
boundary O
velocity O
but O
on O
the O
rate O
of O
phase O
- O
transformation O
initiation O
. O

Pharmacological O
chaperones O
as O
therapeutics O
for O
lysosomal O
storage O
diseases O
. O

Lysosomal O
enzymes O
are O
responsible O
for O
the O
degradation O
of O
a O
wide O
variety O
of O
glycolipids O
, O
oligosaccharides O
, O
proteins O
, O
and O
glycoproteins O
. O

Inherited O
mutations O
in O
the O
genes O
that O
encode O
these O
proteins O
can O
lead O
to O
reduced O
stability O
of O
newly O
synthesized O
lysosomal O
enzymes O
. O

While O
often O
catalytically O
competent O
, O
the O
mutated O
enzymes O
are O
unable O
to O
efficiently O
pass O
the O
quality O
control O
mechanisms O
of O
the O
endoplasmic O
reticulum O
, O
resulting O
in O
reduced O
lysosomal O
trafficking O
, O
substrate O
accumulation O
, O
and O
cellular O
dysfunction O
. O

Pharmacological O
chaperones O
( O
PCs O
) O
are O
small O
molecules O
that O
bind O
and O
stabilize O
mutant O
lysosomal O
enzymes O
, O
thereby O
allowing O
proper O
cellular O
translocation O
. O

Such O
compounds O
have O
been O
shown O
to O
increase O
enzyme O
activity O
and O
reduce O
substrate O
burden O
in O
a O
number O
of O
preclinical O
models O
and O
clinical O
studies O
. O

In O
this O
Perspective O
, O
we O
review O
several O
of O
the O
lysosomal O
diseases O
for O
which O
PCs O
have O
been O
studied O
and O
the O
SAR O
of O
the O
various O
classes O
of O
molecules O
. O

In O
vitro O
study O
of O
injury O
on O
human O
bronchial O
epithelial O
cells O
caused O
by O
gunpowder O
smog O
. O

Smog O
inhalation O
is O
associated O
with O
acute O
respiratory O
symptoms O
in O
exposed O
victims O
. O

However O
, O
despite O
the O
evidence O
from O
cell O
injury O
caused O
by O
smog O
, O
a O
stable O
and O
practical O
apparatus O
used O
to O
treat O
cells O
with O
smog O
is O
necessary O
. O

The O
aim O
of O
this O
study O
is O
to O
develop O
a O
cell O
research O
platform O
of O
smoke O
inhalation O
injury O
. O

In O
the O
smog O
- O
generation O
device O
, O
a O
wireless O
electromagnetic O
heater O
was O
used O
to O
ignite O
gunpowder O
and O
generate O
smog O
. O

The O
quality O
of O
black O
powder O
was O
checked O
by O
the O
black O
powder O
burn O
rate O
, O
and O
experimental O
smog O
was O
indirectly O
checked O
by O
the O
amount O
of O
cell O
damage O
. O

The O
temperature O
and O
humidity O
were O
set O
at O
37 O
degrees O
C O
+ O
/ O
- O
1 O
degrees O
C O
and O
> O
= O
95 O
% O
in O
the O
smog O
- O
cells O
reaction O
chamber O
, O
respectively O
. O

Factors O
including O
gunpowder O
dosages O
, O
smog O
- O
exposure O
time O
, O
the O
cell O
density O
, O
modes O
of O
exposure O
, O
volumes O
of O
smog O
, O
test O
durations O
, O
volumes O
of O
the O
cell O
culture O
medium O
and O
combustion O
velocity O
were O
measured O
. O

Coefficient O
variation O
of O
different O
batches O
of O
gunpowder O
and O
smog O
were O
less O
than O
4 O
% O
and O
9 O
% O
, O
respectively O
. O

With O
larger O
gunpowder O
dosage O
and O
longer O
exposure O
time O
, O
cell O
injury O
appeared O
to O
increase O
. O

When O
cells O
were O
cultured O
in O
4 O
x O
10 O
( O
4 O
) O
/ O
well O
density O
in O
culture O
medium O
( O
1 O
mL O
/ O
well O
) O
, O
exposed O
to O
more O
than O
10 O
L O
smog O
with O
filter O
screens O
above O
plates O
, O
detected O
after O
24 O
h O
culture O
in O
cell O
incubator O
and O
gunpowder O
burned O
out O
within O
5 O
s O
, O
smog O
had O
the O
best O
effect O
on O
cell O
injury O
. O

In O
conclusion O
, O
the O
experimental O
device O
can O
produce O
test O
smog O
stably O
and O
safely O
. O

The O
apparatus O
treating O
cells O
with O
smog O
can O
induce O
cell O
injury O
effectively O
, O
and O
the O
injury O
is O
positively O
correlated O
with O
smog O
concentration O
and O
exposure O
time O
. O

Computationally O
assisted O
assignment O
of O
kahalalide B
Y I
configuration O
using O
an O
NMR O
- O
constrained O
conformational O
search O
. O

Assignment O
of O
the O
absolute O
configuration O
of O
cyclic O
peptides O
frequently O
yields O
challenges O
, O
leaving O
one O
or O
more O
stereogenic O
centers O
unassigned O
due O
to O
small O
quantities O
of O
sample O
and O
the O
limited O
utility O
of O
Marfey O
' O
s O
or O
other O
methods O
for O
assigning O
amino B
or I
hydroxy I
acids I
. O

Here O
, O
we O
report O
isolation O
of O
kahalalide B
Y I
( O
1 O
) O
from O
Bryopsis O
pennata O
for O
the O
first O
time O
; O
in O
addition O
, O
the O
application O
of O
a O
combination O
of O
molecular O
modeling O
and O
NOE O
distance O
constraint O
calculations O
was O
utilized O
to O
determine O
the O
conformation O
of O
1 O
and O
the O
absolute O
configuration O
of O
the O
final O
stereogenic O
center O
of O
1 O
. O

Using O
the O
Schr O
o O
dinger O
suite O
, O
the O
structure O
of O
1 O
was O
sketched O
in O
Maestro O
and O
minimized O
using O
the O
OPLS2005 O
force O
field O
in O
Macromodel O
. O

A O
conformational O
search O
was O
performed O
separately O
for O
structures O
having O
an O
R O
or O
S O
configuration O
at O
C O
- O
3 O
of O
the O
beta B
- I
hydroxy I
fatty I
acid I
subunit O
that O
completes O
the O
cyclic O
scaffold O
of O
1 O
, O
after O
which O
multiple O
minimizations O
for O
all O
generated O
conformers O
were O
carried O
out O
. O

The O
lowest O
energy O
conformers O
of O
R O
and O
S O
stereoisomers O
were O
then O
subjected O
to O
B3LYP O
geometry O
optimizations O
including O
solvent O
effects O
. O

The O
S O
stereoisomer O
was O
shown O
to O
be O
in O
excellent O
agreement O
with O
the O
NOE O
- O
derived O
distance O
constraints O
and O
hydrogen B
- O
bonding O
stability O
studies O
. O

Surfactant O
adsorption O
and O
interfacial O
tension O
investigations O
on O
cyclopentane B
hydrate I
. O

Gas O
hydrates O
represent O
an O
unconventional O
methane B
resource O
and O
a O
production O
/ O
safety O
risk O
to O
traditional O
oil O
and O
gas O
flowlines O
. O

In O
both O
systems O
, O
hydrate B
may O
share O
interfaces O
with O
both O
aqueous O
and O
hydrocarbon B
fluids O
. O

To O
accurately O
model O
macroscopic O
properties O
, O
such O
as O
relative O
permeability O
in O
unconventional O
systems O
or O
dispersion O
viscosity O
in O
traditional O
systems O
, O
knowledge O
of O
hydrate B
interfacial O
properties O
is O
required O
. O

This O
work O
presents O
hydrate O
cohesive O
force O
results O
measured O
on O
a O
micromechanical O
force O
apparatus O
, O
and O
complementary O
water O
- O
hydrocarbon B
interfacial O
tension O
data O
. O

By O
combining O
a O
revised O
cohesive O
force O
model O
with O
experimental O
data O
, O
two O
interfacial O
properties O
of O
cyclopentane B
hydrate I
were O
estimated O
: O
hydrate B
- O
water O
and O
hydrate B
- O
cyclopentane B
interfacial O
tension O
values O
at O
0 O
. O
32 O
+ O
/ O
- O
0 O
. O
05 O
mN O
/ O
m O
and O
47 O
+ O
/ O
- O
5 O
mN O
/ O
m O
, O
respectively O
. O

These O
fundamental O
physiochemical O
properties O
have O
not O
been O
estimated O
or O
measured O
for O
cyclopentane B
hydrate I
to O
date O
. O

The O
addition O
of O
surfactants O
in O
the O
cyclopentane B
phase O
significantly O
reduced O
the O
cyclopentane B
hydrate I
cohesive O
force O
; O
we O
hypothesize O
this O
behavior O
to O
be O
the O
result O
of O
surfactant O
adsorption O
on O
the O
hydrate B
- O
oil O
interface O
. O

Surface O
excess O
quantities O
were O
estimated O
for O
hydrate O
- O
oil O
and O
water O
- O
oil O
interfaces O
using O
four O
carboxylic B
and I
sulfonic I
acids I
. O

The O
results O
suggest O
the O
density O
of O
adsorbed O
surfactant O
may O
be O
2 O
x O
larger O
for O
the O
hydrate O
- O
oil O
interface O
than O
the O
water O
- O
oil O
interface O
. O

Additionally O
, O
hydrate O
- O
oil O
interfacial O
tension O
was O
observed O
to O
begin O
decreasing O
from O
the O
baseline O
value O
at O
significantly O
lower O
surfactant O
concentrations O
( O
1 O
- O
3 O
orders O
of O
magnitude O
) O
than O
those O
for O
the O
water O
- O
oil O
interfacial O
tension O
. O

Neurotoxic O
potential O
and O
cellular O
uptake O
of O
T B
- I
2 I
toxin I
in O
human O
astrocytes O
in O
primary O
culture O
. O

The O
trichothecene B
mycotoxin O
T B
- I
2 I
toxin I
, O
which O
is O
produced O
by O
fungi O
of O
the O
Fusarium O
species O
, O
is O
a O
worldwide O
occurring O
contaminant O
of O
cereal O
based O
food O
and O
feed O
. O

The O
cytotoxic O
properties O
of O
T O
- O
2 O
toxin O
are O
already O
well O
described O
with O
apoptosis O
being O
a O
major O
mechanism O
of O
action O
in O
various O
cell O
lines O
as O
well O
as O
in O
primary O
cells O
of O
different O
origin O
. O

However O
, O
only O
few O
data O
on O
neurotoxic O
properties O
of O
T B
- I
2 I
toxin I
are O
reported O
so O
far O
, O
but O
in O
vivo O
studies O
showed O
different O
effects O
of O
T B
- I
2 I
toxin I
on O
behavior O
as O
well O
as O
on O
levels O
of O
brain O
amines B
in O
animals O
. O

To O
further O
investigate O
the O
cytotoxic O
properties O
of O
T O
- O
2 O
toxin O
on O
cells O
derived O
from O
brain O
tissue O
, O
normal O
human O
astrocytes O
in O
primary O
culture O
( O
NHA O
) O
were O
used O
in O
this O
study O
. O

Besides O
studies O
of O
cytotoxicity O
, O
apoptosis O
( O
caspase O
- O
3 O
- O
activation O
, O
Annexin O
V O
) O
and O
necrosis O
( O
LDH O
- O
release O
) O
, O
the O
cellular O
uptake O
and O
metabolism O
of O
T B
- I
2 I
toxin I
in O
NHA O
was O
analyzed O
and O
compared O
to O
the O
uptake O
in O
an O
established O
human O
cell O
line O
( O
HT O
- O
29 O
) O
. O

The O
results O
show O
that O
human O
astrocytes O
were O
highly O
sensitive O
to O
the O
cytotoxic O
properties O
of O
T B
- I
2 I
toxin O
, O
and O
apoptosis O
, O
induced O
at O
low O
concentrations O
, O
was O
identified O
for O
the O
first O
time O
as O
the O
mechanism O
of O
toxic O
action O
in O
NHA O
. O

Furthermore O
, O
a O
strong O
accumulation O
of O
T B
- I
2 I
toxin I
in O
NHA O
and O
HT O
- O
29 O
cells O
was O
detected O
, O
and O
T B
- I
2 I
toxin I
was O
subjected O
to O
metabolism O
leading O
to O
HT B
- I
2 I
toxin I
, O
a O
commonly O
found O
metabolite O
after O
T B
- I
2 I
toxin I
incubation O
in O
both O
cell O
types O
. O

This O
formation O
seems O
to O
occur O
within O
the O
cells O
since O
incubations O
of O
T B
- I
2 I
toxin O
with O
cell O
depleted O
culture O
medium O
did O
not O
lead O
to O
any O
degradation O
of O
the O
parent O
toxin O
. O

The O
results O
of O
this O
study O
emphasize O
the O
neurotoxic O
potential O
of O
T B
- I
2 I
toxin O
in O
human O
astrocytes O
at O
low O
concentrations O
after O
short O
incubation O
times O
. O

Direct O
atomic O
- O
level O
observation O
and O
chemical O
analysis O
of O
ZnSe B
synthesized O
by O
in O
situ O
high O
- O
throughput O
reactive O
fiber O
drawing O
. O

We O
demonstrate O
a O
high O
- O
throughput O
method O
for O
synthesizing O
zinc B
selenide I
( O
ZnSe B
) O
in O
situ O
during O
fiber O
drawing O
. O

Central O
to O
this O
method O
is O
a O
thermally O
activated O
chemical O
reaction O
occurring O
across O
multiple O
interfaces O
between O
alternately O
layered O
elemental O
zinc B
- O
( O
Zn B
- O
) O
and O
selenium B
- O
( O
Se B
- O
) O
rich O
films O
embedded O
in O
a O
preform O
and O
drawn O
into O
meters O
of O
fiber O
at O
a O
temperature O
well O
below O
the O
melting O
temperature O
of O
either O
Zn B
or O
ZnSe B
. O

By O
depositing O
50 O
nm O
thick O
layers O
of O
Zn B
interleaved O
between O
1 O
mu O
m O
thick O
Se B
layers O
, O
a O
controlled O
breakup O
of O
the O
Zn B
sheet O
is O
achieved O
, O
thereby O
enabling O
a O
complete O
and O
controlled O
chemical O
reaction O
. O

The O
thermodynamics O
and O
kinetics O
of O
this O
synthesis O
process O
are O
studied O
using O
thermogravimetric O
analysis O
and O
differential O
scanning O
calorimetry O
, O
and O
the O
in O
- O
fiber O
compound O
is O
analyzed O
by O
a O
multiplicity O
of O
materials O
characterization O
tools O
, O
including O
transmission O
electron O
microscopy O
, O
Raman O
microscopy O
, O
energy O
- O
dispersive O
X O
- O
ray O
spectroscopy O
, O
and O
X O
- O
ray O
diffraction O
, O
all O
resulting O
in O
unambiguous O
identification O
of O
ZnSe B
as O
the O
compound O
produced O
from O
the O
reactive O
fiber O
draw O
. O

Furthermore O
, O
we O
characterize O
the O
in O
- O
fiber O
ZnSe B
/ O
Se97S3 B
heterojunction O
to O
demonstrate O
the O
prospect O
of O
ZnSe B
- O
based O
fiber O
optoelectronic O
devices O
. O

The O
ability O
to O
synthesize O
new O
compounds O
during O
fiber O
drawing O
at O
nanometer O
scale O
precision O
and O
to O
characterize O
them O
at O
the O
atomic O
- O
level O
extends O
the O
architecture O
and O
materials O
selection O
compatible O
with O
multimaterial O
fiber O
drawing O
, O
thus O
paving O
the O
way O
toward O
more O
complex O
and O
sophisticated O
functionality O
. O

Zinc B
- O
dependent O
lysosomal O
enlargement O
in O
TRPML1 O
- O
deficient O
cells O
involves O
MTF O
- O
1 O
transcription O
factor O
and O
ZnT4 O
( O
Slc30a4 O
) O
transporter O
. O

Zinc B
is O
critical O
for O
a O
multitude O
of O
cellular O
processes O
, O
including O
gene O
expression O
, O
secretion O
and O
enzymatic O
activities O
. O

Cellular O
zinc B
is O
controlled O
by O
zinc B
- O
chelating O
proteins O
and O
by O
zinc B
transporters O
. O

The O
recent O
identification O
of O
zinc B
permeability O
of O
the O
lysosomal O
ion O
channel O
TRPML1 O
( O
transient O
receptor O
potential O
mucolipin O
1 O
) O
, O
and O
the O
evidence O
of O
abnormal O
zinc B
levels O
in O
cells O
deficient O
in O
TRPML1 O
, O
suggested O
a O
role O
for O
TRPML1 O
in O
zinc B
transport O
. O

In O
the O
present O
study O
we O
provide O
new O
evidence O
for O
such O
a O
role O
and O
identify O
additional O
cellular O
components O
responsible O
for O
it O
. O

In O
agreement O
with O
the O
previously O
published O
data O
, O
an O
acute O
siRNA O
( O
small O
interfering O
RNA O
) O
- O
driven O
TRPML1 O
KD O
( O
knockdown O
) O
leads O
to O
the O
build O
- O
up O
of O
large O
cytoplasmic O
vesicles O
positive O
for O
LysoTracker O
( O
TM O
) O
and O
zinc B
staining O
, O
when O
cells O
are O
exposed O
to O
high O
concentrations O
of O
zinc B
. O

We O
now O
show O
that O
lysosomal O
enlargement O
and O
zinc B
build O
- O
up O
in O
TRPML1 O
- O
KD O
cells O
exposed O
to O
zinc B
are O
ameliorated O
by O
KD O
of O
the O
zinc B
- O
sensitive O
transcription O
factor O
MTF O
- O
1 O
( O
metal O
- O
regulatory O
- O
element O
- O
binding O
transcription O
factor O
- O
1 O
) O
or O
the O
zinc B
transporter O
ZnT4 O
. O

TRPML1 O
KD O
is O
associated O
with O
a O
build O
- O
up O
of O
cytoplasmic O
zinc B
and O
with O
enhanced O
transcriptional O
response O
of O
mRNA O
for O
MT2a O
( O
metallothionein O
2a O
) O
. O

TRPML1 O
KD O
did O
not O
suppress O
lysosomal O
secretion O
, O
but O
it O
did O
delay O
zinc B
leak O
from O
the O
lysosomes O
into O
the O
cytoplasm O
. O

These O
results O
underscore O
a O
role O
for O
TRPML1 O
in O
zinc B
metabolism O
. O

Furthermore O
, O
they O
suggest O
that O
TRPML1 O
works O
in O
concert O
with O
ZnT4 O
to O
regulate O
zinc B
translocation O
between O
the O
cytoplasm O
and O
lysosomes O
. O

Hydrogenated O
ZnO B
core O
- O
shell O
nanocables O
for O
flexible O
supercapacitors O
and O
self O
- O
powered O
systems O
. O

Although O
MnO2 B
is O
a O
promising O
material O
for O
supercapacitors O
( O
SCs O
) O
due O
to O
its O
excellent O
electrochemical O
performance O
and O
natural O
abundance O
, O
its O
wide O
application O
is O
limited O
by O
poor O
electrical O
conductivity O
. O

Inspired O
by O
our O
results O
that O
the O
electrochemical O
activity O
and O
electrical O
conductivity O
of O
ZnO B
nanowires O
were O
greatly O
improved O
after O
hydrogenation O
, O
we O
designed O
and O
fabricated O
hydrogenated O
single O
- O
crystal O
ZnO B
@ O
amorphous O
ZnO B
- O
doped O
MnO2 B
core O
- O
shell O
nanocables O
( O
HZM O
) O
on O
carbon B
cloth O
as O
SC O
electrodes O
, O
showing O
excellent O
performance O
such O
as O
areal O
capacitance O
of O
138 O
. O
7 O
mF O
/ O
cm O
( O
2 O
) O
and O
specific O
capacitance O
of O
1260 O
. O
9 O
F O
/ O
g O
. O

Highly O
flexible O
all O
- O
solid O
- O
state O
SCs O
were O
subsequently O
assembled O
with O
these O
novel O
HZM O
electrodes O
using O
polyvinyl B
alcohol I
/ O
LiCl B
electrolyte O
. O

The O
working O
devices O
achieved O
very O
high O
total O
areal O
capacitance O
of O
26 O
mF O
/ O
cm O
( O
2 O
) O
and O
retained O
87 O
. O
5 O
% O
of O
the O
original O
capacitance O
even O
after O
10 O
000 O
charge O
/ O
discharge O
cycles O
. O

An O
integrated O
power O
pack O
incorporating O
series O
- O
wound O
SCs O
and O
dye O
- O
sensitized O
solar O
cells O
was O
demonstrated O
for O
stand O
- O
alone O
self O
- O
powered O
systems O
. O

Influence O
of O
chain O
length O
and O
double O
bond O
on O
the O
aqueous O
behavior O
of O
choline B
carboxylate I
soaps O
. O

In O
preceding O
studies O
, O
we O
demonstrated O
that O
choline B
carboxylates I
ChC B
( I
m I
) I
with O
alkyl O
chain O
lengths O
of O
m O
= O
12 O
- O
18 O
are O
highly O
water O
- O
soluble O
( O
for O
m O
= O
12 O
, O
soluble O
up O
to O
93 O
wt O
% O
soap B
and O
0 O
degrees O
C O
) O
. O

In O
addition O
, O
choline B
soaps O
are O
featured O
by O
an O
extraordinary O
lyotropic O
phase O
behavior O
. O

With O
decreasing O
water O
concentration O
, O
the O
following O
phases O
were O
found O
: O
micellar O
phase O
( O
L O
( O
1 O
) O
) O
, O
discontinuous O
cubic O
phase O
( O
I O
( O
1 O
) O
' O
and O
I O
( O
1 O
) O
" O
) O
, O
hexagonal O
phase O
( O
H O
( O
1 O
) O
) O
, O
bicontinuous O
cubic O
phase O
( O
V O
( O
1 O
) O
) O
, O
and O
lamellar O
phase O
( O
L O
( O
alpha O
) O
) O
. O

The O
present O
work O
is O
also O
focused O
on O
the O
lyotropic O
phase O
behavior O
of O
choline B
soaps O
but O
with O
shorter O
alkyl O
chains O
or O
different O
alkyl B
chain O
properties O
. O

We O
have O
investigated O
the O
aqueous O
phase O
behavior O
of O
choline B
soaps O
with O
C O
( O
8 O
) O
and O
C O
( O
10 O
) O
chain O
- O
lengths O
( O
choline B
octanoate I
and O
choline B
decanoate I
) O
and O
with O
a O
C O
( O
18 O
) O
chain O
- O
length O
with O
a O
cis O
- O
double O
bond O
( O
choline B
oleate I
) O
. O

We O
found O
that O
choline B
decanoate I
follows O
the O
lyotropic O
phase O
behavior O
of O
the O
longer O
- O
chain O
homologues O
mentioned O
above O
. O

Choline B
octanoate I
in O
water O
shows O
no O
discontinuous O
cubic O
phases O
, O
but O
an O
extended O
, O
isotropic O
micellar O
solution O
phase O
. O

In O
addition O
, O
choline B
octanoate I
is O
at O
the O
limit O
between O
a O
surfactant O
and O
a O
hydrotrope O
. O

The O
double O
bond O
in O
choline B
oleate I
leads O
also O
to O
a O
better O
solubility O
in O
water O
and O
a O
decrease O
of O
the O
solubilization O
temperature O
. O

It O
also O
influences O
the O
Gaussian O
curvature O
of O
the O
aggregates O
which O
results O
in O
a O
loss O
of O
discontinuous O
cubic O
phases O
in O
the O
binary O
phase O
diagram O
. O

The O
different O
lyotropic O
mesophases O
were O
identified O
by O
the O
penetration O
scan O
technique O
with O
polarizing O
light O
microscope O
and O
visual O
observations O
. O

To O
clarify O
the O
structural O
behavior O
small O
( O
SAXS O
) O
and O
wide O
( O
WAXS O
) O
angle O
X O
- O
ray O
scattering O
were O
performed O
. O

To O
further O
characterize O
the O
extended O
, O
isotropic O
micellar O
solution O
phase O
in O
the O
binary O
phase O
diagram O
of O
choline B
octanoate I
viscosity O
and O
conductivity O
measurements O
were O
also O
carried O
out O
. O

Preparation O
, O
characterization O
, O
in O
vivo O
biodistribution O
and O
pharmacokinetic O
studies O
of O
donepezil B
- O
loaded O
PLGA B
nanoparticles O
for O
brain O
targeting O
. O

Abstract O
Objective O
: O
Alzheimer O
' O
s O
disease O
( O
AD O
) O
is O
a O
progressive O
neurodegenerative O
disorder O
manifested O
by O
cognitive O
, O
memory O
deterioration O
and O
variety O
of O
neuropsychiatric O
symptoms O
. O

Donepezil B
is O
a O
reversible O
cholinesterase O
inhibitor O
used O
for O
the O
treatment O
of O
AD O
. O

The O
purpose O
of O
this O
work O
is O
to O
prepare O
a O
nanoparticulate O
drug O
delivery O
system O
of O
donepezil B
using O
poly B
( I
lactic I
- I
co I
- I
glycolic I
acid I
) I
( O
PLGA B
) O
for O
sustained O
release O
and O
efficient O
brain O
targeting O
. O

Materials O
and O
methods O
: O
PLGA B
nanoparticles O
( O
NPs O
) O
were O
prepared O
by O
the O
solvent O
emulsification O
diffusion O
- O
evaporation O
technique O
and O
characterized O
for O
particle O
size O
, O
particle O
- O
size O
distribution O
, O
zeta O
potential O
, O
entrapment O
efficiency O
, O
drug O
loading O
and O
interaction O
studies O
and O
in O
vivo O
studies O
using O
gamma O
scintigraphy O
techniques O
. O

Results O
and O
discussion O
: O
The O
size O
of O
drug O
- O
loaded O
NPs O
( O
drug O
polymer O
ratio O
1 O
: O
1 O
) O
was O
found O
to O
be O
89 O
. O
67 O
+ O
/ O
- O
6 O
. O
43 O
nm O
. O

The O
TEM O
and O
SEM O
images O
of O
the O
formulation O
suggested O
that O
particle O
size O
was O
within O
20 O
- O
100 O
nm O
and O
spherical O
in O
shape O
, O
smooth O
morphology O
and O
coating O
of O
Tween B
- I
80 I
on O
the O
NPs O
was O
clearly O
observed O
. O

The O
release O
behavior O
of O
donepezil B
exhibited O
a O
biphasic O
pattern O
characterized O
by O
an O
initial O
burst O
release O
followed O
by O
a O
slower O
and O
continuous O
sustained O
release O
. O

The O
biodistribution O
studies O
of O
donepezil B
- O
loaded O
PLGA B
NPs O
and O
drug O
solution O
via O
intravenous O
route O
revealed O
higher O
percentage O
of O
radioactivity O
per O
gram O
in O
the O
brain O
for O
the O
nanoparticulate O
formulation O
as O
compared O
with O
the O
drug O
solution O
( O
p O
< O
0 O
. O
05 O
) O
. O

Conclusion O
: O
The O
high O
concentrations O
of O
donepezil B
uptake O
in O
brain O
due O
to O
coated O
NPs O
may O
help O
in O
a O
significant O
improvement O
for O
treating O
AD O
. O

But O
further O
, O
more O
extensive O
clinical O
studies O
are O
needed O
to O
check O
and O
confirm O
the O
efficacy O
of O
the O
prepared O
drug O
delivery O
system O
. O

Synthesis O
and O
biological O
evaluation O
of O
nucleoside B
analogues O
than O
contain O
silatrane B
on O
the O
basis O
of O
the O
structure O
of O
acyclovir B
( O
ACV B
) O
as O
novel O
inhibitors O
of O
hepatitis O
B O
virus O
( O
HBV O
) O
. O

Hepatitis O
B O
virus O
( O
HBV O
) O
infection O
causes O
major O
public O
health O
problems O
worldwide O
. O

Acyclovir B
( O
ACV B
) O
is O
mainly O
used O
to O
inhibit O
herpes O
simplex O
virus O
( O
HSV O
) O
rather O
than O
HBV O
. O

In O
this O
study O
, O
we O
used O
the O
combination O
principle O
to O
design O
and O
synthesize O
nucleoside B
analogues O
that O
contain O
silatrane B
on O
the O
basis O
of O
the O
structure O
of O
ACV B
. O

We O
found O
that O
the O
compounds O
were O
effective O
inhibitors O
of O
HBV O
, O
both O
in O
vitro O
and O
in O
vivo O
. O

All O
of O
the O
compounds O
showed O
suppressive O
activity O
on O
the O
expression O
of O
HBV O
surface O
antigen O
( O
HBsAg O
) O
and O
HBV O
e O
antigen O
( O
HBeAg O
) O
in O
the O
HepG2 O
. O
2 O
. O
15 O
cell O
line O
with O
low O
cytotoxicity O
. O

One O
of O
compounds O
was O
studied O
in O
HBV O
transgenic O
mice O
model O
, O
and O
the O
test O
results O
showed O
its O
ability O
to O
reduce O
the O
levels O
of O
HBsAg O
, O
HBeAg O
and O
HBV O
DNA O
by O
ELASE O
and O
qPCR O
. O

Furthermore O
, O
significant O
improvement O
of O
T O
lymphocyte O
was O
observed O
after O
treatment O
, O
as O
evaluated O
by O
flow O
cytometry O
( O
FCM O
) O
. O

Serum O
amyloid O
A O
upsurge O
precedes O
standard O
biomarkers O
of O
hepatotoxicity O
in O
ritodrine B
- O
injected O
mice O
. O

The O
tocolytic O
agent O
ritodrine B
acts O
on O
the O
beta O
2 O
- O
adrenoceptor O
and O
is O
an O
effective O
treatment O
option O
for O
preterm O
labor O
. O

However O
, O
several O
adverse O
effects O
of O
ritodrine B
therapy O
, O
including O
liver O
damage O
, O
have O
been O
noted O
. O

To O
elucidate O
the O
underlying O
mechanisms O
of O
ritodrine B
- O
induced O
adverse O
effects O
, O
development O
of O
sensitive O
biomarkers O
of O
these O
adverse O
events O
is O
necessary O
. O

Here O
, O
we O
report O
the O
development O
and O
analysis O
of O
an O
animal O
model O
of O
ritodrine B
- O
induced O
liver O
damage O
. O

Female O
mice O
received O
daily O
ritodrine B
injections O
for O
2 O
weeks O
; O
liver O
samples O
were O
then O
collected O
and O
subjected O
to O
DNA O
microarray O
analysis O
. O

Ritodrine B
significantly O
altered O
the O
expression O
of O
genes O
related O
to O
steroid B
and O
lipid O
metabolism O
, O
as O
well O
as O
the O
metabolism O
of O
ritodrine B
itself O
. O

Importantly O
, O
expression O
of O
the O
acute O
- O
phase O
reactant O
serum O
amyloid O
A O
( O
SAA O
) O
significantly O
increased O
after O
ritodrine B
injection O
, O
with O
values O
indicating O
the O
largest O
fold O
- O
change O
. O

This O
large O
increase O
in O
blood O
SAA O
levels O
serves O
as O
a O
more O
sensitive O
biomarker O
than O
conventional O
liver O
enzymes O
, O
such O
as O
aspartate B
aminotransferase O
and O
alanine B
aminotransferase O
. O

The O
increase O
in O
SAA O
expression O
is O
specific O
to O
ritodrine B
- O
induced O
liver O
damage O
, O
because O
SAA O
expression O
was O
not O
induced O
by O
other O
hepatotoxic O
drugs O
such O
as O
acetaminophen B
, O
valproic B
acid I
, O
or O
metformin B
. O

Our O
in O
vitro O
studies O
showed O
that O
cyclic B
adenosine I
3 I
' I
, I
5 I
' I
- I
monophosphate I
( O
cAMP B
) O
accumulation O
was O
not O
a O
primary O
cause O
of O
the O
ritodrine B
- O
induced O
SAA O
increase O
. O

Instead O
, O
SAA O
expression O
was O
enhanced O
by O
indirect O
phosphorylation O
of O
the O
signal O
transducer O
and O
activator O
of O
transcription O
- O
3 O
( O
STAT3 O
) O
mediated O
by O
interleukin O
- O
6 O
. O

Therefore O
, O
our O
study O
provides O
a O
method O
for O
sensitive O
and O
early O
detection O
of O
hepatic O
injury O
, O
and O
may O
thus O
help O
preclude O
serious O
liver O
damage O
due O
to O
ritodrine B
use O
in O
preterm O
labor O
. O

L O
- O
type O
voltage O
- O
dependent O
calcium B
channel O
is O
involved O
in O
the O
snake O
venom O
group O
IA O
secretory O
phospholipase O
A2 O
- O
induced O
neuronal O
apoptosis O
. O

Snake O
venom O
group O
IA O
secretory O
phospholipase O
A2 O
( O
sPLA2 O
- O
IA O
) O
is O
known O
as O
a O
neurotoxin O
. O

Snake O
venom O
sPLA2s O
are O
neurotoxic O
in O
vivo O
and O
in O
vitro O
, O
causing O
synergistic O
neurotoxicity O
to O
cortical O
cultures O
when O
applied O
with O
toxic O
concentrations O
of O
glutamate B
. O

However O
, O
it O
has O
not O
yet O
been O
cleared O
sufficiently O
how O
sPLA2 O
- O
IA O
exerts O
neurotoxicity O
. O

Here O
, O
we O
found O
sPLA2 O
- O
IA O
induced O
neuronal O
cell O
death O
in O
a O
concentration O
- O
dependent O
manner O
. O

This O
death O
was O
a O
delayed O
response O
requiring O
a O
latent O
time O
for O
6h O
. O

sPLA2 O
- O
IA O
- O
induced O
neuronal O
cell O
death O
was O
accompanied O
with O
apoptotic O
blebbing O
, O
condensed O
chromatin O
, O
and O
fragmented O
DNA O
, O
exhibiting O
apoptotic O
features O
. O

NMDA B
receptor O
blockers O
suppressed O
the O
neurotoxicity O
of O
sPLA2 O
- O
IA O
, O
but O
an O
AMPA B
receptor O
blocker O
did O
not O
. O

Interestingly O
, O
L O
- O
type O
voltage O
- O
dependent O
Ca B
( I
2 I
+ I
) I
channel O
( O
L O
- O
VDCC O
) O
blocker O
significantly O
protected O
neurons O
from O
the O
sPLA2 O
- O
IA O
- O
induced O
apoptosis O
. O

On O
the O
other O
hand O
, O
neither O
N O
- O
VDCC O
blockers O
nor O
P O
/ O
Q O
- O
VDCC O
blocker O
did O
. O

In O
conclusion O
, O
we O
demonstrated O
that O
sPLA2 O
- O
IA O
induced O
neuronal O
cell O
death O
via O
apoptosis O
. O

Furthermore O
, O
the O
present O
study O
suggests O
that O
not O
only O
NMDA B
receptor O
but O
also O
L O
- O
VDCC O
contributed O
to O
the O
neurotoxicity O
of O
snake O
venom O
sPLA2 O
- O
IA O
. O

Chemo O
- O
responsive O
, O
self O
- O
oscillating O
gels O
that O
undergo O
biomimetic O
communication O
. O

Species O
ranging O
from O
single O
- O
cell O
organisms O
to O
social O
insects O
can O
undergo O
auto O
- O
chemotaxis O
, O
where O
the O
entities O
move O
towards O
a O
chemo O
- O
attractant O
that O
they O
themselves O
emit O
. O

Polymer O
gels O
undergoing O
the O
self O
- O
oscillating O
Belousov O
- O
Zhabotinsky O
( O
BZ O
) O
reaction O
exhibit O
autonomous O
, O
periodic O
pulsations O
, O
which O
produce O
chemical O
species O
collectively O
referred O
to O
as O
the O
activator O
. O

The O
diffusion O
of O
this O
activator O
into O
the O
surrounding O
solution O
affects O
the O
dynamic O
behavior O
of O
neighboring O
BZ O
gels O
and O
hence O
, O
the O
BZ O
gels O
not O
only O
emit O
, O
but O
also O
respond O
to O
self O
- O
generated O
chemical O
gradients O
. O

This O
review O
describes O
recent O
experimental O
and O
computational O
studies O
that O
reveal O
how O
this O
biomimetic O
behavior O
effectively O
allows O
neighboring O
BZ O
gels O
to O
undergo O
cooperative O
, O
self O
- O
propelled O
motion O
. O

These O
distinctive O
properties O
of O
the O
BZ O
gels O
provide O
a O
route O
for O
creating O
reconfigurable O
materials O
that O
autonomously O
communicate O
with O
neighboring O
units O
and O
thereby O
actively O
participate O
in O
constructing O
the O
desired O
structures O
. O

Mitogen O
- O
activated O
protein O
kinases O
as O
therapeutic O
targets O
for O
rheumatoid O
arthritis O
. O

Rheumatoid O
arthritis O
( O
RA O
) O
is O
a O
chronic O
autoimmune O
disease O
in O
which O
imbalances O
in O
pro O
- O
and O
anti O
- O
inflammatory O
cytokines O
promote O
the O
induction O
of O
autoimmunity O
, O
inflammation O
and O
joint O
destruction O
. O

Methotrexate B
, O
the O
standard O
disease O
- O
modifying O
anti O
- O
rheumatic O
drug O
( O
DMARD O
) O
, O
has O
shown O
a O
gradual O
loss O
of O
efficacy O
in O
a O
significant O
proportion O
of O
patients O
, O
probably O
due O
to O
the O
onset O
of O
drug O
resistance O
, O
and O
thus O
it O
was O
hoped O
that O
the O
development O
of O
biologics O
would O
revolutionise O
RA O
management O
. O

Even O
though O
biologics O
have O
improved O
the O
therapy O
of O
patients O
refractive O
to O
DMARDs O
, O
they O
require O
parenteral O
administration O
and O
may O
leave O
patients O
open O
to O
serious O
infection O
and O
cancer O
. O

Therefore O
, O
attention O
has O
also O
been O
focused O
on O
inhibitors O
of O
mitogen O
- O
activated O
protein O
kinases O
( O
MAPKs O
) O
, O
signalling O
enzymes O
that O
play O
key O
roles O
in O
pathogenic O
cytokine O
production O
, O
and O
their O
downstream O
effector O
pathways O
, O
in O
order O
to O
create O
safe O
and O
effective O
oral O
drugs O
. O

This O
article O
therefore O
provides O
an O
overview O
of O
the O
structure O
and O
function O
of O
MAPKs O
and O
their O
role O
in O
the O
pathogenesis O
of O
RA O
as O
context O
to O
describing O
the O
advances O
in O
the O
development O
of O
specific O
, O
druggable O
MAPK O
inhibitors O
. O

Their O
potential O
as O
therapies O
in O
the O
management O
of O
RA O
is O
also O
discussed O
. O

Genotoxicity O
and O
carcinogenicity O
of O
the O
light O
emitted O
by O
artificial O
illumination O
systems O
. O

The O
light O
delivered O
by O
artificial O
illumination O
systems O
, O
and O
in O
particular O
by O
halogen B
quartz B
bulbs O
, O
contains O
UVA O
, O
UVB O
, O
and O
UVC O
radiation O
, O
is O
genotoxic O
to O
both O
bacterial O
and O
human O
cells O
and O
is O
potently O
carcinogenic O
to O
hairless O
mice O
. O

Since O
IARC O
has O
classified O
UV O
radiation O
in O
Group O
1 O
, O
any O
source O
of O
UV O
light O
poses O
a O
carcinogenic O
hazard O
to O
humans O
. O

Suitable O
regulations O
would O
be O
needed O
in O
order O
to O
control O
the O
safety O
of O
the O
light O
emitted O
by O
artificial O
light O
sources O
. O

Impaired O
social O
behavior O
in O
chicks O
exposed O
to O
sodium B
valproate I
during O
the O
last O
week O
of O
embryogenesis O
. O

RATIONALE O
AND O
OBJECTIVES O
: O
To O
evaluate O
direct O
exposure O
to O
sodium B
valproate I
( O
VPA B
) O
during O
embryogenesis O
, O
we O
administered O
VPA B
to O
chick O
embryos O
and O
examined O
their O
social O
behaviors O
after O
hatching O
. O

METHODS O
AND O
RESULTS O
: O
Embryos O
treated O
with O
VPA B
( O
35 O
mu O
mol O
/ O
egg O
) O
on O
day O
14 O
were O
similar O
to O
controls O
for O
hatching O
date O
( O
day O
21 O
) O
and O
hatchlings O
' O
abilities O
, O
such O
as O
motor O
, O
imprinting O
, O
and O
surface O
righting O
. O

However O
, O
these O
VPA B
chicks O
on O
posthatching O
day O
3 O
scored O
significantly O
low O
in O
the O
chick O
' O
s O
social O
separation O
stress O
( O
SSS O
) O
test O
as O
follows O
. O

Aggregation O
test O
evaluated O
the O
speed O
of O
four O
chicks O
, O
individually O
isolated O
by O
a O
cardboard O
in O
a O
box O
, O
to O
aggregate O
upon O
removal O
of O
the O
cardboards O
. O

Belongingness O
test O
evaluated O
the O
speed O
of O
a O
chick O
isolated O
at O
a O
corner O
to O
join O
the O
group O
of O
three O
chicks O
placed O
at O
the O
opposite O
corner O
. O

Vocalization O
test O
for O
each O
chick O
was O
performed O
in O
an O
isolated O
corner O
by O
using O
a O
sound O
level O
meter O
. O

The O
results O
demonstrated O
that O
compared O
with O
controls O
, O
VPA B
chicks O
were O
significantly O
slow O
in O
aggregation O
( O
12 O
. O
7 O
+ O
/ O
- O
2 O
. O
5 O
s O
vs O
. O
2 O
. O
9 O
+ O
/ O
- O
0 O
. O
9 O
s O
, O
p O
= O
0 O
. O
006 O
) O
and O
belongingness O
( O
3 O
. O
6 O
+ O
/ O
- O
0 O
. O
28 O
s O
/ O
40 O
cm O
vs O
. O
2 O
. O
6 O
+ O
/ O
- O
0 O
. O
14 O
s O
/ O
40 O
cm O
, O
P O
= O
0 O
. O
003 O
) O
and O
weak O
in O
vocalization O
( O
13 O
. O
4 O
+ O
/ O
- O
2 O
. O
8 O
dB O
/ O
30 O
s O
vs O
. O
26 O
. O
7 O
+ O
/ O
- O
1 O
. O
3 O
dB O
/ O
30 O
s O

, O
P O
= O
0 O
. O
001 O
) O
, O
respectively O
. O

Weight O
of O
cerebellum O
of O
VAP O
chick O
was O
15 O
% O
lighter O
than O
controls O
( O
P O
= O
0 O
. O
004 O
) O
. O

CONCLUSIONS O
: O
Chick O
embryos O
exposed O
to O
VPA B
during O
the O
last O
week O
of O
embryogenesis O
had O
impaired O
social O
behaviors O
in O
spite O
of O
normal O
mortar O
and O
imprinting O
ability O
. O

The O
present O
method O
will O
be O
a O
useful O
animal O
model O
for O
assessing O
the O
effects O
of O
environment O
during O
embryogenesis O
on O
social O
behaviors O
in O
later O
life O
. O

Abstinence O
from O
repeated O
amphetamine B
treatment O
induces O
depressive O
- O
like O
behaviors O
and O
oxidative O
damage O
in O
rat O
brain O
. O

RATIONALE O
: O
Amphetamine B
has O
a O
significant O
potential O
for O
abuse O
and O
addiction O
. O

Among O
prolonged O
abusers O
, O
amphetamine B
withdrawal O
- O
induced O
depressive O
symptoms O
are O
common O
; O
however O
, O
their O
pathophysiological O
mechanism O
is O
not O
fully O
understood O
. O

Previously O
, O
we O
found O
that O
repeated O
treatment O
with O
amphetamine B
for O
2 O
weeks O
induced O
oxidative O
stress O
in O
rat O
brain O
. O

OBJECTIVES O
: O
The O
purpose O
of O
the O
current O
study O
is O
to O
analyze O
whether O
abstinence O
from O
repeated O
amphetamine B
treatment O
in O
rats O
induces O
depressive O
- O
like O
behaviors O
and O
if O
oxidative O
damage O
in O
the O
brain O
continues O
during O
abstinence O
. O

METHODS O
: O
Rats O
were O
given O
repeated O
treatment O
with O
amphetamine B
once O
daily O
at O
1 O
, O
2 O
, O
or O
4 O
mg O
/ O
kg O
for O
14 O
days O
. O

From O
10 O
to O
14 O
days O
after O
final O
amphetamine B
treatment O
, O
behavioral O
changes O
were O
monitored O
using O
open O
field O
test O
, O
novel O
object O
recognition O
test O
, O
and O
forced O
swim O
test O
. O

Oxidative O
damage O
in O
the O
medial O
frontal O
cortex O
and O
hippocampus O
was O
analyzed O
by O
immunohistochemistry O
. O

RESULTS O
: O
We O
found O
that O
drug O
abstinence O
after O
repeated O
amphetamine B
stimulation O
decreased O
locomotor O
activity O
and O
exploratory O
behavior O
in O
the O
open O
field O
test O
, O
increased O
immobility O
in O
the O
forced O
swim O
test O
, O
and O
had O
no O
significant O
effect O
on O
the O
recognition O
index O
in O
the O
novel O
object O
recognition O
test O
. O

We O
also O
found O
that O
amphetamine B
abstinence O
increased O
levels O
of O
4 B
- I
hydroxynonenal I
- O
protein O
adducts O
and O
8 B
- I
hydroxyguanosine I
in O
rat O
medial O
frontal O
cortex O
and O
in O
CA3 O
and O
dentate O
gyrus O
regions O
of O
the O
hippocampus O
. O

CONCLUSIONS O
: O
These O
results O
suggest O
that O
amphetamine B
abstinence O
displays O
depressive O
- O
like O
behaviors O
in O
rats O
and O
induces O
oxidative O
damage O
to O
lipids O
and O
RNA O
in O
rat O
brain O
. O

Our O
findings O
indicate O
that O
the O
process O
of O
oxidative O
stress O
may O
play O
a O
role O
in O
pathophysiological O
changes O
during O
drug O
abstinence O
from O
repeated O
amphetamine B
stimulation O
. O

Oroxylin B
A I
improves O
attention O
deficit O
hyperactivity O
disorder O
- O
like O
behaviors O
in O
the O
spontaneously O
hypertensive O
rat O
and O
inhibits O
reuptake O
of O
dopamine B
in O
vitro O
. O

In O
previous O
studies O
we O
have O
demonstrated O
that O
the O
gamma B
- I
aminobutryic I
acid I
- O
A O
( O
GABA B
- O
A O
) O
receptor O
antagonist O
oroxylin B
A I
has O
an O
awakening O
effect O
and O
it O
also O
represses O
ADHD O
- O
like O
behaviors O
( O
hyperactivity O
, O
impulsivity O
and O
inattention O
) O
in O
the O
spontaneously O
hypertensive O
rat O
( O
SHR O
) O
model O
of O
attention O
- O
deficit O
hyperactivity O
disorder O
( O
ADHD O
) O
. O

We O
hypothesized O
that O
the O
effects O
of O
oroxylin B
A I
were O
exerted O
via O
the O
GABA B
- O
A O
receptor O
given O
the O
important O
role O
of O
the O
GABAergic O
system O
in O
ADHD O
. O

However O
, O
it O
is O
possible O
that O
aside O
from O
the O
GABAergic O
system O
, O
oroxylin B
A I
may O
influence O
other O
systems O
especially O
those O
implicated O
in O
ADHD O
( O
e O
. O
g O
. O
DAergic O
, O
etc O
. O
) O
. O

To O
test O
this O
hypothesis O
, O
we O
evaluated O
the O
effects O
of O
GABA B
agonist O
, O
or O
dopamine B
( O
DA O
) O
antagonist O
in O
oroxylin B
A I
- O
induced O
alleviation O
of O
ADHD O
- O
like O
behaviors O
in O
SHR O
. O

SHR O
showed O
inattention O
and O
impulsivity O
as O
measured O
by O
the O
Y O
- O
maze O
and O
the O
electro O
- O
foot O
shock O
aversive O
water O
drinking O
tests O
, O
respectively O
. O

Oroxylin B
A I
significantly O
improved O
these O
behaviors O
, O
furthermore O
, O
its O
effect O
on O
SHR O
impulsivity O
was O
attenuated O
by O
haloperidol B
, O
a O
DA O
antagonist O
, O
but O
not O
by O
baicalein B
, O
an O
agonist O
of O
the O
GABA B
- O
A O
receptor O
. O

In O
vitro O
studies O
showed O
that O
oroxylin B
A I
inhibited O
DA O
uptake O
similar O
to O
methylphenidate B
, O
a O
dopamine B
transporter O
blocker O
, O
but O
did O
not O
influence O
norepinephrine B
uptake O
unlike O
atomoxetine B
, O
a O
selective O
NE O
reuptake O
inhibitor O
. O

Collectively O
, O
the O
present O
findings O
suggest O
that O
oroxylin B
A I
improves O
ADHD O
- O
like O
behaviors O
in O
SHR O
via O
enhancement O
of O
DA O
neurotransmission O
and O
not O
modulation O
of O
GABA B
pathway O
as O
previously O
reported O
. O

Importantly O
, O
the O
present O
study O
indicates O
the O
potential O
therapeutic O
value O
of O
oroxylin B
A I
in O
the O
treatment O
of O
ADHD O
. O

The O
toxicity O
of O
a O
ternary O
biocide O
mixture O
to O
two O
consecutive O
earthworm O
( O
Eisenia O
fetida O
) O
Generations O
. O

The O
aim O
of O
the O
present O
study O
was O
to O
determine O
the O
toxicity O
of O
a O
mixture O
containing O
the O
biocides O
picoxystrobin B
, O
esfenvalerate B
, O
and O
triclosan B
to O
the O
reproduction O
and O
adult O
survival O
of O
two O
consecutive O
generations O
of O
Eisenia O
fetida O
( O
Savigny O
, O
1826 O
) O
. O

Concentration O
addition O
and O
independent O
action O
were O
used O
to O
predict O
mixture O
toxicity O
. O

Due O
to O
degradation O
of O
mixture O
components O
during O
the O
course O
of O
the O
experiment O
, O
predictions O
were O
based O
both O
on O
the O
mixture O
composition O
at O
the O
beginning O
and O
the O
end O
of O
the O
exposure O
period O
. O

As O
degradations O
were O
dose O
- O
dependent O
, O
none O
of O
the O
calculated O
predictions O
were O
precise O
for O
the O
entire O
concentration O
range O
, O
although O
combining O
both O
predictions O
led O
us O
to O
conclude O
that O
lethal O
toxicity O
was O
well O
predicted O
by O
concentration O
addition O
and O
sublethal O
toxicity O
by O
independent O
action O
. O

Reproduction O
of O
the O
F1 O
generation O
was O
inhibited O
more O
( O
p O
< O
0 O
. O
0001 O
) O
than O
reproduction O
of O
the O
F0 O
generation O
. O

Adult O
survival O
did O
not O
differ O
between O
generations O
. O

The O
accuracy O
of O
the O
mixture O
toxicity O
predictions O
thus O
depended O
on O
both O
the O
time O
- O
dependent O
mixture O
composition O
and O
the O
earthworm O
generation O
. O

The O
results O
of O
this O
study O
underline O
the O
need O
for O
more O
advanced O
mixture O
toxicity O
prediction O
models O
that O
consider O
degradation O
kinetics O
and O
changes O
in O
toxic O
effects O
over O
time O
. O

Inadequate O
levothyroxine B
replacement O
for O
primary O
hypothyroidism O
is O
associated O
with O
poor O
health O
- O
related O
quality O
of O
life O
- O
a O
Brazilian O
multicentre O
study O
. O

This O
study O
aimed O
to O
verify O
the O
impact O
of O
levothyroxine B
replacement O
on O
health O
- O
related O
quality O
of O
life O
( O
HRQoL O
) O
in O
a O
Brazilian O
sample O
of O
primary O
hypothyroidism O
patients O
. O

A O
cross O
- O
sectional O
study O
was O
performed O
with O
2 O
, O
057 O
consecutive O
primary O
hypothyroidism O
patients O
on O
levothyroxine B
( O
LT4 B
) O
replacement O
at O
four O
referral O
centers O
in O
Brazil O
( O
median O
age O
= O
53 O
; O
25th O
percentile O
= O
43 O
; O
75th O
percentile O
= O
61 O
years O
) O
. O

Patient O
biochemical O
data O
were O
acquired O
from O
medical O
records O
, O
and O
patients O
completed O
a O
questionnaire O
on O
socioeconomic O
issues O
and O
clinical O
signs O
and O
symptoms O
of O
hypothyroidism O
. O

HRQoL O
was O
assessed O
using O
the O
SF O
- O
36v2 O
. O

Patients O
were O
divided O
into O
three O
groups O
according O
to O
TSH O
levels O
: O
overtreated O
( O
OvT O
; O
TSH O
< O
0 O
. O
4 O
mU O
/ O
L O
) O
, O
appropriately O
treated O
( O
AT O
; O
TSH O
between O
0 O
. O
4 O
and O
4 O
. O
0 O
mU O
/ O
L O
) O
, O
and O
undertreated O
( O
UnT O
; O
TSH O
> O
4 O
. O
0 O
mU O
/ O
L O
) O
. O

Patients O
were O
also O
analyzed O
by O
TSH O
and O
FT4 O
serum O
levels O
: O
overt O
hyperthyroidism O
( O
OHyper O
; O
TSH O
< O
0 O
. O
4 O
mU O
/ O
L O
and O
FT4 O
> O
1 O
. O
9 O
ng O
/ O
dL O
) O
, O
subclinical O
hyperthyroidism O
( O
SHyper O
; O
TSH O
< O
0 O
. O
4 O
mU O
/ O
L O
and O
FT4 O
0 O
. O
8 O
- O
1 O
. O
9 O
ng O
/ O
dL O
) O
, O
subclinical O
hypothyroidism O
( O
SHypo O
; O
TSH O
> O
4 O
. O
0 O
mU O
/ O
L O
and O
FT4 O
0 O
. O
8 O

- O
1 O
. O
9 O
ng O
/ O
dL O
) O
, O
and O
overt O
hypothyroidism O
( O
OHypo O
; O
TSH O
> O
4 O
. O
0 O
mU O
/ O
L O
and O
FT4 O
< O
0 O
. O
8 O
ng O
/ O
dL O
) O
. O

A O
total O
of O
14 O
. O
4 O
% O
of O
patients O
were O
OvT O
, O
with O
13 O
. O
0 O
% O
SHyper O
and O
1 O
. O
4 O
% O
OHyper O
. O

The O
prevalence O
of O
UnT O
was O
25 O
. O
9 O
% O
, O
with O
21 O
. O
5 O
% O
SHypo O
and O
4 O
. O
4 O
% O
OHypo O
. O

Overtreatment O
was O
not O
associated O
with O
HRQoL O
impairment O
. O

UnT O
patients O
had O
worse O
HRQoL O
than O
AT O
patients O
, O
especially O
for O
physical O
and O
emotional O
aspects O
, O
independent O
of O
SHypo O
or O
OHypo O
status O
. O

Hypothyroidism O
undertreatment O
is O
associated O
with O
poor O
patient O
HRQoL O
. O

Therefore O
, O
adequate O
LT4 B
therapy O
should O
be O
given O
to O
maintain O
serum O
TSH O
within O
the O
reference O
range O
. O

Novel O
locus O
including O
FGF21 O
is O
associated O
with O
dietary O
macronutrient O
intake O
. O

Dietary O
intake O
of O
macronutrients O
( O
carbohydrate B
, O
protein O
, O
and O
fat O
) O
has O
been O
associated O
with O
risk O
of O
chronic O
conditions O
such O
as O
obesity O
and O
diabetes O
. O

Family O
studies O
have O
reported O
a O
moderate O
contribution O
of O
genetics O
to O
variation O
in O
macronutrient O
intake O
. O

In O
a O
genome O
- O
wide O
meta O
- O
analysis O
of O
a O
population O
- O
based O
discovery O
cohort O
( O
n O
= O
33 O
533 O
) O
, O
rs838133 O
in O
FGF21 O
( O
19q13 O
. O
33 O
) O
, O
rs197273 O
near O
TRAF O
family O
member O
- O
associated O
NF O
- O
kappa O
- O
B O
activator O
( O
TANK O
) O
( O
2p24 O
. O
2 O
) O
, O
and O
rs10163409 O
in O
FTO O
( O
16q12 O
. O
2 O
) O
were O
among O
the O
top O
associations O
( O
P O
< O
10 O
( O
- O
5 O
) O
) O
for O
percentage O
of O
total O
caloric O
intake O
from O
protein O
and O

carbohydrate B
. O

rs838133 O
was O
replicated O
in O
silico O
in O
an O
independent O
sample O
from O
the O
Cohorts O
for O
Heart O
and O
Aging O
Research O
in O
Genomic O
Epidemiology O
Consortium O
( O
CHARGE O
) O
Nutrition O
Working O
Group O
( O
n O
= O
38 O
360 O
) O
and O
attained O
genome O
- O
wide O
significance O
in O
combined O
analysis O
( O
Pjoint O
= O
7 O
. O
9 O
x O
10 O
( O
- O
9 O
) O
) O
. O

A O
cytokine O
involved O
in O
cellular O
metabolism O
, O
FGF21 O
is O
a O
potential O
susceptibility O
gene O
for O
obesity O
and O
type O
2 O
diabetes O
. O

Our O
results O
highlight O
the O
potential O
of O
genetic O
variation O
for O
determining O
dietary O
macronutrient O
intake O
. O

Effect O
of O
phospholipid O
composition O
and O
phase O
on O
nanodisc O
films O
at O
the O
solid O
- O
liquid O
interface O
as O
studied O
by O
neutron O
reflectivity O
. O

Nanodiscs O
are O
disc O
- O
like O
self O
- O
assembled O
structures O
formed O
by O
phospholipids O
and O
amphipatic O
proteins O
. O

The O
proteins O
wrap O
like O
a O
belt O
around O
the O
hydrophobic O
part O
of O
the O
lipids O
, O
basically O
producing O
nanometer O
- O
sized O
patches O
of O
lipid O
bilayers O
. O

The O
bilayer O
in O
the O
nanodisc O
constitutes O
a O
native O
- O
like O
model O
of O
the O
cell O
membrane O
and O
can O
act O
as O
a O
nanometer O
- O
sized O
container O
for O
functional O
single O
membrane O
proteins O
. O

In O
this O
study O
, O
we O
present O
a O
general O
nanodisc O
- O
based O
system O
, O
intended O
for O
structural O
and O
functional O
studies O
of O
membrane O
proteins O
. O

In O
this O
method O
, O
the O
nanodiscs O
are O
aligned O
at O
a O
solid O
surface O
, O
providing O
the O
ability O
to O
determine O
the O
average O
structure O
of O
the O
film O
along O
an O
axis O
perpendicular O
to O
the O
interface O
as O
measured O
by O
neutron O
reflectivity O
. O

The O
nanodisc O
film O
was O
optimized O
in O
terms O
of O
nanodisc O
coverage O
, O
reduced O
film O
roughness O
, O
and O
stability O
for O
time O
- O
consuming O
studies O
. O

This O
was O
achieved O
by O
a O
systematic O
variation O
of O
the O
lipid O
phase O
, O
charge O
, O
and O
length O
of O
lipid O
tails O
. O

Herein O
, O
we O
show O
that O
, O
although O
all O
studied O
nanodiscs O
align O
with O
their O
lipid O
bilayer O
parallel O
to O
the O
interface O
, O
gel O
- O
phase O
DMPC B
nanodiscs O
form O
the O
most O
suitable O
film O
for O
future O
membrane O
protein O
studies O
since O
they O
yield O
a O
dense O
irreversibly O
adsorbed O
film O
with O
low O
roughness O
and O
high O
stability O
over O
time O
. O

This O
may O
be O
explained O
by O
the O
appropriate O
matching O
between O
the O
thickness O
of O
the O
hydrophobic O
lipid O
core O
of O
gel O
phase O
DMPC B
and O
the O
height O
of O
the O
belt O
protein O
. O

Moreover O
, O
once O
formed O
the O
gel O
- O
phase O
DMPC B
nanodiscs O
film O
can O
be O
heated O
up O
to O
melt O
the O
lipid O
bilayer O
, O
thus O
providing O
a O
more O
biologically O
friendly O
environment O
for O
membrane O
proteins O
. O

The O
GABA B
A O
receptor O
subunits O
heterologously O
expressed O
in O
Xenopus O
oocytes O
. O

The O
gamma B
- I
aminobutyric I
acid I
( O
GABA B
) O
A O
receptor O
is O
composed O
of O
a O
variety O
of O
subunits O
and O
combinations O
and O
shows O
a O
characteristic O
distribution O
in O
the O
CNS O
. O

To O
date O
, O
20 O
subunits O
of O
the O
GABA B
A O
receptor O
have O
been O
cloned O
: O
alpha O
1 O
- O
6 O
, O
beta O
1 O
- O
4 O
, O
gamma O
1 O
- O
3 O
, O
delta O
, O
pi O
, O
epsilon O
, O
Theta O
, O
and O
rho O
1 O
- O
3 O
. O

Oocyte O
of O
Xenopus O
laevis O
is O
one O
of O
the O
most O
frequently O
used O
heterologous O
expression O
systems O
, O
which O
are O
used O
to O
design O
and O
analyze O
specific O
combinations O
of O
GABA B
A O
receptor O
subunits O
. O

In O
oocytes O
, O
a O
certain O
GABA B
A O
receptor O
function O
is O
studied O
only O
by O
comparing O
the O
amplitude O
of O
the O
response O
to O
GABA B
and O
other O
drugs O
by O
physiological O
and O
pharmacological O
methods O
. O

According O
to O
the O
studies O
on O
Xenopus O
laevis O
oocytes O
, O
the O
alpha O
1 O
beta O
2 O
gamma O
2S O
receptor O
combination O
is O
mostly O
used O
. O

The O
alpha O
1 O
- O
containing O
receptors O
mediate O
sedative O
and O
anticonvulsant O
acts O
. O

The O
results O
of O
studies O
on O
oocytes O
show O
that O
PKA O
, O
NKCC1 O
, O
P2X3 O
receptors O
, O
and O
GABA B
A O
receptor O
- O
associated O
protein O
, O
etc O
. O
, O
are O
existing O
systems O
that O
show O
different O
reactivity O
to O
the O
GABA B
A O
receptors O
. O

The O
GABA B
A O
receptor O
subunits O
contain O
distinct O
binding O
sites O
for O
BZDs B
, O
neurosteroids O
, O
general O
anesthetics O
, O
etc O
. O
, O
which O
are O
responsible O
for O
the O
numerous O
functions O
of O
the O
GABA B
A O
receptor O
. O

A O
variety O
of O
other O
drugs O
, O
such O
as O
topiramate B
, O
TG41 B
, O
( B
+ I
) I
- I
and I
( I
- I
) I
- I
borneol I
, O
apigenin B
, O
and O
6 B
- I
methylflavone I
could O
also O
have O
modulatory O
effects O
on O
the O
GABA B
A O
receptors O
. O

Some O
of O
the O
different O
models O
and O
hypotheses O
on O
GABA B
A O
receptor O
structure O
and O
function O
have O
been O
achieved O
by O
using O
the O
two O
- O
electrode O
voltage O
clamp O
method O
in O
oocytes O
. O

Bioactive O
natural O
products O
from O
the O
antarctic O
and O
arctic O
organisms O
. O

Polar O
regions O
are O
remote O
and O
challenging O
areas O
on O
the O
earth O
. O

In O
view O
of O
the O
unique O
environment O
and O
the O
severe O
competition O
in O
polar O
regions O
, O
it O
' O
s O
considered O
that O
the O
ecological O
system O
might O
be O
the O
producer O
of O
new O
compounds O
with O
diversity O
biological O
activities O
. O

This O
review O
is O
an O
attempt O
to O
consolidate O
the O
studies O
about O
97 O
natural O
products O
isolated O
from O
Antarctic O
and O
Arctic O
organisms O
including O
microbes O
, O
algae O
, O
sponges O
, O
bryozoans O
, O
and O
tunicates O
and O
so O
on O
published O
in O
the O
recent O
years O
. O

The O
emphasis O
is O
mainly O
about O
the O
new O
compounds O
, O
source O
organisms O
and O
biological O
activities O
, O
which O
signifies O
the O
immense O
competence O
of O
Antarctic O
and O
Arctic O
organisms O
as O
bioactive O
natural O
products O
producers O
. O

Taxol B
: O
efficacy O
against O
oral O
squamous O
cell O
carcinoma O
. O

In O
medicinal O
chemistry O
, O
one O
of O
the O
most O
studied O
molecules O
in O
recent O
history O
is O
taxol B
. O

Taxol B
is O
a O
versatile O
natural O
product O
that O
is O
used O
in O
various O
cancer O
treatment O
regimens O
. O

It O
is O
administered O
to O
patients O
with O
breast O
, O
lung O
, O
and O
ovarian O
cancers O
, O
and O
is O
currently O
being O
studied O
for O
the O
treatment O
of O
squamous O
cell O
carcinoma O
of O
the O
oral O
cavity O
and O
tongue O
. O

Taxol B
has O
been O
tested O
in O
a O
number O
of O
research O
and O
clinical O
phase O
trials O
to O
determine O
feasibility O
, O
toxicity O
, O
and O
cytotoxicity O
against O
oral O
squamous O
cell O
carcinoma O
as O
a O
single O
drug O
regimen O
and O
as O
a O
contributing O
drug O
component O
in O
treatment O
plans O
. O

This O
paper O
reviews O
over O
forty O
articles O
that O
examine O
cell O
lines O
, O
murine O
models O
, O
and O
human O
results O
for O
the O
response O
of O
taxol B
against O
squamous O
cell O
carcinoma O
( O
SCC O
) O
of O
the O
oral O
cavity O
and O
the O
tongue O
. O

The O
evolution O
of O
drugs O
on O
schistosoma O
treatment O
: O
looking O
to O
the O
past O
to O
improve O
the O
future O
. O

Schistosomiasis O
is O
a O
devastating O
worldwide O
widespread O
tropical O
disease O
that O
currently O
affects O
more O
than O
230 O
million O
people O
, O
making O
it O
an O
issue O
of O
great O
socioeconomic O
and O
public O
health O
importance O
. O

Unfortunatelly O
there O
is O
a O
single O
drug O
for O
the O
treatment O
of O
all O
forms O
of O
schistosomiasis O
, O
praziquantel B
, O
which O
was O
introduced O
in O
therapy O
in O
1980 O
. O

The O
article O
goes O
by O
antimony B
compounds O
, O
emetine B
, O
hydantoin B
, O
nitrofurans B
, O
lucanthone B
, O
hycanthone B
, O
oxamniquine B
derivatives O
and O
organophosphates B
until O
it O
finally O
gets O
to O
praziquantel B
derivatives O
. O

The O
intent O
of O
this O
review O
is O
to O
provide O
a O
panorama O
of O
drugs O
that O
were O
and O
are O
being O
used O
in O
human O
chemotherapy O
looking O
to O
the O
past O
to O
improve O
rational O
design O
drugs O
in O
the O
future O
. O

Not O
only O
clinical O
used O
compounds O
will O
be O
shown O
but O
also O
synthesized O
and O
tested O
compounds O
in O
vitro O
and O
in O
vivo O
in O
animal O
models O
which O
haven O
' O
t O
yet O
to O
be O
used O
in O
humans O
. O

Prospects O
for O
drug O
discovery O
and O
vaccines O
to O
be O
used O
in O
the O
treatment O
and O
prevention O
of O
schistosomiasis O
, O
clinical O
trials O
, O
concerns O
about O
the O
resistance O
/ O
decreased O
effectiveness O
of O
the O
treatment O
, O
and O
patent O
database O
will O
also O
be O
discussed O
. O

At O
the O
end O
of O
the O
review O
the O
reader O
will O
notice O
that O
much O
has O
been O
done O
but O
much O
still O
needs O
to O
be O
done O
yet O
. O

Electrochemiluminesc O
biosensor O
based O
on O
conducting O
poly B
( I
5 I
- I
formylindole I
) I
for O
sensitive O
detection O
of O
Ramos O
cells O
. O

A O
signal O
- O
on O
electrochemiluminesc O
( O
ECL O
) O
biosensor O
devoted O
to O
the O
detection O
of O
Ramos O
cells O
was O
fabricated O
based O
on O
a O
novel O
conducting O
polymer O
, O
poly B
( I
5 I
- I
formylindole I
) I
( O
P5FIn B
) O
, O
which O
was O
synthesized O
electrochemically O
by O
direct O
anodic O
oxidation O
of O
5 B
- I
formylindole I
( O
5FIn B
) O
. O

This O
ECL O
platform O
was O
presented O
by O
covalently O
coupling O
the O
18 O
- O
mer O
amino B
- O
substituted O
oligonucleotide O
( O
ODN O
) O
probes O
with O
aldehyde B
groups O
that O
are O
strongly O
reactive O
toward O
a O
variety O
of O
nucleophiles O
on O
the O
surface O
of O
solid O
substrates O
. O

The O
specific O
identification O
and O
high O
- O
affinity O
between O
aptamers O
and O
target O
cells O
, O
gold O
nanoparticles O
( O
AuNPs O
) O
enhanced O
ECL O
nanoprobes O
, O
along O
with O
P5FIn O
induced O
ECL O
quenching O
contributed O
greatly O
to O
the O
sensitivity O
and O
selectivity O
. O

The O
ECL O
signals O
were O
logarithmically O
linear O
with O
the O
concentration O
of O
Ramos O
cells O
in O
a O
wide O
determination O
range O
from O
500 O
to O
1 O
. O
0 O
x O
10 O
( O
5 O
) O
cells O
mL O
( O
- O
1 O
) O
, O
and O
the O
corresponding O
detection O
limit O
was O
300 O
cells O
mL O
( O
- O
1 O
) O
. O

How O
the O
quantum O
efficiency O
of O
a O
highly O
emissive O
binuclear O
copper B
complex O
is O
enhanced O
by O
changing O
the O
processing O
solvent O
. O

Polymorphism O
is O
often O
linked O
to O
the O
choice O
of O
processing O
solvents O
. O

Packing O
effects O
or O
the O
preference O
of O
one O
certain O
conformer O
as O
possible O
causes O
of O
this O
phenomenon O
are O
strongly O
dependent O
on O
solvents O
and O
especially O
on O
their O
polarity O
. O

Even O
in O
amorphous O
solids O
, O
the O
microstructure O
can O
be O
controlled O
by O
the O
choice O
of O
solvents O
. O

Polymorphs O
or O
amorphous O
solids O
featuring O
different O
packing O
densities O
can O
exhibit O
different O
properties O
in O
terms O
of O
stability O
or O
optical O
effects O
. O

The O
influence O
of O
these O
effects O
on O
a O
binuclear O
, O
strongly O
luminescent O
copper B
( I
I I
) I
complex O
was O
investigated O
. O

Many O
possible O
applications O
for O
luminescent O
, O
amorphous O
coordination O
compounds O
, O
such O
as O
organic O
light O
- O
emitting O
diodes O
, O
sensors O
, O
and O
organic O
lasers O
, O
rely O
on O
photophysical O
properties O
like O
quantum O
efficiency O
to O
be O
repeatable O
. O

The O
effect O
of O
processing O
solvents O
in O
this O
context O
is O
often O
underestimated O
, O
but O
very O
relevant O
for O
utilization O
in O
device O
manufacturing O
and O
should O
therefore O
be O
understood O
more O
deeply O
. O

In O
this O
work O
, O
theoretical O
derivations O
, O
DFT O
calculations O
, O
X O
- O
ray O
- O
diffraction O
, O
photoluminescence O
spectroscopy O
, O
and O
the O
time O
- O
dependent O
single O
- O
photon O
- O
counting O
- O
technique O
( O
TDSPC O
) O
were O
used O
to O
understand O
this O
phenomenon O
more O
deeply O
. O

The O
influence O
of O
five O
different O
solvents O
on O
Cu2I2 B
( I
MePyrPHOS I
) I
3 I
was O
probed O
. O

This O
resulted O
in O
a O
modulation O
of O
the O
photoluminescence O
quantum O
yield O
phi O
between O
0 O
. O
5 O
and O
0 O
. O
9 O
in O
amorphous O
solid O
state O
. O

A O
new O
polymorph O
of O
the O
material O
with O
slightly O
reduced O
values O
for O
phi O
has O
been O
identified O
. O

The O
reduced O
efficiency O
could O
be O
correlated O
with O
a O
higher O
porosity O
and O
a O
reduced O
packing O
density O
. O

Dense O
packing O
reduces O
nonradiative O
decay O
by O
geometrical O
fixation O
and O
thus O
increases O
the O
quantum O
efficiency O
. O

The O
existence O
of O
similar O
effects O
on O
aluminum B
and O
iridium B
compounds O
has O
been O
confirmed O
by O
application O
of O
different O
processing O
solvents O
on O
Alq3 B
and O
Ir B
( I
ppy I
) I
3 I
. O

These O
results O
show O
that O
a O
tuning O
of O
the O
efficiency O
of O
a O
emissive O
metal O
complexes O
by O
choosing O
a O
proper O
processing O
solvent O
is O
possible O
. O

If O
highly O
efficient O
materials O
for O
practical O
applications O
are O
desired O
, O
an O
evaluation O
of O
multiple O
solvents O
has O
to O
be O
considered O
. O

Heavy O
- O
enzyme O
kinetic O
isotope O
effects O
on O
proton O
transfer O
in O
alanine B
racemase O
. O

The O
catalytic O
effects O
of O
perdeuterating O
the O
pyridoxal B
phosphate I
- O
dependent O
enzyme O
alanine B
racemase O
from O
Geobacillus O
stearothermophilus O
are O
reported O
. O

The O
mass O
of O
the O
heavy O
perdeuterated O
form O
is O
~ O
5 O
. O
5 O
% O
greater O
than O
that O
of O
the O
protiated O
form O
, O
causing O
kinetic O
isotope O
effects O
( O
KIEs O
) O
of O
~ O
1 O
. O
3 O
on O
k O
( O
cat O
) O
and O
k O
( O
cat O
) O
/ O
K O
( O
M O
) O
for O
both O
L B
- I
and I
D I
- I
alanine I
. O

These O
values O
increase O
when O
C B
alpha I
- I
deuterated I
alanine I
is O
used O
as O
the O
substrate O
. O

The O
heavy O
- O
enzyme O
KIEs O
of O
~ O
3 O
on O
k O
( O
cat O
) O
/ O
K O
( O
M O
) O
with O
deuterated O
substrates O
are O
greater O
than O
the O
product O
of O
the O
individual O
heavy O
- O
enzyme O
and O
primary O
substrate O
KIEs O
. O

This O
breakdown O
of O
the O
rule O
of O
the O
geometric O
mean O
is O
likely O
due O
to O
coupled O
motion O
between O
the O
protein O
and O
the O
proton O
- O
transfer O
reaction O
coordinate O
in O
the O
rate O
- O
limiting O
step O
. O

These O
data O
implicate O
a O
direct O
role O
for O
protein O
vibrational O
motions O
in O
barrier O
crossing O
for O
proton O
- O
transfer O
steps O
in O
alanine B
racemase O
. O

Gene O
copy O
- O
number O
alterations O
: O
a O
cost O
- O
benefit O
analysis O
. O

Changes O
in O
DNA O
copy O
number O
, O
whether O
confined O
to O
specific O
genes O
or O
affecting O
whole O
chromosomes O
, O
have O
been O
identified O
as O
causes O
of O
diseases O
and O
developmental O
abnormalities O
and O
as O
sources O
of O
adaptive O
potential O
. O

Here O
, O
we O
discuss O
the O
costs O
and O
benefits O
of O
DNA O
copy O
- O
number O
alterations O
. O

Changes O
in O
DNA O
copy O
number O
are O
largely O
detrimental O
. O

Amplifications O
or O
deletions O
of O
specific O
genes O
can O
elicit O
discrete O
defects O
. O

Large O
- O
scale O
changes O
in O
DNA O
copy O
number O
can O
also O
cause O
detrimental O
phenotypes O
that O
are O
due O
to O
the O
cumulative O
effects O
of O
copy O
- O
number O
alterations O
of O
many O
genes O
simultaneously O
. O

On O
the O
other O
hand O
, O
studies O
in O
microorganisms O
show O
that O
DNA O
copy O
- O
number O
alterations O
can O
be O
beneficial O
, O
increasing O
survival O
under O
selective O
pressure O
. O

As O
DNA O
copy O
- O
number O
alterations O
underlie O
many O
human O
diseases O
, O
we O
will O
end O
with O
a O
discussion O
of O
gene O
copy O
- O
number O
changes O
as O
therapeutic O
targets O
. O

Conformational O
coupling O
across O
the O
plasma O
membrane O
in O
activation O
of O
the O
EGF O
receptor O
. O

How O
the O
epidermal O
growth O
factor O
receptor O
( O
EGFR O
) O
activates O
is O
incompletely O
understood O
. O

The O
intracellular O
portion O
of O
the O
receptor O
is O
intrinsically O
active O
in O
solution O
, O
and O
to O
study O
its O
regulation O
, O
we O
measured O
autophosphorylation O
as O
a O
function O
of O
EGFR O
surface O
density O
in O
cells O
. O

Without O
EGF O
, O
intact O
EGFR O
escapes O
inhibition O
only O
at O
high O
surface O
densities O
. O

Although O
the O
transmembrane O
helix O
and O
the O
intracellular O
module O
together O
suffice O
for O
constitutive O
activity O
even O
at O
low O
densities O
, O
the O
intracellular O
module O
is O
inactivated O
when O
tethered O
on O
its O
own O
to O
the O
plasma O
membrane O
, O
and O
fluorescence O
cross O
- O
correlation O
shows O
that O
it O
fails O
to O
dimerize O
. O

NMR O
and O
functional O
data O
indicate O
that O
activation O
requires O
an O
N B
- O
terminal O
interaction O
between O
the O
transmembrane O
helices O
, O
which O
promotes O
an O
antiparallel O
interaction O
between O
juxtamembrane O
segments O
and O
release O
of O
inhibition O
by O
the O
membrane O
. O

We O
conclude O
that O
EGF O
binding O
removes O
steric O
constraints O
in O
the O
extracellular O
module O
, O
promoting O
activation O
through O
N B
- O
terminal O
association O
of O
the O
transmembrane O
helices O
. O

LBR O
and O
lamin O
A O
/ O
C O
sequentially O
tether O
peripheral O
heterochromatin O
and O
inversely O
regulate O
differentiation O
. O

Eukaryotic O
cells O
have O
a O
layer O
of O
heterochromatin O
at O
the O
nuclear O
periphery O
. O

To O
investigate O
mechanisms O
regulating O
chromatin O
distribution O
, O
we O
analyzed O
heterochromatin O
organization O
in O
different O
tissues O
and O
species O
, O
including O
mice O
with O
mutations O
in O
the O
lamin O
B O
receptor O
( O
Lbr O
) O
and O
lamin O
A O
( O
Lmna O
) O
genes O
that O
encode O
nuclear O
envelope O
( O
NE O
) O
proteins O
. O

We O
identified O
LBR O
- O
and O
lamin O
- O
A O
/ O
C O
- O
dependent O
mechanisms O
tethering O
heterochromatin O
to O
the O
NE O
. O

The O
two O
tethers O
are O
sequentially O
used O
during O
cellular O
differentiation O
and O
development O
: O
first O
the O
LBR O
- O
and O
then O
the O
lamin O
- O
A O
/ O
C O
- O
dependent O
tether O
. O

The O
absence O
of O
both O
LBR O
and O
lamin O
A O
/ O
C O
leads O
to O
loss O
of O
peripheral O
heterochromatin O
and O
an O
inverted O
architecture O
with O
heterochromatin O
localizing O
to O
the O
nuclear O
interior O
. O

Myoblast O
transcriptome O
analyses O
indicated O
that O
selective O
disruption O
of O
the O
LBR O
- O
or O
lamin O
- O
A O
- O
dependent O
heterochromatin O
tethers O
have O
opposite O
effects O
on O
muscle O
gene O
expression O
, O
either O
increasing O
or O
decreasing O
, O
respectively O
. O

These O
results O
show O
how O
changes O
in O
NE O
composition O
contribute O
to O
regulating O
heterochromatin O
positioning O
, O
gene O
expression O
, O
and O
cellular O
differentiation O
during O
development O
. O

Vitamin B
D I
metabolism O
in O
human O
bone O
marrow O
stromal O
( O
mesenchymal O
stem O
) O
cells O
. O

There O
are O
many O
human O
extra O
- O
renal O
tissues O
and O
cells O
that O
biosynthesize O
1 B
alpha I
, I
25 I
- I
dihydroxyvitamin I
D I
( O
1 B
alpha I
, I
25 I
( I
OH I
) I
( I
2 I
) I
D I
) O
by O
the O
action O
of O
CYP27B1 O
/ O
1 O
alpha O
- O
hydroxylase O
. O

Human O
marrow O
stromal O
cells O
( O
hMSCs O
) O
, O
also O
known O
as O
mesenchymal O
stem O
cells O
, O
were O
isolated O
from O
marrow O
discarded O
from O
well O
- O
characterized O
, O
consented O
subjects O
during O
common O
orthopedic O
procedures O
. O

Human O
MSCs O
can O
give O
rise O
to O
osteoblasts O
, O
chondrocytes O
, O
adipocytes O
, O
and O
other O
lineages O
. O

Their O
in O
vitro O
differentiation O
to O
osteoblasts O
is O
stimulated O
by O
1 B
alpha I
, I
25 I
( I
OH I
) I
( I
2 I
) I
D I
, O
and O
recent O
evidence O
indicates O
that O
they O
have O
the O
capacity O
to O
metabolize O
vitamin B
D I
in O
a O
regulated O
manner O
. O

Human O
MSCs O
express O
the O
vitamin B
D I
receptor O
, O
25 O
- O
hydroxylases O
, O
1 O
alpha O
- O
hydroxylase O
, O
and O
24 O
- O
hydroxylase O
; O
stimulation O
of O
in O
vitro O
osteoblastogenesis O
by O
25 B
( I
OH I
) I
D I
depends O
on O
the O
activity O
of O
CYP27B1 O
/ O
1 O
alpha O
- O
hydroxylase O
. O

The O
finding O
that O
hMSCs O
are O
a O
both O
a O
producer O
and O
target O
of O
1 B
alpha I
, I
25 I
( I
OH I
) I
( I
2 I
) I
D I
suggests O
a O
potential O
autocrine O
/ O
paracrine O
role O
of O
vitamin B
D I
metabolism O
in O
osteoblast O
differentiation O
. O

Expression O
and O
enzyme O
activity O
of O
CYP27B1 O
/ O
1 O
alpha O
- O
hydroxylase O
are O
upregulated O
by O
substrate O
25 B
( I
OH I
) I
D I
and O
Parathyroid O
Hormone O
( O
PTH O
) O
and O
are O
downregulated O
by O
1 B
alpha I
, I
25 I
( I
OH I
) I
( I
2 I
) I
D I
. O

With O
subject O
age O
, O
there O
are O
decreases O
in O
basal O
osteoblast O
potential O
and O
in O
stimulation O
of O
osteoblastogenesis O
by O
1 B
alpha I
, I
25 I
( I
OH I
) I
( I
2 I
) I
D I
, O
25 B
( I
OH I
) I
D I
, O
and O
PTH O
. O

In O
vitro O
treatment O
with O
a O
combination O
of O
25 B
( I
OH I
) I
D I
and O
PTH O
rejuvenated O
osteoblastogenesis O
with O
hMSCs O
from O
elders O
; O
this O
was O
attributable O
to O
increases O
in O
CYP27B1 O
/ O
1 O
alpha O
- O
hydroxylase O
and O
in O
receptor O
for O
each O
hormone O
by O
the O
reciprocal O
factor O
. O

Other O
clinical O
variables O
beside O
age O
, O
i O
. O
e O
. O
low O
serum O
25 B
( I
OH I
) I
D I
or O
low O
estimated O
glomerular O
filtration O
rate O
, O
are O
correlated O
with O
reduced O
osteoblastogenesis O
. O

These O
studies O
suggest O
that O
osteoblastogenesis O
may O
not O
be O
optimal O
unless O
there O
is O
sufficient O
serum O
25 B
( I
OH I
) I
D I
substrate O
for O
hMSCs O
to O
synthesize O
and O
respond O
to O
local O
1 B
alpha I
, I
25 I
( I
OH I
) I
( I
2 I
) I
D I
. O

Branched O
chain O
amino B
acids I
are O
novel O
biomarkers O
for O
discrimination O
of O
metabolic O
wellness O
. O

OBJECTIVE O
: O
To O
identify O
novel O
biomarkers O
through O
metabolomic O
profiles O
that O
distinguish O
metabolically O
well O
( O
MW O
) O
from O
metabolically O
unwell O
( O
MUW O
) O
individuals O
, O
independent O
of O
body O
mass O
index O
( O
BMI O
) O
. O

MATERIALS O
/ O
METHODS O
: O
This O
study O
was O
conducted O
as O
part O
of O
the O
Measurement O
to O
Understand O
the O
Reclassification O
of O
Disease O
of O
Cabarrus O
/ O
Kannapolis O
( O
MURDOCK O
) O
project O
. O

Individuals O
from O
3 O
cohorts O
were O
classified O
as O
lean O
( O
BMI O
< O
25kg O
/ O
m O
( O
2 O
) O
) O
, O
overweight O
( O
BMI O
> O
= O
25kg O
/ O
m O
( O
2 O
) O
, O
BMI O
< O
30kg O
/ O
m O
( O
2 O
) O
) O
or O
obese O
( O
BMI O
> O
= O
30kg O
/ O
m O
( O
2 O
) O
) O
. O

Cardiometabolic O
abnormalities O
were O
defined O
as O
: O
( O
1 O
) O
impaired O
fasting O
glucose B
( O
> O
= O
100mg O
/ O
dL O
and O
< O
= O
126mg O
/ O
dL O
) O
; O
( O
2 O
) O
hypertension O
; O
( O
3 O
) O
triglycerides B
> O
= O
150mg O
/ O
dL O
; O
( O
4 O
) O
HDL O
- O
C O
< O
40mg O
/ O
dL O
in O
men O
, O
< O
50mg O
/ O
dL O
in O
women O
; O
and O
( O
5 O
) O
insulin O
resistance O
( O
calculated O
Homeostatic O
Model O
Assessment O
( O
HOMA O
- O
IR O
) O
index O
of O
> O
5 O
. O
13 O
) O
. O

MW O
individuals O
were O
defined O
as O
having O
< O
2 O
cardiometabolic O
abnormalities O
and O
MUW O
individuals O
had O
> O
= O
two O
cardiometabolic O
abnormalities O
. O

Targeted O
profiling O
of O
55 O
metabolites O
used O
mass O
- O
spectroscopy O
- O
based O
methods O
. O

Principal O
components O
analysis O
( O
PCA O
) O
was O
used O
to O
reduce O
the O
large O
number O
of O
correlated O
metabolites O
into O
clusters O
of O
fewer O
uncorrelated O
factors O
. O

RESULTS O
: O
Of O
1872 O
individuals O
, O
410 O
were O
lean O
, O
610 O
were O
overweight O
, O
and O
852 O
were O
obese O
. O

Of O
lean O
individuals O
, O
67 O
% O
were O
categorized O
as O
MUW O
, O
whereas O
80 O
% O
of O
overweight O
and O
87 O
% O
of O
obese O
individuals O
were O
MUW O
. O

PCA O
- O
derived O
factors O
with O
levels O
that O
differed O
the O
most O
between O
MW O
and O
MUW O
groups O
were O
factors O
4 O
( O
branched O
chain O
amino B
acids I
[ O
BCAA O
] O
) O
[ O
p O
< O
. O
0001 O
] O
, O
8 O
( O
various O
metabolites O
) O
[ O
p O
< O
. O
0001 O
] O
, O
9 O
( O
C4 O
/ O
Ci4 O
, O
C3 O
, O
C5 O
acylcarnitines B
) O
[ O
p O
< O
. O
0001 O
] O
and O
10 O
( O
amino B
acids I
) O
[ O
p O
< O
. O
0002 O
] O
. O

Further O
, O
Factor O
4 O
, O
distinguishes O
MW O
from O
MUW O
individuals O
independent O
of O
BMI O
. O

CONCLUSION O
: O
BCAA O
and O
related O
metabolites O
are O
promising O
biomarkers O
that O
may O
aid O
in O
understanding O
cardiometabolic O
health O
independent O
of O
BMI O
category O
. O

Critical O
role O
of O
a O
methyl B
group O
on O
the O
gamma B
- I
lactone I
ring O
of O
annonaceous O
acetogenins I
in O
the O
potent O
inhibition O
of O
mitochondrial O
complex O
I O
. O

C34 O
- O
epi O
and O
C34 O
- O
epi O
- O
C35 O
- O
trifluoro B
analogues O
of O
solamin B
, O
a O
mono B
- I
THF I
annonaceous I
acetogenin I
, O
were O
synthesized O
. O

Their O
inhibitory O
activity O
, O
along O
with O
previously O
synthesized O
analogues O
( O
C35 B
- I
fluoro I
, O
C35 I
- I
difluoro I
, O
and O
C35 B
- I
trifluorosolamins I
) O
, O
against O
bovine O
mitochondrial O
NADH B
- O
ubiquinone B
oxidoreductase O
( O
complex O
I O
) O
was O
determined O
. O

The O
present O
study O
revealed O
that O
the O
methyl B
group O
on O
the O
gamma B
- I
lactone I
moiety O
is O
critical O
to O
the O
potent O
inhibition O
of O
complex O
I O
by O
natural O
acetogenins B
. O

Synthesis O
and O
antibacterial O
activity O
of O
9 B
- I
oxime I
ether I
non O
- O
ketolides B
, O
and O
novel O
binding O
mode O
of O
alkylides O
with O
bacterial O
rRNA O
. O

We O
report O
a O
series O
of O
new O
9 B
- I
oxime I
ether I
non O
- O
ketolides B
, O
including O
3 B
- I
hydroxyl I
, I
3 I
- I
O I
- I
acyl I
and I
3 I
- I
O I
- I
alkyl I
clarithromycin I
derivatives O
, O
and O
thiophene B
- O
containing O
ketolides B
1b O
- O
1d O
. O

Unlike O
previously O
reported O
ketolide B
1a O
, O
none O
of O
them O
is O
comparable O
to O
telithromycin B
. O

A O
molecular O
modeling O
study O
was O
performed O
to O
gain O
insight O
into O
the O
binding O
mode O
of O
alkylides O
17 O
- O
20 O
with O
bacterial O
rRNA O
and O
to O
rationalize O
the O
great O
disparity O
of O
their O
SAR O
. O

The O
3 O
- O
O O
- O
sidechains O
of O
19 O
and O
20 O
point O
to O
the O
so O
- O
called O
hydrophilic O
side O
of O
the O
macrolide B
ring O
, O
as O
seen O
in O
clarithromycin B
. O

In O
contrast O
, O
the O
3 B
- I
O I
- O
sidechains O
of O
17 O
and O
18 O
bend O
to O
the O
backside O
, O
the O
so O
- O
called O
hydrophobic O
side O
of O
the O
macrolide B
ring O
. O

The O
results O
clearly O
indicated O
the O
alkylides O
with O
improved O
antibacterial O
activity O
might O
possess O
a O
novel O
binding O
mode O
, O
which O
is O
different O
from O
clarithromycin B
and O
the O
alkylides O
with O
poor O
activity O
. O

Influence O
of O
GluN2 O
subunit O
identity O
on O
NMDA B
receptor O
function O
. O

N B
- I
methyl I
- I
d I
- I
aspartate I
receptors O
( O
NMDARs O
) O
are O
ligand O
- O
gated O
ion O
channels O
( O
' O
ionotropic O
' O
receptors O
) O
activated O
by O
the O
major O
excitatory O
neurotransmitter O
, O
l B
- I
glutamate I
. O

While O
the O
term O
' O
the O
NMDAR O
' O
is O
often O
used O
it O
obscures O
the O
fact O
that O
this O
class O
of O
receptor O
contains O
within O
it O
members O
whose O
properties O
are O
as O
different O
as O
they O
are O
similar O
. O

This O
heterogeneity O
was O
evident O
from O
early O
electrophysiological O
, O
pharmacological O
and O
biochemical O
assessments O
of O
the O
functional O
properties O
of O
NMDARs O
and O
while O
the O
molecular O
basis O
of O
this O
heterogeneity O
has O
taken O
many O
years O
to O
elucidate O
, O
it O
indicated O
from O
the O
outset O
that O
the O
diversity O
of O
NMDAR O
phenotypes O
could O
allow O
this O
receptor O
family O
to O
subserve O
a O
variety O
of O
functions O
in O
the O
mammalian O
central O
nervous O
system O
. O

In O
this O
review O
we O
highlight O
some O
recent O
studies O
that O
have O
identified O
structural O
elements O
within O
GluN2 O
subunits O
that O
contribute O
to O
the O
heterogeneous O
biophysical O
properties O
of O
NMDARs O
, O
consider O
why O
some O
recently O
described O
novel O
pharmacological O
tools O
may O
permit O
better O
identification O
of O
native O
NMDAR O
subtypes O
, O
examine O
the O
evidence O
that O
NMDAR O
subtypes O
differentially O
contribute O
to O
the O
induction O
of O
long O
- O
term O
potentiation O
and O
long O
- O
term O
depression O
and O
discuss O
how O
through O
the O
use O
of O
chimeric O
proteins O
additional O
insights O
have O
been O
obtained O
that O
account O
for O
NMDAR O
subtype O
- O
dependency O
of O
physiological O
and O
pathophysiological O
signalling O
. O

This O
article O
is O
part O
of O
a O
Special O
Issue O
entitled O
' O
GluR O
- O
dep O
synaptic O
plasticity O
' O
. O

Arsenic B
induced O
neuronal O
apoptosis O
in O
guinea O
pigs O
is O
Ca2 B
+ I
dependent O
and O
abrogated O
by O
chelation O
therapy O
: O
role O
of O
voltage O
gated O
calcium B
channels O
. O

Arsenic B
contaminated O
drinking O
water O
has O
affected O
more O
than O
200 O
million O
people O
globally O
. O

Chronic O
arsenicism O
has O
also O
been O
associated O
with O
numerous O
neurological O
diseases O
. O

One O
of O
the O
prime O
mechanisms O
postulated O
for O
arsenic B
toxicity O
is O
reactive O
oxygen B
species O
( O
ROS O
) O
mediated O
oxidative O
stress O
. O

In O
this O
study O
, O
we O
explored O
the O
kinetic O
relationship O
of O
ROS O
with O
calcium B
and O
attempted O
to O
dissect O
the O
calcium B
ion O
channels O
responsible O
for O
calcium B
imbalance O
after O
arsenic B
exposure O
. O

We O
also O
explored O
if O
mono O
- O
or O
combinational O
chelation O
therapy O
prevents O
arsenic B
- O
induced O
( O
25ppm O
in O
drinking O
water O
for O
4 O
months O
) O
neuronal O
apoptosis O
in O
a O
guinea O
pig O
animal O
model O
. O

Results O
indicate O
that O
chronic O
arsenic B
exposure O
caused O
a O
significant O
increase O
in O
ROS O
followed O
by O
NO B
and O
calcium B
influx O
. O

This O
calcium B
influx O
is O
mainly O
dependent O
on O
L O
- O
type O
voltage O
gated O
channels O
that O
disrupt O
mitochondrial O
membrane O
potential O
, O
increase O
bax O
/ O
bcl2 O
levels O
and O
caspase O
3 O
activity O
leading O
to O
apoptosis O
. O

Interestingly O
, O
blocking O
of O
ROS O
could O
completely O
reduce O
calcium B
influx O
whereas O
calcium B
blockage O
partially O
reduced O
ROS O
increase O
. O

While O
in O
general O
mono O
- O
and O
combinational O
chelation O
therapies O
were O
effective O
in O
reversing O
arsenic B
induced O
alteration O
, O
combinational O
therapy O
of O
DMSA B
and O
MiADMSA B
was O
most O
effective O
. O

Our O
results O
provide O
evidence O
for O
the O
role O
of O
L O
- O
type O
calcium B
channels O
in O
regulating O
arsenic B
- O
induced O
calcium B
influx O
and O
DMSA B
+ O
MiADMSA B
combinational O
therapy O
may O
be O
a O
better O
protocol O
than O
monotherapy O
in O
mitigating O
chronic O
arsenicosis O
. O

Gastrodin O
attenuation O
of O
the O
inflammatory O
response O
in O
H9c2 O
cardiomyocytes O
involves O
inhibition O
of O
NF O
- O
kappa O
B O
and O
MAPKs O
activation O
via O
the O
phosphatidylinositol B
3 O
- O
kinase O
signaling O
. O

The O
phenolic B
glucoside I
gastrodin B
, O
a O
main O
constituent O
of O
a O
Chinese O
traditional O
herbal O
medicine O
, O
has O
been O
known O
to O
display O
several O
biological O
and O
pharmacological O
properties O
. O

However O
, O
the O
role O
and O
precise O
molecular O
mechanisms O
explaining O
how O
gastrodin O
suppresses O
the O
inflammatory O
response O
in O
septic O
cardiac O
dysfunction O
are O
unknown O
. O

To O
study O
this O
, O
rat O
H9c2 O
cardiomyocytes O
were O
treated O
with O
gastrodin O
and O
/ O
or O
lipopolysaccharide O
( O
LPS O
) O
. O

Our O
results O
showed O
that O
gastrodin B
treatment O
strongly O
suppressed O
nuclear O
factor O
- O
kappa O
B O
( O
NF O
- O
kappa O
B O
) O
and O
mitogen O
- O
activated O
protein O
kinases O
( O
MAPKs O
) O
family O
activation O
and O
upregulation O
of O
the O
expression O
of O
inducible O
nitric B
oxide I
synthase O
( O
iNOS O
) O
, O
cyclooxygenase O
- O
2 O
( O
COX O
- O
2 O
) O
, O
tumor O
necrosis O
factor O
- O
alpha O
( O
TNF O
- O
alpha O
) O
, O
and O
interleukin O
- O
6 O
( O
IL O
- O
6 O
) O
in O
LPS O
- O
stimulated O
H9c2 O
cardiomyocytes O
. O

Simultaneously O
, O
gastrodin B
obviously O
upregulated O
the O
phosphatidylinositol B
3 O
- O
kinase O
( O
PI3 O
- O
K O
) O
/ O
Akt O
signaling O
in O
a O
dose O
- O
dependent O
manner O
. O

However O
, O
wortmannin B
, O
a O
specific O
PI3 O
- O
K O
inhibitor O
, O
blocked O
the O
inhibitory O
effects O
of O
gastrodin B
on O
LPS O
- O
stimulated O
H9c2 O
cardiomyocytes O
. O

Furthermore O
, O
PI3 O
- O
K O
/ O
Akt O
inhibition O
partially O
abolished O
the O
inhibitory O
effects O
of O
gastrodin B
on O
the O
phosphorylation O
of O
inhibitor O
kappa O
B O
- O
alpha O
( O
I O
kappa O
B O
- O
alpha O
) O
, O
extracellular O
signal O
- O
regulated O
kinase O
1 O
/ O
2 O
( O
ERK1 O
/ O
2 O
) O
, O
c O
- O
Jun O
N B
- O
terminal O
protein O
kinase O
( O
JNK O
) O
, O
and O
p38 O
mitogen O
- O
activated O
protein O
kinase O
( O
p38 O
MAPK O
) O
, O
and O
activity O
of O
NF O
- O
kappa O
B O
. O

Here O
we O
report O
activation O
of O
the O
PI3 O
- O
K O
/ O
Akt O
signaling O
by O
gastrodin B
and O
that O
inhibition O
of O
this O
pathway O
reverses O
the O
inhibitory O
effects O
of O
gastrodin B
on O
NF O
- O
kappa O
B O
and O
MAPKs O
activation O
in O
H9c2 O
cardiomyocytes O
. O

Catalytic O
- O
site O
conformational O
equilibrium O
in O
nerve O
- O
agent O
adducts O
of O
acetylcholinesterase O
: O
Possible O
implications O
for O
the O
HI B
- I
6 I
antidote O
substrate O
specificity O
. O

Nerve O
agents O
such O
as O
tabun B
, O
cyclosarin B
and O
Russian O
VX O
inhibit O
the O
essential O
enzyme O
acetylcholinesterase O
( O
AChE O
) O
by O
organophosphorylatin B
the O
catalytic O
serine B
residue O
. O

Nucleophiles O
, O
such O
as O
oximes B
, O
are O
used O
as O
antidotes O
as O
they O
can O
reactivate O
and O
restore O
the O
function O
of O
the O
inhibited O
enzyme O
. O

The O
oxime B
HI B
- I
6 I
shows O
a O
notably O
low O
activity O
on O
tabun O
adducts O
but O
can O
effectively O
reactivate O
adducts O
of O
cyclosarin B
and O
Russian O
VX O
. O

To O
examine O
the O
structural O
basis O
for O
the O
pronounced O
substrate O
specificity O
of O
HI B
- I
6 I
, O
we O
determined O
the O
binary O
crystal O
structures O
of O
Mus O
musculus O
AChE O
( O
mAChE O
) O
conjugated O
by O
cyclosarin B
and O
Russian O
VX O
and O
found O
a O
conformational O
mobility O
of O
the O
side O
chains O
of O
Phe338 B
and O
His447 B
. O

The O
interaction O
between O
HI B
- I
6 I
and O
tabun B
- O
adducts O
of O
AChE O
were O
subsequently O
investigated O
using O
a O
combination O
of O
time O
resolved O
fluorescence O
spectroscopy O
and O
X O
- O
ray O
crystallography O
. O

Our O
findings O
show O
that O
HI B
- I
6 I
binds O
to O
tabun B
inhibited O
Homo O
sapiens O
AChE O
( O
hAChE O
) O
with O
an O
IC50 O
value O
of O
300 O
mu O
M O
and O
suggest O
that O
the O
reactive O
nucleophilic O
moiety O
of O
HI B
- I
6 I
is O
excluded O
from O
the O
phosphorus B
atom O
of O
tabun B
. O

We O
propose O
that O
a O
conformational O
mobility O
of O
the O
side O
- O
chains O
of O
Phe338 B
and O
His447 B
is O
a O
common O
feature O
in O
nerve O
- O
agent O
adducts O
of O
AChE O
. O

We O
also O
suggest O
that O
the O
conformational O
mobility O
allow O
HI B
- I
6 I
to O
reactivate O
conjugates O
of O
cyclosarin B
and O
Russian O
VX O
while O
a O
reduced O
mobility O
in O
tabun B
conjugated O
AChE O
results O
in O
steric O
hindrance O
that O
prevents O
efficient O
reactivation O
. O

Hepatocytes O
display O
a O
compensatory O
survival O
response O
against O
cadmium B
toxicity O
by O
a O
mechanism O
mediated O
by O
EGFR O
and O
Src O
. O

Although O
the O
liver O
is O
a O
cadmium B
- O
target O
organ O
, O
hepatocyte O
response O
involved O
in O
its O
toxicity O
is O
not O
yet O
elucidated O
. O

A O
link O
between O
this O
heavy O
metal O
treatment O
and O
Stat3 O
signaling O
pathways O
was O
examined O
in O
primary O
mouse O
hepatocytes O
. O

We O
provided O
evidence O
of O
a O
novel O
link O
among O
NADPH B
oxidase O
and O
Stat3 O
signaling O
, O
mediated O
by O
Src O
, O
EGFR O
, O
and O
Erk1 O
/ O
2 O
. O

Cadmium B
activates O
NADPH B
oxidase O
. O

ROS O
produced O
by O
this O
oxidase O
activates O
Src O
, O
enable O
that O
in O
turn O
, O
transactivates O
EGFR O
that O
activates O
Stat3 O
in O
tyrosine B
, O
allowing O
its O
dimerization O
. O

Also O
, O
ROS O
from O
NADPH B
oxidase O
favors O
ERK1 O
/ O
2 O
activation O
that O
phosphorylates O
Stat3 O
in O
serine B
, O
resulting O
in O
a O
compensatory O
or O
adaptive O
survival O
response O
such O
as O
production O
of O
metallothionein O
- O
II O
in O
short O
Cd B
exposure O
times O
. O

However O
, O
after O
12h O
CdCl2 B
treatment O
, O
cell O
viability O
diminished O
in O
50 O
% O
, O
accompanied O
by O
a O
drastic O
decrease O
of O
metallothionein O
- O
II O
production O
, O
and O
an O
increase O
in O
p53 O
activation O
and O
the O
pro O
- O
apoptotic O
protein O
Bax O
. O

Catalpol B
suppresses O
advanced O
glycation O
end O
- O
products O
- O
induced O
inflammatory O
responses O
through O
inhibition O
of O
reactive O
oxygen B
species O
in O
human O
monocytic O
THP O
- O
1 O
cells O
. O

Advanced O
glycation O
end O
- O
products O
( O
AGEs O
) O
play O
a O
pivotal O
role O
in O
the O
development O
of O
diabetic O
complications O
by O
inducing O
inflammation O
. O

We O
previously O
reported O
that O
the O
fresh O
roots O
of O
Rehmannia O
glutinosa O
Libosch O
. O
, O
which O
have O
been O
used O
for O
the O
treatment O
of O
diabetes O
in O
traditional O
Korean O
medicine O
, O
also O
have O
the O
potential O
to O
suppress O
AGE O
- O
mediated O
inflammatory O
response O
in O
THP O
- O
1 O
cells O
. O

In O
the O
present O
study O
, O
we O
isolated O
catalpol B
from O
R O
. O
glutinosa O
, O
and O
examined O
whether O
it O
has O
anti O
- O
inflammatory O
effects O
on O
AGE O
- O
stimulated O
THP O
- O
1 O
cells O
. O

Catalpol B
reduced O
the O
expression O
of O
pro O
- O
inflammatory O
mediates O
, O
such O
as O
monocyte O
chemotactic O
protein O
- O
1 O
( O
MCP O
- O
1 O
) O
, O
tumor O
necrosis O
factor O
- O
alpha O
( O
TNF O
- O
alpha O
) O
, O
inducible O
NO B
synthase O
( O
iNOS O
) O
, O
and O
receptor O
for O
AGE O
( O
RAGE O
) O
. O

Promoter O
and O
electromobility O
shift O
assays O
showed O
that O
transcriptional O
activation O
of O
NF O
- O
kappa O
B O
was O
significantly O
reduced O
by O
catalpol B
treatment O
, O
while O
AP O
- O
1 O
was O
not O
. O

Catalpol B
also O
suppressed O
AGE O
- O
induced O
phosphorylation O
of O
mitogen O
activated O
protein O
( O
MAP O
) O
kinases O
, O
degradation O
of O
I O
kappa O
B O
alpha O
and O
the O
nuclear O
localization O
of O
NF O
- O
kappa O
B O
. O

Moreover O
, O
the O
production O
of O
intracellular O
reactive O
oxygen B
species O
( O
ROS O
) O
elicited O
by O
AGE O
was O
also O
suppressed O
by O
catalpol B
treatment O
, O
through O
dual O
action O
of O
reducing O
ROS O
itself O
and O
inhibiting O
NADPH B
oxidase O
activity O
. O

Our O
findings O
indicate O
that O
catalpol B
suppresses O
AGE O
- O
mediated O
inflammation O
by O
inhibiting O
ROS O
production O
and O
NF O
- O
kappa O
B O
activity O
. O

We O
suggest O
that O
catalpol B
, O
a O
major O
constituent O
of O
the O
fresh O
roots O
of O
R O
. O
glutinosa O
, O
contributes O
to O
the O
prevention O
of O
AGE O
- O
mediated O
diabetic O
complications O
. O

New O
insights O
toward O
the O
discovery O
of O
antibacterial O
agents O
: O
multi O
- O
tasking O
QSBER O
model O
for O
the O
simultaneous O
prediction O
of O
anti O
- O
tuberculosis O
activity O
and O
toxicological O
profiles O
of O
drugs O
. O

Tuberculosis O
( O
TB O
) O
constitutes O
one O
of O
the O
most O
dangerous O
and O
serious O
health O
problems O
around O
the O
world O
. O

It O
is O
a O
very O
lethal O
disease O
caused O
by O
microorganisms O
of O
the O
genus O
mycobacterium O
, O
principally O
Mycobacterium O
tuberculosis O
( O
MTB O
) O
which O
affects O
humans O
. O

A O
very O
active O
field O
for O
the O
search O
of O
more O
efficient O
anti O
- O
TB O
chemotherapies O
is O
the O
use O
in O
silico O
methodologies O
for O
the O
discovery O
of O
potent O
anti O
- O
TB O
agents O
. O

The O
battle O
against O
MTB O
by O
using O
antimicrobial O
chemotherapies O
will O
depend O
on O
the O
design O
of O
new O
chemicals O
with O
high O
anti O
- O
TB O
activity O
and O
low O
toxicity O
as O
possible O
. O

Multi O
- O
target O
methodologies O
focused O
on O
quantitative O
- O
structure O
activity O
relationships O
( O
mt O
- O
QSAR O
) O
have O
played O
a O
very O
important O
role O
for O
the O
rationalization O
of O
drug O
design O
, O
providing O
a O
better O
understanding O
about O
the O
molecular O
patterns O
related O
with O
diverse O
pharmacological O
profiles O
including O
antimicrobial O
activity O
. O

Nowadays O
, O
almost O
all O
mt O
- O
QSAR O
models O
have O
considered O
the O
study O
of O
biological O
activity O
or O
toxicity O
separately O
. O

In O
the O
present O
study O
, O
we O
develop O
by O
the O
first O
time O
, O
a O
unified O
multitasking O
model O
based O
on O
quantitative O
- O
structure O
biological O
effect O
relationships O
( O
mtk O
- O
QSBER O
) O
for O
the O
simultaneous O
prediction O
of O
anti O
- O
TB O
activity O
and O
toxicity O
against O
Mus O
musculus O
and O
Rattus O
norvegicus O
. O

The O
mtk O
- O
QSBER O
model O
was O
created O
by O
using O
linear O
discriminant O
analysis O
( O
LDA O
) O
for O
the O
classification O
of O
compounds O
as O
positive O
( O
high O
biological O
activity O
and O
/ O
or O
low O
toxicity O
) O
or O
negative O
( O
otherwise O
) O
under O
many O
experimental O
conditions O
. O

Our O
mtk O
- O
QSBER O
model O
, O
correctly O
classified O
more O
than O
90 O
% O
of O
the O
case O
in O
the O
whole O
database O
( O
more O
than O
12 O
, O
000 O
cases O
) O
, O
serving O
as O
a O
powerful O
tool O
for O
the O
computer O
- O
assisted O
screening O
of O
potent O
and O
safe O
anti O
- O
TB O
drugs O
. O

Excessive O
ethanol B
consumption O
under O
exposure O
to O
lead O
intensifies O
disorders O
in O
bone O
metabolism O
: O
A O
study O
in O
a O
rat O
model O
. O

It O
was O
investigated O
whether O
ethanol B
( O
Et O
) O
modifies O
the O
damaging O
impact O
of O
lead O
( O
Pb B
) O
on O
bone O
metabolism O
in O
a O
rat O
model O
reflecting O
excessive O
alcohol B
consumption O
by O
humans O
exposed O
to O
relatively O
high O
levels O
of O
this O
metal O
. O

For O
this O
purpose O
, O
markers O
of O
bone O
formation O
( O
osteocalcin O
, O
procollagen O
I O
, O
osteoprotegerin O
, O
alkaline O
phosphatase O
) O
and O
resorption O
( O
telopeptides O
of O
collagen O
I O
, O
soluble O
receptor O
activator O
of O
nuclear O
factor O
- O
kappa O
B O
ligand O
) O
, O
calciotropic O
hormones O
( O
parathormone O
, O
calcitonin O
, O
25 B
- I
hydroxyvitamin I
D I
and O
1 B
, I
25 I
- I
dihydroxyvitamin I
D I
) O
in O
the O
serum O
, O
and O
the O
femur O
content O
of O
mineral O
( O
including O
calcium B
- O

Ca B
and O
inorganic O
phosphorus B
- O
Pi O
) O
and O
organic O
components O
were O
estimated O
in O
the O
rats O
exposed O
to O
500mg O
Pb B
/ O
l O
( O
in O
drinking O
water O
) O
or O
/ O
and O
Et O
( O
5g O
/ O
kg O
b O
. O
wt O
. O
/ O
24h O
, O
by O
oral O
gavage O
) O
for O
12weeks O
. O

Moreover O
, O
Ca B
and O
Pi O
in O
the O
serum O
and O
urine O
, O
alkaline O
phosphatase O
in O
the O
bone O
tissue O
and O
Pb B
in O
the O
blood O
and O
femur O
were O
determined O
. O

The O
exposure O
to O
Pb B
or O
/ O
and O
Et O
decreased O
bone O
formation O
and O
increased O
its O
resorption O
resulting O
in O
the O
bone O
demineralization O
. O

These O
effects O
were O
accompanied O
by O
destroying O
the O
hormonal O
regulation O
of O
mineral O
metabolism O
, O
and O
Ca B
and O
Pi O
imbalance O
. O

The O
co O
- O
exposure O
to O
Pb B
and O
Et O
- O
induced O
disorders O
in O
bone O
metabolism O
were O
more O
advanced O
than O
those O
caused O
by O
Pb B
alone O
. O

Et O
co O
- O
administration O
increased O
Pb B
concentration O
in O
the O
blood O
and O
decreased O
its O
accumulation O
in O
the O
bone O
. O

This O
paper O
is O
the O
first O
report O
providing O
evidence O
that O
consumption O
of O
Et O
under O
exposure O
to O
Pb B
intensifies O
disorders O
in O
bone O
metabolism O
and O
that O
destroying O
of O
the O
receptor O
activator O
nuclear O
factor O
- O
kappa O
B O
( O
RANK O
) O
/ O
RANK O
ligand O
/ O
osteoprotegerin O
system O
is O
involved O
in O
the O
mechanisms O
of O
interactive O
action O
of O
these O
xenobiotics O
on O
the O
skeleton O
. O

The O
modifying O
impact O
of O
Et O
may O
be O
an O
effect O
of O
its O
independent O
osteotropic O
action O
and O
interaction O
with O
Pb B
. O

Based O
on O
the O
results O
it O
can O
be O
concluded O
that O
alcohol B
abuse O
by O
subjects O
excessively O
exposed O
to O
Pb B
considerably O
increases O
the O
risk O
of O
bone O
damage O
. O

Cellular O
mechanisms O
of O
the O
cytotoxic O
effects O
of O
the O
zearalenone B
metabolites O
alpha B
- I
zearalenol I
and O
beta B
- I
zearalenol I
on O
RAW264 O
. O
7 O
macrophages O
. O

Zearalenone B
( O
ZEN B
) O
and O
its O
metabolites O
are O
commonly O
found O
in O
many O
food O
commodities O
and O
are O
known O
to O
cause O
reproductive O
disorders O
and O
genotoxic O
effects O
. O

The O
major O
ZEN B
metabolites O
are O
alpha B
- I
zearalenol I
( O
alpha B
- I
ZOL I
) O
and O
beta B
- I
zearalenol I
( O
beta B
- I
ZOL I
) O
. O

Although O
many O
studies O
have O
demonstrated O
the O
cytotoxic O
effects O
of O
these O
metabolites O
, O
the O
mechanisms O
by O
which O
alpha B
- I
ZOL I
or O
beta B
- I
ZOL I
mediates O
their O
cytotoxic O
effects O
appear O
to O
differ O
according O
to O
cell O
type O
and O
the O
exposed O
toxins O
. O

We O
evaluated O
the O
toxicity O
of O
alpha B
- I
ZOL I
and O
beta B
- I
ZOL I
on O
RAW264 O
. O
7 O
macrophages O
and O
investigated O
the O
underlying O
mechanisms O
. O

beta B
- I
ZOL I
not O
only O
more O
strongly O
reduced O
the O
viability O
of O
cells O
than O
did O
alpha B
- I
ZOL I
, O
but O
it O
also O
induced O
cell O
death O
mainly O
by O
apoptosis O
rather O
than O
necrosis O
. O

The O
ZEN O
metabolites O
induced O
loss O
of O
mitochondrial O
membrane O
potential O
( O
MMP O
) O
, O
mitochondrial O
changes O
in O
Bcl O
- O
2 O
and O
Bax O
proteins O
, O
and O
cytoplasmic O
release O
of O
cytochrome O
c O
and O
apoptosis O
- O
inducing O
factor O
( O
AIF O
) O
. O

Use O
of O
an O
inhibitor O
specific O
to O
c O
- O
Jun O
N B
- O
terminal O
kinase O
( O
JNK O
) O
, O
p38 O
kinase O
or O
p53 O
, O
but O
not O
pan O
- O
caspase O
or O
caspase O
- O
8 O
, O
decreased O
the O
toxin O
- O
induced O
generation O
of O
reactive O
oxygen B
species O
( O
ROS O
) O
and O
also O
attenuated O
the O
alpha B
- I
ZOL I
- O
or O
beta B
- I
ZOL I
- O
induced O
decrease O
of O
cell O
viability O
. O

Antioxidative O
enzyme O
or O
compounds O
such O
as O
catalase O
, O
acteoside B
, O
and O
( B
E I
) I
- I
1 I
- I
( I
3 I
, I
4 I
- I
dihydroxyphenethyl I
) I
- I
3 I
- I
( I
4 I
- I
hydroxystyryl I
) I
urea I
suppressed O
the O
ZEN O
metabolite O
- O
mediated O
reduction O
of O
cell O
viability O
. O

Further O
, O
knockdown O
of O
AIF O
via O
siRNA O
transfection O
diminished O
the O
ZEN B
metabolite O
- O
induced O
cell O
death O
. O

Collectively O
, O
these O
results O
suggest O
that O
the O
activation O
of O
p53 O
, O
JNK O
or O
p38 O
kinase O
by O
ZEN B
metabolites O
is O
the O
main O
upstream O
signal O
required O
for O
the O
mitochondrial O
alteration O
of O
Bcl O
- O
2 O
/ O
Bax O
signaling O
pathways O
and O
intracellular O
ROS O
generation O
, O
while O
MMP O
loss O
and O
nuclear O
translocation O
of O
AIF O
are O
the O
critical O
downstream O
events O
for O
ZEN B
metabolite O
- O
mediated O
apoptosis O
in O
macrophages O
. O

Sodium B
arsenite I
induces O
cyclooxygenase O
- O
2 O
expression O
in O
human O
uroepithelial O
cells O
through O
MAPK O
pathway O
activation O
and O
reactive O
oxygen B
species O
induction O
. O

Arsenic B
can O
induce O
reactive O
oxygen B
species O
( O
ROS O
) O
leading O
to O
oxidative O
stress O
and O
carcinogenesis O
. O

Bladder O
is O
one O
of O
the O
major O
target O
organs O
of O
arsenic B
, O
and O
cyclooxygenase O
- O
2 O
( O
COX O
- O
2 O
) O
may O
play O
an O
important O
role O
in O
arsenic B
- O
induced O
bladder O
cancer O
. O

However O
, O
the O
mechanism O
by O
which O
arsenic B
induces O
COX O
- O
2 O
in O
bladder O
cells O
remains O
unclear O
. O

This O
study O
aimed O
at O
investigating O
arsenic B
- O
mediated O
intracellular O
redox O
status O
and O
signaling O
cascades O
leading O
to O
COX O
- O
2 O
induction O
in O
human O
uroepithelial O
cells O
( O
SV O
- O
HUC O
- O
1 O
) O
. O

SV O
- O
HUC O
- O
1 O
cells O
were O
exposed O
to O
sodium B
arsenite I
and O
COX O
- O
2 O
expression O
, O
mitogen O
- O
activated O
protein O
kinase O
( O
MAPK O
) O
phosphorylation O
, O
glutathione B
( O
GSH B
) O
levels O
, O
ROS O
induction O
and O
Nrf2 O
expression O
were O
quantified O
. O

Our O
results O
demonstrate O
that O
arsenite B
( O
1 O
- O
10 O
mu O
M O
) O
elevates O
COX O
- O
2 O
expression O
, O
GSH B
levels O
, O
ROS O
and O
Nrf2 O
expression O
. O

Arsenite B
treatment O
for O
24h O
stimulates O
phosphorylation O
of O
ERK O
and O
p38 O
, O
but O
not O
JNK O
in O
SV O
- O
HUC O
- O
1 O
cells O
. O

Induction O
of O
Cox O
- O
2 O
mRNA O
levels O
by O
arsenite B
was O
attenuated O
by O
inhibitors O
of O
ERK O
, O
p38 O
and O
JNK O
. O

Arsenite B
- O
induced O
ROS O
generation O
and O
COX O
- O
2 O
expression O
were O
significantly O
attenuated O
by O
treatment O
with O
melatonin B
( O
a O
ROS O
scavenger O
) O
, O
but O
enhanced O
by O
DL B
- I
buthionine I
- I
( I
S I
, I
R I
) I
- I
sulfoximine I
( O
BSO B
, O
an O
inhibitor O
of O
gamma B
- I
glutamylcysteine I
synthetase O
( O
gamma O
- O
GCS O
) O
resulting O
in O
lower O
GSH B
and O
increased O
ROS O
levels O
) O
. O

These O
data O
indicate O
that O
arsenite B
promotes O
an O
induction O
of O
ROS O
, O
which O
results O
in O
an O
induction O
of O
COX O
- O
2 O
expression O
through O
activation O
of O
the O
MAPK O
pathway O
. O

OGG1 O
Ser326Cys O
polymorphism O
interacts O
with O
cigarette O
smoking O
to O
increase O
oxidative O
DNA O
damage O
in O
human O
sperm O
and O
the O
risk O
of O
male O
infertility O
. O

8 B
- I
Oxoguanine I
DNA O
glycosylase O
1 O
( O
OGG1 O
) O
plays O
an O
important O
role O
in O
repairing O
oxidative O
DNA O
damage O
induced O
by O
chemical O
agents O
, O
such O
as O
tobacco O
. O

This O
study O
examined O
the O
effects O
of O
OGG1 O
Ser326Cys O
polymorphism O
and O
cigarette O
smoking O
, O
alone O
or O
combined O
, O
on O
sperm O
oxidative O
DNA O
damage O
and O
the O
risk O
of O
male O
infertility O
. O

A O
total O
of O
620 O
idiopathic O
infertile O
subjects O
and O
480 O
fertile O
controls O
were O
recruited O
in O
this O
study O
. O

Sperm O
8 B
- I
hydroxydeoxyguanine I
( O
8 B
- I
OHdG I
) O
was O
measured O
by O
immunofluorescent O
assay O
using O
flow O
cytometry O
and O
genotypes O
were O
determined O
by O
OpenArray O
platform O
with O
a O
chip O
- O
based O
Taq O
- O
Man O
genotyping O
technology O
. O

Our O
results O
demonstrated O
that O
both O
cigarette O
smoking O
and O
OGG1 O
polymorphism O
can O
affect O
the O
sperm O
8 B
- I
OHdG I
levels O
. O

Individuals O
with O
variant O
Cys B
/ O
Cys B
homozygote O
showed O
higher O
levels O
of O
sperm O
8 B
- I
OHdG I
than O
wide O
- O
type O
homozygote O
carriers O
( O
Ser B
/ O
Ser B
) O
. O

Stratified O
analysis O
found O
that O
the O
association O
between O
OGG1 O
polymorphism O
and O
sperm O
8 B
- I
OHdG I
levels O
was O
only O
observed O
among O
smokers O
with O
pack O
- O
years O
> O
= O
5 O
but O
not O
among O
those O
subjects O
with O
pack O
- O
years O
< O
5 O
( O
pack O
- O
years O
= O
packs O
smoked O
per O
day O
x O
years O
as O
a O
smoker O
) O
. O

Further O
analysis O
based O
on O
the O
case O
- O
control O
study O
revealed O
that O
variant O
allele O
( O
Cys O
) O
of O
OGG1 O
was O
significantly O
associated O
with O
male O
infertility O
risk O
in O
a O
dominant O
model O
( O
OR O
= O
1 O
. O
35 O
, O
95 O
% O
CI O
: O
1 O
. O
01 O
- O
1 O
. O
82 O
; O
trend O
P O
< O
0 O
. O
001 O
) O
. O

Furthermore O
, O
we O
found O
a O
significant O
gene O
- O
environment O
interaction O
between O
OGG1 O
Ser326Cys O
polymorphism O
and O
cigarette O
smoking O
in O
relation O
to O
male O
infertility O
risk O
( O
Pinteration O
= O
0 O
. O
0003 O
) O
. O

These O
findings O
provided O
the O
first O
evidence O
about O
potential O
interactive O
effects O
of O
OGG1 O
polymorphism O
and O
cigarette O
smoking O
on O
male O
infertility O
risk O
. O

Lycorine B
hydrochloride I
selectively O
inhibits O
human O
ovarian O
cancer O
cell O
proliferation O
and O
tumor O
neovascularization O
with O
very O
low O
toxicity O
. O

Uncontrolled O
tumor O
cell O
proliferation O
and O
robust O
neovascularization O
are O
prominent O
features O
of O
aggressive O
ovarian O
cancers O
. O

Although O
great O
efforts O
in O
anti O
- O
ovarian O
cancer O
therapy O
have O
been O
made O
in O
the O
past O
4 O
decades O
, O
the O
5 O
- O
year O
survival O
rates O
for O
ovarian O
cancer O
patients O
are O
still O
poor O
, O
and O
effective O
drugs O
to O
cure O
ovarian O
cancer O
patients O
are O
absent O
. O

In O
this O
study O
, O
we O
evaluated O
the O
anti O
- O
cancer O
effects O
of O
lycorine B
hydrochloride I
( O
LH O
) O
, O
a O
novel O
anti O
- O
ovarian O
cancer O
agent O
, O
using O
the O
highly O
- O
invasive O
ovarian O
cancer O
cell O
line O
, O
Hey1B O
, O
as O
a O
model O
. O

Our O
data O
showed O
that O
LH O
effectively O
inhibited O
mitotic O
proliferation O
of O
Hey1B O
cells O
( O
half O
maximal O
inhibitory O
concentration O
= O
1 O
. O
2 O
mu O
M O
) O
with O
very O
low O
toxicity O
, O
resulting O
in O
cell O
cycle O
arrest O
at O
the O
G2 O
/ O
M O
transition O
through O
enhanced O
expression O
of O
the O
cell O
cycle O
inhibitor O
p21 O
and O
marked O
down O
- O
regulation O
of O
cyclin O
D3 O
expression O
. O

Moreover O
, O
LH O
suppressed O
both O
the O
formation O
of O
capillary O
- O
like O
tubes O
by O
Hey1B O
cells O
cultured O
in O
vitro O
and O
the O
ovarian O
cancer O
cell O
- O
dominant O
neovascularization O
in O
vivo O
when O
administered O
to O
Hey1B O
- O
xenotransplanted O
mice O
. O

LH O
also O
suppressed O
the O
expression O
of O
several O
key O
angiogenic O
genes O
, O
including O
VE O
- O
cadherin O
, O
vascular O
endothelial O
growth O
factor O
, O
and O
Sema4D O
, O
and O
reduced O
Akt O
phosphorylation O
in O
Hey1B O
cells O
. O

These O
results O
suggest O
that O
LH O
selectively O
inhibits O
ovarian O
cancer O
cell O
proliferation O
and O
neovascularization O
and O
is O
a O
potential O
drug O
candidate O
for O
anti O
- O
ovarian O
cancer O
therapy O
. O

Catechins B
are O
not O
major O
components O
responsible O
for O
the O
beneficial O
effect O
of O
Camellia O
sinensis O
on O
the O
ovarian O
delta B
- I
ALA I
- O
D O
activity O
inhibited O
by O
cadmium B
. O

Cadmium B
has O
been O
associated O
with O
a O
wide O
spectrum O
of O
deleterious O
effects O
on O
the O
reproductive O
tissues O
, O
including O
ovary O
. O

This O
investigation O
evaluated O
the O
protective O
role O
of O
Camellia O
sinensis O
( O
green O
, O
white O
and O
red O
teas O
) O
in O
the O
cadmium B
- O
induced O
inhibition O
of O
ovarian O
delta B
- I
aminolevulinate I
dehydratase O
( O
delta B
- I
ALA I
- O
D O
) O
activity O
in O
vitro O
and O
ex O
vivo O
. O

This O
study O
demonstrated O
that O
green O
and O
white O
teas O
restored O
the O
cow O
ovary O
delta B
- I
ALA I
- O
D O
activity O
inhibited O
by O
cadmium B
whereas O
red O
tea O
had O
no O
effect O
in O
vitro O
. O

In O
addition O
, O
green O
tea O
was O
able O
to O
restore O
enzyme O
activity O
inhibited O
after O
acute O
cadmium B
exposure O
in O
mice O
ovary O
. O

Teas O
infusions O
composition O
was O
assessed O
by O
HPLC O
in O
a O
quantitative O
assay O
for O
catechins B
, O
purine B
alkaloids I
and O
gallic B
acid I
as O
well O
as O
total O
polyphenol B
content O
. O

The O
greatest O
effect O
of O
green O
tea O
observed O
in O
vitro O
as O
well O
as O
the O
protective O
role O
presented O
in O
the O
ex O
vivo O
study O
could O
be O
attributed O
to O
the O
major O
content O
of O
phenols B
, O
but O
not O
catechins B
. O

In O
fact O
, O
catechins B
were O
not O
able O
to O
restore O
enzyme O
activity O
inhibited O
by O
cadmium B
, O
demonstrating O
that O
these O
compounds O
are O
not O
major O
components O
responsible O
for O
the O
beneficial O
effect O
of O
green O
tea O
observed O
in O
this O
study O
. O

This O
study O
demonstrated O
the O
helpful O
effect O
of O
green O
tea O
infusion O
in O
ameliorating O
a O
marker O
protein O
of O
cadmium B
intoxication O
in O
ovarian O
tissue O
. O

4 B
- I
Nerolidylcatechol I
and O
its O
synthetic O
analogues O
: O
Antioxidant O
activity O
and O
toxicity O
evaluation O
. O

4 B
- I
Nerolidylcatechol I
( O
1 O
) O
is O
a O
secondary O
metabolite O
of O
plants O
and O
is O
described O
as O
a O
promising O
anti O
- O
inflammatory O
, O
antimalarial O
, O
antiulcerogenic O
, O
analgesic O
and O
cytotoxic O
compound O
possibly O
due O
to O
its O
antioxidant O
profile O
. O

In O
this O
study O
, O
we O
evaluated O
the O
pharmacologic O
activity O
and O
the O
antioxidant O
and O
toxicological O
profiles O
of O
compound O
( O
1 O
) O
and O
its O
synthetic O
analogues O
( O
2 O
- O
6 O
) O
. O

The O
synthetic O
analogues O
were O
designed O
from O
the O
lead O
compound O
, O
( O
1 O
) O
, O
using O
a O
molecular O
- O
simplification O
strategy O
. O

Compound O
5 O
showed O
, O
by O
1 B
, I
1 I
- I
diphenyl I
- I
2 I
- I
picrylhydrazyl I
( O
DPPH B
) O
and O
beta B
- I
carotene I
systems O
, O
similar O
antioxidant O
activity O
when O
compared O
to O
compound O
( O
1 O
) O
. O

The O
oxidative O
stress O
in O
erythrocyte O
membrane O
demonstrated O
the O
highly O
protective O
effect O
of O
compounds O
( O
4 O
) O
, O
( O
5 O
) O
and O
( O
6 O
) O
and O
high O
antioxidant O
/ O
pro O
- O
oxidant O
activity O
in O
relation O
to O
the O
concentrations O
of O
compounds O
( O
1 O
) O
and O
( O
3 O
) O
. O

Compounds O
( O
2 O
) O
, O
( O
4 O
) O
, O
( O
5 O
) O
and O
( O
6 O
) O
were O
haemobiocompatible O
. O

All O
compounds O
( O
1 O
- O
6 O
) O
showed O
cytotoxic O
effects O
in O
3T3 O
cells O
, O
but O
compounds O
( O
2 O
) O
and O
( O
6 O
) O
were O
highly O
cytotoxic O
in O
this O
lineage O
when O
compared O
to O
compound O
( O
1 O
) O
. O

Compound O
( O
5 O
) O
had O
a O
lower O
myelosuppressive O
effect O
in O
haematopoietic O
progenitor O
cells O
compared O
to O
( O
1 O
) O
. O

Both O
compounds O
, O
( O
1 O
) O
and O
( O
5 O
) O
, O
showed O
low O
genotoxic O
effects O
in O
vitro O
, O
on O
human O
lymphocyte O
cells O
. O

In O
addition O
, O
these O
compounds O
also O
showed O
low O
- O
toxicity O
in O
vivo O
as O
defined O
a O
LD50 O
> O
2000 O
mg O
/ O
kg O
. O

In O
this O
assay O
, O
we O
did O
not O
observe O
death O
in O
the O
animals O
exposed O
to O
treatment O
with O
( O
1 O
) O
and O
( O
5 O
) O
compound O
. O

In O
conclusion O
, O
the O
structural O
design O
of O
the O
analogues O
as O
validated O
once O
compound O
( O
5 O
) O
was O
found O
to O
have O
an O
antioxidant O
profile O
that O
was O
as O
potent O
as O
the O
lead O
compound O
( O
1 O
) O
. O

In O
addition O
, O
considering O
the O
safety O
profile O
, O
these O
compounds O
are O
promising O
as O
preventive O
and O
/ O
or O
therapeutic O
agents O
against O
oxidative O
damage O
. O

Isolation O
of O
a O
flavonoid B
, O
apigenin B
7 I
- I
O I
- I
glucoside I
, O
from O
Mentha O
longifolia O
( O
L O
. O
) O
Hudson O
subspecies O
longifolia O
and O
its O
genotoxic O
potency O
. O

Mentha O
is O
a O
medicinal O
and O
aromatic O
plant O
belonging O
to O
the O
Lamiaceae O
family O
, O
which O
is O
widely O
used O
in O
food O
, O
flavor O
, O
cosmetic O
and O
pharmaceutical O
industries O
. O

Recently O
, O
it O
has O
been O
found O
that O
the O
use O
of O
Mentha O
as O
a O
pharmaceutical O
source O
is O
based O
on O
its O
phytochemical O
constituents O
that O
have O
far O
been O
identified O
as O
tannins B
, O
saponins B
, O
phenolic B
acids I
and O
flavonoids B
. O

This O
study O
was O
designed O
to O
evaluate O
the O
mutagenic O
and O
antimutagenic O
activities O
of O
apigenin B
7 I
- I
O I
- I
glucoside I
( O
A7G B
) O
, O
a O
flavonoid B
isolated O
from O
Mentha O
longifolia O
( O
L O
. O
) O
Hudson O
subspecies O
longifolia O
( O
ML O
) O
. O

The O
possible O
antimutagenic O
potential O
of O
A7G O
was O
examined O
against O
mutagens O
ethyl B
methanesulfonate I
and O
acridine B
in O
an O
eukaryotic O
cell O
system O
Saccharomyces O
cerevisiae O
and O
sodium B
azide I
in O
Salmonella O
typhimurium O
TA1535 O
and O
9 B
- I
aminoacridine I
in O
S O
. O
typhimurium O
TA1537 O
. O

According O
to O
our O
findings O
, O
any O
concentrations O
of O
the O
A7G O
used O
did O
not O
show O
mutagenic O
activity O
but O
exerted O
strong O
antimutagenic O
activities O
at O
tested O
concentrations O
. O

The O
inhibition O
rates O
for O
the O
Ames O
test O
ranged O
from O
27 O
. O
2 O
% O
( O
S O
. O
typhimurium O
TA1535 O
: O
0 O
. O
4 O
mu O
M O
/ O
plate O
) O
to O
91 O
. O
1 O
% O
( O
S O
. O
typhimurium O
TA1537 O
: O
0 O
. O
2 O
mu O
M O
/ O
plate O
) O
and O
for O
the O
yeast O
deletion O
assay O
from O
4 O
% O
to O
57 O
. O
7 O
% O
. O

This O
genotoxicological O
study O
suggests O
that O
a O
flavonoid B
from O
ML O
owing O
to O
antimutagenic O
properties O
is O
of O
great O
pharmacological O
importance O
and O
might O
be O
beneficial O
to O
industries O
producing O
food O
additives O
, O
cosmetics O
and O
pharmaceuticals O
products O
. O

Influence O
of O
pesticide O
exposure O
on O
carbonic O
anhydrase O
II O
from O
sheep O
stomach O
. O

Carbonic O
anhydrase O
( O
CA O
) O
is O
a O
widely O
distributed O
enzyme O
and O
has O
a O
crucial O
role O
in O
the O
cells O
, O
tissues O
and O
organs O
of O
living O
organisms O
. O

It O
is O
found O
that O
CA O
- O
II O
is O
one O
of O
the O
most O
abundant O
CA O
isoenzymes O
in O
the O
gastrointestinal O
system O
. O

It O
plays O
an O
important O
role O
in O
the O
gastric O
acid O
secretion O
in O
stomach O
. O

In O
this O
study O
, O
we O
purified O
CA O
- O
II O
isoenzyme O
from O
sheep O
stomach O
with O
a O
615 O
. O
2 O
purification O
fold O
, O
78 O
% O
purification O
yield O
and O
5562 O
. O
02 O
specific O
activity O
. O

Moreover O
, O
the O
in O
vitro O
effects O
of O
some O
commonly O
used O
pesticides O
including O
chlorpyrifos B
, O
cypermethrin B
, O
dichlorvos B
, O
glyphosate B
isopropylamine I
and O
lambda B
cyhalomethrin I
on O
the O
enzyme O
activity O
were O
investigated O
. O

Of O
these O
compounds O
, O
glyphosate B
isopropylamine I
and O
dichlorvos B
showed O
an O
inhibition O
on O
CA O
- O
II O
esterase O
activity O
. O

They O
have O
IC O
( O
50 O
) O
values O
of O
0 O
. O
155 O
micro O
M O
and O
2 O
. O
690 O
micro O
M O
and O
K O
( O
i O
) O
values O
of O
0 O
. O
329 O
micro O
M O
and O
3 O
. O
654 O
micro O
M O
, O
respectively O
. O

Both O
glyphosate B
isopropylamine I
and O
dichlorvos B
inhibited O
CA O
- O
II O
isoenzyme O
in O
a O
noncompetitive O
manner O
. O

Trim24 O
- O
repressed O
VL30 O
retrotransposons O
regulate O
gene O
expression O
by O
producing O
noncoding O
RNA O
. O

Trim24 O
( O
Tif1 O
alpha O
) O
and O
Trim33 O
( O
Tif1 O
gamma O
) O
interact O
to O
form O
a O
co O
- O
repressor O
complex O
that O
suppresses O
murine O
hepatocellular O
carcinoma O
. O

Here O
we O
show O
that O
Trim24 O
and O
Trim33 O
cooperatively O
repress O
retinoic B
acid I
receptor O
- O
dependent O
activity O
of O
VL30 O
- O
class O
endogenous O
retroviruses O
( O
ERVs O
) O
in O
liver O
. O

In O
Trim24 O
- O
knockout O
hepatocytes O
, O
VL30 O
derepression O
leads O
to O
accumulation O
of O
reverse O
- O
transcribed O
VL30 O
cDNA O
in O
the O
cytoplasm O
that O
correlates O
with O
activation O
of O
the O
viral O
- O
defense O
interferon O
responses O
mimicking O
the O
preneoplastic O
inflammatory O
state O
seen O
in O
human O
liver O
following O
exogenous O
viral O
infection O
. O

Furthermore O
, O
upon O
derepression O
, O
VL30 O
long O
terminal O
repeats O
( O
LTRs O
) O
act O
as O
promoter O
and O
enhancer O
elements O
deregulating O
expression O
of O
neighboring O
genes O
and O
generating O
enhancer O
RNAs O
that O
are O
required O
for O
LTR O
enhancer O
activity O
in O
hepatocytes O
in O
vivo O
. O

These O
data O
reinforce O
the O
role O
of O
the O
TRIM O
family O
of O
proteins O
in O
retroviral O
restriction O
and O
antiviral O
defense O
and O
provide O
an O
example O
of O
an O
ERV O
- O
derived O
oncogenic O
regulatory O
network O
. O

Association O
between O
bisphenol B
A I
and O
abnormal O
free O
thyroxine B
level O
in O
men O
. O

Bisphenol B
A I
( O
BPA B
) O
is O
a O
chemical O
that O
is O
used O
in O
a O
variety O
of O
consumer O
products O
, O
and O
exposure O
to O
BPA B
is O
widespread O
among O
the O
general O
population O
. O

Recent O
studies O
have O
suggested O
that O
BPA B
may O
affect O
the O
thyroid O
and O
related O
pathways O
. O

However O
, O
human O
studies O
are O
still O
limited O
. O

The O
aim O
of O
this O
study O
was O
to O
determine O
the O
relationship O
between O
BPA B
exposure O
and O
thyroid O
function O
. O

We O
obtained O
survey O
data O
and O
blood O
samples O
from O
The O
Thai O
National O
Health O
Examination O
Survey O
IV O
2009 O
, O
a O
nationally O
representative O
cross O
- O
sectional O
survey O
using O
a O
multistage O
, O
stratified O
sampling O
of O
the O
Thai O
population O
. O

A O
total O
of O
2 O
, O
340 O
subjects O
aged O
18 O
- O
94 O
years O
were O
sampled O
for O
the O
present O
study O
. O

Serum O
BPA B
, O
TSH O
, O
FT O
( O
4 O
) O
, O
and O
related O
covariates O
were O
measured O
. O

BPA B
was O
log O
- O
transformed O
prior O
to O
analysis O
. O

BPA B
was O
detected O
in O
52 O
. O
8 O
% O
of O
serum O
samples O
with O
a O
median O
concentration O
of O
0 O
. O
33 O
( O
range O
0 O
- O
66 O
. O
91 O
) O
ng O
/ O
mL O
. O

We O
excluded O
subjects O
who O
tested O
positive O
for O
thyroid O
autoantibody O
and O
then O
stratified O
the O
remaining O
subjects O
by O
gender O
; O
the O
analysis O
showed O
a O
significantly O
negative O
correlation O
between O
serum O
BPA B
and O
FT B
( I
4 I
) I
levels O
in O
males O
( O
r O
= O
- O
0 O
. O
14 O
, O
P O
< O
0 O
. O
001 O
) O
. O

In O
contrast O
, O
no O
association O
was O
observed O
in O
females O
. O

BPA B
was O
not O
associated O
with O
TSH O
in O
either O
gender O
. O

This O
gender O
- O
related O
discrepancy O
is O
possibly O
related O
to O
androgen B
- O
related O
differences O
in O
the O
metabolism O
of O
BPA B
. O

Our O
preliminary O
results O
provide O
evidence O
of O
a O
negative O
association O
between O
BPA B
and O
FT O
( O
4 O
) O
levels O
. O

Additional O
detailed O
studies O
are O
needed O
to O
investigate O
the O
temporal O
relationship O
and O
potential O
public O
health O
implications O
of O
such O
an O
association O
. O

Genetics O
of O
type O
2 O
diabetes O
and O
potential O
clinical O
implications O
. O

Type O
2 O
diabetes O
( O
T2DM O
) O
is O
a O
common O
complex O
metabolic O
disorder O
that O
has O
a O
strong O
genetic O
component O
. O

Recent O
advances O
in O
genome O
- O
wide O
association O
studies O
have O
revolutionized O
our O
knowledge O
regarding O
the O
genetics O
of O
T2DM O
. O

There O
are O
at O
least O
64 O
common O
genetic O
variants O
that O
are O
strongly O
associated O
with O
T2DM O
. O

However O
, O
the O
pathophysiologic O
roles O
of O
these O
variants O
are O
mostly O
unknown O
and O
require O
further O
functional O
characterization O
. O

The O
variants O
identified O
so O
far O
have O
a O
small O
effect O
size O
and O
their O
added O
effect O
explains O
less O
than O
10 O
% O
of O
the O
T2DM O
heritability O
. O

The O
current O
ongoing O
whole O
exome O
and O
whole O
genome O
studies O
of O
T2DM O
are O
focused O
on O
identifying O
functionally O
important O
rare O
variants O
that O
have O
a O
stronger O
effect O
. O

Through O
these O
efforts O
, O
we O
will O
have O
a O
better O
understanding O
of O
the O
genetic O
architecture O
of O
T2DM O
and O
its O
pathophysiology O
. O

The O
potential O
clinical O
applications O
of O
genetic O
studies O
of O
T2DM O
include O
risk O
prediction O
, O
identification O
of O
novel O
therapeutic O
targets O
, O
genetic O
prediction O
of O
efficacy O
and O
toxicity O
of O
anti O
- O
diabetic O
medications O
, O
and O
eventually O
optimization O
of O
patient O
care O
through O
personalized O
genomic O
medicine O
. O

We O
hope O
further O
research O
in O
genetics O
of O
T2DM O
could O
aid O
patient O
care O
and O
improve O
outcomes O
of O
T2DM O
patients O
. O

Acute O
viral O
infections O
of O
the O
central O
nervous O
system O
in O
immunocompetent O
adults O
: O
diagnosis O
and O
management O
. O

Patients O
with O
viral O
infections O
of O
the O
central O
nervous O
system O
( O
CNS O
) O
may O
present O
with O
a O
variety O
of O
neurological O
symptoms O
, O
most O
commonly O
dominated O
by O
either O
encephalitis O
or O
meningitis O
. O

The O
aetiological O
panorama O
varies O
in O
different O
parts O
of O
the O
world O
as O
well O
as O
over O
time O
. O

Thus O
, O
virological O
first O
- O
line O
diagnostics O
must O
be O
adapted O
to O
the O
current O
epidemiological O
situation O
and O
to O
the O
individual O
patient O
history O
, O
including O
recent O
travels O
. O

This O
review O
focuses O
on O
the O
diagnostics O
and O
treatment O
of O
viral O
CNS O
infections O
in O
the O
immunocompetent O
host O
from O
a O
Northern O
European O
perspective O
. O

Effective O
vaccines O
are O
available O
for O
viruses O
such O
as O
poliovirus O
and O
tick O
- O
borne O
encephalitis O
virus O
( O
TBEV O
) O
and O
for O
the O
childhood O
diseases O
morbilli O
( O
measles O
) O
, O
rubella O
( O
German O
measles O
) O
, O
parotitis O
( O
mumps O
) O
and O
varicella O
( O
chickenpox O
) O
. O

However O
, O
cases O
do O
appear O
due O
to O
suboptimal O
immunization O
rates O
. O

In O
viral O
CNS O
infections O
, O
epidemiological O
surveillance O
is O
essential O
for O
establishing O
preventive O
strategies O
and O
for O
detecting O
emerging O
viruses O
. O

Knowledge O
of O
the O
possibilities O
and O
limitations O
of O
diagnostic O
methods O
for O
specific O
viral O
CNS O
infections O
is O
vital O
. O

A O
positive O
cerebral O
spinal O
fluid O
( O
CSF O
) O
polymerase O
chain O
reaction O
( O
PCR O
) O
finding O
is O
usually O
reliable O
for O
aetiological O
diagnosis O
. O

The O
demonstration O
of O
intrathecal O
antibody O
synthesis O
is O
useful O
for O
confirming O
the O
aetiology O
in O
a O
later O
stage O
of O
disease O
, O
hitherto O
sufficiently O
evaluated O
in O
herpes O
simplex O
encephalitis O
( O
HSE O
) O
and O
tick O
- O
borne O
encephalitis O
( O
TBE O
) O
. O

Despite O
improved O
virological O
and O
differential O
diagnostic O
methods O
, O
aetiology O
remains O
unknown O
in O
about O
half O
of O
the O
cases O
with O
suspected O
viral O
encephalitis O
. O

Antiviral O
treatment O
is O
available O
chiefly O
for O
infections O
caused O
by O
herpesviruses O
, O
and O
acyclovir B
( O
aciclovir B
) O
is O
the O
drug O
of O
choice O
for O
empirical O
therapy O
in O
suspected O
viral O
encephalitis O
. O

However O
, O
randomized O
, O
controlled O
antiviral O
trials O
have O
only O
been O
conducted O
for O
HSE O
, O
while O
such O
studies O
are O
lacking O
in O
other O
viral O
CNS O
infections O
. O

Viral O
cytolysis O
and O
immune O
- O
mediated O
mechanisms O
may O
contribute O
to O
varying O
extents O
to O
neurological O
damage O
. O

Although O
the O
brain O
damage O
is O
believed O
to O
depend O
, O
to O
a O
varying O
degree O
, O
on O
the O
intrathecal O
host O
immune O
response O
, O
the O
use O
of O
corticosteroids O
in O
viral O
CNS O
infections O
is O
scarcely O
studied O
, O
as O
is O
specific O
treatment O
for O
neuroinflammation O
. O

Improved O
antiviral O
and O
immunomodulating O
treatment O
is O
desirable O
. O

Since O
neurological O
sequelae O
are O
still O
abundant O
, O
follow O
- O
up O
after O
severe O
viral O
CNS O
disease O
must O
include O
a O
neuropsychological O
assessment O
and O
an O
individually O
adapted O
rehabilitation O
plan O
. O

Sediment O
- O
associated O
pesticides O
in O
an O
urban O
stream O
in O
guangzhou O
, O
china O
: O
implication O
of O
a O
shift O
in O
pesticide O
use O
patterns O
. O

Pesticide O
use O
patterns O
in O
China O
have O
changed O
in O
recent O
years O
; O
however O
, O
the O
study O
of O
the O
environmental O
fate O
of O
current O
- O
use O
pesticides O
( O
CUPs O
) O
and O
their O
ecotoxicological O
significance O
in O
aquatic O
ecosystems O
is O
limited O
. O

In O
the O
present O
study O
, O
sediments O
were O
collected O
from O
an O
urban O
stream O
in O
the O
Chinese O
city O
of O
Guangzhou O
. O

Sediment O
- O
associated O
legacy O
organochlorine B
pesticides O
and O
CUPs O
- O
including O
organophosphates B
, O
pyrethroids B
, O
fipronil B
, O
and O
abamectin B
- O
were O
analyzed O
. O

Additionally O
, O
the O
relative O
toxicity O
of O
the O
sediments O
was O
evaluated O
with O
10 O
- O
d O
bioassays O
using O
Chironomus O
dilutus O
. O

Fifteen O
of O
16 O
sediments O
collected O
from O
the O
stream O
were O
acutely O
toxic O
to O
C O
. O
dilutus O
, O
with O
81 O
% O
of O
the O
samples O
causing O
100 O
% O
mortality O
. O

Abamectin B
, O
fipronil B
, O
and O
pyrethroids B
( O
mainly O
cypermethrin B
) O
were O
identified O
as O
the O
principal O
contributors O
to O
the O
noted O
toxicity O
in O
the O
midges O
, O
with O
median O
predicted O
toxic O
units O
of O
1 O
. O
63 O
, O
1 O
. O
63 O
, O
and O
1 O
. O
03 O
, O
respectively O
. O

Sediments O
taken O
from O
downstream O
sites O
, O
where O
residential O
and O
industrial O
regions O
were O
located O
, O
had O
elevated O
CUP O
concentrations O
and O
sediment O
toxicity O
compared O
with O
upstream O
sites O
. O

The O
present O
study O
is O
the O
first O
of O
its O
kind O
to O
link O
sediment O
CUPs O
, O
fipronil B
, O
and O
abamectin B
concentrations O
with O
toxicity O
in O
urban O
streams O
in O
China O
with O
a O
focus O
on O
shifting O
pesticide O
usage O
patterns O
. O

Environ O
. O

Toxicol O
. O

Chem O
. O

2013 O
; O
32 O
: O
1040 O
- O
1047 O
. O

( O
c O
) O
2013 O
SETAC O
. O

Pancreatic O
beta O
- O
Cell O
Dysfunction O
and O
Risk O
of O
New O
- O
Onset O
Diabetes O
After O
Kidney O
Transplantation O
. O

OBJECTIVEChronic O
exposure O
to O
calcineurin O
inhibitors O
and O
corticosteroids O
poses O
renal O
transplant O
recipients O
( O
RTR O
) O
at O
high O
risk O
for O
development O
of O
new O
- O
onset O
diabetes O
after O
transplantation O
( O
NODAT O
) O
. O

Pancreatic O
beta O
- O
cell O
dysfunction O
may O
be O
crucial O
to O
the O
pathophysiology O
of O
NODAT O
and O
specific O
markers O
for O
beta O
- O
cell O
dysfunction O
may O
have O
additive O
value O
for O
predicting O
NODAT O
in O
this O
population O
. O

Therefore O
, O
we O
prospectively O
investigated O
whether O
proinsulin O
, O
as O
a O
marker O
of O
pancreatic O
beta O
- O
cell O
dysfunction O
, O
is O
associated O
with O
future O
development O
of O
NODAT O
and O
improves O
prediction O
of O
it O
. O
RESEARCH O
DESIGN O
AND O
METHODSAll O
RTR O
between O
2001 O
and O
2003 O
with O
a O
functioning O
graft O
for O
> O
= O
1 O
year O
were O
considered O
eligible O
for O
inclusion O
, O
except O
for O
subjects O
with O
diabetes O
at O
baseline O
who O
were O
excluded O
. O

We O
recorded O
incidence O
of O
NODAT O
until O
April O
2012 O
. O
RESULTSA O
total O
of O
487 O
RTR O
( O
age O
50 O
+ O
/ O
- O
12 O
years O
, O
55 O
% O
men O
) O
participated O
at O
a O
median O
time O
of O
6 O
. O
0 O
( O
interquartile O
range O
[ O
IQR O
] O
, O
2 O
. O
6 O
- O
11 O
. O
5 O
) O
years O
after O
transplantation O
. O

Median O
fasting O
proinsulin O
levels O
were O
16 O
. O
6 O
( O
IQR O
, O
11 O
. O
0 O
- O
24 O
. O
2 O
) O
pmol O
/ O
L O
. O

During O
median O
follow O
- O
up O
for O
10 O
. O
1 O
( O
IQR O
, O
9 O
. O
1 O
- O
10 O
. O
4 O
) O
years O
, O
42 O
( O
35 O
% O
) O
RTR O
had O
development O
of O
NODAT O
in O
the O
highest O
quartile O
of O
the O
distribution O
of O
proinsulin O
versus O
34 O
( O
9 O
% O
) O
in O
the O
lowest O
three O
quartiles O
( O
P O
< O
0 O
. O
001 O
) O
. O

In O
Cox O
regression O
analyses O
, O
proinsulin O
( O
hazard O
ratio O
, O
2 O
. O
29 O
; O
95 O
% O
confidence O
interval O
, O
1 O
. O
85 O
- O
2 O
. O
83 O
; O
P O
< O
0 O
. O
001 O
) O
was O
strongly O
associated O
with O
NODAT O
development O
. O

This O
was O
independent O
of O
age O
, O
sex O
, O
calcineurine O
inhibitors O
, O
prednisolone B
use O
, O
components O
of O
the O
metabolic O
syndrome O
, O
or O
homeostasis O
model O
assessment O
. O
CONCLUSIONSIn O
conclusion O
, O
fasting O
proinsulin O
is O
strongly O
associated O
with O
NODAT O
development O
in O
RTR O
. O

Our O
results O
highlight O
the O
role O
of O
beta O
- O
cell O
dysfunction O
in O
the O
pathophysiology O
of O
NODAT O
and O
indicate O
the O
potential O
value O
of O
proinsulin O
for O
identification O
of O
RTR O
at O
increased O
risk O
for O
NODAT O
. O

Glycation O
Gap O
Is O
Associated O
With O
Macroproteinuria O
but O
Not O
With O
Other O
Complications O
in O
Patients O
With O
Type O
2 O
Diabetes O
. O

OBJECTIVEWe O
investigated O
whether O
glycation O
gap O
( O
G O
- O
Gap O
) O
, O
an O
index O
of O
intracellular O
glycation O
of O
proteins O
, O
was O
associated O
with O
diabetes O
complications O
. O
RESEARCH O
DESIGN O
AND O
METHODSWe O
measured O
concomitantly O
HbA O
( O
1c O
) O
and O
fructosamine B
in O
925 O
patients O
with O
type O
2 O
diabetes O
to O
calculate O
the O
G O
- O
Gap O
, O
defined O
as O
the O
difference O
between O
measured O
HbA O
( O
1c O
) O
, O
and O
fructosamine B
- O
based O
predicted O
HbA O
( O
1c O
) O
. O

Patients O
were O
explored O
for O
retinopathy O
, O
nephropathy O
, O
peripheral O
neuropathy O
, O
cardiac O
autonomic O
neuropathy O
( O
n O
= O
512 O
) O
, O
and O
silent O
myocardial O
ischemia O
( O
n O
= O
506 O
) O
. O
RESULTSMacroproteinu O
was O
the O
only O
complication O
that O
was O
associated O
with O
G O
- O
Gap O
( O
prevalence O
in O
the O
first O
, O
second O
, O
and O
third O
tertile O
of O
G O
- O
Gap O
: O
2 O
. O
9 O
, O
6 O
. O
2 O
, O
and O
11 O
. O
0 O
% O
, O
respectively O
; O
P O
< O
0 O
. O
001 O
) O
. O

The O
G O
- O
Gap O
was O
higher O
in O
patients O
with O
macroproteinuria O
than O
in O
those O
without O
( O
1 O
. O
06 O
+ O
/ O
- O
1 O
. O
62 O
vs O
. O
0 O
. O
03 O
+ O
/ O
- O
1 O
. O
30 O
% O
; O
P O
< O
0 O
. O
0001 O
) O
. O

Because O
HbA O
( O
1c O
) O
was O
associated O
with O
both O
G O
- O
Gap O
( O
HbA O
( O
1c O
) O
7 O
. O
0 O
+ O
/ O
- O
1 O
. O
4 O
, O
7 O
. O
9 O
+ O
/ O
- O
1 O
. O
4 O
, O
and O
10 O
. O
1 O
+ O
/ O
- O
1 O
. O
8 O
% O
in O
the O
first O
, O
second O
, O
and O
third O
G O
- O
Gap O
tertile O
, O
respectively O
; O
P O
< O
0 O
. O
0001 O
) O
and O
macroproteinuria O
( O
HbA O
( O
1c O
) O
8 O
. O
8 O
+ O
/ O
- O
2 O
. O
2 O
% O
if O
macroproteinuria O
, O
8 O
. O
3 O
+ O
/ O
- O
2 O
. O
0 O
% O
if O
none O
; O
P O
< O
0 O
. O

05 O
) O
, O
and O
because O
it O
could O
have O
been O
a O
confounder O
, O
we O
matched O
54 O
patients O
with O
macroproteinuria O
and O
200 O
patients O
without O
for O
HbA O
( O
1c O
) O
. O

Because O
macroproteinuria O
was O
associated O
with O
lower O
serum O
albumin O
and O
fructosamine B
levels O
, O
which O
might O
account O
for O
higher O
G O
- O
Gap O
, O
we O
calculated O
in O
this O
subpopulation O
albumin O
- O
indexed O
fructosamine B
and O
G O
- O
Gap O
; O
macroproteinuria O
was O
independently O
associated O
with O
male O
gender O
( O
odds O
ratio O
[ O
OR O
] O
, O
3 O
. O
2 O
; O
95 O
% O
CI O
, O
1 O
. O
5 O
- O
6 O
. O
7 O
; O
P O
< O
0 O
. O
01 O
) O
, O
hypertension O
( O
2 O
. O
9 O
; O
[ O
1 O
. O
1 O
- O
7 O
. O
5 O
] O
; O
P O
< O
0 O
. O
05 O
) O
, O
and O
the O
third O
tertile O

of O
albumin O
- O
indexed O
G O
- O
Gap O
( O
2 O
. O
3 O
; O
[ O
1 O
. O
1 O
- O
4 O
. O
4 O
] O
; O
P O
< O
0 O
. O
05 O
) O
in O
multivariate O
analysis O
. O
CONCLUSIONIn O
type O
2 O
diabetic O
patients O
, O
G O
- O
Gap O
was O
associated O
with O
macroproteinuria O
, O
independently O
of O
HbA O
( O
1c O
) O
, O
albumin O
levels O
, O
and O
confounding O
factors O
, O
suggesting O
a O
specific O
role O
of O
intracellular O
glycation O
susceptibility O
on O
kidney O
glomerular O
changes O
. O

Activation O
of O
the O
anti O
- O
cancer O
agent O
upamostat O
by O
the O
mARC O
enzyme O
system O
. O

Abstract O
1 O
. O

Upamostat O
( O
Mesupron B
( O
R O
) O
) O
is O
a O
new O
small O
molecule O
serine B
protease O
inhibitor O
. O

The O
drug O
candidate O
was O
developed O
to O
inhibit O
the O
urokinase O
- O
type O
plasminogen O
activator O
( O
uPA O
) O
system O
, O
which O
plays O
a O
major O
role O
in O
tumor O
invasion O
and O
metastasis O
. O

Upamostat O
is O
currently O
in O
clinical O
development O
as O
an O
anti O
- O
metastatic O
and O
non O
- O
cytotoxic O
agent O
against O
pancreatic O
and O
breast O
cancer O
. O

2 O
. O

Upamostat O
is O
the O
orally O
available O
amidoxime B
- O
( O
i O
. O
e O
. O
hydroxyamidine B
- O
) O
prodrug O
of O
the O
pharmacologically O
active O
form O
, O
WX O
- O
UK1 O
. O

In O
this O
study O
, O
the O
reductive O
enzymatic O
activation O
of O
upamostat O
to O
its O
corresponding O
amidine B
WX O
- O
UK1 O
was O
analyzed O
. O

3 O
. O

The O
recently O
discovered O
molybdenum B
enzyme O
" O
mitochondrial O
Amidoxime B
Reducing O
Component O
" O
( O
mARC O
) O
catalyses O
together O
with O
its O
electron O
transport O
proteins O
cytochrome O
b O
( O
5 O
) O
and O
NADH B
cytochrome O
b O
( O
5 O
) O
reductase O
the O
reduction O
of O
N B
- O
hydroxylated O
prodrugs O
. O

In O
vitro O
biotransformation O
assays O
with O
porcine O
subcellular O
fractions O
and O
the O
reconstituted O
human O
enzymes O
demonstrate O
an O
mARC O
- O
dependent O
N O
- O
reduction O
of O
upamostat O
. O

Nuclease O
- O
resistant O
DNA O
via O
high O
- O
density O
packing O
in O
polymeric O
micellar O
nanoparticle O
coronas O
. O

Herein O
, O
we O
describe O
a O
polymeric O
micellar O
nanoparticle O
capable O
of O
rendering O
nucleic O
acids O
resistant O
to O
nuclease O
digestion O
. O

This O
approach O
relies O
on O
utilizing O
DNA O
as O
the O
polar O
headgroup O
of O
a O
DNA O
- O
polymer O
amphiphile O
in O
order O
to O
assemble O
well O
- O
defined O
, O
discrete O
nanoparticles O
. O

Dense O
packing O
of O
DNA O
in O
the O
micelle O
corona O
allows O
for O
hybridization O
of O
complementary O
oligonucleotides O
while O
prohibiting O
enzymatic O
degradation O
. O

We O
demonstrate O
the O
preparation O
, O
purification O
, O
and O
characterization O
of O
the O
nanoparticles O
, O
then O
describe O
their O
resistance O
to O
treatment O
with O
endo O
- O
and O
exonucleases O
including O
snake O
- O
venom O
phosphodiesterase O
( O
SVP O
) O
, O
a O
common O
, O
general O
DNA O
digestion O
enzyme O
. O

Diversification O
in O
a O
biodiversity O
hot O
spot O
: O
landscape O
correlates O
of O
phylogeographic O
patterns O
in O
the O
African O
spotted O
reed O
frog O
. O

The O
Eastern O
Afromontane O
Biodiversity O
Hotspot O
is O
known O
for O
microendemism O
and O
exceptional O
population O
genetic O
structure O
. O

The O
region O
' O
s O
landscape O
heterogeneity O
is O
thought O
to O
limit O
gene O
flow O
between O
fragmented O
populations O
and O
create O
opportunities O
for O
regional O
adaptation O
, O
but O
the O
processes O
involved O
are O
poorly O
understood O
. O

Using O
a O
combination O
of O
phylogeographic O
analyses O
and O
circuit O
theory O
, O
I O
investigate O
how O
characteristics O
of O
landscape O
heterogeneity O
including O
regional O
distributions O
of O
slope O
, O
rivers O
and O
streams O
, O
habitat O
and O
hydrological O
basins O
( O
drainages O
) O
impact O
genetic O
distance O
among O
populations O
of O
the O
endemic O
spotted O
reed O
frog O
( O
Hyperolius O
substriatus O
) O
, O
identifying O
corridors O
of O
connectivity O
as O
well O
as O
barriers O
to O
dispersal O
. O

Results O
show O
that O
genetic O
distance O
among O
populations O
is O
most O
strongly O
correlated O
to O
regional O
and O
local O
hydrologic O
structure O
and O
the O
distribution O
of O
suitable O
habitat O
corridors O
, O
not O
isolation O
by O
distance O
. O

Contrary O
to O
expectations O
, O
phylogeographic O
structure O
is O
not O
coincident O
with O
the O
two O
montane O
systems O
, O
but O
instead O
corresponds O
to O
the O
split O
between O
the O
region O
' O
s O
two O
major O
hydrological O
basins O
( O
Zambezi O
and O
East O
Central O
Coastal O
) O
. O

This O
results O
in O
a O
paraphyletic O
relationship O
for O
the O
Malawian O
Highlands O
populations O
with O
respect O
to O
the O
Eastern O
Arc O
Mountains O
and O
implies O
that O
the O
northern O
Malawian O
Highlands O
are O
the O
diversity O
centre O
for O
H O
. O
substriatus O
. O

Although O
the O
Malawian O
Highlands O
collectively O
hold O
the O
greatest O
genetic O
diversity O
, O
individual O
populations O
have O
lower O
diversity O
than O
their O
Eastern O
Arc O
counterparts O
, O
with O
an O
overall O
pattern O
of O
decreasing O
population O
diversity O
from O
north O
to O
south O
. O

Through O
the O
study O
of O
intraspecific O
differentiation O
across O
a O
mosaic O
of O
ecosystem O
and O
geographic O
heterogeneity O
, O
we O
gain O
insight O
into O
the O
processes O
of O
diversification O
and O
a O
broader O
understanding O
of O
the O
role O
of O
landscape O
in O
evolution O
. O

Multifunctional O
conducting O
fibres O
with O
electrically O
controlled O
release O
of O
ciprofloxacin B
. O

We O
hereby O
present O
a O
new O
method O
of O
producing O
coaxial O
conducting O
polymer O
fibres O
loaded O
with O
an O
antibiotic O
drug O
that O
can O
then O
be O
subsequently O
released O
( O
or O
sustained O
) O
in O
response O
to O
electrical O
stimulation O
. O

The O
method O
involves O
wet O
- O
spinning O
of O
poly B
( I
3 I
, I
4 I
- I
ethylenedioxythiophe I
) I
poly B
( I
styrenesulfonate I
) I
( O
PEDOT B
: O
PSS B
) O
fibre O
, O
which O
served O
as O
the O
inner O
core O
to O
the O
electropolymerised O
outer O
shell O
layer O
of O
polypyrrole B
( O
Ppy B
) O
. O

Ciprofloxacin B
hydrochloride I
( O
Cipro B
) O
was O
selected O
as O
the O
model O
drug O
and O
as O
the O
dopant O
in O
the O
Ppy O
synthesis O
. O

The O
release O
of O
Cipro B
in O
phosphate B
buffered O
saline O
( O
PBS O
) O
from O
the O
fibres O
was O
controlled O
by O
switching O
the O
redox O
state O
of O
Ppy B
. O
Cipro B
layer O
. O

Released O
Cipro B
under O
passive O
and O
stimulated O
conditions O
were O
tested O
against O
Gram O
positive O
( O
Streptococcus O
pyogenes O
) O
and O
Gram O
negative O
( O
Escherichia O
coli O
) O
bacteria O
. O

Significant O
inhibition O
of O
bacterial O
growth O
was O
observed O
against O
both O
strains O
tested O
. O

These O
results O
confirm O
that O
Cipro B
retains O
antibacterial O
properties O
during O
fibre O
fabrication O
and O
electrochemically O
controlled O
release O
. O

In O
vitro O
cytotoxicity O
testing O
utilising O
the O
neural O
B35 O
cell O
line O
confirmed O
the O
cytocompatibility O
of O
the O
drug O
loaded O
conducting O
fibres O
. O

Electrical O
conductivity O
, O
cytocompatibility O
and O
tuning O
release O
profile O
from O
this O
flexible O
fibre O
can O
lead O
to O
promising O
bionic O
applications O
such O
as O
neuroprosthetics O
and O
localised O
drug O
delivery O
. O

DNA O
delivery O
with O
hyperbranched O
polylysine B
: O
A O
comparative O
study O
with O
linear O
and O
dendritic O
polylysine B
. O

PEI B
and O
polylysine B
are O
among O
the O
most O
investigated O
synthetic O
polymeric O
carriers O
for O
DNA O
delivery O
. O

Apart O
from O
their O
practical O
use O
, O
these O
2 O
classes O
of O
polymers O
are O
also O
of O
interest O
from O
a O
fundamental O
point O
of O
view O
as O
they O
both O
can O
be O
prepared O
in O
different O
architectures O
( O
linear O
and O
branched O
/ O
dendritic O
) O
and O
in O
a O
wide O
range O
of O
molecular O
weights O
, O
which O
is O
attractive O
to O
establish O
basic O
structure O
- O
activity O
relationships O
. O

This O
manuscript O
reports O
the O
results O
of O
an O
extensive O
study O
on O
the O
influence O
of O
molecular O
weight O
and O
architecture O
of O
a O
library O
of O
polylysine B
variants O
that O
includes O
linear O
, O
dendritic O
and O
hyperbranched O
polylysine B
. O

Hyperbranched O
polylysine B
is O
a O
new O
polylysine B
- O
based O
carrier O
that O
is O
structurally O
related O
to O
dendritic O
polylysine B
but O
possesses O
a O
randomly O
branched O
structure O
. O

Hyperbranched O
polylysine B
is O
attractive O
as O
it O
can O
be O
prepared O
in O
a O
one O
- O
step O
process O
on O
a O
large O
scale O
. O

The O
performance O
of O
these O
3 O
classes O
of O
polylysine B
analogs O
was O
evaluated O
by O
assessing O
eGFP O
and O
IgG O
production O
in O
transient O
gene O
expression O
experiments O
with O
CHO O
DG44 O
cells O
, O
which O
revealed O
that O
protein O
production O
generally O
increased O
with O
increasing O
molecular O
weight O
and O
that O
at O
comparable O
molecular O
weight O
, O
the O
hyperbranched O
analogs O
were O
superior O
as O
compared O
to O
the O
dendritic O
and O
linear O
polylysines B
. O

To O
understand O
the O
differences O
between O
the O
gene O
delivery O
properties O
of O
the O
hyperbranched O
polylysine B
analogs O
on O
the O
one O
hand O
and O
the O
dendritic O
and O
linear O
polylysines B
on O
the O
other O
hand O
, O
the O
uptake O
and O
trafficking O
of O
the O
corresponding O
polyplexes O
were O
investigated O
. O

These O
experiments O
allowed O
us O
to O
identify O
( O
i O
) O
polyplex B
- O
external O
cell O
membrane O
binding O
, O
( O
ii O
) O
free O
, O
unbound O
polylysine B
coexisting O
with O
polyplexes B
as O
well O
as O
( O
iii O
) O
polymer O
buffer O
capacity O
as O
three O
possible O
factors O
that O
may O
contribute O
to O
the O
superior O
transfection O
properties O
of O
the O
hyperbranched O
polylysines B
as O
compared O
to O
their O
linear O
and O
dendritic O
analogs O
. O

Altogether O
, O
the O
results O
of O
this O
study O
indicate O
that O
hyperbranched O
polylysine B
is O
an O
interesting O
, O
alternative O
synthetic O
gene O
carrier O
. O

Hyperbranched O
polylysine B
can O
be O
produced O
at O
low O
costs O
and O
in O
large O
quantities O
, O
is O
partially O
biodegradable O
, O
which O
may O
help O
to O
prevent O
cumulative O
cytotoxicity O
, O
and O
possesses O
transfection O
properties O
that O
can O
approach O
those O
of O
PEI B
. O

Titanium B
dioxide I
nanoparticles O
increase O
inflammatory O
responses O
in O
vascular O
endothelial O
cells O
. O

Atherosclerosis O
is O
a O
chronic O
inflammatory O
disease O
that O
remains O
the O
leading O
cause O
of O
death O
in O
the O
United O
States O
. O

Numerous O
risk O
factors O
for O
endothelial O
cell O
inflammation O
and O
the O
development O
of O
atherosclerosis O
have O
been O
identified O
, O
including O
inhalation O
of O
ultrafine O
particles O
. O

Recently O
, O
engineered O
nanoparticles O
( O
NPs O
) O
such O
as O
titanium B
( O
TiO2 B
) O
NPs O
have O
attracted O
much O
attention O
due O
to O
their O
wide O
range O
of O
applications O
. O

However O
, O
there O
are O
also O
great O
concerns O
surrounding O
potential O
adverse O
health O
effects O
in O
vascular O
systems O
. O

Although O
TiO2 B
NPs O
are O
known O
to O
induce O
oxidative O
stress O
and O
inflammation O
, O
the O
associated O
signaling O
pathways O
have O
not O
been O
well O
studied O
. O

The O
focus O
of O
this O
work O
, O
therefore O
, O
deals O
with O
examination O
of O
the O
cellular O
signaling O
pathways O
responsible O
for O
TiO2 B
NP O
- O
induced O
endothelial O
oxidative O
stress O
and O
inflammation O
. O

In O
this O
study O
, O
primary O
vascular O
endothelial O
cells O
were O
treated O
with O
TiO2 B
NPs O
for O
2 O
- O
16h O
at O
concentrations O
of O
0 O
- O
50 O
mu O
g O
/ O
mL O
. O

TiO2 B
NP O
exposure O
increased O
cellular O
oxidative O
stress O
and O
DNA O
binding O
of O
NF O
- O
kappa O
B O
. O

Further O
, O
phosphorylation O
of O
Akt O
, O
ERK O
, O
JNK O
and O
p38 O
was O
increased O
in O
cells O
exposed O
to O
TiO2 B
NPs O
. O

TiO2 B
NPs O
also O
significantly O
increased O
induction O
of O
mRNA O
and O
protein O
levels O
of O
vascular O
cell O
adhesion O
molecule O
- O
1 O
( O
VCAM O
- O
1 O
) O
and O
mRNA O
levels O
of O
monocyte O
chemoattractant O
protein O
- O
1 O
( O
MCP O
- O
1 O
) O
. O

Pretreatment O
with O
inhibitors O
for O
NF O
- O
kappa O
B O
( O
pyrrolidine B
dithiocarbamate I
) O
, O
oxidative O
stress O
( O
epigallocatechin B
gallate I
and O
apocynin B
) O
, O
Akt O
( O
LY294002 B
) O
, O
ERK O
( O
PD98059 B
) O
, O
JNK O
( O
SP600125 B
) O
and O
p38 O
( O
SB203580 B
) O
significantly O
attenuated O
TiO2 B
NP O
- O
induced O
MCP O
- O
1 O
and O
VCAM O
- O
1 O
gene O
expression O
. O

These O
data O
indicate O
that O
TiO2 B
NPs O
can O
induce O
endothelial O
inflammatory O
responses O
via O
redox O
- O
sensitive O
cellular O
signaling O
pathways O
. O

Cinnamic B
acid I
derivatives O
as O
inhibitors O
for O
chorismatases O
and O
isochorismatases O
. O

Chorismatases O
and O
isochorismatases O
catalyse O
the O
hydrolysis O
of O
chorismate B
or O
isochorismate B
leading O
to O
unsaturated B
cyclohexenoic I
acid I
derivatives O
. O

Based O
on O
simplification O
of O
the O
physiological O
substrates O
, O
two O
cinnamic B
acid I
- O
derived O
compounds O
, O
differing O
in O
the O
saturation O
of O
the O
side O
chain O
, O
were O
developed O
. O

In O
contrast O
to O
earlier O
inhibitor O
studies O
, O
the O
compounds O
described O
here O
do O
not O
have O
an O
ether B
bond O
and O
therefore O
can O
be O
synthesised O
very O
easily O
in O
one O
or O
two O
steps O
without O
the O
need O
for O
protective O
groups O
. O

Both O
substances O
demonstrate O
inhibition O
of O
the O
isochorismatase O
EntB O
from O
Escherichia O
coli O
and O
the O
chorismatases O
FkbO O
and O
Hyg5 O
from O
Streptomyces O
. O

For O
chorismatases O
, O
the O
unsaturated O
compound O
shows O
IC O
( O
50 O
) O
values O
in O
the O
millimolar O
range O
, O
while O
the O
saturated O
compound O
is O
the O
better O
inhibitor O
with O
IC O
( O
50 O
) O
values O
in O
the O
micromolar O
/ O
low O
millimolar O
range O
; O
for O
the O
isochorismatase O
tested O
both O
compounds O
inhibit O
in O
the O
micromolar O
range O
. O

Further O
, O
an O
analysis O
of O
the O
apparent O
K O
( O
m O
) O
values O
for O
FkbO O
and O
EntB O
was O
performed O
, O
showing O
that O
both O
inhibitors O
act O
in O
a O
competitive O
manner O
. O

Due O
to O
the O
ease O
of O
modifying O
these O
new O
inhibitors O
they O
are O
a O
suitable O
starting O
point O
for O
exploring O
further O
functionalised O
derivatives O
. O

Carbon B
monoxide I
protects O
against O
ovariectomy O
- O
induced O
bone O
loss O
by O
inhibiting O
osteoclastogenesis O
. O

Carbon B
monoxide I
( O
CO B
) O
has O
been O
shown O
to O
have O
remarkable O
therapeutic O
value O
at O
low O
dosage O
by O
suppressing O
inflammation O
via O
inhibitory O
effects O
on O
macrophages O
, O
which O
are O
also O
precursors O
of O
osteoclasts O
( O
OC O
) O
. O

The O
objective O
of O
the O
present O
study O
was O
to O
determine O
whether O
CO B
limits O
bone O
loss O
through O
its O
effects O
on O
osteoclastogenesis O
. O

Intraperitoneal O
injection O
of O
CO B
- O
releasing O
molecule O
2 O
( O
CORM2 O
) O
into O
mice O
with O
reduced O
bone O
mass O
due O
to O
ovariectomy O
( O
OVX O
) O
resulted O
in O
significantly O
elevated O
bone O
mass O
. O

Increased O
serum O
levels O
of O
collagen O
- O
type O
I O
fragments O
, O
tartrate B
- O
resistant O
acid O
phosphatase O
5b O
, O
and O
reactive O
oxygen B
species O
( O
ROS O
) O
due O
to O
OVX O
were O
also O
decreased O
when O
treated O
with O
CORM2 B
. O

In O
vitro O
, O
CORM2 O
inhibited O
receptor O
activator O
of O
nuclear O
factor O
- O
kappa O
B O
ligand O
( O
RANKL O
) O
- O
induced O
OC O
formation O
without O
affecting O
bone O
resorption O
. O

CORM2 O
reduced O
long O
- O
lasting O
ROS O
levels O
and O
nuclear O
factor O
- O
kappa O
B O
( O
NF O
- O
kappa O
B O
) O
activation O
in O
response O
to O
RANKL O
. O

Inhibition O
of O
NADPH B
oxidase O
partially O
reduced O
the O
inhibitory O
effect O
of O
CO B
. O

CO B
induced O
increase O
of O
peroxiredoxin O
1 O
( O
PRX1 O
) O
in O
BMM O
. O

Down O
- O
regulation O
of O
PRX1 O
reduced O
the O
inhibitory O
effect O
of O
CO B
on O
OC O
formation O
and O
sustained O
the O
ROS O
levels O
induced O
by O
RANKL O
, O
suggesting O
that O
CO B
reduces O
generation O
of O
ROS O
and O
scavenges O
ROS O
to O
inhibit O
osteoclastogenesis O
. O

These O
data O
suggest O
that O
the O
inhibitory O
effect O
of O
CO B
on O
osteoclastogenesis O
is O
caused O
by O
impaired O
RANKL O
signaling O
through O
defective O
NF O
- O
kappa O
B O
activation O
and O
reduced O
levels O
of O
long O
- O
lasting O
ROS O
. O

These O
changes O
result O
in O
decreased O
bone O
loss O
. O

Our O
data O
highlight O
the O
potential O
utility O
of O
CO B
for O
ameliorating O
bone O
loss O
induced O
by O
loss O
of O
ovarian O
function O
. O

Rescue O
of O
hearing O
and O
vestibular O
function O
by O
antisense O
oligonucleotides O
in O
a O
mouse O
model O
of O
human O
deafness O
. O

Hearing O
impairment O
is O
the O
most O
common O
sensory O
disorder O
, O
with O
congenital O
hearing O
impairment O
present O
in O
approximately O
1 O
in O
1 O
, O
000 O
newborns O
. O

Hereditary O
deafness O
is O
often O
mediated O
by O
the O
improper O
development O
or O
degeneration O
of O
cochlear O
hair O
cells O
. O

Until O
now O
, O
it O
was O
not O
known O
whether O
such O
congenital O
failures O
could O
be O
mitigated O
by O
therapeutic O
intervention O
. O

Here O
we O
show O
that O
hearing O
and O
vestibular O
function O
can O
be O
rescued O
in O
a O
mouse O
model O
of O
human O
hereditary O
deafness O
. O

An O
antisense O
oligonucleotide O
( O
ASO O
) O
was O
used O
to O
correct O
defective O
pre O
- O
mRNA O
splicing O
of O
transcripts O
from O
the O
USH1C O
gene O
with O
the O
c O
. O
216G O
> O
A O
mutation O
, O
which O
causes O
human O
Usher O
syndrome O
, O
the O
leading O
genetic O
cause O
of O
combined O
deafness O
and O
blindness O
. O

Treatment O
of O
neonatal O
mice O
with O
a O
single O
systemic O
dose O
of O
ASO O
partially O
corrects O
Ush1c O
c O
. O
216G O
> O
A O
splicing O
, O
increases O
protein O
expression O
, O
improves O
stereocilia O
organization O
in O
the O
cochlea O
, O
and O
rescues O
cochlear O
hair O
cells O
, O
vestibular O
function O
and O
low O
- O
frequency O
hearing O
in O
mice O
. O

These O
effects O
were O
sustained O
for O
several O
months O
, O
providing O
evidence O
that O
congenital O
deafness O
can O
be O
effectively O
overcome O
by O
treatment O
early O
in O
development O
to O
correct O
gene O
expression O
and O
demonstrating O
the O
therapeutic O
potential O
of O
ASOs O
in O
the O
treatment O
of O
deafness O
. O

Formation O
of O
polymersomes O
with O
double O
bilayers O
templated O
by O
quadruple O
emulsions O
. O

Polymersomes O
, O
vesicles O
composed O
of O
bilayer O
membranes O
of O
amphiphilic O
block O
- O
copolymers O
, O
are O
promising O
delivery O
vehicles O
for O
long O
- O
term O
storage O
and O
controlled O
release O
of O
bioactives O
; O
enhanced O
stability O
of O
the O
membrane O
makes O
polymersomes O
potentially O
useful O
in O
a O
wide O
range O
of O
biological O
delivery O
applications O
by O
comparison O
with O
liposomes O
. O

However O
, O
unilamellar O
structure O
is O
intrinsically O
fragile O
when O
subjected O
to O
external O
stress O
. O

Here O
, O
we O
report O
a O
microfluidic O
approach O
to O
produce O
polymersomes O
with O
double O
bilayers O
, O
providing O
higher O
stability O
and O
lower O
permeability O
than O
unilamellar O
polymersomes O
. O

To O
achieve O
this O
, O
we O
developed O
a O
new O
design O
of O
a O
capillary O
microfluidic O
device O
to O
produce O
quadruple O
- O
emulsion O
drops O
which O
serve O
as O
a O
template O
for O
the O
polymersomes O
- O
in O
- O
polymersomes O
. O

When O
two O
bilayers O
are O
attracted O
by O
depletion O
in O
polymersomes O
- O
in O
- O
polymersomes O
, O
the O
inner O
polymersomes O
protrude O
and O
bud O
, O
forming O
double O
bilayers O
. O

We O
confirm O
these O
structures O
are O
indeed O
double O
bilayers O
using O
microaspiration O
and O
selective O
doping O
of O
the O
leaflets O
with O
nanoparticles O
. O

The O
resultant O
polymersomes O
have O
great O
potential O
as O
highly O
stable O
and O
biocompatible O
microcarriers O
for O
robust O
encapsulation O
and O
storage O
of O
bioactives O
such O
as O
drugs O
, O
cosmetics O
and O
nutrients O
. O

Kocurin B
, O
the O
true O
structure O
of O
PM181104 B
, O
an O
anti O
- O
methicillin B
- O
resistant O
Staphylococcus O
aureus O
( O
MRSA O
) O
thiazolyl B
peptide O
from O
the O
marine O
- O
derived O
bacterium O
Kocuria O
palustris O
. O

A O
new O
thiazolyl B
peptide O
, O
kocurin B
( O
1 O
) O
, O
was O
isolated O
from O
culture O
broths O
of O
a O
marine O
- O
derived O
Kocuria O
palustris O
. O

Its O
structural O
elucidation O
was O
accomplished O
using O
a O
combination O
of O
spectroscopic O
and O
chemical O
methods O
, O
including O
HRMS O
, O
extensive O
1D O
and O
2D O
NMR O
analysis O
, O
MS O
/ O
MS O
fragmentation O
, O
and O
chemical O
degradation O
and O
Marfey O
' O
s O
analysis O
of O
the O
resulting O
amino B
acid I
residues O
. O

The O
structure O
herein O
reported O
corrects O
that O
previously O
assigned O
to O
PM181104 O
( O
3 O
) O
. O

Kocurin B
displayed O
activity O
against O
methicillin B
- O
resistant O
Staphylococcus O
aureus O
( O
MRSA O
) O
, O
with O
MIC O
values O
in O
the O
submicromolar O
range O
. O

Anisole B
hydrolysis O
in O
high O
temperature O
water O
. O

We O
investigated O
the O
hydrolysis O
of O
anisole B
to O
phenol B
in O
high O
- O
temperature O
water O
with O
and O
without O
water O
- O
tolerant O
Lewis B
acid I
catalysis O
. O

With O
no O
catalyst O
present O
, O
anisole B
hydrolyzes O
to O
phenol B
in O
97 O
% O
yield O
after O
24 O
hours O
at O
365 O
degrees O
C O
, O
our O
experimentally O
determined O
optimal O
temperature O
and O
time O
. O

Experiments O
with O
varied O
water O
density O
and O
analysis O
of O
comparable O
literature O
data O
suggest O
that O
anisole B
hydrolysis O
is O
almost O
third O
order O
in O
water O
, O
when O
the O
S O
( O
N O
) O
2 O
mechanism O
dominates O
. O

Of O
the O
water O
- O
tolerant O
Lewis B
acid I
catalysts O
studied O
, O
In B
( I
OTf I
) I
( I
3 I
) I
offered O
the O
best O
phenol B
yield O
. O

Anisole B
hydrolysis O
was O
first O
order O
in O
catalyst O
and O
first O
order O
in O
substrate O
. O

Introducing O
In B
( I
OTf I
) I
( I
3 I
) I
catalysis O
lowered O
the O
activation O
energy O
for O
anisole B
hydrolysis O
to O
31 O
+ O
/ O
- O
1 O
kcal O
mol O
( O
- O
1 O
) O
. O

Anisole B
hydrolysis O
in O
high O
- O
temperature O
water O
with O
In B
( I
OTf I
) I
( I
3 I
) I
catalysis O
is O
competitive O
with O
other O
techniques O
in O
the O
literature O
based O
on O
rate O
and O
yield O
. O

In O
the O
presence O
of O
5 O
mol O
% O
In B
( I
OTf I
) I
( I
3 I
) I
catalyst O
, O
anisole B
hydrolyzes O
to O
phenol B
in O
97 O
% O
yield O
after O
90 O
minutes O
at O
300 O
degrees O
C O
. O

Application O
of O
MCD O
spectroscopy O
and O
TD O
- O
DFT O
to O
endohedral O
metallofullerenes O
for O
characterization O
of O
their O
electronic O
transitions O
. O

We O
describe O
, O
for O
the O
first O
time O
, O
the O
application O
of O
magnetic O
circular O
dichroism O
( O
MCD O
) O
spectroscopy O
and O
time O
- O
dependent O
density O
functional O
theory O
( O
TD O
- O
DFT O
) O
calculations O
using O
B3LYP O
and O
M06 O
- O
2X O
functionals O
to O
characterize O
the O
electronic O
transitions O
of O
endohedral B
metallofullerenes I
( O
EMFs B
) O
. O

Results O
revealed O
that O
the O
electronic O
transitions O
of O
La O
@ O
C O
( O
2v O
) O
- O
C O
( O
82 O
) O
, O
La O
( O
2 O
) O
@ O
I O
( O
h O
) O
- O
C O
( O
80 O
) O
, O
and O
Sc B
( I
3 I
) I
N I
@ O
I O
( O
h O
) O
- O
C O
( O
80 O
) O
can O
be O
assigned O
using O
these O
techniques O
. O

Particularly O
, O
a O
difference O
in O
the O
electronic O
transitions O
between O
La B
( I
2 I
) I
@ O
I B
( I
h I
) I
- I
C I
( I
80 I
) I
and O
Sc B
( I
3 I
) I
N I
@ O
I B
( I
h I
) I
- I
C I
( I
80 I
) I
, O
which O
is O
invisible O
in O
absorption O
spectra O
, O
was O
observed O
clearly O
in O
MCD O
spectra O
. O

The O
observed O
MCD O
bands O
agree O
well O
with O
the O
oscillator O
strengths O
calculated O
using O
the O
B3LYP O
functional O
. O

In O
addition O
, O
the O
MCD O
bands O
of O
La B
( I
2 I
) I
@ O
I B
( I
h I
) I
- I
C I
( I
80 I
) I
were O
altered O
upon O
[ O
5 O
, O
6 O
] O
- O
addition O
, O
demonstrating O
that O
the O
MCD O
spectroscopy O
is O
sensitive O
to O
chemical O
functionalization O
of O
EMFs O
, O
and O
that O
it O
is O
therefore O
powerful O
to O
distinguish O
[ O
5 O
, O
6 O
] O
- O
adducts O
from O
pristine O
La B
( I
2 I
) I
@ O
I B
( I
h I
) I
- I
C I
( I
80 I
) I
, O
although O
no O
marked O
difference O
exists O
in O
their O
absorption O
spectra O
. O

Properties O
and O
mechanisms O
of O
action O
of O
naturally O
occurring O
antifungal O
peptides O
. O

Antimicrobial O
peptides O
are O
a O
vital O
component O
of O
the O
innate O
immune O
system O
of O
all O
eukaryotic O
organisms O
and O
many O
of O
these O
peptides O
have O
potent O
antifungal O
activity O
. O

They O
have O
potential O
application O
in O
the O
control O
of O
fungal O
pathogens O
that O
are O
a O
serious O
threat O
to O
both O
human O
health O
and O
food O
security O
. O

Development O
of O
antifungal O
peptides O
as O
therapeutics O
requires O
an O
understanding O
of O
their O
mechanism O
of O
action O
on O
fungal O
cells O
. O

To O
date O
, O
most O
research O
on O
antimicrobial O
peptides O
has O
focused O
on O
their O
activity O
against O
bacteria O
. O

Several O
antimicrobial O
peptides O
specifically O
target O
fungal O
cells O
and O
are O
not O
active O
against O
bacteria O
. O

Others O
with O
broader O
specificity O
often O
have O
different O
mechanisms O
of O
action O
against O
bacteria O
and O
fungi O
. O

This O
review O
focuses O
on O
the O
mechanism O
of O
action O
of O
naturally O
occurring O
antifungal O
peptides O
from O
a O
diverse O
range O
of O
sources O
including O
plants O
, O
mammals O
, O
amphibians O
, O
insects O
, O
crabs O
, O
spiders O
, O
and O
fungi O
. O

While O
antimicrobial O
peptides O
were O
originally O
proposed O
to O
act O
via O
membrane O
permeabilization O
, O
the O
mechanism O
of O
antifungal O
activity O
for O
these O
peptides O
is O
generally O
more O
complex O
and O
often O
involves O
entry O
of O
the O
peptide O
into O
the O
cell O
. O

Bayesian O
methods O
for O
pharmacokinetic O
/ O
pharmacodynamic O
modeling O
of O
pazopanib B
- O
induced O
increases O
in O
blood O
pressure O
and O
transaminases O
. O

Relationships O
between O
plasma O
pazopanib B
concentrations O
and O
the O
probability O
of O
elevations O
in O
blood O
pressure O
, O
a O
marker O
of O
vascular O
endothelial O
growth O
factor O
receptor O
inhibition O
, O
and O
alanine B
aminotransferase O
( O
ALT O
) O
were O
investigated O
with O
logistic O
regression O
models O
. O

Data O
from O
a O
Phase O
I O
dose O
- O
escalation O
study O
in O
cancer O
patients O
( O
n O
= O
57 O
) O
were O
examined O
to O
determine O
the O
relationship O
between O
steady O
- O
state O
trough O
plasma O
pazopanib B
concentrations O
( O
C O
tau O
) O
and O
a O
clinically O
significant O
blood O
pressure O
increase O
, O
using O
a O
Bayesian O
logistic O
regression O
model O
. O

Data O
from O
5 O
monotherapy O
studies O
in O
cancer O
patients O
( O
n O
= O
344 O
) O
were O
pooled O
to O
investigate O
the O
relationship O
between O
C O
tau O
and O
maximum O
ALT O
> O
= O
3 O
x O
the O
upper O
limit O
of O
normal O
( O
ULN O
) O
, O
using O
a O
Bayesian O
logistic O
regression O
model O
incorporating O
an O
asymptote O
. O

Both O
models O
were O
fit O
using O
WinBUGS O
. O

The O
median O
( O
95 O
% O
credible O
interval O
, O
CrI O
) O
C O
tau O
at O
which O
the O
probability O
of O
a O
clinically O
significant O
increase O
in O
blood O
pressure O
was O
50 O
% O
( O
EC50 O
) O
was O
12 O
. O
3 O
mu O
g O
/ O
mL O
( O
6 O
. O
12 O
, O
18 O
. O
4 O
) O
. O

The O
median O
( O
95 O
% O
CrI O
) O
EC50 O
for O
the O
maximum O
probability O
of O
ALT O
> O
= O
3 O
x O
ULN O
was O
15 O
. O
4 O
mu O
g O
/ O
mL O
( O
3 O
. O
8 O
, O
41 O
. O
2 O
) O
and O
the O
median O
( O
95 O
% O
CrI O
) O
maximum O
probability O
of O
ALT O
> O
= O
3 O
x O
ULN O
was O
21 O
% O
( O
14 O
. O
5 O
, O
43 O
. O
1 O
) O
. O

Results O
suggest O
that O
dose O
adjustments O
could O
be O
useful O
in O
managing O
the O
potential O
for O
hepatotoxicity O
. O

Clopidogrel B
, O
CYP2C19 O
, O
and O
a O
Black O
Box O
. O

It O
has O
been O
presumed O
that O
CYP2C19 O
has O
a O
major O
role O
in O
the O
metabolism O
of O
clopidogrel B
. O

This O
presumption O
has O
been O
based O
on O
in O
vitro O
drug O
metabolism O
studies O
using O
microsomes O
from O
baculovirus O
infected O
insect O
cells O
( O
BD O
- O
Supersomes O
( O
TM O
) O
) O
. O

If O
clopidogrel B
were O
primarily O
a O
CYP2C19 O
substrate O
, O
a O
drug O
/ O
drug O
interaction O
with O
CYP2C19 O
inhibitors O
, O
such O
as O
proton O
pump O
inhibitors O
( O
PPIs O
) O
, O
for O
example O
, O
omeprazole B
and O
lansoprazole B
would O
be O
anticipated O
. O

Several O
ex O
vivo O
studies O
, O
using O
ADP B
stimulated O
platelet O
aggregation O
, O
suggested O
that O
there O
was O
such O
an O
interaction O
. O

The O
data O
from O
these O
studies O
served O
as O
a O
basis O
for O
FDA O
to O
provide O
a O
" O
Black O
Box O
" O
warning O
for O
the O
clopidogrel B
label O
in O
March O
of O
2010 O
. O

However O
, O
a O
prospective O
clinical O
study O
, O
COGENT O
, O
and O
several O
large O
meta O
- O
analyses O
have O
failed O
to O
demonstrate O
a O
negative O
effect O
on O
major O
adverse O
cardiovascular O
events O
( O
MACE O
) O
, O
with O
concomitant O
administration O
of O
clopidogrel B
and O
PPIs B
. O

The O
in O
vitro O
work O
using O
" O
Supersomes O
" O
was O
revisited O
. O

In O
vitro O
metabolism O
using O
hepatosomes O
, O
which O
resemble O
the O
native O
cytochrome O
P O
- O
450 O
enzyme O
expression O
, O
has O
confirmed O
the O
earlier O
work O
that O
clopidogrel B
is O
primarily O
a O
CYP3A O
substrate O
. O

This O
result O
correlates O
better O
with O
clinical O
findings O
. O

The O
absence O
of O
an O
increase O
in O
MACE O
by O
concomitant O
administration O
of O
PPIs O
, O
which O
are O
CYP2C19 O
inhibitors O
, O
to O
a O
regimen O
including O
clopidogrel B
, O
is O
therefore O
not O
surprising O
. O

A O
hypothesis O
is O
offered O
to O
explain O
why O
subjects O
, O
who O
carry O
two O
reduced O
function O
alleles O
of O
CYP2C19 O
, O
may O
have O
more O
reactive O
platelets O
. O

A O
decision O
- O
analysis O
tool O
for O
benefit O
- O
risk O
assessment O
of O
nonprescription O
drugs O
. O

A O
decision O
analysis O
tool O
is O
proposed O
for O
regulatory O
assessment O
of O
nonprescription O
drugs O
. O

The O
tool O
is O
based O
on O
evaluation O
of O
each O
of O
the O
drug O
' O
s O
potential O
benefit O
and O
risk O
attributes O
identified O
using O
a O
value O
- O
tree O
framework O
. O

The O
decision O
tool O
is O
designed O
as O
two O
- O
factor O
, O
two O
- O
stage O
instrument O
. O

Each O
attribute O
is O
independently O
assessed O
based O
on O
both O
the O
frequency O
of O
occurrence O
and O
clinical O
impact O
of O
the O
attribute O
. O

Frequency O
and O
clinical O
impact O
are O
scored O
on O
a O
0 O
- O
3 O
scale O
where O
a O
0 O
score O
means O
no O
occurrence O
or O
no O
clinical O
impact O
, O
and O
a O
3 O
means O
high O
frequency O
of O
occurrence O
or O
high O
clinical O
impact O
. O

The O
tool O
is O
initially O
used O
early O
in O
drug O
development O
to O
facilitate O
communication O
amongst O
stakeholders O
and O
to O
identify O
important O
data O
gaps O
. O

After O
new O
data O
are O
generated O
during O
the O
development O
program O
the O
tool O
is O
used O
again O
across O
the O
same O
attributes O
to O
yield O
a O
final O
benefit O
- O
risk O
assessment O
. O

In O
both O
the O
early O
assessment O
and O
subsequent O
evaluation O
use O
of O
the O
Group O
- O
Delphi O
technique O
and O
a O
benefit O
- O
risk O
trade O
- O
off O
heuristic O
may O
yield O
more O
consistent O
and O
coherent O
outputs O
. O

The O
tool O
allows O
regulators O
to O
maintain O
flexibility O
with O
respect O
to O
how O
final O
decisions O
are O
made O
, O
yet O
allows O
specificity O
and O
transparency O
during O
the O
evaluation O
. O

Further O
modifications O
can O
be O
incorporated O
to O
address O
drug O
- O
specific O
requirements O
or O
regulatory O
preferences O
. O

Ultralow O
reflection O
from O
a O
- O
Si B
nanograss O
/ O
Si B
nanofrustum O
double O
layers O
. O

A O
double O
- O
layer O
nanostructure O
comprising O
amorphous O
Si B
nanograss O
on O
top O
of O
Si B
nanofrustums O
( O
NFs O
) O
with O
a O
total O
height O
of O
680 O
nm O
exhibits O
ultralow O
reflection O
. O

Almost O
near O
- O
unity O
absorption O
and O
near O
- O
zero O
reflectance O
result O
in O
this O
layered O
nanostructure O
, O
over O
a O
broad O
range O
of O
wavelengths O
and O
a O
wide O
range O
of O
angles O
of O
incidence O
, O
due O
to O
the O
low O
packing O
density O
of O
a O
- O
Si B
and O
the O
smooth O
transition O
of O
the O
refractive O
index O
from O
the O
air O
to O
the O
Si B
substrate O
across O
both O
the O
nanograss O
and O
NF O
layers O
. O

A O
high O
- O
confidence O
interaction O
map O
identifies O
SIRT1 O
as O
a O
mediator O
of O
acetylation O
of O
USP22 O
and O
the O
SAGA O
coactivator O
complex O
. O

Although O
many O
functions O
and O
targets O
have O
been O
attributed O
to O
the O
histone O
and O
protein O
deacetylase O
SIRT1 O
, O
a O
comprehensive O
analysis O
of O
SIRT1 O
binding O
proteins O
yielding O
a O
high O
- O
confidence O
interaction O
map O
has O
not O
been O
established O
. O

Using O
a O
comparative O
statistical O
analysis O
of O
binding O
partners O
, O
we O
have O
assembled O
a O
high O
- O
confidence O
SIRT1 O
interactome O
. O

Employing O
this O
method O
, O
we O
identified O
the O
deubiquitinating O
enzyme O
ubiquitin O
- O
specific O
protease O
22 O
( O
USP22 O
) O
, O
a O
component O
of O
the O
deubiquitinating O
module O
( O
DUBm O
) O
of O
the O
SAGA O
transcriptional O
coactivating O
complex O
, O
as O
a O
SIRT1 O
- O
interacting O
partner O
. O

We O
found O
that O
this O
interaction O
is O
highly O
specific O
, O
requires O
the O
ZnF O
- O
UBP O
domain O
of O
USP22 O
, O
and O
is O
disrupted O
by O
the O
inactivating O
H363Y O
mutation O
within O
SIRT1 O
. O

Moreover O
, O
we O
show O
that O
USP22 O
is O
acetylated O
on O
multiple O
lysine B
residues O
and O
that O
alteration O
of O
a O
single O
lysine B
( O
K129 O
) O
within O
the O
ZnF O
- O
UBP O
domain O
is O
sufficient O
to O
alter O
interaction O
of O
the O
DUBm O
with O
the O
core O
SAGA O
complex O
. O

Furthermore O
, O
USP22 O
- O
mediated O
recruitment O
of O
SIRT1 O
activity O
promotes O
the O
deacetylation O
of O
individual O
SAGA O
complex O
components O
. O

Our O
results O
indicate O
an O
important O
role O
of O
SIRT1 O
- O
mediated O
deacetylation O
in O
regulating O
the O
formation O
of O
DUBm O
subcomplexes O
within O
the O
larger O
SAGA O
complex O
. O

Mammalian O
myosin O
- O
18A O
, O
a O
highly O
divergent O
myosin O
. O

The O
Mus O
musculus O
myosin O
- O
18A O
gene O
is O
expressed O
as O
two O
alternatively O
spliced O
isoforms O
, O
alpha O
and O
beta O
, O
with O
reported O
roles O
in O
Golgi O
localization O
, O
in O
maintenance O
of O
cytoskeleton O
, O
and O
as O
receptors O
for O
immunological O
surfactant O
proteins O
. O

Both O
myosin O
- O
18A O
isoforms O
feature O
a O
myosin O
motor O
domain O
, O
a O
single O
predicted O
IQ O
motif O
, O
and O
a O
long O
coiled O
- O
coil O
reminiscent O
of O
myosin O
- O
2 O
. O

The O
myosin O
- O
18A O
alpha O
isoform O
, O
additionally O
, O
has O
an O
N B
- O
terminal O
PDZ O
domain O
. O

Recombinant O
heavy O
meromyosin O
- O
and O
subfragment O
- O
1 O
( O
S1 O
) O
- O
like O
constructs O
for O
both O
myosin O
- O
18A O
alpha O
and O
- O
18 O
beta O
species O
were O
purified O
from O
the O
baculovirus O
/ O
Sf9 O
cell O
expression O
system O
. O

These O
constructs O
bound O
both O
essential O
and O
regulatory O
light O
chains O
, O
indicating O
an O
additional O
noncanonical O
light O
chain O
binding O
site O
in O
the O
neck O
. O

Myosin O
- O
18A O
alpha O
- O
S1 O
and O
- O
18A O
beta O
- O
S1 O
molecules O
bound O
actin O
weakly O
with O
Kd O
values O
of O
4 O
. O
9 O
and O
54 O
mu O
m O
, O
respectively O
. O

The O
actin O
binding O
data O
could O
be O
modeled O
by O
assuming O
an O
equilibrium O
between O
two O
myosin O
conformations O
, O
a O
competent O
and O
an O
incompetent O
form O
to O
bind O
actin O
. O

Actin O
binding O
was O
unchanged O
by O
presence O
of O
nucleotide B
. O

Both O
myosin O
- O
18A O
isoforms O
bound O
N B
- I
methylanthraniloyl I
- I
nucleotides I
, O
but O
the O
rate O
of O
ATP B
hydrolysis O
was O
very O
slow O
( O
< O
0 O
. O
002 O
s O
( O
- O
1 O
) O
) O
and O
not O
significantly O
enhanced O
by O
actin O
. O

Phosphorylation O
of O
the O
regulatory O
light O
chain O
had O
no O
effect O
on O
ATP B
hydrolysis O
, O
and O
neither O
did O
the O
addition O
of O
tropomyosin O
or O
of O
GOLPH3 O
, O
a O
myosin O
- O
18A O
binding O
partner O
. O

Electron O
microscopy O
of O
myosin O
- O
18A O
- O
S1 O
showed O
that O
the O
lever O
is O
strongly O
angled O
with O
respect O
to O
the O
long O
axis O
of O
the O
motor O
domain O
, O
suggesting O
a O
pre O
- O
power O
stroke O
conformation O
regardless O
of O
the O
presence O
of O
ATP B
. O

These O
data O
lead O
us O
to O
conclude O
that O
myosin O
- O
18A O
does O
not O
operate O
as O
a O
traditional O
molecular O
motor O
in O
cells O
. O

Supervillin B
- O
mediated O
suppression O
of O
p53 O
protein O
enhances O
cell O
survival O
. O

Integrin O
- O
based O
adhesions O
promote O
cell O
survival O
as O
well O
as O
cell O
motility O
and O
invasion O
. O

We O
show O
here O
that O
the O
adhesion O
regulatory O
protein O
supervillin O
increases O
cell O
survival O
by O
decreasing O
levels O
of O
the O
tumor O
suppressor O
protein O
p53 O
and O
downstream O
target O
genes O
. O

RNAi O
- O
mediated O
knockdown O
of O
a O
new O
splice O
form O
of O
supervillin O
( O
isoform O
4 O
) O
or O
both O
isoforms O
1 O
and O
4 O
increases O
the O
amount O
of O
p53 O
and O
cell O
death O
, O
whereas O
p53 O
levels O
decrease O
after O
overexpression O
of O
either O
supervillin O
isoform O
. O

Cellular O
responses O
to O
DNA O
damage O
induced O
by O
etoposide B
or O
doxorubicin B
include O
down O
- O
regulation O
of O
endogenous O
supervillin O
coincident O
with O
increases O
in O
p53 O
. O

In O
DNA O
- O
damaged O
supervillin O
knockdown O
cells O
, O
p53 O
knockdown O
or O
inhibition O
partially O
rescues O
the O
loss O
of O
cell O
metabolic O
activity O
, O
a O
measure O
of O
cell O
proliferation O
. O

Knockdown O
of O
the O
p53 O
deubiquitinating O
enzyme O
USP7 O
/ O
HAUSP O
also O
reverses O
the O
supervillin O
phenotype O
, O
blocking O
the O
increase O
in O
p53 O
levels O
seen O
after O
supervillin O
knockdown O
and O
accentuating O
the O
decrease O
in O
p53 O
levels O
triggered O
by O
supervillin O
overexpression O
. O

Conversely O
, O
supervillin O
overexpression O
decreases O
the O
association O
of O
USP7 O
and O
p53 O
and O
attenuates O
USP7 O
- O
mediated O
p53 O
deubiquitination O
. O

USP7 O
binds O
directly O
to O
the O
supervillin O
N B
terminus O
and O
can O
deubiquitinate O
and O
stabilize O
supervillin O
. O

Supervillin O
also O
is O
stabilized O
by O
derivatization O
with O
the O
ubiquitin O
- O
like O
protein O
SUMO1 O
. O

These O
results O
show O
that O
supervillin O
regulates O
cell O
survival O
through O
control O
of O
p53 O
levels O
and O
suggest O
that O
supervillin O
and O
its O
interaction O
partners O
at O
sites O
of O
cell O
- O
substrate O
adhesion O
constitute O
a O
locus O
for O
cross O
- O
talk O
between O
survival O
signaling O
and O
cell O
motility O
pathways O
. O

Menopause O
, O
estrogens B
and O
frailty O
. O

Abstract O
The O
controversy O
surrounding O
the O
results O
from O
the O
Women O
' O
s O
Health O
Initiative O
( O
WHI O
) O
trials O
published O
a O
decade O
ago O
caused O
a O
significant O
decline O
in O
the O
use O
of O
menopausal O
hormone O
replacement O
therapy O
. O

However O
, O
these O
results O
have O
been O
vehemently O
contested O
and O
several O
lines O
of O
evidence O
suggest O
that O
in O
perimenopausal O
and O
non O
- O
obese O
women O
, O
estrogen B
therapy O
may O
indeed O
be O
of O
benefit O
. O

There O
is O
ample O
proof O
that O
menopause O
causes O
a O
loss O
of O
musculoskeletal O
tissue O
mass O
and O
quality O
, O
thereby O
causing O
a O
loss O
of O
health O
and O
quality O
of O
life O
. O

There O
is O
also O
solid O
evidence O
that O
hormone O
replacement O
therapy O
in O
itself O
prevents O
most O
of O
these O
effects O
in O
connective O
tissue O
in O
it O
self O
. O

Besides O
the O
independent O
, O
direct O
effects O
on O
the O
musculoskeletal O
tissues O
, O
estrogen B
deficiency O
also O
reduces O
the O
ability O
to O
adequately O
respond O
and O
adapt O
to O
external O
mechanical O
and O
metabolic O
stressors O
, O
e O
. O
g O
. O
exercise O
, O
which O
are O
otherwise O
the O
main O
stimuli O
that O
should O
maintain O
musculoskeletal O
integrity O
and O
metabolic O
function O
. O

Thus O
, O
normophysiological O
estrogen B
levels O
appear O
to O
exert O
a O
permissive O
effect O
on O
musculoskeletal O
adaptations O
to O
loading O
, O
thereby O
likely O
improving O
the O
outcome O
of O
rehabilitation O
following O
critical O
illness O
, O
musculoskeletal O
trauma O
or O
orthopedic O
surgical O
therapy O
. O

These O
effects O
add O
to O
the O
evidence O
supporting O
the O
use O
of O
estrogen B
therapy O
, O
particularly O
accelerated O
gain O
of O
functional O
capacity O
and O
independence O
following O
musculoskeletal O
disuse O
. O

Isolation O
of O
a O
mixed O
valence O
diiron B
hydride I
: O
evidence O
for O
a O
spectator O
hydride B
in O
hydrogen B
evolution O
catalysis O
. O

The O
mixed O
- O
valence O
diiron B
hydrido I
complex O
( B
mu I
- I
H I
) I
Fe2 I
( I
pdt I
) I
( I
CO I
) I
2 I
( I
dppv I
) I
2 I
( O
[ B
H1 I
] I
( I
0 I
) I
, O
where O
pdt B
= O
1 B
, I
3 I
- I
propanedithiolate I
and O
dppv B
= O
cis B
- I
1 I
, I
2 I
- I
C2H2 I
( I
PPh2 I
) I
2 I
) O
, O
was O
generated O
by O
reduction O
of O
the O
differous B
hydride I
[ B
H1 I
] I
( I
+ I
) I
using O
decamethylcobaltocen B
. O

Crystallographic O
analysis O
shows O
that O
[ O
H1 O
] O
( O
0 O
) O
retains O
the O
stereochemistry O
of O
its O
precursor O
, O
where O
one O
dppv O
ligand O
spans O
two O
basal O
sites O
and O
the O
other O
spans O
apical O
and O
basal O
positions O
. O

The O
Fe B
- I
- I
- I
Fe I
bond O
elongates O
to O
2 O
. O
80 O
from O
2 O
. O
66 O
A O
, O
but O
the O
Fe B
- I
P I
bonds O
only O
change O
subtly O
. O

Although O
the O
Fe B
- I
H I
distances O
are O
indistinguishable O
in O
the O
precursor O
, O
they O
differ O
by O
0 O
. O
2 O
A O
in O
[ O
H1 B
] O
( I
0 O
) I
. O

The O
X O
- O
band O
electron O
paramagnetic O
resonance O
( O
EPR O
) O
spectrum O
reveals O
the O
presence O
of O
two O
stereoisomers O
, O
the O
one O
characterized O
crystallographically O
and O
a O
contribution O
of O
about O
10 O
% O
from O
a O
second O
symmetrical O
( O
sym O
) O
isomer O
wherein O
both O
dppv B
ligands O
occupy O
apical O
- O
basal O
sites O
. O

The O
unsymmetrical O
( O
unsym O
) O
arrangement O
of O
the O
dppv B
ligands O
is O
reflected O
in O
the O
values O
of O
A O
( O
( B
31 I
) I
P I
) O
, O
which O
range O
from O
31 O
MHz O
for O
the O
basal O
phosphines B
to O
284 O
MHz O
for O
the O
apical O
phosphine B
. O

Density O
functional O
theory O
calculations O
were O
employed O
to O
rationalize O
the O
electronic O
structure O
of O
[ B
H1 I
] I
( I
0 I
) I
and O
to O
facilitate O
spectral O
simulation O
and O
assignment O
of O
EPR O
parameters O
including O
( B
1 I
) I
H I
and O
( B
31 I
) I
P I
hyperfine O
couplings O
. O

The O
EPR O
spectra O
of O
[ O
H1 O
] O
( O
0 O
) O
and O
[ O
D1 O
] O
( O
0 O
) O
demonstrate O
that O
the O
singly O
occupied O
molecular O
orbital O
is O
primarily O
localized O
on O
the O
Fe B
center O
with O
the O
longer O
bond O
to O
H B
, O
that O
is O
, O
Fe B
( I
II I
) I
- I
H I
. O
. O
. O
Fe B
( I
I I
) I
. O

The O
coupling O
to O
the O
hydride B
is O
A O
( O
( B
1 I
) I
H I
) O
= O
55 O
and O
74 O
MHz O
for O
unsym O
- O
amd O
sym B
- I
[ I
H1 I
] I
( I
0 I
) I
, O
respectively O
. O

Treatment O
of O
[ B
H1 I
] I
( I
0 I
) I
with O
H B
( I
+ I
) I
gives O
0 O
. O
5 O
equiv O
of O
H2 B
and O
[ B
H1 I
] I
( I
+ I
) I
. O

Reduction O
of O
D B
( I
+ I
) I
affords O
D2 B
, O
leaving O
the O
hydride B
ligand O
intact O
. O

These O
experiments O
demonstrate O
that O
the O
bridging O
hydride B
ligand O
in O
this O
complex O
is O
a O
spectator O
in O
the O
hydrogen B
evolution O
reaction O
. O

Femtosecond O
Dynamics O
of O
Excitons O
and O
Hole O
- O
Polarons O
in O
Composite O
P3HT B
/ O
PCBM B
Nanoparticles O
. O

The O
dynamics O
of O
charge O
separation O
in O
aqueous O
suspensions O
of O
regioregular O
P3HT B
nanoparticles O
containing O
PCBM B
were O
investigated O
for O
the O
first O
time O
using O
femtosecond O
transient O
absorption O
spectroscopy O
. O

This O
investigation O
is O
supported O
by O
the O
recently O
reported O
use O
of O
regioregular O
P3HT B
/ O
PCBM B
nanoparticles O
as O
charge O
trapping O
and O
storage O
devices O
. O

In O
this O
study O
, O
the O
presence O
of O
excited O
- O
state O
and O
charge O
- O
separated O
species O
, O
including O
singlet O
excitons O
, O
polymer O
polarons O
and O
free O
charges O
, O
generated O
in O
rr O
- O
P3HT B
/ O
PCBM B
nanoparticles O
was O
identified O
through O
visible O
pump O
and O
visible O
/ O
near O
- O
infrared O
probe O
femtosecond O
transient O
absorption O
spectroscopy O
at O
a O
range O
of O
electron O
acceptor O
concentrations O
. O

The O
decrease O
of O
the O
singlet O
exciton O
lifetime O
by O
charge O
transfer O
to O
PCBM B
is O
well O
described O
by O
a O
one O
- O
dimensional O
diffusion O
model O
with O
a O
P3HT B
domain O
size O
of O
approximately O
5 O
nm O
for O
5 O
- O
50 O
wt O
% O
PCBM B
. O

This O
model O
also O
indicates O
that O
bimolecular O
recombination O
is O
the O
dominant O
charge O
recombination O
mechanism O
at O
20 O
wt O
% O
PCBM B
and O
above O
. O

Surface O
behavior O
of O
malonic B
acid I
adsorption O
at O
the O
air O
/ O
water O
interface O
. O

The O
presence O
of O
organic O
materials O
adsorbed O
to O
the O
surfaces O
of O
aerosol O
particles O
has O
been O
demonstrated O
to O
be O
a O
determining O
factor O
in O
relevant O
atmospheric O
processes O
. O

Malonic B
acid I
is O
a O
small O
, O
water O
- O
soluble O
organic O
acid O
that O
is O
common O
in O
aerosols O
and O
is O
surface O
- O
active O
. O

A O
comprehensive O
investigation O
of O
the O
adsorption O
of O
malonic B
acid I
to O
the O
air O
/ O
water O
interface O
was O
accomplished O
using O
vibrational O
sum O
frequency O
spectroscopy O
( O
VSFS O
) O
and O
surface O
tension O
measurements O
as O
functions O
of O
concentration O
and O
pH O
. O

Malonic B
acid I
was O
found O
to O
be O
weakly O
solvated O
at O
the O
air O
/ O
water O
interface O
, O
and O
its O
orientation O
as O
a O
function O
of O
concentration O
was O
explored O
through O
different O
VSFS O
polarization O
schemes O
. O

pH O
- O
dependent O
experiments O
revealed O
that O
the O
surface O
- O
active O
species O
is O
the O
fully O
protonated O
species O
. O

Computational O
analyses O
were O
used O
to O
obtain O
depth O
- O
specific O
geometries O
of O
malonic B
acid I
at O
the O
air O
/ O
water O
interface O
that O
confirm O
and O
enrich O
the O
experimental O
results O
. O

Development O
of O
quantitative O
structure O
- O
metabolism O
( O
QSMR O
) O
relationships O
for O
substituted O
anilines B
based O
on O
computational O
chemistry O
. O

Abstract O
1 O
. O

A O
novel O
stepwise O
classification O
approach O
for O
predicting O
the O
metabolic O
fate O
of O
substituted O
anilines B
, O
based O
on O
calculated O
physicochemical O
parameters O
of O
the O
parent O
anilines B
, O
was O
developed O
. O

Based O
on O
multivariate O
pattern O
recognition O
methods O
( O
PLS O
- O
DA O
or O
soft O
independent O
modelling O
of O
class O
analogy O
[ O
SIMCA O
] O
) O
, O
these O
models O
allowed O
prediction O
of O
N B
- O
acetylation O
and O
subsequent O
N B
- I
oxanilic I
acid I
formation O
. O

These O
classification O
methods O
provided O
an O
improved O
classification O
success O
when O
compared O
with O
existing O
quantitative O
structure O
- O
metabolism O
relationship O
models O
for O
substituted O
anilines B
. O

2 O
. O

Modelling O
the O
physicochemical O
properties O
of O
the O
N B
- O
acetylated O
compounds O
was O
considered O
as O
an O
addition O
to O
the O
stepwise O
model O
. O

Inclusion O
of O
parameters O
describing O
the O
N B
- I
acetyl I
moiety O
had O
little O
effect O
on O
the O
predictive O
ability O
of O
a O
stepwise O
parent O
to O
N B
- I
acetyl I
to O
N B
- I
oxanilic I
acid I
PLS O
- O
DA O
model O
, O
and O
had O
a O
negative O
impact O
on O
that O
of O
SIMCA O
models O
. O

This O
was O
attributed O
to O
the O
relatively O
small O
contribution O
to O
the O
total O
parameter O
variance O
caused O
by O
differences O
arising O
as O
a O
result O
of O
N B
- O
acetylation O
compared O
to O
the O
contribution O
made O
by O
the O
substituent O
effects O
. O

3 O
. O

Calculation O
of O
physicochemical O
properties O
incorporating O
the O
effect O
of O
solvation O
using O
ab O
initio O
methods O
improved O
the O
classification O
model O
in O
terms O
of O
both O
the O
visual O
separation O
in O
multivariate O
projections O
and O
prediction O
accuracy O
. O

Frequency O
- O
multiplication O
high O
- O
output O
triboelectric O
nanogenerator O
for O
sustainably O
powering O
biomedical O
microsystems O
. O

An O
attractive O
method O
to O
response O
the O
current O
energy O
crisis O
and O
produce O
sustainable O
nonpolluting O
power O
source O
is O
harvesting O
energy O
from O
our O
living O
environment O
. O

However O
, O
the O
energy O
in O
our O
living O
environment O
always O
exists O
in O
low O
- O
frequency O
form O
, O
which O
is O
very O
difficult O
to O
be O
utilized O
directly O
. O

Here O
, O
we O
demonstrated O
a O
novel O
sandwich O
- O
shape O
triboelectric O
nanogenerator O
to O
convert O
low O
- O
frequency O
mechanical O
energy O
to O
electric O
energy O
with O
double O
frequency O
. O

An O
aluminum B
film O
was O
placed O
between O
two O
polydimethylsiloxane B
( O
PDMS B
) O
membranes O
to O
realize O
frequency O
multiplication O
by O
twice O
contact O
electrifications O
within O
one O
cycle O
of O
external O
force O
. O

The O
working O
mechanism O
was O
studied O
by O
finite O
element O
simulation O
. O

Additionally O
, O
the O
well O
- O
designed O
micro O
/ O
nano O
dual O
- O
scale O
structures O
( O
i O
. O
e O
. O
, O
pyramids O
and O
V O
- O
shape O
grooves O
) O
fabricated O
atop O
PDMS B
surface O
was O
employed O
to O
enhance O
the O
device O
performance O
. O

The O
output O
peak O
voltage O
, O
current O
density O
, O
and O
energy O
volume O
density O
achieved O
465 O
V O
, O
13 O
. O
4 O
mu O
A O
/ O
cm O
( O
2 O
) O
, O
and O
53 O
. O
4 O
mW O
/ O
cm O
( O
3 O
) O
, O
respectively O
. O

This O
novel O
nanogenerator O
was O
systematically O
investigated O
and O
also O
demonstrated O
as O
a O
reliable O
power O
source O
, O
which O
can O
be O
directly O
used O
to O
not O
only O
lighten O
five O
commercial O
light O
- O
emitting O
diodes O
( O
LEDs O
) O
but O
also O
drive O
an O
implantable O
3 O
- O
D O
microelectrode O
array O
for O
neural O
prosthesis O
without O
any O
energy O
storage O
unit O
or O
rectification O
circuit O
. O

This O
is O
the O
first O
demonstration O
of O
the O
nanogenerator O
for O
directly O
driving O
biomedical O
microsystems O
, O
which O
extends O
the O
application O
fields O
of O
the O
nanogenerator O
and O
drives O
it O
closer O
to O
practical O
applications O
. O

The O
salicylate B
1 O
, O
2 O
- O
dioxygenase O
as O
a O
model O
for O
a O
conventional O
gentisate B
1 O
, O
2 O
- O
dioxygenase O
: O
crystal O
structures O
of O
the O
G106A O
mutant O
and O
its O
adducts O
with O
gentisate B
and O
salicylate B
. O

The O
salicylate B
1 O
, O
2 O
- O
dioxygenase O
( O
SDO O
) O
from O
the O
bacterium O
Pseudaminobacter O
salicylatoxidans O
BN12 O
is O
a O
versatile O
gentisate B
1 O
, O
2 O
- O
dioxygenase O
( O
GDO O
) O
that O
converts O
both O
gentisate B
( O
2 B
, I
5 I
- I
dihydroxybenzoate I
) O
and O
various O
monohydroxylated O
substrates O
. O

Several O
variants O
of O
this O
enzyme O
were O
rationally O
designed O
based O
on O
the O
previously O
determined O
enzyme O
structure O
and O
sequence O
differences O
between O
the O
SDO O
and O
the O
' O
conventional O
' O
GDO O
from O
Corynebacterium O
glutamicum O
. O

This O
was O
undertaken O
in O
order O
to O
define O
the O
structural O
elements O
that O
give O
the O
SDO O
its O
unique O
ability O
to O
dioxygenolytically O
cleave O
( B
substituted I
) I
salicylates I
. O

SDO O
variants O
M103L O
, O
G106A O
, O
G111A O
, O
R113G O
, O
S147R O
and O
F159Y O
were O
constructed O
and O
it O
was O
found O
that O
G106A O
oxidized O
only O
gentisate B
; O
1 B
- I
hydroxy I
- I
2 I
- I
naphthoate I
and O
salicylate B
were O
not O
converted O
. O

This O
indicated O
that O
this O
enzyme O
variant O
behaves O
like O
previously O
known O
' O
conventional O
' O
GDOs O
. O

Crystals O
of O
the O
G106A O
SDO O
variant O
and O
its O
complexes O
with O
salicylate B
and O
gentisate B
were O
obtained O
under O
anaerobic O
conditions O
, O
and O
the O
structures O
were O
solved O
and O
analyzed O
. O

The O
amino B
acid I
residue O
Gly106 O
is O
located O
inside O
the O
SDO O
active O
site O
cavity O
but O
does O
not O
directly O
interact O
with O
the O
substrates O
. O

Crystal O
structures O
of O
G106A O
SDO O
complexes O
with O
gentisate B
and O
salicylate B
showed O
a O
different O
binding O
mode O
for O
salicylate B
when O
compared O
with O
the O
wild O
- O
type O
enzyme O
. O

Thus O
, O
salicylate B
coordinated O
in O
the O
G106A O
variant O
with O
the O
catalytically O
active O
Fe B
( I
II I
) I
ion O
in O
an O
unusual O
and O
unproductive O
manner O
because O
of O
the O
inability O
of O
salicylate B
to O
displace O
a O
hydrogen B
bond O
that O
was O
formed O
between O
Trp104 B
and O
Asp174 B
in O
the O
G106A O
variant O
. O

It O
is O
proposed O
that O
this O
type O
of O
unproductive O
substrate O
binding O
might O
generally O
limit O
the O
substrate O
spectrum O
of O
' O
conventional O
' O
GDOs O
. O

DATABASE O
: O
Structural O
data O
are O
available O
in O
the O
Protein O
Data O
Bank O
databases O
under O
the O
accession O
numbers O
3NST O
, O
3NWA O
, O
3NVC O
. O

Three O
- O
dimensional O
high O
- O
resolution O
rotational O
tracking O
with O
superlocalization O
reveals O
conformations O
of O
surface O
- O
bound O
anisotropic O
nanoparticles O
. O

The O
ability O
to O
directly O
follow O
three O
- O
dimensional O
rotational O
movement O
of O
anisotropic O
nanoparticles O
will O
greatly O
enhance O
our O
understanding O
of O
the O
way O
nanoparticles O
interact O
with O
surfaces O
. O

Herein O
, O
we O
demonstrate O
dual O
- O
color O
total O
internal O
reflection O
scattering O
microscopy O
as O
a O
tool O
to O
probe O
the O
interactions O
of O
plasmonic O
gold O
nanorods O
with O
functional O
surfaces O
. O

By O
taking O
advantage O
of O
both O
the O
short O
and O
long O
axis O
surface O
plasmon O
resonance O
scattering O
enhancement O
, O
we O
are O
able O
to O
decipher O
both O
in O
- O
plane O
and O
out O
- O
of O
- O
plane O
gold O
nanorod O
motion O
relative O
to O
the O
sample O
surface O
with O
equally O
high O
resolution O
. O

In O
combination O
with O
superlocalization O
through O
point O
spread O
function O
fitting O
, O
we O
overcome O
the O
four O
- O
quadrant O
angular O
degeneracy O
of O
gold O
nanorods O
in O
the O
focal O
plane O
of O
the O
objective O
and O
resolve O
conformations O
of O
surface O
- O
bound O
anisotropic O
nanoparticles O
in O
unprecedented O
detail O
. O

The O
transferrin O
receptor O
- O
1 O
membrane O
stub O
undergoes O
intramembrane O
proteolysis O
by O
signal O
peptide O
peptidase O
- O
like O
2b O
. O

The O
successive O
events O
of O
shedding O
and O
regulated O
intramembrane O
proteolysis O
are O
known O
to O
comprise O
a O
fundamental O
biological O
process O
of O
type O
I O
and O
II O
membrane O
proteins O
( O
e O
. O
g O
. O
amyloid O
precursor O
protein O
, O
Notch O
receptor O
and O
pro O
- O
tumor O
necrosis O
factor O
- O
alpha O
) O
. O

Some O
of O
the O
resulting O
fragments O
were O
shown O
to O
be O
involved O
in O
important O
intra O
- O
and O
extracellular O
signalling O
events O
. O

Although O
shedding O
of O
the O
human O
transferrin O
receptor O
- O
1 O
( O
TfR1 O
) O
has O
been O
known O
for O
> O
30 O
years O
and O
soluble O
TfR1 O
is O
an O
accepted O
diagnostic O
marker O
, O
the O
fate O
of O
the O
remaining O
N B
- O
terminal O
fragment O
( O
NTF O
) O
remains O
unknown O
. O

In O
the O
present O
study O
, O
we O
demonstrate O
for O
the O
first O
time O
that O
TfR1 O
- O
NTF O
is O
subject O
to O
regulated O
intramembrane O
proteolysis O
and O
, O
using O
MALDI O
- O
TOF O
- O
TOF O
- O
MS O
, O
we O
have O
identified O
the O
cleavage O
site O
as O
being O
located O
C B
- O
terminal O
from O
Gly B
- O
84 O
. O

We O
showed O
that O
the O
resulting O
C B
- O
terminal O
peptide O
is O
extracellularly O
released O
after O
regulated O
intramembrane O
proteolysis O
and O
it O
was O
detected O
as O
a O
monomer O
with O
an O
internal O
disulfide B
bridge O
. O

We O
further O
identified O
signal O
peptide O
peptidase O
- O
like O
2a O
and O
mainly O
signal O
peptide O
peptidase O
- O
like O
2b O
as O
being O
responsible O
for O
the O
intramembrane O
proteolysis O
of O
TfR1 O
- O
NTF O
. O

Northern O
contaminant O
mixtures O
induced O
morphological O
and O
functional O
changes O
in O
human O
coronary O
artery O
endothelial O
cells O
under O
culture O
conditions O
typifying O
high O
fat O
/ O
sugar B
diet O
and O
ethanol B
exposure O
. O

It O
has O
been O
reported O
that O
Northern O
populations O
are O
exposed O
to O
mixtures O
of O
various O
environmental O
contaminants O
unique O
to O
the O
Arctic O
( O
Northern O
contaminant O
mixtures O
- O
NCM O
) O
at O
a O
large O
range O
of O
concentrations O
, O
depending O
on O
their O
geological O
location O
, O
age O
, O
lifestyle O
and O
dietary O
habits O
. O

To O
determine O
if O
these O
contaminants O
may O
contribute O
to O
a O
cardiovascular O
health O
risk O
, O
especially O
when O
combined O
with O
a O
high O
fat O
and O
sugar B
diet O
and O
ethanol B
exposure O
, O
we O
treated O
human O
coronary O
artery O
endothelial O
cells O
( O
HCAEC O
) O
with O
two O
mixtures O
of O
4 O
organic O
( O
NCM1 O
) O
or O
22 O
organic O
and O
inorganic O
( O
NCM2 O
) O
chemicals O
detected O
in O
Northerners O
' O
blood O
during O
2004 O
- O
2005 O
in O
the O
presence O
or O
absence O
of O
low O
- O
density O
lipoprotein O
( O
1 O
. O
5mg O
/ O
ml O
) O
, O
very O
- O
low O
- O
density O
lipoprotein O
( O
1 O
. O
0mg O
/ O
ml O

) O
and O
glucose B
( O
10mmol O
/ O
L O
) O
( O
LVG B
) O
, O
and O
in O
the O
absence O
or O
presence O
of O
0 O
. O
1 O
% O
ethanol B
. O

After O
24h O
of O
exposure O
, O
cell O
morphology O
and O
markers O
of O
cytotoxicity O
and O
endothelial O
function O
were O
examined O
. O

NCM1 O
treatment O
did O
not O
affect O
cell O
viability O
, O
but O
increased O
cell O
size O
, O
disrupted O
cell O
membrane O
integrity O
, O
and O
decreased O
cell O
density O
, O
uptake O
of O
small O
peptides O
, O
release O
of O
endothelin O
- O
1 O
( O
ET O
- O
1 O
) O
and O
plasminogen O
activator O
inhibitor O
( O
PAI O
) O
, O
while O
causing O
no O
changes O
in O
endothelial O
nitric B
oxide I
synthase O
( O
eNOS O
) O
protein O
expression O
and O
nitric B
oxide I
( O
NO B
) O
release O
. O

In O
contrast O
, O
NCM2 O
decreased O
cell O
viability O
, O
total O
protein O
yield O
, O
uptake O
of O
small O
peptides O
, O
eNOS O
protein O
expression O
, O
and O
NO B
release O
and O
caused O
membrane O
damage O
, O
but O
caused O
no O
changes O
in O
the O
secretion O
of O
ET O
- O
1 O
, O
prostacyclin B
and O
PAI O
. O

The O
presence O
of O
LVG B
and O
/ O
or O
alcohol B
did O
or O
did O
not O
influence O
the O
effects O
of O
NCM1 O
or O
NCM2 O
depending O
on O
the O
endpoint O
and O
the O
mixture O
examined O
. O

These O
results O
suggested O
that O
the O
effects O
of O
one O
or O
one O
group O
of O
contaminants O
may O
be O
altered O
by O
the O
presence O
of O
other O
contaminants O
, O
and O
that O
with O
or O
without O
the O
interaction O
of O
high O
fat O
and O
sugar B
diet O
and O
/ O
or O
ethanol B
exposure O
, O
NCMs O
at O
the O
concentrations O
used O
caused O
endothelial O
dysfunction O
in O
vitro O
. O

It O
remains O
to O
be O
investigated O
if O
these O
effects O
of O
NCMs O
also O
occur O
in O
vivo O
. O

Epigenetic O
modifications O
in O
rheumatoid O
arthritis O
, O
a O
review O
. O

Rheumatoid O
arthritis O
is O
an O
autoimmune O
disease O
characterized O
by O
chronic O
joint O
inflammation O
and O
progressive O
destruction O
of O
cartilage O
and O
bone O
which O
leads O
to O
ultimately O
loss O
of O
function O
and O
pain O
. O

Activated O
synovial O
fibroblasts O
are O
key O
effector O
cells O
in O
the O
pathogenesis O
of O
rheumatoid O
arthritis O
. O

In O
the O
recent O
years O
, O
epigenetic O
changes O
including O
DNA O
methylation O
, O
histone O
acetylation O
and O
other O
histone O
modifications O
were O
identified O
that O
are O
associated O
with O
an O
intrinsic O
activation O
and O
the O
aggressive O
phenotype O
of O
these O
cells O
. O

So O
far O
, O
no O
therapies O
targeting O
rheumatoid O
arthritis O
synovial O
fibroblasts O
exist O
. O

This O
review O
comprises O
recent O
research O
efforts O
that O
propose O
epigenetic O
mechanisms O
behind O
the O
activation O
of O
rheumatoid O
arthritis O
synovial O
fibroblasts O
and O
other O
cell O
types O
. O

Antitumor O
drug O
delivery O
in O
multicellular O
spheroids O
by O
electropermeabilizat O
. O

Electrochemotherapy O
( O
ECT O
) O
is O
a O
physical O
technique O
that O
allows O
cytotoxic O
molecules O
to O
be O
efficiently O
released O
in O
tumor O
cells O
by O
inducing O
transient O
cell O
plasma O
membrane O
permeabilization O
. O

The O
main O
antitumoral O
drugs O
used O
in O
ECT O
are O
nonpermeant O
bleomycin B
and O
low O
permeant O
cisplatin B
. O

The O
method O
is O
nowadays O
applied O
in O
clinics O
as O
a O
palliative O
treatment O
. O

In O
order O
to O
improve O
it O
, O
we O
took O
advantage O
of O
a O
human O
3D O
multicellular O
tumor O
spheroid O
as O
a O
model O
of O
tumor O
to O
visually O
and O
molecularly O
assess O
the O
effect O
of O
ECT O
. O

We O
used O
bleomycin B
and O
cisplatin B
to O
confirm O
its O
relevance O
and O
doxorubicin B
to O
show O
its O
potential O
to O
screen O
new O
antitumor O
drug O
candidates O
for O
ECT O
. O

Confocal O
microscopy O
was O
used O
to O
visualize O
the O
topological O
distribution O
of O
permeabilized O
cells O
in O
3D O
spheroids O
subjected O
to O
electric O
pulses O
. O

Our O
results O
revealed O
that O
all O
cells O
were O
efficiently O
permeabilized O
, O
whatever O
their O
localization O
in O
the O
spheroid O
, O
even O
those O
in O
the O
core O
. O

The O
combination O
of O
antitumor O
drugs O
and O
electric O
pulses O
( O
ECT O
) O
led O
to O
changes O
in O
spheroid O
macroscopic O
morphology O
and O
cell O
cohesion O
, O
to O
tumor O
spheroid O
growth O
arrest O
and O
finally O
to O
its O
complete O
apoptosis O
- O
mediated O
dislocation O
, O
mimicking O
previously O
observed O
in O
vivo O
situations O
. O

Taken O
together O
, O
these O
results O
indicate O
that O
the O
spheroid O
model O
is O
relevant O
for O
the O
study O
and O
optimization O
of O
electromediated O
drug O
delivery O
protocols O
. O

Transdermal O
delivery O
of O
human O
epidermal O
growth O
factor O
facilitated O
by O
a O
peptide O
chaperon O
. O

Peptide O
chaperon O
TD1 O
was O
discovered O
to O
facilitate O
several O
proteins O
' O
transdermal O
delivery O
via O
topical O
co O
- O
administration O
. O

To O
design O
a O
practical O
, O
safe O
system O
for O
advanced O
transdermal O
peptide O
, O
a O
novel O
method O
was O
carried O
out O
. O

Human O
epidermal O
growth O
factor O
( O
hEGF O
) O
was O
selected O
as O
the O
model O
biological O
agent O
and O
a O
fusion O
protein O
: O
TD1 O
- O
hEGF O
was O
designed O
. O

Study O
showed O
that O
TD1 O
- O
hEGF O
not O
only O
had O
the O
similar O
bioactivity O
with O
native O
hEGF O
, O
but O
also O
possessed O
considerable O
higher O
transdermal O
ability O
than O
hEGF O
and O
a O
co O
- O
administration O
of O
TD1 O
and O
hEGF O
. O

These O
results O
provided O
convincing O
evidence O
for O
the O
advantages O
of O
TD1 O
- O
hEGF O
in O
cosmetic O
and O
medical O
applications O
. O

Moreover O
, O
the O
fusion O
pattern O
between O
the O
cargoes O
and O
TD1 O
offered O
a O
new O
approach O
to O
facilitate O
other O
hydrophilic O
drugs O
' O
transdermal O
delivery O
for O
therapeutic O
application O
. O

New O
pyrazole B
derivatives O
containing O
1 B
, I
2 I
, I
4 I
- I
triazoles I
and O
benzoxazoles B
as O
potent O
antimicrobial O
and O
analgesic O
agents O
. O

Azole B
class O
of O
compounds O
are O
well O
known O
for O
their O
excellent O
therapeutic O
properties O
. O

Present O
paper O
describes O
about O
the O
synthesis O
of O
three O
series O
of O
new O
1 B
, I
2 I
, I
4 I
- I
triazole I
and O
benzoxazole B
derivatives O
containing O
substituted O
pyrazole B
moiety O
( O
11a O
- O
d O
, O
12a O
- O
d O
and O
13a O
- O
d O
) O
. O

The O
newly O
synthesized O
compounds O
were O
characterized O
by O
spectral O
studies O
and O
also O
by O
C B
, O
H B
, O
N B
analyses O
. O

All O
the O
synthesized O
compounds O
were O
screened O
for O
their O
analgesic O
activity O
by O
the O
tail O
flick O
method O
. O

The O
antimicrobial O
activity O
of O
the O
new O
derivatives O
was O
also O
performed O
by O
Minimum O
Inhibitory O
Concentration O
( O
MIC O
) O
by O
the O
serial O
dilution O
method O
. O

The O
results O
revealed O
that O
the O
compound O
11c O
having O
2 B
, I
5 I
- I
dichlorothiophene I
substituent O
on O
pyrazole B
moiety O
and O
a O
triazole B
ring O
showed O
significant O
analgesic O
and O
antimicrobial O
activity O
. O

Transcriptional O
Analysis O
of O
Hair O
Follicle O
- O
Derived O
Keratinocytes O
from O
Donors O
with O
Atopic O
Dermatitis O
Reveals O
Enhanced O
Induction O
of O
IL32 O
Gene O
by O
IFN O
- O
gamma O
. O

We O
cultured O
human O
hair O
follicle O
- O
derived O
keratinocytes O
( O
FDKs O
) O
from O
plucked O
hairs O
. O

To O
gain O
insight O
into O
gene O
expression O
signatures O
that O
can O
distinguish O
atopic O
dermatitis O
from O
non O
- O
atopic O
controls O
without O
skin O
biopsies O
, O
we O
undertook O
a O
comparative O
study O
of O
gene O
expression O
in O
FDKs O
from O
adult O
donors O
with O
atopic O
dermatitis O
and O
non O
- O
atopic O
donors O
. O

FDK O
primary O
cultures O
( O
atopic O
dermatitis O
, O
n O
= O
11 O
; O
non O
- O
atopic O
controls O
, O
n O
= O
7 O
) O
before O
and O
after O
interferon O
gamma O
( O
IFN O
- O
gamma O
) O
treatment O
were O
used O
for O
microarray O
analysis O
and O
quantitative O
RT O
- O
PCR O
. O

Comparison O
of O
FDKs O
from O
atopic O
and O
non O
- O
atopic O
donors O
indicated O
that O
the O
former O
showed O
activated O
pathways O
with O
innate O
immunity O
and O
decreased O
pathways O
of O
cell O
growth O
, O
as O
indicated O
by O
increased O
NLRP2 O
expression O
and O
decreased O
DKK1 O
expression O
, O
respectively O
. O

Treatment O
with O
IFN O
- O
gamma O
induced O
the O
enhanced O
expression O
of O
IL32 O
, O
IL1B O
, O
IL8 O
, O
and O
CXCL1 O
in O
the O
cells O
from O
atopic O
donors O
compared O
to O
that O
in O
cells O
from O
non O
- O
atopic O
donors O
at O
24 O
h O
after O
treatment O
. O

IL1B O
expression O
in O
FDKs O
after O
IFN O
- O
gamma O
treatment O
correlated O
with O
IL32 O
expression O
. O

We O
hypothesized O
that O
overexpression O
of O
IL32 O
in O
hair O
follicle O
keratinocytes O
of O
patients O
with O
atopic O
dermatitis O
would O
lead O
to O
the O
excessive O
production O
of O
pro O
- O
IL1 O
beta O
and O
that O
the O
activation O
of O
IL1 O
beta O
from O
pro O
- O
IL1 O
beta O
by O
inflammasome O
complex O
, O
in O
which O
NLRP2 O
protein O
might O
be O
involved O
, O
would O
be O
augmented O
. O

This O
is O
the O
first O
report O
to O
show O
enhanced O
induction O
of O
cytokine O
/ O
chemokine O
genes O
by O
IFN O
- O
gamma O
in O
atopic O
dermatitis O
using O
cultured O
FDKs O
. O

Selenite B
and O
tellurite B
form O
mixed O
seleno B
- I
and I
tellurotrisulfides I
with O
CstR O
from O
Staphylococcus O
aureus O
. O

Staphylococcus O
aureus O
CstR O
( O
CsoR O
- O
like O
sulfur B
transferase O
repressor O
) O
is O
a O
member O
of O
the O
CsoR O
family O
of O
transition O
metal O
sensing O
metalloregulatory O
proteins O
. O

Unlike O
CsoR B
, O
CstR O
does O
not O
form O
a O
stable O
complex O
with O
transition B
metals I
but O
instead O
reacts O
with O
sulfite B
to O
form O
a O
mixture O
of O
di B
- I
and I
trisulfide I
species O
, O
CstR2 O
( O
RS B
- I
SR I
' I
) O
and O
CstR2 O
( O
RS B
- I
S I
- I
SR I
' I
) I
n I
) O
n O
= O
1 O
or O
2 O
, O
respectively O
. O

Here O
, O
we O
investigate O
if O
CstR O
performs O
similar O
chemistry O
with O
related O
chalcogen B
oxyanions I
selenite B
and O
tellurite B
. O

In O
this O
work O
we O
show O
by O
high O
resolution O
tandem O
mass O
spectrometry O
that O
CstR O
is O
readily O
modified O
by O
selenite B
( O
SeO3 B
( I
2 I
- I
) I
) O
or O
tellurite B
( O
TeO3 B
( I
2 I
- I
) I
) O
to O
form O
a O
mixture O
of O
intersubunit O
disulfides B
and O
selenotrisulfides B
or O
tellurotrisulfides B
, O
respectively O
, O
between O
Cys31 B
and O
Cys60 B
' O
. O

Analogous O
studies O
with O
S O
. O
aureus O
CsoR O
reveals O
no O
reaction O
with O
selenite B
and O
minimal O
reaction O
with O
tellurite B
. O

All O
cross O
- O
linked O
forms O
of O
CstR O
exhibit O
reduced O
DNA O
binding O
affinity O
. O

We O
show O
that O
Cys31 B
initiates O
the O
reaction O
with O
sulfite B
through O
the O
formation O
of O
S B
- I
sulfocysteine I
( O
RS B
- I
SO3 I
( I
2 I
- I
) I
) O
and O
Cys60 B
is O
required O
to O
fully O
derivatize O
CstR O
to O
CstR2 O
( O
RS O
- O
SR O
' O
) O
and O
CstR2 O
( O
RS O
- O
S O
- O
SR O
' O
) O
. O

The O
modification O
of O
Cys31 B
also O
drives O
an O
allosteric O
switch O
that O
negatively O
regulates O
DNA O
binding O
while O
derivatization O
of O
Cys60 B
alone O
has O
no O
effect O
on O
DNA O
binding O
. O

These O
results O
highlight O
the O
differences O
between O
CstRs O
and O
CsoRs O
in O
chemical O
reactivity O
and O
metal O
ion O
selectivity O
and O
establish O
Cys31 B
as O
the O
functionally O
important O
cysteine B
residue O
in O
CstRs O
. O

Study O
of O
Environmental O
and O
Antimicrobial O
Agents O
Impact O
on O
Features O
of O
Bacterial O
Growth O
. O

Continuous O
, O
real O
- O
time O
observation O
of O
bacterial O
growth O
has O
a O
great O
advantage O
for O
studying O
the O
mechanisms O
of O
interactions O
of O
various O
compounds O
with O
the O
bacterial O
cell O
membrane O
. O

With O
the O
use O
of O
physical O
methods O
, O
which O
are O
specific O
for O
assessment O
of O
continuous O
changes O
in O
turbidity O
over O
time O
, O
we O
have O
shown O
that O
bacterial O
growth O
was O
affected O
by O
not O
only O
on O
types O
of O
antibiotics O
and O
phages O
, O
but O
also O
by O
their O
concentration O
in O
media O
. O

Low O
concentration O
of O
antibiotics O
and O
bacteriophages O
in O
media O
has O
no O
effect O
on O
the O
bacterial O
growth O
process O
. O

Our O
research O
has O
shown O
that O
if O
bacterial O
cell O
membrane O
is O
not O
completely O
saturated O
with O
antibiotics O
membrane O
sensitive O
sites O
( O
MSS O
) O
, O
or O
bacteriophages O
free O
unbounded O
receptors O
are O
remained O
, O
bacterial O
growth O
continues O
unimpeded O
. O

Manganese B
- O
exposed O
developing O
rats O
display O
motor O
deficits O
and O
striatal O
oxidative O
stress O
that O
are O
reversed O
by O
Trolox B
. O

While O
manganese B
( O
Mn B
) O
is O
essential O
for O
proper O
central O
nervous O
system O
( O
CNS O
) O
development O
, O
excessive O
Mn B
exposure O
may O
lead O
to O
neurotoxicity O
. O

Mn B
preferentially O
accumulates O
in O
the O
basal O
ganglia O
, O
and O
in O
adults O
it O
may O
cause O
Parkinson O
' O
s O
disease O
- O
like O
disorder O
. O

Compared O
to O
adults O
, O
younger O
individuals O
accumulate O
greater O
Mn B
levels O
in O
the O
CNS O
and O
are O
more O
vulnerable O
to O
its O
toxicity O
. O

Moreover O
, O
the O
mechanisms O
mediating O
developmental O
Mn B
- O
induced O
neurotoxicity O
are O
not O
completely O
understood O
. O

The O
present O
study O
investigated O
the O
developmental O
neurotoxicity O
elicited O
by O
Mn B
exposure O
( O
5 O
, O
10 O
and O
20 O
mg O
/ O
kg O
; O
i O
. O
p O
. O
) O
from O
postnatal O
day O
8 O
to O
PN27 O
in O
rats O
. O

Neurochemical O
analyses O
were O
carried O
out O
on O
PN29 O
, O
with O
a O
particular O
focus O
on O
striatal O
alterations O
in O
intracellular O
signaling O
pathways O
( O
MAPKs O
, O
Akt O
and O
DARPP O
- O
32 O
) O
, O
oxidative O
stress O
generation O
and O
cell O
death O
. O

Motor O
alterations O
were O
evaluated O
later O
in O
life O
at O
3 O
, O
4 O
or O
5 O
weeks O
of O
age O
. O

Mn B
exposure O
( O
20 O
mg O
/ O
kg O
) O
increased O
p38 O
( O
MAPK O
) O
and O
Akt O
phosphorylation O
, O
but O
decreased O
DARPP O
- O
32 O
- O
Thr B
- O
34 O
phosphorylation O
. O

Mn B
( O
10 O
and O
20 O
mg O
/ O
kg O
) O
increased O
caspase O
activity O
and O
F O
( O
2 O
) O
- O
isoprostane B
production O
( O
a O
biological O
marker O
of O
lipid O
peroxidation O
) O
. O

Paralleling O
the O
changes O
in O
striatal O
biochemical O
parameters O
, O
Mn B
( O
20 O
mg O
/ O
kg O
) O
also O
caused O
motor O
impairment O
, O
evidenced O
by O
increased O
falling O
latency O
in O
the O
rotarod O
test O
, O
decreased O
distance O
traveled O
and O
motor O
speed O
in O
the O
open O
- O
field O
test O
. O

Notably O
, O
the O
antioxidant O
Trolox B
( O
TM O
) O
reversed O
the O
Mn B
( O
20 O
mg O
/ O
kg O
) O
- O
dependent O
augmentation O
in O
p38 O
( O
MAPK O
) O
phosphorylation O
and O
reduced O
the O
Mn B
( O
20 O
mg O
/ O
kg O
) O
- O
induced O
caspase O
activity O
and O
F O
( O
2 O
) O
- O
isoprostane B
production O
. O

Trolox B
( O
TM O
) O
also O
reversed O
the O
Mn B
- O
induced O
motor O
coordination O
deficits O
. O

These O
findings O
are O
the O
first O
to O
show O
that O
long O
- O
term O
exposure O
to O
Mn B
during O
a O
critical O
period O
of O
neurodevelopment O
causes O
motor O
coordination O
dysfunction O
with O
parallel O
increment O
in O
oxidative O
stress O
markers O
, O
p38 O
( O
MAPK O
) O
phosphorylation O
and O
caspase O
activity O
in O
the O
striatum O
. O

Moreover O
, O
we O
establish O
Trolox B
( O
TM O
) O
as O
a O
potential O
neuroprotective O
agent O
given O
its O
efficacy O
in O
reversing O
the O
Mn B
- O
induced O
neurodevelopmental O
effects O
. O

Dose O
finding O
by O
concentration O
- O
response O
versus O
dose O
- O
response O
: O
a O
simulation O
- O
based O
comparison O
. O

AIM O
: O
The O
investigations O
reported O
here O
aimed O
to O
evaluate O
the O
incremental O
benefit O
for O
dose O
finding O
by O
concentration O
- O
response O
analysis O
versus O
dose O
- O
response O
analysis O
. O

METHODS O
: O
Trials O
were O
simulated O
using O
an O
Emax O
model O
for O
a O
range O
of O
scenarios O
of O
drug O
properties O
, O
trial O
design O
options O
and O
target O
response O
levels O
. O

The O
simulated O
data O
were O
analysed O
by O
concentration O
- O
response O
and O
dose O
- O
response O
modelling O
; O
a O
dose O
was O
then O
chosen O
to O
target O
a O
specific O
response O
level O
in O
a O
confirmatory O
trial O
. O

The O
two O
approaches O
were O
compared O
in O
terms O
of O
the O
quality O
of O
model O
parameter O
estimation O
and O
the O
success O
rate O
for O
the O
confirmatory O
trial O
. O

RESULTS O
: O
While O
the O
accuracy O
for O
ED50 O
estimation O
was O
comparably O
good O
with O
both O
approaches O
, O
the O
precision O
was O
up O
to O
90 O
% O
higher O
with O
concentration O
- O
response O
approach O
. O

The O
difference O
was O
most O
notable O
when O
clearance O
was O
highly O
variable O
between O
subjects O
and O
the O
top O
dose O
was O
relatively O
low O
. O

The O
higher O
precision O
by O
the O
concentration O
- O
response O
analysis O
lead O
to O
better O
dose O
selection O
and O
up O
to O
20 O
% O
higher O
success O
rate O
for O
the O
subsequent O
confirmatory O
trial O
. O

The O
relatively O
small O
difference O
in O
success O
rate O
translated O
into O
a O
remarkable O
difference O
in O
sample O
size O
requirement O
. O

CONCLUSION O
: O
By O
customising O
these O
parameters O
, O
the O
approach O
and O
the O
findings O
can O
be O
applied O
to O
assessing O
the O
value O
of O
pharmacokinetic O
sampling O
in O
particular O
trial O
situations O
. O

Refining O
the O
UGT1A O
haplotype O
associated O
with O
irinotecan B
- O
induced O
hematological O
toxicity O
in O
metastatic O
colorectal O
cancer O
patients O
treated O
with O
5 B
- I
fluorouracil I
/ O
irinotecan B
- O
based O
regimens O
. O

Despite O
the O
importance O
of O
UDP B
- O
glucuronosyltransfer O
( O
UGT O
) O
1A1 O
* O
28 O
in O
irinotecan B
pharmacogenetics O
, O
our O
capability O
to O
predict O
drug O
- O
induced O
severe O
toxicity O
remains O
limited O
. O

We O
aimed O
at O
identifying O
novel O
genetic O
markers O
that O
would O
improve O
prediction O
of O
irinotecan B
toxicity O
and O
response O
in O
advanced O
colorectal O
cancer O
patients O
treated O
with O
folic B
acid I
( O
leucovorin B
) O
, O
fluorouracil B
( O
5 B
- I
FU I
) O
, O
and O
irinotecan B
( O
camptosar B
) O
- O
based O
regimens O
. O

The O
relationships O
between O
UGT1A O
candidate O
markers O
across O
the O
gene O
( O
n O
= O
21 O
) O
and O
toxicity O
were O
prospectively O
evaluated O
in O
167 O
patients O
. O

We O
included O
variants O
in O
the O
3 O
' O
untranscribed O
region O
( O
3 O
' O
UTR O
) O
of O
the O
UGT1A O
locus O
, O
not O
studied O
in O
this O
context O
yet O
. O

These O
genetic O
markers O
were O
further O
investigated O
in O
250 O
Italian O
FOLFIRI O
- O
treated O
patients O
. O

Several O
functional O
UGT1A O
variants O
, O
including O
UGT1A1 O
* O
28 O
, O
significantly O
influenced O
risk O
of O
severe O
hematologic O
toxicity O
. O

As O
previously O
reported O
in O
the O
Italian O
cohort O
, O
a O
5 O
- O
marker O
risk O
haplotype O
[ O
haplotype O
II O
( O
HII O
) O
; O
UGTs O
1A9 O
/ O
1A7 O
/ O
1A1 O
] O
was O
associated O
with O
severe O
neutropenia O
in O
our O
cohort O
[ O
odds O
ratio O
( O
OR O
) O
= O
2 O
. O
43 O
; O
P O
= O
0 O
. O
004 O
] O
. O

The O
inclusion O
of O
a O
3 O
' O
UTR O
single O
- O
nucleotide O
polymorphism O
( O
SNP O
) O
permitted O
refinement O
of O
the O
previously O
defined O
HI O
, O
in O
which O
HIa O
was O
associated O
with O
the O
absence O
of O
severe O
neutropenia O
in O
combined O
cohorts O
( O
OR O
= O
0 O
. O
55 O
; O
P O
= O
0 O
. O
038 O
) O
. O

Among O
all O
tested O
UGT1A O
variations O
and O
upon O
multivariate O
analyses O
, O
no O
UGT1A1 O
SNPs O
remained O
significant O
, O
whereas O
three O
SNPs O
located O
in O
the O
central O
region O
of O
UGT1A O
were O
linked O
to O
neutropenia O
grade O
3 O
- O
4 O
. O

Haplotype O
analyses O
of O
these O
markers O
with O
the O
3 O
' O
UTR O
SNP O
allowed O
the O
identification O
of O
a O
protective O
HI O
( O
OR O
= O
0 O
. O
50 O
; O
P O
= O
0 O
. O
048 O
) O
and O
two O
risk O
haplotypes O
, O
HII O
and O
HIII O
, O
characterized O
by O
2 O
and O
3 O
unfavorable O
alleles O
, O
respectively O
, O
revealing O
a O
dosage O
effect O
( O
ORs O
of O
2 O
. O
15 O
and O
5 O
. O
28 O
; O
P O
< O
= O
0 O
. O
030 O
) O
. O

Our O
results O
suggest O
that O
specific O
SNPs O
in O
UGT1A O
, O
other O
than O
UGT1A1 O
* O
28 O
, O
may O
influence O
irinotecan B
toxicity O
and O
should O
be O
considered O
to O
refine O
pharmacogenetic O
testing O
. O

Structural O
and O
Optoelectronic O
Characterization O
of O
RF O
Sputtered O
ZnSnN2 B
. O

ZnSnN2 B
, O
a O
new O
earth O
- O
abundant O
semiconductor O
, O
is O
synthesized O
and O
characterized O
for O
use O
as O
a O
photovoltaic O
absorber O
material O
. O

Results O
confirm O
the O
predicted O
orthorhombic O
Pna21 O
crystal O
structure O
in O
RF O
sputtered O
thin O
films O
. O

Additionally O
, O
optical O
measurements O
reveal O
a O
direct O
bandgap O
of O
about O
2 O
eV O
, O
which O
is O
larger O
than O
our O
calculated O
bandgap O
of O
1 O
. O
42 O
eV O
due O
to O
the O
Burstein O
- O
Moss O
effect O
. O

PHI O
: O
A O
powerful O
new O
program O
for O
the O
analysis O
of O
anisotropic O
monomeric O
and O
exchange O
- O
coupled O
polynuclear O
d O
- O
and O
f O
- O
block O
complexes O
. O

A O
new O
program O
, O
PHI O
, O
with O
the O
ability O
to O
calculate O
the O
magnetic O
properties O
of O
large O
spin O
systems O
and O
complex O
orbitally O
degenerate O
systems O
, O
such O
as O
clusters O
of O
d O
- O
block O
and O
f O
- O
block O
ions O
, O
is O
presented O
. O

The O
program O
can O
intuitively O
fit O
experimental O
data O
from O
multiple O
sources O
, O
such O
as O
magnetic O
and O
spectroscopic O
data O
, O
simultaneously O
. O

PHI O
is O
extensively O
parallelized O
and O
can O
operate O
under O
the O
symmetric O
multiprocessing O
, O
single O
process O
multiple O
data O
, O
or O
GPU O
paradigms O
using O
a O
threaded O
, O
MPI O
or O
GPU O
model O
, O
respectively O
. O

For O
a O
given O
problem O
PHI O
is O
been O
shown O
to O
be O
almost O
12 O
times O
faster O
than O
the O
well O
- O
known O
program O
MAGPACK O
, O
limited O
only O
by O
available O
hardware O
. O

( O
c O
) O
2013 O
Wiley O
Periodicals O
, O
Inc O
. O

Androgen B
Receptor O
mRNA O
Measured O
by O
Quantitative O
Real O
Time O
PCR O
is O
Decreased O
in O
the O
Urethral O
Mucosa O
of O
Patients O
with O
Middle O
Idiopathic O
Hypospadias O
. O

Androgen B
action O
is O
exerted O
through O
the O
androgen B
receptor O
. O

The O
normal O
46 O
, O
XY O
genital O
virilization O
depends O
on O
androgen B
receptor O
gene O
expression O
, O
which O
is O
tissue O
specific O
, O
and O
requires O
normal O
androgen B
receptor O
mRNA O
levels O
in O
androgen B
sensitive O
tissues O
. O

Hypospadias O
is O
a O
frequent O
male O
genital O
abnormality O
, O
potentially O
related O
to O
reduced O
androgen B
sensitivity O
in O
genital O
tissues O
. O

The O
aim O
of O
this O
study O
was O
to O
compare O
, O
by O
quantitative O
real O
time O
PCR O
, O
the O
amount O
of O
androgen B
receptor O
mRNA O
in O
cells O
obtained O
from O
the O
urethral O
mucosa O
of O
patients O
with O
middle O
idiopathic O
hypospadias O
with O
the O
androgen B
receptor O
mRNA O
levels O
observed O
in O
control O
phimosis O
subjects O
with O
eutopic O
urethral O
opening O
. O

Prepubertal O
individuals O
were O
studied O
, O
including O
41 O
controls O
and O
17 O
hypospadias O
patients O
with O
mean O
( O
SD O
) O
ages O
of O
4 O
. O
7 O
( O
2 O
. O
1 O
) O
years O
and O
4 O
. O
0 O
( O
3 O
. O
0 O
) O
years O
, O
respectively O
. O

We O
observed O
significantly O
less O
androgen B
receptor O
mRNA O
in O
the O
urethral O
mucosa O
of O
patients O
with O
hypospadias O
than O
in O
the O
controls O
( O
p O
= O
0 O
. O
002 O
) O
. O

The O
correlation O
between O
the O
level O
of O
androgen B
receptor O
mRNA O
expression O
and O
the O
penile O
size O
was O
almost O
statistically O
significant O
only O
in O
hypospadias O
patients O
( O
r O
= O
0 O
. O
47 O
; O
p O
= O
0 O
. O
053 O
) O
. O

We O
also O
established O
the O
number O
of O
CAG O
repeats O
in O
exon O
1 O
of O
the O
androgen B
receptor O
gene O
by O
GeneScan O
analysis O
. O

No O
significant O
difference O
was O
observed O
in O
the O
number O
of O
CAG O
repeats O
when O
patients O
and O
controls O
were O
compared O
. O

A O
negative O
correlation O
between O
the O
CAG O
repeats O
and O
penile O
size O
was O
detected O
in O
patients O
with O
hypospadias O
, O
but O
not O
in O
controls O
. O

Our O
data O
suggest O
that O
a O
critical O
lower O
level O
of O
androgen B
receptor O
mRNA O
expression O
could O
be O
a O
determining O
factor O
in O
the O
development O
of O
middle O
hypospadias O
. O

Identification O
and O
characterization O
of O
bacterial O
diterpene B
cyclases O
that O
synthesize O
the O
cembrane B
skeleton O
. O

Digging O
up O
skeletons O
: O
We O
report O
the O
identification O
and O
the O
functional O
characterization O
of O
two O
terpene B
cyclases O
( O
DtcycA O
and O
DtcycB O
) O
that O
were O
mined O
from O
the O
genome O
of O
Streptomyces O
sp O
. O

SANK O
60404 O
. O

DtcycA O
and O
DtcycB O
are O
novel O
bacterial O
diterpene B
cyclases O
for O
the O
synthesis O
of O
the O
cembrane B
skeleton O
. O

A O
case O
- O
based O
approach O
to O
the O
practical O
application O
of O
dexmedetomidine B
in O
critically O
ill O
adults O
. O

Dexmedetomidine B
is O
a O
selective O
alpha O
( O
2 O
) O
- O
adrenoceptor O
agonist O
that O
offers O
unique O
sedation O
because O
patients O
are O
readily O
awakened O
while O
administration O
continues O
and O
the O
drug O
does O
not O
suppress O
the O
respiratory O
center O
. O

Limitations O
of O
use O
include O
higher O
acquisition O
cost O
, O
inability O
to O
produce O
deep O
sedation O
, O
and O
bradycardia O
and O
hypotension O
. O

Using O
a O
case O
- O
based O
approach O
, O
the O
purpose O
of O
this O
review O
was O
to O
qualitatively O
assess O
the O
role O
of O
dexmedetomidine B
in O
the O
care O
of O
the O
critically O
ill O
and O
in O
the O
management O
of O
alcohol B
withdrawal O
, O
and O
to O
formulate O
recommendations O
regarding O
its O
clinical O
application O
. O

Sixty O
- O
six O
studies O
were O
identified O
that O
investigated O
dexmedetomidine B
for O
the O
provision O
of O
sedation O
. O

These O
studies O
were O
heterogeneous O
in O
design O
and O
patient O
populations O
; O
most O
investigated O
patients O
did O
not O
require O
heavy O
sedation O
, O
and O
few O
used O
propofol B
as O
the O
comparator O
. O

In O
general O
, O
though O
, O
the O
aggregate O
results O
of O
all O
studies O
demonstrate O
that O
dexmedetomidine B
provides O
comfort O
, O
possibly O
shortens O
the O
duration O
of O
mechanical O
ventilation O
to O
facilitate O
extubation O
, O
reduces O
the O
occurrence O
of O
acute O
brain O
dysfunction O
, O
and O
facilitates O
communication O
, O
but O
the O
drug O
is O
associated O
with O
hemodynamic O
instability O
and O
requires O
the O
supplemental O
use O
of O
traditional O
sedative O
and O
analgesic O
agents O
. O

These O
outcomes O
need O
to O
be O
substantiated O
in O
additional O
studies O
that O
include O
assessments O
of O
cost O
- O
effectiveness O
. O

Dexmedetomidine B
should O
be O
considered O
when O
patients O
require O
mild O
to O
moderate O
levels O
of O
sedation O
of O
short O
to O
intermediate O
time O
frames O
, O
and O
they O
qualify O
for O
daily O
awakenings O
with O
traditional O
sedative O
therapies O
. O

The O
data O
for O
dexmedetomidine B
in O
relation O
to O
alcohol B
withdrawal O
are O
limited O
to O
12 O
retrospective O
reports O
representing O
a O
total O
of O
127 O
patients O
. O

Its O
role O
for O
this O
indication O
requires O
further O
study O
, O
but O
it O
may O
be O
considered O
as O
adjunctive O
therapy O
when O
clinicians O
are O
concerned O
about O
respiratory O
suppression O
associated O
with O
escalating O
doses O
of O
gamma B
- I
aminobutyric I
acid I
agonists O
. O

Regardless O
of O
the O
indication O
for O
dexmedetomidine B
, O
the O
practitioner O
must O
closely O
monitor O
patient O
comfort O
and O
the O
occurrence O
of O
hemodynamic O
deviations O
with O
the O
realization O
that O
as O
- O
needed O
administration O
of O
traditional O
sedatives O
and O
analgesics O
will O
be O
required O
and O
some O
degree O
of O
bradycardia O
and O
hypotension O
expected O
but O
intervention O
rarely O
required O
. O

The O
Sec7 O
Guanine B
Nucleotide I
Exchange O
Factor O
GBF1 O
Regulates O
Membrane O
Recruitment O
of O
BIG1 O
and O
BIG2 O
Guanine B
Nucleotide I
Exchange O
Factors O
to O
the O
Trans O
- O
Golgi O
Network O
( O
TGN O
) O
. O

Three O
Sec7 O
guanine B
nucleotide I
exchange O
factors O
( O
GEFs O
) O
activate O
ADP B
- O
ribosylation O
factors O
( O
ARFs O
) O
to O
facilitate O
coating O
of O
transport O
vesicles O
within O
the O
secretory O
and O
endosomal O
pathways O
. O

GBF1 O
recruits O
COPI O
to O
pre O
- O
Golgi O
and O
Golgi O
compartments O
, O
whereas O
BIG1 O
and O
BIG2 O
recruit O
AP1 O
and O
GGA O
clathrin O
adaptors O
to O
the O
trans O
- O
Golgi O
network O
( O
TGN O
) O
and O
endosomes O
. O

Here O
, O
we O
report O
a O
functional O
cascade O
between O
these O
GEFs O
by O
showing O
that O
GBF1 O
- O
activated O
ARFs O
( O
ARF4 O
and O
ARF5 O
, O
but O
not O
ARF3 O
) O
facilitate O
BIG1 O
and O
BIG2 O
recruitment O
to O
the O
TGN O
. O

We O
localize O
GBF1 O
ultrastructurally O
to O
the O
pre O
- O
Golgi O
, O
the O
Golgi O
, O
and O
also O
the O
TGN O
. O

Our O
findings O
suggest O
a O
model O
in O
which O
GBF1 O
localized O
within O
pre O
- O
Golgi O
and O
Golgi O
compartments O
mediates O
ARF O
activation O
to O
facilitate O
recruitment O
of O
COPI O
to O
membranes O
, O
whereas O
GBF1 O
localized O
at O
the O
TGN O
mediates O
ARF O
activation O
that O
leads O
to O
the O
recruitment O
of O
BIG1 O
and O
BIG2 O
to O
the O
TGN O
. O

Membrane O
- O
associated O
BIG1 O
/ O
2 O
then O
activates O
ARFs O
that O
recruit O
clathrin O
adaptors O
. O

In O
this O
cascade O
, O
an O
early O
acting O
GEF O
( O
GBF1 O
) O
activates O
ARFs O
that O
mediate O
recruitment O
of O
late O
acting O
GEFs O
( O
BIG1 O
/ O
2 O
) O
to O
coordinate O
coating O
events O
within O
the O
pre O
- O
Golgi O
/ O
Golgi O
/ O
TGN O
continuum O
. O

Such O
coordination O
may O
optimize O
the O
efficiency O
and O
/ O
or O
selectivity O
of O
cargo O
trafficking O
through O
the O
compartments O
of O
the O
secretory O
pathway O
. O

Investigating O
the O
enteroenteric O
recirculation O
of O
apixaban B
, O
a O
factor O
Xa O
inhibitor O
: O
administration O
of O
activated O
charcoal O
to O
bile O
duct O
- O
cannulated O
rats O
and O
dogs O
receiving O
an O
intravenous O
dose O
and O
use O
of O
drug O
transporter O
knockout O
rats O
. O

The O
study O
described O
here O
investigated O
the O
impact O
of O
intestinal O
excretion O
( O
IE O
; O
excretion O
of O
drug O
directly O
from O
circulation O
to O
intestinal O
lumen O
) O
, O
enteroenteric O
recirculation O
( O
EER O
) O
, O
and O
renal O
tubule O
recirculation O
( O
RTR O
) O
on O
apixaban B
pharmacokinetics O
and O
disposition O
. O

The O
experimental O
approaches O
involve O
integrating O
apixaban B
elimination O
pathways O
with O
pharmacokinetic O
profiles O
obtained O
from O
bile O
duct O
- O
cannulated O
( O
BDC O
) O
rats O
and O
dogs O
receiving O
i O
. O
v O
. O
doses O
together O
with O
oral O
administration O
of O
activated O
charcoal O
( O
AC O
) O
. O

Additionally O
, O
the O
role O
of O
P O
- O
gp O
( O
P O
- O
glycoprotein O
; O
abcb1 O
) O
and O
BCRP O
( O
breast O
cancer O
resistance O
protein O
; O
abcg2 O
) O
in O
apixaban O
disposition O
was O
evaluated O
in O
experiments O
using O
transporter O
inhibitors O
and O
transporter O
knockout O
( O
KO O
) O
rats O
. O

Approximately O
20 O
- O
50 O
% O
of O
an O
apixaban B
i O
. O
v O
. O
dose O
was O
found O
in O
feces O
of O
BDC O
rats O
and O
dogs O
, O
suggesting O
IE O
leading O
to O
fecal O
elimination O
and O
intestinal O
clearance O
( O
IC O
) O
. O

The O
fecal O
elimination O
, O
IC O
, O
and O
systemic O
clearance O
of O
apixaban B
were O
increased O
upon O
AC O
administration O
in O
both O
BDC O
rats O
and O
dogs O
and O
were O
decreased O
in O
BDC O
rats O
dosed O
with O
GF B
- I
120918 I
, O
a O
dual O
BCRP O
and O
P O
- O
gp O
inhibitor O
) O
. O

BCRP O
appeared O
to O
play O
a O
more O
important O
role O
for O
absorption O
and O
intestinal O
and O
renal O
elimination O
of O
apixaban B
than O
P O
- O
gp O
in O
transporter O
- O
KO O
rats O
after O
oral O
and O
i O
. O
v O
. O
dosing O
, O
which O
led O
to O
a O
higher O
level O
of O
active O
renal O
excretion O
in O
rat O
than O
other O
species O
. O

These O
data O
demonstrate O
that O
apixaban B
undergoes O
IE O
, O
EER O
, O
and O
RTR O
that O
are O
facilitated O
by O
efflux O
transporters O
. O

Intestinal O
reabsorption O
of O
apixaban B
could O
be O
interrupted O
by O
AC O
even O
at O
3 O
hours O
post O
- O
drug O
dose O
in O
dogs O
( O
late O
charcoal O
effect O
) O
. O

This O
study O
demonstrates O
that O
the O
intestine O
is O
an O
organ O
for O
direct O
clearance O
and O
redistribution O
of O
apixaban B
. O

The O
IE O
, O
EER O
, O
and O
RTR O
contribute O
to O
overall O
pharmacokinetic O
profiles O
of O
apixaban B
. O

IE O
as O
a O
clearance O
pathway O
, O
balanced O
with O
metabolism O
and O
renal O
excretion O
, O
helps O
decrease O
the O
impacts O
of O
intrinsic O
( O
renal O
or O
hepatic O
impairment O
) O
and O
extrinsic O
( O
drug O
- O
drug O
interactions O
) O
factors O
on O
apixaban B
disposition O
. O

Removal O
of O
molecular O
adsorbates O
on O
gold O
nanoparticles O
using O
sodium B
borohydride I
in O
water O
. O

The O
mechanism O
of O
sodium B
borohydride I
removal O
of O
organothiols B
from O
gold O
nanoparticles O
( O
AuNPs O
) O
was O
studied O
using O
an O
experimental O
investigation O
and O
computational O
modeling O
. O

Organothiols B
and O
other O
AuNP O
surface O
adsorbates O
such O
as O
thiophene B
, O
adenine B
, O
rhodamine B
, O
small O
anions O
( O
Br B
( I
- I
) I
and O
I B
( I
- I
) I
) O
, O
and O
a O
polymer O
( O
PVP B
, O
poly B
( I
N I
- I
vinylpyrrolidone I
) I
) O
can O
all O
be O
rapidly O
and O
completely O
removed O
from O
the O
AuNP O
surfaces O
. O

A O
computational O
study O
showed O
that O
hydride B
derived O
from O
sodium B
borohydride I
has O
a O
higher O
binding O
affinity O
to O
AuNPs O
than O
organothiols B
. O

Thus O
, O
it O
can O
displace O
organothiols B
and O
all O
the O
other O
adsorbates O
tested O
from O
AuNPs O
. O

Sodium B
borohydride I
may O
be O
used O
as O
a O
hazard O
- O
free O
, O
general O
- O
purpose O
detergent O
that O
should O
find O
utility O
in O
a O
variety O
of O
AuNP O
applications O
including O
catalysis O
, O
biosensing O
, O
surface O
enhanced O
Raman O
spectroscopy O
, O
and O
AuNP O
recycle O
and O
reuse O
. O

Synthesis O
of O
MoS2 B
and O
MoSe2 B
films O
with O
vertically O
aligned O
layers O
. O

Layered O
materials O
consist O
of O
molecular O
layers O
stacked O
together O
by O
weak O
interlayer O
interactions O
. O

They O
often O
crystallize O
to O
form O
atomically O
smooth O
thin O
films O
, O
nanotubes O
, O
and O
platelet O
or O
fullerene B
- O
like O
nanoparticles O
due O
to O
the O
anisotropic O
bonding O
. O

Structures O
that O
predominately O
expose O
edges O
of O
the O
layers O
exhibit O
high O
surface O
energy O
and O
are O
often O
considered O
unstable O
. O

In O
this O
communication O
, O
we O
present O
a O
synthesis O
process O
to O
grow O
MoS2 B
and O
MoSe2 B
thin O
films O
with O
vertically O
aligned O
layers O
, O
thereby O
maximally O
exposing O
the O
edges O
on O
the O
film O
surface O
. O

Such O
edge O
- O
terminated O
films O
are O
metastable O
structures O
of O
MoS2 B
and O
MoSe2 B
, O
which O
may O
find O
applications O
in O
diverse O
catalytic O
reactions O
. O

We O
have O
confirmed O
their O
catalytic O
activity O
in O
a O
hydrogen B
evolution O
reaction O
( O
HER O
) O
, O
in O
which O
the O
exchange O
current O
density O
correlates O
directly O
with O
the O
density O
of O
the O
exposed O
edge O
sites O
. O

Nevirapine B
bioactivation O
and O
covalent O
binding O
in O
the O
skin O
. O

Nevirapine B
( O
NVP B
) O
treatment O
is O
associated O
with O
serious O
skin O
rashes O
that O
appear O
to O
be O
immune O
- O
mediated O
. O

We O
previously O
developed O
a O
rat O
model O
of O
this O
skin O
rash O
that O
is O
immune O
- O
mediated O
and O
is O
very O
similar O
to O
the O
rash O
in O
humans O
. O

Treatment O
of O
rats O
with O
the O
major O
NVP B
metabolite O
, O
12 B
- I
OH I
- I
NVP I
, O
also O
caused O
the O
rash O
. O

Most O
idiosyncratic O
drug O
reactions O
are O
caused O
by O
reactive O
metabolites O
; O
12 B
- I
OH I
- I
NVP I
forms O
a O
benzylic B
sulfate I
, O
which O
was O
detected O
in O
the O
blood O
of O
animals O
treated O
with O
NVP B
or O
12 B
- I
OH I
- I
NVP I
. O

This O
sulfate B
is O
presumably O
formed O
in O
the O
liver O
; O
however O
, O
the O
skin O
also O
has O
significant O
sulfotransferase O
activity O
. O

In O
this O
study O
, O
we O
used O
a O
serum O
against O
NVP B
to O
detect O
covalent O
binding O
in O
the O
skin O
of O
rats O
. O

There O
was O
a O
large O
artifact O
band O
in O
immunoblots O
of O
whole O
skin O
homogenates O
that O
interfered O
with O
detection O
of O
covalent O
binding O
; O
however O
, O
when O
the O
skin O
was O
separated O
into O
dermal O
and O
epidermal O
fractions O
, O
covalent O
binding O
was O
clearly O
present O
in O
the O
epidermis O
, O
which O
is O
also O
the O
location O
of O
sulfotransferases O
. O

In O
contrast O
to O
rats O
, O
treatment O
of O
mice O
with O
NVP B
did O
not O
result O
in O
covalent O
binding O
in O
the O
skin O
or O
skin O
rash O
. O

Although O
the O
reaction O
of O
12 B
- I
OH I
- I
NVP I
sulfate I
with O
nucleophiles O
such O
as O
glutathione B
is O
slow O
, O
incubation O
of O
this O
sulfate B
with O
homogenized O
human O
and O
rat O
skin O
led O
to O
extensive O
covalent O
binding O
. O

Incubations O
of O
12 B
- I
OH I
- I
NVP I
with O
the O
soluble O
fraction O
from O
a O
9 O
, O
000g O
centrifugation O
( O
S9 O
) O
of O
rat O
or O
human O
skin O
homogenate O
in O
the O
presence O
of O
3 B
' I
- I
phosphoadenosine I
- I
5 I
' I
- I
phosphosulfate I
( O
PAPS B
) O
produced O
extensive O
covalent O
binding O
, O
but O
no O
covalent O
binding O
was O
detected O
with O
mouse O
skin O
S9 O
, O
which O
suggests O
that O
the O
reason O
mice O
do O
not O
develop O
a O
rash O
is O
that O
they O
lack O
the O
required O
sulfotransferase O
. O

This O
is O
the O
first O
study O
to O
report O
covalent O
binding O
of O
NVP B
to O
rat O
and O
human O
skin O
. O

These O
data O
provide O
strong O
evidence O
that O
covalent O
binding O
of O
NVP B
in O
the O
skin O
is O
due O
to O
12 B
- I
OH I
- I
NVP I
sulfate I
, O
which O
is O
likely O
responsible O
for O
NVP B
- O
induced O
skin O
rash O
. O

Sulfation O
may O
represent O
a O
bioactivation O
pathway O
for O
other O
drugs O
that O
cause O
a O
skin O
rash O
. O

Development O
of O
Bacteriostatic O
DNA O
Aptamers O
for O
Salmonella O
. O

Salmonella O
is O
one O
of O
the O
most O
dangerous O
and O
common O
food O
- O
borne O
pathogens O
. O

The O
overuse O
of O
antibiotics O
for O
disease O
prevention O
has O
led O
to O
the O
development O
of O
multidrug O
resistant O
Salmonella O
. O

Now O
, O
more O
than O
ever O
, O
there O
is O
a O
need O
for O
new O
antimicrobial O
drugs O
to O
combat O
these O
resistant O
bacteria O
. O

Aptamers O
have O
grown O
in O
popularity O
since O
their O
discovery O
, O
and O
their O
properties O
make O
them O
attractive O
candidates O
for O
therapeutic O
use O
. O

In O
this O
work O
, O
we O
describe O
the O
selection O
of O
highly O
specific O
DNA O
aptamers O
to O
S O
. O
enteritidis O
and O
S O
. O
typhimurium O
. O

To O
evolve O
species O
- O
specific O
aptamers O
, O
twelve O
rounds O
of O
selection O
to O
live O
S O
. O
enteritidis O
and O
S O
. O
typhimurium O
were O
performed O
, O
alternating O
with O
a O
negative O
selection O
against O
a O
mixture O
of O
related O
pathogens O
. O

Studies O
have O
shown O
that O
synthetic O
pools O
combined O
from O
individual O
aptamers O
have O
the O
capacity O
to O
inhibit O
growth O
of O
S O
. O
enteritidis O
and O
S O
. O
typhimurium O
in O
bacterial O
cultures O
; O
this O
was O
the O
result O
of O
a O
decrease O
in O
their O
membrane O
potential O
. O

Minimal O
peptide O
motif O
for O
non O
- O
covalent O
peptide O
- O
heparin O
hydrogels O
. O

Reduction O
of O
complexity O
of O
the O
extracellular O
matrix O
( O
ECM O
) O
to O
a O
non O
- O
covalent O
structure O
with O
minimal O
chemically O
defined O
components O
represents O
an O
attractive O
avenue O
for O
understanding O
the O
biology O
of O
the O
ECM O
. O

The O
resulting O
system O
could O
lead O
to O
the O
design O
of O
tailor O
- O
made O
biomaterials O
that O
incorporate O
varying O
functionalities O
. O

Negatively O
charged O
glycosaminoglycans O
are O
the O
major O
components O
of O
the O
ECM O
. O

Their O
interaction O
with O
positively O
charged O
proteins O
is O
important O
for O
dynamic O
three O
- O
dimensional O
scaffold O
formation O
and O
function O
. O

We O
designed O
and O
screened O
minimal O
peptide O
motifs O
whose O
conjugates O
with O
polyethylene B
glycol I
interact O
with O
heparin O
to O
form O
non O
- O
covalent O
hydrogels O
. O

Here O
we O
show O
the O
structure O
/ O
function O
relationship O
of O
the O
( O
RA O
) O
( O
n O
) O
and O
( O
KA O
) O
( O
n O
) O
motifs O
and O
determined O
that O
both O
basic O
residues O
and O
the O
heparin O
- O
induced O
alpha O
- O
helix O
formation O
are O
important O
for O
the O
assembly O
process O
. O

Simple O
rules O
allowed O
us O
to O
tune O
various O
aspects O
of O
the O
matrix O
system O
such O
as O
the O
gelation O
rates O
, O
biodegradability O
, O
rheological O
properties O
, O
and O
biofunctionality O
. O

The O
hydrogels O
can O
encapsulate O
cells O
and O
support O
cell O
survival O
. O

Natural O
products O
as O
a O
source O
for O
treating O
neglected O
parasitic O
diseases O
. O

Infectious O
diseases O
caused O
by O
parasites O
are O
a O
major O
threat O
for O
the O
entire O
mankind O
, O
especially O
in O
the O
tropics O
. O

More O
than O
1 O
billion O
people O
world O
- O
wide O
are O
directly O
exposed O
to O
tropical O
parasites O
such O
as O
the O
causative O
agents O
of O
trypanosomiasis O
, O
leishmaniasis O
, O
schistosomiasis O
, O
lymphatic O
filariasis O
and O
onchocerciasis O
, O
which O
represent O
a O
major O
health O
problem O
, O
particularly O
in O
impecunious O
areas O
. O

Unlike O
most O
antibiotics O
, O
there O
is O
no O
" O
general O
" O
antiparasitic O
drug O
available O
. O

Here O
, O
the O
selection O
of O
antiparasitic O
drugs O
varies O
between O
different O
organisms O
. O

Some O
of O
the O
currently O
available O
drugs O
are O
chemically O
de O
novo O
synthesized O
, O
however O
, O
the O
majority O
of O
drugs O
are O
derived O
from O
natural O
sources O
such O
as O
plants O
which O
have O
subsequently O
been O
chemically O
modified O
to O
warrant O
higher O
potency O
against O
these O
human O
pathogens O
. O

In O
this O
review O
article O
we O
will O
provide O
an O
overview O
of O
the O
current O
status O
of O
plant O
derived O
pharmaceuticals O
and O
their O
chemical O
modifications O
to O
target O
parasite O
- O
specific O
peculiarities O
in O
order O
to O
interfere O
with O
their O
proliferation O
in O
the O
human O
host O
. O

Oxidative O
Stress O
and O
DNA O
Damage O
in O
Human O
Gastric O
Carcinoma O
: O
8 B
- I
Oxo I
- I
7 I
' I
8 I
- I
dihydro I
- I
2 I
' I
- I
deoxyguanosine I
( O
8 B
- I
oxo I
- I
dG I
) O
as O
a O
Possible O
Tumor O
Marker O
. O

We O
characterized O
the O
oxidative O
stress O
( O
OS O
) O
status O
by O
the O
levels O
of O
reduced O
/ O
oxidized O
glutathione I
( O
GSH B
/ O
GSSG B
) O
, O
malondialdehyde B
( O
MDA B
) O
and O
the O
mutagenic O
base O
8 B
- I
oxo I
- I
7 I
' I
8 I
- I
dihydro I
- I
2 I
' I
- I
deoxyguanosine I
( O
8 B
- I
oxo I
- I
dG I
) O
in O
human O
gastric O
carcinoma O
( O
HGC O
) O
samples O
and O
compared O
the O
results O
with O
normal O
tissue O
from O
the O
same O
patients O
. O

We O
also O
analyzed O
8 B
- I
oxo I
- I
dG I
in O
peripheral O
mononuclear O
cells O
( O
PMNC O
) O
and O
urine O
from O
healthy O
control O
subjects O
and O
in O
affected O
patients O
in O
the O
basal O
state O
and O
one O
, O
three O
, O
six O
, O
nine O
and O
twelve O
months O
after O
tumor O
resection O
. O

The O
levels O
of O
DNA O
repair O
enzyme O
mRNA O
expression O
( O
hOGG1 O
, O
RAD51 O
, O
MUYTH O
and O
MTH1 O
) O
were O
determined O
in O
tumor O
specimens O
and O
compared O
with O
normal O
mucosa O
. O

Tumor O
specimens O
exhibited O
increased O
levels O
of O
MDA B
and O
8 B
- I
oxo I
- I
dG I
compared O
with O
normal O
gastric O
tissue O
. O

GSH B
levels O
were O
also O
increased O
, O
while O
GSSG B
levels O
remained O
stable O
. O

DNA O
repair O
enzyme O
mRNA O
expression O
was O
induced O
in O
the O
tumor O
tissues O
. O

Levels O
of O
8 B
- I
oxo I
- I
dG I
were O
significantly O
elevated O
in O
both O
urine O
and O
PMNC O
of O
gastric O
cancer O
patients O
compared O
with O
healthy O
controls O
. O

After O
gastrectomy O
, O
the O
levels O
of O
the O
damaged O
base O
in O
urine O
and O
PMNC O
decreased O
progressively O
to O
values O
close O
to O
those O
found O
in O
the O
healthy O
population O
. O

The O
high O
levels O
of O
8 B
- I
oxo I
- I
dG I
in O
urine O
may O
be O
related O
to O
the O
increased O
induction O
of O
DNA O
repair O
activity O
in O
tumor O
tissue O
, O
and O
the O
changes O
observed O
after O
tumor O
resection O
support O
its O
potential O
use O
as O
a O
tumor O
marker O
. O

Process O
engineering O
with O
planetary O
ball O
mills O
. O

Planetary O
ball O
mills O
are O
well O
known O
and O
used O
for O
particle O
size O
reduction O
on O
laboratory O
and O
pilot O
scales O
for O
decades O
while O
during O
the O
last O
few O
years O
the O
application O
of O
planetary O
ball O
mills O
has O
extended O
to O
mechanochemical O
approaches O
. O

Processes O
inside O
planetary O
ball O
mills O
are O
complex O
and O
strongly O
depend O
on O
the O
processed O
material O
and O
synthesis O
and O
, O
thus O
, O
the O
optimum O
milling O
conditions O
have O
to O
be O
assessed O
for O
each O
individual O
system O
. O

The O
present O
review O
focuses O
on O
the O
insight O
into O
several O
parameters O
like O
properties O
of O
grinding O
balls O
, O
the O
filling O
ratio O
or O
revolution O
speed O
. O

It O
gives O
examples O
of O
the O
aspects O
of O
grinding O
and O
illustrates O
some O
general O
guidelines O
to O
follow O
for O
modelling O
processes O
in O
planetary O
ball O
mills O
in O
terms O
of O
refinement O
, O
synthesis O
' O
yield O
and O
contamination O
from O
wear O
. O

The O
amount O
of O
energy O
transferred O
from O
the O
milling O
tools O
to O
the O
powder O
is O
significant O
and O
hardly O
measurable O
for O
processes O
in O
planetary O
ball O
mills O
. O

Thus O
numerical O
simulations O
based O
on O
a O
discrete O
- O
element O
- O
method O
are O
used O
to O
describe O
the O
energy O
transfer O
to O
give O
an O
adequate O
description O
of O
the O
process O
by O
correlation O
with O
experiments O
. O

The O
simulations O
illustrate O
the O
effect O
of O
the O
geometry O
of O
planetary O
ball O
mills O
on O
the O
energy O
entry O
. O

In O
addition O
the O
imaging O
of O
motion O
patterns O
inside O
a O
planetary O
ball O
mill O
from O
simulations O
and O
video O
recordings O
is O
shown O
. O

Cloning O
, O
characterization O
and O
heterologous O
expression O
of O
the O
indolocarbazole B
biosynthetic O
gene O
cluster O
from O
marine O
- O
derived O
Streptomyces O
sanyensis O
FMA O
. O

The O
indolocarbazole B
( O
ICZ B
) O
alkaloids O
have O
attracted O
much O
attention O
due O
to O
their O
unique O
structures O
and O
potential O
therapeutic O
applications O
. O

A O
series O
of O
ICZs O
were O
recently O
isolated O
and O
identified O
from O
a O
marine O
- O
derived O
actinomycete O
strain O
, O
Streptomyces O
sanyensis O
FMA O
. O

To O
elucidate O
the O
biosynthetic O
machinery O
associated O
with O
ICZs O
production O
in O
S O
. O
sanyensis O
FMA O
, O
PCR O
using O
degenerate O
primers O
was O
carried O
out O
to O
clone O
the O
FAD B
- O
dependent O
monooxygenase O
gene O
fragment O
for O
ICZ O
ring O
formation O
, O
which O
was O
used O
as O
a O
probe O
to O
isolate O
the O
34 O
. O
6 O
- O
kb O
DNA O
region O
containing O
the O
spc O
gene O
cluster O
. O

Sequence O
analysis O
revealed O
genes O
for O
ICZ O
ring O
formation O
( O
spcO O
, O
D O
, O
P O
, O
C O
) O
, O
sugar B
unit O
formation O
( O
spcA O
, O
B O
, O
E O
, O
K O
, O
J O
, O
I O
) O
, O
glycosylation O
( O
spcN O
, O
G O
) O
, O
methylation O
( O
spcMA O
, O
MB O
) O
, O
as O
well O
as O
regulation O
( O
spcR O
) O
. O

Their O
involvement O
in O
ICZ O
biosynthesis O
was O
confirmed O
by O
gene O
inactivation O
and O
heterologous O
expression O
in O
Streptomyces O
coelicolor O
M1152 O
. O

This O
work O
represents O
the O
first O
cloning O
and O
characterization O
of O
an O
ICZ O
gene O
cluster O
isolated O
from O
a O
marine O
- O
derived O
actinomycete O
strain O
and O
would O
be O
helpful O
for O
thoroughly O
understanding O
the O
biosynthetic O
mechanism O
of O
ICZ B
glycosides O
. O

Antimicrobial O
N B
- I
halamine I
polymers O
and O
coatings O
: O
a O
review O
of O
their O
synthesis O
, O
characterization O
, O
and O
applications O
. O

Antimicrobial O
N B
- I
halamine I
polymers O
and O
coatings O
have O
been O
studied O
extensively O
over O
the O
past O
decade O
thanks O
to O
their O
numerous O
qualities O
such O
as O
effectiveness O
toward O
a O
broad O
spectrum O
of O
microorganisms O
, O
long O
- O
term O
stability O
, O
regenerability O
, O
safety O
to O
humans O
and O
environment O
and O
low O
cost O
. O

In O
this O
review O
, O
recent O
developments O
are O
described O
by O
emphasizing O
the O
synthesis O
of O
polymers O
and O
/ O
or O
coatings O
having O
N B
- I
halamine I
moieties O
. O

Actually O
, O
three O
main O
approaches O
of O
preparation O
are O
given O
in O
detail O
: O
polymerization O
, O
generation O
by O
electrochemical O
route O
with O
proteins O
as O
monomers O
and O
grafting O
with O
precursor O
monomers O
. O

Identification O
and O
characterization O
of O
the O
formation O
of O
the O
N B
- I
halamine I
bonds O
( O
> O
N B
- O
X O
with O
X O
= O
Cl B
or O
Br B
or O
I B
) O
by O
physical O
techniques O
such O
as O
Fourier O
transform O
infrared O
spectroscopy O
( O
FTIR O
) O
, O
nuclear O
magnetic O
resonance O
spectroscopy O
( O
NMR O
) O
, O
energy O
- O
dispersive O
X O
- O
ray O
spectroscopy O
( O
EDX O
) O
, O
X O
- O
ray O
photoelectron O
spectroscopy O
( O
XPS O
) O
, O
and O
by O
chemical O
reactions O
are O
described O
. O

In O
order O
to O
check O
the O
antimicrobial O
activity O
of O
the O
N B
- I
halamine I
compounds O
, O
bacterial O
tests O
are O
also O
described O
. O

Finally O
, O
some O
examples O
of O
application O
of O
these O
N B
- I
halamines I
in O
the O
water O
treatment O
, O
paints O
, O
healthcare O
equipment O
, O
and O
textile O
industries O
are O
presented O
and O
discussed O
. O

Hollow O
block O
copolymer O
nanoparticles O
through O
a O
spontaneous O
one O
- O
step O
structural O
reorganization O
. O

The O
spontaneous O
one O
- O
step O
synthesis O
of O
hollow O
nanocages O
and O
nanotubes O
from O
spherical O
and O
cylindrical O
micelles O
based O
on O
poly B
( I
acrylic I
acid I
) I
- I
b I
- O
polylactide B
( O
P B
( I
AA I
) I
- I
b I
- I
P I
( I
LA I
) I
) O
block O
copolymers O
( O
BCPs O
) O
has O
been O
achieved O
. O

This O
structural O
reorganization O
, O
which O
occurs O
simply O
upon O
drying O
of O
the O
samples O
, O
was O
elucidated O
by O
transmission O
electron O
microscopy O
( O
TEM O
) O
and O
atomic O
force O
microscopy O
( O
AFM O
) O
. O

We O
show O
that O
it O
was O
necessary O
to O
use O
stain O
- O
free O
imaging O
to O
examine O
these O
nanoscale O
assemblies O
, O
as O
the O
hollow O
nature O
of O
the O
particles O
was O
obscured O
by O
application O
of O
a O
heavy O
metal O
stain O
. O

Additionally O
, O
the O
internal O
topology O
of O
the O
P O
( O
AA O
) O
- O
b O
- O
P O
( O
LA O
) O
particles O
could O
be O
tuned O
by O
manipulating O
the O
drying O
conditions O
to O
give O
solid O
or O
compartmentalized O
structures O
. O

Upon O
resuspension O
, O
these O
reorganized O
nanoparticles O
retain O
their O
hollow O
structure O
and O
display O
significantly O
enhanced O
loading O
of O
a O
hydrophobic O
dye O
compared O
to O
the O
original O
solid O
cylinders O
. O

Photoelectrochemical O
properties O
of O
nanomultiple O
CaFe2O4 B
/ O
ZnFe2O4 B
pn B
junction O
photoelectrodes O
. O

Nanomultiple O
CaFe2O4 B
/ O
ZnFe2O4pn B
junctions O
are O
prepared O
by O
a O
pulsed O
laser O
deposition O
method O
to O
explore O
their O
photoelectrochemical O
properties O
as O
the O
photoelectrodes O
. O

It O
is O
demonstrated O
that O
the O
multiple O
- O
pn B
- O
junction O
structure O
is O
favorable O
to O
enhancing O
the O
photocurrent O
density O
and O
the O
onset O
potential O
of O
the O
photoelectrode O
. O

Furthermore O
, O
the O
20 O
- O
junction O
photoelectrode O
- O
based O
PEC O
cell O
yields O
a O
high O
open O
circuit O
photovoltage O
of O
up O
to O
0 O
. O
97 O
V O
, O
which O
is O
much O
higher O
than O
that O
for O
a O
single O
pn O
junction O
photoelectrode O
PEC O
cell O
that O
yields O
an O
open O
circuit O
photovoltage O
of O
0 O
. O
13 O
V O
. O

A O
multiple O
- O
junction O
band O
structure O
model O
is O
assumed O
to O
describe O
the O
behavior O
of O
the O
CaFe2O4 B
/ O
ZnFe2O4 B
multiple O
- O
junction O
photoelectrodes O
. O

It O
is O
suggested O
that O
the O
open O
circuit O
photovoltage O
is O
dominated O
by O
the O
number O
of O
pn O
junctions O
in O
a O
multiple O
- O
junction O
photoelectrode O
and O
the O
carrier O
transfer O
inside O
the O
photoelectrode O
is O
improved O
by O
narrowing O
the O
single O
- O
layer O
thickness O
. O

These O
findings O
provide O
a O
new O
approach O
to O
designing O
the O
multiple O
- O
junction O
structure O
to O
improve O
the O
PEC O
properties O
of O
the O
photoelectrodes O
. O

Preparation O
of O
novel O
porous O
starch O
microsphere O
foam O
for O
loading O
and O
release O
of O
poorly O
water O
soluble O
drug O
. O

Abstract O
Background O
: O
Organic O
porous O
material O
is O
a O
promising O
carrier O
for O
enhancing O
the O
dissolution O
of O
poorly O
water O
soluble O
drug O
. O

The O
aim O
of O
the O
present O
study O
was O
to O
enhance O
dissolution O
and O
oral O
bioavailability O
of O
lovastatin B
( O
LV O
) O
by O
preparing O
a O
porous O
starch O
microsphere O
foam O
( O
PSM O
) O
using O
a O
novel O
method O
, O
meanwhile O
, O
looking O
into O
the O
mechanism O
of O
improving O
dissolution O
of O
LV O
. O

Methods O
: O
PSM O
was O
prepared O
by O
the O
W O
/ O
O O
emulsion O
- O
freeze O
thawing O
method O
. O

The O
porous O
structure O
of O
PSM O
was O
characterized O
by O
scanning O
electron O
microscopy O
( O
SEM O
) O
and O
nitrogen B
adsorption O
/ O
desorption O
analysis O
. O

The O
adsorption O
role O
of O
nanopores O
on O
the O
drug O
dissolution O
and O
physical O
state O
of O
LV O
was O
systematically O
studied O
by O
instrumental O
analysis O
, O
and O
in O
vitro O
and O
in O
vivo O
drug O
dissolution O
studies O
. O

3 B
- I
( I
4 I
, I
5 I
- I
Dimethylthiazol I
- I
2 I
- I
yl I
) I
- I
2 I
, I
5 I
- I
diphenyltetrazolium I
bromide I
( O
MTT B
) O
assay O
was O
used O
to O
evaluate O
carrier O
cytotoxicity O
. O

Results O
: O
The O
SEM O
images O
of O
PSM O
showed O
nanometer O
- O
sized O
pores O
. O

Physical O
state O
characterization O
indicated O
that O
porous O
structure O
effectively O
limited O
the O
degree O
of O
crystallinity O
of O
LV O
. O

The O
results O
of O
in O
vitro O
and O
in O
vivo O
tests O
testified O
that O
PSM O
accelerated O
the O
release O
of O
LV O
and O
enhanced O
its O
oral O
bioavailability O
in O
comparison O
with O
crude O
LV O
and O
commercial O
capsules O
. O

The O
loaded O
PSM O
powder O
indicated O
a O
good O
physical O
stability O
under O
storage O
for O
12 O
months O
. O

MTT B
assay O
shows O
PSM O
has O
no O
toxicity O
for O
Caco O
- O
2 O
cell O
. O

Conclusion O
: O
The O
preparation O
was O
a O
promising O
method O
to O
produce O
small O
and O
uniform O
PSM O
with O
markedly O
enhanced O
dissolution O
rate O
and O
oral O
bioavailability O
due O
to O
the O
spatial O
confinement O
effect O
of O
porous O
structure O
. O

The O
present O
work O
demonstrates O
the O
significant O
potential O
for O
the O
use O
of O
PSM O
as O
a O
novel O
delivery O
system O
for O
poorly O
water O
soluble O
drugs O
. O

Different O
pharmacokinetics O
of O
the O
two O
structurally O
similar O
dammarane B
sapogenins O
, O
protopanaxatriol B
and O
protopanaxadiol B
, O
in O
rats O
. O

Dammarane B
Sapogenins O
( O
DS O
) O
, O
with O
main O
ingredients O
of O
protopanaxatriol B
( O
PPT B
, O
33 O
% O
) O
and O
protopanaxadiol B
( O
PPD B
, O
16 O
% O
) O
, O
is O
an O
alkaline O
hydrolyzed O
product O
of O
ginsenosides B
and O
had O
significant O
activities O
in O
improving O
learning O
and O
memory O
and O
decreasing O
chemotherapy O
- O
induced O
myelosuppression O
. O

In O
the O
present O
study O
, O
the O
pharmacokinetics O
and O
oral O
bioavailabilities O
of O
PPT O
and O
PPD B
were O
investigated O
when O
a O
single O
dose O
of O
DS O
was O
administrated O
orally O
( O
75mg O
/ O
kg O
) O
and O
intravenously O
( O
i O
. O
v O
. O
, O
30mg O
/ O
kg O
) O
to O
rats O
. O

Their O
in O
vitro O
stabilities O
in O
the O
GI O
tract O
were O
also O
investigated O
. O

PPT O
and O
PPD B
concentrations O
were O
measured O
by O
LC O
- O
MS O
. O

The O
results O
showed O
that O
PPT O
was O
eliminated O
rapidly O
from O
the O
body O
with O
an O
average O
t1 O
/ O
2 O
, O
lambda O
z O
value O
of O
0 O
. O
80h O
and O
CL O
of O
4 O
. O
27l O
/ O
h O
/ O
kg O
after O
i O
. O
v O
. O
administration O
, O
while O
PPD B
was O
eliminated O
relatively O
slowly O
with O
a O
t1 O
/ O
2 O
, O
lambda O
z O
of O
6 O
. O
25h O
and O
CL O
of O
0 O
. O
98l O
/ O
h O
/ O
kg O
. O

After O
oral O
administration O
, O
both O
PPD B
and O
PPT B
could O
be O
absorbed O
into O
the O
body O
, O
but O
their O
systemic O
exposures O
were O
quite O
different O
. O

PPT O
was O
absorbed O
into O
the O
body O
quickly O
, O
with O
a O
Tmax O
of O
0 O
. O
58h O
and O
a O
Cmax O
of O
0 O
. O
13 O
mu O
g O
/ O
ml O
, O
while O
PPD B
was O
absorbed O
relatively O
slowly O
with O
a O
Tmax O
of O
1 O
. O
82h O
and O
a O
Cmax O
of O
1 O
. O
04 O
mu O
g O
/ O
ml O
. O

The O
absolute O
bioavailabilities O
of O
PPT O
and O
PPD O
were O
estimated O
as O
3 O
. O
69 O
% O
and O
48 O
. O
12 O
% O
, O
respectively O
. O

The O
stability O
test O
found O
that O
PPT O
was O
instable O
in O
the O
stomach O
with O
40 O
% O
degradation O
after O
4h O
incubation O
at O
37 O
degrees O
C O
, O
both O
in O
pH1 O
. O
2 O
buffer O
and O
in O
the O
stomach O
content O
solution O
. O

The O
instability O
in O
the O
stomach O
might O
be O
one O
of O
the O
reasons O
for O
PPT O
' O
s O
poor O
bioavailability O
. O

Image O
- O
guided O
percutaneous O
ablation O
therapies O
for O
local O
recurrences O
of O
thyroid O
tumors O
. O

The O
incidence O
of O
thyroid O
carcinoma O
has O
increased O
steadily O
over O
the O
last O
few O
decades O
. O

Most O
differentiated O
thyroid O
carcinomas O
( O
DTC O
) O
are O
cured O
thanks O
to O
the O
initial O
treatment O
with O
surgery O
and O
radioiodine B
therapy O
. O

Nevertheless O
, O
neck O
lymph O
node O
metastases O
are O
found O
in O
a O
few O
of O
these O
patients O
during O
their O
long O
- O
term O
clinical O
and O
ultrasound O
follow O
- O
up O
. O

In O
some O
of O
these O
cases O
radioiodine B
treatment O
may O
not O
be O
effective O
in O
eradicating O
nodal O
metastases O
due O
to O
scant O
131 B
- I
I I
uptake O
. O

Additionally O
, O
a O
few O
of O
these O
patients O
undergo O
repeated O
neck O
explorations O
and O
/ O
or O
resections O
. O

Based O
on O
these O
considerations O
and O
on O
the O
frequently O
indolent O
course O
of O
DTC O
neck O
metastases O
, O
a O
non O
- O
surgical O
therapeutic O
approach O
should O
be O
considered O
to O
control O
small O
local O
foci O
of O
DTC O
. O

There O
is O
increasing O
interest O
in O
mini O
- O
invasive O
image O
- O
guided O
procedures O
that O
can O
be O
performed O
under O
local O
anesthesia O
which O
do O
not O
affect O
the O
performance O
status O
of O
the O
patient O
. O

Image O
- O
guided O
minimally O
invasive O
ablative O
therapies O
delivered O
by O
using O
needle O
- O
like O
applicators O
include O
both O
thermal O
and O
non O
- O
thermal O
source O
techniques O
. O

Over O
the O
past O
25 O
years O
, O
these O
therapies O
have O
gained O
widespread O
attention O
and O
, O
in O
many O
cases O
, O
broad O
clinical O
acceptance O
as O
methods O
for O
treating O
focal O
malignancies O
. O

In O
an O
attempt O
to O
overcome O
the O
limitations O
of O
treating O
certain O
unresectable O
tumor O
types O
not O
amenable O
to O
a O
further O
surgical O
treatment O
, O
a O
few O
investigators O
have O
reported O
successfully O
combining O
percutaneous O
therapies O
with O
other O
oncologic O
treatment O
strategies O
( O
combined O
treatments O
) O
. O

In O
this O
review O
, O
we O
reported O
mini O
- O
invasive O
techniques O
more O
commonly O
employed O
in O
selected O
cases O
to O
ameliorate O
local O
compressive O
symptoms O
, O
control O
hormonal O
production O
, O
and O
reduce O
the O
volume O
of O
neoplastic O
tissue O
prior O
to O
traditional O
palliative O
treatment O
. O

Impact O
of O
Baseline O
Insulin O
Regimen O
on O
Glycemic O
Response O
to O
a O
Group O
Medical O
Clinic O
Intervention O
. O

OBJECTIVEGroup O
medical O
clinics O
( O
GMC O
) O
combine O
medication O
management O
and O
self O
- O
management O
training O
, O
and O
may O
improve O
diabetes O
outcomes O
. O

It O
remains O
unclear O
which O
patients O
benefit O
most O
from O
GMC O
. O

This O
secondary O
analysis O
examined O
the O
impact O
of O
baseline O
insulin O
regimen O
on O
GMC O
response O
. O
RESEARCH O
DESIGN O
AND O
METHODSWe O
analyzed O
a O
trial O
of O
239 O
veterans O
with O
type O
2 O
diabetes O
randomized O
to O
GMC O
or O
usual O
care O
( O
UC O
) O
. O

We O
categorized O
baseline O
insulin O
regimen O
as O
the O
following O
: O
no O
insulin O
; O
basal O
insulin O
only O
; O
or O
complex O
insulin O
( O
basal O
- O
prandial O
or O
mixed O
regimens O
) O
. O

Using O
linear O
mixed O
models O
adjusted O
for O
clustering O
within O
GMC O
, O
we O
evaluated O
the O
differential O
impact O
of O
GMC O
relative O
to O
UC O
on O
hemoglobin O
A O
( O
1c O
) O
( O
HbA O
( O
1c O
) O
) O
and O
self O
- O
efficacy O
among O
patients O
on O
different O
baseline O
insulin O
regimens O
. O
RESULTSFrom O
linear O
mixed O
models O
, O
the O
effect O
of O
GMC O
on O
HbA O
( O
1c O
) O
differed O
by O
baseline O
insulin O
regimen O
versus O
UC O
( O
P O
= O
0 O
. O
05 O
) O
; O
there O
was O
no O
differential O
effect O
on O
self O
- O
efficacy O
( O
P O
= O
0 O
. O
29 O
) O
. O

Among O
those O
using O
complex O
insulin O
regimens O
at O
baseline O
, O
GMC O
reduced O
HbA O
( O
1c O
) O
by O
study O
end O
compared O
with O
UC O
( O
- O
1 O
. O
0 O
% O
; O
95 O
% O
CI O
- O
1 O
. O
8 O
to O
- O
0 O
. O
2 O
; O
P O
= O
0 O
. O
01 O
) O
. O

We O
found O
no O
such O
HbA O
( O
1c O
) O
difference O
between O
GMC O
and O
UC O
patients O
using O
no O
insulin O
( O
P O
= O
0 O
. O
65 O
) O
or O
basal O
insulin O
only O
( O
P O
= O
0 O
. O
71 O
) O
. O

There O
were O
no O
clinically O
significant O
differences O
in O
hypoglycemia O
by O
baseline O
insulin O
regimen O
and O
intervention O
group O
. O
CONCLUSIONSWe O
found O
that O
compared O
with O
UC O
, O
GMC O
lowered O
HbA O
( O
1c O
) O
specifically O
among O
patients O
using O
complex O
insulin O
regimens O
at O
study O
baseline O
, O
which O
may O
relate O
to O
this O
group O
' O
s O
demanding O
medication O
and O
self O
- O
management O
requirements O
. O

Implementing O
GMC O
among O
patients O
using O
complex O
insulin O
regimens O
may O
maximize O
this O
care O
delivery O
strategy O
' O
s O
potential O
. O

Polymer O
- O
coated O
echogenic O
lipid O
nanoparticles O
with O
dual O
release O
triggers O
. O

Although O
lipid O
nanoparticles O
are O
promising O
drug O
delivery O
vehicles O
, O
passive O
release O
of O
encapsulated O
contents O
at O
the O
target O
site O
is O
often O
slow O
. O

Herein O
, O
we O
report O
contents O
release O
from O
targeted O
, O
polymer O
- O
coated O
, O
echogenic O
lipid O
nanoparticles O
in O
the O
cell O
cytoplasm O
by O
redox O
trigger O
and O
simultaneously O
enhanced O
by O
diagnostic O
frequency O
ultrasound O
. O

The O
lipid O
nanoparticles O
were O
polymerized O
on O
the O
external O
leaflet O
using O
a O
disulfide B
cross O
- O
linker O
. O

In O
the O
presence O
of O
cytosolic O
concentrations O
of O
glutathione B
, O
the O
lipid O
nanoparticles O
released O
76 O
% O
of O
encapsulated O
contents O
. O

Plasma O
concentrations O
of O
glutathione B
failed O
to O
release O
the O
encapsulated O
contents O
. O

Application O
of O
3 O
MHz O
ultrasound O
for O
2 O
min O
simultaneously O
with O
the O
reducing O
agent O
enhanced O
the O
release O
to O
96 O
% O
. O

Folic B
acid I
conjugated O
, O
doxorubicin B
- O
loaded O
nanoparticles O
showed O
enhanced O
uptake O
and O
higher O
cytotoxicity O
in O
cancer O
cells O
overexpressing O
the O
folate B
receptor O
( O
compared O
to O
the O
control O
) O
. O

With O
further O
developments O
, O
these O
lipid O
nanoparticles O
have O
the O
potential O
to O
be O
used O
as O
multimodal O
nanocarriers O
for O
simultaneous O
targeted O
drug O
delivery O
and O
ultrasound O
imaging O
. O

Discovery O
of O
4 B
- I
{ I
4 I
- I
[ I
( I
3R I
) I
- I
3 I
- I
Methylmorpholin I
- I
4 I
- I
yl I
] I
- I
6 I
- I
[ I
1 I
- I
( I
methylsulfonyl I
) I
cyclopropyl I
] I
pyrimidin I
- I
2 I
- I
yl I
} I
- I
1H I
- I
indole I
( O
AZ20 B
) O
: O
a O
potent O
and O
selective O
inhibitor O
of O
ATR O
protein O
kinase O
with O
monotherapy O
in O
vivo O
antitumor O
activity O
. O

ATR O
is O
an O
attractive O
new O
anticancer O
drug O
target O
whose O
inhibitors O
have O
potential O
as O
chemo O
- O
or O
radiation O
sensitizers O
or O
as O
monotherapy O
in O
tumors O
addicted O
to O
particular O
DNA O
- O
repair O
pathways O
. O

We O
describe O
the O
discovery O
and O
synthesis O
of O
a O
series O
of O
sulfonylmorpholinopy B
that O
show O
potent O
and O
selective O
ATR O
inhibition O
. O

Optimization O
from O
a O
high O
quality O
screening O
hit O
within O
tight O
SAR O
space O
led O
to O
compound O
6 O
( O
AZ20 B
) O
which O
inhibits O
ATR O
immunoprecipitated O
from O
HeLa O
nuclear O
extracts O
with O
an O
IC50 O
of O
5 O
nM O
and O
ATR O
mediated O
phosphorylation O
of O
Chk1 O
in O
HT29 O
colorectal O
adenocarcinoma O
tumor O
cells O
with O
an O
IC50 O
of O
50 O
nM O
. O

Compound O
6 O
potently O
inhibits O
the O
growth O
of O
LoVo O
colorectal O
adenocarcinoma O
tumor O
cells O
in O
vitro O
and O
has O
high O
free O
exposure O
in O
mouse O
following O
moderate O
oral O
doses O
. O

At O
well O
tolerated O
doses O
6 O
leads O
to O
significant O
growth O
inhibition O
of O
LoVo O
xenografts O
grown O
in O
nude O
mice O
. O

Compound O
6 O
is O
a O
useful O
compound O
to O
explore O
ATR O
pharmacology O
in O
vivo O
. O

Surface O
structures O
of O
PDMS B
incorporated O
with O
quaternary B
ammonium I
salts I
designed O
for O
antibiofouling O
and O
fouling O
release O
applications O
. O

Poly B
( I
dimethylsiloxane I
) I
( O
PDMS B
) O
materials O
have O
been O
extensively O
shown O
to O
function O
as O
excellent O
fouling O
- O
release O
( O
FR O
) O
coatings O
in O
the O
marine O
environment O
. O

The O
incorporation O
of O
biocide O
moieties O
, O
such O
as O
quaternary B
ammonium I
salts I
( O
QAS B
) O
, O
can O
impart O
additional O
antibiofouling O
properties O
to O
PDMS B
- O
based O
FR O
coating O
systems O
. O

In O
this O
study O
, O
the O
molecular O
surface O
structures O
of O
two O
different O
types O
of O
QAS B
- O
incorporated O
PDMS B
systems O
were O
investigated O
in O
different O
chemical O
environments O
using O
sum O
frequency O
generation O
vibrational O
spectroscopy O
( O
SFG O
) O
. O

Specifically O
, O
a O
series O
of O
PDMS B
coatings O
containing O
either O
a O
QAS O
with O
a O
single O
ammonium B
salt O
group O
per O
molecule O
or O
a O
quaternary B
ammonium I
- O
functionalized O
polyhedral B
oligomeric I
silsesquioxane I
( O
Q B
- I
POSS I
) O
were O
measured O
with O
SFG O
in O
air O
, O
water O
, O
and O
artificial O
seawater O
( O
ASW O
) O
to O
investigate O
the O
relationships O
between O
the O
interfacial O
surface O
structures O
of O
these O
materials O
and O
their O
antifouling O
properties O
. O

Although O
previous O
studies O
have O
shown O
that O
the O
above O
- O
mentioned O
materials O
are O
promising O
contact O
- O
active O
antifouling O
coatings O
, O
slight O
variations O
of O
the O
QAS O
structure O
can O
lead O
to O
substantial O
differences O
in O
the O
antifouling O
performance O
. O

Indeed O
, O
the O
SFG O
results O
presented O
here O
indicated O
that O
the O
surface O
structures O
of O
these O
materials O
depend O
on O
several O
factors O
, O
such O
as O
the O
extent O
of O
quaternization O
, O
the O
molecular O
weight O
of O
the O
PDMS B
component O
, O
and O
the O
functional O
groups O
of O
the O
QAS B
used O
for O
incorporation O
into O
the O
PDMS B
matrix O
. O

It O
was O
concluded O
that O
in O
aqueous O
environments O
a O
lower O
extent O
of O
Q O
- O
POSS O
quaternization O
and O
the O
use O
of O
ethoxy B
( O
instead O
of O
methoxy B
) O
functional O
groups O
for O
QAS B
incorporation O
facilitated O
the O
extension O
of O
the O
alkyl O
chains O
away O
from O
the O
nitrogen B
atom O
of O
the O
QAS B
on O
the O
surface O
. O

The O
SFG O
results O
correlated O
well O
with O
the O
antifouling O
activity O
studies O
that O
indicated O
that O
the O
coatings O
exhibiting O
a O
lower O
concentration O
of O
longer O
alkyl O
chains O
protruding O
out O
of O
the O
surface O
can O
neutralize O
microorganisms O
more O
effectively O
, O
ultimately O
leading O
to O
better O
antifouling O
performance O
. O

Furthermore O
, O
the O
results O
of O
this O
study O
provide O
additional O
evidence O
that O
incorporated O
QAS O
exert O
their O
antimicrobial O
activity O
through O
a O
two O
- O
step O
interaction O
. O

The O
first O
step O
is O
the O
adsorption O
of O
the O
bacteria O
on O
the O
surface O
as O
a O
result O
of O
the O
electrostatic O
attraction O
between O
the O
negatively O
charged O
microorganisms O
and O
the O
positively O
charged O
QAS O
nitrogen B
atoms O
on O
the O
surface O
. O

The O
second O
step O
is O
the O
disruption O
of O
the O
cell O
membranes O
by O
the O
penetration O
of O
the O
QAS O
long O
, O
extended O
alkyl O
chains O
. O

Glargine O
safety O
, O
diabetes O
and O
cancer O
. O

INTRODUCTION O
: O
In O
2009 O
, O
several O
epidemiological O
studies O
suggested O
a O
higher O
frequency O
of O
malignancy O
in O
insulin O
glargine O
- O
treated O
patients O
. O

A O
number O
of O
follow O
- O
up O
epidemiological O
population O
studies O
as O
well O
as O
two O
randomized O
, O
controlled O
clinical O
studies O
, O
one O
a O
5000 O
- O
patient O
retinopathy O
study O
and O
the O
other O
a O
12 O
, O
000 O
- O
patient O
cardiovascular O
outcomes O
trial O
( O
ORIGIN O
) O
, O
found O
no O
higher O
frequency O
of O
malignancy O
in O
glargine O
- O
treated O
patients O
. O

AREAS O
COVERED O
: O
We O
reviewed O
the O
existing O
literature O
as O
well O
as O
U O
. O
S O
. O

FDA O
records O
to O
investigate O
the O
association O
of O
cancer O
, O
diabetes O
, O
and O
insulin O
. O

There O
is O
a O
20 O
- O
40 O
% O
higher O
incidence O
of O
malignancy O
in O
type O
2 O
diabetes O
patients O
. O

Certain O
cancers O
are O
more O
common O
, O
including O
hepatocellular O
and O
pancreatic O
carcinoma O
, O
colorectal O
cancer O
, O
renal O
cancer O
, O
and O
breast O
and O
endometrial O
cancer O
, O
and O
non O
- O
Hodgkin O
' O
s O
lymphoma O
. O

There O
are O
numerous O
inter O
- O
related O
factors O
which O
may O
promote O
both O
diabetes O
and O
malignancy O
, O
including O
dietary O
patterns O
, O
obesity O
, O
insulin O
resistance O
, O
and O
alcoholism O
. O

Patients O
who O
receive O
insulin O
treatment O
are O
typically O
older O
and O
" O
sicker O
" O
than O
those O
who O
receive O
oral O
agents O
. O

EXPERT O
OPINION O
: O
It O
is O
very O
difficult O
to O
prove O
causal O
associations O
between O
diabetes O
and O
cancer O
due O
to O
the O
host O
of O
confounding O
factors O
. O

The O
hypothesis O
that O
hyperinsulinemia O
and O
IGF O
- O
1 O
receptor O
activation O
promote O
cancer O
is O
strong O
, O
but O
confounded O
by O
the O
association O
of O
hyperinsulinemia O
with O
obesity O
, O
which O
separately O
promotes O
malignancy O
. O

Although O
statistical O
techniques O
to O
adjust O
for O
confounding O
variables O
can O
improve O
epidemiological O
comparisons O
, O
the O
lesson O
of O
the O
glargine O
cancer O
controversy O
is O
that O
controlled O
clinical O
trials O
are O
the O
only O
means O
to O
definitely O
prove O
hypotheses O
. O

Transforming O
drug O
discovery O
and O
development O
through O
innovation O
: O
past O
, O
present O
and O
future O
. O

This O
annual O
meeting O
began O
in O
1998 O
and O
was O
the O
first O
industry O
- O
led O
event O
to O
focus O
on O
the O
specific O
needs O
of O
industry O
researchers O
. O

The O
goal O
of O
Clinical O
and O
Pharmaceutical O
Solutions O
Through O
Analysis O
( O
CPSA O
) O
is O
to O
provide O
an O
in O
- O
depth O
review O
of O
innovative O
technology O
and O
industry O
practices O
through O
open O
discussion O
of O
industry O
- O
related O
issues O
and O
needs O
. O

Education O
and O
specialized O
training O
are O
the O
foundation O
of O
all O
CPSA O
events O
. O

As O
the O
industry O
has O
evolved O
so O
has O
CPSA O
. O

Thus O
, O
the O
year O
the O
name O
was O
changed O
from O
Chemical O
and O
Pharmaceutical O
Structural O
Analysis O
to O
CPSA O
was O
to O
reflect O
the O
growing O
focus O
on O
clinical O
applications O
and O
the O
emergence O
of O
personalized O
medicine O
. O

Most O
importantly O
, O
the O
CPSA O
annual O
meeting O
has O
retained O
the O
same O
high O
- O
quality O
scientific O
content O
, O
open O
interaction O
from O
industry O
opinion O
leaders O
and O
a O
collegial O
environment O
. O

Personalized O
medicine O
for O
targeted O
and O
platinum B
- O
based O
chemotherapy O
of O
lung O
and O
bladder O
cancer O
. O

The O
personalized O
medicine O
revolution O
is O
occurring O
for O
cancer O
chemotherapy O
. O

Biomarkers O
are O
increasingly O
capable O
of O
distinguishing O
genotypic O
or O
phenotypic O
traits O
of O
individual O
tumors O
, O
and O
are O
being O
linked O
to O
the O
selection O
of O
treatment O
protocols O
. O

This O
review O
covers O
the O
molecular O
basis O
for O
biomarkers O
of O
response O
to O
targeted O
and O
cytotoxic O
lung O
and O
bladder O
cancer O
treatment O
with O
an O
emphasis O
on O
platinum B
- O
based O
chemotherapy O
. O

Platinum B
derivatives O
are O
a O
class O
of O
drugs O
commonly O
employed O
against O
solid O
tumors O
that O
kill O
cells O
by O
covalent O
attachment O
to O
DNA O
. O

Platinum B
- O
DNA O
adduct O
levels O
in O
patient O
tissues O
have O
been O
correlated O
to O
response O
and O
survival O
. O

The O
sensitivity O
and O
precision O
of O
adduct O
detection O
has O
increased O
to O
the O
point O
of O
enabling O
subtherapeutic O
dosing O
for O
diagnostics O
applications O
, O
termed O
diagnostic O
microdosing O
, O
prior O
to O
the O
initiation O
of O
full O
- O
dose O
therapy O
. O

The O
clinical O
status O
of O
this O
unique O
phenotypic O
marker O
for O
lung O
and O
bladder O
cancer O
applications O
is O
detailed O
along O
with O
discussion O
of O
future O
applications O
. O

Fbxl10 O
/ O
Kdm2b O
recruits O
polycomb O
repressive O
complex O
1 O
to O
CpG O
islands O
and O
regulates O
H2A O
ubiquitylation O
. O

Polycomb O
repressive O
complex O
1 O
( O
PRC1 O
) O
catalyzes O
lysine B
119 O
monoubiquitylation O
on O
H2A O
( O
H2AK119ub1 O
) O
and O
regulates O
pluripotency O
in O
embryonic O
stem O
cells O
( O
ESCs O
) O
. O

However O
, O
the O
mechanisms O
controlling O
the O
binding O
of O
PRC1 O
to O
genomic O
sites O
and O
its O
catalytic O
activity O
are O
poorly O
understood O
. O

Here O
, O
we O
show O
that O
Fbxl10 O
interacts O
with O
Ring1B O
and O
Nspc1 O
, O
forming O
a O
noncanonical O
PRC1 O
that O
is O
required O
for O
H2AK119ub1 O
in O
mouse O
ESCs O
. O

Genome O
- O
wide O
analyses O
reveal O
that O
Fbxl10 O
preferentially O
binds O
to O
CpG O
islands O
and O
colocalizes O
with O
Ring1B O
on O
Polycomb O
target O
genes O
. O

Notably O
, O
Fbxl10 O
depletion O
causes O
a O
decrease O
in O
Ring1B O
binding O
to O
target O
genes O
and O
a O
major O
loss O
of O
H2AK119ub1 O
. O

Furthermore O
, O
genetic O
analyses O
demonstrate O
that O
Fbxl10 O
DNA O
binding O
capability O
and O
integration O
into O
PRC1 O
are O
required O
for O
H2AK119 O
ubiquitylation O
. O

ESCs O
lacking O
Fbxl10 O
, O
like O
previously O
characterized O
Polycomb O
mutants O
, O
cannot O
differentiate O
properly O
. O

These O
results O
demonstrate O
that O
Fbxl10 O
has O
a O
key O
role O
in O
regulating O
Ring1B O
recruitment O
to O
its O
target O
genes O
and O
H2AK119 O
ubiquitylation O
in O
ESCs O
. O

Uncoupling O
of O
endothelial O
NO B
synthase O
in O
atherosclerosis O
and O
vascular O
disease O
. O

Nitric B
oxide I
( O
NO B
) O
produced O
by O
the O
endothelial O
NO B
synthase O
( O
eNOS O
) O
is O
an O
antihypertensive O
, O
antithrombotic O
and O
anti O
- O
atherosclerotic O
molecule O
. O

Hypercholesterolemia O
leads O
to O
a O
reduction O
in O
vascular O
NO B
bioavailability O
. O

This O
is O
attributed O
to O
a O
dysfunction O
of O
the O
eNOS O
enzyme O
and O
a O
reduced O
eNOS O
activity O
. O

NADPH B
oxidase O
- O
mediated O
oxidative O
stress O
leads O
to O
oxidation O
of O
tetrahydrobiopterin B
( O
BH4 B
) O
, O
the O
essential O
cofactor O
of O
eNOS O
. O

In O
BH4 B
deficiency O
, O
oxygen B
reduction O
uncouples O
from O
NO B
synthesis O
, O
thereby O
converting O
eNOS O
to O
a O
superoxide B
- O
producing O
enzyme O
. O

As O
a O
consequence O
of O
eNOS O
uncoupling O
, O
NO B
production O
is O
reduced O
and O
the O
pre O
- O
existing O
oxidative O
stress O
is O
enhanced O
, O
which O
contribute O
significantly O
to O
atherogenesis O
. O

Therefore O
, O
pharmacological O
approaches O
that O
prevent O
eNOS O
uncoupling O
and O
enhance O
eNOS O
activity O
are O
of O
therapeutic O
interest O
. O

Angiotensin O
- O
converting O
enzyme O
inhibitors O
, O
AT1 O
receptor O
blockers O
, O
statins B
, O
nebivolol B
and O
resveratrol B
have O
been O
shown O
to O
reverse O
eNOS O
uncoupling O
and O
to O
stimulate O
eNOS O
activity O
concurrently O
. O

Molecular O
mechanisms O
of O
the O
aforementioned O
drugs O
/ O
compounds O
on O
eNOS O
functionality O
is O
summarized O
and O
discussed O
in O
this O
review O
. O

How O
sugar B
tunes O
your O
clock O
. O

While O
cellular O
circadian O
clocks O
are O
set O
by O
the O
light O
/ O
dark O
cycle O
, O
these O
clocks O
can O
be O
reset O
by O
what O
we O
eat O
. O

Two O
papers O
in O
this O
issue O
of O
Cell O
Metabolism O
reveal O
that O
O B
- O
GlcNAcylation O
of O
clock O
proteins O
, O
which O
is O
dependent O
on O
nutrients O
, O
adjusts O
our O
circadian O
clock O
( O
Kaasik O
et O
al O
. O
, O
2013 O
; O
Li O
et O
al O
. O
, O
2013 O
) O
. O

Synthesis O
and O
characterization O
of O
novel O
quick O
- O
release O
propofol B
prodrug O
via O
lactonization O
. O

The O
water O
- O
soluble O
derivatives O
of O
propofol B
have O
gained O
attention O
as O
a O
method O
to O
increase O
solubility O
of O
propofol B
. O

According O
to O
the O
principle O
of O
lactonization O
, O
the O
lead O
compound O
HX0969 B
was O
synthesized O
first O
and O
then O
the O
pharmacological O
features O
of O
HX0969 B
were O
evaluated O
in O
a O
comparison O
with O
those O
of O
propofol B
in O
the O
SD O
rats O
. O

Then O
, O
HX0969 B
disodium I
phosphate I
monoester I
( O
HX0969W B
) O
and O
glycine B
ester I
trifluoroacetic I
acid I
salt O
( O
HX101230 B
) O
were O
synthesized O
, O
and O
their O
pharmacological O
features O
were O
compared O
with O
those O
of O
Lusedra B
( O
R O
) O
, O
which O
has O
been O
recognized O
and O
marketed O
as O
a O
water O
- O
soluble O
prodrug O
of O
propofol B
since O
2008 O
. O

The O
results O
showed O
that O
HX0969 B
could O
produce O
an O
anesthetic O
effect O
within O
a O
few O
seconds O
( O
3 O
. O
6 O
+ O
/ O
- O
3 O
. O
0s O
) O
and O
its O
therapeutic O
index O
was O
4 O
. O
66 O
in O
the O
SD O
rat O
. O

The O
pharmacodynamic O
characteristics O
of O
HX0969W B
were O
similar O
to O
those O
of O
the O
Lusedra B
( O
R O
) O
. O

HX101230 B
could O
still O
produce O
an O
anesthetic O
effect O
within O
60s O
in O
the O
rats O
though O
its O
therapeutic O
index O
was O
not O
so O
high O
( O
TI O
= O
2 O
. O
96 O
) O
. O

Therefore O
, O
our O
study O
has O
indicated O
that O
HX0969 B
is O
a O
potentially O
useful O
lead O
compound O
of O
propofol B
derivative O
. O

Its O
rapid O
anesthetic O
effect O
is O
probably O
associated O
with O
lactonization O
. O

Chemical O
probes O
of O
a O
trisubstituted B
pyrrole I
to O
identify O
its O
protein O
target O
( O
s O
) O
in O
Plasmodium O
sporozoites O
. O

Malaria O
is O
a O
disease O
that O
has O
a O
major O
impact O
in O
many O
developing O
nations O
, O
especially O
on O
the O
African O
continent O
. O

There O
is O
a O
need O
to O
develop O
new O
therapeutics O
and O
prophylactic O
treatments O
against O
it O
. O

A O
trisubstituted B
pyrrole I
was O
recently O
found O
to O
inhibit O
infection O
of O
mammalian O
hepatocytes O
by O
Plasmodium O
sporozoites O
, O
but O
the O
target O
of O
this O
agent O
is O
not O
known O
. O

In O
this O
study O
trisubstituted B
pyrrole I
derivatives O
with O
different O
substituents O
on O
a O
piperidinyl B
nitrogen I
were O
prepared O
. O

We O
determined O
if O
modifications O
of O
the O
piperidinyl B
nitrogen B
would O
accommodate O
a O
drug O
- O
biotin B
linking O
strategy O
for O
affinity O
purification O
of O
the O
trisubstituted B
pyrrole I
' O
s O
target O
protein O
( O
s O
) O
. O

Growth O
factor O
delivery O
from O
hydrogel O
particle O
aggregates O
to O
promote O
tubular O
regeneration O
after O
acute O
kidney O
injury O
. O

Local O
delivery O
of O
growth O
factors O
( O
GFs O
) O
can O
accelerate O
regeneration O
of O
injured O
tissue O
, O
but O
for O
many O
medical O
applications O
, O
injectable O
GF O
delivery O
systems O
are O
required O
for O
clinical O
success O
. O

Viscoelastic O
, O
injectable O
aggregates O
of O
micrometer O
- O
sized O
hydrogel O
particles O
made O
of O
multiarmed O
polyethylene B
glycol I
( O
starPEG O
) O
and O
heparin O
were O
prepared O
and O
tested O
for O
site O
- O
specific O
paracrine O
stimulation O
of O
tissue O
regeneration O
. O

Heparin O
was O
used O
as O
it O
binds O
, O
protects O
and O
releases O
numerous O
GFs O
. O

Hydrogel O
based O
delivery O
of O
basic O
fibroblast O
growth O
factor O
( O
bFGF O
) O
and O
murine O
epidermal O
growth O
factor O
( O
EGF O
) O
was O
monitored O
utilizing O
enzyme O
- O
linked O
immunosorbent O
assay O
( O
ELISA O
) O
. O

bFGF O
was O
released O
slowly O
because O
of O
its O
high O
affinity O
to O
the O
heparin O
while O
the O
significantly O
higher O
release O
of O
the O
non O
- O
specific O
binding O
EGF O
was O
controlled O
by O
diffusion O
only O
. O

To O
investigate O
GF O
delivery O
in O
vivo O
, O
a O
hydrogel O
loaded O
with O
murine O
EGF O
or O
bFGF O
was O
injected O
subcapsularly O
into O
the O
left O
kidney O
of O
mice O
with O
experimental O
acute O
kidney O
injury O
caused O
by O
glycerol B
induced O
rhabdomyolysis O
. O

Visual O
examination O
confirmed O
sustained O
stability O
of O
the O
injected O
gel O
aggregates O
during O
the O
timescale O
of O
the O
experiment O
. O

The O
number O
of O
proliferating O
kidney O
tubular O
epithelial O
cells O
was O
quantified O
both O
in O
the O
injected O
kidney O
and O
the O
non O
- O
injected O
contralateral O
kidney O
. O

bFGF O
delivery O
from O
hydrogels O
induced O
a O
significant O
increase O
in O
cell O
proliferation O
in O
the O
injected O
kidney O
, O
although O
small O
effects O
were O
also O
seen O
in O
the O
non O
- O
injected O
kidney O
due O
to O
a O
systemic O
effect O
. O

EGF O
delivery O
strongly O
increased O
cell O
proliferation O
for O
both O
kidneys O
, O
but O
also O
showed O
a O
local O
effect O
on O
the O
injected O
kidney O
. O

The O
hydrogel O
without O
loaded O
GFs O
was O
used O
as O
a O
control O
and O
showed O
no O
increase O
in O
cell O
proliferation O
. O

Our O
results O
suggest O
that O
this O
novel O
starPEG O
- O
heparin O
hydrogel O
system O
can O
be O
an O
effective O
approach O
to O
deliver O
GFs O
locally O
. O

Ozonolysis O
efficiency O
and O
safety O
evaluation O
of O
aflatoxin B
B1 I
in O
peanuts O
. O

Ozonolysis O
efficiency O
of O
aflatoxin B
- O
contaminated O
peanuts O
( O
ACPs O
) O
was O
investigated O
, O
and O
the O
safety O
of O
ACPs O
untreated O
/ O
treated O
by O
ozone B
was O
evaluated O
after O
28 O
- O
day O
intragastrically O
administration O
in O
male O
and O
female O
Wistar O
rats O
. O

89 O
. O
40 O
% O
of O
aflatoxin B
B1 I
( O
AFB1 B
) O
in O
peanuts O
was O
decomposed O
by O
ozone B
with O
a O
concentration O
of O
50mg O
/ O
L O
, O
flow O
rate O
of O
5L O
/ O
min O
for O
60h O
. O

After O
60h O
, O
the O
ozonolysis O
efficiency O
of O
AFB1 B
was O
not O
further O
improved O
. O

In O
the O
subchronic O
toxicity O
experiment O
, O
all O
rats O
did O
not O
have O
unusual O
changes O
in O
behavior O
, O
and O
no O
signs O
of O
intoxication O
were O
observed O
except O
for O
several O
dead O
rats O
due O
to O
inappropriate O
gavage O
or O
anesthesia O
. O

The O
results O
of O
subchronic O
toxicity O
indicated O
that O
rats O
fed O
on O
ACPs O
alone O
had O
significantly O
decreased O
in O
body O
weight O
gain O
and O
feed O
conversion O
efficiency O
. O

Most O
serum O
biochemical O
indexes O
of O
rats O
had O
apparently O
changed O
compared O
with O
those O
in O
the O
negative O
control O
, O
and O
gender O
difference O
significantly O
affected O
most O
indexes O
of O
subchronic O
toxicity O
except O
for O
the O
ratios O
of O
organ O
to O
body O
weight O
and O
histopathological O
observation O
. O

Rats O
fed O
on O
ACPs O
treated O
by O
ozone B
showed O
significant O
beneficial O
health O
effects O
. O

All O
the O
results O
suggested O
that O
the O
deleterious O
effects O
of O
AFB1 B
could O
be O
highly O
reduced O
by O
ozone B
, O
and O
ozone B
itself O
did O
not O
show O
any O
toxic O
effects O
on O
animals O
in O
this O
processing O
. O

Elevation O
of O
4 B
- I
hydroxynonenal I
and O
malondialdehyde B
modified O
protein O
levels O
in O
cerebral O
cortex O
with O
cognitive O
dysfunction O
in O
rats O
exposed O
to O
1 B
- I
bromopropane I
. O

1 B
- I
Bromopropane I
( O
1 B
- I
BP I
) O
, O
an O
alternative O
to O
ozone B
- O
depleting O
solvents O
( O
ODS O
) O
, O
exhibits O
central O
nervous O
system O
( O
CNS O
) O
toxicity O
in O
animals O
and O
humans O
. O

This O
study O
was O
designed O
to O
relate O
CNS O
damage O
by O
Morris O
water O
maze O
( O
MWM O
) O
test O
and O
oxidative O
stress O
to O
1 B
- I
BP I
exposure O
in O
the O
rat O
. O

Male O
Wistar O
rats O
were O
randomly O
divided O
into O
4 O
groups O
( O
n O
= O
10 O
) O
, O
and O
treated O
with O
0 O
, O
200 O
, O
400 O
and O
800mg O
/ O
kgbw O
1 O
- O
BP O
for O
consecutive O
12 O
days O
, O
respectively O
. O

From O
day O
8 O
to O
day O
12 O
of O
the O
experiment O
, O
MWM O
test O
was O
employed O
to O
assess O
the O
cognitive O
function O
of O
rats O
. O

The O
cerebral O
cortex O
of O
rats O
was O
obtained O
immediately O
following O
the O
24h O
after O
MWM O
test O
conclusion O
. O

Glutathione B
( O
GSH B
) O
, O
oxidized B
glutathione I
( O
GSSG B
) O
and O
total O
thiol B
( O
total O
- O
SH B
) O
content O
, O
GSH B
reductase O
( O
GR O
) O
and O
GSH B
peroxidase O
( O
GSH B
- O
Px O
) O
activities O
, O
malondialdehyde B
( O
MDA B
) O
level O
, O
as O
well O
as O
4 B
- I
hydroxynonenal I
( O
4 B
- I
HNE I
) O
and O
MDA B
modified O
proteins O
in O
homogenates O
of O
cerebral O
cortex O
were O
measured O
. O

The O
obtained O
results O
showed O
that O
1 B
- I
BP I
led O
to O
cognitive O
dysfunction O
of O
rats O
, O
which O
was O
evidenced O
by O
delayed O
escape O
latency O
time O
and O
swimming O
distances O
in O
MWM O
performance O
. O

GSH B
and O
total O
- O
SH B
content O
, O
GSH B
/ O
GSSG B
ratio O
, O
GR O
activity O
significantly O
decreased O
in O
cerebral O
cortex O
of O
rats O
, O
coupling O
with O
the O
increase O
of O
MDA B
level O
. O

4 B
- I
HNE I
and O
MDA B
modified O
protein O
levels O
obviously O
elevated O
after O
1 B
- I
BP I
exposure O
. O

GSH B
- O
Px O
activities O
in O
cerebral O
cortex O
of O
rats O
also O
increased O
. O

These O
data O
suggested O
that O
1 B
- I
BP I
resulted O
in O
enhanced O
lipid O
peroxidation O
of O
brain O
, O
which O
might O
play O
an O
important O
role O
in O
CNS O
damage O
induced O
by O
1 B
- I
BP I
. O

RNA O
polymerase O
II O
acts O
as O
an O
RNA O
- O
dependent O
RNA O
polymerase O
to O
extend O
and O
destabilize O
a O
non O
- O
coding O
RNA O
. O

RNA O
polymerase O
II O
( O
Pol O
II O
) O
is O
a O
well O
- O
characterized O
DNA O
- O
dependent O
RNA O
polymerase O
, O
which O
has O
also O
been O
reported O
to O
have O
RNA O
- O
dependent O
RNA O
polymerase O
( O
RdRP O
) O
activity O
. O

Natural O
cellular O
RNA O
substrates O
of O
mammalian O
Pol O
II O
, O
however O
, O
have O
not O
been O
identified O
and O
the O
cellular O
function O
of O
the O
Pol O
II O
RdRP O
activity O
is O
unknown O
. O

We O
found O
that O
Pol O
II O
can O
use O
a O
non O
- O
coding O
RNA O
, O
B2 O
RNA O
, O
as O
both O
a O
substrate O
and O
a O
template O
for O
its O
RdRP O
activity O
. O

Pol O
II O
extends O
B2 O
RNA O
by O
18 O
nt O
on O
its O
3 O
' O
- O
end O
in O
an O
internally O
templated O
reaction O
. O

The O
RNA O
product O
resulting O
from O
extension O
of O
B2 O
RNA O
by O
the O
Pol O
II O
RdRP O
can O
be O
removed O
from O
Pol O
II O
by O
a O
factor O
present O
in O
nuclear O
extracts O
. O

Treatment O
of O
cells O
with O
alpha B
- I
amanitin I
or O
actinomycin B
D I
revealed O
that O
extension O
of O
B2 O
RNA O
by O
Pol O
II O
destabilizes O
the O
RNA O
. O

Our O
studies O
provide O
compelling O
evidence O
that O
mammalian O
Pol O
II O
acts O
as O
an O
RdRP O
to O
control O
the O
stability O
of O
a O
cellular O
RNA O
by O
extending O
its O
3 O
' O
- O
end O
. O

Effect O
of O
repeated O
dosing O
on O
rifampin B
exposure O
in O
BALB O
/ O
c O
mice O
. O

The O
discovery O
of O
novel O
therapeutics O
for O
the O
treatment O
of O
tuberculosis O
involves O
routine O
testing O
in O
a O
mouse O
model O
over O
four O
weeks O
of O
daily O
dosing O
with O
test O
compounds O
. O

In O
this O
model O
, O
daily O
oral O
administration O
of O
rifampin B
( O
10mg O
/ O
kg O
) O
showed O
significantly O
lower O
plasma O
exposure O
on O
day O
5 O
compared O
to O
day O
1 O
. O

The O
absence O
of O
PXR O
- O
mediated O
induction O
of O
mouse O
Cyp3a O
isoforms O
was O
confirmed O
in O
the O
present O
study O
by O
incubating O
liver O
microsomes O
prepared O
from O
control O
and O
rifampin B
treated O
mice O
with O
probe O
substrates O
of O
CYP3A O
. O

To O
test O
whether O
the O
reduction O
in O
exposure O
was O
due O
to O
Pgp O
- O
mediated O
efflux O
, O
verapamil B
, O
a O
known O
Pgp O
inhibitor O
, O
was O
dosed O
to O
the O
rifampin B
pre O
- O
treated O
mice O
which O
led O
to O
an O
increase O
in O
exposure O
to O
that O
obtained O
after O
a O
single O
dose O
of O
rifampin B
, O
suggesting O
the O
role O
of O
Pgp O
induction O
in O
reducing O
exposure O
to O
rifampin B
. O

To O
further O
confirm O
Pgp O
induction O
in O
rifampin B
treated O
mice O
, O
digoxin B
, O
a O
known O
substrate O
of O
Pgp O
, O
was O
administered O
to O
the O
rifampin B
pre O
- O
treated O
mice O
, O
and O
a O
significant O
drop O
in O
the O
digoxin B
exposure O
was O
observed O
compared O
to O
the O
control O
group O
. O

Collectively O
, O
our O
results O
show O
that O
repeated O
administration O
of O
rifampin B
in O
mice O
leads O
to O
a O
reduction O
in O
oral O
exposure O
due O
to O
induction O
of O
Pgp O
- O
mediated O
efflux O
of O
rifampin B
, O
and O
not O
via O
induction O
of O
CYP3A O
isoforms O
. O

Mini O
- O
review O
: O
Foldosome O
regulation O
of O
androgen B
receptor O
action O
in O
prostate O
cancer O
. O

Steroid B
hormone O
receptors O
play O
diverse O
roles O
in O
many O
aspects O
of O
human O
physiology O
including O
cell O
division O
, O
apoptosis O
and O
homeostasis O
, O
tissue O
differentiation O
, O
sexual O
development O
and O
response O
to O
stress O
. O

These O
ligand O
- O
activated O
transcription O
factors O
require O
the O
functional O
activity O
of O
numerous O
chaperone O
and O
chaperone O
- O
associated O
proteins O
, O
collectively O
termed O
the O
foldosome O
, O
at O
the O
crucial O
step O
of O
ligand O
recognition O
and O
binding O
. O

Since O
the O
initial O
isolation O
of O
foldosome O
components O
and O
pioneering O
research O
by O
Pratt O
, O
Toft O
and O
colleagues O
we O
understand O
much O
regarding O
cytosolic O
receptor O
function O
. O

The O
classical O
view O
, O
that O
the O
role O
of O
foldosome O
components O
is O
restricted O
to O
the O
cytosol O
, O
has O
been O
modified O
over O
recent O
years O
by O
research O
highlighting O
additional O
roles O
of O
chaperone O
proteins O
in O
nuclear O
translocation O
and O
target O
gene O
expression O
. O

Further O
, O
dysregulation O
of O
chaperone O
activity O
and O
expression O
has O
been O
implicated O
in O
various O
cancers O
, O
including O
breast O
and O
prostate O
cancer O
. O

Consequently O
, O
the O
foldosome O
provides O
an O
attractive O
therapeutic O
target O
in O
steroid B
hormone O
receptor O
- O
driven O
malignancies O
. O

This O
review O
summarises O
current O
knowledge O
of O
how O
the O
foldosome O
impacts O
upon O
androgen B
receptor O
signalling O
, O
which O
is O
the O
key O
therapeutic O
target O
on O
prostate O
cancer O
, O
and O
how O
foldosome O
components O
may O
be O
used O
as O
biomarkers O
or O
therapeutic O
targets O
in O
this O
disease O
. O

Interspecies O
extrapolation O
based O
on O
the O
RepDose O
database O
- O
- O
a O
probabilistic O
approach O
. O

Repeated O
dose O
toxicity O
studies O
from O
the O
RepDose O
database O
( O
DB O
) O
were O
used O
to O
determine O
interspecies O
differences O
for O
rats O
and O
mice O
. O

NOEL O
( O
no O
observed O
effect O
level O
) O
ratios O
based O
on O
systemic O
effects O
were O
investigated O
for O
three O
different O
types O
of O
exposure O
: O
inhalation O
, O
oral O
food O
/ O
drinking O
water O
and O
oral O
gavage O
. O

Furthermore O
, O
NOEL O
ratios O
for O
local O
effects O
in O
inhalation O
studies O
were O
evaluated O
. O

On O
the O
basis O
of O
the O
NOEL O
ratio O
distributions O
, O
interspecies O
assessment O
factors O
( O
AF O
) O
are O
evaluated O
. O

All O
data O
sets O
were O
best O
described O
by O
a O
lognormal O
distribution O
. O

No O
difference O
was O
seen O
between O
inhalation O
and O
oral O
exposure O
for O
systemic O
effects O
. O

Rats O
and O
mice O
were O
on O
average O
equally O
sensitive O
at O
equipotent O
doses O
with O
geometric O
mean O
( O
GM O
) O
values O
of O
1 O
and O
geometric O
standard O
deviation O
( O
GSD O
) O
values O
ranging O
from O
2 O
. O
30 O
to O
3 O
. O
08 O
. O

The O
local O
AF O
based O
on O
inhalation O
exposure O
resulted O
in O
a O
similar O
distribution O
with O
GM O
values O
of O
1 O
and O
GSD O
values O
between O
2 O
. O
53 O
and O
2 O
. O
70 O
. O

Our O
analysis O
confirms O
former O
analyses O
on O
interspecies O
differences O
, O
including O
also O
dog O
and O
human O
data O
. O

Furthermore O
it O
supports O
the O
principle O
of O
allometric O
scaling O
according O
to O
caloric O
demand O
in O
the O
case O
that O
body O
doses O
are O
applied O
. O

In O
conclusion O
, O
an O
interspecies O
distribution O
animal O
/ O
human O
with O
a O
GM O
equal O
to O
allometric O
scaling O
and O
a O
GSD O
of O
2 O
. O
5 O
was O
derived O
. O

Molecular O
dissection O
of O
botulinum O
neurotoxin O
reveals O
interdomain O
chaperone O
function O
. O

Clostridium O
botulinum O
neurotoxin O
( O
BoNT O
) O
is O
a O
multi O
- O
domain O
protein O
made O
up O
of O
the O
approximately O
100 O
kDa O
heavy O
chain O
( O
HC O
) O
and O
the O
approximately O
50 O
kDa O
light O
chain O
( O
LC O
) O
. O

The O
HC O
can O
be O
further O
subdivided O
into O
two O
halves O
: O
the O
N B
- O
terminal O
translocation O
domain O
( O
TD O
) O
and O
the O
C B
- O
terminal O
Receptor O
Binding O
Domain O
( O
RBD O
) O
. O

We O
have O
investigated O
the O
minimal O
requirements O
for O
channel O
activity O
and O
LC O
translocation O
. O

We O
utilize O
a O
cellular O
protection O
assay O
and O
a O
single O
channel O
/ O
single O
molecule O
LC O
translocation O
assay O
to O
characterize O
in O
real O
time O
the O
channel O
and O
chaperone O
activities O
of O
BoNT O
/ O
A O
truncation O
constructs O
in O
Neuro O
2A O
cells O
. O

The O
unstructured O
, O
elongated O
belt O
region O
of O
the O
TD O
is O
demonstrated O
to O
be O
dispensable O
for O
channel O
activity O
, O
although O
may O
be O
required O
for O
productive O
LC O
translocation O
. O

We O
show O
that O
the O
RBD O
is O
not O
necessary O
for O
channel O
activity O
or O
LC O
translocation O
, O
however O
it O
dictates O
the O
pH O
threshold O
of O
channel O
insertion O
into O
the O
membrane O
. O

These O
findings O
indicate O
that O
each O
domain O
functions O
as O
a O
chaperone O
for O
the O
others O
in O
addition O
to O
their O
individual O
functions O
, O
working O
in O
concert O
to O
achieve O
productive O
intoxication O
. O

Photochemical O
activation O
of O
TRPA1 O
channels O
in O
neurons O
and O
animals O
. O

Optogenetics O
is O
a O
powerful O
research O
tool O
because O
it O
enables O
high O
- O
resolution O
optical O
control O
of O
neuronal O
activity O
. O

However O
, O
current O
optogenetic O
approaches O
are O
limited O
to O
transgenic O
systems O
expressing O
microbial O
opsins O
and O
other O
exogenous O
photoreceptors O
. O

Here O
, O
we O
identify O
optovin O
, O
a O
small O
molecule O
that O
enables O
repeated O
photoactivation O
of O
motor O
behaviors O
in O
wild O
- O
type O
zebrafish O
and O
mice O
. O

To O
our O
surprise O
, O
optovin O
' O
s O
behavioral O
effects O
are O
not O
visually O
mediated O
. O

Rather O
, O
photodetection O
is O
performed O
by O
sensory O
neurons O
expressing O
the O
cation O
channel O
TRPA1 O
. O

TRPA1 O
is O
both O
necessary O
and O
sufficient O
for O
the O
optovin O
response O
. O

Optovin O
activates O
human O
TRPA1 O
via O
structure O
- O
dependent O
photochemical O
reactions O
with O
redox O
- O
sensitive O
cysteine O
residues O
. O

In O
animals O
with O
severed O
spinal O
cords O
, O
optovin O
treatment O
enables O
control O
of O
motor O
activity O
in O
the O
paralyzed O
extremities O
by O
localized O
illumination O
. O

These O
studies O
identify O
a O
light O
- O
based O
strategy O
for O
controlling O
endogenous O
TRPA1 O
receptors O
in O
vivo O
, O
with O
potential O
clinical O
and O
research O
applications O
in O
nontransgenic O
animals O
, O
including O
humans O
. O

Overcoming O
chemotherapy O
resistance O
of O
ovarian O
cancer O
cells O
by O
liposomal O
cisplatin B
: O
molecular O
mechanisms O
unveiled O
by O
gene O
expression O
profiling O
. O

Previously O
we O
reported O
that O
liposomal O
cisplatin B
( O
CDDP B
) O
overcomes O
CDDP B
resistance O
of O
ovarian O
A2780cis O
cancer O
cells O
( O
Krieger O
et O
al O
. O
, O
Int O
. O
J O
. O
Pharm O
. O
389 O
, O
2010 O
, O
10 O
- O
17 O
) O
. O

Here O
we O
find O
that O
the O
cytotoxic O
activity O
of O
liposomal O
CDDP B
is O
not O
associated O
with O
detectable O
DNA O
platination O
in O
resistant O
ovarian O
cancer O
cells O
. O

This O
suggests O
that O
the O
mode O
of O
action O
of O
liposomal O
CDDP B
is O
different O
from O
the O
free O
drug O
. O

To O
gain O
insight O
into O
mechanisms O
of O
liposomal O
CDDP B
activity O
, O
we O
performed O
a O
transcriptome O
analysis O
of O
untreated O
A2780cis O
cells O
, O
and O
A2780cis O
cells O
in O
response O
to O
exposure O
with O
IC50 O
values O
of O
free O
or O
liposomal O
CDDP B
. O

A O
process O
network O
analysis O
of O
upregulated O
genes O
showed O
that O
liposomal O
CDDP B
induced O
a O
highly O
different O
gene O
expression O
profile O
in O
comparison O
to O
the O
free O
drug O
. O

p53 O
was O
identified O
as O
a O
key O
player O
directing O
transcriptional O
responses O
to O
free O
or O
liposomal O
CDDP B
. O

The O
free O
drug O
induced O
expression O
of O
essential O
genes O
of O
the O
intrinsic O
( O
mitochondrial O
) O
apoptosis O
pathway O
( O
BAX O
, O
BID O
, O
CASP9 O
) O
most O
likely O
through O
p38MAPK O
activation O
. O

In O
contrast O
, O
liposomal O
CDDP B
induced O
expression O
of O
genes O
from O
DNA O
damage O
pathways O
and O
several O
genes O
of O
the O
extrinsic O
pathway O
of O
apoptosis O
( O
TNFRSF10B O
- O
DR5 O
, O
CD70 O
- O
TNFSF7 O
) O
. O

It O
thus O
appears O
that O
liposomal O
CDDP B
overcomes O
CDDP B
resistance O
by O
inducing O
DNA O
damage O
and O
in O
consequence O
programmed O
cell O
death O
by O
the O
extrinsic O
pathway O
. O

Predictions O
from O
gene O
expression O
data O
with O
respect O
to O
apoptosis O
activation O
were O
confirmed O
at O
the O
protein O
level O
by O
an O
apoptosis O
antibody O
array O
. O

This O
sheds O
new O
light O
on O
liposomal O
drug O
carrier O
approaches O
in O
cancer O
and O
suggests O
liposomal O
CDDP B
as O
promising O
strategy O
for O
the O
treatment O
of O
CDDP B
resistant O
ovarian O
carcinomas O
. O

Protective O
effect O
of O
Codium O
fragile O
against O
UVB O
- O
induced O
pro O
- O
inflammatory O
and O
oxidative O
damages O
in O
HaCaT O
cells O
and O
BALB O
/ O
c O
mice O
. O

Acute O
exposure O
to O
ultraviolet O
( O
UV O
) O
radiation O
causes O
pro O
- O
inflammatory O
responses O
via O
diverse O
mechanisms O
including O
oxidative O
stress O
. O

Codium O
fragile O
is O
a O
green O
alga O
of O
Codiales O
family O
and O
has O
been O
reported O
to O
exhibit O
anti O
- O
edema O
, O
anti O
- O
allergic O
, O
anti O
- O
protozoal O
and O
anti O
- O
mycobacterial O
activities O
. O

In O
this O
study O
, O
we O
have O
investigated O
a O
novel O
anti O
- O
inflammatory O
potential O
of O
C O
. O
fragile O
using O
in O
vitro O
cell O
culture O
as O
well O
as O
in O
vivo O
animal O
models O
. O

In O
HaCaT O
cells O
, O
buthanol B
and O
ethylacetate B
fractions O
of O
80 O
% O
methanol B
C O
. O
fragile O
extract O
( O
CFB O
or O
CFE O
) O
and O
a O
single O
compound O
, O
clerosterol B
( O
CLS O
) O
isolated O
from O
CFE O
attenuated O
UVB O
( O
60mJ O
/ O
cm O
( O
2 O
) O
) O
- O
induced O
cytotoxicity O
and O
reduced O
expression O
of O
pro O
- O
inflammatory O
proteins O
including O
cyclooxygenase O
- O
2 O
( O
COX O
- O
2 O
) O
, O
inducible O
nitric B
oxide I
synthase O
( O
iNOS O
) O
, O
and O
tumor O
necrosis O
factor O
- O
alpha O
( O
TNF O

- O
alpha O
) O
. O

Moreover O
, O
CFB O
, O
CFE O
and O
CLS O
effectively O
suppressed O
UVB O
- O
induced O
production O
of O
pro O
- O
inflammatory O
mediators O
such O
as O
prostaglandin B
E2 I
( O
PGE2 B
) O
and O
nitric B
oxide I
( O
NO B
) O
. O

In O
another O
experiment O
, O
topical O
application O
of O
CFB O
, O
CFE O
or O
CLS O
prior O
to O
UVB O
irradiation O
( O
200mJ O
/ O
cm O
( O
2 O
) O
) O
on O
BALB O
/ O
c O
mice O
, O
inhibited O
the O
UVB O
- O
elevated O
protein O
levels O
of O
COX O
- O
2 O
, O
iNOS O
, O
and O
TNF O
- O
alpha O
. O

Furthermore O
, O
CFB O
, O
CFE O
and O
CLS O
suppressed O
oxidative O
damages O
caused O
by O
UVB O
irradiation O
for O
example O
lipid O
peroxidation O
and O
/ O
or O
protein O
carbonylation O
, O
which O
seemed O
to O
be O
mediated O
by O
up O
- O
regulation O
of O
antioxidant O
defense O
enzymes O
. O

These O
results O
suggest O
that O
C O
. O
fragile O
could O
be O
an O
effective O
therapeutic O
agent O
providing O
protection O
against O
UVB O
- O
induced O
inflammatory O
and O
oxidative O
skin O
damages O
. O

Involvement O
of O
organic O
anion O
- O
transporting O
polypeptides O
in O
the O
hepatic O
uptake O
of O
dioscin B
in O
rats O
and O
humans O
. O

The O
objective O
of O
this O
study O
was O
to O
clarify O
the O
mechanism O
underlying O
hepatic O
uptake O
of O
dioscin B
( O
diosgenyl B
2 I
, I
4 I
- I
di I
- I
O I
- I
a I
- I
L I
- I
rhamnopyranosyl I
- I
p I
- I
D I
- I
glucopyranoside I
) O
, O
an O
herbal O
ingredient O
with O
antihepatitis O
activity O
, O
in O
rats O
and O
humans O
. O

The O
liver O
uptake O
index O
( O
LUI O
) O
in O
vivo O
, O
perfused O
rat O
liver O
in O
situ O
, O
rat O
liver O
slices O
, O
isolated O
rat O
hepatocytes O
, O
and O
human O
organic O
anion O
- O
transporting O
polypeptide O
( O
OATP O
) O
- O
transfected O
cells O
in O
vitro O
were O
used O
to O
evaluate O
hepatic O
uptake O
of O
dioscin B
. O

Values O
of O
11 O
. O
9 O
% O
+ O
/ O
- O
1 O
. O
6 O
% O
and O
15 O
. O
0 O
% O
+ O
/ O
- O
0 O
. O
9 O
% O
of O
dose O
for O
uptake O
of O
dioscin B
were O
observed O
by O
LUI O
in O
vivo O
and O
perfused O
rat O
livers O
in O
situ O
, O
respectively O
. O

The O
time O
course O
of O
dioscin B
uptake O
by O
rat O
liver O
slices O
was O
temperature O
- O
dependent O
. O

Uptake O
of O
dioscin B
by O
rat O
liver O
slices O
and O
isolated O
rat O
hepatocytes O
was O
inhibited O
significantly O
by O
Oatp O
modulators O
, O
such O
as O
ibuprofen B
( O
Oatp1a1 O
inhibitor O
) O
, O
digoxin B
( O
Oatp1a4 O
substrate O
) O
, O
and O
glycyrrhizic B
acid I
( O
Oatp1b2 O
inhibitor O
) O
, O
but O
not O
by O
TEA B
or O
p B
- I
aminohippurate I
. O

Uptake O
of O
dioscin B
in O
rat O
hepatocytes O
and O
OATP1B3 O
- O
human O
embryonic O
kidney O
( O
HEK O
) O
293 O
cells O
indicated O
a O
saturable O
process O
with O
a O
Km O
of O
3 O
. O
75 O
+ O
/ O
- O
0 O
. O
51 O
mu O
M O
and O
2 O
. O
08 O
+ O
/ O
- O
0 O
. O
27 O
mu O
M O
, O
respectively O
. O

( B
- I
) I
- I
Epigallocatechin I
gallate I
, O
cyclosporin B
A I
, O
rifampicin B
, O
and O
telmisartan B
inhibited O
transport O
of O
dioscin B
in O
OATP1B3 O
- O
HEK293 O
cells O
. O

However O
, O
transcellular O
transport O
of O
dioscin B
in O
OATP1B1 O
- O
or O
OATP1B1 O
/ O
multidrug O
resistance O
- O
associated O
protein O
2 O
- O
Madin O
- O
Darby O
canine O
kidney O
strain O
II O
cells O
was O
not O
observed O
. O

These O
results O
indicate O
that O
hepatic O
uptake O
of O
dioscin B
is O
involved O
in O
OATP1B3 O
in O
humans O
, O
and O
multiple O
Oatps O
might O
participate O
in O
this O
process O
in O
rats O
. O

Study O
of O
PcaV O
from O
Streptomyces O
coelicolor O
yields O
new O
insights O
into O
ligand O
- O
responsive O
MarR O
family O
transcription O
factors O
. O

MarR O
family O
proteins O
constitute O
a O
group O
of O
> O
12 O
000 O
transcriptional O
regulators O
encoded O
in O
bacterial O
and O
archaeal O
genomes O
that O
control O
gene O
expression O
in O
metabolism O
, O
stress O
responses O
, O
virulence O
and O
multi O
- O
drug O
resistance O
. O

There O
is O
much O
interest O
in O
defining O
the O
molecular O
mechanism O
by O
which O
ligand O
binding O
attenuates O
the O
DNA O
- O
binding O
activities O
of O
these O
proteins O
. O

Here O
, O
we O
describe O
how O
PcaV O
, O
a O
MarR O
family O
regulator O
in O
Streptomyces O
coelicolor O
, O
controls O
transcription O
of O
genes O
encoding O
beta B
- I
ketoadipate I
pathway O
enzymes O
through O
its O
interaction O
with O
the O
pathway O
substrate O
, O
protocatechuate B
. O

This O
transcriptional O
repressor O
is O
the O
only O
MarR O
protein O
known O
to O
regulate O
this O
essential O
pathway O
for O
aromatic O
catabolism O
. O

In O
in O
vitro O
assays O
, O
protocatechuate B
and O
other O
phenolic B
compounds O
disrupt O
the O
PcaV B
- O
DNA O
complex O
. O

We O
show O
that O
PcaV B
binds O
protocatechuate B
in O
a O
1 O
: O
1 O
stoichiometry O
with O
the O
highest O
affinity O
of O
any O
MarR O
family O
member O
. O

Moreover O
, O
we O
report O
structures O
of O
PcaV B
in O
its O
apo O
form O
and O
in O
complex O
with O
protocatechuate B
. O

We O
identify O
an O
arginine B
residue O
that O
is O
critical O
for O
ligand O
coordination O
and O
demonstrate O
that O
it O
is O
also O
required O
for O
binding O
DNA O
. O

We O
propose O
that O
interaction O
of O
ligand O
with O
this O
arginine B
residue O
dictates O
conformational O
changes O
that O
modulate O
DNA O
binding O
. O

Our O
results O
provide O
new O
insights O
into O
the O
molecular O
mechanism O
by O
which O
ligands O
attenuate O
DNA O
binding O
in O
this O
large O
family O
of O
transcription O
factors O
. O

Arylamine B
organic O
dyes O
for O
dye O
- O
sensitized O
solar O
cells O
. O

Arylamine B
organic O
dyes O
with O
donor O
( O
D O
) O
, O
pi O
- O
bridge O
( O
pi O
) O
and O
acceptor O
( O
A O
) O
moieties O
for O
dye O
- O
sensitized O
solar O
cells O
( O
DSCs O
) O
have O
received O
great O
attention O
in O
the O
last O
decade O
because O
of O
their O
high O
molar O
absorption O
coefficient O
, O
low O
cost O
and O
structural O
variety O
. O

In O
the O
early O
stages O
, O
the O
efficiency O
of O
DSCs O
with O
arylamine B
organic O
dyes O
with O
D O
- O
pi O
- O
A O
character O
was O
far O
behind O
that O
of O
DSCs O
with O
ruthenium B
( I
II I
) I
complexes O
partly O
due O
to O
the O
lack O
of O
information O
about O
the O
relationship O
between O
the O
chemical O
structures O
and O
the O
photovoltaic O
performance O
. O

However O
, O
exciting O
progress O
has O
been O
recently O
made O
, O
and O
power O
conversion O
efficiencies O
over O
10 O
% O
were O
obtained O
for O
DSCs O
with O
arylamine B
organic O
dyes O
. O

It O
is O
thus O
that O
the O
recent O
research O
and O
development O
in O
the O
field O
of O
arylamine B
organic O
dyes O
employing O
an O
iodide B
/ O
triiodide B
redox O
couple O
or O
polypyridyl B
cobalt I
redox O
shuttles O
as O
the O
electrolytes O
for O
either O
DSCs O
or O
solid O
- O
state O
DSCs O
has O
been O
summarized O
. O

The O
cell O
performance O
of O
the O
arylamine B
organic O
dyes O
are O
compared O
, O
providing O
a O
comprehensive O
overview O
of O
arylamine B
organic O
dyes O
, O
demonstrating O
the O
advantages O
/ O
disadvantages O
of O
each O
class O
, O
and O
pointing O
out O
the O
field O
that O
needs O
to O
reinforce O
the O
research O
direction O
in O
the O
further O
application O
of O
DSCs O
. O

Impaired O
cliff O
avoidance O
reaction O
in O
dopamine B
transporter O
knockout O
mice O
. O

RATIONALE O
: O
Impulsivity O
is O
a O
key O
feature O
of O
disorders O
that O
include O
attention O
- O
deficit O
/ O
hyperactivity O
disorder O
( O
ADHD O
) O
. O

The O
cliff O
avoidance O
reaction O
( O
CAR O
) O
assesses O
maladaptive O
impulsive O
rodent O
behavior O
. O

Dopamine B
transporter O
knockout O
( O
DAT O
- O
KO O
) O
mice O
display O
features O
of O
ADHD O
and O
are O
candidates O
in O
which O
to O
test O
other O
impulsive O
phenotypes O
. O

OBJECTIVES O
: O
Impulsivity O
of O
DAT O
- O
KO O
mice O
was O
assessed O
in O
the O
CAR O
paradigm O
. O

For O
comparison O
, O
attentional O
deficits O
were O
also O
assessed O
in O
prepulse O
inhibition O
( O
PPI O
) O
in O
which O
DAT O
- O
KO O
mice O
have O
been O
shown O
to O
exhibit O
impaired O
sensorimotor O
gating O
. O

RESULTS O
: O
DAT O
- O
KO O
mice O
exhibited O
a O
profound O
CAR O
impairment O
compared O
to O
wild O
- O
type O
( O
WT O
) O
mice O
. O

As O
expected O
, O
DAT O
- O
KO O
mice O
showed O
PPI O
deficits O
compared O
to O
WT O
mice O
. O

Furthermore O
, O
the O
DAT O
- O
KO O
mice O
with O
the O
most O
impaired O
CAR O
exhibited O
the O
most O
severe O
PPI O
deficits O
. O

Treatment O
with O
methylphenidate B
or O
nisoxetine B
ameliorated O
CAR O
impairments O
in O
DAT O
- O
KO O
mice O
. O

CONCLUSION O
: O
These O
results O
suggest O
that O
DAT O
- O
KO O
mice O
exhibit O
impulsive O
CAR O
behavior O
that O
correlates O
with O
their O
PPI O
deficits O
. O

Blockade O
of O
monoamine B
transporters O
, O
especially O
the O
norepinephrine B
transporter O
( O
NET O
) O
in O
the O
prefrontal O
cortex O
( O
PFC O
) O
, O
may O
contribute O
to O
pharmacological O
improvement O
of O
impulsivity O
in O
these O
mice O
. O

The O
atypical O
antipsychotic O
risperidone B
reverses O
the O
recognition O
memory O
deficits O
induced O
by O
post O
- O
weaning O
social O
isolation O
in O
rats O
. O

RATIONALE O
: O
Rearing O
rats O
in O
isolation O
from O
weaning O
is O
an O
established O
preclinical O
neurodevelopmental O
model O
which O
induces O
behavioural O
deficits O
with O
apparent O
translational O
relevance O
to O
some O
core O
symptoms O
of O
schizophrenia O
. O

OBJECTIVE O
: O
This O
study O
evaluated O
the O
ability O
of O
the O
atypical O
antipsychotic O
risperidone B
to O
reverse O
behavioural O
deficits O
induced O
by O
post O
- O
weaning O
social O
isolation O
of O
rat O
pups O
and O
to O
further O
characterise O
the O
predictive O
validity O
of O
this O
model O
. O

METHOD O
: O
Forty O
- O
five O
male O
Lister O
hooded O
rats O
were O
housed O
in O
groups O
of O
3 O
- O
4 O
( O
n O
= O
16 O
) O
or O
singly O
( O
n O
= O
29 O
) O
for O
4 O
weeks O
immediately O
after O
weaning O
on O
postnatal O
day O
( O
PND O
) O
22 O
- O
24 O
. O

On O
PND O
51 O
, O
novel O
cage O
- O
induced O
locomotor O
activity O
( O
LMA O
) O
was O
assessed O
to O
subdivide O
rats O
into O
groups O
balanced O
for O
behavioural O
response O
. O

On O
PNDs O
58 O
, O
59 O
, O
65 O
and O
72 O
, O
rats O
received O
either O
vehicle O
( O
1 O
ml O
/ O
kg O
; O
i O
. O
p O
. O
) O
or O
risperidone B
( O
0 O
. O
2 O
or O
0 O
. O
5 O
mg O
/ O
kg O
; O
i O
. O
p O
. O
) O
30 O
min O
prior O
to O
testing O
in O
LMA O
, O
novel O
object O
discrimination O
( O
NOD O
) O
, O
prepulse O
inhibition O
( O
PPI O
) O
of O
acoustic O
startle O
and O
conditioned O
emotional O
response O
( O
CER O
) O
learning O
paradigms O
, O
respectively O
. O

RESULTS O
: O
Isolation O
rearing O
had O
no O
effect O
on O
PPI O
, O
but O
produced O
LMA O
hyperactivity O
and O
impaired O
NOD O
and O
CER O
compared O
to O
group O
- O
housed O
controls O
. O

Risperidone B
caused O
a O
dose O
- O
dependent O
reduction O
in O
LMA O
, O
irrespective O
of O
rearing O
condition O
, O
but O
selectively O
reversed O
the O
NOD O
deficit O
in O
isolation O
- O
reared O
rats O
. O

Risperidone B
did O
not O
reverse O
the O
isolation O
rearing O
- O
induced O
CER O
deficit O
. O

CONCLUSIONS O
: O
Similar O
to O
its O
clinical O
profile O
, O
risperidone B
only O
partially O
reverses O
the O
schizophrenic O
symptomology O
; O
since O
it O
reversed O
some O
, O
but O
not O
all O
, O
of O
the O
learning O
and O
memory O
deficits O
induced O
by O
post O
- O
weaning O
isolation O
, O
the O
isolation O
rearing O
model O
may O
be O
useful O
to O
predict O
antipsychotic O
activity O
of O
novel O
therapeutic O
agents O
. O

Impaired O
function O
of O
prejunctional O
adenosine B
A1 O
receptors O
expressed O
by O
perivascular O
sympathetic O
nerves O
in O
DOCA B
- O
salt O
hypertensive O
rats O
. O

Increased O
sympathetic O
nervous O
system O
activity O
contributes O
to O
deoxycorticosterone B
acetate I
( O
DOCA B
) O
- O
salt O
hypertension O
in O
rats O
. O

ATP B
and O
norepinephrine B
( O
NE O
) O
are O
coreleased O
from O
perivascular O
sympathetic O
nerves O
. O

NE O
acts O
at O
prejunctional O
alpha O
2 O
- O
adrenergic O
receptors O
( O
alpha O
2ARs O
) O
to O
inhibit O
NE O
release O
, O
and O
alpha O
2AR O
function O
is O
impaired O
in O
DOCA B
- O
salt O
rats O
. O

Adenosine B
, O
an O
enzymatic O
ATP B
degradation O
product O
, O
acts O
at O
prejunctional O
A1 O
adenosine B
receptors O
( O
A1Rs O
) O
to O
inhibit O
NE O
release O
. O

We O
tested O
the O
hypothesis O
that O
prejunctional O
A1R O
function O
is O
impaired O
in O
sympathetic O
nerves O
supplying O
mesenteric O
arteries O
( O
MAs O
) O
and O
veins O
( O
MVs O
) O
of O
DOCA B
- O
salt O
rats O
. O

Electrically O
evoked O
NE O
release O
and O
constrictions O
of O
blood O
vessels O
were O
studied O
in O
vitro O
with O
use O
of O
amperometry O
to O
measure O
NE O
oxidation O
currents O
and O
video O
microscopy O
, O
respectively O
. O

Immunohistochemical O
methods O
were O
used O
to O
localize O
tyrosine B
hydroxylase O
( O
TH O
) O
and O
A1Rs O
in O
perivascular O
sympathetic O
nerves O
. O

TH O
and O
A1Rs O
colocalized O
to O
perivascular O
sympathetic O
nerves O
. O

Adenosine B
and O
N B
( I
6 I
) I
- I
cyclopentyl I
- I
adenosine I
( O
CPA B
, O
A1R O
agonist O
) O
constricted O
MVs O
but O
not O
MAs O
. O

Adenosine B
and O
CPA B
( O
0 O
. O
001 O
- O
10 O
micro O
M O
) O
inhibited O
neurogenic O
constrictions O
and O
NE O
release O
in O
MAs O
and O
MVs O
. O

DOCA B
- O
salt O
arteries O
were O
resistant O
to O
adenosine B
and O
CPA B
- O
mediated O
inhibition O
of O
NE O
release O
and O
constriction O
. O

The O
A2A O
adenosine B
receptor O
agonist O
CGS21680 B
( O
C23H29N7O6 B
. I
HCl I
. I
xH2O I
) O
( O
0 O
. O
001 O
- O
0 O
. O
1 O
mu O
M O
) O
did O
not O
alter O
NE O
oxidation O
currents O
. O

We O
conclude O
that O
there O
are O
prejunctional O
A1Rs O
in O
arteries O
and O
both O
pre O
- O
and O
postjunctional O
A1Rs O
in O
veins O
; O
thus O
, O
adenosine B
selectively O
constricts O
the O
veins O
. O

Prejunctional O
A1R O
function O
is O
impaired O
in O
arteries O
, O
but O
not O
veins O
, O
from O
DOCA B
- O
salt O
rats O
. O

Sympathetic O
autoreceptor O
dysfunction O
is O
not O
specific O
to O
alpha O
2ARs O
, O
but O
there O
is O
a O
more O
general O
disruption O
of O
prejunctional O
mechanisms O
controlling O
sympathetic O
neurotransmitter O
release O
in O
DOCA B
- O
salt O
hypertension O
. O

Temperature O
Effects O
of O
Sputtering O
of O
Langmuir O
- O
Blodgett O
Multilayers O
. O

Time O
- O
of O
- O
flight O
secondary O
ion O
mass O
spectrometry O
( O
TOF O
- O
SIMS O
) O
and O
atomic O
force O
microscopy O
( O
AFM O
) O
are O
employed O
to O
characterize O
a O
wedge O
- O
shaped O
crater O
eroded O
by O
a O
40 O
keV O
C B
( I
60 I
) I
( I
+ I
) I
cluster O
ion O
beam O
on O
an O
organic O
thin O
film O
of O
402 O
nm O
of O
barium B
arachidate I
( O
AA O
) O
multilayers O
prepared O
by O
the O
Langmuir O
- O
Blodgett O
( O
LB O
) O
technique O
. O

Sample O
cooling O
to O
90 O
K O
was O
used O
to O
help O
reduce O
chemical O
damage O
, O
improve O
depth O
resolution O
and O
maintain O
constant O
erosion O
rate O
during O
depth O
profiling O
. O

The O
film O
was O
characterized O
at O
90 O
K O
, O
135 O
K O
, O
165 O
K O
, O
205 O
K O
, O
265 O
K O
and O
300 O
K O
. O

It O
is O
shown O
that O
sample O
cooling O
to O
205 O
K O
or O
lower O
helps O
to O
inhibit O
erosion O
rate O
decay O
, O
whereas O
at O
300 O
K O
and O
265 O
K O
the O
erosion O
rate O
continues O
to O
drop O
after O
250 O
nm O
of O
erosion O
, O
reaching O
about O
half O
of O
the O
initial O
value O
after O
removal O
of O
the O
entire O
film O
. O

Depth O
profiles O
are O
acquired O
from O
the O
SIMS O
images O
of O
the O
eroded O
wedge O
crater O
. O

The O
results O
suggest O
that O
sample O
cooling O
only O
slightly O
improves O
the O
altered O
layer O
thickness O
, O
but O
eliminates O
the O
decrease O
in O
erosion O
rate O
observed O
above O
265 O
K O
. O

Lipid O
Efflux O
Mediated O
by O
Alkylphospholipids B
in O
HepG2 O
Cells O
. O

Antitumoural O
alkylphospholipid B
( O
APL O
) O
analogues O
alter O
cholesterol B
homoeostasis O
in O
HepG2 O
cells O
by O
interfering O
with O
cholesterol B
transport O
from O
the O
plasma O
membrane O
to O
the O
endoplasmic O
reticulum O
( O
ER O
) O
and O
at O
the O
same O
time O
stimulating O
the O
release O
of O
considerable O
quantities O
of O
membrane O
cholesterol B
. O

The O
capacity O
of O
APLs O
to O
stimulate O
cholesterol B
efflux O
is O
suppressed O
when O
cells O
are O
incubated O
simultaneously O
with O
APLs O
and O
serum O
whilst O
the O
inhibition O
of O
cholesterol B
transport O
to O
the O
ER O
( O
measured O
in O
terms O
of O
the O
synthesis O
of O
esterified O
cholesterol B
) O
persists O
, O
indicating O
that O
both O
effects O
are O
independent O
of O
each O
other O
. O

Interestingly O
, O
our O
results O
suggest O
that O
both O
raft O
and O
non O
- O
raft O
membrane O
domains O
contribute O
to O
the O
cholesterol B
released O
to O
APLs O
. O

In O
addition O
, O
a O
marked O
efflux O
of O
choline B
- O
bearing O
phospholipids O
( O
phosphatidylcholine B
( O
PC O
) O
and O
sphingomyelins B
( O
SM O
) O
) O
was O
found O
to O
be O
related O
to O
this O
release O
of O
cholesterol B
. O

Finally O
, O
we O
observed O
that O
APL O
micelles O
composed O
of O
cholesterol B
might O
act O
as O
donor O
/ O
acceptor O
cholesterol B
systems O
. O

Thus O
, O
the O
findings O
of O
this O
study O
clearly O
demonstrate O
that O
antitumoural O
APLs O
act O
as O
extracellular O
acceptors O
, O
stimulating O
cholesterol B
and O
phospholipid O
efflux O
, O
although O
they O
may O
also O
play O
a O
role O
as O
cholesterol B
donors O
. O

Prolactin O
and O
sex O
steroids B
levels O
in O
congenital O
lifetime O
isolated O
GH O
deficiency O
. O

Growth O
hormone O
( O
GH O
) O
and O
prolactin O
share O
similarities O
in O
structure O
and O
function O
. O

We O
have O
previously O
shown O
that O
women O
with O
congenital O
isolated O
GH O
deficiency O
( O
IGHD O
) O
caused O
by O
a O
homozygous O
mutation O
in O
the O
GHRH O
receptor O
gene O
( O
GHRHR O
) O
( O
MUT O
/ O
MUT O
) O
have O
a O
short O
reproductive O
life O
, O
with O
anticipated O
climacteric O
. O

At O
climacteric O
, O
they O
have O
lower O
prolactin O
levels O
than O
normal O
controls O
( O
N O
/ O
N O
) O
. O

Because O
they O
are O
able O
to O
breast O
feed O
, O
we O
hypothesized O
that O
this O
prolactin O
reduction O
is O
limited O
to O
climacteric O
, O
as O
result O
of O
lower O
estradiol B
exposure O
of O
the O
lactotrophs O
. O

The O
purposes O
of O
this O
work O
were O
to O
assess O
prolactin O
levels O
in O
broader O
age O
adults O
homozygous O
and O
heterozygous O
( O
MUT O
/ O
N O
) O
for O
the O
mutation O
and O
in O
normal O
controls O
( O
N O
/ O
N O
) O
, O
and O
to O
correlate O
them O
to O
sex O
steroids B
levels O
. O

We O
enrolled O
24 O
GH O
- O
na O
i O
ve O
MUT O
/ O
MUT O
( O
12 O
female O
) O
, O
25 O
MUT O
/ O
N O
( O
14 O
female O
) O
, O
and O
25 O
N O
/ O
N O
( O
11 O
female O
) O
subjects O
, O
aged O
25 O
- O
65 O
years O
. O

Anthropometric O
data O
and O
serum O
prolactin O
, O
estradiol B
, O
total O
testosterone B
, O
and O
sex O
hormone O
binding O
globulin O
( O
SHBG O
) O
were O
measured O
. O

Free O
testosterone B
was O
calculated O
. O

Prolactin O
levels O
were O
similar O
in O
the O
three O
groups O
. O

In O
males O
, O
testosterone B
and O
SHBG O
levels O
were O
higher O
in O
MUT O
/ O
MUT O
in O
comparison O
to O
N O
/ O
N O
. O

There O
was O
no O
difference O
in O
free O
testosterone B
among O
groups O
. O

In O
all O
74 O
individuals O
, O
prolactin O
correlated O
inversely O
with O
age O
( O
p O
< O
0 O
. O
0001 O
) O
and O
directly O
with O
serum O
estradiol B
( O
p O
= O
0 O
. O
018 O
) O
. O

Prolactin O
levels O
in O
subjects O
with O
IGHD O
due O
to O
a O
homozygous O
GHRHR O
mutation O
are O
similar O
to O
heterozygous O
and O
normal O
homozygous O
, O
but O
total O
testosterone B
and O
SHBG O
are O
higher O
in O
male O
MUT O
/ O
MUT O
, O
with O
no O
difference O
in O
free O
testosterone B
. O

The O
reduced O
prolactin O
level O
is O
limited O
to O
climacteric O
period O
, O
possibly O
due O
to O
reduced O
estrogen B
exposure O
. O

Lithium B
/ O
sulfur B
batteries O
with O
high O
specific O
energy O
: O
old O
challenges O
and O
new O
opportunities O
. O

In O
this O
review O
, O
we O
begin O
with O
a O
brief O
discussion O
of O
the O
operating O
principles O
and O
scientific O
/ O
technical O
challenges O
faced O
by O
the O
development O
of O
lithium B
/ O
sulfur B
cells O
. O

We O
then O
introduce O
some O
recent O
progress O
in O
exploring O
cathodes O
, O
anodes O
, O
and O
electrolytes O
for O
lithium B
/ O
sulfur B
cells O
. O

In O
particular O
, O
several O
effective O
strategies O
used O
to O
enhance O
energy O
/ O
power O
density O
, O
obtain O
good O
efficiencies O
, O
and O
prolong O
cycle O
life O
will O
be O
highlighted O
. O

We O
also O
discuss O
recent O
advancements O
in O
techniques O
for O
investigating O
electrode O
reactions O
in O
real O
time O
and O
monitoring O
structural O
/ O
morphological O
changes O
of O
electrode O
materials O
under O
cell O
operating O
conditions O
to O
gain O
a O
better O
understanding O
of O
the O
mechanistic O
details O
of O
electrode O
processes O
. O

Finally O
, O
the O
opportunities O
and O
perspective O
for O
future O
research O
directions O
will O
be O
discussed O
. O

Monitoring O
of O
deiodinase O
deficiency O
based O
on O
transcriptomic O
responses O
in O
SH O
- O
SY5Y O
cells O
. O

Iodothyronine O
deiodinase O
types O
I O
, O
II O
, O
and O
III O
( O
D1 O
, O
D2 O
, O
and O
D3 O
, O
respectively O
) O
, O
which O
constitute O
a O
family O
of O
selenoenzymes O
, O
activate O
and O
inactivate O
thyroid O
hormones O
through O
the O
removal O
of O
specific O
iodine B
moieties O
from O
thyroxine B
and O
its O
derivatives O
. O

These O
enzymes O
are O
important O
in O
the O
biological O
effects O
mediated O
by O
thyroid O
hormones O
. O

The O
expression O
of O
activating O
and O
inactivating O
deiodinases O
plays O
a O
critical O
role O
in O
a O
number O
of O
cell O
systems O
, O
including O
the O
neuronal O
system O
, O
during O
development O
as O
well O
as O
in O
adult O
vertebrates O
. O

To O
investigate O
deiodinase O
- O
disrupting O
chemicals O
based O
on O
transcriptomic O
responses O
, O
we O
examined O
differences O
in O
gene O
expression O
profiles O
between O
T3 O
- O
treated O
and O
deiodinase O
- O
knockdown O
SH O
- O
SY5Y O
cells O
using O
microarray O
analysis O
and O
quantitative O
real O
- O
time O
RT O
- O
PCR O
. O

A O
total O
of O
1 O
, O
558 O
genes O
, O
consisting O
of O
755 O
upregulated O
and O
803 O
downregulated O
genes O
, O
were O
differentially O
expressed O
between O
the O
T3 O
- O
treated O
and O
deiodinase O
- O
knockdown O
cells O
. O

The O
expression O
levels O
of O
10 O
of O
these O
genes O
( O
ID2 O
, O
ID3 O
, O
CCL2 O
, O
TBX3 O
, O
TGOLN2 O
, O
C1orf71 O
, O
ZNF676 O
, O
GULP1 O
, O
KLF9 O
, O
and O
ITGB5 O
) O
were O
altered O
by O
deiodinase O
- O
disrupting O
chemicals O
( O
2 B
, I
3 I
, I
7 I
, I
8 I
- I
tetrachlorodibenzo I
- I
p I
- I
dioxin I
, O
polychlorinated B
biphenyls I
, O
propylthiouracil B
, O
iodoacetic B
acid I
, O
methylmercury B
, O
beta B
- I
estradiol I

, O
methimazole B
, O
3 B
- I
methylcholanthrene I
, O
aminotriazole B
, O
amiodarone B
, O
cadmium B
chloride I
, O
dimethoate B
, O
fenvalerate B
, O
octylmethoxycinnamat B
, O
iopanoic B
acid I
, O
methoxychlor B
, O
and O
4 B
- I
methylbenzylidene I
- I
camphor I
) O
. O

These O
genes O
are O
potential O
biomarkers O
for O
detecting O
deiodinase O
deficiency O
and O
predicting O
their O
effects O
on O
thyroid O
hormone O
production O
. O

Treatment O
of O
pretibial O
myxedema O
with O
dexamethazone B
injected O
subcutaneously O
by O
mesotherapy O
needles O
. O

Pretibial O
myxedema O
( O
PTM O
) O
is O
a O
rare O
extrathyroidal O
manifestation O
of O
Graves O
' O
disease O
that O
requires O
treatment O
when O
the O
clinical O
picture O
is O
markedly O
evident O
. O

In O
addition O
to O
topical O
treatment O
with O
steroid B
ointments O
, O
there O
have O
been O
previous O
reports O
of O
subcutaneous O
injections O
of O
steroids B
. O

This O
procedure O
may O
cause O
nodular O
degeneration O
of O
the O
skin O
due O
to O
fat O
atrophy O
when O
standard O
needles O
are O
used O
. O

In O
the O
present O
study O
, O
we O
have O
tried O
a O
novel O
modality O
of O
treatment O
of O
PTM B
by O
injecting O
a O
solution O
of O
dexamethasone B
in O
the O
subcutaneous O
tissue O
using O
needles O
employed O
for O
mesotherapy O
. O

These O
needles O
are O
< O
= O
4 O
mm O
long O
and O
deliver O
the O
medication O
within O
the O
dermis O
or O
the O
first O
layer O
of O
the O
subcutaneous O
fat O
. O

We O
have O
treated O
five O
patients O
, O
four O
with O
diffuse O
and O
one O
with O
elephanthiasic O
PTM B
. O

We O
utilized O
multiple O
injections O
of O
a O
solution O
of O
dexamethasone B
, O
lidocaine B
, O
and O
saline O
in O
the O
PTM B
plaque O
and O
in O
the O
pretibial O
area O
, O
both O
in O
the O
PTM B
plaque O
and O
in O
the O
area O
surrounding O
the O
lesions O
, O
once O
a O
week O
for O
three O
consecutive O
weeks O
. O

Two O
patients O
with O
a O
more O
severe O
form O
of O
PTM B
underwent O
another O
two O
cycles O
four O
to O
six O
weeks O
after O
initial O
treatment O
. O

Patients O
were O
studied O
before O
and O
after O
treatment O
by O
clinical O
assessment O
and O
ultrasound O
of O
the O
pretibial O
skin O
. O

The O
treatment O
was O
well O
- O
tolerated O
, O
with O
only O
moderate O
pain O
upon O
injection O
of O
the O
solution O
. O

One O
month O
after O
treatment O
, O
all O
patients O
showed O
improvement O
of O
PTM O
at O
clinical O
assessment O
and O
a O
reduction O
of O
the O
thickness O
of O
the O
lesions O
at O
ultrasound O
of O
~ O
15 O
% O
, O
involving O
mostly O
the O
dermis O
. O

Moreover O
, O
all O
patients O
reported O
amelioration O
of O
the O
leg O
appearance O
. O

The O
present O
study O
, O
although O
preliminary O
, O
shows O
that O
intralesion O
steroid O
injection O
with O
mesotherapy O
needles O
in O
PTM B
is O
effective O
and O
well O
tolerated O
, O
and O
does O
not O
cause O
undesired O
long O
- O
term O
modifications O
of O
the O
skin O
. O

More O
studies O
are O
warranted O
to O
standardize O
such O
treatment O
in O
larger O
groups O
of O
patients O
. O

Predicting O
temperature O
- O
dependent O
solid O
vapor O
pressures O
of O
explosives O
and O
related O
compounds O
using O
a O
quantum O
mechanical O
continuum O
solvation O
model O
. O

Temperature O
- O
dependent O
vapor O
pressures O
of O
solid O
explosives O
and O
their O
byproducts O
are O
calculated O
to O
an O
accuracy O
of O
0 O
. O
32 O
log O
units O
using O
a O
modified O
form O
of O
the O
conductor O
- O
like O
screening O
model O
for O
real O
solvents O
( O
COSMO O
- O
RS O
) O
. O

Accurate O
predictions O
for O
solids O
within O
COSMO O
- O
RS O
require O
correction O
for O
the O
free O
energy O
of O
fusion O
as O
well O
as O
other O
effects O
such O
as O
van O
der O
Waals O
interactions O
. O

Limited O
experimental O
data O
on O
explosives O
is O
available O
to O
determine O
these O
corrections O
, O
and O
thus O
we O
have O
extended O
the O
COSMO O
- O
RS O
model O
by O
introducing O
a O
quantitative O
structure O
- O
property O
relationship O
to O
estimate O
a O
lumped O
correction O
factor O
using O
only O
information O
from O
standard O
quantum O
chemistry O
calculations O
. O

This O
modification O
improves O
the O
COSMO O
- O
RS O
estimate O
of O
ambient O
vapor O
pressure O
by O
more O
than O
1 O
order O
of O
magnitude O
for O
a O
range O
of O
nitrogen B
- O
rich O
explosives O
and O
their O
derivatives O
, O
bringing O
the O
theoretical O
predictions O
to O
within O
typical O
experimental O
error O
bars O
for O
vapor O
pressure O
measurements O
. O

The O
estimated O
temperature O
dependence O
of O
these O
vapor O
pressures O
also O
agrees O
well O
with O
available O
experimental O
data O
, O
which O
is O
particularly O
important O
for O
estimating O
environmental O
transport O
and O
gas O
evolution O
for O
buried O
explosives O
or O
environmentally O
contaminated O
locations O
. O

This O
technique O
is O
then O
used O
to O
predict O
vapor O
pressures O
for O
a O
number O
of O
explosives O
and O
degradation O
products O
for O
which O
experimental O
data O
is O
not O
readily O
available O
. O

Inductive O
tuning O
of O
Fano O
- O
resonant O
metasurfaces O
using O
plasmonic O
response O
of O
graphene B
in O
the O
mid O
- O
infrared O
. O

Graphene B
is O
widely O
known O
for O
its O
anomalously O
strong O
broadband O
optical O
absorptivity O
of O
2 O
. O
3 O
% O
that O
enables O
seeing O
its O
single O
- O
atom O
layer O
with O
the O
naked O
eye O
. O

However O
, O
in O
the O
mid O
- O
infrared O
part O
of O
the O
spectrum O
graphene B
represents O
a O
quintessential O
lossless O
zero O
- O
volume O
plasmonic O
material O
. O

We O
experimentally O
demonstrate O
that O
, O
when O
integrated O
with O
Fano O
- O
resonant O
plasmonic O
metasurfaces O
, O
single O
- O
layer O
graphene B
( O
SLG O
) O
can O
be O
used O
to O
tune O
their O
mid O
- O
infrared O
optical O
response O
. O

SLG O
' O
s O
plasmonic O
response O
is O
shown O
to O
induce O
large O
blue O
shifts O
of O
the O
metasurface O
' O
s O
resonance O
without O
reducing O
its O
spectral O
sharpness O
. O

This O
effect O
is O
explained O
by O
a O
generalized O
perturbation O
theory O
of O
SLG O
- O
metamaterial O
interaction O
that O
accounts O
for O
two O
unique O
properties O
of O
the O
SLG O
that O
set O
it O
apart O
from O
all O
other O
plasmonic O
materials O
: O
its O
anisotropic O
response O
and O
zero O
volume O
. O

These O
results O
pave O
the O
way O
to O
using O
gated O
SLG O
as O
a O
platform O
for O
dynamical O
spectral O
tuning O
of O
infrared O
metamaterials O
and O
metasurfaces O
. O

SiO2 B
@ O
Au B
core O
- O
shell O
nanospheres O
self O
- O
assemble O
to O
form O
colloidal O
crystals O
that O
can O
be O
sintered O
and O
surface O
modified O
to O
produce O
pH O
- O
controlled O
membranes O
. O

We O
prepared O
colloidal O
crystals O
by O
self O
- O
assembly O
of O
gold O
- O
coated O
silica B
nanospheres O
, O
and O
free O
- O
standing O
nanoporous O
membranes O
by O
sintering O
these O
colloidal O
crystals O
. O

We O
modified O
the O
nanopore O
surface O
with O
ionizable O
functional O
groups O
, O
by O
forming O
a O
monolayer O
of O
L B
- I
cysteine I
or O
by O
surface O
- O
initiated O
polymerization O
of O
methacrylic B
acid I
. O

Diffusion O
experiments O
for O
the O
cationic O
dye O
Rhodamine B
B I
through O
L B
- I
cysteine I
- O
modified O
membranes O
showed O
a O
decrease O
in O
flux O
upon O
addition O
of O
an O
acid O
due O
to O
the O
nanopore O
surface O
becoming O
positively O
charged O
. O

Diffusion O
experiments O
for O
the O
neutral O
dye O
, O
ferrocenecarboxaldeh B
, O
through O
the O
PMAA B
- O
modified O
membranes O
showed O
a O
13 O
- O
fold O
increase O
in O
flux O
upon O
addition O
of O
an O
acid O
resulting O
from O
the O
protonated O
polymer O
collapsing O
onto O
the O
nanopore O
surface O
leading O
to O
larger O
pore O
size O
. O

Our O
results O
demonstrate O
that O
SiO2 B
@ O
Au B
core O
- O
shell O
nanospheres O
can O
self O
- O
assemble O
into O
colloidal O
crystals O
and O
that O
transport O
through O
the O
corresponding O
surface O
- O
modified O
Au B
- O
coated O
colloidal O
membranes O
can O
be O
controlled O
by O
pH O
. O

Mexican O
antidiabetic O
herbs O
: O
valuable O
sources O
of O
inhibitors O
of O
alpha O
- O
glucosidases O
. O

Type O
II O
- O
diabetes O
mellitus O
( O
TII O
- O
DM O
) O
has O
been O
regarded O
as O
one O
of O
the O
most O
important O
public O
health O
problems O
in O
all O
nations O
in O
the O
21st O
century O
. O

Although O
allopathic O
therapies O
remain O
the O
most O
important O
for O
the O
initial O
management O
of O
TII O
- O
DM O
, O
herbal O
remedies O
have O
gained O
wide O
acceptance O
for O
treating O
this O
condition O
. O

These O
alternative O
therapies O
are O
particularly O
valued O
in O
countries O
such O
as O
Mexico O
, O
rich O
in O
medicinal O
plants O
strongly O
attached O
to O
the O
cultural O
values O
of O
the O
population O
. O

Medicinal O
plants O
are O
prized O
sources O
of O
alpha O
- O
glucosidase O
inhibitors O
, O
which O
delay O
the O
liberation O
of O
glucose B
from O
complex O
carbohydrates B
, O
retarding O
glucose B
absorption O
, O
and O
thus O
controlling O
the O
characteristic O
hyperglycemia O
of O
TII O
- O
DM O
. O

Among O
the O
plant O
species O
used O
for O
treating O
diabetes O
in O
Mexico O
only O
38 O
have O
been O
analyzed O
for O
their O
inhibitory O
activity O
of O
alpha O
- O
glucosidases O
. O

Most O
of O
these O
studies O
, O
reviewed O
in O
the O
present O
work O
, O
have O
focused O
on O
the O
evaluation O
of O
different O
types O
of O
extracts O
on O
the O
activity O
of O
alpha O
- O
glucosidases O
from O
diverse O
sources O
. O

Four O
species O
have O
been O
thoroughly O
analyzed O
in O
order O
to O
discover O
novel O
alpha O
- O
glucosidase O
inhibitors O
, O
namely O
, O
Hintonia O
latiflora O
and O
Hintonia O
standleyana O
( O
Rubiaceae O
) O
, O
Ligusticum O
porteri O
( O
Apiaceae O
) O
, O
and O
Brickellia O
cavanillesii O
( O
Asteraceae O
) O
. O

Their O
ethnomedical O
uses O
, O
pharmacological O
and O
toxicological O
studies O
, O
chemical O
composition O
, O
and O
antihyperglycemic O
principles O
with O
alpha O
- O
glucosidase O
inhibitory O
activity O
are O
summarized O
. O

Lessons O
in O
microcapsule O
assembly O
from O
imaging O
delivery O
of O
a O
bioluminescent O
enzyme O
. O

Layer O
- O
by O
- O
layer O
assembled O
microcapsules O
have O
potential O
applications O
as O
delivery O
and O
biosensing O
systems O
, O
which O
make O
them O
attractive O
tools O
for O
use O
in O
various O
aspects O
of O
nanomedicine O
. O

We O
examined O
the O
effect O
of O
microcapsule O
location O
on O
activity O
of O
the O
bioluminescent O
enzyme O
luciferase O
in O
both O
intact O
capsules O
and O
following O
cell O
uptake O
. O

In O
intact O
capsules O
, O
the O
rate O
of O
reaction O
of O
luciferase O
was O
greatest O
for O
luciferase O
in O
the O
outer O
layer O
and O
least O
in O
the O
core O
. O

Following O
cell O
uptake O
, O
luciferase O
in O
the O
outer O
layer O
was O
rapidly O
reactive O
, O
and O
a O
similar O
rate O
of O
reaction O
and O
activity O
was O
observed O
for O
luciferase O
placed O
in O
capsule O
interior O
( O
core O
) O
. O

By O
contrast O
, O
there O
was O
minimal O
activity O
detected O
when O
microcapsules O
with O
luciferase O
sandwiched O
between O
polyelectrolytes O
in O
a O
middle O
layer O
were O
delivered O
to O
cells O
. O

This O
study O
informs O
us O
of O
the O
availability O
of O
bioactive O
molecules O
located O
in O
different O
positions O
within O
microcapsules O
and O
will O
enable O
better O
microcapsule O
construction O
in O
line O
with O
the O
intended O
application O
, O
particularly O
delivery O
of O
functional O
proteins O
to O
cells O
. O

Magnetoelectric O
control O
of O
superparamagnetism O
. O

Here O
we O
demonstrate O
electric O
- O
field O
induced O
magnetic O
anisotropy O
in O
a O
multiferroic O
composite O
containing O
nickel B
nanocrystals O
strain O
coupled O
to O
a O
piezoelectric O
substrate O
. O

This O
system O
can O
be O
switched O
between O
a O
superparamagnetic O
state O
and O
a O
single O
- O
domain O
ferromagnetic O
state O
at O
room O
temperature O
. O

The O
nanocrystals O
show O
a O
shift O
in O
the O
blocking O
temperature O
of O
40 O
K O
upon O
electric O
poling O
. O

We O
believe O
this O
is O
the O
first O
example O
of O
a O
system O
where O
an O
electric O
field O
can O
be O
used O
to O
switch O
on O
and O
off O
a O
permanent O
magnetic O
moment O
. O

Daily O
physical O
activity O
assessment O
with O
accelerometers O
: O
new O
insights O
and O
validation O
studies O
. O

The O
field O
of O
application O
of O
accelerometry O
is O
diverse O
and O
ever O
expanding O
. O

Because O
by O
definition O
all O
physical O
activities O
lead O
to O
energy O
expenditure O
, O
the O
doubly O
labelled O
water O
( O
DLW O
) O
method O
as O
gold O
standard O
to O
assess O
total O
energy O
expenditure O
over O
longer O
periods O
of O
time O
is O
the O
method O
of O
choice O
to O
validate O
accelerometers O
in O
their O
ability O
to O
assess O
daily O
physical O
activities O
. O

The O
aim O
of O
this O
paper O
was O
to O
provide O
a O
systematic O
overview O
of O
all O
recent O
( O
2007 O
- O
2011 O
) O
accelerometer O
validation O
studies O
using O
DLW O
as O
the O
reference O
. O

The O
PubMed O
Central O
database O
was O
searched O
using O
the O
following O
keywords O
: O
doubly O
or O
double O
labelled O
or O
labeled O
water O
in O
combination O
with O
accelerometer O
, O
accelerometry O
, O
motion O
sensor O
, O
or O
activity O
monitor O
. O

Limits O
were O
set O
to O
include O
articles O
from O
2007 O
to O
2011 O
, O
as O
earlier O
publications O
were O
covered O
in O
a O
previous O
review O
. O

In O
total O
, O
38 O
articles O
were O
identified O
, O
of O
which O
25 O
were O
selected O
to O
contain O
sufficient O
new O
data O
. O

Eighteen O
different O
accelerometers O
were O
validated O
. O

There O
was O
a O
large O
variability O
in O
accelerometer O
output O
and O
their O
validity O
to O
assess O
daily O
physical O
activity O
. O

Activity O
type O
recognition O
has O
great O
potential O
to O
improve O
the O
assessment O
of O
physical O
activity O
- O
related O
health O
outcomes O
. O

So O
far O
, O
there O
is O
little O
evidence O
that O
adding O
other O
physiological O
measures O
such O
as O
heart O
rate O
significantly O
improves O
the O
estimation O
of O
energy O
expenditure O
. O

Increased O
PD O
- O
1 O
on O
CD4 O
( O
+ O
) O
CD28 O
( O
- O
) O
T O
cell O
and O
soluble O
PD O
- O
1 O
ligand O
- O
1 O
in O
patients O
with O
T2DM O
: O
Association O
with O
atherosclerotic O
macrovascular O
diseases O
. O

OBJECTIVE O
: O
To O
study O
the O
role O
of O
the O
programmed O
death O
- O
1 O
( O
PD O
- O
1 O
) O
/ O
programmed O
death O
- O
1 O
ligand O
1 O
( O
PD O
- O
L1 O
) O
coinhibitory O
pathway O
in O
regulating O
CD4 O
( O
+ O
) O
CD28 O
( O
- O
) O
T O
cells O
, O
and O
to O
explore O
the O
association O
of O
soluble O
PD O
- O
L1 O
( O
sPD O
- O
L1 O
) O
in O
the O
development O
of O
T2DM O
with O
atherosclerotic O
macrovascular O
diseases O
. O

METHODS O
: O
The O
percentage O
of O
CD4 O
( O
+ O
) O
CD28 O
( O
- O
) O
T O
lymphocyte O
subsets O
from O
peripheral O
blood O
mononuclear O
cells O
( O
PBMCs O
) O
and O
the O
expression O
of O
PD O
- O
1 O
/ O
PD O
- O
L1 O
on O
lymphocytes O
were O
analyzed O
by O
immunostaining O
and O
flow O
cytometry O
, O
respectively O
. O

The O
serum O
levels O
of O
sPD O
- O
L1 O
and O
IFN O
- O
gamma O
were O
determined O
by O
ELISA O
system O
. O

T O
cell O
proliferation O
was O
determined O
by O
cocultivation O
and O
WST O
- O
8 O
incorporation O
. O

RESULTS O
: O
In O
125 O
T2DM O
patients O
and O
48 O
healthy O
donors O
, O
CD4 O
( O
+ O
) O
CD28 O
( O
- O
) O
T O
cells O
from O
patients O
with O
T2DM O
expressed O
higher O
PD O
- O
1 O
than O
that O
of O
the O
cells O
from O
healthy O
individuals O
, O
and O
the O
proliferation O
response O
of O
CD4 O
( O
+ O
) O
CD28 O
( O
- O
) O
T O
cells O
could O
be O
enhanced O
by O
advanced O
glycation O
end O
products O
( O
AGEs O
) O
. O

The O
levels O
of O
sPD O
- O
L1 O
in O
patients O
were O
also O
much O
higher O
than O
those O
of O
healthy O
donors O
, O
and O
the O
increase O
was O
displayed O
in O
an O
exacerbation O
- O
dependent O
manner O
in O
the O
T2DM O
with O
atherosclerotic O
macrovascular O
patients O
especially O
with O
acute O
coronary O
syndrome O
( O
ACS O
) O
. O

The O
production O
of O
sPD O
- O
L1 O
was O
significantly O
positively O
correlated O
with O
the O
level O
of O
IFN O
- O
gamma O
and O
could O
enhance O
T O
cell O
proliferation O
. O

CONCLUSION O
: O
Both O
the O
upregulation O
of O
PD O
- O
1 O
and O
the O
increase O
of O
sPD O
- O
L1 O
were O
closely O
associated O
with O
the O
severity O
of O
diabetic O
atherosclerotic O
macrovascular O
diseases O
. O

sPD O
- O
L1 O
may O
contribute O
to O
the O
continuous O
T O
cell O
activation O
and O
development O
of O
diabetic O
macrovascular O
diseases O
. O

Synthesis O
and O
biological O
evaluation O
of O
guanidino B
analogues O
of O
roscovitine B
. O

A O
series O
of O
2 B
, I
9 I
- I
substituted I
6 I
- I
guanidinopurines I
, O
structurally O
related O
to O
the O
cyclin O
- O
dependent O
kinase O
( O
CDK O
) O
inhibitors O
olomoucine B
and O
roscovitine B
, O
has O
been O
synthesized O
and O
characterized O
. O

A O
new O
copper B
- O
catalyzed O
method O
for O
the O
synthesis O
of O
2 B
- I
substituted I
6 I
- I
guanidino I
- I
9 I
- I
isopropylpurines I
under O
mild O
reaction O
conditions O
has O
been O
developed O
. O

All O
prepared O
compounds O
were O
screened O
for O
their O
CDK1 O
and O
CDK2 O
inhibitory O
activities O
, O
cytotoxicity O
and O
antiproliferative O
effects O
in O
the O
breast O
cancer O
- O
derived O
cell O
line O
MCF7 O
. O

The O
most O
active O
derivative O
16g O
possessed O
an O
identical O
side O
chain O
in O
the O
C2 O
position O
to O
roscovitine B
; O
this O
compound O
displayed O
approximately O
five O
fold O
higher O
inhibitory O
activity O
towards O
CDK2 O
/ O
cyclin O
E O
and O
more O
than O
ten O
fold O
increase O
in O
cytotoxicity O
in O
MCF7 O
cells O
. O

Interestingly O
and O
in O
contrast O
to O
previously O
described O
findings O
, O
( B
S I
) I
- I
6 I
- I
guanidinopurine I
derivatives O
were O
generally O
more O
active O
than O
their O
( O
R O
) O
- O
counterparts O
. O

Kinase O
selectivity O
profiling O
of O
( O
R O
) O
- O
and O
( O
S O
) O
- O
enantiomers O
16e O
and O
16g O
, O
respectively O
, O
revealed O
that O
introduction O
of O
a O
guanidino B
group O
at O
the O
C6 O
position O
of O
the O
purine B
moiety O
decreased O
selectivity O
towards O
protein O
kinases O
compared O
to O
roscovitine B
. O

Nevertheless O
, O
increased O
inhibitory O
activity O
and O
decreased O
selectivity O
offer O
a O
good O
starting O
point O
for O
further O
development O
of O
new O
protein O
kinase O
inhibitors O
. O

Agmatine B
attenuates O
acquisition O
but O
not O
the O
expression O
of O
ethanol B
conditioned O
place O
preference O
in O
mice O
: O
a O
role O
for O
imidazoline B
receptors O
. O

The O
present O
study O
investigated O
the O
effect O
of O
agmatine B
on O
acquisition O
and O
expression O
of O
ethanol B
conditioned O
place O
preference O
( O
CPP O
) O
and O
its O
modulation O
by O
imidazoline B
agents O
. O

Swiss O
albino O
mice O
were O
treated O
intraperitoneally O
with O
saline O
or O
agmatine B
( O
20 O
- O
40 O
mg O
/ O
kg O
) O
before O
injection O
of O
ethanol B
( O
1 O
. O
25 O
mg O
/ O
kg O
) O
during O
conditioning O
days O
or O
on O
a O
test O
day O
( O
20 O
- O
120 O
mg O
/ O
kg O
) O
, O
to O
observe O
the O
effect O
on O
acquisition O
or O
expression O
of O
CPP O
, O
respectively O
. O

Agmatine B
inhibited O
the O
acquisition O
but O
not O
the O
expression O
of O
ethanol B
CPP O
. O

Furthermore O
, O
both O
the O
I O
( O
1 O
) O
receptor O
antagonist O
, O
efaroxan B
( O
9 O
mg O
/ O
kg O
) O
and O
the O
I O
( O
2 O
) O
receptor O
antagonist O
, O
BU224 B
( O
5 O
mg O
/ O
kg O
) O
attenuated O
the O
agmatine B
- O
induced O
inhibition O
of O
the O
ethanol B
CPP O
acquisition O
. O

In O
contrast O
, O
the O
I O
( O
2 O
) O
receptor O
agonist O
, O
2 B
- I
BFI I
( O
5 O
mg O
/ O
kg O
) O
and O
I O
( O
1 O
) O
receptor O
agonist O
, O
moxonidine B
( O
0 O
. O
4 O
mg O
/ O
kg O
) O
alone O
, O
or O
a O
combination O
of O
their O
subeffective O
doses O
, O
significantly O
attenuated O
the O
effect O
of O
agmatine B
( O
20 O
mg O
/ O
kg O
) O
on O
acquisition O
of O
ethanol B
CPP O
. O

Agmatine B
or O
imidazoline B
agents O
alone O
produced O
neither O
place O
preference O
nor O
aversion O
, O
and O
at O
the O
doses O
used O
in O
the O
present O
study O
did O
not O
affect O
locomotor O
activity O
. O

Thus O
, O
agmatine B
attenuates O
the O
acquisition O
of O
ethanol B
CPP O
at O
least O
in O
part O
by O
imidazoline B
( O
I O
( O
1 O
) O
or O
I O
( O
2 O
) O
) O
receptors O
. O

In O
future O
studies O
, O
agmatine B
or O
agents O
acting O
at O
the O
imidazoline B
receptors O
could O
be O
explored O
for O
their O
therapeutic O
potential O
in O
ethanol B
dependence O
. O

The O
critical O
effect O
of O
polarization O
on O
the O
dynamical O
structure O
of O
guanine B
quadruplex O
DNA O
. O

Guanine B
quadruplex O
DNA O
( O
G O
- O
DNA O
) O
, O
found O
in O
eukaryotic O
telomeres O
and O
recently O
in O
non O
- O
telomeric O
genomic O
DNA O
, O
plays O
important O
biological O
roles O
and O
their O
structures O
are O
being O
explored O
as O
potential O
targets O
for O
therapeutic O
intervention O
. O

Since O
the O
quadruplex O
structure O
of O
G O
- O
DNA O
is O
stabilized O
by O
cations O
, O
electrostatic O
interaction O
is O
expected O
to O
play O
important O
roles O
in O
the O
dynamical O
structure O
of O
G O
- O
DNA O
. O

In O
current O
work O
, O
MD O
simulation O
was O
carried O
out O
to O
study O
the O
dynamical O
structure O
of O
a O
special O
G O
- O
DNA O
( O
with O
sequence O
d O
( O
G O
( O
4 O
) O
T O
( O
4 O
) O
G O
( O
4 O
) O
) O
) O
complexed O
with O
five O
K B
( I
+ I
) I
ions O
. O

In O
order O
to O
properly O
include O
polarization O
in O
MD O
simulation O
, O
a O
new O
set O
of O
polarized O
nucleic O
acid O
specific O
charge O
based O
on O
fragment O
quantum O
chemistry O
calculation O
was O
developed O
for O
G O
- O
DNA O
. O

Our O
study O
showed O
that O
polarization O
of O
the O
nucleobases B
by O
K B
( I
+ I
) I
enhanced O
electrostatic O
attraction O
between O
the O
base O
and O
ions O
. O

This O
increased O
attractive O
interaction O
is O
critical O
to O
stabilizing O
the O
stem O
- O
loop O
junction O
ions O
in O
G O
- O
DNA O
. O

Without O
this O
polarization O
effect O
, O
as O
in O
MD O
simulation O
using O
a O
standard O
( O
nonpolarizable O
) O
force O
field O
, O
the O
top O
and O
bottom O
cations O
escaped O
into O
the O
solvent O
within O
just O
a O
few O
nanoseconds O
. O

Furthermore O
, O
an O
incorrect O
bifurcated O
bonding O
geometry O
of O
G O
- O
DNA O
, O
found O
in O
previous O
MD O
simulation O
study O
under O
a O
standard O
force O
field O
but O
not O
observed O
in O
experiments O
, O
disappeared O
in O
the O
present O
stimulation O
using O
the O
new O
polarized O
force O
field O
. O

The O
current O
study O
bridged O
an O
important O
gap O
between O
the O
simulation O
study O
and O
experimental O
observation O
on O
the O
dynamical O
structure O
of O
G O
- O
DNA O
. O

Chemically O
- O
synthesised O
, O
atomically O
- O
precise O
gold O
clusters O
deposited O
and O
activated O
on O
titania B
. O

Synchrotron O
XPS O
was O
used O
to O
investigate O
a O
series O
of O
chemically O
- O
synthesised O
, O
atomically O
- O
precise O
gold O
clusters O
Au B
( I
n I
) I
( I
PPh I
( I
3 I
) I
) I
( I
y I
) I
( O
n O
= O
8 O
, O
9 O
, O
11 O
and O
101 O
, O
with O
y O
depending O
on O
cluster O
size O
) O
immobilized O
on O
titania B
nanoparticles O
. O

The O
gold O
clusters O
were O
washed O
with O
toluene O
at O
100 O
degrees O
C O
or O
calcined O
at O
200 O
degrees O
C O
to O
remove O
the O
organic O
ligand O
. O

From O
the O
position O
of O
the O
Au B
4f O
( O
7 O
/ O
2 O
) O
peak O
it O
is O
concluded O
that O
cluster O
size O
is O
not O
altered O
through O
the O
deposition O
. O

From O
the O
analysis O
of O
the O
phosphorous B
spectra O
, O
it O
can O
be O
concluded O
that O
the O
applied O
heat O
treatment O
removes O
the O
organic O
ligands O
. O

Washing O
and O
calcination O
leads O
to O
partial O
oxidation O
and O
partial O
agglomeration O
of O
the O
clusters O
. O

Oxidation O
of O
the O
clusters O
is O
most O
likely O
due O
to O
the O
interaction O
of O
the O
cluster O
core O
with O
the O
oxygen B
of O
the O
titania B
surface O
after O
removal O
of O
ligands O
. O

The O
position O
of O
the O
Au B
4f O
( O
7 O
/ O
2 O
) O
peak O
indicates O
that O
the O
size O
of O
the O
agglomerated O
clusters O
is O
still O
smaller O
than O
that O
of O
Au B
( O
101 O
) O
. O

Population O
pharmacokinetic O
/ O
pharmacodynamic O
modeling O
to O
assist O
dosing O
schedule O
selection O
for O
dovitinib B
. O

Dovitinib B
is O
an O
oral O
multitargeted O
kinase O
inhibitor O
with O
potent O
activity O
against O
receptors O
for O
vascular O
endothelial O
growth O
factor O
, O
platelet O
- O
derived O
growth O
factor O
, O
and O
basic O
fibroblast O
growth O
factor O
. O

Initial O
phase O
1 O
to O
2 O
studies O
of O
dovitinib B
using O
a O
continuous O
daily O
dosing O
schedule O
has O
shown O
that O
dovitinib B
exhibits O
a O
prolonged O
and O
overproportional O
increase O
in O
dose O
and O
exposure O
relationship O
above O
400 O
mg O
/ O
d O
. O

To O
address O
this O
, O
intermittent O
dosing O
schedules O
were O
explored O
using O
a O
model O
- O
based O
approach O
. O

A O
semi O
- O
mechanistic O
population O
pharmcokinetic O
/ O
pharmacodynamic O
( O
PD O
) O
model O
was O
developed O
from O
4 O
dovitinib B
phase O
1 O
studies O
with O
daily O
dosing O
schedules O
. O

Autoinduction O
of O
cytochrome O
P450 O
1A O
( O
CYP1A O
) O
responsible O
for O
dovitinib B
metabolism O
was O
described O
using O
an O
indirect O
response O
model O
. O

Simulation O
of O
dovitinib B
plasma O
concentration O
profiles O
following O
4 O
intermittent O
dosing O
schedules O
suggested O
that O
intermittent O
dosing O
could O
prevent O
prolonged O
drug O
accumulation O
. O

Based O
on O
the O
simulated O
plasma O
profiles O
, O
PD O
response O
, O
and O
patient O
compliance O
, O
a O
5 O
- O
days O
- O
on O
/ O
2 O
- O
days O
- O
off O
intermittent O
dosing O
schedule O
was O
selected O
for O
a O
phase O
1 O
to O
2 O
clinical O
study O
. O

The O
observed O
dovitinib B
plasma O
concentrations O
in O
this O
study O
confirmed O
the O
model O
predictions O
. O

Furthermore O
, O
dovitinib B
was O
well O
tolerated O
, O
and O
antitumor O
activity O
was O
observed O
as O
well O
in O
this O
new O
study O
. O

The O
5 O
- O
days O
- O
on O
/ O
2 O
- O
days O
- O
off O
dosing O
schedule O
is O
currently O
used O
in O
a O
dovitinib B
registration O
trial O
and O
other O
clinical O
trials O
. O

Effects O
of O
amlodipine B
on O
the O
oral O
bioavailability O
of O
cephalexin B
and O
cefuroxime B
axetil I
in O
healthy O
volunteers O
. O

In O
this O
study O
, O
the O
authors O
compared O
the O
effects O
of O
amlodipine B
( O
AML B
) O
on O
the O
bioavailability O
of O
cephalexin B
( O
LEX B
) O
and O
cefuroxime B
axetil I
( O
CXM B
) O
. O

Twenty O
- O
four O
healthy O
men O
were O
randomized O
to O
4 O
treatments O
according O
to O
a O
crossover O
design O
with O
a O
14 O
- O
day O
washout O
. O

After O
an O
overnight O
fast O
, O
they O
were O
administered O
orally O
LEX B
500 O
mg O
alone O
, O
LEX B
500 O
mg O
2 O
hours O
after O
oral O
administration O
of O
AML O
5 O
mg O
, O
CXM B
500 O
mg O
alone O
, O
and O
CXM B
500 O
mg O
2 O
hours O
after O
oral O
administration O
of O
AML O
5 O
mg O
. O

All O
participants O
completed O
the O
whole O
study O
without O
side O
effects O
being O
observed O
. O

Pharmacokinetic O
data O
were O
analyzed O
by O
noncompartmental O
modeling O
with O
WinNonlin O
software O
. O

The O
geometric O
mean O
( O
GM O
) O
ratios O
were O
1 O
. O
38 O
( O
90 O
% O
confidence O
interval O
[ O
CI O
] O
, O
1 O
. O
32 O
- O
1 O
. O
45 O
) O
for O
the O
area O
under O
the O
concentration O
- O
time O
curve O
( O
AUC O
) O
for O
LEX B
and O
1 O
. O
27 O
( O
1 O
. O
18 O
- O
1 O
. O
36 O
) O
for O
the O
maximum O
concentration O
of O
drug O
in O
serum O
( O
C O
( O
max O
) O
) O
for O
LEX B
followed O
by O
AML O
versus O
alone O
. O

In O
contrast O
, O
no O
significant O
differences O
were O
found O
in O
the O
pharmacokinetic O
parameters O
of O
CXM B
between O
treatments O
( O
P O
< O
. O
05 O
) O
. O

They O
authors O
conclude O
that O
AML O
possesses O
an O
enhancement O
effect O
in O
beta B
- I
lactam I
antibiotic O
bioavailability O
( O
in O
this O
case O
, O
LEX O
) O
, O
and O
this O
interaction O
may O
be O
specific O
to O
the O
peptidomimetic O
beta B
- I
lactam I
antibiotics O
. O

Correlation O
between O
carbapenem B
consumption O
and O
antimicrobial O
resistance O
rates O
of O
Acinetobacter O
baumannii O
in O
a O
university O
- O
affiliated O
hospital O
in O
China O
. O

To O
investigate O
the O
correlation O
between O
carbapenem B
consumption O
and O
rates O
of O
antimicrobial O
resistance O
in O
Acinetobacter O
baumannii O
, O
carbapenem B
consumption O
was O
expressed O
as O
defined O
daily O
dose O
based O
on O
the O
World O
Health O
Organization O
( O
WHO O
) O
anatomical O
therapeutic O
chemical O
classification O
index O
. O

Clinical O
isolates O
from O
2001 O
- O
2009 O
were O
collected O
and O
analyzed O
using O
WHONET O
5 O
. O
4 O
software O
. O

Results O
show O
that O
the O
consumption O
of O
imipenem B
/ O
cilastatin B
, O
meropenem B
, O
and O
total O
carbapenem B
is O
significantly O
correlated O
with O
imipenem B
resistance O
in O
A O
baumannii O
( O
r O
= O
0 O
. O
818 O
, O
P O
= O
. O
007 O
; O
r O
= O
0 O
. O
817 O
, O
P O
= O
. O
007 O
; O
r O
= O
0 O
. O
827 O
, O
P O
= O
. O
006 O
) O
. O

Furthermore O
, O
total O
carbapenem B
consumption O
is O
significantly O
correlated O
with O
meropenem B
resistance O
in O
A O
baumannii O
( O
r O
= O
0 O
. O
900 O
, O
P O
= O
. O
037 O
) O
. O

In O
addition O
, O
consumption O
of O
imipenem B
/ O
cilastatin B
, O
meropenem B
, O
and O
total O
carbapenem B
is O
associated O
with O
A O
baumannii O
resistance O
to O
piperacillin B
- O
tazobactam B
, O
ceftazidime B
, O
cefepime B
, O
amikacin B
, O
and O
levofloxacin B
. O

These O
drugs O
are O
mainly O
beta B
- I
lactams I
, O
aminoglycosides B
, O
and O
fluoroquinolones B
. O

The O
imipenem B
and O
meropenem B
resistance O
rates O
are O
significantly O
correlated O
with O
resistance O
rates O
to O
numerous O
antimicrobial O
drugs O
( O
eg O
, O
beta B
- I
lactams I
, O
aminoglycosides B
, O
and O
fluoroquinolones B
) O
in O
A O
baumannii O
. O

Therefore O
, O
increased O
consumption O
of O
carbapenem B
may O
contribute O
to O
the O
development O
of O
resistance O
in O
A O
baumannii O
to O
imipenem B
, O
meropenem B
, O
and O
other O
antimicrobial O
drugs O
. O

Cross O
- O
resistance O
possibly O
occurs O
among O
imipenem B
/ O
cilastatin B
and O
meropenem B
, O
as O
well O
as O
with O
beta B
- I
lactams I
, O
aminoglycosides B
, O
and O
fluoroquinolones B
. O

Environmental O
fate O
of O
three O
novel O
brominated O
flame O
retardants O
in O
aquatic O
mesocosms O
. O

Currently O
, O
little O
is O
known O
about O
the O
environmental O
fate O
and O
persistence O
of O
novel O
brominated O
flame O
retardants O
( O
NBFRs O
) O
. O

The O
recent O
detection O
of O
NBFRs O
in O
sediment O
cores O
and O
air O
samples O
provides O
insight O
into O
their O
persistence O
and O
potential O
for O
transport O
. O

Limited O
numbers O
of O
laboratory O
studies O
have O
examined O
the O
fate O
and O
behavior O
of O
these O
compounds O
, O
but O
field O
- O
based O
fate O
studies O
have O
been O
especially O
lacking O
. O

The O
authors O
conducted O
an O
aquatic O
mesocosm O
experiment O
to O
assess O
the O
behavior O
of O
three O
NBFRs O
: O
bis B
( I
tribromophenoxy I
) I
ethane I
( O
BTBPE B
) O
, O
tetrabromobisphenol B
A I
bis I
( I
2 I
, I
3 I
- I
dibromopropyl I
ether I
; O
TBBPA B
- I
DBPE I
) O
, O
and O
Firemaster B
BZ I
- I
54 I
, O
a O
commercial O
mixture O
containing O
bis B
( I
2 I
- I
ethylhexyl I
) I
tetrabromophthalate I
( O
BEHTBP B
) O
and O
2 B
- I
ethylhexyl I
- I
2 I
, I
3 I
, I
4 I

, I
5 I
- I
tetrabromobenzoate I
( O
EHTeBB B
) O
in O
a O
ratio O
of O
1 O
: O
4 O
. O

Analysis O
by O
gas O
chromatography O
- O
mass O
spectrometry O
, O
operated O
in O
the O
electron O
capture O
negative O
ionization O
mode O
, O
revealed O
partitioning O
between O
the O
particulate O
and O
sediment O
phases O
, O
with O
BTBPE B
, O
TBBPA B
- I
DBPE I
, O
and O
BEHTBP B
identified O
as O
being O
environmentally O
persistent O
in O
both O
the O
particulate O
and O
the O
sediment O
compartments O
. O

The O
median O
dissipation O
times O
( O
DT50 O
) O
differed O
in O
each O
compartment O
, O
with O
more O
rapid O
disappearance O
in O
the O
particulate O
( O
9 O
- O
30 O
d O
) O
compared O
with O
the O
sediment O
compartment O
( O
> O
100 O
d O
) O
for O
each O
compound O
. O

The O
degradation O
products O
were O
more O
concentrated O
in O
the O
particulate O
compartment O
and O
corresponded O
to O
known O
photodegradation O
products O
. O

The O
ratio O
of O
EHTeBB B
to O
BEHTBP B
differed O
in O
the O
mesocosm O
compartments O
compared O
with O
the O
technical O
product O
used O
for O
treatment O
, O
indicating O
increased O
degradation O
of O
EHTeBB B
relative O
to O
BETHBP B
. O

Environ O
. O

Toxicol O
. O

Chem O
. O

2013 O
; O
32 O
: O
1060 O
- O
1068 O
. O

( O
c O
) O
2013 O
SETAC O
. O

Acute O
exposure O
to O
DE B
- I
71 I
causes O
alterations O
in O
visual O
behavior O
in O
zebrafish O
larvae O
. O

Polybrominated B
diphenyl I
ethers I
( O
PBDEs B
) O
cause O
neurobehavioral O
toxicity O
, O
but O
their O
effects O
on O
visual O
behavior O
remain O
unknown O
. O

In O
the O
present O
study O
, O
the O
impact O
of O
PBDEs B
on O
visual O
behavior O
was O
examined O
using O
optokinetic O
responses O
and O
phototaxis O
in O
zebrafish O
larvae O
. O

Zebrafish O
embryos O
were O
exposed O
to O
pentabrominated B
diphenyl I
ethers I
mixture O
( O
DE B
- I
71 I
) O
at O
concentrations O
of O
0 O
, O
0 O
. O
32 O
, O
3 O
. O
58 O
, O
and O
31 O
. O
0 O
micro O
g O
/ O
L O
until O
15 O
d O
postfertilization O
. O

The O
authors O
then O
assessed O
photoreceptor O
opsin O
expression O
, O
retinal O
histology O
, O
and O
visual O
behavior O
of O
the O
larvae O
. O

The O
results O
showed O
that O
the O
transcriptions O
of O
the O
opsin O
genes O
, O
zfrho O
and O
zfgr1 O
, O
were O
significantly O
upregulated O
. O

Western O
blotting O
further O
demonstrated O
a O
significant O
increase O
in O
rhodopsin O
protein O
expression O
after O
exposure O
of O
the O
larvae O
to O
DE B
- I
71 I
. O

Histological O
examination O
revealed O
the O
following O
morphological O
alterations O
in O
the O
retina O
: O
increased O
area O
of O
inner O
nuclear O
layer O
, O
decreased O
area O
of O
inner O
plexiform O
layer O
, O
and O
decreased O
density O
of O
ganglion O
cells O
. O

Tests O
of O
optokinetic O
and O
phototactic O
behavior O
showed O
hyperactive O
responses O
on O
exposure O
to O
DE B
- I
71 I
, O
including O
increased O
saccadic O
eye O
movements O
and O
phototactic O
response O
. O

The O
present O
study O
is O
the O
first O
to O
demonstrate O
that O
the O
acute O
exposure O
of O
zebrafish O
larvae O
to O
DE B
- I
71 I
causes O
biochemical O
and O
structural O
changes O
in O
the O
eye O
that O
lead O
to O
behavioral O
alterations O
. O

Analysis O
of O
these O
visual O
behavioral O
paradigms O
may O
be O
useful O
in O
predicting O
the O
adverse O
effects O
of O
toxicants O
on O
visual O
function O
in O
fish O
. O

Environ O
Toxicol O
Chem O
2013 O
; O
32 O
: O
1370 O
- O
1375 O
. O

( O
c O
) O
2013 O
SETAC O
. O

Rash O
associated O
with O
dabigatran B
etexilate I
. O

Patients O
experiencing O
atrial O
fibrillation O
are O
at O
an O
increased O
risk O
for O
thromboembolic O
events O
. O

Therefore O
, O
anticoagulation O
therapy O
is O
imperative O
to O
prevent O
thrombus O
formation O
and O
stroke O
. O

Dabigatran B
etexilate I
was O
approved O
by O
the O
Food O
and O
Drug O
Administration O
in O
2010 O
as O
anticoagulant O
prophylaxis O
for O
patients O
with O
nonvalvular O
atrial O
fibrillation O
. O

The O
frequency O
of O
dermatologic O
reactions O
to O
dabigatran B
etexilate I
is O
estimated O
in O
the O
product O
labeling O
to O
be O
less O
than O
0 O
. O
1 O
% O
. O

To O
date O
, O
five O
cases O
of O
dabigatran B
etexilate I
- O
associated O
rash O
have O
reported O
, O
including O
three O
published O
cases O
. O

We O
describe O
the O
sixth O
reported O
case O
of O
dabigatran B
etexilate I
- O
associated O
rash O
, O
in O
a O
59 O
- O
year O
- O
old O
man O
with O
a O
history O
of O
atrial O
fibrillation O
who O
received O
dabigatran B
etexilate I
150 O
mg O
twice O
/ O
day O
for O
atrial O
flutter O
before O
cardioversion O
. O

The O
patient O
had O
taken O
dabigatran B
etexilate I
for O
5 O
days O
before O
the O
rash O
was O
noted O
on O
hospital O
admission O
. O

He O
had O
no O
known O
previous O
drug O
allergies O
, O
and O
his O
platelet O
count O
, O
serum O
creatinine B
concentration O
, O
and O
hepatic O
function O
were O
normal O
. O

The O
rash O
resolved O
7 O
days O
after O
the O
discontinuation O
of O
dabigatran B
etexilate I
, O
and O
the O
patient O
was O
stabilized O
on O
warfarin B
therapy O
. O

Use O
of O
the O
Naranjo O
Adverse O
Drug O
Reaction O
Probability O
Scale O
indicated O
a O
probable O
relationship O
( O
score O
of O
5 O
) O
between O
the O
patient O
' O
s O
development O
of O
the O
rash O
and O
dabigatran B
etexilate I
therapy O
. O

Clinicians O
should O
be O
aware O
of O
this O
adverse O
effect O
of O
dabigatran B
etexilate I
and O
monitor O
for O
dermatologic O
reactions O
during O
follow O
- O
up O
visits O
. O

Relaxin O
: O
New O
Pathophysiological O
Aspects O
and O
Pharmacological O
Perspectives O
for O
an O
Old O
Protein O
. O

Human O
relaxin O
- O
2 O
( O
hereafter O
simply O
defined O
as O
" O
relaxin O
" O
) O
is O
a O
6 O
- O
kDa O
peptidic O
hormone O
best O
known O
for O
the O
physiological O
role O
played O
during O
pregnancy O
in O
the O
growth O
and O
differentiation O
of O
the O
reproductive O
tract O
and O
in O
the O
renal O
and O
systemic O
hemodynamic O
changes O
. O

This O
factor O
can O
also O
be O
involved O
in O
the O
pathophysiology O
of O
arterial O
hypertension O
and O
heart O
failure O
, O
in O
the O
molecular O
pathways O
of O
fibrosis O
and O
cancer O
, O
and O
in O
angiogenesis O
and O
bone O
remodeling O
. O

It O
belongs O
to O
the O
relaxin O
peptide O
family O
, O
whose O
members O
comprehensively O
exert O
numerous O
effects O
through O
interaction O
with O
different O
types O
of O
receptors O
, O
classified O
as O
relaxin O
family O
peptide O
( O
RXFP O
) O
receptors O
( O
RXFP1 O
, O
RXFP2 O
, O
RXFP3 O
, O
RXFP4 O
) O
. O

Research O
looks O
toward O
the O
in O
- O
depth O
examination O
and O
complete O
understanding O
of O
relaxin O
in O
its O
various O
pleiotropic O
actions O
. O

The O
intent O
is O
to O
evaluate O
the O
likelihood O
of O
employing O
this O
substance O
for O
therapeutic O
purposes O
, O
for O
instance O
in O
diseases O
where O
a O
deficit O
could O
be O
part O
of O
the O
underlying O
pathophysiological O
mechanisms O
, O
also O
avoiding O
any O
adverse O
effect O
. O

Relaxin O
is O
already O
being O
considered O
as O
a O
promising O
drug O
, O
especially O
in O
acute O
heart O
failure O
. O

A O
careful O
study O
of O
the O
different O
RXFPs O
and O
their O
receptors O
and O
the O
comprehension O
of O
all O
biological O
activities O
of O
these O
hormones O
will O
probably O
provide O
new O
drugs O
with O
a O
potential O
wide O
range O
of O
therapeutic O
applications O
in O
the O
near O
future O
. O

Quantum O
Dot O
- O
Based O
Thermal O
Spectroscopy O
and O
Imaging O
of O
Optically O
Trapped O
Microspheres O
and O
Single O
Cells O
. O

Laser O
- O
induced O
thermal O
effects O
in O
optically O
trapped O
microspheres O
and O
single O
cells O
are O
investigated O
by O
quantum O
dot O
luminescence O
thermometry O
. O

Thermal O
spectroscopy O
has O
revealed O
a O
non O
- O
localized O
temperature O
distribution O
around O
the O
trap O
that O
extends O
over O
tens O
of O
micrometers O
, O
in O
agreement O
with O
previous O
theoretical O
models O
besides O
identifying O
water O
absorption O
as O
the O
most O
important O
heating O
source O
. O

The O
experimental O
results O
of O
thermal O
loading O
at O
a O
variety O
of O
wavelengths O
reveal O
that O
an O
optimum O
trapping O
wavelength O
exists O
for O
biological O
applications O
close O
to O
820 O
nm O
. O

This O
is O
corroborated O
by O
a O
simultaneous O
analysis O
of O
the O
spectral O
dependence O
of O
cellular O
heating O
and O
damage O
in O
human O
lymphocytes O
during O
optical O
trapping O
. O

This O
quantum O
dot O
luminescence O
thermometry O
demonstrates O
that O
optical O
trapping O
with O
820 O
nm O
laser O
radiation O
produces O
minimum O
intracellular O
heating O
, O
well O
below O
the O
cytotoxic O
level O
( O
43 O
degrees O
C O
) O
, O
thus O
, O
avoiding O
cell O
damage O
. O

A O
self O
- O
organized O
anisotropic O
liquid O
- O
crystal O
plasmonic O
metamaterial O
. O

A O
composite O
material O
that O
leads O
to O
self O
organization O
of O
mesogen O
- O
coated O
gold O
nanospheres O
is O
synthesized O
and O
shows O
enhanced O
anisotropic O
optical O
properties O
due O
to O
synergistic O
effects O
of O
the O
mesogens O
intrinsic O
birefringence O
and O
its O
ability O
to O
drive O
the O
self O
- O
assembly O
process O
into O
highly O
anisotropic O
architectures O
with O
densely O
packed O
nanospheres O
. O

Such O
nanoengineered O
matter O
sustains O
a O
response O
beyond O
that O
achievable O
by O
its O
individual O
constituents O
, O
i O
. O
e O
. O
, O
a O
metamaterial O
. O

Nonribosomal O
assembly O
of O
natural O
lipocyclocarbamate B
lipoprotein O
- O
associated O
phospholipase O
inhibitors O
. O

EXPANDING O
OUR O
KNOWLEDGE O
: O
Natural O
lipocyclocarbamate B
natural O
products O
have O
provided O
the O
inspiration O
for O
the O
first O
- O
in O
- O
class O
synthetic O
phospholipase O
inhibitor O
darapladib B
, O
currently O
in O
phase O
III O
clinical O
trials O
for O
the O
treatment O
of O
atherosclerosis O
. O

Here O
, O
we O
discuss O
their O
biosynthesis O
by O
a O
nonribosomal O
peptide O
synthetase O
. O

Engineering O
new O
protein O
- O
protein O
interactions O
on O
the O
beta O
- O
propeller O
fold O
by O
yeast O
cell O
surface O
display O
. O

REINVENTING O
THE O
WHEEL O
: O
The O
beta O
- O
propeller O
domain O
folds O
like O
a O
wheel O
to O
provide O
key O
protein O
- O
protein O
interactions O
in O
the O
cell O
. O

Here O
we O
used O
high O
- O
throughput O
yeast O
sorting O
to O
" O
invent O
" O
beta O
- O
propellers O
of O
new O
binding O
specificities O
with O
cellular O
targets O
. O

Joining O
Copper B
Oxide I
Nanotube O
Arrays O
Driven O
by O
the O
Nanoscale O
Kirkendall O
effect O
. O

Various O
annealing O
conditions O
( O
environment O
, O
temperature O
, O
and O
duration O
) O
are O
applied O
to O
study O
the O
nanoscale O
Kirkendall O
effect O
of O
copper B
( O
Cu B
) O
nanowire O
( O
NW O
) O
arrays O
on O
a O
Si B
substrate O
. O

The O
results O
show O
that O
an O
appropriate O
amount O
of O
oxygen B
supply O
is O
crucial O
for O
uniform O
transformation O
from O
Cu B
NWs O
( O
average O
diameter O
~ O
50 O
nm O
) O
into O
Cu B
oxide B
nanotube O
arrays O
. O

An O
annealing O
duration O
of O
30 O
min O
at O
200 O
degrees O
C O
in O
a O
low O
vacuum O
environment O
reveals O
that O
the O
voids O
are O
not O
uniformly O
distributed O
at O
the O
Cu B
/ O
Cu B
oxide B
interface O
. O

This O
suggests O
that O
void O
growth O
is O
due O
to O
surface O
diffusion O
of O
Cu B
along O
void O
surfaces O
. O

Annealing O
above O
200 O
degrees O
C O
for O
60 O
min O
resulted O
in O
complete O
transformation O
from O
Cu B
NWs O
into O
Cu B
oxide I
nanotubes O
. O

X O
- O
ray O
photoelectron O
spectroscopy O
characterization O
indicates O
that O
the O
Cu B
oxides I
formed O
at O
200 O
degrees O
C O
and O
300 O
degrees O
C O
are O
Cu B
( I
2 I
) I
O I
and O
CuO B
, O
respectively O
. O

It O
is O
demonstrated O
that O
the O
transformation O
from O
Cu B
NW O
arrays O
into O
Cu B
oxide I
nanotube O
arrays O
can O
be O
combined O
with O
the O
joining O
of O
stacked O
Si B
chips O
in O
a O
single O
- O
process O
step O
with O
reasonable O
joint O
shear O
strength O
. O

Transmission O
electron O
microscopy O
- O
electron O
energy O
loss O
spectroscopy O
elemental O
mapping O
analysis O
reveals O
that O
the O
joint O
interface O
is O
Cu B
oxide I
. O

The O
outward O
diffusion O
of O
Cu B
driven O
by O
the O
nanoscale O
Kirkendall O
effect O
is O
believed O
to O
enhance O
the O
joining O
process O
. O

By O
controlling O
the O
environment O
, O
temperature O
, O
and O
duration O
, O
joined O
Cu B
( I
2 I
) I
O I
or O
CuO B
nanotube O
stacked O
chips O
can O
be O
achieved O
, O
which O
serve O
as O
a O
platform O
for O
the O
further O
development O
of O
nanostructured O
, O
stacked O
devices O
. O

Protein O
- O
Carbohydrate B
Complex O
Reveals O
Circulating O
Metastatic O
Cells O
in O
a O
Microfluidic O
Assay O
. O

Advances O
in O
carbohydrate B
sequencing O
technologies O
reveal O
the O
tremendous O
complexity O
of O
the O
glycome O
and O
the O
role O
that O
glycomics O
might O
have O
to O
bring O
insight O
into O
the O
biological O
functions O
. O

Carbohydrate B
- O
protein O
interactions O
, O
in O
particular O
, O
are O
known O
to O
be O
crucial O
to O
most O
mammalian O
physiological O
processes O
as O
mediators O
of O
cell O
adhesion O
and O
metastasis O
, O
signal O
transducers O
, O
and O
organizers O
of O
protein O
interactions O
. O

An O
assay O
is O
developed O
here O
to O
mimic O
the O
multivalency O
of O
biological O
complexes O
that O
selectively O
and O
sensitively O
detect O
carbohydrate B
- O
protein O
interactions O
. O

The O
binding O
of O
beta O
- O
galactosides O
and O
galectin O
- O
3 O
- O
a O
protein O
that O
is O
correlated O
to O
the O
progress O
of O
tumor O
and O
metastasis O
- O
is O
examined O
. O

The O
efficiency O
of O
the O
assay O
is O
related O
to O
the O
expression O
of O
the O
receptor O
while O
anchoring O
to O
the O
interaction O
' O
s O
strength O
. O

Comparative O
binding O
experiments O
reveal O
molecular O
binding O
preferences O
. O

This O
study O
establishes O
that O
the O
assay O
is O
robust O
to O
isolate O
metastatic O
cells O
from O
colon O
affected O
patients O
and O
paves O
the O
way O
to O
personalized O
medicine O
. O

Modulation O
of O
photophysics O
and O
pKa O
shift O
of O
the O
anti O
- O
cancer O
drug O
camptothecin B
in O
the O
nanocavities O
of O
supramolecular O
hosts O
. O

This O
article O
reports O
the O
pK O
( O
a O
) O
shift O
of O
an O
anti O
- O
cancer O
drug O
, O
20 B
( I
S I
) I
- I
camptothecin I
( O
CPT B
) O
, O
upon O
encapsulation O
into O
the O
nanocavity O
of O
a O
cucurbit O
[ O
7 O
] O
uril O
( O
CB7 O
) O
macrocycle O
. O

Steady O
- O
state O
, O
time O
- O
resolved O
fluorescence O
and O
electrospray O
ionisation O
mass O
spectrometry O
( O
ESI O
- O
MS O
) O
studies O
provide O
evidence O
for O
the O
formation O
of O
both O
1 O
: O
1 O
and O
2 O
: O
1 O
( O
CB7 O
. O
CPT B
) O
stoichiometries O
. O

Astonishingly O
, O
we O
have O
found O
that O
protonation O
of O
CPT B
takes O
place O
at O
a O
higher O
concentration O
of O
macrocycle O
( O
> O
= O
50 O
mu O
M O
) O
when O
the O
2 O
: O
1 O
stoichiometric O
complex O
develops O
. O

However O
, O
we O
did O
not O
find O
any O
proof O
for O
protonation O
of O
CPT B
when O
it O
is O
encased O
by O
a O
beta B
- I
cyclodextrin I
cavity O
, O
which O
has O
a O
cavity O
size O
almost O
the O
same O
as O
that O
of O
CB7 O
. O

Hence O
, O
we O
conclude O
that O
electron O
- O
rich O
carbonyl B
portals O
of O
CB7 O
have O
an O
important O
role O
in O
protonation O
of O
the O
drug O
in O
the O
2 O
: O
1 O
inclusion O
complex O
. O

Docking O
and O
semi O
- O
empirical O
quantum O
chemical O
calculations O
have O
been O
employed O
to O
gain O
an O
insight O
into O
the O
molecular O
picture O
of O
orientation O
of O
CPT B
in O
the O
inclusion O
complexes O
. O

It O
is O
clearly O
seen O
from O
the O
optimised O
structure O
of O
the O
2 O
: O
1 O
( O
CB7 O
. O
CPT B
) O
inclusion O
complex O
that O
the O
quinoline B
nitrogen I
of O
CPT B
does O
not O
reside O
within O
either O
of O
the O
CB7 O
cavities O
, O
rather O
it O
is O
almost O
sandwiched O
between O
two O
CB7 O
rings O
, O
and O
therefore O
, O
it O
experiences O
huge O
electron O
density O
exerted O
by O
both O
carbonyl B
portals O
of O
the O
macrocycles O
. O

As O
a O
result O
, O
the O
pK O
( O
a O
) O
of O
CPT B
shifts O
from O
1 O
. O
2 O
to O
6 O
. O
2 O
. O

Finally O
, O
controlled O
release O
of O
the O
drug O
has O
been O
achieved O
through O
the O
introduction O
of O
NaCl B
, O
which O
is O
rich O
in O
cells O
, O
as O
an O
external O
stimulus O
. O

We O
hope O
this O
recognition O
- O
mediated O
binding O
and O
release O
mechanism O
can O
be O
useful O
for O
activation O
of O
the O
drug O
and O
controlled O
release O
of O
the O
drug O
in O
therapeutic O
uses O
. O

Species O
difference O
in O
the O
mechanism O
of O
nonlinear O
pharmacokinetics O
of O
e2074 B
, O
a O
novel O
sodium B
channel O
inhibitor O
, O
in O
rats O
, O
dogs O
, O
and O
monkeys O
. O

New O
chemical O
entities O
often O
exhibit O
nonlinear O
pharmacokinetics O
( O
PK O
) O
profiles O
in O
experimental O
animals O
. O

However O
, O
the O
number O
of O
studies O
that O
have O
focused O
on O
species O
differences O
in O
nonlinear O
PK O
is O
very O
limited O
; O
thus O
, O
the O
aim O
of O
this O
study O
was O
to O
clarify O
the O
mechanism O
of O
the O
nonlinear O
PK O
of O
E2074 B
( O
2 B
- I
[ I
( I
2R I
) I
- I
2 I
- I
fluoro I
- I
3 I
- I
{ I
( I
3r I
) I
- I
[ I
( I
3 I
- I
fluorobenzyl I
) I
oxy I
] I
- I
8 I
- I
azabicyclo I
[ I
3 I
. I
2 I
. I
1 I
] I
oct I
- I
8 I
- I
yl I
} I
propyl I
] I
- I
4 I
, I
5 I
- I
dimethyl I
- I
2 I
, I
4 I
- I
dihydro I
- I

3H B
- I
1 I
, I
2 I
, I
4 I
- I
triazol I
- I
3 I
- I
one I
) O
, O
a O
novel O
sodium B
channel O
inhibitor O
, O
in O
rats O
, O
dogs O
, O
and O
monkeys O
. O

Nonlinear O
PK O
profiles O
with O
more O
than O
dose O
- O
proportional O
increases O
of O
Cmax O
and O
area O
under O
the O
plasma O
concentration O
curve O
were O
observed O
in O
all O
species O
after O
oral O
administration O
. O

The O
Michaelis O
- O
Menten O
constant O
( O
Km O
) O
values O
of O
hepatic O
microsomal O
metabolism O
were O
7 O
. O
23 O
and O
0 O
. O
41 O
mu O
M O
in O
rats O
and O
dogs O
in O
vitro O
, O
respectively O
, O
which O
were O
lower O
than O
the O
unbound O
maximum O
plasma O
concentrations O
after O
oral O
administration O
in O
vivo O
, O
indicating O
that O
the O
nonlinear O
PK O
in O
rats O
and O
dogs O
was O
attributable O
to O
the O
saturation O
of O
hepatic O
metabolism O
. O

However O
, O
we O
do O
not O
believe O
that O
the O
saturation O
of O
hepatic O
metabolism O
was O
the O
mechanism O
of O
nonlinearity O
in O
monkeys O
because O
of O
the O
high O
Km O
value O
( O
42 O
. O
44 O
mu O
M O
) O
observed O
in O
liver O
microsomes O
. O

Intestinal O
metabolism O
was O
observed O
in O
monkey O
intestinal O
microsomes O
but O
not O
in O
rats O
and O
dogs O
, O
and O
the O
nonlinear O
PK O
in O
monkeys O
was O
diminished O
by O
inhibition O
of O
intestinal O
metabolism O
with O
a O
concomitant O
oral O
dose O
of O
ketoconazole B
. O

These O
results O
suggest O
that O
saturation O
of O
the O
intestinal O
metabolism O
is O
the O
potential O
mechanism O
of O
nonlinearity O
in O
monkeys O
. O

P O
- O
glycoprotein O
was O
not O
involved O
in O
the O
nonlinear O
PK O
profiles O
in O
any O
species O
. O

In O
conclusion O
, O
the O
mechanism O
of O
the O
nonlinear O
PK O
of O
E2074 B
is O
species O
dependent O
, O
with O
the O
saturation O
of O
hepatic O
metabolism O
in O
rats O
and O
dogs O
and O
that O
of O
intestinal O
metabolism O
in O
monkeys O
being O
the O
primary O
cause O
. O

Interaction O
of O
silymarin O
flavonolignans B
with O
organic O
anion O
- O
transporting O
polypeptides O
. O

Organic O
anion O
- O
transporting O
polypeptides O
( O
OATPs O
) O
are O
multispecific O
transporters O
mediating O
the O
uptake O
of O
endogenous O
compounds O
and O
xenobiotics O
in O
tissues O
that O
are O
important O
for O
drug O
absorption O
and O
elimination O
, O
including O
the O
intestine O
and O
liver O
. O

Silymarin B
is O
a O
popular O
herbal O
supplement O
often O
used O
by O
patients O
with O
chronic O
liver O
disease O
; O
higher O
oral O
doses O
than O
those O
customarily O
used O
( O
140 O
mg O
three O
times O
/ O
day O
) O
are O
being O
evaluated O
clinically O
. O

The O
present O
study O
examined O
the O
effect O
of O
silymarin O
flavonolignans B
on O
OATP1B1 O
- O
, O
OATP1B3 O
- O
, O
and O
OATP2B1 O
- O
mediated O
transport O
in O
cell O
lines O
stably O
expressing O
these O
transporters O
and O
in O
human O
hepatocytes O
. O

In O
overexpressing O
cell O
lines O
, O
OATP1B1 O
- O
and O
OATP1B3 O
- O
mediated O
estradiol B
- I
17 I
beta I
- I
glucuronide I
uptake O
and O
OATP2B1 O
- O
mediated O
estrone B
- I
3 I
- I
sulfate I
uptake O
were O
inhibited O
by O
most O
of O
the O
silymarin B
flavonolignans B
investigated O
. O

OATP1B1 O
- O
, O
OATP1B3 O
- O
, O
and O
OATP2B1 O
- O
mediated O
substrate O
transport O
was O
inhibited O
efficiently O
by O
silymarin B
( O
IC50 O
values O
of O
1 O
. O
3 O
, O
2 O
. O
2 O
and O
0 O
. O
3 O
micro O
M O
, O
respectively O
) O
, O
silybin B
A I
( O
IC50 O
values O
of O
9 O
. O
7 O
, O
2 O
. O
7 O
and O
4 O
. O
5 O
micro O
M O
, O
respectively O
) O
, O
silybin B
B I
( O
IC50 O
values O
of O
8 O
. O
5 O
, O
5 O
. O
0 O
and O
0 O
. O
8 O
micro O
M O
, O
respectively O
) O
, O
and O
silychristin B
( O
IC50 O
values O
of O

9 O
. O
0 O
, O
36 O
. O
4 O
, O
and O
3 O
. O
6 O
micro O
M O
, O
respectively O
) O
. O

Furthermore O
, O
silymarin O
, O
silybin B
A I
, O
and O
silybin B
B I
( O
100 O
micro O
M O
) O
significantly O
inhibited O
OATP O
- O
mediated O
estradiol B
- I
17 I
beta I
- I
glucuronide I
and O
rosuvastatin B
uptake O
into O
human O
hepatocytes O
. O

Calculation O
of O
the O
maximal O
unbound O
portal O
vein O
concentrations O
/ O
IC50 O
values O
indicated O
a O
low O
risk O
for O
silymarin O
- O
drug O
interactions O
in O
hepatic O
uptake O
with O
a O
customary O
silymarin O
dose O
. O

The O
extent O
of O
silymarin O
- O
drug O
interactions O
depends O
on O
OATP O
isoform O
specificity O
and O
concentrations O
of O
flavonolignans B
at O
the O
site O
of O
drug O
transport O
. O

Higher O
than O
customary O
doses O
of O
silymarin O
, O
or O
formulations O
with O
improved O
bioavailability O
, O
may O
increase O
the O
risk O
of O
flavonolignan B
interactions O
with O
OATP O
substrates O
in O
patients O
. O

Thiolates B
chemically O
induce O
redox O
activation O
of O
BTZ043 B
and O
related O
potent O
nitroaromatic O
anti O
- O
tuberculosis O
agents O
. O

The O
development O
of O
multidrug O
resistant O
( O
MDR O
) O
and O
extensively O
drug O
resistant O
( O
XDR O
) O
forms O
of O
tuberculosis O
( O
TB O
) O
has O
stimulated O
research O
efforts O
globally O
to O
expand O
the O
new O
drug O
pipeline O
. O

Nitroaromatic B
compounds O
, O
including O
1 B
, I
3 I
- I
benzothiazin I
- I
4 I
- I
ones I
( O
BTZs B
) O
and O
related O
agents O
, O
are O
a O
promising O
new O
class O
for O
the O
treatment O
of O
TB O
. O

Research O
has O
shown O
that O
the O
nitroso B
intermediates O
of O
BTZs B
that O
are O
generated O
in O
vivo O
cause O
suicide O
inhibition O
of O
decaprenylphosphoryl B
- I
beta I
- I
D I
- I
ribose I
2 O
' O
oxidase O
( O
DprE1 O
) O
, O
which O
is O
responsible O
for O
cell O
wall O
arabinogalactan O
biosynthesis O
. O

We O
have O
designed O
and O
synthesized O
novel O
anti O
- O
TB O
agents O
inspired O
from O
BTZs O
and O
other O
nitroaromatic B
compounds O
. O

Computational O
studies O
indicated O
that O
the O
unsubstituted O
aromatic B
carbons I
of O
BTZ043 B
and O
related O
nitroaromatic B
compounds O
are O
the O
most O
electron O
- O
deficient O
and O
might O
be O
prone O
to O
nucleophilic O
attack O
. O

Our O
chemical O
studies O
on O
BTZ043 B
and O
the O
additional O
nitroaromatic B
compounds O
synthesized O
by O
us O
and O
others O
confirmed O
the O
postulated O
reactivity O
. O

The O
results O
indicate O
that O
nucleophiles O
such O
as O
thiolates B
, O
cyanide B
, O
and O
hydride B
induce O
nonenzymatic O
reduction O
of O
the O
nitro B
groups O
present O
in O
these O
compounds O
to O
the O
corresponding O
nitroso B
intermediates O
by O
addition O
at O
the O
unsubstituted O
electron O
- O
deficient O
aromatic B
carbon I
present O
in O
these O
compounds O
. O

Furthermore O
, O
we O
demonstrate O
here O
that O
these O
compounds O
are O
good O
candidates O
for O
the O
classical O
von O
Richter O
reaction O
. O

These O
chemical O
studies O
offer O
an O
alternate O
hypothesis O
for O
the O
mechanism O
of O
action O
of O
nitroaromatic O
anti O
- O
TB O
agents O
, O
in O
that O
the O
cysteine B
thiol I
( O
ate B
) O
or O
a O
hydride B
source O
at O
the O
active O
site O
of O
DprE1 O
may O
trigger O
the O
reduction O
of O
the O
nitro B
groups O
in O
a O
manner O
similar O
to O
the O
von O
Richter O
reaction O
to O
the O
nitroso B
intermediates O
, O
to O
initiate O
the O
inhibition O
of O
DprE1 O
. O

A O
low O
- O
overpotential O
potassium B
- O
oxygen B
battery O
based O
on O
potassium B
superoxide I
. O

Li B
- I
O I
( I
2 I
) I
battery O
is O
regarded O
as O
one O
of O
the O
most O
promising O
energy O
storage O
systems O
for O
future O
applications O
. O

However O
, O
its O
energy O
efficiency O
is O
greatly O
undermined O
by O
the O
large O
overpotentials O
of O
the O
discharge O
( O
formation O
of O
Li B
( I
2 I
) I
O I
( I
2 I
) I
) O
and O
charge O
( O
oxidation O
of O
Li B
( I
2 I
) I
O I
( I
2 I
) I
) O
reactions O
. O

The O
parasitic O
reactions O
of O
electrolyte O
and O
carbon B
electrode O
induced O
by O
the O
high O
charging O
potential O
cause O
the O
decay O
of O
capacity O
and O
limit O
the O
battery O
life O
. O

Here O
, O
a O
K B
- O
O B
( I
2 I
) I
battery O
is O
report O
that O
uses O
K B
( I
+ I
) I
ions O
to O
capture O
O B
( I
2 I
) I
( I
- I
) I
to O
form O
the O
thermodynamically O
stable O
KO B
( I
2 I
) I
product O
. O

This O
allows O
for O
the O
battery O
to O
operate O
through O
the O
one O
- O
electron O
redox O
process O
of O
O B
( I
2 I
) I
/ O
O B
( I
2 I
) I
( I
- I
) I
. O

Our O
studies O
confirm O
the O
formation O
and O
removal O
of O
KO B
( I
2 I
) I
in O
the O
battery O
cycle O
test O
. O

Furthermore O
, O
without O
the O
use O
of O
catalysts O
, O
the O
battery O
shows O
a O
low O
discharge O
/ O
charge O
potential O
gap O
of O
less O
than O
50 O
mV O
at O
a O
modest O
current O
density O
, O
which O
is O
the O
lowest O
one O
that O
has O
ever O
been O
reported O
in O
metal O
- O
oxygen B
batteries O
. O

A O
membrane O
vesicle O
- O
based O
assay O
to O
enable O
prediction O
of O
human O
biliary O
excretion O
. O

Abstract O
1 O
. O

Prediction O
of O
biliary O
excretion O
is O
a O
challenge O
due O
to O
the O
lack O
of O
in O
vitro O
assays O
. O

Our O
laboratory O
previously O
demonstrated O
a O
highly O
significant O
correlation O
between O
in O
vitro O
IC O
( O
50 O
) O
values O
against O
mrp2 O
using O
rat O
canalicular O
liver O
plasma O
membrane O
vesicles O
and O
in O
vivo O
biliary O
excretion O
( O
Colombo O
et O
al O
. O
, O
2012 O
) O
. O

This O
study O
explores O
the O
possibility O
of O
predicting O
in O
vivo O
biliary O
excretion O
in O
human O
using O
membrane O
vesicles O
prepared O
from O
MDCKII O
cells O
transfected O
with O
human O
ABCC2 O
. O

2 O
. O

In O
vitro O
MRP2 O
activity O
was O
determined O
by O
measuring O
the O
ATP B
- O
dependent O
uptake O
of O
5 B
( I
6 I
) I
- I
carboxy I
- I
2 I
' I
, I
7 I
' I
- I
dichlorofluorescein I
( O
CDCF B
) O
in O
inside O
- O
out O
membrane O
vesicles O
isolated O
from O
MDCK O
- O
ABCC2 O
cells O
. O

CDCF O
uptake O
was O
time O
- O
and O
concentration O
- O
dependent O
( O
K O
( O
m O
) O
of O
4 O
. O
0 O
+ O
/ O
- O
1 O
. O
2 O
micro O
M O
and O
a O
V O
( O
max O
) O
of O
7 O
. O
8 O
+ O
/ O
- O
0 O
. O
9 O
pmol O
/ O
mg O
/ O
min O
) O
and O
inhibited O
by O
benzbromarone B
and O
MK B
- I
571 I
with O
IC O
( O
50 O
) O
values O
of O
1 O
. O
2 O
and O
7 O
. O
6 O
micro O
M O
, O
respectively O
. O

3 O
. O

A O
significant O
linear O
correlation O
( O
r O
( O
2 O
) O
= O
0 O
. O
790 O
) O
between O
the O
in O
vitro O
IC O
( O
50 O
) O
values O
from O
the O
described O
MRP2 O
assay O
and O
in O
vivo O
biliary O
excretion O
in O
humans O
was O
observed O
using O
11 O
well O
- O
documented O
drugs O
covering O
low O
to O
high O
biliary O
excretions O
. O

4 O
. O

This O
study O
demonstrates O
, O
for O
the O
first O
time O
, O
that O
inhibition O
of O
CDCF O
uptake O
in O
MDCKII O
- O
ABCC2 O
vesicles O
not O
only O
provides O
a O
screening O
assay O
to O
assess O
MRP2 O
drug O
- O
drug O
interaction O
potential O
, O
but O
is O
also O
predictive O
of O
human O
MRP2 O
- O
mediated O
biliary O
excretion O
. O

Effects O
of O
hydrogen B
bonding O
on O
internal O
conversion O
of O
GFP O
- O
like O
chromophores O
. O

II O
. O

The O
meta B
- I
amino I
systems O
. O

To O
rationalize O
the O
efficient O
quenching O
of O
the O
fluorescence O
and O
the O
Z O
- O
- O
> O
E O
photoisomerization O
of O
m B
- I
ABDI I
, O
the O
meta B
- I
amino I
analogue O
of O
the O
green O
fluorescent O
protein O
( O
GFP O
) O
chromophore O
, O
in O
protic O
solvents O
, O
the O
femtosecond O
time O
- O
resolved O
fluorescence O
and O
transient O
infrared O
( O
TRIR O
) O
spectra O
of O
m O
- I
ABDI I
in O
CD3CN B
, O
CH3OH B
, O
and O
CD3OD B
are O
determined O
. O

For O
solutions O
in O
CD3CN B
, O
the O
fluorescence O
decay O
lifetime O
is O
~ O
7 O
. O
9 O
ns O
and O
IR O
absorption O
lines O
near O
1513 O
, O
1531 O
, O
1557 O
, O
and O
1613 O
cm O
( O
- O
1 O
) O
of O
m O
- O
ABDI O
in O
its O
electronically O
excited O
state O
were O
observed O
with O
a O
decay O
time O
> O
5 O
ns O
. O

For O
solutions O
in O
CH3OH B
, O
the O
fluorescence O
decay O
is O
double O
exponential O
with O
time O
constants O
of O
~ O
16 O
and O
62 O
ps O
. O

In O
addition O
to O
IR O
absorption O
lines O
of O
m O
- O
ABDI O
in O
its O
electronically O
excited O
state O
with O
a O
decay O
time O
of O
~ O
16 O
ps O
, O
new O
features O
near O
1513 O
, O
1532 O
, O
1554 O
, O
and O
1592 O
cm O
( O
- O
1 O
) O
were O
observed O
to O
have O
a O
rise O
time O
of O
~ O
19 O
ps O
and O
a O
decay O
constant O
of O
~ O
58 O
ps O
, O
indicating O
formation O
of O
an O
intermediate O
. O

The O
assignments O
for O
the O
IR O
spectra O
of O
the O
ground O
and O
excited O
states O
were O
assisted O
with O
DFT O
and O
TDDFT O
calculations O
, O
respectively O
. O

We O
conclude O
that O
the O
torsion O
of O
the O
exocyclic O
C B
= I
C I
bond O
( O
the O
tau O
torsion O
) O
is O
responsible O
for O
the O
nonradiative O
decay O
of O
electronically O
excited O
m O
- O
ABDI O
in O
CD3CN B
. O

However O
, O
in O
CH3OH B
and O
CD3OD B
, O
the O
solute O
- O
solvent O
hydrogen B
bonding O
( O
SSHB O
) O
interactions O
diminish O
significantly O
the O
barrier O
of O
the O
tau O
torsion O
and O
induce O
a O
new O
pathway O
that O
competes O
successfully O
with O
the O
tau O
torsion O
, O
consistent O
with O
the O
efficient O
fluorescence O
quenching O
and O
the O
diminished O
yield O
for O
Z O
- O
- O
> O
E O
photoisomerization O
. O

The O
new O
pathway O
is O
likely O
associated O
with O
excited O
- O
state O
proton O
transfer O
( O
ESPT O
) O
from O
the O
solvent O
to O
m O
- O
ABDI O
, O
particularly O
the O
carbonyl B
group O
, O
and O
generates O
an O
intermediate O
( O
ESPT O
* O
) O
that O
is O
weakly O
fluorescent O
. O

Oxidation O
of O
tertiary B
amine I
- O
derivatized O
surfaces O
to O
control O
protein O
adhesion O
. O

Selective O
oxidation O
of O
omega B
- I
tertiary I
amine I
self O
- O
assembled O
thiol B
monolayers O
to O
tertiary B
amine I
N I
- I
oxides I
is O
shown O
to O
transform O
the O
adhesion O
of O
model O
proteins O
lysozyme O
and O
fibrinogen O
upon O
them O
. O

Efficient O
preparation O
of O
both O
secondary B
and I
tertiary I
linker O
amides B
as O
judged O
by O
X O
- O
ray O
photoelectron O
spectroscopy O
( O
XPS O
) O
and O
water O
droplet O
contact O
angle O
was O
achieved O
with O
an O
improved O
amide B
bond O
formation O
on O
gold O
quartz B
crystal O
microbalance O
( O
QCM O
) O
sensors O
using O
2 B
- I
( I
1H I
- I
7 I
- I
azabenzotriazol I
- I
1 I
- I
yl I
) I
- I
1 I
, I
1 I
, I
3 I
, I
3 I
- I
tetramethyl I
hexafluorophosphate I
methanaminium I
uronium I
( O
HATU B
) O
. O

Oxidation O
with O
hydrogen B
peroxide I
was O
similarly O
assessed O
, O
and O
adhesion O
of O
lysozyme O
and O
fibrinogen O
from O
phosphate B
buffered O
saline O
was O
then O
assayed O
by O
QCM O
and O
imaged O
by O
AFM O
. O

Tertiary B
amine I
- O
functionalized O
sensors O
adsorbed O
multilayers O
of O
aggregated O
lysozyme O
, O
whereas O
tertiary B
amine I
N I
- I
oxides I
and O
triethylene B
glycol I
- O
terminated O
monolayers O
are O
consistent O
with O
small O
protein O
aggregates O
. O

The O
surface O
containing O
a O
dimethylamine B
N I
- I
oxide I
headgroup O
and O
ethyl B
secondary I
amide I
linker O
showed O
the O
largest O
difference O
in O
adsorption O
of O
both O
proteins O
. O

Oxidation O
of O
tertiary B
amine I
decorated O
surfaces O
therefore O
holds O
the O
potential O
for O
selective O
deposition O
of O
proteins O
and O
cells O
through O
masking O
and O
other O
patterning O
techniques O
. O

Innate O
immune O
response O
and O
programmed O
cell O
death O
following O
carrier O
- O
mediated O
delivery O
of O
unmodified O
mRNA O
to O
respiratory O
cells O
. O

In O
this O
report O
we O
show O
that O
carrier O
- O
mediated O
delivery O
of O
mRNA O
may O
activate O
TLR3 O
signaling O
in O
respiratory O
cells O
. O

This O
activation O
of O
the O
innate O
immune O
system O
was O
accompanied O
with O
a O
massive O
production O
of O
type O
1 O
interferons O
and O
other O
immunostimulating O
cytokines O
. O

The O
recognition O
of O
mRNA O
by O
the O
innate O
immune O
system O
was O
also O
associated O
with O
cell O
death O
, O
which O
proceeded O
in O
human O
respiratory O
cells O
via O
pyroptosis O
, O
a O
form O
of O
programmed O
cell O
death O
mediated O
by O
substantial O
overexpression O
of O
caspase O
- O
1 O
. O

This O
indicated O
that O
the O
delivered O
mRNA O
is O
most O
likely O
also O
recognized O
by O
NOD O
- O
like O
receptors O
which O
regulate O
caspase O
- O
1 O
production O
. O

The O
viability O
of O
murine O
respiratory O
cells O
was O
less O
affected O
by O
mRNA O
transfection O
, O
which O
is O
in O
line O
with O
the O
lower O
transfection O
efficiency O
, O
lower O
innate O
immune O
response O
and O
the O
absence O
of O
a O
massive O
caspase O
- O
1 O
upregulation O
in O
these O
cells O
. O

Finally O
, O
we O
also O
demonstrated O
that O
the O
recognition O
of O
the O
delivered O
mRNA O
by O
the O
innate O
immune O
system O
had O
a O
negative O
effect O
on O
mRNA O
translation O
. O

Sexually O
dimorphic O
behavior O
after O
developmental O
exposure O
to O
characterize O
endocrine O
- O
mediated O
effects O
of O
different O
non O
- O
dioxin B
- O
like O
PCBs B
in O
rats O
. O

Many O
chemicals O
are O
known O
to O
exhibit O
endocrine O
activity O
and O
affect O
reproductive O
functions O
in O
vertebrates O
and O
invertebrates O
. O

Endocrine O
effects O
include O
influences O
on O
sexual O
differentiation O
of O
the O
brain O
during O
development O
and O
reproductive O
and O
non O
- O
reproductive O
behavior O
in O
adult O
offspring O
. O

We O
previously O
demonstrated O
that O
developmental O
exposure O
to O
a O
mixture O
of O
polychlorinated B
biphenyls I
( O
PCBs B
) O
which O
was O
reconstituted O
according O
to O
the O
congener O
pattern O
found O
in O
human O
breast O
milk O
caused O
feminization O
of O
sweet O
preference O
as O
a O
sexually O
dimorphic O
behavior O
in O
adult O
male O
rats O
, O
following O
decreases O
in O
aromatase O
activity O
in O
the O
brain O
of O
newborn O
male O
pups O
. O

This O
result O
may O
be O
due O
to O
dioxin B
- O
like O
or O
non O
- O
dioxin B
- O
like O
( O
NDL O
) O
PCBs B
and O
their O
respective O
effects O
on O
steroid B
hormones O
. O

The O
aim O
of O
the O
present O
experiments O
was O
to O
determine O
if O
exposure O
to O
highly O
purified O
NDL B
- I
PCBs I
( O
to O
remove O
Ah O
receptor O
active O
contaminants O
) O
also O
results O
in O
alteration O
of O
sweet O
preference O
. O

Pregnant O
rats O
were O
orally O
exposed O
to O
PCB52 B
( O
6 O
dose O
groups O
, O
total O
dose O
of O
0 O
- O
3000mg O
/ O
kg O
body O
weight O
) O
or O
PCB180 B
( O
6 O
dose O
groups O
, O
total O
dose O
of O
0 O
- O
1000mg O
/ O
kg O
body O
weight O
) O
. O

In O
a O
further O
experiment O
rat O
dams O
were O
treated O
with O
equimolar O
doses O
of O
PCB74 B
or O
PCB95 B
( O
total O
dose O
, O
760 O
mu O
mol O
/ O
kg O
body O
weight O
, O
corresponding O
to O
229mg O
/ O
kg O
or O
248mg O
/ O
kg O
body O
weight O
of O
PCB74 B
and O
PCB95 B
, O
respectively O
) O
. O

Adult O
male O
and O
female O
offspring O
were O
given O
a O
choice O
between O
a O
bottle O
of O
saccharin B
solution O
( O
0 O
. O
25 O
% O
) O
and O
a O
bottle O
of O
tap O
water O
on O
five O
consecutive O
days O
. O

Control O
females O
consumed O
approximately O
twice O
as O
much O
sweetened O
solution O
compared O
with O
control O
males O
, O
thus O
, O
demonstrating O
sexual O
dimorphism O
of O
this O
behavior O
. O

Only O
non O
- O
significant O
reduction O
of O
sweet O
preference O
was O
found O
at O
the O
top O
dose O
level O
in O
female O
offspring O
after O
exposure O
to O
PCB52 B
. O

Female O
offspring O
exposed O
to O
PCB180 B
exhibited O
signs O
of O
supernormal O
behavior O
as O
illustrated O
by O
increased O
saccharin B
consumption O
at O
intermediate O
dose O
levels O
. O

Decreased O
sweet O
preference O
was O
observed O
in O
females O
after O
developmental O
PCB74 B
, O
whereas O
males O
were O
unaffected O
. O

Only O
PCB95 B
increased O
saccharin B
consumption O
in O
exposed O
males O
, O
leading O
to O
decreased O
sexual O
dimorphism O
of O
this O
behavior O
and O
behavioral O
feminization O
. O

The O
results O
demonstrate O
that O
different O
NDL B
- I
PCBs I
exhibit O
differential O
effects O
on O
sexually O
dimorphic O
behavior O
and O
that O
feminization O
occurs O
after O
removal O
of O
Ah O
receptor O
active O
contaminants O
. O

Comparison O
with O
data O
from O
the O
literature O
reveals O
little O
evidence O
for O
a O
relation O
to O
anti O
- O
androgenic O
activity O
of O
the O
studied O
NDL B
- I
PCBs I
. O

Characterization O
of O
anti O
- O
crotalic O
antibodies O
. O

Crotalus O
durissus O
terrificus O
, O
C O
. O

d O
. O
collilineatus O
, O
C O
. O

d O
. O
cascavella O
and O
C O
. O

d O
. O
marajoensis O
are O
responsible O
minor O
but O
severe O
snake O
bites O
in O
Brazil O
. O

The O
venoms O
of O
these O
snakes O
share O
the O
presence O
of O
crotoxin O
, O
a O
neurotoxin O
comprising O
of O
two O
associated O
components O
, O
crotapotin O
and O
phospholipase O
A2 O
( O
PLA2 O
) O
. O

Treatment O
of O
the O
victims O
with O
specific O
antiserum O
is O
the O
unique O
effective O
therapeutic O
measure O
. O

The O
ability O
of O
anti O
- O
Crotalus O
antisera O
produced O
by O
the O
routine O
using O
crude O
venom O
to O
immunize O
horses O
or O
purified O
crotoxin O
and O
PLA2 O
as O
individual O
immunogens O
was O
compared O
. O

Antisera O
obtained O
from O
horses O
immunized O
with O
C O
. O
durissus O
terrificus O
crude O
venom O
were O
able O
to O
recognize O
and O
neutralize O
not O
only O
the O
toxins O
presents O
in O
C O
. O
durissus O
terrificus O
, O
but O
also O
the O
ones O
present O
in O
the O
venoms O
from O
C O
. O

d O
. O
collilineatus O
, O
C O
. O

d O
. O
cascavella O
and O
C O
. O

d O
. O
marajoensis O
. O

Antisera O
from O
horses O
immunized O
with O
individual O
crotoxin O
or O
PLA2 O
, O
although O
in O
lesser O
titers O
, O
were O
also O
able O
of O
recognizing O
the O
toxins O
in O
all O
four O
Crotalus O
species O
and O
neutralize O
the O
lethality O
of O
the O
C O
. O

d O
. O
terrificus O
venom O
. O

Combined O
effects O
of O
organochlorine B
pesticides O
heptachlor B
and O
hexachlorobenzene B
on O
the O
promotion O
stage O
of O
hepatocarcinogenesis O
in O
rats O
. O

We O
aimed O
to O
investigate O
the O
combined O
effect O
of O
organochlorine B
pesticides O
heptachlor B
( O
HEP B
) O
and O
hexachlorobenzene B
( O
HCB B
) O
by O
using O
a O
medium O
- O
term O
rat O
liver O
bioassay O
. O

Male O
F344 O
rats O
were O
initially O
administered O
diethylnitrosamine B
( O
DEN B
, O
200mg O
/ O
kgi O
. O
p O
. O
) O
; O
after O
a O
2 O
- O
week O
non O
- O
dosing O
period O
, O
they O
were O
given O
diets O
containing O
HEP O
( O
5 O
or O
25ppm O
) O
, O
HCB B
( O
70 O
or O
350ppm O
) O
, O
or O
their O
mixtures O
( O
5 O
and O
70ppm O
or O
25 O
and O
350ppm O
) O
for O
6weeks O
. O

All O
rats O
were O
subjected O
to O
partial O
hepatectomy O
at O
week O
3 O
and O
killed O
at O
week O
8 O
. O

We O
observed O
additive O
or O
synergistic O
effects O
of O
HEP B
and O
HCB B
in O
groups O
treated O
with O
mixtures O
of O
these O
pesticides O
. O

Number O
and O
area O
of O
preneoplastic O
foci O
positive O
for O
glutathione B
S B
- O
transferase O
placental O
form O
( O
GST O
- O
P O
) O
were O
consistently O
higher O
in O
these O
groups O
than O
the O
sum O
of O
individual O
values O
in O
the O
groups O
treated O
with O
HEP O
or O
HCB B
alone O
. O

Consistent O
with O
these O
findings O
, O
HEP B
and O
HCB B
had O
additive O
or O
synergistic O
effects O
on O
cell O
proliferation O
induction O
within O
the O
preneoplastic O
foci O
and O
cytochrome O
P450 O
( O
CYP O
) O
2B1 O
and O
3A1 O
induction O
, O
which O
may O
lead O
to O
more O
efficient O
metabolic O
activation O
of O
HEP B
and O
HCB B
. O

On O
the O
basis O
of O
these O
findings O
, O
we O
conclude O
that O
HEP O
and O
HCB B
have O
additive O
and O
synergistic O
effects O
on O
the O
development O
of O
GST O
- O
P O
- O
positive O
foci O
and O
that O
higher O
risks O
are O
associated O
with O
a O
combination O
of O
residual O
organochlorine B
pesticides O
in O
foods O
than O
with O
individual O
residual O
organochlorine B
pesticides O
. O

Monitoring O
of O
arsenic B
levels O
in O
some O
ready O
- O
to O
- O
use O
anti O
- O
malaria O
herbal O
products O
from O
drug O
sales O
outlets O
in O
the O
Madina O
area O
of O
Accra O
, O
Ghana O
. O

In O
Ghana O
anti O
- O
malaria O
herbal O
medicines O
or O
products O
are O
used O
to O
compliment O
commercial O
drugs O
in O
treatment O
and O
prevention O
of O
Plasmodium O
falciparum O
infections O
. O

In O
this O
study O
, O
four O
common O
aqueous O
based O
anti O
- O
malaria O
herbal O
products O
( O
coded O
HEB O
, O
KFE O
, O
MDM O
and O
NIB O
) O
which O
are O
used O
by O
Ghanaian O
population O
from O
pharmacy O
/ O
herbal O
stores O
in O
the O
Madina O
area O
, O
Accra O
were O
blindly O
and O
randomly O
sampled O
for O
cadmium B
( O
Cd B
) O
, O
arsenic B
( O
As B
) O
and O
Lead O
( O
Pb B
) O
analysis O
using O
Atomic O
Absorption O
Spectrophotometry O
technique O
. O

Arsenic B
concentrations O
were O
1 O
. O
087 O
mu O
g O
/ O
mL O
( O
108 O
. O
7 O
% O
) O
, O
1 O
. O
027 O
mu O
g O
/ O
mL O
( O
102 O
. O
7 O
% O
) O
, O
0 O
. O
330 O
mu O
g O
/ O
mL O
( O
33 O
. O
0 O
% O
) O
and O
0 O
. O
274 O
mu O
g O
/ O
mL O
( O
27 O
. O
4 O
% O
) O
in O
MDM O
, O
KFE O
, O
NIB O
and O
HEB O
respectively O
. O

Arsenic B
concentration O
determined O
in O
MDM O
and O
KFE O
were O
above O
the O
maximum O
permissible O
limit O
of O
1 O
. O
0ppm O
determined O
by O
WHO O
/ O
FAO O
. O

Cadmium B
concentration O
in O
each O
of O
the O
four O
products O
as O
well O
as O
lead O
concentration O
in O
KFE O
, O
NIB O
and O
HEB O
were O
below O
the O
detection O
limit O
of O
< O
0 O
. O
002mg O
/ O
mL O
( O
Cd B
) O
and O
< O
0 O
. O
005mg O
/ O
mL O
( O
Pb B
) O
respectively O
. O

The O
maximum O
permissible O
limits O
for O
Pb B
and O
Cd B
determined O
by O
WHO O
/ O
FAO O
are O
10 O
. O
0ppm O
and O
0 O
. O
3ppm O
respectively O
. O

Thus O
, O
random O
assessment O
on O
the O
safety O
of O
some O
ready O
- O
to O
- O
use O
aqueous O
based O
anti O
- O
malaria O
herbal O
products O
on O
the O
market O
is O
necessary O
to O
prevent O
public O
health O
hazards O
associated O
with O
consuming O
these O
plant O
extracts O
. O

Although O
lead O
and O
cadmium B
concentration O
in O
the O
anti O
- O
malaria O
herbal O
products O
were O
below O
the O
maximum O
permissible O
limits O
, O
their O
cumulative O
effect O
on O
the O
health O
of O
an O
individual O
which O
consume O
recommended O
volume O
of O
not O
less O
than O
1000 O
mL O
for O
effective O
malaria O
parasite O
clearance O
cannot O
be O
ignored O
. O

Enzymatic O
catalyzed O
palm O
oil O
hydrolysis O
under O
ultrasound O
irradiation O
: O
diacylglycerol B
synthesis O
. O

Diacylglycerol B
( O
DAG B
) O
rich O
oils O
have O
an O
organoleptic O
property O
like O
that O
of O
regular O
edible O
oils O
, O
but O
these O
oils O
do O
not O
tend O
to O
be O
accumulated O
as O
fat O
. O

Palm O
oil O
ranks O
first O
in O
the O
world O
in O
terms O
of O
edible O
oil O
production O
owing O
to O
its O
low O
cost O
. O

The O
aim O
of O
this O
study O
was O
to O
propose O
a O
new O
methodology O
to O
produce O
diacylglycerol B
by O
hydrolysis O
of O
palm O
oil O
using O
Lipozyme O
RM O
IM O
commercial O
lipase O
as O
a O
catalyst O
under O
ultrasound O
irradiation O
. O

The O
reactions O
were O
carried O
out O
at O
55 O
degrees O
C O
with O
two O
different O
methods O
. O

First O
, O
the O
reaction O
system O
was O
exposed O
to O
ultrasonic O
waves O
for O
the O
whole O
reaction O
time O
, O
which O
led O
to O
enzymatic O
inactivation O
and O
water O
evaporation O
. O

Ultrasound O
was O
then O
used O
to O
promote O
emulsification O
of O
the O
water O
/ O
oil O
system O
before O
the O
hydrolysis O
reaction O
, O
avoiding O
contact O
between O
the O
probe O
and O
the O
enzymes O
. O

An O
experimental O
design O
was O
used O
to O
optimize O
the O
ultrasound O
- O
related O
parameters O
and O
maximize O
the O
hydrolysis O
rate O
, O
and O
in O
these O
conditions O
, O
with O
a O
change O
in O
equilibrium O
, O
DAG B
production O
was O
evaluated O
. O

Better O
reaction O
conditions O
were O
achieved O
for O
the O
second O
method O
: O
11 O
. O
20 O
wt O
. O
% O
( O
water O
+ O
oil O
mass O
) O
water O
content O
, O
1 O
. O
36 O
wt O
. O
% O
( O
water O
+ O
oil O
mass O
) O
enzyme O
load O
, O
12 O
h O
of O
reaction O
time O
, O
1 O
. O
2 O
min O
and O
200 O
W O
of O
exposure O
to O
ultrasound O
. O

In O
these O
conditions O
diacylglycerol B
yield O
was O
34 O
. O
17 O
wt O
. O
% O
. O

Clearance O
and O
bioavailability O
study O
through O
arterio O
- O
venous O
drug O
concentrations O
relationship O
. O

Venous O
plasma O
drug O
concentrations O
are O
routinely O
monitored O
in O
order O
to O
determine O
pharmacokinetic O
parameters O
or O
to O
establish O
relationships O
with O
drug O
pharmacodynamic O
and O
clinical O
effects O
. O

Arterial O
drug O
concentration O
is O
higher O
than O
the O
respective O
venous O
concentration O
during O
the O
period O
where O
drug O
input O
of O
the O
substance O
predominates O
, O
whereas O
venous O
drug O
concentration O
is O
higher O
during O
the O
long O
period O
where O
drug O
elimination O
becomes O
the O
main O
process O
. O

This O
arterial O
- O
venous O
difference O
responds O
to O
current O
bioavailability O
and O
clearance O
of O
the O
drug O
- O
individual O
systems O
. O

Following O
the O
vein O
/ O
artery O
plasma O
drug O
concentration O
ratio O
at O
a O
non O
- O
eliminating O
organ O
it O
is O
possible O
to O
monitor O
both O
parameters O
time O
by O
time O
. O

This O
way O
of O
following O
up O
the O
pharmacokinetic O
systems O
allows O
us O
to O
detect O
any O
changes O
in O
drug O
absorption O
or O
disposition O
more O
efficiently O
, O
without O
the O
need O
of O
a O
long O
period O
of O
time O
and O
regardless O
the O
duration O
of O
such O
system O
modification O
. O

Spray O
- O
dried O
casein O
- O
based O
micelles O
as O
a O
vehicle O
for O
solubilization O
and O
controlled O
delivery O
of O
flutamide B
: O
Formulation O
, O
characterization O
, O
and O
in O
vivo O
pharmacokinetics O
. O

Novel O
casein O
( O
CAS O
) O
- O
based O
micelles O
loaded O
with O
the O
poorly O
soluble O
anti O
- O
cancer O
drug O
, O
flutamide B
( O
FLT B
) O
, O
were O
successfully O
developed O
in O
a O
powdered O
form O
via O
spray O
- O
drying O
technique O
. O

Genipin B
( O
GNP O
) O
was O
used O
to O
crosslink O
CAS O
micelles O
as O
demonstrated O
by O
color O
variation O
of O
the O
micelles O
. O

Drug O
solubilization O
was O
enhanced O
by O
incorporation O
within O
the O
hydrophobic O
micellar O
core O
which O
was O
confirmed O
by O
solubility O
study O
and O
UV O
spectra O
. O

Spherical O
core O
- O
shell O
micelles O
were O
obtained O
with O
a O
particle O
size O
below O
100nm O
and O
zeta O
potential O
around O
- O
30mV O
. O

At O
low O
drug O
loading O
, O
FLT B
was O
totally O
incorporated O
within O
micellar O
core O
as O
revealed O
by O
thermal O
analysis O
. O

However O
, O
at O
higher O
loading O
, O
excess O
non O
- O
incorporated O
drug O
at O
micelle O
surface O
caused O
a O
significant O
reduction O
in O
the O
surface O
charge O
density O
. O

Turbidity O
measurements O
demonstrated O
the O
high O
physical O
stability O
of O
micelles O
for O
2weeks O
dependent O
on O
GNP O
- O
crosslinking O
degree O
. O

In O
a O
dry O
powdered O
form O
, O
the O
micelles O
were O
stable O
for O
6months O
with O
no O
significant O
changes O
in O
drug O
content O
or O
particle O
size O
. O

A O
sustained O
drug O
release O
from O
CAS O
micelles O
up O
to O
5days O
was O
observed O
. O

After O
i O
. O
v O
. O
administration O
into O
rats O
, O
CAS O
micelles O
exhibited O
a O
prolonged O
plasma O
circulation O
of O
FLT B
compared O
to O
drug O
solution O
. O

Furthermore O
, O
a O
more O
prolonged O
drug O
systemic O
circulation O
was O
observed O
for O
GNP O
- O
crosslinked O
micelles O
. O

Overall O
, O
this O
study O
reports O
the O
application O
of O
spray O
- O
dried O
natural O
protein O
- O
based O
micelles O
for O
i O
. O
v O
. O
delivery O
of O
hydrophobic O
anti O
- O
cancer O
drugs O
such O
as O
FLT B
. O

Neuroprotective O
effects O
of O
mercaptoethylleonuri B
and O
mercaptoethylguanidi B
analogs O
on O
hydrogen B
peroxide I
- O
induced O
apoptosis O
in O
human O
neuronal O
SH O
- O
SY5Y O
cells O
. O

A O
series O
of O
mercaptoethylleonuri B
and O
mercaptoethylguanidi B
derivatives O
were O
designed O
and O
synthesized O
. O

Their O
neuroprotective O
effects O
toward O
H2O2 B
- O
induced O
apoptosis O
were O
investigated O
in O
human O
SH O
- O
SY5Y O
cells O
. O

The O
results O
from O
these O
studies O
identified O
several O
potent O
compounds O
, O
with O
compound O
8k O
emerging O
as O
the O
most O
effective O
. O

Further O
investigation O
demonstrated O
that O
8k O
reduced O
H2O2 B
- O
induced O
activation O
of O
mitochondrial O
apoptosis O
by O
inhibiting O
the O
expression O
of O
Bax O
and O
elevating O
the O
expression O
of O
Bcl O
- O
2 O
. O

Moreover O
, O
the O
molecular O
mechanism O
underlying O
the O
observed O
neuroprotective O
effects O
of O
8k O
was O
exerted O
via O
the O
Akt O
and O
JNK O
pathways O
. O

Compound O
8k O
can O
be O
a O
lead O
compound O
for O
further O
discovery O
of O
neuroprotective O
medicine O
. O

Paeoniflorin B
protects O
human O
EA O
. O
hy926 O
endothelial O
cells O
against O
gamma O
- O
radiation O
induced O
oxidative O
injury O
by O
activating O
the O
NF O
- O
E2 O
- O
related O
factor O
2 O
/ O
heme O
oxygenase O
- O
1 O
pathway O
. O

Pulmonary O
endothelial O
cells O
have O
been O
demonstrated O
to O
have O
a O
critical O
role O
in O
the O
pathogenesis O
of O
radiation O
- O
induced O
lung O
injury O
. O

Our O
preliminary O
experiments O
indicated O
that O
Paeoniflorin B
protected O
human O
EA O
. O
hy926 O
endothelial O
cells O
from O
radiation O
- O
induced O
oxidative O
injury O
. O

This O
study O
was O
designed O
to O
confirm O
the O
protective O
effect O
of O
Paeoniflorin B
against O
radiation O
- O
induced O
endothelial O
cellular O
damage O
and O
to O
elucidate O
the O
underlying O
mechanisms O
. O

Preincubation O
of O
EA O
. O
hy926 O
cells O
with O
Paeoniflorin B
before O
gamma O
- O
radiation O
resulted O
in O
significant O
inhibition O
of O
apoptosis O
, O
a O
decrease O
in O
mitochondrial O
membrane O
potential O
and O
enhanced O
cell O
viability O
. O

In O
particular O
, O
we O
showed O
that O
Paeoniflorin B
significantly O
reduced O
the O
formation O
of O
intracellular O
reactive O
oxygen B
species O
( O
ROS O
) O
, O
the O
level O
of O
malondialdehyde B
( O
MDA B
) O
and O
lactate B
dehydrogenase O
( O
LDH O
) O
leakage O
, O
and O
enhanced O
production O
of O
the O
endogenous O
antioxidants O
, O
glutathione B
( O
GSH B
) O
and O
superoxide B
dismutase O
( O
SOD O
) O
in O
EA O
. O
hy926 O
cells O
. O

Treatment O
of O
these O
cells O
with O
Paeoniflorin B
significantly O
induced O
HO O
- O
1 O
expression O
. O

Moreover O
, O
Paeoniflorin B
promoted O
the O
nuclear O
translocation O
of O
nuclear O
factor O
erythroid O
2 O
related O
factor O
- O
2 O
( O
Nrf O
- O
2 O
) O
. O

The O
Paeoniflorin B
- O
induced O
HO O
- O
1 O
expression O
was O
abrogated O
by O
Nrf2 O
siRNA O
. O

Furthermore O
, O
inhibition O
of O
HO O
- O
1 O
with O
zinc B
protoporphyrin I
IX I
( O
ZNPP B
) O
significantly O
reversed O
the O
protective O
effect O
of O
Paeoniflorin B
against O
radiation O
- O
induced O
damage O
in O
EA O
. O
hy926 O
cells O
. O

Our O
findings O
confirmed O
that O
Paeoniflorin B
protected O
EA O
. O
hy926 O
cells O
against O
radiation O
- O
induced O
injury O
through O
the O
Nrf2 O
/ O
HO O
- O
1 O
pathway O
. O

Stimuli O
- O
responsive O
copolymer O
solution O
and O
surface O
assemblies O
for O
biomedical O
applications O
. O

Stimuli O
- O
responsive O
polymeric O
materials O
is O
one O
of O
the O
fastest O
growing O
fields O
of O
the O
21st O
century O
, O
with O
the O
annual O
number O
of O
papers O
published O
more O
than O
quadrupling O
in O
the O
last O
ten O
years O
. O

The O
responsiveness O
of O
polymer O
solution O
assemblies O
and O
surfaces O
to O
biological O
stimuli O
( O
e O
. O
g O
. O
pH O
, O
reduction O
- O
oxidation O
, O
enzymes O
, O
glucose B
) O
and O
externally O
applied O
triggers O
( O
e O
. O
g O
. O
temperature O
, O
light O
, O
solvent O
quality O
) O
shows O
particular O
promise O
for O
various O
biomedical O
applications O
including O
drug O
delivery O
, O
tissue O
engineering O
, O
medical O
diagnostics O
, O
and O
bioseparations O
. O

Furthermore O
, O
the O
integration O
of O
copolymer O
architectures O
into O
stimuli O
- O
responsive O
materials O
design O
enables O
exquisite O
control O
over O
the O
locations O
of O
responsive O
sites O
within O
self O
- O
assembled O
nanostructures O
. O

The O
combination O
of O
new O
synthesis O
techniques O
and O
well O
- O
defined O
copolymer O
self O
- O
assembly O
has O
facilitated O
substantial O
developments O
in O
stimuli O
- O
responsive O
materials O
in O
recent O
years O
. O

In O
this O
tutorial O
review O
, O
we O
discuss O
several O
methods O
that O
have O
been O
employed O
to O
synthesize O
self O
- O
assembling O
and O
stimuli O
- O
responsive O
copolymers O
for O
biomedical O
applications O
, O
and O
we O
identify O
common O
themes O
in O
the O
response O
mechanisms O
among O
the O
targeted O
stimuli O
. O

Additionally O
, O
we O
highlight O
parallels O
between O
the O
chemistries O
used O
for O
generating O
solution O
assemblies O
and O
those O
employed O
for O
creating O
copolymer O
surfaces O
. O

Anatomical O
connection O
strength O
predicts O
dopaminergic O
drug O
effects O
on O
fronto O
- O
striatal O
function O
. O

RATIONALE O
: O
The O
neurotransmitter O
dopamine B
plays O
a O
key O
role O
in O
cognitive O
functions O
that O
are O
associated O
with O
fronto O
- O
striatal O
circuitry O
and O
has O
been O
implicated O
in O
many O
neuropsychiatric O
disorders O
. O

However O
, O
there O
is O
a O
large O
variability O
in O
the O
direction O
and O
extent O
of O
dopaminergic O
drug O
effects O
across O
individuals O
. O

OBJECTIVES O
: O
We O
investigated O
whether O
individual O
differences O
in O
dopaminergic O
drug O
effects O
on O
human O
fronto O
- O
striatal O
functioning O
are O
associated O
with O
individual O
differences O
in O
white O
matter O
tracts O
. O

METHODS O
: O
The O
effects O
of O
the O
dopamine B
receptor O
agonist O
bromocriptine B
were O
assessed O
using O
functional O
magnetic O
resonance O
imaging O
in O
22 O
healthy O
volunteers O
in O
a O
placebo O
- O
controlled O
, O
double O
- O
blind O
, O
within O
- O
subject O
design O
. O

Human O
psychopharmacology O
and O
functional O
neuroimaging O
were O
combined O
with O
functional O
connectivity O
analyses O
and O
structural O
connectivity O
analyses O
to O
establish O
a O
link O
between O
dopaminergic O
drug O
effects O
on O
fronto O
- O
striatal O
function O
and O
fronto O
- O
striatal O
anatomy O
. O

RESULTS O
: O
We O
demonstrate O
that O
bromocriptine B
alters O
functional O
signals O
associated O
with O
attention O
switching O
in O
the O
basal O
ganglia O
. O

Crucially O
, O
individual O
differences O
in O
the O
drug O
' O
s O
effect O
on O
these O
signals O
could O
be O
predicted O
from O
individual O
differences O
in O
fronto O
- O
striato O
- O
thalamic O
white O
matter O
tracts O
, O
as O
indexed O
by O
diffusion O
tensor O
imaging O
. O

Anatomical O
fronto O
- O
striatal O
connectivity O
also O
predicted O
drug O
effects O
on O
switch O
- O
related O
functional O
connectivity O
between O
the O
basal O
ganglia O
and O
the O
prefrontal O
cortex O
. O

CONCLUSIONS O
: O
These O
data O
reinforce O
the O
link O
between O
dopamine B
, O
cognition O
and O
the O
basal O
ganglia O
and O
have O
implications O
for O
the O
individual O
tailoring O
of O
dopaminergic O
drug O
therapy O
based O
on O
anatomical O
fronto O
- O
striatal O
connection O
strength O
. O

Management O
of O
chemotherapy O
- O
induced O
nausea O
and O
vomiting O
: O
focus O
on O
newer O
agents O
and O
new O
uses O
for O
older O
agents O
. O

Chemotherapy O
- O
induced O
nausea O
and O
vomiting O
( O
CINV O
) O
is O
associated O
with O
a O
significant O
deterioration O
in O
quality O
of O
life O
. O

The O
emetogenicity O
of O
the O
chemotherapeutic O
agents O
, O
repeated O
chemotherapy O
cycles O
, O
and O
patient O
risk O
factors O
significantly O
influence O
CINV O
. O

The O
use O
of O
a O
combination O
of O
a O
serotonin B
5 O
- O
HT3 O
receptor O
antagonist O
, O
dexamethasone B
and O
a O
neurokinin O
1 O
( O
NK1 O
) O
receptor O
antagonist O
has O
significantly O
improved O
the O
control O
of O
acute O
and O
delayed O
emesis O
in O
single O
- O
day O
chemotherapy O
. O

Palonosetron B
, O
a O
second O
- O
generation O
5 O
- O
HT3 O
receptor O
antagonist O
with O
a O
different O
half O
- O
life O
, O
a O
different O
binding O
capacity O
and O
a O
different O
mechanism O
of O
action O
than O
the O
first O
- O
generation O
5 O
- O
HT3 O
receptor O
antagonists O
appears O
to O
be O
the O
most O
effective O
agent O
in O
its O
class O
. O

Aprepitant B
, O
the O
first O
and O
only O
agent O
clinically O
available O
in O
the O
NK1 O
receptor O
antagonist O
drug O
class O
has O
been O
used O
effectively O
as O
an O
additive O
agent O
to O
the O
5 O
- O
HT3 O
receptor O
antagonists O
and O
dexamethasone B
to O
control O
CINV O
. O

Rolapitant B
and O
netupitant B
are O
other O
NK1 O
receptor O
antagonists O
that O
are O
currently O
in O
phase O
III O
clinical O
trials O
. O

Despite O
the O
control O
of O
emesis O
, O
nausea O
has O
not O
been O
well O
controlled O
by O
current O
agents O
. O

Olanzapine B
, O
a O
US O
- O
FDA O
approved O
antipsychotic O
, O
has O
emerged O
in O
recent O
trials O
as O
an O
effective O
preventative O
agent O
for O
CINV O
, O
as O
well O
as O
a O
very O
effective O
agent O
for O
the O
treatment O
of O
breakthrough O
emesis O
and O
nausea O
. O

Clinical O
trials O
using O
gabapentin B
, O
cannabinoids B
and O
ginger O
have O
not O
been O
definitive O
regarding O
their O
efficacy O
in O
the O
prevention O
of O
CINV O
. O

Additional O
studies O
are O
necessary O
for O
the O
control O
of O
nausea O
and O
for O
the O
control O
of O
CINV O
in O
the O
clinical O
settings O
of O
multiple O
- O
day O
chemotherapy O
and O
bone O
marrow O
transplantation O
. O

Predicting O
the O
Optimal O
Basal O
Insulin O
Infusion O
Pattern O
in O
Children O
and O
Adolescents O
on O
Insulin O
Pumps O
. O

OBJECTIVEWe O
aimed O
at O
developing O
and O
cross O
- O
validating O
a O
mathematical O
prediction O
model O
for O
an O
optimal O
basal O
insulin O
infusion O
pattern O
for O
children O
with O
type O
1 O
diabetes O
on O
continuous O
subcutaneous O
insulin O
infusion O
therapy O
( O
CSII O
) O
. O
RESEARCH O
DESIGN O
AND O
METHODSWe O
used O
the O
German O
/ O
Austrian O
DPV O
- O
Wiss O
database O
for O
quality O
control O
and O
scientific O
surveys O
in O
pediatric O
diabetology O
and O
retrieved O
all O
CSII O
patients O
< O
20 O
years O
of O
age O
( O
November O
2009 O
) O
. O

A O
total O
of O
1 O
, O
248 O
individuals O
from O
our O
previous O
study O
were O
excluded O
( O
dataset O
1 O
) O
, O
resulting O
in O
6 O
, O
063 O
CSII O
patients O
( O
dataset O
2 O
) O
( O
mean O
age O
10 O
. O
6 O
+ O
/ O
- O
4 O
. O
3 O
years O
) O
. O

Only O
the O
most O
recent O
basal O
insulin O
infusion O
rates O
( O
BRs O
) O
were O
considered O
. O

BR O
patterns O
were O
identified O
and O
corresponding O
patients O
sorted O
by O
unsupervised O
clustering O
. O

Logistic O
regression O
analysis O
was O
applied O
to O
calculate O
the O
probabilities O
for O
each O
BR O
pattern O
. O

Equations O
were O
based O
on O
both O
independent O
datasets O
separately O
, O
and O
probabilities O
for O
BR O
patterns O
were O
cross O
- O
validated O
using O
typical O
test O
patients O
. O
RESULTSOf O
the O
6 O
, O
063 O
children O
, O
5 O
, O
903 O
clustered O
in O
one O
of O
four O
major O
circadian O
BR O
patterns O
, O
confirming O
our O
previous O
study O
. O

The O
oldest O
age O
- O
group O
( O
mean O
age O
12 O
. O
8 O
years O
) O
was O
represented O
by O
2 O
, O
490 O
patients O
( O
42 O
. O
18 O
% O
) O
with O
a O
biphasic O
dawn O
- O
dusk O
pattern O
( O
BC O
) O
. O

A O
broad O
single O
insulin O
maximum O
at O
9 O
- O
10 O
p O
. O
m O
. O

( O
F O
) O
was O
unveiled O
by O
853 O
patients O
( O
14 O
. O
45 O
% O
) O
( O
mean O
age O
6 O
. O
3 O
years O
) O
. O

Logistic O
regression O
analysis O
revealed O
that O
age O
, O
to O
a O
lesser O
extent O
duration O
of O
diabetes O
, O
and O
partly O
sex O
predicted O
BR O
patterns O
. O

Cross O
- O
validation O
revealed O
almost O
identical O
probabilities O
for O
BR O
patterns O
BC O
and O
F O
in O
the O
two O
datasets O
but O
some O
variation O
in O
the O
remaining O
two O
BR O
patterns O
. O
CONCLUSIONSReconfirm O
of O
four O
key O
BR O
patterns O
in O
two O
very O
large O
independent O
cohorts O
supports O
that O
these O
patterns O
are O
realistic O
approximations O
of O
the O
circadian O
distribution O
of O
insulin O
needs O
in O
children O
with O
type O
1 O
diabetes O
. O

Prediction O
of O
an O
optimal O
pattern O
a O
priori O
can O
improve O
initiation O
and O
clinical O
follow O
- O
up O
of O
CSII O
in O
children O
and O
adolescents O
. O

In O
addition O
, O
these O
BR O
patterns O
represent O
valuable O
information O
for O
insulin O
- O
infusion O
algorithms O
in O
closed O
- O
loop O
CSII O
. O

Metabolism O
- O
Dependent O
Inhibition O
of O
CYP3A4 O
by O
Lapatinib B
: O
Evidence O
for O
Formation O
of O
a O
Metabolic O
Intermediate O
Complex O
with O
a O
Nitroso B
/ O
Oxime B
Metabolite O
Formed O
via O
a O
Nitrone B
Intermediate O
. O

Metabolism O
- O
dependent O
inhibition O
( O
MDI O
) O
of O
cytochrome O
P450 O
( O
P450 O
) O
enzymes O
has O
the O
potential O
to O
cause O
clinically O
relevant O
drug O
- O
drug O
interactions O
. O

In O
the O
case O
of O
several O
alkylamine B
drugs O
, O
MDI O
of O
P450 O
involves O
formation O
of O
a O
metabolite O
that O
binds O
quasi O
- O
irreversibly O
to O
the O
ferrous B
heme I
iron B
to O
form O
a O
metabolic O
intermediate O
( O
MI O
) O
complex O
. O

The O
specific O
metabolites O
coordinately O
bound O
to O
ferrous B
iron B
and O
the O
pathways O
leading O
to O
MI O
complex O
formation O
are O
the O
subject O
of O
debate O
. O

We O
describe O
an O
approach O
combining O
heme B
iron I
oxidation O
with O
potassium B
ferricyanide I
and O
metabolite O
profiling O
to O
probe O
the O
mechanism O
of O
MI O
complex O
- O
based O
CYP3A4 O
inactivation O
by O
the O
secondary O
alkylamine O
drug O
lapatinib B
. O

Ten O
metabolites O
formed O
from O
lapatinib B
by O
CYP3A4 O
- O
mediated O
heteroatom O
dealkylation O
, O
C B
- O
hydroxylation O
, O
N B
- O
oxygenation O
with O
or O
without O
further O
oxidation O
, O
or O
a O
combination O
thereof O
, O
were O
detected O
by O
accurate O
mass O
spectrometry O
. O

The O
abundance O
of O
one O
metabolite O
, O
the O
N B
- I
dealkylated I
nitroso I
/ I
oxime I
lapatinib I
metabolite O
( O
M9 O
) O
, O
correlated O
directly O
with O
the O
prevalence O
or O
the O
disruption O
of O
the O
MI O
complex O
with O
CYP3A4 O
. O

Nitroso B
/ O
oxime B
metabolite O
formation O
from O
secondary B
alkylamines I
has O
been O
proposed O
to O
occur O
through O
two O
possible O
pathways O
: O
( O
1 O
) O
sequential O
N B
- O
dealkylation O
, O
N B
- O
hydroxylation O
, O
and O
dehydrogenation O
( O
primary B
hydroxylamine I
pathway O
) O
or O
( O
2 O
) O
N B
- O
hydroxylation O
with O
dehydrogenation O
to O
yield O
a O
nitrone B
followed O
by O
N B
- O
dealkylation O
( O
secondary B
hydroxylamine I
pathway O
) O
. O

All O
intermediates O
for O
the O
secondary O
hydroxylamine B
pathway O
were O
detected O
but O
the O
primary O
N B
- I
hydroxylamine I
intermediate O
of O
the O
primary O
hydroxylamine B
pathway O
was O
not O
. O

Our O
findings O
support O
the O
mechanism O
of O
lapatinib B
CYP3A4 O
inactivation O
as O
MI O
complex O
formation O
with O
the O
nitroso B
metabolite O
formed O
through O
the O
secondary B
hydroxylamine I
and O
nitrone B
pathway O
, O
rather O
than O
by O
N B
- O
dealkylation O
to O
the O
primary B
amine I
followed O
by O
N B
- O
hydroxylation O
and O
dehydrogenation O
as O
is O
usually O
assumed O
. O

Interpretation O
of O
optoelectronic O
transient O
and O
charge O
extraction O
measurements O
in O
dye O
- O
sensitized O
solar O
cells O
. O

Tools O
that O
assess O
the O
limitations O
of O
dye O
sensitized O
solar O
cells O
( O
DSSCs O
) O
made O
with O
new O
materials O
are O
critical O
for O
progress O
. O

Measuring O
the O
transient O
electrical O
signals O
( O
voltage O
or O
current O
) O
after O
optically O
perturbing O
a O
DSSC O
is O
an O
approach O
which O
can O
give O
information O
about O
electron O
concentration O
, O
transport O
and O
recombination O
. O

Here O
we O
describe O
the O
theory O
and O
practice O
of O
this O
class O
of O
optoelectronic O
measurements O
, O
illustrated O
with O
numerous O
examples O
. O

The O
measurements O
are O
interpreted O
with O
the O
multiple O
trapping O
continuum O
model O
which O
describes O
electrons O
in O
a O
semiconductor O
with O
an O
exponential O
distribution O
of O
trapping O
states O
. O

We O
review O
standard O
small O
perturbation O
photocurrent O
and O
photovoltage O
transients O
, O
and O
introduce O
the O
photovoltage O
time O
of O
flight O
measurement O
which O
allows O
the O
simultaneous O
derivation O
of O
both O
effective O
diffusion O
and O
recombination O
coefficients O
. O

We O
then O
consider O
the O
utility O
of O
large O
perturbation O
measurements O
such O
as O
charge O
extraction O
and O
the O
current O
interrupt O
technique O
for O
finding O
the O
internal O
charge O
and O
voltage O
within O
a O
device O
. O

Combining O
these O
measurements O
allows O
differences O
between O
DSSCs O
to O
be O
understood O
in O
terms O
such O
as O
electron O
collection O
efficiency O
, O
semiconductor O
conduction O
band O
edge O
shifts O
and O
recombination O
kinetics O
. O

Functional O
UDP B
- O
glucuronyltransferas O
2B15 O
polymorphism O
and O
bisphenol B
A I
concentrations O
in O
blood O
: O
results O
from O
physiologically O
based O
kinetic O
modelling O
. O

Bisphenol B
A I
( O
BPA B
) O
is O
a O
chemical O
in O
widespread O
use O
that O
is O
under O
scientific O
discussion O
due O
to O
its O
endocrine O
activity O
. O

Controversies O
exist O
about O
how O
to O
interpret O
reportedly O
high O
blood O
concentrations O
measured O
in O
uncontrolled O
situations O
. O

Physiologically O
based O
pharmaco O
- O
/ O
toxicokinetic O
modelling O
resulted O
in O
10 O
- O
100 O
- O
fold O
lower O
blood O
concentrations O
than O
those O
reported O
. O

Moreover O
, O
in O
controlled O
situations O
, O
BPA B
did O
not O
exceed O
the O
level O
of O
detection O
( O
< O
0 O
. O
3 O
ng O
/ O
ml O
) O
in O
human O
blood O
or O
urine O
. O

Using O
a O
validated O
human O
PBK O
model O
, O
this O
study O
investigated O
the O
influence O
of O
functionally O
relevant O
polymorphic O
UGT2B15 O
, O
the O
enzyme O
mediating O
BPA B
metabolism O
, O
on O
the O
BPA B
concentration O
- O
time O
profile O
in O
human O
blood O
. O

Maximum O
concentrations O
( O
C O
( O
max O
) O
) O
and O
areas O
under O
the O
curves O
( O
AUCs O
) O
in O
blood O
from O
high O
and O
low O
metabolisers O
differed O
by O
a O
factor O
of O
4 O
. O
7 O
and O
4 O
. O
6 O
, O
respectively O
( O
doses O
: O
1 O
and O
0 O
. O
05 O
mu O
g O
/ O
kg O
/ O
day O
) O
. O

Low O
metabolisers O
excreted O
a O
greater O
proportion O
of O
BPA B
via O
the O
sulphate B
pathway O
compared O
to O
high O
metabolisers O
. O

This O
finding O
explains O
why O
C O
( O
max O
) O
and O
AUC O
increased O
to O
a O
smaller O
extent O
, O
as O
predicted O
from O
in O
vitro O
data O
obtained O
with O
transfected O
cells O
possessing O
only O
the O
UGT2B15 O
variants O
. O

The O
highest O
C O
( O
max O
) O
value O
calculated O
in O
the O
subject O
with O
the O
lowest O
metabolic O
clearance O
was O
roughly O
40 O
pg O
/ O
ml O
, O
which O
is O
far O
lower O
than O
reported O
high O
blood O
concentrations O
, O
which O
in O
turn O
cannot O
be O
explained O
by O
genetically O
impaired O
UGT2B15 O
activity O
. O

From O
the O
risk O
assessment O
perspective O
, O
our O
results O
indicate O
that O
the O
traditional O
uncertainty O
factor O
is O
sufficient O
to O
account O
for O
the O
variability O
in O
the O
polymorphic O
glucuronidation O
of O
BPA B
. O

Current O
- O
use O
pesticides O
in O
stream O
water O
and O
suspended O
particles O
following O
runoff O
: O
Exposure O
, O
effects O
, O
and O
mitigation O
requirements O
. O

The O
European O
Union O
' O
s O
directive O
for O
sustainable O
use O
of O
pesticides O
requires O
implementing O
risk O
mitigation O
measures O
at O
streams O
threatened O
by O
pesticide O
entries O
. O

The O
need O
for O
mitigation O
measures O
was O
investigated O
at O
10 O
stream O
sites O
within O
an O
intensively O
used O
arable O
region O
in O
central O
Germany O
by O
characterizing O
pesticide O
exposure O
following O
edge O
- O
of O
- O
field O
runoff O
and O
effects O
on O
the O
aquatic O
macroinvertebrates O
. O

Moreover O
, O
the O
influence O
of O
riparian O
buffer O
strip O
width O
( O
as O
a O
mitigation O
measure O
) O
at O
the O
sampling O
sites O
was O
considered O
. O

Generally O
, O
invertebrate O
fauna O
was O
dominated O
by O
pesticide O
- O
tolerant O
species O
, O
suggesting O
a O
high O
pesticide O
exposure O
at O
almost O
all O
sites O
. O

This O
result O
is O
also O
reflected O
by O
the O
elevated O
levels O
of O
suspended O
particle O
contamination O
in O
terms O
of O
toxic O
units O
( O
logTUMax O
> O
- O
2 O
) O
, O
corresponding O
to O
one O
- O
hundredth O
of O
the O
median O
lethal O
concentration O
( O
LC50 O
) O
to O
Daphnia O
magna O
. O

At O
two O
sites O
that O
received O
high O
aqueous O
- O
phase O
entries O
of O
the O
pyrethroid B
lambda B
- I
cyhalothrin I
( O
logTUMax O
> O
- O
0 O
. O
6 O
) O
, O
the O
abundance O
and O
number O
of O
sensitive O
species O
in O
terms O
of O
the O
species O
at O
risk O
index O
decreased O
during O
the O
pesticide O
application O
period O
. O

In O
contrast O
, O
no O
acute O
significant O
negative O
effects O
on O
macroinvertebrates O
were O
observed O
at O
sites O
characterised O
by O
low O
water O
- O
phase O
toxicity O
( O
logTUMax O
< O
- O
3 O
. O
5 O
) O
. O

An O
influence O
of O
riparian O
buffer O
strip O
width O
on O
pesticide O
exposure O
was O
not O
observed O
, O
supposedly O
because O
of O
the O
presence O
of O
erosion O
rills O
and O
ephemeral O
ditches O
. O

In O
conclusion O
, O
results O
show O
that O
mitigation O
measures O
( O
such O
as O
the O
improvement O
of O
currently O
present O
riparian O
buffer O
strips O
) O
are O
needed O
in O
the O
study O
area O
. O

Environ O
Toxicol O
Chem O
2013 O
; O
32 O
: O
1254 O
- O
1263 O
. O

( O
c O
) O
2013 O
SETAC O
. O

ERK O
- O
mediated O
phosphorylation O
of O
fibroblast O
growth O
factor O
receptor O
1 O
on O
Ser777 B
inhibits O
signaling O
. O

Fibroblast O
growth O
factor O
1 O
( O
FGF1 O
) O
controls O
cellular O
activities O
through O
the O
activation O
of O
specific O
cell O
- O
surface O
FGF O
receptors O
( O
FGFRs O
) O
. O

Transphosphorylation O
of O
tyrosine B
residues O
in O
the O
kinase O
domain O
of O
FGFRs O
leads O
to O
activation O
of O
intracellular O
signaling O
cascades O
, O
including O
those O
mediated O
by O
mitogen O
- O
activated O
protein O
kinases O
( O
MAPKs O
) O
. O

FGFRs O
also O
contain O
a O
serine B
- O
rich O
C B
- O
terminal O
tail O
. O

We O
identified O
a O
regulatory O
mechanism O
of O
FGFR O
signaling O
involving O
phosphorylation O
of O
Ser B
( O
777 O
) O
in O
the O
C B
- O
terminal O
region O
of O
FGFR1 O
by O
the O
MAPKs O
extracellular O
signal O
- O
regulated O
kinase O
1 O
( O
ERK1 O
) O
and O
ERK2 O
. O

Prevention O
of O
the O
phosphorylation O
of O
Ser B
( O
777 O
) O
in O
FGFR1 O
or O
mutation O
of O
Ser B
( O
777 O
) O
to O
alanine B
enhanced O
FGF O
- O
stimulated O
receptor O
tyrosine B
phosphorylation O
and O
increased O
cell O
proliferation O
, O
cell O
migration O
, O
and O
axonal O
growth O
. O

A O
form O
of O
FGFR1 O
with O
a O
phosphomimetic O
mutation O
at O
Ser B
( O
777 O
) O
exhibited O
reduced O
signaling O
. O

Activation O
of O
MAPKs O
by O
other O
receptor O
tyrosine B
kinases O
also O
resulted O
in O
phosphorylation O
of O
Ser B
( O
777 O
) O
in O
FGFR1 O
, O
thereby O
enabling O
crosstalk O
regulation O
of O
FGFR O
activity O
by O
other O
signaling O
pathways O
. O

Our O
data O
reveal O
a O
negative O
feedback O
mechanism O
that O
controls O
FGF O
signaling O
and O
thereby O
protects O
the O
cell O
from O
excessive O
activation O
of O
FGFR O
. O

Indolizine B
derivatives O
as O
HIV O
- O
1 O
VIF O
- O
ElonginC O
interaction O
inhibitors O
. O

Compound O
1 O
( O
VEC O
- O
5 O
) O
was O
identified O
as O
a O
potent O
small O
molecular O
HIV O
- O
1 O
VIF O
inhibitor O
that O
targets O
the O
VIF O
- O
ElonginC O
interaction O
. O

A O
structure O
- O
activity O
relationship O
study O
was O
carried O
out O
to O
develop O
compounds O
with O
improved O
efficacy O
against O
HIV O
- O
1 O
and O
49 O
indolizine B
derivatives O
of O
three O
categories O
were O
designed O
and O
synthesized O
. O

We O
found O
that O
5 O
compounds O
exhibited O
promising O
anti O
- O
HIV O
- O
1 O
activity O
and O
the O
most O
active O
compound O
2g O
had O
an O
IC O
( O
50 O
) O
value O
of O
11 O
. O
0 O
mu O
M O
. O

These O
results O
provide O
new O
information O
to O
develop O
highly O
potent O
small O
- O
molecule O
HIV O
- O
1 O
VIF O
inhibitors O
. O

( O
c O
) O
2013 O
John O
Wiley O
& O
Sons O
A O
/ O
S O
. O

Solution O
structure O
and O
in O
silico O
binding O
of O
a O
cyclic O
peptide O
with O
hepatitis O
B O
surface O
antigen O
. O

A O
specific O
ligand O
targeting O
the O
immunodominant O
region O
of O
hepatitis O
B O
virus O
( O
HBV O
) O
is O
desired O
in O
neutralizing O
the O
infectivity O
of O
the O
virus O
. O

In O
a O
previous O
study O
, O
a O
disulfide B
constrained O
cyclic O
peptide O
cyclo B
S I
( I
1 I
) I
, O
S B
( I
9 I
) I
Cys I
- I
Glu I
- I
Thr I
- I
Gly I
- I
Ala I
- I
Lys I
- I
Pro I
- I
His I
- I
Cys I
( O
S B
( O
1 O
) O
, O
S B
( I
9 I
) I
- I
cyclo I
- I
CETGAKPHC I
) O
was O
isolated O
from O
a O
phage O
displayed O
cyclic O
peptide O
library O
using O
an O
affinity O
selection O
method O
against O
HBV O
surface O
antigen O
( O
HBsAg O
) O
. O

The O
cyclic O
peptide O
binds O
tightly O
to O
HBsAg O
with O
a O
relative O
dissociation O
constant O
( O
K O
( O
D O
) O
( O
rel O
) O
) O
of O
2 O
. O
9 O
nM O
. O

The O
binding O
site O
of O
the O
peptide O
was O
located O
at O
the O
immunodominant O
region O
on O
HBsAg O
. O

Consequently O
, O
this O
study O
was O
aimed O
to O
elucidate O
the O
structure O
of O
the O
cyclic O
peptide O
and O
its O
interaction O
with O
HBsAg O
in O
silico O
. O

The O
solution O
structure O
of O
this O
cyclic O
peptide O
was O
solved O
using O
( B
1 I
) I
H I
, O
( B
13 I
) I
C I
and O
( B
15 I
) I
N I
NMR O
spectroscopy O
and O
molecular O
dynamics O
( O
MD O
) O
simulations O
with O
NMR O
- O
derived O
distance O
and O
torsion O
angle O
restraints O
. O

The O
cyclic O
peptide O
adopted O
two O
distinct O
conformations O
due O
to O
the O
isomerization O
of O
the O
Pro B
residue O
with O
one O
structured O
region O
in O
the O
ETGA O
sequence O
. O

Docking O
studies O
of O
the O
peptide O
ensemble O
with O
a O
model O
structure O
of O
HBsAg O
revealed O
that O
the O
cyclic O
peptide O
can O
potentially O
be O
developed O
as O
a O
therapeutic O
drug O
that O
inhibits O
the O
virus O
- O
host O
interactions O
. O

( O
c O
) O
2013 O
John O
Wiley O
& O
Sons O
A O
/ O
S O
. O

Adsorption O
of O
model O
perfumes O
at O
the O
air O
- O
solution O
interface O
by O
coadsorption O
with O
an O
anionic O
surfactant O
. O

The O
adsorption O
of O
the O
model O
perfumes O
phenyl B
ethanol I
, O
PE O
, O
and O
linalool B
, O
LL O
, O
at O
the O
air O
- O
solution O
interface O
by O
coadsorption O
with O
the O
anionic O
surfactant O
sodium B
dodecyl I
6 I
- I
benezene I
sulfonate I
, O
LAS B
- I
6 I
, O
has O
been O
studied O
primarily O
by O
neutron O
reflectivity O
, O
NR O
. O

The O
variation O
in O
the O
mixed O
surface O
adsorption O
with O
solution O
composition O
is O
highly O
nonideal O
, O
and O
the O
more O
hydrophobic O
LL O
is O
more O
surface O
active O
. O

At O
a O
LAS B
- I
6 I
concentration O
of O
0 O
. O
5 O
mM O
the O
adsorption O
of O
PE O
and O
LL O
is O
broadly O
similar O
but O
with O
the O
LL O
systematically O
more O
surface O
active O
, O
and O
at O
2 O
mM O
the O
LL O
completes O
more O
effectively O
for O
the O
surface O
than O
the O
PE O
. O

The O
variation O
in O
surface O
composition O
with O
solution O
composition O
and O
concentration O
reflect O
the O
greater O
hydrophobicity O
and O
hence O
surface O
activity O
of O
LL O
, O
and O
the O
greater O
solubility O
of O
PE O
in O
aqueous O
solution O
. O

Changing O
the O
geometry O
of O
the O
LAS B
isomer O
, O
from O
the O
symmetrical O
LAS B
- I
6 I
geometry O
to O
the O
more O
asymmetrical O
LAS B
- I
4 I
, O
results O
in O
the O
LL O
competing O
more O
effectively O
for O
the O
surface O
due O
to O
changes O
in O
the O
packing O
constraints O
associated O
with O
the O
hydrophobic O
region O
. O

The O
results O
provide O
insights O
into O
the O
factors O
that O
affect O
coadsorption O
that O
can O
be O
more O
broadly O
applied O
to O
the O
surface O
delivery O
of O
a O
wide O
range O
of O
molecules O
other O
than O
perfumes O
. O

In O
vitro O
polyphenolics O
erythrocyte O
model O
and O
in O
vivo O
chicken O
embryo O
model O
revealed O
gallic B
acid I
to O
be O
a O
potential O
hemorrhage O
inducer O
: O
physicochemical O
action O
mechanisms O
. O

The O
in O
vivo O
chicken O
embryo O
model O
( O
CEM O
) O
demonstrated O
that O
gallic B
acid I
( O
GA O
) O
induced O
dysvascularization O
and O
hypoxia O
. O

Inflammatory O
edema O
, O
Zenker O
' O
s O
necrosis O
, O
hemolysis O
, O
and O
liposis O
of O
cervical O
muscles O
were O
the O
common O
symptoms O
. O

Levels O
of O
the O
gene O
hif O
- O
1 O
alpha O
, O
HIF O
- O
1 O
alpha O
, O
TNF O
- O
alpha O
, O
IL O
- O
6 O
, O
and O
NF O
kappa O
B O
in O
cervical O
muscles O
were O
all O
significantly O
upregulated O
, O
while O
the O
vascular O
endothelial O
growth O
factor O
( O
VEGF O
) O
was O
downregulated O
in O
a O
dose O
- O
responsive O
manner O
. O

Consequently O
, O
the O
cervical O
muscle O
inflammation O
and O
hemolysis O
could O
have O
been O
stimulated O
en O
route O
to O
the O
tissue O
TNF O
- O
alpha O
- O
canonical O
and O
the O
atypical O
pathways O
. O

We O
hypothesized O
that O
GA O
could O
deplete O
the O
dissolved O
oxygen B
( O
DO O
) O
at O
the O
expense O
of O
semiquinone B
and O
quinone B
formation O
, O
favoring O
the O
reactive O
oxygen B
species O
( O
ROS O
) O
production O
to O
induce O
RBC O
disruption O
and O
Fe B
( I
2 I
+ I
) I
ion O
release O
. O

To O
explore O
this O
, O
the O
in O
vitro O
polyphenolics B
- O
erythrocyte O
model O
( O
PEM O
) O
was O
established O
. O

PEM O
revealed O
that O
the O
DO O
was O
rapidly O
depleted O
, O
leading O
to O
the O
release O
of O
a O
huge O
amount O
of O
Fe B
( I
II I
) I
ions O
and O
hydrogen B
peroxide I
( O
HPO B
) O
in O
a O
two O
- O
phase O
kinetic O
pattern O
. O

The O
kinetic O
coefficients O
for O
Fe B
( I
II I
) I
ion O
release O
ranged O
from O
0 O
. O
347 O
h O
( O
- O
1 O
) O
to O
0 O
. O
774 O
h O
( O
- O
1 O
) O
; O
and O
those O
for O
Fe B
( I
III I
) I
ion O
production O
were O
from O
6 O
. O
66 O
x O
10 O
( O
- O
3 O
) O
h O
( O
- O
1 O
) O
to O
8 O
. O
93 O
x O
10 O
( O
- O
3 O
) O
h O
( O
- O
1 O
) O
. O

For O
phase O
I O
HPO O
production O
, O
they O
ranged O
from O
0 O
. O
236 O
h O
( O
- O
1 O
) O
to O
0 O
. O
774 O
h O
( O
- O
1 O
) O
and O
for O
phase O
II O
HPO O
production O
from O
0 O
. O
764 O
h O
( O
- O
1 O
) O
to O
2 O
. O
560 O
h O
( O
- O
1 O
) O
at O
GA O
within O
6 O
mu O
M O
to O
14 O
mu O
M O
. O

Thus O
, O
evidence O
obtained O
from O
PEM O
could O
strongly O
support O
the O
phenomena O
of O
CEM O
. O

To O
conclude O
, O
GA O
tends O
to O
elicit O
hypoxia O
- O
related O
inflammation O
and O
hemolysis O
in O
chicken O
cervical O
muscles O
through O
its O
extremely O
high O
prooxidant O
activity O
. O

A O
genetically O
encoded O
and O
gate O
for O
cell O
- O
targeted O
metabolic O
labeling O
of O
proteins O
. O

We O
describe O
a O
genetic O
AND O
gate O
for O
cell O
- O
targeted O
metabolic O
labeling O
and O
proteomic O
analysis O
in O
complex O
cellular O
systems O
. O

The O
centerpiece O
of O
the O
AND O
gate O
is O
a O
bisected O
methionyl B
- O
tRNA O
synthetase O
( O
MetRS O
) O
that O
charges O
the O
Met B
surrogate O
azidonorleucine B
( O
Anl B
) O
to O
tRNA O
( O
Met B
) O
. O

Cellular O
protein O
labeling O
occurs O
only O
upon O
activation O
of O
two O
different O
promoters O
that O
drive O
expression O
of O
the O
N B
- O
and O
C B
- O
terminal O
fragments O
of O
the O
bisected O
MetRS O
. O

Anl O
- O
labeled O
proteins O
can O
be O
tagged O
with O
fluorescent O
dyes O
or O
affinity O
reagents O
via O
either O
copper B
- O
catalyzed O
or O
strain O
- O
promoted O
azide B
- O
alkyne B
cycloaddition O
. O

Protein O
labeling O
is O
apparent O
within O
5 O
min O
after O
addition O
of O
Anl O
to O
bacterial O
cells O
in O
which O
the O
AND O
gate O
has O
been O
activated O
. O

This O
method O
allows O
spatial O
and O
temporal O
control O
of O
proteomic O
labeling O
and O
identification O
of O
proteins O
made O
in O
specific O
cellular O
subpopulations O
. O

The O
approach O
is O
demonstrated O
by O
selective O
labeling O
of O
proteins O
in O
bacterial O
cells O
immobilized O
in O
the O
center O
of O
a O
laminar O
- O
flow O
microfluidic O
channel O
, O
where O
they O
are O
exposed O
to O
overlapping O
, O
opposed O
gradients O
of O
inducers O
of O
the O
N B
- O
and O
C B
- O
terminal O
MetRS O
fragments O
. O

The O
observed O
labeling O
profile O
is O
predicted O
accurately O
from O
the O
strengths O
of O
the O
individual O
input O
signals O
. O

Improving O
the O
second O
- O
order O
nonlinear O
optical O
response O
of O
fluorescent O
proteins O
: O
the O
symmetry O
argument O
. O

We O
have O
successfully O
designed O
and O
expressed O
a O
new O
fluorescent O
protein O
with O
improved O
second O
- O
order O
nonlinear O
optical O
properties O
. O

It O
is O
the O
first O
time O
that O
a O
fluorescent O
protein O
has O
been O
rationally O
altered O
for O
this O
particular O
characteristic O
. O

On O
the O
basis O
of O
the O
specific O
noncentrosymmetry O
requirements O
for O
second O
- O
order O
nonlinear O
optical O
effects O
, O
we O
had O
hypothesized O
that O
the O
surprisingly O
low O
first O
hyperpolarizability O
( O
beta O
) O
of O
the O
enhanced O
yellow O
fluorescent O
protein O
( O
eYFP O
) O
could O
be O
explained O
by O
centrosymmetric O
stacking O
of O
the O
chromophoric O
Tyr66 B
and O
the O
neighboring O
Tyr203 B
residue O
. O

The O
inversion O
center O
was O
removed O
by O
mutating O
Tyr203 B
into O
Phe203 B
, O
with O
minor O
changes O
in O
the O
linear O
optical O
properties O
and O
even O
an O
improved O
fluorescence O
quantum O
yield O
. O

Structure O
determination O
by O
X O
- O
ray O
crystallography O
as O
well O
as O
linear O
optical O
characterization O
corroborate O
a O
correct O
folding O
and O
maturation O
. O

Measurement O
of O
beta O
by O
means O
of O
hyper O
- O
Rayleigh O
scattering O
( O
HRS O
) O
as O
well O
as O
their O
analysis O
using O
quantum O
chemistry O
calculations O
validate O
our O
hypothesis O
. O

This O
observation O
can O
eventually O
lead O
to O
improved O
red O
fluorescent O
proteins O
for O
even O
better O
performance O
. O

On O
the O
basis O
of O
the O
specific O
function O
( O
second O
- O
harmonic O
generation O
) O
, O
the O
color O
of O
its O
emission O
, O
and O
in O
analogy O
with O
the O
" O
fruit O
" O
names O
, O
we O
propose O
SHardonnay O
as O
the O
name O
for O
this O
Tyr203Phe B
mutant O
of O
eYFP O
. O

Raman O
spectra O
of O
interchanging O
beta O
- O
lactamase O
inhibitor O
intermediates O
on O
the O
millisecond O
time O
scale O
. O

Rapid O
mix O
- O
rapid O
freeze O
is O
a O
powerful O
method O
to O
study O
the O
mechanisms O
of O
enzyme O
- O
substrate O
reactions O
in O
solution O
. O

Here O
we O
report O
a O
protocol O
that O
combines O
this O
method O
with O
normal O
( O
non O
- O
resonance O
) O
Raman O
microscopy O
to O
enable O
us O
to O
define O
molecular O
details O
of O
intermediates O
at O
early O
time O
points O
. O

With O
this O
combined O
method O
, O
SHV O
- O
1 O
, O
a O
class O
A O
beta O
- O
lactamase O
, O
and O
tazobactam B
, O
a O
commercially O
available O
beta O
- O
lactamase O
inhibitor O
, O
were O
rapidly O
mixed O
on O
the O
millisecond O
time O
scale O
and O
then O
were O
flash O
- O
frozen O
by O
injection O
into O
an O
isopentane B
solution O
surrounded O
by O
liquid O
nitrogen O
. O

The O
" O
ice O
" O
was O
finally O
freeze O
- O
dried O
and O
characterized O
by O
Raman O
microscopy O
. O

We O
found O
that O
the O
reaction O
is O
almost O
complete O
in O
solution O
at O
25 O
ms O
, O
giving O
rise O
to O
a O
major O
population O
composed O
of O
the O
trans B
- I
enamine I
intermediate O
. O

Between O
25 O
and O
500 O
ms O
, O
minor O
populations O
of O
protonated O
imine B
are O
detected O
that O
have O
previously O
been O
postulated O
to O
precede O
enamine B
intermediates O
. O

However O
, O
within O
1 O
s O
, O
the O
imines B
are O
converted O
entirely O
to O
enamines B
. O

Interestingly O
, O
with O
this O
method O
, O
we O
can O
measure O
directly O
the O
turnover O
number O
of O
SHV O
- O
1 O
and O
tazobactam B
. O

The O
enzyme O
is O
completely O
inhibited O
at O
1 O
: O
4 O
ratio O
( O
enzyme O
: O
inhibitor O
) O
or O
greater O
, O
a O
number O
that O
agrees O
with O
the O
turnover O
number O
derived O
from O
steady O
- O
state O
kinetic O
methods O
. O

This O
application O
, O
employing O
non O
- O
intensity O
- O
enhanced O
Raman O
spectroscopy O
, O
provides O
a O
general O
and O
effective O
route O
to O
study O
the O
early O
events O
in O
enzyme O
- O
substrate O
reactions O
. O

Preparation O
of O
lipase O
- O
coated O
, O
stabilized O
, O
hydrophobic O
magnetic O
particles O
for O
reversible O
conjugation O
of O
biomacromolecules O
. O

This O
Communication O
presents O
the O
development O
of O
a O
novel O
strategy O
for O
the O
easy O
conjugation O
of O
biomolecules O
to O
hydrophobic O
magnetic O
microparticles O
via O
reversible O
coating O
with O
previously O
functionalized O
lipase O
molecules O
. O

First O
, O
the O
ability O
of O
lipase O
to O
be O
strongly O
adsorbed O
onto O
hydrophobic O
surfaces O
was O
exploited O
for O
the O
stabilization O
of O
microparticles O
in O
aqueous O
medium O
by O
the O
creation O
of O
a O
hydrophilic O
surface O
. O

Second O
, O
the O
surface O
amino B
acids I
of O
lipase O
can O
be O
tailored O
to O
suit O
biomolecule O
conjugation O
. O

This O
approach O
has O
been O
demonstrated O
by O
amino B
- O
epoxy B
activation O
of O
lipase O
, O
enabling O
the O
conjugation O
of O
different O
biomolecules O
to O
the O
magnetic O
particle O
' O
s O
surface O
. O

For O
example O
, O
it O
was O
possible O
to O
immobilize O
70 O
% O
of O
Escherichia O
coli O
proteins O
on O
the O
recovered O
particles O
. O

Furthermore O
, O
this O
strategy O
could O
be O
extended O
to O
other O
lipase O
chemical O
modification O
protocols O
, O
enabling O
fine O
control O
of O
biomolecule O
coupling O
. O

These O
conjugation O
techniques O
constitute O
a O
modular O
methodology O
that O
also O
permits O
the O
recycling O
of O
the O
magnetic O
carrier O
following O
use O
. O

Exposure O
to O
lambda B
- I
cyhalothrin I
, O
a O
synthetic O
pyrethroid B
, O
increases O
reactive O
oxygen B
species O
production O
and O
induces O
genotoxicity O
in O
rat O
peripheral O
blood O
. O

Lambda B
- I
cyhalothrin I
( O
LTC B
) O
is O
a O
synthetic O
pyrethroid B
with O
a O
broad O
spectrum O
of O
insecticidal O
and O
acaricidal O
activities O
used O
to O
control O
a O
wide O
range O
of O
insect O
pests O
in O
a O
variety O
of O
applications O
. O

However O
, O
there O
is O
little O
known O
about O
its O
adverse O
effects O
, O
in O
particular O
those O
related O
to O
its O
genotoxicity O
in O
humans O
. O

To O
elucidate O
the O
genotoxicity O
mechanisms O
of O
LTC O
, O
the O
micronuclei O
( O
MN O
) O
frequencies O
, O
the O
levels O
of O
reactive O
oxygen B
species O
( O
ROS O
) O
, O
erythrocyte O
osmotic O
fragility O
, O
nitrite B
( O
NO B
) O
formation O
, O
protein O
carbonyl B
( O
PCO O
) O
levels O
and O
malondialdehyde B
( O
MDA B
) O
production O
were O
evaluated O
for O
a O
period O
of O
7 O
, O
14 O
and O
21 O
days O
. O

Our O
results O
show O
that O
exposure O
rat O
to O
LTC O
( O
1 O
/ O
10DL50 O
= O
6 O
. O
23 O
mg O
/ O
kg O
) O
for O
a O
period O
of O
7 O
, O
14 O
and O
21 O
days O
induced O
a O
noticeable O
genotoxic O
effect O
in O
rat O
peripheral O
blood O
evidenced O
by O
a O
significant O
increase O
in O
the O
frequency O
of O
MN O
only O
at O
day O
21 O
of O
treatment O
. O

Significant O
differences O
between O
the O
two O
groups O
were O
observed O
in O
erythrocyte O
osmotic O
fragility O
. O

Further O
, O
a O
significant O
( O
p O
< O
0 O
. O
01 O
) O
increase O
in O
ROS O
contents O
, O
NO B
formation O
, O
PCO O
levels O
and O
lipid O
peroxidation O
in O
erythrocytes O
were O
observed O
at O
different O
times O
of O
treatments O
, O
suggesting O
the O
implication O
of O
oxidative O
stress O
in O
its O
toxicity O
. O

These O
results O
confirm O
the O
genotoxic O
and O
the O
pro O
- O
oxidant O
effects O
of O
LTC O
in O
rat O
peripheral O
blood O
. O

The O
periodontal O
health O
of O
lead O
- O
exposed O
children O
living O
in O
a O
shipyard O
industrial O
area O
. O

In O
a O
cross O
- O
sectional O
design O
, O
292 O
schoolchildren O
living O
around O
a O
shipyard O
area O
, O
known O
to O
be O
contaminated O
with O
lead O
from O
shipyard O
industry O
, O
were O
examined O
to O
verify O
the O
association O
between O
lead O
exposure O
and O
periodontal O
health O
. O

The O
probing O
pocket O
depth O
( O
PD O
) O
, O
bleeding O
on O
probing O
, O
plaque O
and O
calculus O
, O
and O
the O
presence O
of O
Aggregatibacter O
actinomycetemcomitan O
( O
Aa O
) O
in O
subgingival O
crevices O
were O
recorded O
. O

Gingival O
inflammation O
was O
the O
most O
common O
( O
98 O
% O
) O
among O
children O
in O
the O
area O
. O

No O
significant O
difference O
in O
gingival O
inflammation O
was O
observed O
between O
high O
blood O
lead O
( O
PbB O
) O
and O
low O
PbB O
children O
. O

The O
prevalence O
rate O
of O
probing O
PD O
of O
> O
= O
5 O
mm O
was O
14 O
% O
. O

The O
high O
PbB B
group O
showed O
more O
deep O
pockets O
at O
tooth O
16 O
( O
upper O
right O
first O
permanent O
molar O
) O
and O
tooth O
46 O
( O
lower O
right O
first O
permanent O
molar O
) O
than O
the O
low O
PbB B
group O
. O

The O
odds O
ratios O
( O
ORs O
) O
for O
having O
probing O
PD O
> O
= O
5 O
mm O
after O
adjusting O
for O
other O
factors O
were O
3 O
. O
63 O
( O
95 O
% O
confidence O
interval O
( O
CI O
) O
, O
1 O
. O
24 O
- O
10 O
. O
61 O
; O
p O
= O
0 O
. O
02 O
) O
for O
tooth O
16 O
and O
3 O
. O
93 O
( O
95 O
% O
CI O
, O
1 O
. O
18 O
- O
13 O
. O
00 O
; O
p O
= O
0 O
. O
02 O
) O
for O
tooth O
46 O
. O

The O
presence O
of O
Aa O
was O
observed O
in O
17 O
% O
of O
the O
children O
and O
it O
significantly O
increased O
in O
high O
PbB O
compared O
with O
low O
PbB O
children O
at O
tooth O
46 O
( O
OR O
= O
5 O
. O
53 O
, O
95 O
% O
CI O
: O
1 O
. O
68 O
- O
18 O
. O
15 O
; O
p O
= O
0 O
. O
005 O
) O
. O

This O
study O
may O
suggest O
no O
association O
between O
lead O
exposure O
and O
gingival O
inflammation O
, O
yet O
there O
was O
the O
involvement O
of O
deeper O
periodontal O
tissue O
in O
lead O
- O
exposed O
children O
. O

Protective O
role O
of O
L B
- I
carnitine I
and O
vitamin B
E I
on O
the O
testis O
of O
atherosclerotic O
rats O
. O

Atherosclerosis O
is O
a O
condition O
caused O
by O
lipid O
build O
- O
up O
and O
inflammation O
in O
the O
arteries O
, O
so O
hyperlipidemia O
is O
the O
major O
reason O
for O
atherosclerosis O
. O

Testis O
was O
found O
to O
be O
negatively O
affected O
by O
hyperlipidemia O
which O
leads O
to O
its O
impaired O
functions O
. O

Vitamin B
E I
and O
< B
sc I
> I
l I
< I
/ I
sc I
> I
- I
carnitine I
have O
well O
- O
known O
lipid O
- O
lowering O
and O
antioxidative O
activities O
. O

Triton B
WR I
1339 I
is O
a O
non O
- O
ionic O
detergent O
, O
which O
induces O
severe O
hyperlipidemia O
by O
inhibition O
of O
lipoprotein O
lipase O
. O

The O
present O
study O
evaluates O
the O
protective O
role O
of O
vitamin B
E I
and O
< B
sc I
> I
l I
< I
/ I
sc I
> I
- I
carnitine I
on O
the O
testis O
in O
atherosclerosis O
and O
detects O
the O
most O
effective O
choice O
for O
protection O
against O
atherosclerosis O
; O
vitamin B
E I
, O
< B
sc I
> I
l I
< I
/ I
sc I
> I
- I
carnitine I
or O
a O
combination O
of O
both O
. O

A O
total O
of O
80 O
albino O
male O
rats O
were O
divided O
into O
eight O
groups O
( O
10 O
rats O
for O
each O
group O
) O
: O
control O
( O
G O
( O
1 O
) O
) O
, O
triton B
( O
G O
( O
2 O
) O
) O
, O
< B
sc I
> I
l I
< I
/ I
sc I
> I
- I
carnitine I
( O
G O
( O
3 O
) O
) O
, O
triton B
+ O
< B
sc I
> I
l I
< I
/ I
sc I
> I
- I
carnitine I
( O
G O
( O
4 O
) O
) O
, O
vitamin B
E I
( O
G O
( O
5 O
) O
) O
, O
triton B
+ O
vitamin B
E I
( O
G O
( O
6 O
) O
) O
, O
< B
sc I
> I
l I
< I
/ I
sc I
> I
- I
carnitine I
+ O
vitamin B
E I
( O
G O

( O
7 O
) O
) O
and O
triton B
+ I
< B
sc I
> I
l I
< I
/ I
sc I
> I
- I
carnitine I
+ O
vitamin B
E I
( O
G O
( O
8 O
) O
) O
. O

Data O
showed O
a O
significant O
increase O
in O
the O
levels O
of O
total O
cholesterol B
( O
TC O
) O
, O
triglycerides B
( O
TGs B
) O
, O
low O
- O
density O
lipoprotein O
cholesterol B
( O
LDL O
- O
C O
) O
, O
17 B
beta I
hydroxysteroid I
dehydrogenase O
( O
17 O
beta O
HSD O
) O
, O
testicular O
catalase O
and O
malondialdehyde B
( O
MDA B
) O
in O
G O
( O
2 O
) O
when O
compared O
with O
G O
( O
1 O
) O
, O
whereas O
high O
- O
density O
lipoprotein O
cholesterol B
( O
HDL O
- O
C O
) O
, O
serum O
testosterone B
, O
testicular O
17 O

ketosteroid B
reductase O
( O
17 O
KSR O
) O
, O
total O
thiol B
and O
glutathione B
- O
S B
- O
transferase O
( O
GST O
) O
data O
showed O
a O
significant O
decrease O
in O
G O
( O
2 O
) O
when O
compared O
with O
G O
( O
1 O
) O
. O

Treatment O
with O
< B
sc I
> I
l I
< I
/ I
sc I
> I
- I
carnitine I
or O
/ O
and O
vitamin B
E I
helps O
in O
improving O
the O
adverse O
effect O
of O
triton B
; O
also O
the O
histological O
changes O
confirm O
this O
finding O
. O

So O
the O
present O
study O
recommends O
all O
people O
to O
include O
< B
sc I
> I
l I
< I
/ I
sc I
> I
- I
carnitine I
and O
vitamin B
E I
in O
their O
diet O
to O
be O
protected O
against O
atherosclerosis O
. O

Critical O
parameters O
in O
exfoliating O
graphite B
into O
graphene B
. O

Dispersing O
graphite B
into O
few O
- O
layers O
graphene B
sheets O
( O
GS O
) O
in O
water O
is O
very O
appealing O
as O
an O
environmental O
- O
friendly O
, O
low O
- O
cost O
, O
low O
- O
energy O
method O
of O
obtaining O
graphene B
. O

Very O
high O
GS O
concentrations O
in O
water O
( O
0 O
. O
7 O
mg O
mL O
( O
- O
1 O
) O
) O
were O
obtained O
by O
optimizing O
the O
nature O
of O
dispersant O
and O
the O
type O
of O
ultra O
- O
sonic O
generator O
. O

We O
find O
that O
a O
multi O
- O
step O
sonication O
procedure O
involving O
both O
tip O
and O
bath O
sources O
considerably O
enhances O
the O
yield O
of O
exfoliated O
GS O
. O

Raman O
and O
transmission O
electron O
microscopy O
indicate O
few O
- O
layers O
graphene B
patches O
with O
typical O
size O
of O
~ O
0 O
. O
65 O
mu O
m O
in O
one O
dimension O
and O
~ O
0 O
. O
35 O
mu O
m O
in O
the O
other O
. O

These O
were O
further O
employed O
in O
combination O
with O
water O
- O
dispersed O
CNTs O
to O
fabricate O
conductive O
transparent O
electrodes O
for O
a O
molecularly O
- O
controlled O
solar O
- O
cell O
with O
an O
open O
- O
circuit O
voltage O
of O
0 O
. O
53 O
V O
. O

The O
CRF O
( O
1 O
) O
receptor O
antagonist O
SSR125543 B
prevents O
stress O
- O
induced O
cognitive O
deficit O
associated O
with O
hippocampal O
dysfunction O
: O
Comparison O
with O
paroxetine B
and O
D B
- I
cycloserine I
. O

RATIONALE O
: O
The O
selective O
CRF O
( O
1 O
) O
( O
corticotropin O
releasing O
factor O
type O
1 O
) O
receptor O
antagonist O
SSR125543 B
has O
been O
previously O
shown O
to O
attenuate O
the O
long O
- O
term O
cognitive O
deficit O
produced O
by O
traumatic O
stress O
exposure O
. O

Memory O
disturbances O
described O
in O
post O
- O
traumatic O
stress O
disorder O
( O
PTSD O
) O
patients O
are O
believed O
to O
be O
associated O
with O
changes O
in O
neuronal O
activity O
, O
in O
particular O
at O
the O
level O
of O
the O
hippocampus O
. O

OBJECTIVES O
: O
The O
present O
study O
aims O
at O
investigating O
whether O
the O
effects O
of O
SSR125543 B
( O
10 O
mg O
/ O
kg O
/ O
day O
for O
2 O
weeks O
) O
on O
cognitive O
impairment O
induced O
by O
traumatic O
stress O
exposure O
are O
associated O
with O
changes O
in O
hippocampal O
excitability O
. O

Effects O
of O
SSR125543 B
were O
compared O
to O
those O
of O
the O
5 B
- I
HT I
reuptake O
inhibitor O
, O
paroxetine B
( O
10 O
mg O
/ O
kg O
/ O
day O
) O
, O
and O
the O
partial O
N B
- I
methyl I
- I
D I
- I
aspartate I
( O
NMDA B
) O
receptor O
agonist O
, O
D B
- I
cycloserine I
( O
10 O
mg O
/ O
kg O
/ O
day O
) O
, O
two O
compounds O
which O
have O
demonstrated O
clinical O
efficacy O
against O
PTSD O
. O

METHODS O
: O
Mice O
received O
two O
unavoidable O
electric O
foot O
- O
shocks O
. O

Then O
, O
1 O
or O
16 O
days O
after O
stress O
, O
they O
were O
tested O
for O
their O
memory O
performance O
using O
the O
object O
recognition O
test O
. O

Neuronal O
excitability O
was O
recorded O
during O
the O
third O
week O
post O
- O
stress O
in O
the O
CA1 O
area O
of O
the O
hippocampus O
. O

Drugs O
were O
administered O
from O
day O
1 O
post O
- O
stress O
to O
the O
day O
preceding O
the O
electrophysiological O
study O
. O

RESULTS O
: O
Application O
of O
electric O
shocks O
produced O
cognitive O
impairment O
16 O
, O
but O
not O
1 O
day O
after O
stress O
, O
an O
effect O
which O
was O
associated O
with O
a O
decrease O
in O
hippocampal O
neuronal O
excitability O
. O

Both O
stress O
- O
induced O
effects O
were O
prevented O
by O
repeated O
administration O
of O
SSR125543 B
, O
paroxetine B
and O
D B
- I
cycloserine I
. O

CONCLUSIONS O
: O
These O
findings O
confirm O
that O
the O
CRF O
( O
1 O
) O
receptor O
antagonist O
SSR125543 B
is O
able O
to O
attenuate O
the O
behavioral O
effects O
of O
traumatic O
stress O
exposure O
and O
indicate O
that O
these O
effects O
are O
associated O
with O
a O
normalization O
of O
hippocampal O
neuronal O
excitability O
impaired O
by O
stress O
. O

Lupenone B
from O
Erica O
multiflora O
leaf O
extract O
stimulates O
melanogenesis O
in O
B16 O
murine O
melanoma O
cells O
through O
the O
inhibition O
of O
ERK1 O
/ O
2 O
activation O
. O

Hypopigmentation O
diseases O
are O
usually O
managed O
using O
UVB O
light O
which O
increases O
the O
patients O
' O
risk O
for O
skin O
cancer O
. O

Here O
, O
we O
evaluated O
the O
melanogenesis O
stimulatory O
effects O
of O
leaf O
extracts O
of O
Erica O
multiflora O
, O
a O
medicinal O
plant O
from O
the O
Mediterranean O
region O
, O
and O
its O
active O
component O
, O
lup B
- I
20 I
( I
29 I
) I
- I
en I
- I
3 I
- I
one I
, O
as O
possible O
therapeutic O
agents O
to O
address O
hypopigmentation O
disorders O
. O

B16 O
murine O
melanoma O
cells O
were O
treated O
with O
E O
. O
multiflora O
extracts O
or O
its O
active O
component O
lupenone B
to O
evaluate O
their O
effects O
on O
melanin O
biosynthesis O
. O

The O
mechanism O
underlying O
the O
observed O
effects O
was O
also O
determined O
. O

Bioactivity O
- O
guided O
fractionation O
of O
fifteen O
ethyl B
acetate I
fractions O
identified O
fraction O
2 O
to O
have O
melanogenesis O
stimulatory O
effects O
due O
to O
its O
ability O
to O
decrease O
mitogen O
- O
activated O
protein O
kinase O
phosphorylated O
extracellular O
signal O
- O
regulated O
kinases O
1 O
and O
2 O
activation O
. O

Preparative O
TLC O
of O
ethyl B
acetate I
fraction O
2 O
revealed O
the O
presence O
of O
lup B
- I
20 I
( I
29 I
) I
- I
en I
- I
3 I
- I
one I
as O
the O
major O
bioactive O
component O
. O

B16 O
cells O
treated O
with O
lup B
- I
20 I
( I
29 I
) I
- I
en I
- I
3 I
- I
one I
increased O
melanin O
content O
without O
cytotoxicity O
. O

To O
determine O
the O
mechanism O
for O
the O
observed O
effects O
of O
lup B
- I
20 I
( I
29 I
) I
- I
en I
- I
3 I
- I
one I
, O
the O
tyrosinase O
enzyme O
activity O
, O
the O
tyrosinase O
protein O
expression O
, O
and O
the O
activation O
of O
phosphorylated O
extracellular O
signal O
- O
regulated O
kinases O
1 O
and O
2 O
were O
determined O
. O

In O
addition O
, O
the O
expression O
of O
the O
tyrosinase O
mRNA O
was O
quantified O
using O
real O
- O
time O
PCR O
. O

Results O
showed O
that O
lup B
- I
20 I
( I
29 I
) I
- I
en I
- I
3 I
- I
one I
has O
no O
effect O
on O
the O
tyrosinase O
enzyme O
activity O
but O
can O
increase O
tyrosinase O
expression O
at O
both O
the O
transcriptional O
and O
translational O
levels O
. O

The O
increase O
in O
the O
tyrosinase O
mRNA O
expression O
was O
most O
likely O
due O
to O
the O
inhibited O
mitogen O
- O
activated O
protein O
kinase O
phosphorylated O
extracellular O
signal O
- O
regulated O
kinases O
1 O
and O
2 O
activation O
. O

We O
report O
for O
the O
first O
time O
that O
E O
. O
multiflora O
ethyl B
acetate I
extract O
and O
its O
active O
compound O
lup B
- I
20 I
( I
29 I
) I
- I
en I
- I
3 I
- I
one I
stimulate O
melanogenesis O
by O
increasing O
the O
tyrosinase O
enzyme O
expression O
via O
mitogen O
- O
activated O
protein O
kinase O
phosphorylated O
extracellular O
signal O
- O
regulated O
kinases O
1 O
and O
2 O
phosphorylation O
inhibition O
, O
making O
it O
a O
possible O
treatment O
for O
hypopigmentation O
diseases O
. O

Peptide O
based O
macrocycles O
: O
selective O
histone O
deacetylase O
inhibitors O
with O
antiproliferative O
activity O
. O

Histone O
deacetylase O
inhibitors O
( O
HDACi O
) O
have O
been O
enthusiastically O
investigated O
as O
a O
novel O
generation O
of O
chemotherapeutics O
for O
cancers O
usually O
called O
as O
epigenetic O
therapeutics O
. O

Histone O
deacetylases O
have O
been O
found O
to O
influence O
cellular O
function O
by O
catalyzing O
the O
removal O
of O
acetyl B
groups O
from O
epsilon B
- I
N I
- I
acetylated I
lysine I
residues O
of O
several O
protein O
substrates O
including O
histones O
, O
transcription O
factors O
, O
alpha O
- O
tubulin O
, O
and O
nuclear O
importers O
. O

Cyclic O
peptides O
represent O
the O
most O
structurally O
complicated O
and O
diverse O
class O
of O
histone O
deacetylase O
inhibitors O
. O

Each O
subtype O
of O
the O
Histone O
Deacetylase O
( O
HDAC O
) O
family O
perform O
a O
distinct O
role O
in O
the O
gene O
expression O
and O
cyclic O
peptides O
with O
their O
plentiful O
set O
of O
surface O
contacts O
, O
zinc B
binding O
group O
and O
macrocyclic O
cap O
, O
can O
target O
enzyme O
precisely O
through O
adequate O
modulation O
of O
the O
amino B
acid I
configurational O
and O
structural O
assortment O
. O

The O
present O
article O
summarizes O
current O
status O
of O
different O
peptide O
based O
macrocyclic O
compounds O
being O
developed O
as O
HDACi O
for O
the O
treatment O
of O
cancer O
. O

Targeting O
multiplicity O
: O
the O
key O
factor O
for O
anti O
- O
cancer O
nanoparticles O
. O

In O
this O
mini O
- O
review O
, O
we O
focus O
on O
different O
strategies O
to O
bring O
nanotools O
specifically O
to O
cancer O
cells O
. O

We O
discuss O
about O
a O
better O
targeting O
of O
tumor O
, O
combining O
the O
characteristics O
of O
tumor O
environment O
, O
the O
increase O
in O
nanoparticles O
life O
time O
, O
the O
biomarkers O
overexpressed O
on O
cancer O
cells O
and O
different O
physical O
methods O
for O
non O
invasive O
therapies O
. O

Here O
we O
detail O
the O
necessity O
of O
a O
synergy O
between O
passive O
and O
active O
targeting O
for O
an O
actual O
specificity O
of O
cancer O
cells O
. O

Computational O
models O
for O
predicting O
interactions O
with O
membrane O
transporters O
. O

Membrane O
transporters O
, O
including O
two O
members O
: O
ATP B
- O
binding O
cassette O
( O
ABC O
) O
transporters O
and O
solute O
carrier O
( O
SLC O
) O
transporters O
are O
proteins O
that O
play O
important O
roles O
to O
facilitate O
molecules O
into O
and O
out O
of O
cells O
. O

Consequently O
, O
these O
transporters O
can O
be O
major O
determinants O
of O
the O
therapeutic O
efficacy O
, O
toxicity O
and O
pharmacokinetics O
of O
a O
variety O
of O
drugs O
. O

Considering O
the O
time O
and O
expense O
of O
bio O
- O
experiments O
taking O
, O
research O
should O
be O
driven O
by O
evaluation O
of O
efficacy O
and O
safety O
. O

Computational O
methods O
arise O
to O
be O
a O
complementary O
choice O
. O

In O
this O
article O
, O
we O
provide O
an O
overview O
of O
the O
contribution O
that O
computational O
methods O
made O
in O
transporters O
field O
in O
the O
past O
decades O
. O

At O
the O
beginning O
, O
we O
present O
a O
brief O
introduction O
about O
the O
structure O
and O
function O
of O
major O
members O
of O
two O
families O
in O
transporters O
. O

In O
the O
second O
part O
, O
we O
focus O
on O
widely O
used O
computational O
methods O
in O
different O
aspects O
of O
transporters O
research O
. O

In O
the O
absence O
of O
a O
high O
- O
resolution O
structure O
of O
most O
of O
transporters O
, O
homology O
modeling O
is O
a O
useful O
tool O
to O
interpret O
experimental O
data O
and O
potentially O
guide O
experimental O
studies O
. O

We O
summarize O
reported O
homology O
modeling O
in O
this O
review O
. O

Researches O
in O
computational O
methods O
cover O
major O
members O
of O
transporters O
and O
a O
variety O
of O
topics O
including O
the O
classification O
of O
substrates O
and O
/ O
or O
inhibitors O
, O
prediction O
of O
protein O
- O
ligand O
interactions O
, O
constitution O
of O
binding O
pocket O
, O
phenotype O
of O
non O
- O
synonymous O
single O
- O
nucleotide O
polymorphisms O
, O
and O
the O
conformation O
analysis O
that O
try O
to O
explain O
the O
mechanism O
of O
action O
. O

As O
an O
example O
, O
one O
of O
the O
most O
important O
transporters O
P O
- O
gp O
is O
elaborated O
to O
explain O
the O
differences O
and O
advantages O
of O
various O
computational O
models O
. O

In O
the O
third O
part O
, O
the O
challenges O
of O
developing O
computational O
methods O
to O
get O
reliable O
prediction O
, O
as O
well O
as O
the O
potential O
future O
directions O
in O
transporter O
related O
modeling O
are O
discussed O
. O

Index O
of O
refraction O
, O
density O
, O
and O
solubility O
of O
ammonium B
iodide I
solutions O
at O
high O
pressure O
. O

An O
asymmetric O
moissanite O
anvil O
cell O
is O
used O
to O
study O
aqueous O
solutions O
of O
ammonium B
iodide I
at O
pressures O
up O
to O
10 O
kbar O
. O

The O
index O
of O
refraction O
is O
measured O
using O
the O
rotating O
Fabry O
- O
Perot O
technique O
, O
with O
an O
accuracy O
of O
approximately O
1 O
% O
. O

The O
mass O
density O
and O
molar O
volume O
of O
the O
solutions O
are O
estimated O
using O
the O
measured O
index O
values O
, O
and O
the O
molar O
volume O
is O
used O
to O
predict O
the O
pressure O
dependence O
of O
the O
solubility O
. O

The O
solubility O
derived O
from O
the O
index O
of O
refraction O
measurements O
is O
shown O
to O
agree O
with O
that O
which O
is O
determined O
by O
direct O
observation O
of O
the O
onset O
of O
crystallization O
. O

Antimalarial O
activities O
of O
6 B
- I
iodouridine I
and O
its O
prodrugs O
and O
potential O
for O
combination O
therapy O
. O

Resistance O
by O
Plasmodium O
falciparum O
to O
almost O
all O
clinically O
used O
antimalarial O
drugs O
requires O
the O
development O
of O
new O
classes O
of O
antimalarials O
. O

6 B
- I
Iodouridine I
( O
15 O
) O
, O
a O
novel O
and O
potent O
inhibitor O
of O
orotidine B
5 I
' I
- I
monophosphate I
decarboxylase O
( O
ODCase O
) O
, O
exhibited O
efficacy O
in O
a O
mouse O
model O
infected O
by O
P O
. O
chabaudi O
chabaudi O
. O

Compound O
15 O
exhibited O
promising O
antimalarial O
activity O
against O
P O
. O
falciparum O
, O
including O
drug O
- O
resistant O
isolates O
, O
and O
no O
rapid O
drug O
- O
resistant O
populations O
of O
the O
parasite O
were O
observed O
when O
challenged O
with O
15 O
. O

Uridine B
provided O
options O
to O
overcome O
any O
toxicity O
in O
the O
host O
but O
still O
suppressing O
the O
parasite O
load O
when O
treated O
with O
15 O
. O

In O
drug O
combination O
studies O
, O
compound O
15 O
showed O
good O
efficacy O
in O
vivo O
with O
artemisinin B
and O
azithromycin B
. O

The O
propionyl B
ester I
of O
15 O
exhibited O
superior O
antimalarial O
efficacy O
. O

Antimalarial O
activities O
of O
15 O
and O
its O
prodrugs O
and O
potential O
for O
combination O
therapy O
are O
discussed O
in O
the O
context O
of O
novel O
strategies O
. O

Solution O
effect O
on O
diazonium B
- O
modified O
Au B
( I
111 I
) I
: O
reactions O
and O
structures O
. O

Surface O
modifications O
of O
a O
Au B
( I
111 I
) I
electrode O
with O
4 B
- I
bromobenzenediazoniu I
tetrafluoroborate I
( O
BBD B
) O
in O
acetonitrile B
( O
ACN B
) O
and O
0 O
. O
1 O
M O
HClO4 B
have O
been O
characterized O
by O
scanning O
tunneling O
microscopy O
( O
STM O
) O
. O

In O
ACN O
, O
STM O
results O
reveal O
the O
formation O
of O
disordered O
thin O
organic O
films O
. O

The O
involvement O
of O
the O
radical O
as O
an O
intermediate O
is O
evidenced O
by O
the O
negative O
effect O
of O
radical O
scavengers O
on O
organic O
thin O
film O
formation O
. O

In O
contrast O
, O
the O
4 B
, I
4 I
' I
- I
dibromobiphenyl I
monolayer O
is O
observed O
when O
the O
aqueous O
solution O
is O
used O
as O
a O
medium O
to O
carry O
out O
the O
grafting O
experiment O
. O

The O
biphenyl B
compound O
is O
considered O
to O
be O
generated O
by O
a O
radical O
- O
radical O
coupling O
reaction O
. O

Genome O
- O
wide O
integrated O
analyses O
of O
androgen B
receptor O
signaling O
in O
prostate O
cancer O
based O
on O
high O
- O
throughput O
technology O
. O

The O
androgen B
receptor O
( O
AR O
) O
is O
a O
steroid B
hormone O
receptor O
that O
functions O
as O
a O
ligand O
- O
dependent O
transcriptional O
factor O
, O
which O
plays O
a O
key O
role O
in O
the O
development O
and O
progression O
of O
prostate O
cancer O
. O

Recent O
advancement O
in O
high O
throughput O
technologies O
including O
microarrays O
and O
deep O
- O
sequencing O
provides O
unbiased O
genome O
- O
wide O
knowledge O
on O
the O
AR O
signaling O
including O
datasets O
for O
androgen B
- O
regulated O
gene O
expression O
and O
genomic O
binding O
sites O
for O
AR O
. O

In O
the O
present O
review O
, O
we O
will O
briefly O
summarize O
the O
main O
features O
of O
the O
AR O
signaling O
as O
well O
as O
the O
individual O
AR O
target O
genes O
identified O
by O
the O
integration O
of O
multiple O
datasets O
in O
prostate O
cancer O
. O

Cap O
analysis O
gene O
expression O
( O
CAGE O
) O
is O
also O
featured O
as O
a O
unique O
transcriptome O
method O
, O
which O
particularly O
determines O
the O
androgen B
- O
dependent O
transcription O
start O
points O
in O
prostate O
cancer O
. O

Recurrent O
rearrangements O
in O
prostate O
cancer O
: O
causes O
and O
therapeutic O
potential O
. O

DNA O
damage O
and O
genetic O
rearrangements O
are O
hallmarks O
of O
cancer O
. O

However O
, O
gene O
fusions O
as O
driver O
mutations O
in O
cancer O
have O
classically O
been O
a O
distinction O
in O
leukemia O
and O
other O
rare O
instances O
until O
recently O
with O
the O
discovery O
of O
gene O
fusion O
events O
occurring O
in O
50 O
to O
75 O
% O
of O
prostate O
cancer O
patients O
. O

The O
discovery O
of O
the O
TMPRSS2 O
- O
ERG O
fusion O
sparked O
an O
onslaught O
of O
discovery O
and O
innovation O
resulting O
in O
a O
delineation O
of O
prostate O
cancer O
via O
a O
molecular O
signature O
of O
gene O
fusion O
events O
. O

The O
increased O
commonality O
of O
high O
- O
throughput O
sequencing O
data O
coupled O
with O
improved O
bioinformatics O
approaches O
not O
only O
elucidated O
the O
molecular O
underpinnings O
of O
prostate O
cancer O
progression O
, O
but O
the O
mechanisms O
of O
gene O
fusion O
biogenesis O
. O

Interestingly O
, O
the O
androgen B
receptor O
( O
AR O
) O
, O
already O
known O
to O
play O
a O
significant O
role O
in O
prostate O
cancer O
tumorigenesis O
, O
has O
recently O
been O
implicated O
in O
the O
processes O
resulting O
in O
gene O
fusions O
by O
inducing O
the O
spatial O
proximity O
of O
genes O
involved O
in O
rearrangements O
, O
promoting O
the O
formation O
of O
double O
- O
strand O
DNA O
breaks O
( O
DSB O
) O
, O
and O
facilitating O
the O
recruitment O
of O
proteins O
for O
non O
- O
homologous O
end O
- O
joining O
( O
NHEJ O
) O
. O

Our O
increased O
understanding O
of O
the O
mechanisms O
inducing O
genomic O
instability O
may O
lead O
to O
improved O
diagnostic O
and O
therapeutic O
strategies O
. O

To O
date O
, O
the O
majority O
of O
prostate O
cancer O
patients O
can O
be O
molecularly O
stratified O
based O
on O
their O
gene O
fusion O
status O
thereby O
increasing O
the O
potential O
for O
tailoring O
more O
specific O
and O
effective O
therapies O
. O

Targeting O
the O
akt O
kinase O
to O
modulate O
survival O
, O
invasiveness O
and O
drug O
resistance O
of O
cancer O
cells O
. O

The O
deregulation O
of O
oncogenic O
signaling O
pathways O
which O
provide O
survival O
advantages O
to O
tumor O
cells O
is O
mediated O
by O
multiple O
cellular O
networks O
. O

Among O
them O
, O
the O
PI3K O
- O
Akt O
- O
mTOR O
axis O
, O
in O
particular O
the O
serine B
/ O
threonine B
kinase O
Akt O
, O
is O
recognized O
as O
a O
key O
player O
. O

The O
kinase O
is O
hyperactivated O
due O
to O
a O
variety O
of O
mechanisms O
including O
loss O
of O
PTEN O
, O
mutations O
in O
the O
PI3K O
catalytic O
subunit O
, O
receptor O
tyrosine B
kinase O
and O
Ras O
activation O
. O

Indeed O
, O
inappropriate O
activation O
of O
the O
Akt O
kinase O
is O
a O
common O
event O
in O
human O
tumors O
and O
Akt O
appears O
to O
be O
a O
critical O
player O
in O
cell O
survival O
that O
may O
also O
account O
for O
the O
therapeutic O
resistance O
and O
the O
invasive O
phenotype O
of O
tumors O
. O

Inhibition O
of O
Akt O
signalling O
results O
in O
apoptosis O
and O
growth O
inhibition O
of O
tumour O
cells O
with O
elevated O
Akt O
activity O
. O

A O
functional O
role O
in O
drug O
resistance O
is O
supported O
by O
evidence O
that O
tumor O
cells O
with O
acquired O
resistance O
to O
antitumor O
agents O
may O
display O
increased O
Akt O
activation O
and O
that O
treatment O
with O
molecularly O
targeted O
agents O
can O
activate O
feed O
- O
back O
loops O
involving O
Akt O
. O

This O
serine B
/ O
threonine B
kinase O
may O
therefore O
represent O
an O
amenable O
target O
for O
modulation O
of O
sensitivity O
to O
compounds O
with O
different O
molecular O
features O
due O
to O
its O
pleiotropic O
role O
in O
cell O
survival O
. O

Different O
types O
of O
Akt O
inhibitors O
[ O
i O
. O
e O
. O
, O
ATP B
mimetics O
and O
pleckstrin O
- O
homology O
( O
PH O
) O
domain O
binders O
] O
have O
been O
generated O
and O
some O
of O
them O
have O
reached O
the O
clinical O
setting O
. O

The O
present O
review O
focuses O
on O
the O
i O
) O
mechanisms O
implicating O
Akt O
in O
increased O
survival O
and O
invasive O
potential O
of O
tumor O
cells O
of O
different O
tumor O
types O
and O
ii O
) O
on O
the O
development O
of O
Akt O
inhibitors O
as O
modulators O
of O
drug O
resistance O
. O

Emerging O
Role O
of O
Colloidal O
Drug O
Delivery O
Systems O
( O
CDDS O
) O
in O
NSAID O
Topical O
Administration O
. O

NSAIDs O
are O
the O
most O
commonly O
prescribed O
category O
of O
drugs O
for O
the O
treatment O
of O
musculoskeletal O
pain O
and O
inflammation O
associated O
with O
many O
conditions O
. O

Topical O
administration O
of O
these O
drugs O
is O
always O
the O
best O
choice O
since O
adverse O
effects O
occur O
commonly O
with O
systemic O
NSAID O
therapy O
. O

Colloidal O
drug O
delivery O
systems O
( O
CDDS O
) O
are O
interesting O
systems O
, O
which O
are O
able O
to O
improve O
the O
duration O
of O
drug O
residence O
in O
the O
skin O
and O
to O
allow O
an O
achievable O
drug O
sustained O
and O
controlled O
release O
compared O
to O
conventional O
topical O
formulations O
. O
This O
review O
focuses O
on O
micro O
and O
nanoemulsions O
, O
vesicular O
carriers O
and O
nanoparticles O
as O
novel O
high O
efficiency O
delivery O
systems O
of O
NSAIDs O
in O
topical O
applications O
. O

Rationally O
designed O
multi O
- O
targeted O
agents O
against O
neurodegenerative O
diseases O
. O

Neurodegenerative O
diseases O
are O
complex O
disorders O
with O
several O
pathoetiological O
pathways O
leading O
to O
cell O
death O
. O

Rationally O
designed O
multi O
- O
targeted O
agents O
, O
or O
" O
multi O
- O
targeted O
designed O
drugs O
" O
( O
MTDD O
) O
show O
significant O
promise O
in O
preclinical O
studies O
as O
neuroprotective O
and O
disease O
- O
modifying O
agents O
. O

In O
this O
review O
, O
we O
highlight O
the O
use O
of O
chemical O
scaffolds O
that O
lend O
themselves O
exquisitely O
to O
the O
development O
of O
MTDDs O
in O
neurodegeneration O
. O

Notably O
, O
synthetic O
polycyclic O
cage O
compounds O
have O
served O
as O
scaffolds O
for O
novel O
voltage O
- O
gated O
calcium B
channel O
blockers O
, O
NMDA B
receptor O
antagonists O
, O
and O
sigma O
- O
receptor O
ligands O
- O
attractive O
targets O
in O
neurodegeneration O
. O

In O
an O
entirely O
different O
approach O
, O
compounds O
containing O
the O
thiazolidinedione B
moiety O
( O
referred O
to O
as O
glitazones B
) O
alter O
mitochondrial O
function O
through O
the O
mitochondrial O
protein O
mitoNEET O
, O
an O
attractive O
new O
drug O
target O
for O
the O
treatment O
of O
neurodegenerative O
diseases O
. O

The O
design O
strategy O
for O
yet O
another O
agent O
, O
ladostigil B
, O
employed O
the O
amalgamation O
of O
active O
chemical O
moieties O
of O
the O
AChE O
inhibitor O
rivastigmine B
, O
and O
the O
monoamine B
oxidase O
- O
B O
( O
MAO O
- O
B O
) O
inhibitor O
rasagiline B
, O
leading O
to O
a O
single O
compound O
that O
targets O
both O
enzymes O
simultaneously O
. O

Natural O
products O
have O
also O
served O
as O
design O
templates O
for O
several O
MTDD O
design O
studies O
. O

In O
particular O
, O
the O
stilbene B
scaffold O
has O
become O
popular O
in O
particular O
due O
to O
the O
neuroprotective O
effects O
of O
the O
non O
- O
flavonoid B
natural O
product O
resveratrol B
. O

Recently O
, O
stilbene B
scaffold O
- O
based O
compounds O
were O
developed O
to O
reduce O
- O
through O
chelation O
with O
metal O
ions O
that O
interact O
with O
beta O
- O
amyloid O
- O
both O
metal O
- O
induced O
beta O
- O
amyloid O
protein O
aggregation O
, O
and O
ROS O
generated O
from O
this O
aggregate O
. O

Other O
subtle O
modifications O
of O
the O
stilbene B
motif O
led O
to O
the O
creation O
of O
reversible O
, O
non O
- O
competitive O
MAO O
inhibitors O
. O

Finally O
, O
compounds O
derived O
from O
the O
xanthine B
scaffold O
afford O
neuroprotection O
in O
Parkinson O
' O
s O
disease O
through O
mechanisms O
that O
include O
dual O
adenosine B
A2A O
receptor O
antagonism O
and O
MAO O
- O
B O
inhibition O
. O

Human O
disease O
and O
drug O
pharmacology O
, O
complex O
as O
real O
life O
. O

In O
the O
past O
decades O
drug O
discovery O
practice O
has O
escaped O
from O
the O
complexity O
of O
the O
formerly O
used O
phenotypic O
screening O
in O
animals O
to O
focus O
on O
assessing O
drug O
effects O
on O
isolated O
protein O
targets O
in O
the O
search O
for O
drugs O
that O
exclusively O
and O
potently O
hit O
one O
selected O
target O
, O
thought O
to O
be O
critical O
for O
a O
given O
disease O
, O
while O
not O
affecting O
at O
all O
any O
other O
target O
to O
avoid O
the O
occurrence O
of O
side O
- O
effects O
. O

However O
, O
reality O
does O
not O
conform O
to O
these O
expectations O
, O
and O
, O
conversely O
, O
this O
approach O
has O
been O
concurrent O
with O
increased O
attrition O
figures O
in O
late O
- O
stage O
clinical O
trials O
, O
precisely O
due O
to O
lack O
of O
efficacy O
and O
safety O
. O

In O
this O
context O
, O
a O
network O
biology O
perspective O
of O
human O
disease O
and O
treatment O
has O
burst O
into O
the O
drug O
discovery O
scenario O
to O
bring O
it O
back O
to O
the O
consideration O
of O
the O
complexity O
of O
living O
organisms O
and O
particularly O
of O
the O
( O
patho O
) O
physiological O
environment O
where O
protein O
targets O
are O
( O
mal O
) O
functioning O
and O
where O
drugs O
have O
to O
exert O
their O
restoring O
action O
. O

Under O
this O
perspective O
, O
it O
has O
been O
found O
that O
usually O
there O
is O
not O
one O
but O
several O
disease O
- O
causing O
genes O
and O
, O
therefore O
, O
not O
one O
but O
several O
relevant O
protein O
targets O
to O
be O
hit O
, O
which O
do O
not O
work O
on O
isolation O
but O
in O
a O
highly O
interconnected O
manner O
, O
and O
that O
most O
known O
drugs O
are O
inherently O
promiscuous O
. O

In O
this O
light O
, O
the O
rationale O
behind O
the O
currently O
prevailing O
single O
- O
target O
- O
based O
drug O
discovery O
approach O
might O
even O
seem O
a O
Utopia O
, O
while O
, O
conversely O
, O
the O
notion O
that O
the O
complexity O
of O
human O
disease O
must O
be O
tackled O
with O
complex O
polypharmacological O
therapeutic O
interventions O
constitutes O
a O
difficult O
- O
torefuse O
argument O
that O
is O
spurring O
the O
development O
of O
multitarget O
therapies O
. O

Photothermal O
tautomerization O
of O
a O
UV O
sunscreen O
( O
4 B
- I
tert I
- I
butyl I
- I
4 I
' I
- I
methoxydibenzoylmeth I
) O
in O
acetonitrile B
studied O
by O
steady O
- O
state O
and O
laser O
flash O
photolysis O
. O

The O
photothermal O
tautomerization O
processes O
between O
enol B
and O
keto B
forms O
of O
4 B
- I
tert I
- I
butyl I
- I
4 I
' I
- I
methoxydibenzoylmeth I
( O
trade O
name O
, O
Avobenzone B
) O
in O
acetonitrile B
have O
been O
studied O
by O
steady O
- O
state O
and O
laser O
flash O
photolysis O
. O

The O
keto B
form O
is O
produced O
upon O
photolysis O
of O
the O
enol B
in O
only O
acetonitrile B
with O
a O
quantum O
yield O
of O
0 O
. O
014 O
. O

The O
molar O
absorptivity O
of O
the O
keto B
form O
was O
determined O
. O

Phototautomerization O
from O
the O
keto B
to O
the O
enol B
form O
was O
not O
seen O
. O

Laser O
flash O
photolysis O
of O
the O
keto B
form O
recognized O
the O
formation O
of O
the O
triplet O
state O
. O

In O
the O
dark O
, O
the O
keto B
form O
underwent O
thermal O
tautomerization O
to O
the O
enol B
with O
a O
lifetime O
of O
5 O
. O
1 O
h O
at O
295 O
K O
. O

The O
enolization O
rate O
in O
acetonitrile B
was O
not O
accelerated O
by O
the O
presence O
of O
alcohols B
and O
/ O
or O
water O
but O
increased O
with O
increasing O
temperature O
and O
followed O
the O
Arrhenius O
expression O
. O

The O
activation O
energy O
and O
the O
frequency O
factor O
were O
determined O
for O
the O
enolization O
process O
from O
the O
keto B
to O
the O
enol B
form O
. O

On O
the O
basis O
of O
the O
energy O
states O
of O
the O
tautomers O
and O
isomers O
as O
estimated O
by O
DFT O
calculations O
, O
a O
schematic O
energy O
diagram O
was O
determined O
for O
the O
photothermal O
tautomerization O
processes O
in O
acetonitrile B
. O

Newly O
observed O
spontaneous O
activation O
of O
ethephon B
as O
a O
butyrylcholinesteras O
inhibitor O
. O

The O
plant O
growth O
regulator O
ethephon B
( O
2 B
- I
chloroethylphosphoni I
acid I
) O
inhibits O
human O
butyrylcholinesteras O
( O
BChE O
) O
by O
making O
a O
covalent O
adduct O
on O
the O
active O
site O
serine B
198 O
. O

Our O
goal O
was O
to O
extend O
earlier O
studies O
on O
ethephon B
inhibition O
. O

Addition O
of O
freshly O
prepared O
ethephon B
to O
BChE O
in O
buffered O
medium O
, O
at O
pH O
7 O
. O
0 O
and O
22 O
degrees O
C O
, O
resulted O
in O
no O
inhibition O
initially O
. O

However O
, O
inhibition O
developed O
progressively O
over O
60 O
min O
of O
incubation O
. O

Preincubation O
of O
ethephon B
in O
pH O
7 O
- O
9 O
buffers O
increased O
its O
initial O
inhibitory O
potency O
. O

These O
observations O
indicated O
that O
ethephon B
itself O
was O
not O
the O
inhibitor O
. O

About O
3 O
% O
of O
the O
initial O
ethephon B
could O
be O
trapped O
as O
a O
BChE O
adduct O
. O

Mass O
spectral O
analysis O
of O
the O
active O
site O
peptide O
from O
inhibited O
BChE O
showed O
that O
the O
inhibitor O
added O
a O
mass O
of O
108 O
Da O
to O
the O
active O
site O
serine B
on O
peptide O
FGES198AGAAS O
. O

This O
result O
rules O
out O
a O
previous O
hypothesis O
that O
ethephon B
adds O
HPO3 B
to O
BChE O
( O
added O
mass O
of O
80 O
Da O
) O
. O

To O
accommodate O
these O
observations O
, O
we O
propose O
that O
in O
aqueous O
media O
at O
neutral O
to O
slightly O
alkaline O
pH O
about O
3 O
% O
of O
the O
ethephon B
is O
converted O
( O
t1 O
/ O
2 O
= O
9 O
. O
9 O
h O
at O
pH O
7 O
. O
0 O
) O
into O
a O
cyclic B
oxaphosphetane I
which O
is O
the O
actual O
BChE O
inhibitor O
forming O
the O
2 B
- I
hydroxyethylphosphon I
adduct O
on O
BChE O
at O
Ser198 B
while O
about O
97 O
% O
of O
the O
ethephon B
breaks O
down O
to O
ethylene B
( O
t1 O
/ O
2 O
= O
11 O
- O
48 O
h O
at O
pH O
7 O
. O
0 O
) O
which O
is O
responsible O
for O
plant O
growth O

regulation O
. O

Neural O
stem O
/ O
progenitor O
cells O
display O
a O
low O
requirement O
for O
oxidative O
metabolism O
independent O
of O
hypoxia O
inducible O
factor O
- O
1alpha O
expression O
. O

Neural O
stem O
/ O
progenitor O
cells O
( O
NSPCs O
) O
are O
multipotent O
cells O
within O
the O
embryonic O
and O
adult O
brain O
that O
give O
rise O
to O
both O
neuronal O
and O
glial O
cell O
lineages O
. O

Maintenance O
of O
NSPC O
multipotency O
is O
promoted O
by O
low O
oxygen B
tension O
, O
although O
the O
metabolic O
underpinnings O
of O
this O
trait O
have O
not O
been O
described O
. O

In O
this O
study O
, O
we O
investigated O
the O
metabolic O
state O
of O
undifferentiated O
NSPCs O
in O
culture O
, O
and O
tested O
their O
relative O
reliance O
on O
oxidative O
versus O
glycolytic O
metabolism O
for O
survival O
, O
as O
well O
as O
their O
dependence O
on O
hypoxia O
inducible O
factor O
- O
1alpha O
( O
HIF O
- O
1 O
alpha O
) O
expression O
for O
maintenance O
of O
metabolic O
phenotype O
. O

Unlike O
primary O
neurons O
, O
NSPCs O
from O
embryonic O
and O
adult O
mice O
survived O
prolonged O
hypoxia O
in O
culture O
. O

In O
addition O
, O
NSPCs O
displayed O
greater O
susceptibility O
to O
glycolytic O
inhibition O
compared O
with O
primary O
neurons O
, O
even O
in O
the O
presence O
of O
alternative O
mitochondrial O
TCA B
substrates O
. O

NSPCs O
were O
also O
more O
resistant O
than O
neurons O
to O
mitochondrial O
cyanide B
toxicity O
, O
less O
capable O
of O
utilizing O
galactose B
as O
an O
alternative O
substrate O
to O
glucose B
, O
and O
more O
susceptible O
to O
pharmacological O
inhibition O
of O
the O
pentose B
phosphate I
pathway O
by O
6 B
- I
aminonicotinamide I
. O

Inducible O
deletion O
of O
exon O
1 O
of O
the O
Hif1a O
gene O
improved O
the O
ability O
of O
NSPCs O
to O
utilize O
pyruvate B
during O
glycolytic O
inhibition O
, O
but O
did O
not O
alter O
other O
parameters O
of O
metabolism O
, O
including O
their O
ability O
to O
withstand O
prolonged O
hypoxia O
. O

Taken O
together O
, O
these O
data O
indicate O
that O
NSPCs O
have O
a O
relatively O
low O
requirement O
for O
oxidative O
metabolism O
for O
their O
survival O
and O
that O
hypoxic O
resistance O
is O
not O
dependent O
upon O
HIF O
- O
1 O
alpha O
signaling O
. O

The O
in O
vitro O
and O
in O
vivo O
effects O
of O
nicotine B
on O
bone O
, O
bone O
cells O
and O
fracture O
repair O
. O

INTRODUCTION O
: O
Cigarette O
smoke O
has O
negative O
effects O
on O
bone O
metabolism O
and O
fracture O
repair O
. O

However O
, O
no O
study O
has O
reviewed O
effects O
of O
nicotine B
on O
bone O
and O
fracture O
repair O
independent O
of O
other O
constituents O
of O
cigarette O
smoke O
. O

The O
authors O
review O
the O
existing O
evidence O
of O
the O
effect O
of O
nicotine B
on O
' O
bone O
' O
and O
' O
bone O
cells O
' O
and O
fracture O
repair O
, O
drawing O
conclusions O
relevant O
to O
clinical O
practice O
and O
future O
research O
. O

AREAS O
COVERED O
: O
A O
literature O
review O
was O
conducted O
using O
PRISMA O
guidelines O
and O
PubMed O
, O
Cochrane O
, O
MEDLINE O
/ O
OVID O
, O
EMBASE O
, O
NHS O
Evidence O
and O
Google O
scholar O
databases O
. O

Articles O
were O
included O
if O
they O
specifically O
investigated O
the O
effects O
of O
nicotine B
on O
' O
bone O
' O
or O
fracture O
repair O
in O
animal O
or O
human O
models O
or O
in O
vitro O
effects O
on O
' O
bone O
cells O
' O
. O

A O
total O
of O
64 O
papers O
were O
included O
in O
this O
review O
, O
of O
which O
15 O
were O
human O
in O
vitro O
studies O
and O
49 O
animal O
studies O
wherein O
9 O
were O
in O
vitro O
and O
40 O
in O
vivo O
. O

In O
vivo O
studies O
of O
the O
effects O
of O
nicotine B
in O
animals O
demonstrated O
widespread O
effects O
on O
bone O
including O
osteoneogenesis O
, O
osseointegration O
, O
steady O
- O
state O
skeletal O
bone O
and O
genes O
and O
cytokines O
relevant O
to O
bone O
cell O
physiology O
and O
bone O
homeostasis O
. O

In O
these O
studies O
, O
nicotine B
' O
s O
effects O
are O
predominately O
negative O
, O
inhibiting O
bone O
cell O
metabolism O
and O
fracture O
repair O
, O
whereas O
most O
in O
vitro O
studies O
reported O
biphasic O
responses O
in O
all O
bone O
cells O
except O
osteoclastic O
cells O
. O

EXPERT O
OPINION O
: O
The O
review O
suggests O
that O
nicotine B
has O
effects O
on O
osteoneogenesis O
, O
osseointegration O
and O
steady O
- O
state O
skeletal O
bone O
in O
animal O
in O
vivo O
models O
, O
as O
well O
as O
effects O
on O
all O
' O
bone O
cells O
' O
, O
via O
several O
mechanisms O
in O
both O
animal O
and O
human O
cell O
in O
vitro O
studies O
. O

The O
effect O
of O
nicotine B
is O
dose O
- O
dependent O
, O
with O
higher O
concentrations O
having O
predominantly O
negative O
effects O
, O
whereas O
at O
low O
concentrations O
a O
stimulatory O
effect O
is O
seen O
. O

Stimulatory O
effects O
on O
certain O
cells O
may O
indicate O
a O
possible O
, O
limited O
therapeutic O
role O
; O
advice O
regarding O
smoking O
cessation O
perioperatively O
should O
remain O
due O
to O
the O
other O
harmful O
components O
of O
cigarette O
smoke O
, O
but O
there O
may O
be O
scope O
for O
allowing O
the O
use O
of O
nicotine B
patches O
instead O
of O
complete O
abstention O
. O

Further O
research O
into O
clinical O
outcomes O
is O
required O
before O
the O
exact O
response O
of O
bone O
and O
fracture O
repair O
in O
humans O
to O
nicotine B
is O
known O
. O

Benchmark O
dose O
for O
estimation O
of O
cadmium B
reference O
level O
for O
osteoporosis O
in O
a O
Chinese O
female O
population O
. O

In O
this O
study O
, O
the O
reference O
level O
of O
cadmium B
in O
urine O
and O
blood O
related O
with O
bone O
damage O
was O
assessed O
using O
benchmark O
dose O
in O
a O
Chinese O
female O
population O
. O

Total O
of O
338 O
women O
was O
recruited O
, O
and O
urine O
and O
blood O
samples O
were O
collected O
from O
each O
individual O
for O
determination O
of O
cadmium B
in O
urine O
( O
UCd O
) O
and O
blood O
( O
BCd O
) O
. O

Bone O
mineral O
density O
was O
measured O
by O
dual O
energy O
X O
- O
ray O
absorptiometry O
. O

BMD O
and O
BMDL O
were O
calculated O
corresponding O
to O
additional O
risk O
of O
5 O
% O
and O
10 O
% O
. O

With O
benchmark O
response O
( O
BMR O
) O
of O
5 O
% O
/ O
10 O
% O
, O
the O
BMD O
of O
BCd O
, O
UCd O
related O
with O
osteoporosis O
was O
1 O
. O
88 O
mu O
g O
/ O
L O
/ O
3 O
. O
23 O
mu O
g O
/ O
L O
and O
5 O
. O
30 O
mu O
g O
/ O
g O
crea O
/ O
9 O
. O
06 O
mu O
g O
/ O
g O
crea O
, O
and O
the O
BMDL O
- O
05 O
was O
1 O
. O
39 O
mu O
g O
/ O
L O
/ O
2 O
. O
38 O
mu O
g O
/ O
L O
and O
3 O
. O
78 O
mu O
g O
/ O
g O
crea O
/ O
6 O
. O
36 O
mu O
g O
/ O
g O
crea O
; O
the O
BMD O
of O
BCd O

, O
UCd O
related O
with O
low O
bone O
mass O
was O
0 O
. O
95 O
mu O
g O
/ O
L O
/ O
3 O
. O
12 O
mu O
g O
/ O
L O
and O
3 O
. O
12 O
mu O
g O
/ O
g O
crea B
/ O
5 O
. O
87 O
mu O
g O
/ O
g O
crea B
, O
and O
the O
BMDL O
- O
05 O
was O
0 O
. O
72 O
mu O
g O
/ O
L O
/ O
1 O
. O
35 O
mu O
g O
/ O
L O
and O
2 O
. O
14 O
mu O
g O
/ O
g O
crea B
/ O
3 O
. O
99 O
mu O
g O
/ O
g O
crea B
. O

The O
BMD O
of O
UCd O
in O
people O
over O
60years O
old O
was O
much O
lower O
than O
that O
of O
people O
less O
than O
60years O
old O
. O

BMD O
value O
was O
related O
with O
ages O
and O
effects O
biomarkers O
. O

Our O
data O
showed O
that O
BMD O
of O
UCd O
associated O
with O
osteoporosis O
was O
lower O
than O
that O
previously O
estimated O
. O

DNA O
damage O
and O
oxidative O
stress O
in O
human O
B O
lymphoblastoid O
cells O
after O
combined O
exposure O
to O
hexavalent B
chromium I
and O
nickel B
compounds O
. O

In O
the O
present O
study O
, O
human O
B O
lymphoblastoid O
cells O
were O
exposed O
to O
potassium B
dichromate I
and O
/ O
or O
nickel B
chloride I
for O
24h O
or O
48h O
. O

The O
cell O
viability O
and O
DNA O
damage O
induced O
by O
these O
compounds O
was O
measured O
with O
the O
CCK O
- O
8 O
assay O
and O
Comet O
assay O
, O
respectively O
. O

In O
addition O
, O
the O
generation O
of O
reactive O
oxygen B
species O
( O
ROS O
) O
and O
the O
levels O
of O
malondialdehyde B
( O
MDA B
) O
were O
measured O
using O
commercially O
available O
kits O
. O

Our O
results O
indicated O
that O
potassium B
dichromate I
could O
decrease O
cell O
viability O
and O
induce O
DNA O
damage O
in O
human O
B O
lymphoblastoid O
cells O
in O
a O
time O
- O
and O
concentration O
- O
dependent O
manner O
, O
but O
the O
toxicity O
of O
nickel B
chloride I
was O
not O
so O
obvious O
at O
concentrations O
used O
in O
our O
study O
. O

The O
results O
of O
ROS O
showed O
that O
both O
two O
compounds O
could O
only O
induce O
weak O
elevation O
of O
ROS O
level O
, O
but O
MDA B
levels O
were O
significantly O
enhanced O
. O

Antagonistic O
effects O
of O
cytotoxicity O
were O
mainly O
found O
between O
Cr B
( I
VI I
) I
and O
Ni B
( I
II I
) I
, O
and O
synergistic O
effects O
of O
DNA O
damage O
and O
oxidative O
stress O
were O
partially O
found O
between O
these O
two O
compounds O
. O

Moreover O
, O
there O
were O
good O
correlations O
between O
the O
results O
of O
comet O
assay O
and O
the O
results O
of O
oxidative O
stress O
assays O
. O

It O
is O
suggested O
that O
synergistic O
DNA O
damage O
induced O
by O
simultaneously O
exposure O
of O
hexavalent B
chromium I
and O
nickel B
compounds O
is O
possibly O
related O
to O
oxidative O
stress O
. O

Spiro O
heterocycles O
as O
potential O
inhibitors O
of O
SIRT1 O
: O
Pd B
/ O
C B
- O
mediated O
synthesis O
of O
novel O
N B
- I
indolylmethyl I
spiroindoline I
- I
3 I
, I
2 I
' I
- I
quinazolines I
. O

Novel O
N B
- I
indolylmethyl I
substituted I
spiroindoline I
- I
3 I
, I
2 I
' I
- I
quinazolines I
were O
designed O
as O
potential O
inhibitiors O
of O
SIRT1 O
. O

These O
compounds O
were O
synthesized O
in O
good O
yields O
by O
using O
Pd B
/ O
C B
- O
Cu B
mediated O
coupling O
- O
cyclization O
strategy O
as O
a O
key O
step O
involving O
the O
reaction O
of O
1 B
- I
( I
prop I
- I
2 I
- I
ynyl I
) I
- I
1 I
' I
H I
- I
spiro I
[ I
indoline I
- I
3 I
, I
2 I
' I
- I
quinazoline I
] I
- I
2 I
, I
4 I
' I
( I
3 I
' I
H I
) I
- I
dione I
with O
2 B
- I
iodoanilides I
. O

Some O
of O
the O
compounds O
synthesized O
have O
shown O
encouraging O
inhibition O
of O
Sir O
2 O
protein O
( O
a O
yeast O
homologue O
of O
mammalian O
SIRT1 O
) O
in O
vitro O
and O
three O
of O
them O
showed O
dose O
dependent O
inhibition O
of O
Sir O
2 O
. O

The O
docking O
results O
suggested O
that O
the O
benzene B
ring O
of O
1 B
, I
2 I
, I
3 I
, I
4 I
- I
tetrahydroquinazolin I
ring O
system O
of O
these O
molecules O
occupied O
the O
deep O
hydrophobic O
pocket O
of O
the O
protein O
and O
one O
of O
the O
NH B
along O
with O
the O
sulfonyl B
group O
participated O
in O
strong O
H B
- O
bonding O
interaction O
with O
the O
amino B
acid I
residues O
. O

Effects O
of O
salinomycin B
on O
human O
bone O
marrow O
- O
derived O
mesenchymal O
stem O
cells O
in O
vitro O
. O

Various O
hypotheses O
on O
the O
origin O
of O
cancer O
stem O
cells O
( O
CSCs O
) O
exist O
, O
including O
that O
CSCs O
develop O
from O
transformed O
human O
bone O
marrow O
mesenchymal O
stem O
cells O
( O
hBMSC O
) O
. O

Since O
the O
polyether B
antibiotic O
salinomycin B
selectively O
kills O
CSCs O
, O
the O
present O
study O
aims O
to O
elucidate O
the O
effects O
of O
salinomycin B
on O
normal O
hBMSC O
. O

The O
immunophenotype O
of O
hBMSC O
after O
salinomycin B
exposure O
was O
observed O
by O
flow O
cytometry O
. O

The O
multi O
- O
differentiation O
capacity O
of O
hBMSC O
was O
evaluated O
by O
Oil O
Red O
O O
and O
van O
Kossa O
staining O
. O

Cytotoxic O
effects O
of O
salinomycin B
were O
monitored O
by O
the O
[ B
3 I
- I
( I
4 I
, I
5 I
- I
dimethylthiazol I
- I
2 I
- I
yl I
) I
- I
2 I
, I
5 I
- I
diphenyl I
tetrazolium I
bromide I
] I
( O
MTT B
) O
assay O
. O

Furthermore O
, O
spheroid O
formation O
and O
migration O
capacity O
were O
assessed O
. O

There O
were O
no O
differences O
in O
the O
immunophenotype O
and O
multi O
- O
differentiation O
capacity O
of O
hBMSC O
induced O
by O
salinomycin B
treatment O
. O

Cytotoxic O
effects O
were O
observed O
at O
concentrations O
of O
30 O
mu O
M O
and O
above O
. O

Neither O
the O
migration O
capability O
nor O
the O
ability O
to O
form O
spheroids O
was O
affected O
. O

Essential O
functional O
properties O
of O
hBMSC O
were O
unaffected O
by O
salinomycin B
. O

However O
, O
dose O
- O
dependent O
cytotoxicity O
effects O
could O
be O
observed O
. O

Overall O
, O
low O
dose O
salinomycin B
showed O
no O
negative O
effects O
on O
hBMSC O
. O

Since O
mesenchymal O
stem O
cells O
from O
various O
sources O
respond O
differently O
, O
further O
in O
vitro O
studies O
are O
needed O
to O
clarify O
the O
effect O
of O
salinomycin B
on O
tissue O
- O
specific O
stem O
cells O
. O

Regulatory O
decisions O
on O
endocrine O
disrupting O
chemicals O
should O
be O
based O
on O
the O
principles O
of O
endocrinology O
. O

For O
years O
, O
scientists O
from O
various O
disciplines O
have O
studied O
the O
effects O
of O
endocrine O
disrupting O
chemicals O
( O
EDCs O
) O
on O
the O
health O
and O
wellbeing O
of O
humans O
and O
wildlife O
. O

Some O
studies O
have O
specifically O
focused O
on O
the O
effects O
of O
low O
doses O
, O
i O
. O
e O
. O
those O
in O
the O
range O
that O
are O
thought O
to O
be O
safe O
for O
humans O
and O
/ O
or O
animals O
. O

Others O
have O
focused O
on O
the O
existence O
of O
non O
- O
monotonic O
dose O
- O
response O
curves O
. O

These O
concepts O
challenge O
the O
way O
that O
chemical O
risk O
assessment O
is O
performed O
for O
EDCs O
. O

Continued O
discussions O
have O
clarified O
exactly O
what O
controversies O
and O
challenges O
remain O
. O

We O
address O
several O
of O
these O
issues O
, O
including O
why O
the O
study O
and O
regulation O
of O
EDCs O
should O
incorporate O
endocrine O
principles O
; O
what O
level O
of O
consensus O
there O
is O
for O
low O
dose O
effects O
; O
challenges O
to O
our O
understanding O
of O
non O
- O
monotonicity O
; O
and O
whether O
EDCs O
have O
been O
demonstrated O
to O
produce O
adverse O
effects O
. O

This O
discussion O
should O
result O
in O
a O
better O
understanding O
of O
these O
issues O
, O
and O
allow O
for O
additional O
dialog O
on O
their O
impact O
on O
risk O
assessment O
. O

Net O
analyte O
signal O
standard O
addition O
method O
for O
simultaneous O
determination O
of O
sulphadiazine B
and O
trimethoprim B
in O
bovine O
milk O
and O
veterinary O
medicines O
. O

Net O
analyte O
signal O
standard O
addition O
method O
has O
been O
used O
for O
the O
simultaneous O
determination O
of O
sulphadiazine B
and O
trimethoprim B
by O
spectrophotometry O
in O
some O
bovine O
milk O
and O
veterinary O
medicines O
. O

The O
method O
combines O
the O
advantages O
of O
standard O
addition O
method O
with O
the O
net O
analyte O
signal O
concept O
which O
enables O
the O
extraction O
of O
information O
concerning O
a O
certain O
analyte O
from O
spectra O
of O
multi O
- O
component O
mixtures O
. O

This O
method O
has O
some O
advantages O
such O
as O
the O
use O
of O
a O
full O
spectrum O
realisation O
, O
therefore O
it O
does O
not O
require O
calibration O
and O
prediction O
step O
and O
only O
a O
few O
measurements O
require O
for O
the O
determination O
. O

Cloud O
point O
extraction O
based O
on O
the O
phenomenon O
of O
solubilisation O
used O
for O
extraction O
of O
sulphadiazine B
and O
trimethoprim B
in O
bovine O
milk O
. O

It O
is O
based O
on O
the O
induction O
of O
micellar O
organised O
media O
by O
using O
Triton B
X I
- I
100 I
as O
an O
extraction O
solvent O
. O

At O
the O
optimum O
conditions O
, O
the O
norm O
of O
NAS O
vectors O
increased O
linearly O
with O
concentrations O
in O
the O
range O
of O
1 O
. O
0 O
- O
150 O
. O
0 O
mu O
molL O
( O
- O
1 O
) O
for O
both O
sulphadiazine B
and O
trimethoprim B
. O

The O
limits O
of O
detection O
( O
LOD O
) O
for O
sulphadiazine B
and O
trimethoprim B
were O
0 O
. O
86 O
and O
0 O
. O
92 O
mu O
molL O
( O
- O
1 O
) O
, O
respectively O
. O

Anti O
- O
inflammatory O
effects O
of O
an O
aqueous O
extract O
of O
Welsh O
onion O
green O
leaves O
in O
mice O
. O

The O
anti O
- O
inflammatory O
effects O
of O
an O
aqueous O
extract O
of O
Welsh O
onion O
green O
leaves O
( O
WOE O
) O
in O
mice O
was O
investigated O
. O

Administration O
of O
WOE O
, O
in O
the O
range O
of O
0 O
. O
25 O
- O
1g O
/ O
kg O
, O
showed O
a O
concentration O
dependent O
inhibition O
on O
paw O
edema O
development O
after O
carrageenan O
treatment O
in O
mice O
. O

The O
anti O
- O
inflammatory O
effects O
of O
WOE O
were O
closely O
attributed O
to O
decreased O
levels O
of O
tissue O
NO B
and O
tumor O
necrosis O
factor O
- O
alpha O
( O
TNF O
- O
alpha O
) O
. O

Further O
evidence O
for O
WOE O
' O
s O
protection O
is O
shown O
in O
the O
reduction O
of O
lipid O
oxidation O
and O
the O
increase O
of O
antioxidant O
enzyme O
activities O
, O
including O
catalase O
( O
CAT O
) O
, O
superoxide B
dismutase O
( O
SOD O
) O
, O
and O
glutathione B
peroxidase O
( O
GPX O
) O
in O
vivo O
. O

Further O
, O
WOE O
also O
decreased O
the O
number O
of O
acetic B
acid I
- O
induced O
writhing O
responses O
and O
formalin B
- O
induced O
pain O
in O
the O
late O
phase O
in O
mice O
. O

Overall O
, O
the O
results O
showed O
that O
WOE O
might O
serve O
as O
a O
natural O
source O
of O
anti O
- O
inflammatory O
compounds O
. O

Apple O
polyphenols B
suppress O
antigen O
presentation O
of O
ovalbumin O
by O
THP O
- O
1 O
- O
derived O
dendritic O
cells O
. O

Apple O
polyphenol B
extract O
( O
AP O
) O
and O
procyanidin B
contained O
in O
AP O
were O
investigated O
for O
their O
immunomodulatory O
effects O
using O
THP O
- O
1 O
- O
derived O
human O
dendritic O
cells O
( O
TDDCs O
) O
. O

The O
expression O
levels O
of O
HLA O
- O
DR O
( O
MHC O
class O
II O
) O
and O
CD86 O
( O
costimulatory O
molecule O
) O
were O
measured O
as O
an O
indicator O
of O
antigen O
presentation O
in O
TDDCs O
. O

A O
significant O
decrease O
in O
HLA O
- O
DR O
expression O
was O
observed O
in O
the O
AP O
and O
fractionated O
procyanidin B
- O
treated O
cells O
in O
the O
presence O
of O
ovalbumin O
( O
OVA O
) O
, O
but O
no O
effect O
on O
CD86 O
expression O
was O
observed O
. O

The O
uptake O
of O
OVA O
was O
not O
inhibited O
by O
AP O
treatment O
, O
and O
the O
gene O
expression O
of O
membrane O
- O
associated O
RING O
- O
CH O
ubiquitin O
E3 O
ligase O
, O
MARCH1 O
, O
was O
up O
- O
regulated O
by O
AP O
treatment O
. O

It O
can O
therefore O
be O
presumed O
that O
AP O
suppresses O
HLA O
- O
DR O
expression O
via O
the O
ubiquitin O
- O
proteasome O
pathway O
. O

Furthermore O
, O
the O
up O
- O
regulation O
of O
IL O
- O
12 O
and O
TNF O
- O
alpha O
was O
found O
in O
the O
procyanidin B
trimers O
- O
treated O
cells O
in O
the O
presence O
of O
OVA O
. O

These O
results O
suggest O
that O
apple O
polyphenols B
would O
be O
an O
effective O
factor O
for O
the O
development O
of O
immunomodulatory O
agents O
with O
suppressive O
effects O
of O
antigen O
presentation O
. O

Comparison O
of O
extraction O
induced O
by O
emulsion O
breaking O
, O
ultrasonic O
extraction O
and O
wet O
digestion O
procedures O
for O
determination O
of O
metals O
in O
edible O
oil O
samples O
in O
Turkey O
using O
ICP O
- O
OES O
. O

The O
content O
of O
elements O
( O
Cd B
, O
Cr B
, O
Cu B
, O
Fe B
, O
Mn B
, O
Ni B
, O
Pb B
and O
Zn B
) O
in O
edible O
oils O
( O
sunflower O
, O
hazelnut O
, O
canola O
, O
corn O
and O
olive O
oils O
) O
from O
Turkey O
was O
determined O
using O
inductively O
coupled O
plasma O
optical O
emission O
spectrometry O
( O
ICP O
- O
OES O
) O
after O
ultrasonic O
extraction O
, O
wet O
digestion O
, O
and O
extraction O
induced O
by O
emulsion O
breaking O
procedures O
( O
EIEB O
) O
. O

In O
order O
to O
evaluate O
the O
best O
sample O
preparation O
procedure O
, O
EIEB O
procedure O
was O
compared O
by O
ultrasonic O
extraction O
and O
wet O
digestion O
procedures O
. O

The O
results O
in O
the O
samples O
( O
minimum O
- O
maximum O
in O
mgkg O
( O
- O
1 O
) O
) O
were O
: O
0 O
. O
022 O
- O
0 O
. O
058 O
, O
Cr B
0 O
. O
126 O
- O
7 O
. O
106 O
, O
Cu B
0 O
. O
570 O
- O
4 O
. O
504 O
, O
Fe B
8 O
. O
004 O
- O
12 O
. O
588 O
, O
Mn B
0 O
. O
035 O
- O
0 O
. O
054 O
, O
Ni B
0 O
. O
908 O
- O
2 O
. O
182 O
, O
Pb B
0 O
. O
099 O
- O
0 O
. O
134 O
and O
Zn B
2 O
. O
206 O
- O
8 O
. O
982 O
. O

The O
EIEB O
procedure O
was O
found O
to O
be O
fast O
, O
reliable O
, O
simple O
, O
and O
excellent O
in O
comparison O
with O
the O
other O
studied O
procedures O
. O

The O
recovery O
test O
was O
performed O
by O
spiking O
the O
samples O
with O
known O
amounts O
of O
the O
metals O
in O
the O
form O
of O
organometallic O
standards O
and O
applying O
the O
EIEB O
procedure O
. O

The O
recoveries O
were O
in O
the O
range O
of O
96 O
- O
109 O
% O
. O

Reduction O
of O
abdominal O
fat O
accumulation O
in O
rats O
by O
8 O
- O
week O
ingestion O
of O
a O
newly O
developed O
sweetener O
made O
from O
high O
fructose B
corn O
syrup I
. O

Many O
studies O
have O
shown O
that O
ingestion O
of O
high B
- I
fructose I
corn I
syrup I
( O
HFCS B
) O
may O
cause O
an O
increase O
in O
body O
weight O
and O
abdominal O
fat O
. O

We O
recently O
developed O
a O
new O
sweetener O
containing O
rare O
sugars B
( O
rare O
sugar B
syrup O
; O
RSS O
) O
by O
slight O
isomerization O
of O
HFCS O
. O

Here O
, O
the O
functional O
effects O
of O
RSS O
on O
body O
weight O
and O
abdominal O
fat O
, O
and O
biochemical O
parameters O
in O
Wistar O
rats O
were O
examined O
. O

Rats O
( O
n O
= O
30 O
) O
were O
randomly O
divided O
into O
three O
groups O
and O
maintained O
for O
8 O
- O
weeks O
on O
starch O
, O
starch O
+ O
HFCS O
( O
50 O
: O
50 O
) O
, O
and O
starch O
+ O
RSS O
( O
50 O
: O
50 O
) O
diets O
. O

Rats O
in O
the O
Starch O
and O
HFCS O
groups O
gained O
significantly O
more O
body O
weight O
and O
abdominal O
fat O
than O
the O
RSS O
group O
. O

Fasting O
serum O
insulin O
in O
the O
RSS O
group O
was O
significantly O
lower O
than O
in O
the O
Starch O
and O
HFCS O
groups O
, O
although O
serum O
glucose B
in O
the O
HFCS O
and O
RSS O
groups O
was O
significantly O
lower O
than O
that O
in O
the O
Starch O
group O
. O

Thus O
, O
the O
substitution O
of O
HFCS O
with O
RSS O
prevents O
obesity O
induced O
by O
the O
consumption O
of O
HFCS O
. O

Analysis O
of O
the O
blackening O
of O
green O
pepper O
( O
Piper O
nigrum O
Linnaeus O
) O
berries O
. O

This O
paper O
investigates O
polyphenol B
oxidase O
( O
PPO O
) O
activity O
, O
reduced O
weight O
percentage O
after O
sun O
drying O
, O
and O
the O
changes O
in O
colour O
and O
appearance O
of O
green O
pepper O
( O
Piper O
nigrum O
Linnaeus O
) O
berries O
after O
blanching O
and O
sun O
drying O
. O

The O
results O
show O
that O
the O
degree O
of O
reduced O
weight O
percentage O
and O
browning O
in O
green O
pepper O
berries O
after O
blanching O
for O
10 O
min O
is O
greater O
at O
100 O
degrees O
C O
than O
at O
90 O
and O
80 O
degrees O
C O
. O

Moreover O
, O
the O
samples O
blanched O
at O
100 O
degrees O
C O
for O
10 O
min O
had O
the O
fastest O
water O
loss O
, O
but O
the O
lowest O
PPO O
activity O
. O

Thus O
, O
the O
PPO O
enzymatic O
oxidation O
of O
polyphenols B
might O
not O
be O
the O
only O
reason O
for O
the O
browning O
of O
green O
pepper O
berries O
. O

This O
result O
is O
significantly O
different O
from O
that O
of O
Variyar O
, O
Pendharkar O
, O
Banerjeea O
, O
and O
Bandyopadhyay O
( O
1988 O
) O
and O
therefore O
deserves O
further O
study O
. O

Nutritional O
value O
and O
antioxidant O
activity O
of O
honeys O
produced O
in O
a O
European O
Atlantic O
area O
. O

One O
hundred O
eighty O
- O
seven O
honey O
samples O
from O
an O
Atlantic O
European O
area O
were O
studied O
to O
determine O
their O
nutritional O
compositions O
and O
antioxidant O
capacities O
, O
as O
well O
as O
the O
relationships O
between O
them O
. O

The O
results O
showed O
that O
heather O
, O
polyfloral O
, O
blackberry O
, O
and O
eucalyptus O
honeys O
had O
the O
highest O
carbohydrate B
contents O
, O
whereas O
honeydew O
and O
chestnut O
honeys O
had O
the O
lowest O
. O

There O
were O
some O
important O
differences O
among O
the O
honey O
types O
, O
which O
were O
related O
to O
the O
presence O
of O
minor O
components O
. O

The O
protein O
contents O
were O
significantly O
higher O
in O
honeydew O
and O
chestnut O
honeys O
, O
and O
the O
same O
results O
were O
obtained O
for O
mineral O
contents O
. O

Related O
to O
the O
presence O
of O
several O
antioxidant O
compounds O
, O
heather O
honey O
had O
the O
highest O
phenolic O
content O
, O
whereas O
honeydew O
and O
chestnut O
honeys O
had O
the O
highest O
flavonoid B
contents O
. O

Multivariate O
analysis O
showed O
that O
some O
variables O
, O
such O
as O
the O
amounts O
of O
flavonoids B
, O
minerals O
, O
proteins O
, O
and O
phenols B
, O
were O
significantly O
correlated O
with O
antioxidant O
activity O
. O

The O
regression O
analysis O
produced O
a O
significant O
model O
( O
R O
( O
2 O
) O
= O
0 O
. O
716 O
; O
F O
= O
154 O
. O
680 O
; O
P O
< O
0 O
. O
001 O
) O
that O
related O
the O
antioxidant O
activity O
and O
the O
flavonoids B
, O
K B
, O
and O
P B
contents O
. O

Assessment O
of O
antimicrobial O
and O
antiprotozoal O
activity O
of O
the O
olive O
oil O
macerate O
samples O
of O
Hypericum O
perforatum O
and O
their O
LC O
- O
DAD O
- O
MS O
analyses O
. O

Twenty O
- O
one O
samples O
of O
traditionally O
- O
prepared O
( O
home O
- O
made O
) O
and O
ready O
- O
made O
( O
commercial O
) O
St O
. O

John O
' O
s O
Wort O
olive O
oil O
macerates O
were O
profiled O
for O
their O
in O
vitro O
antimicrobial O
and O
antiprotozoal O
activity O
. O

Their O
cytotoxic O
potential O
was O
evaluated O
on O
MRC O
- O
5 O
fibroblasts O
. O

In O
the O
antiprotozoal O
assays O
, O
ten O
of O
the O
oils O
inhibited O
Trypanosoma O
brucei O
rhodesiense O
( O
IC O
( O
50 O
) O
15 O
. O
9 O
- O
64 O
. O
5 O
mu O
g O
/ O
mL O
) O
, O
while O
only O
one O
oil O
exerted O
antimicrobial O
activity O
towards O
Staphylococcus O
aureus O
( O
IC O
( O
50 O
) O
= O
88 O
. O
7 O
mu O
g O
/ O
mL O
) O
. O

LC O
- O
DAD O
- O
MS O
data O
revealed O
the O
presence O
of O
pseudohypericin B
( O
0 O
. O
135 O
- O
3 O
. O
280 O
mu O
g O
/ O
g O
) O
and O
hypericin B
( O
0 O
. O
277 O
- O
6 O
. O
634 O
mu O
g O
/ O
g O
) O
in O
all O
the O
oils O
, O
whereas O
chlorogenic B
acid I
( O
1 O
. O
063 O
mu O
g O
/ O
g O
) O
was O
detected O
only O
in O
one O
oil O
sample O
. O

Hyperforin B
was O
detected O
in O
four O
( O
0 O
. O
977 O
- O
2 O
. O
399 O
mu O
g O
/ O
g O
) O
and O
adhyperforin B
in O
six O
samples O
( O
0 O
. O
005 O
- O
3 O
. O
165 O
mu O
g O
/ O
g O
) O
. O

Hypericin B
and O
pseudohypericin B
were O
common O
in O
the O
active O
oils O
, O
whereas O
hyperforin B
, O
adhyperforin B
, O
and O
chlorogenic B
acid I
were O
absent O
in O
these O
samples O
. O

Our O
results O
indicated O
that O
if O
the O
correct O
plant O
material O
is O
used O
, O
the O
infused O
oils O
from O
Hypericum O
perforatum O
may O
contain O
active O
components O
. O

Classification O
of O
Spanish O
extra O
virgin O
olive O
oils O
by O
data O
fusion O
of O
visible O
spectroscopic O
fingerprints O
and O
chemical O
descriptors O
. O

The O
potential O
of O
visible O
fingerprints O
and O
physical O
- O
chemical O
parameters O
in O
combination O
with O
multivariate O
data O
analysis O
was O
examined O
to O
classify O
extra O
virgin O
olive O
oils O
( O
EVOOs O
) O
from O
different O
Spanish O
regions O
according O
to O
their O
geographical O
origin O
. O

Firstly O
, O
spectral O
and O
quality O
parameters O
matrices O
were O
processed O
separately O
and O
subsequently O
were O
joined O
to O
evaluate O
the O
effect O
of O
synergy O
on O
the O
information O
obtained O
from O
the O
different O
methodologies O
. O

Linear O
discriminant O
analysis O
( O
LDA O
) O
and O
partial O
least O
squares O
discriminant O
analysis O
( O
PLS O
- O
DA O
) O
were O
performed O
as O
classification O
methods O
. O

The O
results O
revealed O
a O
perfect O
discrimination O
between O
the O
defined O
categories O
after O
performing O
PLS O
- O
DA O
on O
the O
Fused O
matrix O
, O
reaching O
100 O
% O
of O
correct O
classifications O
and O
showed O
a O
clear O
improvement O
in O
the O
overall O
prediction O
rates O
( O
92 O
. O
5 O
% O
) O
, O
so O
that O
the O
effect O
of O
synergy O
was O
confirmed O
. O

These O
accurate O
results O
emphasise O
the O
feasibility O
of O
the O
proposed O
strategy O
and O
encourage O
the O
development O
of O
similar O
approaches O
based O
on O
visible O
spectroscopy O
in O
olive O
oil O
quality O
and O
traceability O
determination O
. O

Anti O
- O
inflammatory O
effects O
of O
phenolic O
crude O
extracts O
from O
five O
fractions O
of O
Corchorus O
Olitorius O
L O
. O

Corchorus O
olitorius O
L O
. O

is O
grown O
in O
Taiwan O
during O
summer O
. O

Tender O
leaves O
are O
crushed O
and O
washed O
by O
running O
water O
before O
eating O
. O

Five O
fractions O
including O
crude O
phenolic O
extracts O
( O
using O
80 O
per O
cent O
aqueous O
acetone O
) O
of O
whole O
plant O
, O
leaf O
, O
stem O
, O
washed O
leaf O
( O
WL O
) O
and O
dried O
water O
washing O
material O
( O
WW O
) O
were O
used O
in O
this O
study O
. O

Linoleic B
acid I
autoxidation O
inhibitions O
on O
all O
fractions O
were O
higher O
than O
that O
on O
alpha B
- I
tocopherol I
. O

Except O
for O
WL O
and O
WW O
, O
other O
fractions O
also O
showed O
DPPH B
radical O
scavenging O
efficiency O
. O

The O
effect O
of O
all O
fractions O
on O
the O
regulation O
of O
inflammatory O
responses O
in O
lipopolysaccharide O
( O
LPS O
) O
- O
stimulated O
J774A O
. O
1 O
macrophage O
cells O
was O
investigated O
. O

All O
fractions O
diminished O
LPS O
- O
induced O
protein O
expression O
of O
inducible O
nitric B
oxide I
synthase O
( O
iNOS O
) O
and O
cyclooxygenase O
2 O
( O
COX O
- O
2 O
) O
. O

Nitric B
oxide I
( O
NO B
) O
and O
prostaglandin B
E2 I
( O
PGE B
( I
2 I
) I
) O
, O
downstream O
products O
, O
were O
also O
suppressed O
in O
dose O
- O
dependent O
manners O
, O
except O
for O
WL O
and O
WW O
. O

Oxidative O
modification O
and O
loss O
of O
leaf O
phenolics B
after O
kneading O
and O
washing O
greatly O
affected O
DPPH B
radical O
scavenging O
and O
inflammatory O
responses O
. O

Storage O
stability O
of O
hen O
egg O
white O
powders O
in O
three O
protein O
/ O
water O
dough O
model O
systems O
. O

In O
recent O
years O
, O
due O
to O
the O
specific O
health O
benefits O
associated O
with O
bioactive O
peptides O
and O
the O
reduction O
of O
protein O
allergenicity O
by O
enzymatic O
hydrolysis O
, O
the O
utilisation O
of O
protein O
hydrolysates O
in O
the O
intermediate O
- O
moisture O
food O
( O
IMF O
) O
market O
, O
such O
as O
high O
protein O
nutrition O
bars O
( O
HPNB O
) O
, O
has O
significantly O
increased O
. O

Currently O
, O
no O
reported O
study O
is O
related O
to O
the O
storage O
stability O
of O
dried O
hen O
egg O
white O
( O
DEW O
) O
and O
its O
hydrolysates O
( O
HEW O
) O
in O
an O
IMF O
matrix O
. O

Therefore O
, O
three O
DEW O
/ O
HEW O
dough O
model O
systems O
( O
100 O
% O
HEW O
+ O
0 O
% O
DEW O
, O
75 O
% O
HEW O
+ O
25 O
% O
DEW O
and O
50 O
% O
HEW O
+ O
50 O
% O
DEW O
) O
were O
established O
using O
two O
commercial O
spray O
- O
dried O
egg O
white O
powders O
to O
study O
the O
effect O
of O
temperature O
and O
fraction O
of O
HEW O
on O
these O
IMF O
models O
( O
water O
activity O
( O
a O
( O
w O
) O
) O
: O
~ O
0 O
. O
8 O
) O
. O

During O
storage O
at O
three O
different O
temperatures O
( O
23 O
, O
35 O
and O
45 O
degrees O
C O
) O
for O
70 O
days O
, O
the O
selected O
physicochemical O
properties O
of O
the O
dough O
systems O
were O
compared O
. O

Overall O
, O
kinetic O
analysis O
showed O
an O
apparent O
zero O
- O
order O
model O
fit O
for O
the O
change O
in O
the O
colour O
( O
L O
( O
* O
) O
) O
, O
fluorescence O
intensity O
( O
FI O
) O
and O
hardness O
, O
as O
a O
function O
of O
time O
, O
for O
different O
dough O
model O
systems O
. O

As O
expected O
, O
the O
L O
( O
* O
) O
, O
FI O
and O
hardness O
increased O
as O
a O
function O
of O
time O
mainly O
due O
to O
the O
Maillard O
reaction O
. O

The O
amount O
of O
free O
amino B
groups O
decreased O
, O
with O
an O
increase O
in O
rate O
of O
loss O
, O
as O
temperature O
increased O
in O
the O
100 O
% O
HEW O
+ O
0 O
% O
DEW O
model O
. O

When O
DEW O
was O
substituted O
for O
some O
HEW O
, O
the O
regeneration O
of O
the O
free O
amino B
groups O
after O
loss O
was O
observed O
as O
a O
function O
of O
time O
. O

Furthermore O
, O
when O
the O
percentage O
of O
HEW O
was O
decreased O
, O
the O
incidence O
of O
mouldy O
samples O
occurred O
sooner O
, O
which O
indicates O
that O
HEW O
has O
some O
antimicrobial O
ability O
, O
especially O
in O
the O
100 O
% O
HEW O
+ O
0 O
% O
DEW O
system O
where O
mould O
growth O
did O
not O
occur O
. O

Investigation O
of O
isotope O
dilution O
mass O
spectrometric O
( O
ID O
- O
MS O
) O
method O
to O
determine O
niacin B
in O
infant O
formula O
, O
breakfast O
cereals O
and O
multivitamins O
. O

An O
isotope O
dilution O
LC O
/ O
mass O
spectrometric O
( O
ID O
- O
LC O
/ O
MS O
) O
method O
was O
developed O
as O
a O
candidate O
reference O
method O
for O
the O
accurate O
determination O
of O
niacin B
in O
infant O
formula O
, O
breakfast O
cereals O
and O
multivitamin O
. O

After O
spiking O
nicotinamide B
- I
d I
( I
4 I
) I
as O
an O
internal O
standard O
, O
infant O
formula O
and O
breakfast O
cereal O
samples O
were O
hydrolysed O
under O
alkaline O
condition O
. O

Samples O
were O
then O
analysed O
in O
SRM O
mode O
to O
detect O
nicotinic B
acid I
and O
nicotinic B
acid I
- I
d I
( I
4 I
) I
at O
m O
/ O
z O
124 O
- O
- O
> O
80 O
and O
127 O
- O
- O
> O
84 O
, O
respectively O
. O

In O
the O
case O
of O
multivitamin O
sample O
that O
contains O
mainly O
free O
nicotinamide B
, O
LC O
/ O
MS O
monitored O
nicotinamide B
and O
nicotinamide B
- I
d I
( I
4 I
) I
at O
their O
SRM O
channels O
of O
m O
/ O
z O
123 O
- O
- O
> O
80 O
and O
m O
/ O
z O
127 O
- O
- O
> O
84 O
, O
respectively O
, O
after O
simple O
extraction O
. O

The O
repeatability O
and O
reproducibility O
were O
tested O
for O
the O
validation O
of O
the O
developed O
ID O
/ O
LC O
- O
MS O
method O
. O

Additionally O
, O
the O
developed O
analytical O
method O
was O
applied O
to O
determine O
total O
niacin B
contents O
in O
homogenised O
infant O
formula O
, O
homogenised O
multivitamin O
, O
and O
commercially O
available O
products O
including O
different O
types O
of O
infant O
formula O
, O
breakfast O
cereals O
, O
and O
multivitamin O
tablets O
. O

Hypolipidemic O
and O
antioxidant O
activities O
of O
thymoquinone B
and O
limonene B
in O
atherogenic O
suspension O
fed O
rats O
. O

The O
hypolipidemic O
and O
antioxidant O
actions O
of O
thymoquinone B
( O
TQ O
) O
and O
limonene B
( O
LMN O
) O
were O
investigated O
by O
giving O
1 O
ml O
of O
10mg O
TQ O
or O
200mg O
LMN B
suspension O
, O
by O
gavage O
in O
two O
equal O
doses O
( O
morning O
and O
evening O
) O
of O
0 O
. O
5 O
ml O
each O
for O
30 O
days O
, O
in O
rats O
, O
fed O
an O
atherogenic O
suspension O
. O

These O
compounds O
effectively O
ameliorated O
all O
the O
altered O
cardiovascular O
risk O
parameters O
via O
a O
reduction O
in O
HMG B
- I
CoA I
reductase O
activity O
, O
along O
with O
an O
increase O
in O
arylesterase O
activity O
. O

The O
compounds O
significantly O
blocked O
the O
shift O
in O
buoyancy O
from O
less O
atherogenic O
lb O
- O
LDL O
to O
highly O
atherogenic O
sd O
- O
LDL O
, O
restoring O
the O
percent O
distribution O
of O
LDL O
- O
C O
and O
apoB O
into O
sd O
- O
LDL O
and O
lb O
- O
LDL O
to O
near O
normal O
levels O
. O

These O
compounds O
also O
blocked O
basal O
and O
maximal O
formation O
of O
CD B
and O
malondialdehyde B
, O
and O
lengthened O
the O
lag O
times O
of O
LDL O
, O
sd O
- O
LDL O
and O
lb O
- O
LDL O
in O
the O
order O
TQ O
> O
LMN O
. O

Our O
results O
strongly O
suggest O
an O
important O
therapeutic O
use O
of O
test O
compounds O
, O
especially O
TQ O
, O
in O
the O
prevention O
of O
cardiovascular O
disease O
risks O
parameters O
. O

Effects O
of O
sodium B
caseinate O
concentration O
and O
storage O
conditions O
on O
the O
oxidative O
stability O
of O
oil O
- O
in O
- O
water O
emulsions O
. O

The O
oxidative O
stability O
of O
various O
oils O
( O
sunflower O
, O
camelina O
and O
fish O
) O
and O
20 O
% O
oil O
- O
in O
- O
water O
( O
O O
/ O
W O
) O
emulsions O
, O
were O
examined O
. O

The O
mean O
particle O
size O
decreased O
from O
1179 O
to O
325 O
nm O
as O
sodium B
caseinate O
( O
emulsifier O
) O
concentration O
was O
increased O
from O
0 O
. O
25 O
% O
to O
3 O
% O
in O
O O
/ O
W O
emulsions O
( O
P O
< O
0 O
. O
05 O
) O
. O

Increasing O
the O
microfluidisation O
pressure O
from O
21 O
to O
138 O
MPa O
, O
resulted O
in O
a O
particle O
size O
decrease O
from O
289 O
to O
194 O
nm O
( O
P O
< O
0 O
. O
05 O
) O
. O

Emulsified O
oils O
had O
lower O
detectable O
lipid O
hydroperoxide B
and O
p B
- I
Anisidine I
values O
than O
their O
corresponding O
bulk O
oils O
( O
P O
< O
0 O
. O
05 O
) O
. O

The O
lipid O
hydroperoxide B
and O
p B
- I
Anisidine I
values O
of O
emulsions O
generally O
decreased O
as O
sodium B
caseinate O
concentration O
increased O
, O
and O
similarly O
decreased O
as O
microfluidisation O
pressure O
increased O
( O
P O
< O
0 O
. O
05 O
) O
. O

Increasing O
storage O
temperature O
of O
the O
emulsions O
from O
5 O
to O
60 O
degrees O
C O
, O
resulted O
in O
lower O
detectable O
lipid O
oxidation O
products O
during O
storage O
( O
P O
< O
0 O
. O
05 O
) O
. O

Antioxidant O
activity O
and O
nutritional O
quality O
of O
traditional O
red O
- O
grained O
rice O
varieties O
containing O
proanthocyanidins B
. O

Proanthocyanidin B
- O
containing O
rice O
varieties O
have O
been O
rarely O
reported O
. O

Antioxidant O
capacity O
, O
major O
antioxidant O
components O
, O
and O
nutritional O
parameters O
of O
eight O
traditional O
red O
- O
grained O
rice O
varieties O
containing O
proanthocyanidins B
grown O
in O
Sri O
Lanka O
were O
investigated O
. O

The O
tested O
traditional O
red O
varieties O
, O
on O
the O
average O
, O
had O
over O
sevenfold O
higher O
both O
total O
antioxidant O
capacity O
and O
phenolic O
content O
than O
three O
light O
brown O
- O
grained O
new O
- O
improved O
rice O
varieties O
. O

Major O
antioxidant O
phenolic B
compounds O
identified O
in O
this O
study O
included O
proanthocyanidins B
, O
phenolic B
acids I
and O
gamma B
- I
oryzanols I
( O
ferulic B
acid I
derivatives O
) O
. O

Proanthocyanidins B
were O
detected O
only O
in O
the O
traditional O
red O
varieties O
, O
but O
not O
found O
in O
new O
- O
improved O
ones O
. O

Most O
traditional O
red O
varieties O
also O
contained O
significantly O
higher O
levels O
of O
protein O
with O
well O
balanced O
amino B
acids I
and O
higher O
contents O
of O
fat O
, O
fibre O
and O
vitamin B
E I
( O
tocopherols B
and O
tocotrienols B
) O
than O
the O
new O
- O
improved O
ones O
. O

Great O
variations O
in O
antioxidant O
capacity O
, O
major O
phenolics B
, O
and O
nutritional O
parameters O
were O
observed O
among O
different O
rice O
varieties O
. O

These O
Sri O
Lankan O
traditional O
red O
- O
grained O
rice O
varieties O
containing O
proanthocyanidins B
may O
be O
used O
as O
important O
genetic O
sources O
for O
rice O
breeding O
. O

Hydroxytyrosyl B
ethyl I
ether I
exhibits O
stronger O
intestinal O
anticarcinogenic O
potency O
and O
effects O
on O
transcript O
profiles O
compared O
to O
hydroxytyrosol B
. O

The O
anticarcinogenic O
activity O
of O
hydroxytyrosyl B
ethyl I
ether I
( O
HTy B
- I
Et I
) O
compared O
to O
its O
precursor O
hydroxytyrosol B
( O
HTy B
) O
has O
been O
studied O
in O
human O
Caco O
- O
2 O
colon O
adenocarcinoma O
cells O
. O

451 O
and O
977 O
genes O
were O
differentially O
expressed O
in O
Caco O
- O
2 O
cells O
exposed O
to O
HTy O
or O
HTy O
- O
Et O
for O
24h O
, O
respectively O
, O
compared O
with O
untreated O
cells O
( O
P O
< O
0 O
. O
005 O
; O
FDR O
= O
0 O
) O
, O
using O
Affymetrix O
microarrays O
. O

Results O
showed O
that O
both O
HTy O
and O
HTy O
- O
Et O
inhibited O
cell O
proliferation O
and O
arrested O
the O
cell O
cycle O
by O
up O
- O
regulating O
p21 O
and O
CCNG2 O
and O
down O
- O
regulating O
CCNB1 O
protein O
expression O
. O

HTy O
and O
HTy O
- O
Et O
also O
altered O
the O
transcription O
of O
specific O
genes O
involved O
in O
apoptosis O
, O
as O
suggested O
by O
the O
up O
- O
regulation O
of O
BNIP3 O
, O
BNIP3L O
, O
PDCD4 O
and O
ATF3 O
and O
the O
activation O
of O
caspase O
- O
3 O
. O

Moreover O
, O
these O
polyphenols B
up O
- O
regulated O
xenobiotic O
metabolizing O
enzymes O
UGT1A10 O
and O
CYP1A1 O
, O
enhancing O
carcinogen O
detoxification O
. O

In O
conclusion O
, O
these O
results O
highlight O
that O
HTy O
and O
its O
derivative O
HTy O
- O
Et O
modulate O
molecular O
mechanisms O
involved O
in O
colon O
cancer O
, O
with O
HTy O
- O
Et O
being O
more O
effective O
than O
HTy B
. O

Determination O
of O
ethyl B
carbamate I
in O
cacha O
c O
a O
produced O
from O
copper B
stills O
by O
HPLC O
. O

Ethyl B
carbamate I
( O
EC O
) O
is O
a O
common O
substance O
in O
fermented O
foods O
and O
drinks O
, O
and O
its O
quantification O
is O
important O
because O
of O
its O
carcinogenic O
nature O
and O
its O
usually O
presence O
in O
alcoholic O
beverages O
. O

The O
present O
work O
involved O
the O
development O
and O
validation O
of O
an O
analytical O
method O
for O
the O
evaluation O
of O
EC O
in O
cacha O
c O
a O
by O
HPLC O
- O
FLD O
after O
previous O
derivatization O
with O
xanthydrol B
. O

The O
method O
presented O
a O
mean O
recovery O
of O
94 O
. O
88 O
% O
, O
an O
intra O
- O
day O
precision O
of O
4 O
. O
19 O
% O
( O
30 O
. O
0 O
mu O
gL O
( O
- O
1 O
) O
) O
and O
3 O
. O
32 O
% O
( O
75 O
. O
0 O
mu O
gL O
( O
- O
1 O
) O
) O
, O
a O
coefficient O
of O
determination O
( O
r O
( O
2 O
) O
) O
equal O
to O
0 O
. O
9985 O
, O
and O
limits O
of O
detection O
and O
quantification O
equal O
to O
6 O
. O
39 O
and O
21 O
. O
32 O
mu O
gL O
( O
- O
1 O
) O
, O
respectively O
. O

The O
results O
show O
that O
the O
analytical O
method O
is O
accurate O
, O
reproducible O
and O
linear O
over O
the O
concentration O
range O
from O
5 O
. O
0 O
to O
160 O
mu O
g O
of O
EC O
per O
litre O
. O

The O
method O
was O
applied O
to O
the O
analysis O
of O
EC O
in O
cacha O
c O
a O
, O
the O
analyses O
being O
rapid O
and O
efficient O
. O

Moisture O
diffusivity O
in O
food O
materials O
. O

This O
paper O
investigates O
whether O
moisture O
diffusion O
can O
be O
predicted O
for O
food O
materials O
. O

We O
focus O
especially O
on O
mixtures O
of O
glucose B
homopolymers O
and O
water O
. O

The O
predictions O
are O
based O
on O
three O
theories O
: O
( O
1 O
) O
the O
Darken O
relation O
, O
linking O
the O
mutual O
diffusivity O
to O
the O
self O
diffusivities O
, O
( O
2 O
) O
the O
generalised O
Stokes O
- O
Einstein O
relation O
for O
the O
solute O
self O
diffusivity O
, O
and O
( O
3 O
) O
the O
free O
volume O
theory O
for O
water O
self O
diffusivity O
. O

Using O
literature O
data O
obtained O
for O
the O
whole O
class O
of O
glucose B
homopolymer O
, O
we O
show O
that O
these O
theories O
predict O
the O
moisture O
diffusivity O
for O
the O
whole O
range O
of O
volume O
fractions O
, O
from O
zero O
to O
one O
, O
and O
a O
broad O
range O
of O
temperatures O
. O

Furthermore O
, O
we O
show O
that O
the O
theories O
equally O
holds O
for O
other O
hydrophilic O
biopolymers O
one O
finds O
in O
food O
. O

In O
the O
concentrated O
regime O
, O
all O
experimental O
data O
collapse O
to O
a O
single O
curve O
. O

This O
universal O
behaviour O
arises O
because O
these O
biopolymers O
form O
a O
hydrogen B
bonded O
network O
, O
where O
water O
molecules O
move O
via O
rearrangement O
of O
the O
free O
volume O
. O

Investigation O
of O
the O
effect O
of O
gelatine O
, O
egg O
albumin O
and O
cross O
- O
flow O
microfiltration O
on O
the O
phenolic B
composition O
of O
Pinotage O
wine O
. O

The O
effect O
of O
fining O
and O
cross O
- O
flow O
microfiltration O
on O
the O
phenolic O
composition O
of O
red O
wine O
was O
investigated O
. O

Both O
gelatine O
( O
G O
) O
and O
egg O
albumin O
( O
EA O
) O
fining O
decreased O
the O
mean O
degree O
of O
polymerisation O
( O
mDP O
) O
of O
tannin B
significantly O
by O
26 O
. O
4 O
% O
and O
25 O
. O
2 O
% O
, O
respectively O
, O
compared O
to O
the O
control O
( O
C O
) O
. O

Cross O
- O
flow O
microfiltration O
( O
CF O
) O
also O
decreased O
the O
mDP O
significantly O
by O
25 O
% O
. O

Thus O
, O
the O
fining O
agents O
and O
cross O
- O
flow O
microfiltration O
selectively O
removed O
the O
highly O
polymerised O
phenols B
. O

After O
3 O
. O
5 O
months O
of O
bottle O
ageing O
, O
differences O
between O
the O
different O
treatments O
and O
the O
control O
decreased O
. O

CF O
had O
the O
most O
significant O
effect O
on O
the O
flavan B
- I
3 I
- I
ol I
and O
polymeric O
phenol I
( O
tannin B
) O
content O
of O
the O
wines O
compared O
to O
the O
control O
followed O
by O
G O
fining O
. O

CF O
and O
EA O
treatments O
significantly O
decreased O
the O
total O
pigment O
content O
compared O
to O
C O
. O

CF O
was O
also O
the O
only O
treatment O
that O
could O
be O
distinguished O
from O
the O
other O
treatments O
by O
sensory O
analysis O
. O

All O
treatments O
improved O
clarity O
of O
the O
wines O
with O
cross O
- O
flow O
microfiltration O
having O
the O
largest O
effect O
. O

Iron B
and O
zinc B
bioavailability O
in O
Caco O
- O
2 O
cells O
: O
influence O
of O
caseinophosphopeptid O
. O

A O
study O
has O
been O
made O
of O
the O
influence O
of O
two O
pools O
of O
caseinophosphopeptid O
( O
CPPs O
) O
obtained O
from O
alpha O
( O
s O
) O
- O
and O
beta O
- O
casein O
( O
CN O
) O
fractions O
, O
and O
of O
three O
specific O
CPPs O
( O
beta O
- O
CN O
( O
1 O
- O
25 O
) O
4P O
, O
alpha O
( O
s1 O
) O
- O
CN O
( O
64 O
- O
74 O
) O
4P O
and O
alpha O
( O
s2 O
) O
- O
CN O
( O
1 O
- O
19 O
) O
4P O
) O
, O
on O
iron B
bioavailability O
( O
ferritin O
synthesis O
) O
and O
zinc B
bioavailability O
( O
retention O
, O
transport O
and O
uptake O
of O
zinc B
) O
in O

Caco O
- O
2 O
cells O
. O

alpha O
- O
CPP O
and O
beta O
- O
CPP O
pools O
did O
not O
improve O
ferritin O
synthesis O
, O
but O
the O
three O
specific O
CPPs O
showed O
an O
increase O
in O
ferritin O
synthesis O
in O
Caco O
- O
2 O
cells O
versus O
iron B
sulphate I
, O
beta B
- I
CN I
( I
1 I
- I
25 I
) I
4P I
being O
the O
most O
effective O
. O

In O
relation O
to O
zinc B
bioavailability O
, O
alpha O
- O
CPPs O
, O
beta O
- O
CPPs O
, O
alpha O
( O
s1 O
) O
- O
CN B
( O
64 O
- O
74 O
) O
4P O
and O
beta O
- O
CN B
( O
1 O
- O
25 O
) O
4P O
increased O
zinc B
uptake O
. O

However O
, O
this O
increase O
was O
of O
the O
same O
order O
as O
the O
increase O
due O
to O
the O
presence O
of O
zinc B
sulphate I
. O

The O
physical O
characteristics O
and O
emulsification O
properties O
of O
partially O
dephosphorylated O
bovine O
beta O
- O
casein O
. O

Bovine O
beta O
- O
casein O
was O
purified O
from O
phosphocasein O
by O
rennet O
coagulation O
and O
cold O
solubilisation O
from O
the O
resultant O
curd O
. O

beta O
- O
Casein O
was O
then O
dephosphorylated O
using O
potato O
acid O
phosphatase O
. O

Urea B
- O
polyacrylamide B
gel O
electrophoresis O
( O
PAGE O
) O
of O
partially O
dephosphorylated O
beta O
- O
casein O
showed O
a O
number O
of O
bands O
, O
depending O
on O
the O
final O
level O
of O
phosphorylation O
. O

Dephosphorylating O
beta O
- O
casein O
increased O
its O
pH O
of O
minimum O
solubility O
from O
~ O
pH O
5 O
to O
5 O
. O
5 O
and O
reduced O
its O
net O
negative O
charge O
from O
- O
30 O
. O
8 O
to O
- O
27 O
. O
0 O
mV O
. O

During O
the O
acidification O
of O
beta O
- O
casein O
solutions O
, O
partially O
dephosphorylated O
beta O
- O
casein O
failed O
to O
form O
a O
gel O
, O
unlike O
the O
phosphorylated O
( O
i O
. O
e O
. O
, O
control O
) O
beta O
- O
casein O
. O

Use O
of O
partially O
dephosphorylated O
beta O
- O
casein O
to O
stabilise O
oil O
- O
in O
- O
water O
emulsions O
resulted O
in O
larger O
fat O
globules O
compared O
to O
control O
beta O
- O
casein O
, O
but O
such O
globules O
were O
less O
susceptible O
to O
aggregation O
in O
the O
presence O
of O
15 O
or O
30 O
mM O
CaCl B
( I
2 I
) I
. O

Overall O
, O
the O
dephosphorylation O
of O
beta O
- O
casein O
resulted O
in O
a O
protein O
similar O
to O
human O
beta O
- O
casein O
in O
terms O
of O
physicochemical O
functionality O
, O
with O
increased O
stability O
against O
calcium B
- O
induced O
aggregation O
. O

A O
rapid O
determination O
method O
for O
ethylenethiourea B
in O
potato O
and O
cucumber O
by O
modified O
QuEChERS O
- O
high O
performance O
liquid O
chromatography O
- O
tandem O
mass O
spectrometry O
. O

A O
rapid O
and O
sensitive O
analytical O
method O
for O
the O
determination O
of O
ethylenethiourea B
( O
ETU B
) O
in O
potatoes O
and O
cucumbers O
is O
developed O
. O

This O
method O
employs O
modified O
QuEChERS O
followed O
by O
high O
performance O
liquid O
chromatography O
- O
tandem O
mass O
spectrometry O
( O
HPLC O
- O
MS O
/ O
MS O
) O
analysis O
. O

ETU B
was O
extracted O
by O
alkaline O
acetonitrile B
( O
containing O
1 O
% O
NH B
( I
3 I
) I
. I
H I
( I
2 I
) I
0 I
) O
, O
separated O
on O
a O
ZIC O
- O
pHILIC O
column O
, O
confirmed O
by O
multiple O
reaction O
monitoring O
( O
MRM O
) O
mode O
with O
electrospray O
ionisation O
source O
. O

This O
modified O
procedure O
showed O
satisfactory O
recovery O
( O
90 O
. O
6 O
- O
103 O
. O
5 O
% O
) O
fortified O
at O
the O
range O
of O
0 O
. O
005 O
- O
0 O
. O
05 O
mg O
kg O
( O
- O
1 O
) O
with O
relative O
standard O
deviation O
( O
RSD O
) O
< O
7 O
% O
. O

The O
limits O
of O
detection O
( O
LOD O
) O
and O
the O
limits O
of O
quantification O
( O
LOQ O
) O
were O
0 O
. O
002 O
mg O
kg O
( O
- O
1 O
) O
and O
0 O
. O
005 O
mg O
kg O
( O
- O
1 O
) O
, O
respectively O
. O

Matrix O
effect O
and O
HILIC O
retention O
mechanism O
were O
also O
evaluated O
. O

The O
method O
was O
finally O
applied O
to O
detect O
ETU B
in O
potato O
and O
cucumber O
samples O
collected O
at O
harvest O
period O
. O

Residues O
of O
ETU B
were O
detected O
in O
four O
cucumber O
samples O
with O
the O
level O
lower O
than O
LOQ O
. O

Multiple O
mutations O
of O
the O
critical O
amino B
acid I
residues O
for O
the O
sweetness O
of O
the O
sweet O
- O
tasting O
protein O
, O
brazzein O
. O

We O
have O
previously O
identified O
critical O
residues O
important O
for O
sweetness O
of O
the O
sweet O
protein O
brazzein O
by O
site O
- O
directed O
mutagenesis O
( O
Yoon O
, O
Kong O
, O
Jo O
, O
& O
Kong O
, O
2011 O
) O
. O

In O
order O
to O
elucidate O
the O
interaction O
mechanisms O
of O
brazzein B
with O
the O
sweet O
taste O
receptor O
, O
we O
made O
multiple O
mutations O
of O
three O
residues O
( O
His31 B
in O
loop O
30 O
- O
33 O
, O
Glu36 B
in O
beta O
- O
strand O
III O
, O
and O
Glu41 B
in O
loop O
40 O
- O
43 O
) O
. O

We O
found O
that O
all O
double O
mutations O
( O
H31R O
/ O
E36D O
, O
H31R O
/ O
E41A O
and O
E36D O
/ O
E41A O
) O
made O
the O
molecules O
sweeter O
than O
des B
- O
pE1M O
- O
brazzein O
and O
three O
single O
mutants O
. O

Moreover O
, O
the O
triple O
mutation O
( O
H31R O
/ O
E36D O
/ O
E41A O
) O
made O
the O
molecule O
significantly O
sweeter O
than O
three O
double O
mutants O
. O

These O
results O
strongly O
support O
the O
hypothesis O
that O
brazzein B
binds O
to O
the O
multisite O
surface O
of O
the O
sweet O
taste O
receptor O
. O

Our O
findings O
also O
suggest O
that O
mutations O
reducing O
the O
overall O
negative O
charge O
and O
/ O
or O
increasing O
the O
positive O
charge O
favour O
sweet O
- O
tasting O
protein O
potency O
. O

Characterization O
of O
3 B
, I
4 I
- I
DHPEA I
- I
EDA I
oxidation O
products O
in O
virgin O
olive O
oil O
by O
high O
performance O
liquid O
chromatography O
coupled O
with O
mass O
spectrometry O
. O

Secoiridoid B
derivatives O
are O
the O
most O
important O
antioxidants O
of O
virgin O
olive O
oil O
( O
VOO O
) O
, O
and O
their O
oxidation O
products O
could O
be O
used O
as O
molecular O
markers O
of O
VOO O
freshness O
to O
define O
the O
VOO O
autoxidation O
state O
. O

The O
aim O
of O
this O
research O
was O
to O
characterise O
the O
dialdehydic O
form O
of O
decarboxymethyl B
elenolic I
acid I
linked O
to O
hydroxytyrosol B
( O
3 B
, I
4 I
- I
DHPEA I
- I
EDA I
) O
oxidation O
products O
to O
find O
analytical O
indicators O
that O
could O
be O
used O
as O
early O
evaluation O
index O
of O
the O
VOO O
autoxidation O
state O
. O

3 B
, I
4 I
- I
DHPEA I
- I
EDA I
was O
oxidised O
by O
enzymatic O
and O
Fenton O
reactions O
. O

Terpenic B
structure O
oxidation O
products O
accumulated O
in O
VOO O
during O
the O
autoxidation O
process O
, O
thus O
they O
may O
be O
used O
as O
early O
evaluation O
index O
of O
the O
VOO O
autoxidation O
state O
before O
fatty B
acids I
oxidation O
. O

Effects O
of O
Azocompost B
and O
urea B
on O
the O
herbage O
yield O
and O
contents O
and O
compositions O
of O
essential O
oils O
from O
two O
genotypes O
of O
dragonhead O
( O
Dracocephalum O
moldavica O
L O
. O
) O
in O
two O
regions O
of O
Iran O
. O

Dragonhead O
is O
an O
annual O
, O
herbaceous O
, O
balm O
- O
scented O
and O
spicy O
aromatic O
member O
of O
the O
family O
Lamiaceae O
. O

We O
examined O
effects O
of O
different O
sources O
of O
nitrogen B
on O
the O
content O
and O
composition O
of O
essential O
oils O
in O
two O
genotypes O
of O
dragonhead O
in O
two O
regions O
of O
Iran O
. O

The O
sources O
of O
nitrogen B
used O
were O
100 O
% O
urea B
( O
70 O
kg O
N O
ha O
( O
- O
1 O
) O
) O
, O
75 O
% O
urea B
( O
52 O
. O
5 O
kg O
N O
ha O
( O
- O
1 O
) O
) O
+ O
25 O
% O
Azocompost B
( O
3 O
. O
85 O
tonha O
( O
- O
1 O
) O
) O
, O
50 O
% O
urea B
( O
35 O
kg O
N O
ha O
( O
- O
1 O
) O
) O
+ O
50 O
% O
Azocompost B
( O
7 O
. O
77 O
tonha O
( O
- O
1 O
) O
) O
, O
25 O
% O
urea B
( O
17 O
. O
5 O
kg O
N O
ha O
( O
- O
1 O
) O
) O
+ O
75 O
% O
Azocompost B
( O
11 O
. O
55 O
tonha O
( O
- O
1 O
) O
) O
, O
and O
100 O

% O
Azocompost O
( O
15 O
. O
55 O
tonha O
( O
- O
1 O
) O
) O
. O

Optimal O
yield O
and O
content O
of O
essential O
oil O
at O
both O
locations O
for O
both O
genotypes O
were O
obtained O
by O
applying O
50 O
% O
urea B
+ O
50 O
% O
Azocompost B
. O

Geraniol B
, O
geranial B
, O
and O
geranyl B
acetate I
were O
the O
most O
abundant O
compounds O
. O

For O
both O
genotypes O
and O
both O
locations O
, O
application O
of O
50 O
% O
urea B
+ O
50 O
% O
Azocompost B
increased O
levels O
of O
geraniol B
and O
geranial B
, O
and O
application O
of O
Azocompost B
alone O
increased O
levels O
of O
geranyl B
acetate I
. O

Overall O
, O
we O
conclude O
that O
the O
application O
of O
50 O
% O
urea B
with O
50 O
% O
Azocompost B
is O
recommended O
for O
optimising O
the O
content O
and O
composition O
of O
essential O
oils O
in O
dragonhead O
. O

In O
vitro O
digestibility O
and O
starch O
content O
, O
predicted O
glycemic O
index O
and O
potential O
in O
vitro O
antidiabetic O
effect O
of O
lentil O
sprouts O
obtained O
by O
different O
germination O
techniques O
. O

The O
study O
focuses O
on O
changes O
in O
starch O
content O
and O
expected O
glycemic O
index O
( O
eGI O
) O
caused O
by O
different O
sprouting O
methods O
of O
lentil O
. O

On O
germination O
, O
a O
decrease O
was O
observed O
in O
total O
starch O
content O
( O
TS O
) O
, O
alpha O
- O
amylase O
inhibitors O
activity O
( O
alpha O
AI O
) O
and O
eGI O
values O
. O

After O
elicitation O
, O
the O
highest O
TS O
content O
was O
determined O
in O
3 O
- O
day O
- O
old O
control O
sprouts O
( O
100 O
. O
9 O
mg O
/ O
gf O
. O
m O
. O
) O
, O
whereas O
the O
lowest O
was O
in O
4 O
- O
day O
- O
old O
sprouts O
induced O
with O
300 O
mM O
NaCl B
( O
57 O
. O
8 O
mg O
/ O
gf O
. O
m O
. O
) O
. O

Resistant O
starch O
( O
RS O
) O
content O
was O
most O
effectively O
increased O
by O
induction O
with O
600 O
mM O
mannitol B
. O

The O
highest O
eGI O
values O
were O
determined O
for O
3 O
- O
day O
- O
old O
sprouts O
induced O
with O
300 O
mM O
NaCl B
, O
whereas O
the O
lowest O
were O
for O
6 O
- O
day O
- O
old O
sprouts O
induced O
with O
100mM O
NaCl B
. O

In O
treated O
sprouts O
starch O
digestibility O
was O
connected O
with O
alpha O
AI O
activity O
and O
RS O
content O
. O

Sprouting O
conditions O
can O
modify O
starch O
content O
, O
its O
potential O
bioavailability O
and O
eGI O
values O
. O

Optimization O
of O
this O
process O
will O
allow O
for O
the O
maximum O
nutritional O
benefit O
. O

Molecular O
and O
functional O
properties O
of O
gelatin O
from O
the O
skin O
of O
unicorn O
leatherjacket O
as O
affected O
by O
extracting O
temperatures O
. O

Gelatins O
extracted O
from O
the O
skin O
of O
unicorn O
leatherjacket O
at O
different O
temperatures O
( O
45 O
, O
55 O
, O
65 O
and O
75 O
degrees O
C O
) O
in O
the O
presence O
and O
the O
absence O
of O
soybean O
trypsin O
inhibitor O
( O
SBTI O
; O
100 O
units O
/ O
g O
pretreated O
skin O
) O
for O
12h O
were O
characterised O
. O

In O
general O
, O
the O
addition O
of O
SBTI B
resulted O
in O
the O
lower O
yield O
, O
regardless O
of O
extraction O
temperature O
. O

Higher O
yield O
was O
obtained O
when O
higher O
extraction O
temperature O
was O
used O
( O
P O
< O
0 O
. O
05 O
) O
. O

Gelatin O
from O
skin O
extracted O
at O
75 O
degrees O
C O
in O
the O
absence O
of O
SBTI O
showed O
the O
highest O
yield O
( O
10 O
. O
66 O
+ O
/ O
- O
0 O
. O
41 O
% O
) O
( O
based O
on O
dry O
weight O
) O
. O

The O
highest O
alpha B
- I
amino I
group O
content O
was O
observed O
in O
gelatin O
extracted O
at O
55 O
degrees O
C O
without O
SBTI B
incorporated O
. O

The O
band O
intensity O
of O
beta O
- O
chain O
and O
alpha O
- O
chains O
increased O
as O
the O
extraction O
temperature O
increased O
, O
particularly O
above O
55 O
degrees O
C O
. O

Gelatin O
extracted O
at O
65 O
degrees O
C O
with O
and O
without O
SBTI B
incorporation O
exhibited O
the O
highest O
gel O
strength O
( O
178 O
. O
00 O
+ O
/ O
- O
7 O
. O
50 O
g O
and O
170 O
. O
47 O
+ O
/ O
- O
1 O
. O
30 O
g O
, O
respectively O
) O
. O

FTIR O
spectra O
indicated O
that O
a O
greater O
loss O
of O
molecular O
order O
of O
triple O
helix O
with O
a O
higher O
degradation O
was O
found O
in O
gelatin O
extracted O
at O
55 O
degrees O
C O
in O
the O
absence O
SBTI O
. O

Gelatin O
extracted O
at O
65 O
degrees O
C O
, O
either O
with O
or O
without O
SBTI O
, O
had O
the O
highest O
EAI O
and O
ESI O
with O
high O
foam O
expansion O
and O
stability O
. O

Thus O
, O
the O
extraction O
of O
gelatin O
from O
the O
skin O
of O
unicorn O
leatherjacket O
at O
temperature O
sufficiently O
high O
could O
render O
the O
gelatin O
with O
less O
degradation O
. O

Purification O
and O
identification O
of O
lipolysis O
- O
stimulating O
peptides O
derived O
from O
enzymatic O
hydrolysis O
of O
soy O
protein O
. O

The O
aim O
of O
this O
study O
was O
to O
purify O
and O
identify O
lipolysis O
- O
stimulating O
peptides O
derived O
from O
Flavourzyme O
( O
R O
) O
- O
soy O
protein O
isolate O
( O
SPI O
) O
hydrolysate O
( O
F O
- O
SPIH O
) O
. O

Glycerol B
release O
was O
employed O
as O
a O
marker O
for O
lipolysis O
in O
3T3 O
- O
L1 O
adipocytes O
. O

A O
higher O
glycerol B
release O
represents O
a O
better O
lipolysis O
- O
stimulating O
activity O
. O

The O
peptide O
fraction O
with O
highest O
glycerol B
release O
obtained O
from O
F O
- O
SPIH O
fractionated O
by O
sequential O
ultrafiltration O
membranes O
was O
further O
purified O
using O
gel O
filtration O
chromatography O
and O
two O
steps O
of O
reverse O
- O
phase O
high O
- O
performance O
liquid O
chromatography O
. O

The O
peptides O
were O
identified O
using O
liquid O
chromatography O
- O
tandem O
mass O
spectrometry O
( O
LC O
/ O
MS O
/ O
MS O
) O
. O

Three O
lipolysis O
- O
stimulating O
peptides O
were O
obtained O
, O
and O
the O
amino B
acid I
sequences O
were O
ILL O
, O
LLL O
and O
VHVV O
, O
respectively O
. O

The O
in O
vitro O
effect O
of O
gastrointestinal O
proteases O
on O
lipolysis O
- O
stimulating O
activity O
of O
synthetic O
ILL O
, O
LLL O
and O
VHVV O
, O
respectively O
, O
was O
also O
investigated O
. O

The O
result O
suggested O
that O
the O
gastrointestinal O
protease O
did O
not O
affect O
lipolysis O
- O
stimulating O
activity O
of O
the O
three O
novel O
peptides O
, O
which O
reveals O
their O
potential O
to O
act O
as O
anti O
- O
obesity O
ingredients O
. O

Vitexin B
- I
2 I
- I
O I
- I
xyloside I
, O
raphasatin B
and O
( B
- I
) I
- I
epigallocatechin I
- I
3 I
- I
gallate I
synergistically O
affect O
cell O
growth O
and O
apoptosis O
of O
colon O
cancer O
cells O
. O

Cytotoxic O
effects O
of O
the O
combination O
of O
the O
food O
components O
vitexin B
- I
2 I
- I
O I
- I
xyloside I
( O
X O
) O
, O
raphasatin B
( O
4 B
- I
methylsulphanyl I
- I
3 I
- I
butenyl I
isothiocyanates I
; O
G O
) O
and O
( B
- I
) I
- I
epigallocatechin I
- I
3 I
- I
gallate I
( O
E O
) O
were O
investigated O
in O
colon O
( O
LoVo O
and O
CaCo O
- O
2 O
) O
and O
breast O
( O
MDA O
- O
MB O
- O
231 O
and O
MCF O
- O
7 O
) O
cancer O
cells O
. O

Breast O
cancer O
cells O
were O
more O
resistant O
than O
colon O
cells O
to O
X O
, O
G O
and O
E O
inhibition O
. O

On O
the O
contrary O
, O
marked O
synergistic O
effects O
among O
X O
, O
G O
and O
E O
on O
cell O
growth O
were O
found O
in O
both O
colon O
cancer O
cells O
. O

Further O
analysis O
revealed O
a O
G0 O
/ O
G1 O
arrest O
of O
the O
phase O
cell O
progression O
and O
apoptosis O
, O
linked O
to O
modulation O
of O
Bax O
, O
Bcl2 O
, O
caspase O
- O
9 O
and O
poly B
( I
ADP I
- I
ribose I
) I
polymerase O
as O
well O
as O
Reactive O
Oxygen B
Species O
( O
ROS O
) O
generation O
in O
both O
colon O
cancer O
cells O
, O
whereas O
apoptosis O
and O
ROS O
were O
not O
significantly O
detected O
in O
normal O
human O
lymphocytes O
. O

We O
conclude O
that O
the O
X O
, O
G O
and O
E O
mixture O
might O
act O
by O
mitochondrial O
pathway O
activation O
of O
apoptosis O
, O
possibly O
elicited O
by O
ROS O
and O
the O
mixture O
may O
be O
effective O
in O
the O
chemoprevention O
of O
colon O
cancer O
. O

Absorption O
and O
urinary O
excretion O
of O
A O
- O
type O
procyanidin B
oligomers O
from O
Litchi O
chinensis O
pericarp O
in O
rats O
by O
selected O
ion O
monitoring O
liquid O
chromatography O
- O
mass O
spectrometry O
. O

Intervention O
studies O
with O
A O
- O
type O
oligomeric O
procyanidins B
from O
litchi O
( O
Litchi O
chinensis O
) O
pericarp O
( O
LPOPC O
) O
suggested O
its O
protective O
effect O
against O
cardiovascular O
diseases O
. O

However O
, O
there O
is O
no O
consensus O
on O
the O
absorption O
and O
metabolism O
of O
LPOPC O
. O

It O
was O
demonstrated O
that O
the O
main O
components O
in O
LPOPC O
were O
( B
- I
) I
- I
epicatechin I
, O
A O
- O
type O
procyanidin B
dimers O
, O
trimers O
and O
tetramers O
. O

Rats O
were O
orally O
administered O
different O
levels O
of O
LPOPC O
( O
150 O
and O
300 O
mg O
/ O
kgbw O
) O
, O
the O
procyanidins B
and O
their O
microbial O
metabolites O
in O
urine O
were O
identified O
by O
HPLC O
- O
MS O
/ O
MS O
analysis O
18 O
h O
post O
- O
administration O
. O

Data O
indicated O
that O
seven O
aromatic O
acid O
metabolites O
excreted O
were O
significantly O
increased O
by O
300 O
mg O
/ O
kgbw O
of O
LPOPC O
( O
P O
< O
0 O
. O
01 O
) O
. O

However O
, O
only O
( B
- I
) I
- I
epicatechin I
and O
its O
methylated O
derivatives O
were O
detected O
in O
rat O
plasma O
1h O
after O
300 O
mg O
/ O
kgbw O
of O
LPOPC O
administration O
. O

The O
total O
EC O
content O
absorbed O
in O
plasma O
was O
only O
2 O
. O
54 O
+ O
/ O
- O
0 O
. O
53 O
mu O
mol O
/ O
L O
, O
indicating O
that O
the O
biological O
properties O
of O
LPOPC O
should O
be O
probably O
explained O
by O
its O
microbial O
degraded O
phenolic B
acids I
. O

Phenolics B
content O
and O
antioxidant O
and O
anti O
- O
inflammatory O
activities O
of O
legume O
fractions O
. O

Two O
faba O
bean O
( O
Vicia O
faba O
L O
. O
) O
subspecies O
major O
and O
minor O
and O
lentil O
seeds O
grown O
in O
Algeria O
were O
separated O
into O
cotyledons O
and O
hulls O
. O

These O
fractions O
, O
together O
with O
their O
corresponding O
whole O
seeds O
, O
were O
extracted O
with O
two O
solvents O
, O
aqueous O
( O
70 O
% O
) O
acetone B
and O
( O
80 O
% O
) O
ethanol B
, O
and O
evaluated O
for O
antioxidant O
activity O
in O
relation O
to O
their O
phenolic O
contents O
. O

Acetone B
selectively O
extracted O
tannins B
from O
faba O
beans O
. O

The O
hulls O
always O
exhibited O
high O
antioxidant O
activity O
, O
measured O
using O
the O
reducing O
power O
( O
RP O
) O
, O
antiradical O
activity O
( O
DPPH B
) O
or O
oxygen B
radical O
absorbance O
capacity O
( O
ORAC O
) O
assays O
. O

Aqueous O
ethanol B
( O
80 O
% O
) O
extract O
of O
lentil O
hulls O
exhibited O
high O
antioxidant O
and O
anti O
- O
inflammatory O
activities O
preferentially O
inhibiting O
15 O
- O
LOX O
( O
IC O
( O
50 O
) O
, O
55 O
mu O
g O
/ O
ml O
) O
, O
with O
moderate O
COX O
- O
1 O
( O
IC O
( O
50 O
) O
, O
66 O
mu O
g O
/ O
ml O
) O
and O
COX O
- O
2 O
( O
IC O
( O
50 O
) O
, O
119 O
mu O
g O
/ O
ml O
) O
inhibitory O
effects O
on O
the O
COX O
pathway O
, O
whereas O
faba O
bean O
hull O
extracts O
exerted O
relatively O
mild O
LOX O
inhibitory O
activity O
. O

Microbial O
metabolites O
, O
but O
not O
other O
phenolics B
derived O
from O
grape O
seed O
phenolic O
extract O
, O
are O
transported O
through O
differentiated O
Caco O
- O
2 O
cell O
monolayers O
. O

Grape O
seed O
phenolic O
extract O
( O
GSE O
) O
is O
predicted O
to O
have O
health O
benefits O
, O
even O
though O
its O
bioavailability O
, O
including O
digestibility O
, O
permeability O
and O
ultimate O
metabolism O
, O
are O
still O
poorly O
understood O
. O

In O
vitro O
gastric O
and O
pancreatic O
digestion O
and O
in O
vitro O
ileal O
and O
faecal O
fermentation O
were O
combined O
with O
Caco O
- O
2 O
cell O
permeability O
studies O
for O
GSE O
samples O
. O

Qualitatively O
, O
there O
was O
no O
change O
in O
type O
/ O
number O
of O
GSE O
compounds O
following O
gastric O
and O
pancreatic O
digestion O
and O
LC O
- O
MS O
analysis O
. O

However O
, O
the O
monomers O
were O
significantly O
( O
P O
< O
0 O
. O
05 O
) O
increased O
after O
gastric O
digestion O
, O
along O
with O
a O
significant O
( O
P O
< O
0 O
. O
05 O
) O
decrease O
in O
polymers O
. O

In O
addition O
, O
all O
forms O
of O
phenolic B
compounds O
decreased O
following O
pancreatic O
digestion O
. O

However O
, O
none O
of O
the O
original O
GSE O
phenolic B
compounds O
passed O
the O
Caco O
- O
2 O
cell O
monolayer O
, O
since O
all O
were O
recovered O
in O
the O
apical O
compartment O
. O

In O
contrast O
, O
the O
two O
intestinal O
microbiota O
metabolites O
with O
deprotonated O
molecular O
weights O
of O
[ O
M O
- O
H O
] O
- O
165 O
/ O
121 O
and O
193 O
/ O
175 O
, O
that O
were O
found O
both O
in O
the O
ileal O
and O
faecal O
fermented O
samples O
, O
passed O
the O
Caco O
- O
2 O
cell O
monolayer O
. O

Enhancing O
the O
production O
of O
galacto B
- I
oligosaccharides I
by O
mutagenesis O
of O
Sulfolobus O
solfataricus O
beta O
- O
galactosidase O
. O

Galacto B
- I
oligosaccharides I
( O
GOS B
) O
, O
an O
important O
class O
of O
functional O
food O
, O
are O
commonly O
produced O
from O
lactose B
using O
beta O
- O
galactosidase O
. O

In O
the O
present O
study O
, O
beta O
- O
galactosidase O
( O
LacS O
) O
from O
Sulfolobus O
solfataricus O
P2 O
was O
cloned O
and O
site O
- O
directed O
mutagenesis O
was O
performed O
to O
obtain O
two O
mutants O
, O
F359Q O
and O
F441Y O
. O

All O
of O
the O
wild O
- O
type O
enzyme O
and O
mutants O
were O
expressed O
in O
Escherichia O
coli O
BL21 O
( O
DE3 O
) O
and O
purified O
to O
homogeneity O
. O

The O
enzymatic O
properties O
and O
optimal O
condition O
for O
transglycosylation O
reaction O
of O
the O
enzymes O
were O
investigated O
in O
detail O
. O

Under O
their O
individual O
optimal O
conditions O
, O
yields O
of O
GOS O
could O
reach O
50 O
. O
9 O
% O
for O
wild O
- O
type O
enzyme O
, O
58 O
. O
3 O
% O
for O
F359Q O
, O
and O
61 O
. O
7 O
% O
for O
F441Y O
. O

In O
addition O
, O
the O
potential O
mechanism O
for O
this O
enhancement O
was O
analysed O
. O

Detection O
of O
adulteration O
in O
honey O
samples O
added O
various O
sugar B
syrups O
with O
13C B
/ O
12C B
isotope O
ratio O
analysis O
method O
. O

Honey O
can O
be O
adulterated O
in O
various O
ways O
. O

One O
of O
the O
adulteration O
methods O
is O
the O
addition O
of O
different O
sugar B
syrups O
during O
or O
after O
honey O
production O
. O

Starch O
- O
based O
sugar B
syrups O
, O
high O
fructose B
corn O
syrup O
( O
HFCS O
) O
, O
glucose B
syrup O
( O
GS O
) O
and O
saccharose B
syrups O
( O
SS O
) O
, O
which O
are O
produced O
from O
beet O
or O
canes O
, O
can O
be O
used O
for O
adulterating O
honey O
. O

In O
this O
study O
, O
adulterated O
honey O
samples O
were O
prepared O
with O
the O
addition O
of O
HFCS O
, O
GS O
and O
SS O
( O
beet O
sugar O
) O
at O
a O
ratio O
of O
0 O
% O
, O
10 O
% O
, O
20 O
% O
, O
40 O
% O
and O
50 O
% O
by O
weight O
. O

( B
13 I
) I
C I
/ O
( B
12 I
) I
C I
analysis O
was O
conducted O
on O
these O
adulterated O
honey O
samples O
using O
an O
isotope O
ratio O
mass O
spectrometer O
in O
combination O
with O
an O
elemental O
analyser O
( O
EA O
- O
IRMS O
) O
. O

As O
a O
result O
, O
adulteration O
using O
C O
( O
4 O
) O
sugar B
syrups O
( O
HFCS O
and O
GS O
) O
could O
be O
detected O
to O
a O
certain O
extent O
while O
adulteration O
of O
honey O
using O
C O
( O
3 O
) O
sugar B
syrups O
( O
beet O
sugar B
) O
could O
not O
be O
detected O
. O

Adulteration O
by O
using O
SS O
( O
beet O
sugar O
) O
still O
has O
a O
serious O
detection O
problem O
, O
especially O
in O
countries O
in O
which O
beet O
is O
used O
in O
manufacturing O
sugar B
. O

For O
this O
reason O
, O
practice O
and O
analysis O
methods O
are O
needed O
to O
meet O
this O
deficit O
and O
to O
detect O
the O
adulterations O
precisely O
in O
the O
studies O
that O
will O
be O
conducted O
. O

Effect O
of O
TiO2 B
photocatalytic O
activity O
in O
a O
HDPE O
- O
based O
food O
packaging O
on O
the O
structural O
and O
microbiological O
stability O
of O
a O
short O
- O
ripened O
cheese O
. O

A O
high O
density O
polyethylene B
( O
HDPE O
) O
/ O
calcium B
carbonate I
( O
CaCO B
( I
3 I
) I
) O
film O
containing O
TiO B
( I
2 I
) I
was O
prepared O
via O
blown O
film O
extrusion O
process O
. O

The O
photocatalytic O
properties O
of O
this O
film O
were O
evaluated O
by O
voltammetric O
, O
UV O
- O
Vis O
spectrophotometric O
and O
gas O
chromatographic O
measurements O
following O
the O
decomposition O
rate O
of O
suitably O
selected O
molecular O
probes O
, O
such O
as O
4 B
- I
hydroxybenzoic I
acid I
and O
methylene B
blue I
. O

The O
film O
containing O
1 O
% O
w O
/ O
w O
of O
TiO B
( I
2 I
) I
displayed O
a O
profitable O
and O
reproducible O
photoinduced O
degradation O
activity O
towards O
target O
organic O
compounds O
. O

The O
effect O
of O
packaging O
photocatalytic O
activity O
on O
the O
structural O
and O
microbiological O
stability O
of O
a O
short O
- O
ripened O
cheese O
was O
studied O
. O

Cheese O
structure O
was O
assessed O
by O
dynamic O
, O
small O
deformation O
rheological O
tests O
. O

A O
container O
consisting O
of O
a O
multilayer O
material O
, O
where O
the O
layer O
brought O
in O
contact O
with O
the O
food O
, O
made O
from O
the O
HDPE O
+ O
CaCO B
( I
3 I
) I
+ O
TiO B
( I
2 I
) I
composite O
matrix O
, O
was O
able O
to O
provide O
a O
greater O
maintenance O
of O
the O
original O
cheese O
structure O
than O
a O
rigid O
container O
currently O
used O
, O
mainly O
due O
to O
the O
inhibition O
of O
lactic B
acid I
bacteria O
and O
coliforms O
. O

Prediction O
of O
fatty B
acid I
composition O
in O
Camellia O
oleifera O
oil O
by O
near O
infrared O
transmittance O
spectroscopy O
( O
NITS O
) O
. O

Under O
the O
serious O
circumstances O
of O
Camellia O
oleifera O
adulteration O
, O
the O
accurate O
examination O
for O
quality O
trait O
of O
C O
. O
oleifera O
oil O
is O
extremely O
urgent O
. O

For O
rapid O
determination O
of O
FA O
composition O
in O
C O
. O
oleifera O
oil O
, O
the O
feasibility O
of O
NITS O
was O
first O
studied O
. O

The O
quantitative O
models O
for O
FA O
were O
built O
based O
on O
PLS O
regression O
. O

NITS O
spectra O
is O
able O
to O
accurately O
predict O
for O
oleic B
, I
linoleic I
, I
and I
palmitic I
acids I
( O
R O
( O
cv O
) O
> O
0 O
. O
844 O
, O
R O
( O
2 O
) O
> O
0 O
. O
886 O
) O
. O

R O
( O
cv O
) O
are O
0 O
. O
91987 O
, O
0 O
. O
95755 O
, O
and O
0 O
. O
84447 O
, O
and O
R O
( O
2 O
) O
are O
0 O
. O
9424 O
, O
0 O
. O
9682 O
, O
0 O
. O
8862 O
for O
NITS O
models O
of O
oleic B
, I
linoleic I
, I
and I
palmitic I
acids I
, O
respectively O
. O

But O
models O
for O
stearic B
and I
unsaturated I
acids I
are O
less O
accurate O
, O
with O
values O
of O
R O
( O
cv O
) O
from O
0 O
. O
67440 O
to O
0 O
. O
69114 O
, O
and O
R O
( O
2 O
) O
from O
0 O
. O
6834 O
to O
0 O
. O
7587 O
. O

These O
results O
indicate O
that O
NITS O
will O
have O
potential O
to O
be O
used O
in O
predicting O
FA O
composition O
of O
C O
. O
oleifera O
oil O
. O

Cyto O
- O
genotoxic O
and O
oxidative O
effects O
of O
a O
continuous O
UV O
- O
C O
treatment O
of O
liquid O
egg O
products O
. O

UV O
- O
C O
treatment O
of O
food O
is O
a O
promising O
non O
- O
thermal O
processing O
technology O
to O
improve O
food O
safety O
and O
preservation O
. O

Most O
of O
the O
chemical O
constituents O
of O
food O
absorb O
UV O
- O
C O
light O
that O
can O
lead O
to O
chemical O
modifications O
and O
quality O
changes O
. O

This O
work O
investigated O
the O
effects O
of O
UV O
- O
C O
treatment O
of O
liquid O
egg O
products O
on O
lipid O
, O
protein O
oxidations O
and O
potential O
cyto O
- O
and O
genotoxic O
effects O
on O
intestinal O
epithelial O
cells O
in O
vitro O
. O

Egg O
preparations O
( O
egg O
white O
, O
yolk O
, O
liquid O
whole O
egg O
) O
were O
treated O
with O
UV O
- O
C O
( O
254 O
nm O
, O
volumetric O
doses O
between O
0 O
and O
115 O
, O
619 O
J O
L O
( O
- O
1 O
) O
) O
using O
a O
commercial O
UV O
- O
C O
processing O
unit O
equipped O
with O
a O
Dean O
Flow O
reactor O
. O

UV O
- O
C O
treatment O
at O
high O
doses O
( O
from O
32 O
, O
181 O
J O
L O
( O
- O
1 O
) O
, O
about O
2 O
times O
higher O
than O
that O
needed O
to O
inactivate O
5 O
log O
of O
relevant O
microorganisms O
) O
showed O
an O
increased O
lipid O
oxidation O
in O
egg O
yolk O
and O
slight O
effects O
in O
liquid O
whole O
eggs O
; O
this O
was O
confirmed O
by O
slightly O
but O
not O
statistically O
significant O
increased O
peroxide B
values O
. O

UV O
- O
C O
induced O
also O
slight O
protein O
damage O
, O
characterised O
by O
the O
total O
sulfhydryl B
group O
reduction O
. O

These O
UV O
- O
C O
- O
induced O
oxidative O
modifications O
in O
egg O
preparations O
however O
did O
not O
cause O
any O
increase O
in O
the O
cyto O
- O
or O
genotoxic O
( O
DNA O
strand O
breaks O
) O
effects O
in O
intestinal O
Caco O
- O
2 O
cells O
. O

Purification O
and O
characterisation O
of O
a O
novel O
antioxidant O
peptide O
derived O
from O
blue O
mussel O
( O
Mytilus O
edulis O
) O
protein O
hydrolysate O
. O

Protein O
derived O
from O
blue O
mussel O
( O
Mytilus O
edulis O
) O
was O
hydrolysed O
using O
four O
kinds O
of O
proteases O
( O
pepsin O
, O
papain O
, O
neutrase O
and O
alcalase O
) O
, O
and O
the O
neutrase O
hydrolysate O
( O
BNH O
) O
obtained O
by O
3 O
- O
h O
hydrolysis O
exhibited O
the O
highest O
2 B
, I
2 I
- I
diphenyl I
- I
1 I
- I
picrylhydrazyl I
( O
DPPH B
) O
radical O
scavenging O
activity O
compared O
to O
other O
hydrolysates O
. O

By O
using O
ultrafiltration O
, O
gel O
filtration O
chromatography O
and O
reversed O
phase O
high O
performance O
liquid O
chromatography O
( O
RP O
- O
HPLC O
) O
, O
a O
novel O
antioxidant O
peptide O
( O
BNH O
- O
P7 O
) O
was O
isolated O
from O
BNH O
, O
and O
its O
amino B
acid I
sequence O
was O
identified O
as O
YPPAK O
( O
Tyr B
- I
Pro I
- I
Pro I
- I
Ala I
- I
Lys I
) O
with O
molecular O
weight O
of O
574 O
Da O
. O

BNH O
- O
P7 O
exhibited O
good O
scavenging O
activity O
on O
DPPH B
radical O
, O
hydroxyl B
radical O
, O
and O
superoxide B
anion O
radical O
with O
EC O
( O
50 O
) O
of O
2 O
. O
62 O
, O
0 O
. O
228 O
, O
and O
0 O
. O
072 O
mg O
/ O
ml O
, O
respectively O
. O

BNH O
- O
P7 O
was O
also O
effectively O
against O
lipid O
peroxidation O
in O
a O
linoleic B
acid I
model O
system O
. O

The O
high O
activity O
of O
BNH O
- O
P7 O
was O
due O
to O
the O
small O
size O
and O
the O
presence O
of O
antioxidant O
and O
hydrophobic O
amino B
acid I
residues O
( O
Tyr B
and O
Pro B
) O
within O
its O
sequence O
. O

Volatile O
profiling O
of O
high O
quality O
hazelnuts O
( O
Corylus O
avellana O
L O
. O
) O
: O
chemical O
indices O
of O
roasting O
. O

The O
study O
proposes O
an O
investigation O
strategy O
to O
identify O
sensitive O
, O
robust O
and O
reliable O
chemical O
markers O
of O
hazelnut O
roasting O
. O

A O
fully O
- O
automated O
and O
validated O
analytical O
method O
, O
based O
on O
Headspace O
Solid O
Phase O
Microextraction O
( O
HS O
- O
SPME O
) O
coupled O
with O
Gas O
Chromatography O
- O
Mass O
Spectrometric O
detection O
( O
GC O
- O
MS O
) O
, O
for O
effective O
off O
- O
line O
monitoring O
of O
changes O
in O
the O
volatile O
profile O
of O
high O
- O
quality O
hazelnuts O
was O
developed O
. O

Samples O
from O
two O
different O
harvests O
were O
submitted O
to O
roasting O
, O
following O
different O
time O
/ O
temperature O
protocols O
and O
different O
technologies O
, O
enabling O
chemical O
changes O
to O
be O
correlated O
with O
technological O
processing O
and O
sensory O
quality O
. O

Chemical O
indices O
, O
expressed O
as O
analyte O
response O
ratio O
, O
were O
defined O
and O
their O
trend O
observed O
across O
roasting O
profiles O
. O

Reliability O
and O
robustness O
of O
chemical O
indices O
were O
also O
evaluated O
, O
in O
view O
of O
their O
application O
to O
on O
- O
line O
monitoring O
with O
Mass O
Spectrometry O
- O
based O
electronic O
nose O
technology O
( O
MS O
- O
nose O
) O
. O

Experiments O
, O
simulating O
on O
- O
line O
chemical O
characterisation O
of O
the O
volatile O
fraction O
, O
were O
performed O
through O
a O
fully O
- O
automated O
system O
. O

The O
results O
confirmed O
: O
( O
a O
) O
the O
effectiveness O
of O
single O
process O
indicators O
of O
roasting O
selected O
by O
the O
separative O
method O
( O
5 B
- I
methylfurfural I
, O
1 B
( I
H I
) I
- I
pyrrole I
, O
furfuryl B
alcohol I
, O
1 B
( I
H I
) I
- I
pyrrole I
- I
2 I
- I
carboxaldehyde I
, O
1 B
- I
hydroxy I
- I
2 I
- I
propanone I
, O
dihydro B
- I
2 I
( I
3H I
) I
- I
furanone I
, O
5 B
- I
methyl I
- I
( I
E I
) I
- I
2 I
- I
hepten I
- I
4 I
- I
one I
, O
acetic B
acid I
, O
pyridine B
, O
furfural B
, O

pyrazine I
, O
and O
several O
alkyl B
- I
pyrazines I
) O
; O
and O
, O
( O
b O
) O
the O
reliability O
of O
proposed O
chemical O
indices O
: O
5 B
- I
methylfurfural I
/ O
2 B
, I
5 I
- I
dimethylpyrazine I
, O
5 B
- I
methylfurfural I
/ O
2 B
- I
methylpyrazine I
, O
2 B
, I
5 I
- I
dimethylpyrazine I
/ O
2 B
, I
3 I
- I
dimethylpyrazine I
; O
these O
maintained O
a O
consistent O
trend O
versus O
harvest O
and O
sampling O
/ O
analysis O
technology O
. O

Detection O
, O
isolation O
and O
characterisation O
of O
cyclolinopeptides B
J I
and I
K I
in O
ageing O
flax O
. O

Methionine B
sulfone I
containing O
peptides O
CLs O
J O
( O
11 O
) O
and O
K O
( O
12 O
) O
may O
be O
produced O
from O
their O
reduced O
forms O
by O
oxidation O
but O
it O
is O
not O
known O
if O
these O
compounds O
occur O
in O
foods O
that O
contain O
flax O
. O

These O
compounds O
have O
been O
reported O
to O
possess O
greater O
immunosuppressive O
activity O
than O
their O
reduced O
methionine B
sulfoxide I
peptide O
forms O
4 O
and O
6 O
, O
respectively O
. O

Since O
11 O
and O
12 O
have O
not O
been O
detected O
in O
commercial O
flax O
oil O
and O
milled O
flax O
seed O
, O
we O
tested O
for O
their O
presence O
in O
flax O
food O
products O
. O

Here O
we O
report O
that O
11 O
and O
12 O
accumulate O
in O
ground O
flaxseed O
that O
is O
exposed O
to O
air O
and O
heat O
( O
100 O
degrees O
C O
) O
for O
more O
than O
4h O
. O

Standards O
of O
11 O
and O
12 O
were O
prepared O
, O
isolated O
and O
extensively O
characterised O
using O
HPLC O
- O
MS O
/ O
MS O
, O
1D O
and O
2D O
NMR O
methods O
. O

We O
also O
report O
the O
excellent O
thermal O
and O
oxidative O
stability O
of O
these O
peptides O
. O

Due O
to O
the O
harsh O
conditions O
required O
to O
produce O
11 O
and O
12 O
, O
it O
is O
expected O
that O
their O
levels O
in O
flax O
based O
foods O
would O
be O
low O
and O
therefore O
their O
presence O
could O
serve O
as O
an O
indicative O
measure O
of O
severe O
oxidation O
of O
a O
food O
product O
. O

In O
vitro O
antioxidant O
properties O
of O
crude O
extracts O
and O
compounds O
from O
brown O
algae O
. O

Research O
on O
the O
bioactives O
from O
seaweeds O
has O
increased O
in O
recent O
years O
. O

Antioxidant O
activity O
is O
one O
of O
the O
most O
studied O
, O
due O
to O
the O
interest O
of O
these O
compounds O
both O
as O
preservatives O
and O
protectors O
against O
oxidation O
in O
food O
and O
cosmetics O
and O
also O
due O
to O
their O
health O
implications O
, O
mainly O
in O
relation O
to O
their O
potential O
as O
functional O
ingredients O
. O

Brown O
algae O
present O
higher O
antioxidant O
potential O
in O
comparison O
with O
red O
and O
green O
families O
and O
contain O
compounds O
not O
found O
in O
terrestrial O
sources O
. O

In O
vitro O
antioxidant O
chemical O
methods O
, O
used O
as O
a O
first O
approach O
to O
evaluate O
potential O
agents O
to O
protect O
from O
lipid O
oxidation O
in O
foods O
, O
confirmed O
that O
the O
brown O
algae O
crude O
extracts O
, O
fractions O
and O
pure O
components O
are O
comparatively O
similar O
or O
superior O
to O
synthetic O
antioxidants O
. O

Particular O
emphasis O
on O
the O
fucoidan O
and O
phlorotannin B
polymeric O
fractions O
is O
given O
, O
considering O
variations O
associated O
with O
the O
species O
, O
collection O
area O
, O
season O
, O
and O
extraction O
and O
purification O
technologies O
. O

Concentrations O
of O
PCDD B
/ O
Fs O
, O
dioxin B
- O
like O
PCBs B
, O
PBDEs B
, O
and O
hexachlorobenzene B
in O
fat O
samples O
from O
cattle O
of O
different O
ages O
and O
gender O
in O
Korea O
. O

Polychlorinated B
dibenzo I
- I
p I
- I
dioxins I
and O
dibenzofurans B
( O
PCDD B
/ O
Fs O
) O
, O
dioxin B
- O
like O
polychlorinated B
biphenyls I
( O
DL B
- I
PCBs I
) O
, O
polybrominated B
diphenyl I
ethers I
( O
PBDEs B
) O
, O
and O
hexachlorobenzene B
( O
HCB B
) O
concentrations O
were O
determined O
in O
abdominal O
fat O
samples O
from O
30 O
cattle O
. O

The O
relationships O
between O
chemicals O
, O
age O
, O
and O
gender O
were O
investigated O
. O

The O
concentration O
of O
PCDD B
/ O
Fs O
ranged O
from O
0 O
. O
01 O
to O
1 O
. O
36 O
pg O
TEQ O
g O
( O
- O
1 O
) O
fat O
, O
DL B
- I
PCBs I
ranged O
from O
0 O
. O
17 O
to O
1 O
. O
64 O
pg O
TEQ O
g O
( O
- O
1 O
) O
fat O
, O
PBDEs B
ranged O
from O
135 O
to O
725 O
pgg O
( O
- O
1 O
) O
fat O
, O
and O
HCB B
ranged O
from O
25 O
. O
5 O
to O
2061 O
pgg O
( O
- O
1 O
) O
fat O
. O

A O
comparison O
between O
cattle O
' O
s O
age O
and O
gender O
vs O
. O
the O
concentration O
of O
contaminants O
revealed O
higher O
concentrations O
of O
PCDD B
/ O
Fs O
and O
DL B
- I
PCBs I
in O
cattle O
aged O
more O
than O
3 O
years O
; O
no O
difference O
between O
genders O
was O
apparent O
. O

Moreover O
, O
the O
concentrations O
of O
PBDEs B
in O
cattle O
fat O
did O
not O
correspond O
with O
the O
age O
of O
cattle O
. O

Relative O
to O
cattle O
1 O
. O
5 O
- O
2 O
. O
5 O
years O
of O
age O
, O
cattle O
aged O
3 O
and O
4 O
years O
had O
higher O
concentration O
of O
HCB B
but O
the O
concentration O
difference O
was O
not O
clear O
at O
age O
5 O
. O

Human O
exposures O
to O
these O
compounds O
from O
beef O
sources O
were O
calculated O
based O
on O
beef O
consumption O
. O

Effects O
of O
various O
pressing O
programs O
and O
yields O
on O
the O
antioxidant O
activity O
, O
antimicrobial O
activity O
, O
phenolic O
content O
and O
colour O
of O
pomegranate O
juices O
. O

Pomegranate O
juice O
( O
PJ O
) O
samples O
were O
produced O
with O
three O
different O
pressing O
programs O
: O
( O
1 O
) O
1 O
. O
2 O
- O
4 O
. O
8 O
bar O
for O
25 O
min O
, O
( O
2 O
) O
1 O
. O
2 O
- O
2 O
. O
4 O
bar O
for O
15 O
min O
and O
( O
3 O
) O
1 O
. O
2 O
- O
1 O
. O
8 O
bar O
for O
5 O
. O
5 O
min O
. O

Respective O
juice O
yields O
were O
39 O
. O
2 O
% O
, O
33 O
. O
2 O
% O
and O
27 O
. O
2 O
% O
. O

Effects O
of O
pressing O
pressure O
- O
time O
and O
yield O
on O
total O
phenolic O
( O
TP O
) O
content O
, O
condensed O
tannin B
( O
CT O
) O
content O
, O
monomeric O
anthocyanin B
( O
MA O
) O
content O
, O
antioxidant O
activity O
( O
AOA O
) O
and O
antimicrobial O
activity O
( O
AMA O
) O
of O
the O
samples O
were O
determined O
. O

Strong O
positive O
linear O
correlations O
were O
found O
between O
the O
pressing O
pressure O
with O
AOA B
( O
r O
= O
0 O
. O
973 O
) O
and O
TP O
content O
( O
r O
= O
0 O
. O
979 O
) O
, O
while O
negative O
logarithmic O
correlations O
were O
found O
between O
pressing O
pressure O
with O
the O
contents O
of O
CT O
( O
r O
= O
- O
0 O
. O
778 O
) O
and O
MA O
( O
r O
= O
- O
0 O
. O
955 O
) O
. O

Among O
12 O
microorganisms O
tested O
, O
Bacillus O
megaterium O
, O
Bacillus O
subtilis O
, O
Staphyloccocus O
aureus O
and O
Pseudomonas O
sp O
. O
were O
found O
to O
be O
sensitive O
to O
juice O
samples O
. O

However O
, O
increasing O
pressing O
pressure O
and O
yield O
did O
not O
lead O
to O
a O
significant O
change O
on O
the O
AMAs O
of O
the O
juices O
. O

Evolution O
of O
flavonoids B
in O
Mourat O
o O
n O
berries O
taken O
from O
both O
bunch O
halves O
. O

Galicia O
( O
N O
. O
W O
. O
Spain O
) O
is O
a O
Spanish O
region O
with O
several O
old O
- O
traditional O
winegrowing O
areas O
. O

There O
are O
autochthonous O
grapevine O
varieties O
, O
such O
as O
Vitis O
vinifera O
L O
. O

cv O
. O

Mourat O
o O
n O
, O
considered O
a O
biodiversity O
resource O
in O
viticulture O
and O
an O
opportunity O
for O
Galician O
sustainable O
wine O
production O
. O

Therefore O
, O
it O
is O
necessary O
to O
assess O
the O
potential O
of O
traditional O
cultivars O
to O
produce O
quality O
red O
wines O
. O

In O
this O
work O
, O
anthocyanin B
and O
flavonol B
evolution O
was O
followed O
in O
red O
berries O
from O
V O
. O
vinifera O
L O
. O

cv O
. O

Mourat O
o O
n O
. O

The O
novelty O
of O
this O
study O
is O
that O
grapes O
were O
separately O
collected O
from O
two O
different O
positions O
( O
tips O
and O
shoulders O
) O
within O
the O
cluster O
, O
over O
ripening O
to O
examine O
the O
effects O
of O
berry O
position O
within O
the O
fruit O
cluster O
on O
the O
flavonoid B
compounds O
. O

Derivatives O
of O
five O
anthocyanins B
( O
malvidin B
, O
peonidin B
, O
petunidin B
, O
delphinidin B
and O
cyanidin B
) O
and O
derivatives O
of O
six O
flavonols B
( O
quercetin B
, O
myricetin B
, O
kaempherol B
, O
laricitrin B
isorhamnetin I
and O
syringetin B
) O
were O
detected O
in O
both O
positions O
within O
the O
cluster O
. O

Dynamic O
of O
anthocyanins B
( O
from O
819 O
mg O
/ O
kg O
to O
1206 O
mg O
/ O
kg O
in O
tips O
; O
and O
from O
786 O
mg O
/ O
kg O
to O
1077 O
mg O
/ O
kg O
in O
shoulders O
) O
and O
dynamic O
of O
flavonols B
( O
from O
25mg O
/ O
kg O
to O
41 O
mg O
/ O
kg O
in O
tips O
; O
and O
from O
18 O
mg O
/ O
kg O
to O
21 O
mg O
/ O
kg O
in O
shoulders O
) O
confirmed O
their O
upward O
trends O
over O
ripening O
. O

Grapes O
located O
inside O
the O
shoulder O
bunch O
receive O
less O
sunlight O
radiation O
than O
those O
located O
inside O
the O
tip O
bunch O
and O
this O
fact O
could O
explain O
the O
different O
accumulation O
observed O
for O
both O
positions O
. O

These O
results O
can O
be O
useful O
for O
winemakers O
in O
order O
to O
obtain O
different O
final O
red O
wine O
quality O
. O

Influences O
of O
muscle O
composition O
and O
structure O
of O
pork O
from O
different O
breeds O
on O
stability O
and O
textural O
properties O
of O
cooked O
meat O
emulsion O
. O

The O
influences O
of O
composition O
and O
structure O
of O
meats O
from O
different O
pig O
breeds O
, O
including O
Duroc O
( O
D O
) O
, O
Large O
White O
( O
LW O
) O
, O
Landrace O
( O
LR O
) O
, O
two O
- O
way O
cross O
( O
LR O
x O
LW O
) O
and O
three O
- O
way O
cross O
( O
D O
x O
[ O
LR O
x O
LW O
] O
) O
on O
stability O
and O
textural O
characteristics O
of O
cooked O
meat O
emulsions O
were O
studied O
by O
using O
partial O
least O
squares O
( O
PLS O
) O
regression O
. O

Compared O
to O
other O
pig O
breeds O
, O
cooked O
meat O
emulsion O
from O
LW O
exhibited O
superior O
properties O
as O
indicated O
by O
lower O
water O
and O
fat O
released O
as O
well O
as O
higher O
chewiness O
, O
gumminess O
, O
cohesiveness O
, O
resilience O
, O
springiness O
and O
hardness O
. O

The O
univariate O
analyses O
of O
those O
selected O
properties O
indicated O
a O
significant O
correlation O
with O
higher O
contents O
of O
myofibrillar O
and O
sarcoplasmic O
proteins O
, O
smaller O
muscle O
fibre O
diameter O
and O
lower O
myofibril O
fragmentation O
of O
LW O
meat O
, O
as O
compared O
to O
other O
breeds O
. O

Therefore O
properties O
of O
cooked O
pork O
emulsion O
were O
influenced O
by O
composition O
and O
structure O
of O
meat O
, O
which O
varied O
according O
to O
the O
pig O
breeds O
. O

A O
traceability O
study O
on O
the O
Moscato O
wine O
chain O
. O

To O
address O
the O
growing O
interest O
of O
consumers O
for O
information O
on O
the O
provenance O
of O
foodstuffs O
, O
the O
production O
chain O
of O
world O
renowned O
Moscato O
d O
' O
Asti O
white O
wine O
has O
been O
studied O
using O
the O
distribution O
of O
lanthanides B
as O
chemical O
markers O
. O

From O
soil O
to O
must O
, O
upon O
every O
stage O
of O
the O
chain O
, O
samples O
have O
been O
taken O
and O
analysed O
with O
ICP O
- O
MS O
in O
order O
to O
verify O
whether O
the O
original O
fingerprint O
of O
soil O
is O
maintained O
or O
not O
along O
the O
chain O
. O

Results O
of O
this O
traceability O
study O
show O
clearly O
that O
lanthanides B
fingerprint O
is O
kept O
unaltered O
in O
the O
passage O
soil O
- O
grapes O
- O
must O
, O
while O
fractionation O
occurs O
upon O
wine O
clarifying O
with O
bentonites B
. O

The O
second O
part O
of O
the O
work O
involves O
a O
study O
on O
102 O
samples O
of O
Moscato O
d O
' O
Asti O
musts O
in O
order O
to O
verify O
how O
they O
reflect O
the O
features O
of O
the O
different O
geographical O
zones O
where O
they O
come O
from O
, O
and O
to O
build O
a O
basis O
to O
be O
able O
to O
identify O
possible O
adulterations O
performed O
by O
addition O
of O
foreign O
musts O
. O

Development O
of O
a O
standardised O
human O
in O
vitro O
digestion O
protocol O
based O
on O
macronutrient O
digestion O
using O
response O
surface O
methodology O
. O

Bioaccessibility O
studies O
should O
be O
taken O
into O
account O
when O
evaluating O
the O
physiological O
effects O
of O
ingested O
compounds O
at O
the O
intestine O
level O
. O

Several O
in O
vitro O
digestion O
protocols O
have O
been O
described O
, O
with O
a O
wide O
range O
of O
experimental O
conditions O
but O
no O
optimised O
protocol O
exists O
. O

In O
order O
to O
fill O
in O
this O
gap O
, O
we O
evaluated O
the O
influence O
of O
three O
continuous O
factors O
( O
pH O
, O
incubation O
time O
, O
and O
enzyme O
concentrations O
) O
, O
in O
the O
range O
of O
values O
found O
in O
literature O
, O
on O
the O
digestion O
of O
standard O
macronutrients O
( O
starch O
, O
albumin O
, O
triolein B
) O
alone O
or O
in O
mixture O
. O

Three O
central O
composite O
designs O
, O
using O
response O
surface O
methodology O
, O
were O
employed O
to O
model O
the O
three O
abiotic O
steps O
of O
pre O
- O
colonic O
digestion O
. O

A O
validated O
in O
vitro O
digestion O
was O
eventually O
set O
up O
for O
the O
salivary O
step O
( O
pH O
6 O
. O
9 O
, O
5 O
min O
, O
3 O
. O
9 O
units O
alpha O
- O
amylase O
/ O
ml O
) O
, O
the O
gastric O
step O
( O
pH O
2 O
, O
90 O
min O
, O
71 O
. O
2 O
units O
pepsin O
/ O
ml O
) O
, O
and O
the O
abiotic O
duodenal O
step O
( O
pH O
7 O
, O
150 O
min O
, O
9 O
. O
2mg O
pancreatin O
and O
55 O
. O
2mg O
bile O
extract O
/ O
ml O
) O
. O

Purification O
, O
properties O
and O
cDNA O
cloning O
of O
glutamate B
decarboxylase O
in O
germinated O
faba O
bean O
( O
Vicia O
faba O
L O
. O
) O
. O

Gamma B
- I
aminobutyric I
acid I
( O
GABA B
) O
is O
a O
non O
- O
protein O
amino B
acid I
with O
bioactive O
functions O
in O
humans O
. O

In O
this O
work O
, O
glutamate B
decarboxylase O
( O
EC O
4 O
. O
1 O
. O
1 O
. O
15 O
, O
GAD O
) O
which O
is O
key O
in O
the O
GABA B
bioformation O
was O
purified O
from O
5 O
- O
day O
germinated O
faba O
beans O
and O
characterized O
. O

A O
single O
band O
was O
observed O
at O
58 O
kDa O
using O
sodium B
dodecyl I
sulphate I
gel O
electrophoresis O
. O

GAD O
optimal O
activity O
was O
at O
pH O
6 O
. O
0 O
at O
40 O
degrees O
C O
with O
a O
K O
( O
m O
) O
value O
for O
glutamic B
acid I
( O
Glu B
) O
of O
2 O
. O
63 O
mM O
. O

The O
enzyme O
was O
inhibited O
significantly O
by O
Cu B
( I
2 I
+ I
) I
, O
Fe B
( I
3 I
+ I
) I
, O
Mg B
( I
2 I
+ I
) I
, O
Ba B
( I
2 I
+ I
) I
, O
aminoxyacetate B
, O
EGTA B
, O
Na B
( I
2 I
) I
EDTA I
, O
l B
- I
cysteine I
and O
beta B
- I
mercaptoethanol I
; O
and O
activated O
at O
low O
Ca B
( I
2 I
+ I
) I
0 O
. O
2mM O
. O

Using O
RT O
- O
PCR O
, O
the O
GAD O
cDNA O
was O
sequenced O
which O
indicated O
1787 O
bp O
long O
, O
containing O
a O
1527 O
bp O
open O
reading O
frame O
( O
ORF O
) O
that O
encoded O
509 O
amino B
- I
acid I
peptides O
with O
a O
calculated O
molecular O
weight O
of O
57 O
. O
74 O
kDa O
and O
a O
pI O
of O
5 O
. O
41 O
( O
GenBank O
accession O
number O
: O
JX444699 O
) O
. O

Validation O
of O
methods O
for O
the O
detection O
and O
quantification O
of O
engineered O
nanoparticles O
in O
food O
. O

The O
potential O
impact O
of O
nanomaterials O
on O
the O
environment O
and O
on O
human O
health O
has O
already O
triggered O
legislation O
requiring O
labelling O
of O
products O
containing O
nanoparticles O
. O

However O
, O
so O
far O
, O
no O
validated O
analytical O
methods O
for O
the O
implementation O
of O
this O
legislation O
exist O
. O

This O
paper O
outlines O
a O
generic O
approach O
for O
the O
validation O
of O
methods O
for O
detection O
and O
quantification O
of O
nanoparticles O
in O
food O
samples O
. O

It O
proposes O
validation O
of O
identity O
, O
selectivity O
, O
precision O
, O
working O
range O
, O
limit O
of O
detection O
and O
robustness O
, O
bearing O
in O
mind O
that O
each O
" O
result O
" O
must O
include O
information O
about O
the O
chemical O
identity O
, O
particle O
size O
and O
mass O
or O
particle O
number O
concentration O
. O

This O
has O
an O
impact O
on O
testing O
for O
selectivity O
and O
trueness O
, O
which O
also O
must O
take O
these O
aspects O
into O
consideration O
. O

Selectivity O
must O
not O
only O
be O
tested O
against O
matrix O
constituents O
and O
other O
nanoparticles O
, O
but O
it O
shall O
also O
be O
tested O
whether O
the O
methods O
apply O
equally O
well O
to O
particles O
of O
different O
suppliers O
. O

In O
trueness O
testing O
, O
information O
whether O
the O
particle O
size O
distribution O
has O
changed O
during O
analysis O
is O
required O
. O

Results O
are O
largely O
expected O
to O
follow O
normal O
distributions O
due O
to O
the O
expected O
high O
number O
of O
particles O
. O

An O
approach O
of O
estimating O
measurement O
uncertainties O
from O
the O
validation O
data O
is O
given O
. O

Effects O
of O
fish O
protein O
hydrolysate O
and O
freeze O
- O
thaw O
treatment O
on O
physicochemical O
and O
gel O
properties O
of O
natural O
actomyosin O
from O
Pacific O
cod O
. O

The O
properties O
of O
natural O
actomyosin O
( O
NAM O
) O
containing O
2 O
% O
or O
8 O
% O
fish O
protein O
hydrolysate O
( O
FPH O
- O
2 O
, O
FPH O
- O
8 O
) O
or O
8 O
% O
sucrose B
- O
sorbitol B
blend O
( O
SuSo O
) O
were O
compared O
to O
control O
NAM O
before O
and O
after O
freeze O
- O
thaw O
treatment O
. O

Surface O
hydrophobicity O
of O
control O
and O
FPH O
- O
2 O
increased O
after O
freeze O
- O
thaw O
treatment O
, O
while O
that O
of O
FPH O
- O
8 O
did O
not O
change O
, O
which O
may O
be O
related O
to O
greater O
thermostability O
of O
actin O
and O
myosin O
in O
FPH O
- O
8 O
as O
observed O
by O
differential O
scanning O
calorimetry O
. O

The O
cooked O
gel O
of O
freeze O
- O
thawed O
control O
had O
39 O
% O
expressible O
moisture O
after O
an O
8 O
. O
5 O
% O
cook O
loss O
, O
whereas O
gels O
of O
freeze O
- O
thawed O
SuSo O
, O
FPH O
- O
2 O
and O
FPH O
- O
8 O
had O
significantly O
lower O
expressible O
moisture O
( O
15 O
- O
22 O
% O
) O
and O
no O
cook O
loss O
. O

Gels O
of O
freeze O
- O
thawed O
FPH O
- O
2 O
and O
FPH O
- O
8 O
were O
similar O
to O
unfrozen O
control O
gel O
in O
hardness O
, O
cohesiveness O
and O
gumminess O
. O

This O
study O
demonstrates O
that O
FPH O
effectively O
stabilised O
NAM O
protein O
structure O
and O
function O
during O
freeze O
- O
thaw O
treatment O
. O

Rapid O
quantification O
of O
muscle O
fat O
content O
and O
subcutaneous O
adipose O
tissue O
in O
fish O
using O
MRI O
. O

The O
potentiality O
of O
MRI O
to O
quantify O
fat O
content O
in O
flesh O
and O
subcutaneous O
fat O
in O
fish O
cutlets O
was O
investigated O
. O

Low O
measurement O
time O
was O
aimed O
at O
in O
a O
view O
to O
handling O
large O
number O
of O
samples O
needed O
in O
selective O
breeding O
programs O
for O
example O
. O

Results O
on O
fresh O
and O
frozen O
- O
thawed O
cutlets O
were O
compared O
to O
assess O
this O
way O
of O
conservation O
. O

As O
MRI O
generates O
unwanted O
spatial O
variations O
of O
the O
signal O
, O
a O
correction O
method O
was O
developed O
enabling O
the O
measurement O
on O
several O
cutlets O
simultaneously O
in O
less O
than O
3 O
min O
per O
sample O
. O

For O
subcutaneous O
fat O
, O
the O
results O
were O
compared O
with O
vision O
measurements O
. O

High O
correlations O
between O
both O
techniques O
were O
found O
( O
R O
( O
2 O
) O
= O
0 O
. O
77 O
and O
0 O
. O
87 O
for O
the O
ventral O
and O
dorsal O
part O
) O
. O

Fat O
in O
flesh O
was O
validated O
vs O
NMR O
measurements O
. O

No O
statistical O
difference O
was O
found O
between O
fresh O
and O
frozen O
- O
thawed O
cutlets O
. O

RMSE O
was O
respectively O
0 O
. O
8 O
% O
and O
0 O
. O
89 O
% O
. O

These O
results O
confirmed O
the O
potentiality O
of O
MRI O
for O
fat O
measurement O
in O
fish O
particularly O
for O
a O
large O
number O
of O
samples O
. O

Pesticide O
residues O
in O
market O
foods O
in O
Shaanxi O
Province O
of O
China O
in O
2010 O
. O

The O
aim O
of O
this O
study O
was O
to O
investigate O
the O
pesticide O
residues O
in O
market O
vegetables O
in O
Shaanxi O
Province O
of O
China O
. O

The O
concentrations O
of O
33 O
pesticides O
were O
determined O
by O
gas O
chromatography O
( O
GC O
) O
in O
285 O
samples O
. O

Ten O
organophosphorus B
pesticides O
( O
OPs O
) O
were O
found O
in O
concentrations O
ranging O
from O
0 O
. O
004 O
to O
0 O
. O
257 O
mg O
/ O
kg O
. O

The O
mean O
levels O
of O
omethoate B
, O
phorate B
, O
chlorpyrifos B
, O
methidathion B
, O
ethoprophos B
in O
vegetables O
exceeded O
the O
maximum O
residue O
limits O
( O
MRLs O
) O
allowed O
by O
the O
Ministry O
of O
Health O
, O
of O
China O
. O

Other O
detectable O
OP O
pesticide O
residues O
levels O
were O
below O
their O
MRLs O
. O

Dicofol B
were O
detectable O
in O
green O
pepper O
and O
chives O
samples O
. O

Five O
pyrethroid B
pesticides O
( O
PYRs B
) O
were O
detectable O
in O
vegetable O
samples O
respectively O
. O

The O
results O
provide O
useful O
information O
on O
the O
current O
contamination O
status O
of O
a O
key O
agricultural O
area O
in O
China O
, O
and O
point O
to O
the O
need O
for O
urgent O
action O
to O
control O
the O
excessive O
use O
of O
some O
chemicals O
. O

Colour O
and O
stability O
assessment O
of O
blue O
ferric B
anthocyanin I
chelates O
in O
liquid O
pectin O
- O
stabilised O
model O
systems O
. O

The O
formation O
of O
blue O
coloured O
ferric B
anthocyanin I
chelates O
and O
their O
colour O
stability O
during O
storage O
and O
thermal O
treatment O
were O
monitored O
in O
a O
pH O
range O
relevant O
to O
food O
( O
3 O
. O
6 O
- O
5 O
. O
0 O
) O
. O

Liquid O
model O
systems O
were O
composed O
of O
different O
types O
of O
Citrus O
pectins O
, O
juices O
( O
J O
) O
and O
the O
respective O
phenolic O
extracts O
( O
E O
) O
from O
elderberry O
( O
EB O
) O
, O
black O
currant O
( O
BC O
) O
, O
red O
cabbage O
( O
RC O
) O
and O
purple O
carrot O
( O
PC O
) O
in O
the O
presence O
of O
ferric B
ions O
. O

For O
EB O
, O
BC O
and O
PC O
, O
pure O
blue O
colours O
devoid O
of O
a O
violet O
tint O
were O
exclusively O
observed O
for O
the O
phenolic O
extracts O
and O
at O
pH O
values O
> O
= O
4 O
. O
5 O
in O
model O
systems O
containing O
high O
methoxylated O
and O
amidated O
pectins O
, O
respectively O
. O

Colour O
and O
its O
stability O
strongly O
depended O
on O
the O
amount O
of O
ferric B
ions O
and O
the O
plant O
source O
; O
however O
, O
colour O
decay O
could O
generally O
be O
described O
as O
a O
pseudo O
- O
first O
- O
order O
kinetics O
. O

Despite O
optimal O
colour O
hues O
for O
RC O
- O
E O
and O
RC O
- O
J O
, O
storage O
and O
heat O
stabilities O
were O
poor O
. O

Highest O
colour O
intensities O
and O
best O
stabilities O
were O
observed O
for O
model O
systems O
containing O
PC O
- O
E O
at O
a O
molar O
anthocyanin B
: O
ferric B
ion O
ratio O
of O
1 O
: O
2 O
. O

Ascorbic B
and I
lactic I
acids I
interfered O
with O
ferric B
ions O
, O
thus O
significantly O
affecting O
blue O
colour O
evolution O
and O
stability O
. O

Colour O
loss O
strongly O
depended O
on O
heat O
exposure O
with O
activation O
energies O
ranging O
between O
60 O
. O
5 O
and O
78 O
. O
4 O
kJ O
/ O
mol O
. O

The O
comprehensive O
evaluation O
of O
the O
interrelationship O
of O
pigment O
source O
, O
pH O
conditions O
and O
pectin O
type O
on O
chelate O
formation O
and O
stability O
demonstrated O
that O
ferric B
anthocyanin I
chelates O
are O
promising O
natural O
blue O
food O
colourants O
. O

Combined O
effect O
of O
starter O
culture O
and O
temperature O
on O
phenolic B
compounds O
during O
fermentation O
of O
Taggiasca O
black O
olives O
. O

The O
influence O
of O
two O
operative O
parameters O
on O
the O
fermentation O
process O
of O
table O
olives O
from O
Taggiasca O
cultivar O
were O
investigated O
. O

Laboratory O
scale O
fermentations O
were O
performed O
using O
Lactobacillus O
plantarum O
as O
the O
only O
starter O
and O
in O
combination O
with O
Saccharomyces O
cerevisiae O
at O
three O
different O
temperatures O
( O
23 O
, O
30 O
and O
37 O
degrees O
C O
) O
. O

Control O
tests O
used O
for O
each O
trial O
were O
fermented O
only O
by O
indigenous O
microflora O
. O

pH O
and O
phenolic B
compounds O
were O
monitored O
in O
the O
brine O
and O
olive O
flesh O
during O
the O
fermentation O
. O

Higher O
temperatures O
( O
37 O
degrees O
C O
) O
enhanced O
notably O
the O
release O
of O
phenolic B
compounds O
in O
the O
brine O
. O

High O
performance O
liquid O
chromatography O
( O
HPLC O
) O
analysis O
of O
brines O
evidenced O
the O
complete O
hydrolysis O
of O
oleuropein B
after O
100 O
days O
of O
fermentation O
at O
37 O
degrees O
C O
for O
all O
treatments O
. O

The O
antioxidant O
power O
of O
the O
extracts O
was O
linearly O
correlated O
to O
their O
polyphenol B
contents O
. O

The O
results O
confirmed O
the O
efficiency O
of O
treatments O
compared O
with O
the O
control O
tests O
for O
debittering O
process O
of O
table O
black O
olives O
. O

Phenolic B
compounds O
in O
the O
brines O
can O
be O
then O
extracted O
and O
used O
in O
food O
, O
cosmetic O
and O
pharmaceutical O
industries O
. O

Expression O
patterns O
of O
cell O
cycle O
proteins O
in O
the O
livers O
of O
rats O
treated O
with O
hepatocarcinogens O
for O
28 O
days O
. O

Some O
hepatocarcinogens O
induce O
cytomegaly O
, O
which O
reflects O
aberrant O
cell O
cycling O
and O
increased O
ploidy O
, O
from O
the O
early O
stages O
of O
administration O
to O
animals O
. O

To O
clarify O
the O
regulatory O
molecular O
mechanisms O
behind O
cell O
cycle O
aberrations O
related O
to O
the O
early O
stages O
of O
hepatocarcinogenesis O
, O
we O
performed O
gene O
expression O
analysis O
using O
microarrays O
and O
real O
- O
time O
reverse O
transcription O
polymerase O
chain O
reaction O
followed O
by O
immunohistochemical O
analysis O
in O
the O
livers O
of O
rats O
treated O
with O
the O
cytomegaly O
inducing O
hepatocarcinogens O
thioacetamide B
( O
TAA B
) O
, O
fenbendazole B
, O
and O
methyleugenol B
, O
the O
cytomegaly O
non O
- O
inducing O
hepatocarcinogen O
piperonyl B
butoxide I
( O

PBO B
) O
, O
or O
the O
non O
- O
carcinogenic O
hepatotoxicants O
acetaminophen B
and O
alpha B
- I
naphthyl I
isothiocyanate I
, O
for O
28 O
days O
. O

Gene O
expression O
profiling O
showed O
that O
cell O
cycle O
- O
related O
genes O
, O
especially O
those O
of O
G O
( O
2 O
) O
/ O
M O
phase O
, O
were O
mostly O
upregulated O
after O
TAA B
treatment O
. O

Immunohistochemical O
analysis O
was O
performed O
on O
cell O
cycle O
proteins O
that O
were O
upregulated O
by O
TAA B
treatment O
and O
on O
related O
proteins O
. O

All O
hepatocarcinogens O
, O
irrespective O
of O
their O
cytomegaly O
inducing O
potential O
, O
increased O
liver O
cells O
immunoreactive O
for O
p21 O
( O
Cip1 O
) O
, O
which O
acts O
on O
cells O
arrested O
in O
G O
( O
1 O
) O
phase O
, O
and O
for O
Aurora O
B O
or O
Incenp O
, O
which O
is O
suggestive O
of O
an O
increase O
in O
a O
cell O
population O
with O
chromosomal O
instability O
caused O
by O
overexpression O
. O

PBO B
did O
not O
induce O
cell O
proliferation O
after O
28 O
- O
day O
treatment O
. O

Hepatocarcinogens O
that O
induced O
cell O
proliferation O
after O
28 O
- O
day O
treatment O
also O
caused O
an O
increase O
in O
p53 O
( O
+ O
) O
cells O
in O
parallel O
with O
increased O
apoptotic O
cells O
, O
as O
well O
as O
increased O
population O
of O
cells O
expressing O
M O
phase O
- O
related O
proteins O
nuclear O
Cdc2 O
, O
phospho B
- O
Histone O
H3 O
, O
and O
HP1 O
alpha O
. O

These O
results O
suggest O
that O
hepatocarcinogens O
may O
increase O
cellular O
populations O
arrested O
in O
G O
( O
1 O
) O
phase O
or O
showing O
chromosomal O
instability O
after O
28 O
- O
day O
treatment O
. O

Hepatocarcinogens O
that O
induce O
cell O
cycle O
facilitation O
may O
cause O
M O
phase O
arrest O
accompanied O
by O
apoptosis O
. O

End O
- O
faced O
waveguide O
mediated O
optical O
propulsion O
of O
microspheres O
and O
single O
cells O
in O
a O
microfluidic O
device O
. O

Single O
cell O
transport O
in O
microfluidic O
devices O
is O
a O
topic O
of O
interest O
as O
their O
utility O
is O
becoming O
appreciated O
by O
cell O
and O
molecular O
biologist O
. O

Cell O
transport O
should O
minimize O
mechanical O
stress O
due O
to O
friction O
or O
pressure O
gradients O
. O

Optical O
forces O
have O
the O
advantage O
of O
applying O
their O
forces O
across O
the O
cell O
volume O
and O
not O
only O
at O
the O
cell O
membrane O
and O
are O
thus O
preferable O
. O

Optical O
pushing O
by O
scattering O
force O
is O
a O
suitable O
candidate O
so O
highly O
dependent O
on O
the O
photon O
irradiance O
field O
inside O
the O
propagation O
capillary O
which O
in O
turn O
is O
determined O
by O
the O
waveguide O
properties O
delivering O
the O
radiation O
pressure O
. O

Here O
we O
present O
a O
numerical O
approach O
to O
predict O
the O
optical O
scattering O
force O
, O
speed O
and O
trajectory O
of O
cells O
as O
a O
function O
of O
waveguide O
and O
propagation O
capillary O
geometry O
. O

Experimental O
verification O
of O
the O
simulation O
approach O
is O
demonstrated O
using O
polystyrene B
microspheres O
and O
leukemia O
cells O
. O

Effects O
of O
optical O
fibre O
to O
waveguide O
alignment O
, O
capillary O
wall O
angle O
and O
temperature O
on O
the O
dynamic O
viscosity O
on O
speed O
and O
position O
of O
the O
microspheres O
and O
cells O
inside O
the O
propagation O
capillary O
are O
demonstrated O
. O

Adenosine B
2A O
receptor O
modulates O
inflammation O
and O
phenotype O
in O
experimental O
abdominal O
aortic O
aneurysms O
. O

Activation O
of O
the O
adenosine B
2A O
receptor O
( O
A O
( O
2A O
) O
R O
) O
reduces O
inflammation O
in O
models O
of O
acute O
injury O
but O
contribution O
in O
development O
of O
chronic O
abdominal O
aortic O
aneurysms O
( O
AAAs O
) O
is O
unknown O
. O

Elastase O
perfusion O
to O
induce O
AAA O
formation O
in O
A O
( O
2A O
) O
R O
- O
knockout O
( O
A O
( O
2A O
) O
RKO O
) O
and O
C57BL6 O
/ O
J O
wild O
- O
type O
( O
WT O
) O
mice O
resulted O
in O
nearly O
100 O
% O
larger O
aneurysms O
in O
A O
( O
2A O
) O
RKO O
compared O
to O
WT O
at O
d O
14 O
( O
P O
< O
0 O
. O
05 O
) O
, O
with O
evidence O
of O
greater O
elastin O
fragmentation O
, O
more O
immune O
cell O
infiltration O
, O
and O
increased O
matrix O
metallatoproteinase O
( O
MMP O
) O
9 O
expression O
( O
P O
< O
0 O
. O
05 O
) O
. O

Separately O
, O
exogenous O
A O
( O
2A O
) O
R O
antagonism O
in O
elastase O
- O
perfused O
WT O
mice O
also O
resulted O
in O
larger O
aneurysms O
( O
P O
< O
0 O
. O
05 O
) O
, O
while O
A O
( O
2A O
) O
R O
agonism O
limited O
aortic O
dilatation O
( O
P O
< O
0 O
. O
05 O
) O
. O

Activated O
Thy O
- O
1 O
. O
2 O
( O
+ O
) O
T O
lymphocytes O
from O
WT O
mice O
treated O
in O
vitro O
with O
A O
( O
2A O
) O
R O
antagonist O
increased O
cytokine O
production O
, O
and O
treatment O
with O
A O
( O
2A O
) O
R O
agonist O
decreased O
cytokine O
production O
( O
P O
< O
0 O
. O
05 O
for O
all O
) O
. O

Primary O
activated O
CD4 O
( O
+ O
) O
T O
lymphocytes O
from O
A O
( O
2A O
) O
RKO O
mice O
exhibited O
greater O
chemotaxis O
( O
P O
< O
0 O
. O
05 O
) O
. O

A O
( O
2A O
) O
R O
antagonist O
increased O
chemotaxis O
of O
activated O
CD4 O
( O
+ O
) O
cells O
from O
WT O
mice O
in O
vitro O
, O
and O
A O
( O
2A O
) O
R O
agonist O
reduced O
this O
effect O
( O
P O
< O
0 O
. O
05 O
) O
. O

A O
( O
2A O
) O
R O
activation O
attenuates O
AAA O
formation O
partly O
by O
inhibiting O
immune O
cell O
recruitment O
and O
reducing O
elastin O
fragmentation O
. O

These O
findings O
support O
augmenting O
A O
( O
2A O
) O
R O
signaling O
as O
a O
putative O
target O
for O
limiting O
aneurysm O
formation O
. O
- O
Bhamidipati O
, O
C O
. O

M O
. O
, O
Mehta O
, O
G O
. O

S O
. O
, O
Moehle O
, O
C O
. O

W O
. O
, O
Meher O
, O
A O
. O

K O
. O
, O
Su O
, O
G O
. O
, O
Vigneshwar O
, O
N O
. O

G O
. O
, O
Barbery O
, O
C O
. O
, O
Sharma O
, O
A O
. O

K O
. O
, O
Kron O
, O
I O
. O

L O
. O
, O
Laubach O
, O
V O
. O

E O
. O
, O
Owens O
, O
G O
. O

K O
. O
, O
Upchurch O
Jr O
. O
, O
G O
. O

R O
. O
, O
Ailawadi O
, O
G O
. O

Adenosine B
2A O
receptor O
modulates O
inflammation O
and O
phenotype O
in O
experimental O
abdominal O
aortic O
aneurysms O
. O

Spectroscopic O
characterization O
and O
constitutional O
and O
rotational O
isomerism O
of O
ClC O
( O
O O
) O
SCN O
and O
ClC O
( O
O O
) O
NCS O
. O

Chlorocarbonylthio B
- I
and I
isothiocyanate I
( O
ClC B
( I
O I
) I
SCN I
and O
ClC B
( I
O I
) I
NCS I
) O
have O
been O
isolated O
and O
characterized O
by O
IR O
( O
Ar B
matrix O
, O
gas O
) O
, O
Raman O
( O
liquid O
) O
, O
( B
13 I
) I
C I
NMR O
and O
UV O
- O
visible O
spectroscopies O
. O

Vibrational O
and O
quantum O
chemical O
studies O
suggest O
the O
presence O
of O
the O
syn O
and O
anti O
conformers O
( O
SCN B
group O
with O
respect O
to O
the O
C B
= I
O I
bond O
) O
in O
the O
gas O
phase O
for O
both O
constitutional O
isomers O
. O

syn B
- I
ClC I
( I
O I
) I
SCN I
is O
preferred O
by O
Delta O
H O
degrees O
( O
anti O
/ O
syn O
) O
= O
1 O
. O
3 O
( O
0 O
. O
3 O
) O
kcal O
mol O
( O
- O
1 O
) O
. O

The O
solid O
- O
state O
structure O
of O
ClC B
( I
O I
) I
SCN I
has O
been O
determined O
by O
single O
crystal O
X O
- O
ray O
diffraction O
analysis O
at O
low O
temperature O
. O

The O
crystalline O
solid O
consists O
exclusively O
of O
molecules O
in O
the O
syn O
conformation O
. O

On O
the O
other O
hand O
, O
the O
anti O
form O
is O
more O
stable O
for O
the O
ClC B
( I
O I
) I
NCS I
isomer O
. O

The O
structure O
of O
ClC O
( I
O I
) I
NCS O
and O
its O
conformational O
composition O
were O
determined O
by O
gas O
electron O
diffraction O
. O

An O
unusual O
low O
syn O
- O
- O
> O
anti O
interconversion O
energy O
barrier O
of O
0 O
. O
98 O
( O
0 O
. O
15 O
) O
kcal O
mol O
( O
- O
1 O
) O
was O
detected O
for O
ClC O
( O
O O
) O
NCS O
at O
cryogenic O
temperatures O
. O

The O
photochemistry O
of O
both O
constitutional O
isomers O
isolated O
in O
solid O
argon B
at O
15 O
K O
was O
studied O
. O

Rearrangement O
of O
ClC B
( I
O I
) I
SCN I
to O
ClC B
( I
O I
) I
NCS I
was O
observed O
in O
the O
neat O
liquid O
and O
under O
UV O
- O
vis O
irradiation O
of O
ClC B
( I
O I
) I
SCN I
isolated O
in O
solid O
argon B
. O

Properties O
have O
been O
discussed O
in O
terms O
of O
the O
valence O
electronic O
structure O
, O
including O
the O
analysis O
of O
the O
He B
( I
I I
) I
photoelectron O
spectrum O
of O
ClC B
( I
O I
) I
SCN I
. O

Potential O
- O
dependent O
interaction O
of O
DOPC B
liposomes O
with O
an O
octadecanol B
- O
covered O
Au B
( I
111 I
) I
surface O
investigated O
using O
electrochemical O
methods O
coupled O
with O
in O
situ O
fluorescence O
microscopy O
. O

The O
potential O
- O
controlled O
incorporation O
of O
DOPC B
liposomes O
( O
100 O
nm O
diameter O
) O
into O
an O
adsorbed O
octadecanol B
layer O
on O
Au B
( I
111 I
) I
was O
studied O
using O
electrochemical O
and O
in O
situ O
fluorescence O
microscopy O
. O

The O
adsorbed O
layer O
of O
octadecanol B
included O
a O
small O
amount O
of O
a O
lipophilic O
fluorophore O
- O
octadecanol B
modified O
with O
BODIPY B
- O
to O
enable O
fluorescence O
imaging O
. O

The O
deposited O
octadecanol B
layer O
was O
found O
not O
to O
allow O
liposomes O
to O
interact O
unless O
the O
potential O
was O
less O
than O
- O
0 O
. O
4 O
V O
/ O
SCE O
, O
which O
introduces O
defects O
into O
the O
adsorbed O
layer O
. O

Small O
increases O
in O
the O
capacitance O
of O
the O
adsorbed O
layer O
were O
measured O
after O
introducing O
the O
defects O
, O
allowing O
the O
liposomes O
to O
interact O
with O
the O
defects O
and O
then O
annealing O
the O
defects O
at O
0 O
V O
/ O
SCE O
. O

A O
change O
in O
the O
adsorbed O
layer O
was O
also O
signified O
by O
a O
more O
positive O
desorption O
potential O
for O
the O
liposome O
- O
modified O
adsorbed O
layer O
as O
compared O
to O
that O
for O
an O
adsorbed O
layer O
that O
was O
porated O
in O
a O
similar O
fashion O
but O
without O
liposomes O
present O
in O
the O
electrolyte O
. O

These O
subtle O
changes O
in O
capacitance O
are O
difficult O
to O
interpret O
, O
so O
an O
in O
situ O
spectroscopic O
study O
was O
performed O
to O
provide O
a O
more O
direct O
measure O
of O
the O
interaction O
. O

The O
incorporation O
of O
liposomes O
should O
result O
in O
an O
increase O
in O
the O
fluorescence O
measured O
because O
the O
fluorophore O
should O
become O
further O
separated O
from O
the O
gold O
surface O
, O
reducing O
the O
efficiency O
of O
fluorescence O
quenching O
. O

No O
significant O
increase O
in O
the O
fluorescence O
of O
the O
adsorbed O
layer O
was O
observed O
during O
the O
potential O
pulses O
used O
in O
the O
poration O
procedure O
in O
the O
absence O
of O
liposomes O
. O

In O
the O
presence O
of O
liposomes O
, O
the O
fluorescence O
intensity O
was O
found O
to O
depend O
on O
the O
potential O
and O
time O
used O
for O
poration O
. O

At O
0 O
V O
/ O
SCE O
, O
no O
significant O
change O
in O
the O
fluorescence O
was O
observed O
for O
defect O
- O
free O
adsorbed O
layers O
. O

Changing O
the O
poration O
potential O
to O
- O
0 O
. O
4 O
V O
/ O
SCE O
caused O
significant O
increases O
in O
the O
fluorescence O
and O
the O
appearance O
of O
new O
structural O
features O
in O
the O
adsorbed O
layers O
that O
were O
more O
easily O
observed O
during O
the O
desorption O
procedure O
. O

The O
extent O
of O
fluorescence O
changes O
was O
found O
to O
be O
strongly O
dependent O
on O
the O
nature O
of O
the O
adsorbed O
layer O
under O
investigation O
, O
which O
suggests O
that O
the O
poration O
and O
liposome O
interaction O
are O
dependent O
on O
the O
quality O
of O
the O
adsorbed O
layer O
and O
its O
ease O
of O
poration O
through O
changes O
in O
the O
electrode O
potential O
. O

Bifunctional O
electrophiles O
cross O
- O
link O
thioredoxins O
with O
redox O
relay O
partners O
in O
cells O
. O

Thioredoxin O
protects O
cells O
against O
oxidative O
damage O
by O
reducing O
disulfide B
bonds O
in O
improperly O
oxidized O
proteins O
. O

Previously O
, O
we O
found O
that O
the O
baker O
' O
s O
yeast O
cytosolic O
thioredoxin O
Trx2 O
undergoes O
cross O
- O
linking O
to O
form O
several O
protein O
- O
protein O
complexes O
in O
cells O
treated O
with O
the O
bifunctional O
electrophile O
divinyl B
sulfone I
( O
DVSF B
) O
. O

Here O
, O
we O
report O
that O
the O
peroxiredoxin O
Tsa1 O
and O
the O
thioredoxin O
reductase O
Trr1 O
, O
both O
of O
which O
function O
in O
a O
redox O
relay O
network O
with O
thioredoxin O
, O
become O
cross O
- O
linked O
in O
complexes O
with O
Trx2 O
upon O
DVSF O
treatment O
. O

Treatment O
of O
yeast O
with O
other O
bifunctional O
electrophiles O
, O
including O
diethyl B
acetylenedicarboxyla I
( O
DAD B
) O
, O
mechlorethamine B
( O
HN2 B
) O
, O
and O
1 B
, I
2 I
, I
3 I
, I
4 I
- I
diepoxybutane I
( O
DEB B
) O
, O
resulted O
in O
the O
formation O
of O
similar O
cross O
- O
linked O
complexes O
. O

Cross O
- O
linking O
of O
Trx2 O
and O
Tsa1 O
to O
other O
proteins O
by O
DVSF O
and O
DAD O
is O
dependent O
on O
modification O
of O
the O
active O
site O
Cys B
residues O
within O
these O
proteins O
. O

In O
addition O
, O
the O
human O
cytosolic O
thioredoxin O
, O
cytosolic O
thioredoxin O
reductase O
, O
and O
peroxiredoxin O
2 O
form O
cross O
- O
linked O
complexes O
to O
other O
proteins O
in O
the O
presence O
of O
DVSF O
, O
although O
each O
protein O
shows O
different O
susceptibilities O
to O
modification O
by O
DAD O
, O
HN2 O
, O
and O
DEB O
. O

Taken O
together O
, O
our O
results O
indicate O
that O
bifunctional O
electrophiles O
potentially O
disrupt O
redox O
homeostasis O
in O
yeast O
and O
human O
cells O
by O
forming O
cross O
- O
linked O
complexes O
between O
thioredoxins O
and O
their O
redox O
partners O
. O

Bioanalytical O
LC O
separation O
techniques O
for O
quantitative O
analysis O
of O
free O
amino B
acids I
in O
human O
plasma O
. O

The O
quantitative O
analysis O
of O
free O
amino B
acids I
in O
human O
plasma O
has O
become O
an O
important O
and O
essential O
analysis O
parameter O
in O
different O
areas O
of O
life O
sciences O
. O

Free O
amino B
acid I
concentrations O
in O
human O
plasma O
samples O
are O
generally O
determined O
by O
means O
of O
GC O
or O
LC O
after O
chemical O
derivatization O
followed O
by O
UV O
, O
fluorescent O
or O
MS O
detection O
of O
the O
amino B
acid I
derivatives O
. O

Derivatization O
of O
free O
amino B
acids I
is O
done O
either O
pre O
- O
or O
post O
- O
column O
, O
and O
the O
amino B
acid I
derivatives O
obtained O
posess O
improved O
chromatographic O
behavior O
, O
increased O
detection O
sensitivity O
and O
selectivity O
compared O
with O
non O
- O
derivatized O
free O
amino B
acids I
. O

This O
work O
gives O
an O
overview O
of O
different O
chemical O
derivatization O
methods O
applied O
and O
their O
liquid O
separation O
techniques O
in O
bioanalytical O
assays O
for O
quantitative O
free O
amino B
acid I
analysis O
in O
human O
plasma O
samples O
. O

Important O
plasma O
preparation O
procedures O
, O
pre O
- O
and O
post O
- O
column O
derivatization O
, O
and O
different O
LC O
separation O
techniques O
are O
presented O
. O

Application O
of O
the O
compensated O
Arrhenius O
formalism O
to O
fluidity O
data O
of O
polar O
organic O
liquids O
. O

The O
temperature O
dependence O
of O
viscosity O
( O
the O
reciprocal O
of O
fluidity O
) O
in O
polar O
liquids O
has O
been O
studied O
for O
over O
a O
century O
, O
but O
the O
available O
theoretical O
models O
have O
serious O
limitations O
. O

Consequently O
, O
the O
viscosity O
is O
often O
described O
with O
empirical O
equations O
using O
adjustable O
fitting O
parameters O
that O
offer O
no O
insight O
into O
the O
molecular O
mechanism O
of O
transport O
. O

We O
have O
previously O
reported O
a O
novel O
approach O
called O
the O
compensated O
Arrhenius O
formalism O
( O
CAF O
) O
to O
describe O
ionic O
conductivity O
, O
self O
- O
diffusion O
, O
and O
dielectric O
relaxation O
in O
terms O
of O
molecular O
and O
system O
properties O
. O

Here O
the O
CAF O
is O
applied O
to O
fluidity O
data O
of O
pure O
n B
- I
acetates I
, O
2 B
- I
ketones I
, O
n B
- I
nitriles I
, O
and O
n B
- I
alcohols I
over O
the O
temperature O
range O
5 O
- O
85 O
degrees O
C O
. O

The O
fluidity O
is O
represented O
as O
an O
Arrhenius O
- O
like O
expression O
that O
includes O
a O
static O
dielectric O
constant O
dependence O
in O
the O
exponential O
prefactor O
. O

The O
dielectric O
constant O
dependence O
results O
from O
the O
dependence O
of O
mass O
and O
charge O
transport O
on O
the O
molecular O
dipole O
moment O
and O
the O
solvent O
dipole O
density O
. O

The O
CAF O
is O
the O
only O
self O
- O
consistent O
description O
of O
fluid O
transport O
in O
polar O
liquids O
written O
solely O
in O
terms O
of O
molecular O
and O
system O
parameters O
. O

A O
scaling O
procedure O
is O
used O
to O
calculate O
the O
activation O
energy O
for O
transport O
. O

We O
find O
that O
the O
activation O
energies O
for O
fluidity O
of O
the O
aprotic O
liquids O
are O
comparable O
in O
value O
, O
whereas O
a O
higher O
average O
E O
( O
a O
) O
value O
is O
observed O
for O
the O
n B
- I
alcohol I
data O
. O

Finally O
, O
we O
contrast O
the O
molecular O
description O
of O
transport O
presented O
here O
with O
the O
conventional O
hydrodynamic O
model O
. O

Ester B
hydrolysis O
by O
a O
histidine B
- O
containing O
cavitein B
. O

We O
have O
used O
a O
template O
- O
assembled O
synthetic O
protein O
( O
TASP O
) O
to O
investigate O
catalytic O
function O
in O
ester B
hydrolysis O
. O

A O
histidine B
- O
containing O
cavitein O
has O
been O
found O
to O
catalyze O
ester B
hydrolysis O
with O
a O
rate O
increase O
of O
18 O
times O
that O
of O
background O
. O

Triazolo B
and O
imidazo B
dihydropyrazolopyrim I
potassium B
channel O
antagonists O
. O

Previously O
disclosed O
C6 O
amido B
and O
benzimidazole B
dihydropyrazolopyrim B
were O
potent O
and O
selective O
blockers O
of O
IKur O
current O
. O

Syntheses O
and O
SAR O
for O
C6 O
triazolo B
and O
imidazo I
dihydropyrazolopyrim I
series O
are O
described O
. O

Trifluoromethylcyclo B
N I
( I
1 I
) I
triazole I
, O
compound O
51 O
, O
was O
identified O
as O
a O
potent O
and O
selective O
Kv1 O
. O
5 O
inhibitor O
with O
an O
acceptable O
PK O
and O
liability O
profile O
. O

Discovery O
of O
a O
novel O
series O
of O
quinolone B
alpha O
7 O
nicotinic O
acetylcholine B
receptor O
agonists O
. O

High O
throughput O
screening O
led O
to O
the O
identification O
of O
a O
novel O
series O
of O
quinolone B
alpha O
7 O
nicotinic O
acetylcholine B
receptor O
( O
nAChR O
) O
agonists O
. O

Optimization O
of O
an O
HTS O
hit O
( O
1 O
) O
led O
to O
4 B
- I
phenyl I
- I
1 I
- I
( I
quinuclidin I
- I
3 I
- I
ylmethyl I
) I
quinolin I
- I
2 I
( I
1H I
) I
- I
one I
, O
which O
was O
found O
to O
be O
potent O
and O
selective O
. O

Poor O
brain O
penetrance O
in O
this O
series O
was O
attributed O
to O
transporter O
- O
mediated O
efflux O
, O
which O
was O
in O
turn O
due O
to O
high O
pKa O
. O

A O
novel O
4 B
- I
fluoroquinuclidine I
significantly O
lowered O
the O
pKa O
of O
the O
quinuclidine B
moiety O
, O
reducing O
efflux O
as O
measured O
by O
a O
Caco O
- O
2 O
assay O
. O

A O
genetic O
program O
promotes O
C O
. O
elegans O
longevity O
at O
cold O
temperatures O
via O
a O
thermosensitive O
TRP O
channel O
. O

Both O
poikilotherms O
and O
homeotherms O
live O
longer O
at O
lower O
body O
temperatures O
, O
highlighting O
a O
general O
role O
of O
temperature O
reduction O
in O
lifespan O
extension O
. O

However O
, O
the O
underlying O
mechanisms O
remain O
unclear O
. O

One O
prominent O
model O
is O
that O
cold O
temperatures O
reduce O
the O
rate O
of O
chemical O
reactions O
, O
thereby O
slowing O
the O
rate O
of O
aging O
. O

This O
view O
suggests O
that O
cold O
- O
dependent O
lifespan O
extension O
is O
simply O
a O
passive O
thermodynamic O
process O
. O

Here O
, O
we O
challenge O
this O
view O
in O
C O
. O
elegans O
by O
showing O
that O
genetic O
programs O
actively O
promote O
longevity O
at O
cold O
temperatures O
. O

We O
find O
that O
TRPA O
- O
1 O
, O
a O
cold O
- O
sensitive O
TRP O
channel O
, O
detects O
temperature O
drop O
in O
the O
environment O
to O
extend O
lifespan O
. O

This O
effect O
requires O
cold O
- O
induced O
, O
TRPA O
- O
1 O
- O
mediated O
calcium B
influx O
and O
a O
calcium B
- O
sensitive O
PKC O
that O
signals O
to O
the O
transcription O
factor O
DAF O
- O
16 O
/ O
FOXO O
. O

Human O
TRPA1 O
can O
functionally O
substitute O
for O
worm O
TRPA O
- O
1 O
in O
promoting O
longevity O
. O

Our O
results O
reveal O
a O
previously O
unrecognized O
function O
for O
TRP O
channels O
, O
link O
calcium B
signaling O
to O
longevity O
, O
and O
, O
importantly O
, O
demonstrate O
that O
genetic O
programs O
contribute O
to O
lifespan O
extension O
at O
cold O
temperatures O
. O

Beneficial O
effect O
of O
the O
non O
- O
psychotropic O
plant O
cannabinoid O
cannabigerol B
on O
experimental O
inflammatory O
bowel O
disease O
. O

Inflammatory O
bowel O
disease O
( O
IBD O
) O
is O
an O
incurable O
disease O
which O
affects O
millions O
of O
people O
in O
industrialized O
countries O
. O

Anecdotal O
and O
scientific O
evidence O
suggests O
that O
Cannabis O
use O
may O
have O
a O
positive O
impact O
in O
IBD O
patients O
. O

Here O
, O
we O
investigated O
the O
effect O
of O
cannabigerol B
( O
CBG B
) O
, O
a O
non O
- O
psychotropic O
Cannabis O
- O
derived O
cannabinoid O
, O
in O
a O
murine O
model O
of O
colitis O
. O

Colitis O
was O
induced O
in O
mice O
by O
intracolonic O
administration O
of O
dinitrobenzene B
sulphonic I
acid I
( O
DNBS B
) O
. O

Inflammation O
was O
assessed O
by O
evaluating O
inflammatory O
markers O
/ O
parameters O
( O
colon O
weight O
/ O
colon O
length O
ratio O
and O
myeloperoxidase O
activity O
) O
, O
by O
histological O
analysis O
and O
immunohistochemistry O
; O
interleukin O
- O
1 O
beta O
, O
interleukin O
- O
10 O
and O
interferon O
- O
gamma O
levels O
by O
ELISA O
, O
inducible O
nitric B
oxide I
synthase O
( O
iNOS O
) O
and O
cyclooxygenase O
- O
2 O
( O
COX O
- O
2 O
) O
by O
western O
blot O
and O
RT O
- O
PCR O
; O
CuZn B
- O
superoxide B
dismutase O
( O

SOD O
) O
activity O
by O
a O
colorimetric O
assay O
. O

Murine O
macrophages O
and O
intestinal O
epithelial O
cells O
were O
used O
to O
evaluate O
the O
effect O
of O
CBG O
on O
nitric B
oxide I
production O
and O
oxidative O
stress O
, O
respectively O
. O

CBG O
reduced O
colon O
weight O
/ O
colon O
length O
ratio O
, O
myeloperoxidase O
activity O
, O
and O
iNOS O
expression O
, O
increased O
SOD O
activity O
and O
normalized O
interleukin O
- O
1 O
beta O
, O
interleukin O
- O
10 O
and O
interferon O
- O
gamma O
changes O
associated O
to O
DNBS B
administration O
. O

In O
macrophages O
, O
CBG O
reduced O
nitric B
oxide I
production O
and O
iNOS O
protein O
( O
but O
not O
mRNA O
) O
expression O
. O

Rimonabant B
( O
a O
CB1 O
receptor O
antagonist O
) O
did O
not O
change O
the O
effect O
of O
CBG O
on O
nitric B
oxide I
production O
, O
while O
SR144528 B
( O
a O
CB2 O
receptor O
antagonist O
) O
further O
increased O
the O
inhibitory O
effect O
of O
CBG O
on O
nitric B
oxide I
production O
. O

In O
conclusion O
, O
CBG O
attenuated O
murine O
colitis O
, O
reduced O
nitric B
oxide I
production O
in O
macrophages O
( O
effect O
being O
modulated O
by O
the O
CB2 O
receptor O
) O
and O
reduced O
ROS O
formation O
in O
intestinal O
epithelial O
cells O
. O

CBG O
could O
be O
considered O
for O
clinical O
experimentation O
in O
IBD O
patients O
. O

ADAM17 O
, O
shedding O
, O
TACE O
as O
therapeutic O
targets O
. O

ADAM17 O
has O
been O
molecularly O
cloned O
as O
the O
enzyme O
responsible O
for O
cleavage O
of O
the O
transmembrane O
protein O
TNF O
alpha O
( O
TNF O
alpha O
converting O
enzyme O
, O
TACE O
) O
. O

Later O
it O
was O
realized O
that O
ADAM17 O
was O
also O
responsible O
for O
the O
processing O
of O
cell O
adhesion O
proteins O
, O
cytokine O
and O
growth O
factor O
receptors O
and O
many O
ligands O
of O
the O
EGF O
receptor O
. O

Since O
TNF O
alpha O
is O
a O
target O
of O
anti O
- O
inflammatory O
therapies O
, O
it O
was O
speculated O
that O
inhibition O
of O
ADAM17 O
might O
be O
a O
therapeutic O
strategy O
in O
the O
treatment O
of O
inflammation O
or O
inflammation O
associated O
cancer O
. O

Meanwhile O
it O
has O
been O
recognized O
that O
ADAM17 O
governs O
many O
vital O
functions O
in O
the O
body O
and O
loss O
of O
ADAM17 O
leads O
to O
severe O
defects O
in O
the O
skin O
and O
to O
high O
susceptibility O
of O
the O
intestine O
to O
inflammation O
. O

Here O
I O
summarize O
data O
on O
the O
physiologic O
role O
of O
ADAM17 O
and O
the O
feasibility O
of O
specific O
blockade O
of O
this O
enzyme O
. O

11 B
beta I
- I
Hydroxysteroid I
dehydrogenase O
type O
1 O
contributes O
to O
the O
balance O
between O
7 B
- I
keto I
- I
and I
7 I
- I
hydroxy I
- I
oxysterols I
in O
vivo O
. O

11 B
beta I
- I
Hydroxysteroid I
dehydrogenase O
1 O
( O
11 O
beta O
HSD1 O
; O
EC O
1 O
. O
1 O
. O
1 O
. O
146 O
) O
generates O
active O
glucocorticoids O
from O
inert O
11 B
- I
keto I
metabolites O
. O

However O
, O
it O
can O
also O
metabolize O
alternative O
substrates O
, O
including O
7 B
beta I
- I
hydroxy I
- I
and I
7 I
- I
keto I
- I
cholesterol I
( O
7 B
beta I
OHC I
, O
7KC B
) O
. O

This O
has O
been O
demonstrated O
in O
vitro O
but O
its O
consequences O
in O
vivo O
are O
uncertain O
. O

We O
used O
genetically O
modified O
mice O
to O
investigate O
the O
contribution O
of O
11 O
beta O
HSD1 O
to O
the O
balance O
of O
circulating O
levels O
of O
7KC B
and O
7 B
beta I
OHC I
in O
vivo O
, O
and O
dissected O
in O
vitro O
the O
kinetics O
of O
the O
interactions O
between O
oxysterols B
and O
glucocorticoids O
for O
metabolism O
by O
the O
mouse O
enzyme O
. O

Circulating O
levels O
of O
7KC B
and O
7 B
beta I
OHC I
in O
mice O
were O
91 O
. O
3 O
+ O
/ O
- O
22 O
. O
3 O
and O
22 O
. O
6 O
+ O
/ O
- O
5 O
. O
7nM O
respectively O
, O
increasing O
to O
1240 O
+ O
/ O
- O
220 O
and O
406 O
+ O
/ O
- O
39nM O
in O
ApoE O
( O
- O
/ O
- O
) O
mice O
receiving O
atherogenic O
western O
diet O
. O

Disruption O
of O
11 O
beta O
HSD1 O
in O
mice O
increased O
( O
p O
< O
0 O
. O
05 O
) O
the O
7KC B
/ O
7 B
beta I
OHC I
ratio O
in O
plasma O
( O
by O
20 O
% O
) O
and O
also O
in O
isolated O
microsomes O
( O
2 O
fold O
) O
. O

The O
7KC B
/ O
7 B
beta I
OHC I
ratio O
was O
similarly O
increased O
when O
NADPH B
generation O
was O
restricted O
by O
disruption O
of O
hexose B
- I
6 I
- I
phosphate I
dehydrogenase O
. O

Reduction O
and O
oxidation O
of O
7 B
- I
oxysterols I
by O
murine O
11 O
beta O
HSD1 O
proceeded O
more O
slowly O
and O
substrate O
affinity O
was O
lower O
than O
for O
glucocorticoids O
. O
in O
vitro O
7 B
beta I
OHC I
was O
a O
competitive O
inhibitor O
of O
oxidation O
of O
corticosterone B
( O
Ki O
= O
0 O
. O
9 O
mu O
M O
) O
, O
whereas O
7KC B
only O
weakly O
inhibited O
reduction O
of O
11 B
- I
dehydrocorticosteron I
. O

However O
, O
supplementation O
of O
7 B
- I
oxysterols I
in O
cultured O
cells O
, O
secondary O
to O
cholesterol B
loading O
, O
preferentially O
slowed O
reduction O
of O
glucocorticoids O
, O
rather O
than O
oxidation O
. O

Thus O
, O
in O
mouse O
, O
11 O
beta O
HSD1 O
influenced O
the O
abundance O
and O
balance O
of O
circulating O
and O
tissue O
levels O
of O
7 B
beta I
OHC I
and O
7KC B
, O
promoting O
reduction O
of O
7KC B
. O

In O
health O
, O
7 B
- I
oxysterols I
are O
unlikely O
to O
regulate O
glucocorticoid O
metabolism O
. O

However O
, O
in O
hyperlipidaemia O
, O
7 B
- I
oxysterols I
may O
inhibit O
glucocorticoid O
metabolism O
and O
modulate O
signaling O
through O
corticosteroid O
receptors O
. O

Amino B
acid I
derived O
quinazolines B
as O
Rock O
/ O
PKA O
inhibitors O
. O

SAR O
and O
lead O
optimization O
studies O
for O
Rock O
inhibitors O
based O
on O
amino B
acid I
- O
derived O
quinazolines B
are O
described O
. O

Studies O
demonstrated O
that O
these O
amino B
acid I
derived O
quinazolinones B
were O
mainly O
pan O
- O
Rock O
( O
I O
& O
II O
) O
inhibitors O
. O

While O
selectivity O
against O
other O
kinases O
could O
be O
achieved O
, O
selectivity O
for O
most O
of O
these O
compounds O
against O
PKA O
was O
not O
achieved O
. O

This O
is O
distinct O
from O
Rock O
inhibitors O
based O
on O
non O
- O
amino B
acid I
derived O
quinazolinones B
, O
where O
high O
selectivity O
against O
PKA O
could O
be O
obtained O
. O
( O
22 O
) O
The O
inhibitors O
presented O
here O
in O
some O
cases O
possessed O
sub O
- O
nanomolar O
inhibition O
of O
Rock O
, O
nanomolar O
potency O
in O
ppMLC O
cell O
based O
assays O
, O
low O
to O
fair O
cytochrome O
P O
- O
450 O
inhibition O
, O
and O
good O
human O
microsomal O
stability O
. O

Aza B
- I
BODIPY I
: O
improved O
synthesis O
and O
interaction O
with O
soluble O
A O
beta O
1 O
- O
42 O
oligomers O
. O

Dye O
- O
binding O
assays O
that O
are O
used O
to O
evaluate O
anti O
- O
aggregation O
ability O
of O
small O
molecule O
inhibitors O
towards O
amyloids O
are O
known O
to O
be O
prone O
to O
false O
- O
positive O
effects O
due O
to O
spectral O
overlaps O
between O
the O
dye O
and O
the O
inhibitor O
. O

Aza B
- I
BODIPY I
dye O
, O
which O
has O
both O
excitation O
and O
emission O
maxima O
above O
600nm O
, O
exhibits O
a O
significant O
increase O
in O
its O
fluorescence O
intensity O
in O
the O
presence O
of O
soluble O
oligomers O
of O
A O
beta O
1 O
- O
42 O
. O

These O
results O
indicate O
that O
aza B
- I
BODIPY I
could O
serve O
as O
a O
near O
- O
IR O
probe O
for O
detecting O
conformational O
changes O
of O
A O
beta O
1 O
- O
42 O
soluble O
oligomers O
in O
vitro O
, O
and O
it O
should O
eliminate O
false O
- O
positive O
effects O
that O
are O
associated O
with O
currently O
utilized O
thioflavin B
T I
- O
based O
dyes O
. O

In O
addition O
, O
a O
facile O
synthesis O
of O
aza B
- I
BODIPY I
has O
been O
developed O
, O
which O
might O
further O
expand O
the O
applications O
of O
this O
dye O
. O

Effects O
of O
lurasidone B
in O
behavioral O
models O
of O
depression O
. O

Role O
of O
the O
5 O
- O
HT7 O
receptor O
subtype O
. O

Major O
depression O
is O
a O
common O
psychiatric O
disorder O
associated O
with O
high O
symptomatic O
and O
functional O
burdens O
. O

Pharmacological O
treatment O
is O
often O
effective O
, O
but O
there O
remain O
substantial O
unmet O
needs O
in O
the O
form O
of O
non O
- O
responders O
, O
delayed O
onset O
of O
clinical O
effect O
, O
and O
side O
effects O
. O

Recent O
studies O
have O
positioned O
the O
serotonin B
5 O
- O
HT7 O
receptor O
as O
a O
new O
target O
for O
the O
treatment O
of O
depression O
. O

Preclinical O
studies O
have O
shown O
that O
antagonists O
induce O
an O
antidepressant O
- O
like O
response O
, O
a O
phenotype O
that O
can O
also O
be O
observed O
in O
mice O
lacking O
the O
receptor O
. O

Lurasidone B
is O
a O
new O
atypical O
antipsychotic O
agent O
with O
very O
high O
affinity O
for O
the O
5 O
- O
HT7 O
receptor O
. O

Patients O
in O
clinical O
trials O
have O
reported O
improved O
scores O
in O
depression O
ratings O
. O

We O
have O
tested O
lurasidone B
in O
both O
acute O
and O
chronic O
mouse O
models O
of O
depression O
. O

In O
the O
tail O
suspension O
and O
forced O
swim O
tests O
lurasidone B
decreased O
immobility O
, O
an O
antidepressant O
- O
like O
response O
. O

The O
effect O
required O
functional O
5 O
- O
HT7 O
receptors O
as O
it O
was O
absent O
in O
mice O
lacking O
the O
receptor O
. O

In O
the O
repeated O
open O
- O
space O
swim O
test O
lurasidone B
was O
able O
to O
reverse O
the O
despair O
induced O
by O
repeated O
swims O
in O
a O
manner O
similar O
to O
the O
commonly O
used O
antidepressant O
citalopram B
. O

The O
results O
provide O
evidence O
that O
lurasidone B
can O
act O
as O
a O
5 O
- O
HT7 O
receptor O
antagonist O
and O
provide O
a O
possible O
explanation O
for O
the O
antidepressant O
effect O
data O
currently O
emerging O
from O
lurasidone B
clinical O
trials O
. O

Additionally O
, O
the O
results O
give O
further O
support O
for O
targeting O
the O
5 O
- O
HT7 O
receptor O
in O
the O
treatment O
of O
depression O
. O

It O
will O
be O
of O
interest O
to O
clinically O
evaluate O
lurasidone B
as O
an O
antidepressant O
either O
as O
monotherapy O
or O
as O
an O
adjunctive O
therapy O
to O
available O
drugs O
. O

Dexamethasone B
alters O
epithelium O
proliferation O
and O
survival O
and O
suppresses O
Wnt O
/ O
beta O
- O
catenin O
signaling O
in O
developing O
cleft O
palate O
. O

Dexamethasone B
( O
Dex B
) O
contributes O
to O
a O
cleft O
palate O
, O
but O
the O
cellular O
and O
molecular O
mechanisms O
responsible O
for O
the O
deleterious O
effect O
on O
the O
developing O
palate O
are O
unclear O
. O

Wnt O
signaling O
is O
a O
causal O
mechanism O
of O
Dex B
- O
induced O
osteoporosis O
, O
so O
this O
study O
was O
conducted O
to O
determine O
whether O
Dex B
- O
induced O
cleft O
palate O
may O
result O
from O
altered O
Wnt O
signaling O
. O

Administration O
of O
Dex B
to O
mice O
completely O
inhibited O
canonical O
Wnt O
/ O
beta O
- O
catenin O
signaling O
and O
altered O
cell O
proliferation O
and O
apoptosis O
of O
the O
craniofacial O
epithelium O
in O
developing O
embryos O
. O

Thus O
, O
downregulated O
Wnt O
/ O
beta O
- O
catenin O
signaling O
was O
associated O
with O
Dex B
- O
induced O
cleft O
palate O
. O

Moreover O
, O
altered O
cell O
fate O
by O
Dex B
responsible O
for O
small O
palates O
, O
delaying O
shelf O
elevation O
and O
unfused O
palates O
was O
a O
crucial O
mechanism O
in O
cleft O
palate O
. O

Our O
findings O
help O
in O
elucidating O
the O
mechanisms O
of O
Dex B
- O
induced O
cleft O
palate O
. O

Cysteamine B
: O
an O
old O
drug O
with O
new O
potential O
. O

Cysteamine B
is O
an O
amino B
thiol I
with O
the O
chemical O
formula O
HSCH2CH2NH2 B
. O

Endogenously O
, O
cysteamine B
is O
derived O
from O
coenzyme B
A I
degradation O
, O
although O
its O
plasma O
concentrations O
are O
low O
. O

Most O
experience O
with O
cysteamine B
as O
a O
drug O
originates O
from O
the O
field O
of O
the O
orphan O
disease O
cystinosis O
, O
in O
which O
cysteamine B
is O
prescribed O
to O
decrease O
intralysosomal O
cystine O
accumulation O
. O

However O
, O
over O
the O
years O
, O
the O
drug O
has O
been O
used O
for O
several O
other O
applications O
both O
in O
vitro O
and O
in O
vivo O
. O

In O
this O
article O
, O
we O
review O
the O
different O
applications O
of O
cysteamine B
, O
ending O
with O
an O
overview O
of O
ongoing O
clinical O
trials O
for O
new O
indications O
, O
such O
as O
neurodegenerative O
disorders O
and O
nonalcoholic O
fatty O
liver O
disease O
( O
NAFLD O
) O
. O

The O
recent O
development O
of O
an O
enteric O
- O
coated O
cysteamine B
formulation O
makes O
cysteamine B
more O
patient O
friendly O
and O
will O
extend O
its O
applicability O
for O
both O
old O
and O
new O
indications O
. O

Collaborative O
virtual O
organisation O
and O
infrastructure O
for O
drug O
discovery O
. O

A O
virtual O
organisation O
approach O
was O
applied O
to O
collaborative O
drug O
discovery O
integrating O
experimental O
and O
computational O
design O
approaches O
. O

Scientists O
Against O
Malaria O
was O
formed O
with O
the O
goal O
of O
designing O
novel O
antimalarial O
drug O
candidates O
. O

The O
collaboration O
of O
nine O
founding O
partners O
carried O
out O
computational O
and O
laboratory O
work O
that O
produced O
significant O
volumes O
of O
data O
and O
metadata O
, O
the O
interpretation O
for O
the O
analysis O
of O
which O
, O
as O
well O
as O
the O
related O
decision O
making O
, O
was O
challenging O
. O

During O
the O
first O
phase O
the O
partners O
developed O
this O
' O
green O
- O
field O
' O
project O
from O
initiation O
through O
to O
target O
selection O
and O
modelling O
, O
computational O
screening O
, O
biological O
materials O
and O
assay O
preparation O
, O
culminating O
in O
the O
completion O
of O
initial O
experimental O
testing O
. O

A O
support O
infrastructure O
involving O
a O
semantic O
collaborative O
laboratory O
framework O
, O
interoperating O
with O
a O
cloud O
of O
web O
services O
through O
an O
ontology O
describing O
the O
virtual O
and O
experimental O
screening O
data O
, O
was O
designed O
and O
tested O
. O

Modulation O
of O
melanogenesis O
and O
antioxidant O
defense O
system O
in O
melanocytes O
by O
amikacin B
. O

Amikacin B
is O
principally O
used O
to O
treat O
infections O
caused O
by O
microorganisms O
resistant O
to O
other O
aminoglycosides B
. O

Ototoxicity O
is O
one O
of O
the O
side O
effects O
of O
amikacin B
, O
but O
the O
causative O
mechanism O
of O
damage O
to O
the O
ear O
has O
not O
been O
fully O
established O
. O

Thus O
, O
the O
aim O
of O
this O
work O
was O
to O
examine O
the O
impact O
of O
amikacin B
on O
the O
melanogenesis O
and O
antioxidant O
defense O
system O
in O
cultured O
human O
normal O
melanocytes O
( O
HEMa O
- O
LP O
) O
. O

Amikacin B
induced O
the O
concentration O
- O
dependent O
loss O
in O
melanocytes O
viability O
. O

The O
value O
of O
EC50 O
was O
determined O
to O
be O
~ O
7 O
. O
5 O
mM O
. O

The O
analyzed O
antibiotic O
inhibited O
melanin O
biosynthesis O
in O
concentration O
- O
dependent O
manner O
. O

Increasing O
the O
amikacin B
concentration O
also O
resulted O
in O
a O
decrease O
in O
cellular O
tyrosinase O
activity O
. O

To O
study O
the O
antioxidant O
defense O
system O
in O
melanocytes O
, O
the O
activities O
of O
superoxide B
dismutase O
( O
SOD O
) O
, O
catalase O
( O
CAT O
) O
and O
glutathione B
peroxidase O
( O
GPx O
) O
in O
cells O
exposed O
to O
amikacin B
were O
determined O
. O

Significant O
changes O
in O
cellular O
antioxidant O
enzymes O
activities O
were O
observed O
. O

Modulation O
of O
melanogenesis O
and O
the O
antioxidant O
status O
of O
melanocytes O
resulting O
from O
the O
use O
of O
amikacin B
in O
vitro O
may O
explain O
a O
potential O
role O
of O
melanin O
and O
melanocytes O
in O
the O
mechanisms O
of O
aminoglycosides B
ototoxic O
effects O
in O
vivo O
. O

Bioaccessibility O
of O
12 O
trace O
elements O
in O
marine O
molluscs O
. O

We O
conducted O
a O
large O
scale O
investigation O
of O
the O
bioaccessibility O
of O
12 O
trace O
elements O
from O
11 O
marine O
mollusc O
species O
( O
scallop O
, O
oyster O
, O
clam O
, O
abalone O
, O
snail O
, O
and O
mussel O
) O
collected O
from O
five O
locations O
in O
Chinese O
coastal O
waters O
. O

The O
bioaccessibility O
of O
all O
the O
12 O
trace O
elements O
was O
generally O
high O
, O
with O
the O
average O
values O
ranging O
from O
42 O
. O
5 O
% O
to O
90 O
. O
7 O
% O
. O

The O
highest O
bioaccessibility O
was O
observed O
for O
As B
, O
Cu B
, O
Ni B
and O
Se B
, O
and O
the O
lowest O
for O
Fe B
, O
Co B
and O
Pb B
. O

Steaming O
decreased O
the O
bioaccessibility O
of O
all O
12 O
trace O
elements O
and O
thus O
diminished O
their O
risks O
. O

No O
correlation O
was O
observed O
between O
the O
bioaccessibility O
and O
the O
total O
concentration O
of O
the O
12 O
elements O
. O

However O
, O
there O
was O
a O
significant O
correlation O
between O
the O
bioaccessibility O
of O
the O
12 O
elements O
and O
their O
subcellular O
distribution O
. O

For O
most O
trace O
elements O
, O
a O
significantly O
negative O
relationship O
was O
demonstrated O
between O
the O
bioaccessibility O
and O
the O
elemental O
partitioning O
in O
the O
metal O
- O
rich O
granule O
fraction O
or O
in O
the O
cellular O
debris O
fraction O
, O
and O
a O
significantly O
positive O
correlation O
was O
observed O
between O
the O
bioaccessibility O
and O
the O
elemental O
partitioning O
in O
the O
heat O
- O
stable O
protein O
fraction O
and O
in O
the O
trophically O
available O
fraction O
. O

Hence O
, O
the O
elemental O
subcellular O
distribution O
, O
especially O
the O
elemental O
partitioning O
in O
the O
trophically O
available O
fraction O
, O
might O
be O
a O
good O
predictor O
of O
the O
bioaccessibility O
and O
risks O
of O
trace O
elements O
in O
molluscs O
. O

Ameliorating O
effects O
of O
casein O
glycomacropeptide O
on O
obesity O
induced O
by O
high O
- O
fat O
diet O
in O
male O
Sprague O
- O
Dawley O
rats O
. O

The O
effect O
of O
casein O
glycomacropeptide O
( O
GMP O
) O
as O
a O
specific O
regulating O
mediator O
in O
obese O
rats O
induced O
by O
high O
- O
fat O
( O
HF O
) O
diet O
was O
investigated O
. O

Male O
obese O
Sprague O
- O
Dawley O
( O
SD O
) O
rats O
induced O
by O
high O
- O
fat O
diet O
for O
8weeks O
period O
were O
fed O
high O
- O
fat O
, O
high O
- O
fat O
with O
GMP O
of O
100mg O
/ O
kg O
BW O
( O
HFLG O
) O
, O
200mg O
/ O
kg O
BW O
( O
HFMG O
) O
and O
400mg O
/ O
kg O
BW O
( O
HFHG O
) O
for O
6weeks O
. O

Compared O
with O
the O
high O
- O
fat O
control O
( O
HFC O
) O
group O
GMP B
supplementation O
significantly O
decreased O
adipose O
tissue O
weight O
, O
activity O
of O
fatty B
acid I
synthase O
( O
FAS O
) O
and O
glycerol B
- I
3 I
- I
phosphate I
dehydrogenase O
( O
GPDH O
) O
. O

Hepatic O
lipid O
droplet O
size O
, O
plasma O
and O
hepatic O
lipid O
levels O
markedly O
reduced O
. O

Moreover O
, O
GMP B
reduces O
plasma O
total O
cholesterol B
and O
low O
- O
density O
lipoprotein O
( O
LDL O
) O
cholesterol B
as O
well O
as O
hepatic O
- O
cholesterol B
and O
triglycerides B
. O

The O
liver O
steatosis O
observed O
in O
obese O
rats O
was O
also O
prevented O
by O
GMP B
supplement O
. O

In O
addition O
, O
GMP O
significantly O
diminished O
mitochondrial O
and O
liver O
malondialdehyde B
( O
MDA B
) O
production O
, O
and O
obviously O
elevated O
the O
activities O
of O
mitochondrial O
and O
hepatic O
superoxidase O
dismutase O
( O
SOD O
) O
and O
glutathione B
peroxidase O
( O
GSH B
- O
Px O
) O
. O

Leptin O
production O
and O
proinflammatory O
cytokines O
such O
as O
TNF O
- O
alpha O
and O
IL O
- O
6 O
secretion O
decreased O
. O

Taken O
together O
, O
GMP O
can O
reduce O
lipid O
accumulation O
and O
enhance O
antioxidant O
capability O
of O
obese O
rats O
. O

It O
suggests O
that O
GMP B
can O
counteract O
high O
- O
fat O
diet O
- O
induced O
obesity O
, O
which O
might O
make O
it O
a O
potential O
ingredient O
with O
anti O
- O
obesity O
activity O
. O

Central O
administration O
of O
angiotensin O
IV O
rapidly O
enhances O
novel O
object O
recognition O
among O
mice O
. O

Angiotensin O
IV O
( O
Val B
( O
1 O
) O
- O
Tyr B
( O
2 O
) O
- O
Ile I
( O
3 O
) O
- O
His B
( O
4 O
) O
- O
Pro B
( O
5 O
) O
- O
Phe B
( O
6 O
) O
) O
has O
demonstrated O
potential O
cognitive O
- O
enhancing O
effects O
. O

The O
present O
investigation O
assessed O
and O
characterized O
: O
( O
1 O
) O
dose O
- O
dependency O
of O
angiotensin B
IV I
' O
s O
cognitive O
enhancement O
in O
a O
C57BL O
/ O
6J O
mouse O
model O
of O
novel O
object O
recognition O
, O
( O
2 O
) O
the O
time O
- O
course O
for O
these O
effects O
, O
( O
3 O
) O
the O
identity O
of O
residues O
in O
the O
hexapeptide B
important O
to O
these O
effects O
and O
( O
4 O
) O
the O
necessity O
of O
actions O
at O
angiotensin B
IV I
receptors O
for O
procognitive O
activity O
. O

Assessment O
of O
C57BL O
/ O
6J O
mice O
in O
a O
novel O
object O
recognition O
task O
demonstrated O
that O
prior O
administration O
of O
angiotensin O
IV O
( O
0 O
. O
1 O
, O
1 O
. O
0 O
, O
or O
10 O
. O
0 O
, O
but O
not O
0 O
. O
01 O
nmol O
, O
i O
. O
c O
. O
v O
. O
) O
significantly O
enhanced O
novel O
object O
recognition O
in O
a O
dose O
- O
dependent O
manner O
. O

These O
effects O
were O
time O
dependent O
, O
with O
improved O
novel O
object O
recognition O
observed O
when O
angiotensin O
IV O
( O
0 O
. O
1 O
nmol O
, O
i O
. O
c O
. O
v O
. O
) O
was O
administered O
10 O
or O
20 O
, O
but O
not O
30 O
min O
prior O
to O
the O
onset O
of O
the O
novel O
object O
recognition O
testing O
. O

An O
alanine B
scan O
of O
the O
angiotensin O
IV O
peptide O
revealed O
that O
replacement O
of O
the O
Val B
( O
1 O
) O
, O
Ile B
( O
3 O
) O
, O
His B
( O
4 O
) O
, O
or O
Phe B
( O
6 O
) O
residues O
with O
Ala B
attenuated O
peptide O
- O
induced O
improvements O
in O
novel O
object O
recognition O
, O
whereas O
Tyr B
( O
2 O
) O
or O
Pro B
( O
5 O
) O
replacement O
did O
not O
significantly O
affect O
performance O
. O

Administration O
of O
the O
angiotensin O
IV O
receptor O
antagonist O
, O
divalinal B
- I
Ang I
IV I
( O
20 O
nmol O
, O
i O
. O
c O
. O
v O
. O
) O
, O
reduced O
( O
but O
did O
not O
abolish O
) O
novel O
object O
recognition O
; O
however O
, O
this O
antagonist O
completely O
blocked O
the O
procognitive O
effects O
of O
angiotensin B
IV I
( O
0 O
. O
1 O
nmol O
, O
i O
. O
c O
. O
v O
. O
) O
in O
this O
task O
. O

Rotorod O
testing O
demonstrated O
no O
locomotor O
effects O
with O
any O
angiotensin O
IV O
or O
divalinal O
- O
Ang O
IV O
dose O
tested O
. O

These O
data O
demonstrate O
that O
angiotensin O
IV O
produces O
a O
rapid O
enhancement O
of O
associative O
learning O
and O
memory O
performance O
in O
a O
mouse O
model O
that O
was O
dependent O
on O
the O
angiotensin O
IV O
receptor O
. O

Maternal O
exposure O
to O
airborne O
particulate O
matter O
causes O
postnatal O
immunological O
dysfunction O
in O
mice O
offspring O
. O

Evidence O
suggests O
that O
prenatal O
exposure O
to O
air O
pollution O
affects O
the O
ontogeny O
and O
development O
of O
the O
fetal O
immune O
system O
. O

The O
aim O
of O
this O
study O
was O
to O
investigate O
the O
effect O
of O
maternal O
exposure O
to O
airborne O
particulate O
matter O
( O
PM O
) O
on O
immune O
function O
in O
postnatal O
offspring O
. O

Pregnant O
female O
ICR O
mice O
were O
intralaryngopharynge O
administered O
with O
30 O
mu O
l O
of O
phosphate B
buffered O
solution O
( O
the O
control O
group O
) O
or O
resuspended O
PM O
of O
Standard O
Reference O
Material O
1649a O
at O
0 O
. O
09 O
( O
low O
) O
, O
0 O
. O
28 O
( O
medium O
) O
, O
1 O
. O
85 O
( O
high O
) O
or O
6 O
. O
92 O
( O
overdose O
) O
mu O
g O
/ O
mu O
l O
once O
every O
three O
days O
from O
day O
0 O
to O
18 O
of O
pregnancy O
( O
n O
= O
8 O
- O
10 O
) O
. O

Offspring O
were O
sacrificed O
on O
postnatal O
day O
30 O
. O

Interleukin O
- O
4 O
and O
interferon O
- O
gamma O
levels O
in O
plasma O
and O
splenocytes O
, O
splenic O
lymphocyte O
proliferation O
, O
and O
expressions O
of O
GATA O
- O
3 O
and O
T O
- O
bet O
mRNA O
in O
the O
spleen O
were O
tested O
. O

The O
spleen O
and O
thymus O
were O
histopathologically O
examined O
. O

The O
offspring O
of O
the O
medium O
, O
high O
and O
overdose O
PM O
- O
exposed O
dams O
showed O
significantly O
suppressed O
splenocyte O
proliferation O
. O

Decreased O
interferon O
- O
gamma O
and O
increased O
interleukin O
- O
4 O
levels O
in O
the O
blood O
and O
splenocytes O
, O
and O
lowered O
T O
- O
bet O
and O
elevated O
GATA O
- O
3 O
mRNA O
expressions O
were O
found O
in O
the O
spleen O
in O
the O
medium O
, O
high O
and O
overdose O
groups O
when O
compared O
with O
the O
control O
or O
low O
dose O
group O
( O
P O
< O
0 O
. O
05 O
) O
. O

Histopathology O
revealed O
prominent O
tissue O
damage O
in O
the O
spleen O
and O
thymus O
in O
the O
overdose O
group O
. O

These O
results O
suggest O
that O
exposure O
of O
pregnant O
mice O
to O
PM O
modulates O
the O
fetal O
immune O
system O
, O
resulting O
in O
postnatal O
immune O
dysfunction O
by O
exacerbation O
of O
Thl O
/ O
Th2 O
deviation O
. O

This O
deviation O
is O
associated O
with O
altered O
T O
- O
bet O
and O
GATA O
- O
3 O
gene O
expressions O
. O

Dexamethasone B
antagonizes O
the O
in O
vivo O
myotoxic O
and O
inflammatory O
effects O
of O
Bothrops O
venoms O
. O

In O
the O
present O
work O
we O
investigated O
the O
toxic O
activities O
of O
two O
Bothrops O
snake O
venoms O
using O
in O
vivo O
and O
in O
vitro O
experimental O
protocols O
in O
mice O
and O
tested O
the O
protective O
effect O
of O
dexamethasone B
( O
DEXA B
) O
in O
different O
conditions O
, O
comparing O
it O
with O
the O
polyvalent O
antivenom O
. O

We O
also O
expanded O
the O
investigations O
on O
the O
antiophidic O
effect O
of O
the O
Eclipta O
prostrata O
( O
EP O
) O
crude O
extract O
. O

The O
administration O
of O
Bothrops O
jararaca O
and O
Bothrops O
jararacussu O
snake O
venoms O
induced O
muscle O
damage O
demonstrated O
in O
vivo O
by O
the O
elevation O
on O
plasma O
creatine B
kinase O
( O
CK O
) O
activity O
in O
mice O
and O
by O
the O
decrease O
in O
CK O
content O
in O
the O
extensor O
digitorum O
longus O
( O
EDL O
) O
muscle O
of O
these O
animals O
, O
and O
in O
vitro O
by O
the O
increase O
in O
the O
rate O
of O
CK O
release O
from O
the O
isolated O
EDL O
muscle O
. O

We O
also O
observed O
inflammatory O
response O
following O
perimuscular O
injection O
of O
B O
. O
jararacussu O
venom O
( O
1 O
. O
0 O
mg O
/ O
kg O
) O
. O

Treatment O
with O
DEXA B
( O
1 O
. O
0 O
mg O
/ O
kg O
) O
preserved O
over O
50 O
% O
of O
the O
EDL O
muscle O
CK O
content O
in O
vivo O
when O
evaluated O
24 O
and O
72 O
h O
after O
the O
injection O
of O
B O
. O
jararacussu O
venom O
in O
mice O
, O
and O
likewise O
reduced O
about O
20 O
% O
of O
the O
edema O
induced O
by O
this O
venom O
. O

DEXA B
reduced O
in O
50 O
% O
the O
presence O
of O
inflammatory O
cells O
and O
their O
activity O
in O
EDL O
muscle O
. O

The O
EP O
extract O
( O
50 O
mg O
/ O
kg O
) O
showed O
similar O
ability O
in O
preventing O
the O
induction O
of O
edema O
and O
the O
decrease O
in O
muscle O
CK O
content O
, O
and O
its O
association O
with O
DEXA B
showed O
additive O
effect O
. O

EP O
reduced O
over O
77 O
% O
of O
the O
plasma O
CK O
activity O
induced O
by O
the O
B O
. O
jararacussu O
venom O
. O

In O
the O
in O
vitro O
experiments O
, O
DEXA B
was O
not O
able O
to O
change O
the O
rate O
of O
CK O
release O
from O
EDL O
muscles O
exposed O
to O
25 O
mu O
g O
/ O
mL O
of O
B O
. O
jararacussu O
venom O
, O
neither O
to O
prevent O
the O
fall O
in O
the O
amplitude O
of O
the O
indirectly O
evoked O
twitch O
at O
the O
phrenic O
- O
diaphragm O
preparation O
. O

EP O
extract O
showed O
otherwise O
a O
protective O
effect O
on O
these O
protocols O
, O
reaching O
up O
to O
100 O
% O
of O
protection O
when O
concentrations O
of O
50 O
. O
0 O
and O
100 O
. O
0 O
mu O
g O
/ O
mL O
were O
used O
. O

Altogether O
our O
results O
show O
that O
inflammation O
is O
at O
least O
in O
part O
responsible O
for O
the O
tissue O
damage O
induced O
by O
Bothrops O
snake O
venoms O
, O
once O
the O
steroidal O
anti O
- O
inflammatory O
drug O
dexamethasone B
was O
able O
to O
decrease O
the O
myotoxic O
effects O
of O
these O
venoms O
, O
by O
reducing O
the O
inflammatory O
response O
to O
the O
venom O
injection O
. O

Hypothetical O
physiological O
and O
molecular O
basis O
for O
the O
effect O
of O
acupuncture O
in O
the O
treatment O
of O
polycystic O
ovary O
syndrome O
. O

Clinical O
and O
experimental O
evidence O
indicates O
that O
acupuncture O
may O
be O
a O
safe O
alternative O
or O
complement O
in O
the O
treatment O
of O
endocrine O
and O
reproductive O
function O
in O
women O
with O
polycystic O
ovary O
syndrome O
( O
PCOS O
) O
. O

This O
review O
describes O
potential O
etiological O
factors O
of O
PCOS O
with O
the O
aim O
to O
support O
potential O
mechanism O
of O
action O
of O
acupuncture O
to O
relieve O
PCOS O
related O
symptoms O
. O

The O
theory O
that O
increased O
sympathetic O
activity O
contributes O
to O
the O
development O
and O
maintenance O
of O
PCOS O
is O
presented O
, O
and O
that O
the O
effects O
of O
acupuncture O
are O
, O
at O
least O
in O
part O
, O
mediated O
by O
modulation O
of O
sympathetic O
outflow O
. O

While O
there O
are O
no O
relevant O
randomized O
controlled O
studies O
on O
the O
use O
of O
acupuncture O
to O
treat O
metabolic O
abnormalities O
in O
women O
with O
PCOS O
, O
a O
number O
of O
experimental O
studies O
indicate O
that O
acupuncture O
may O
improve O
metabolic O
dysfunction O
. O

For O
each O
aspect O
of O
PCOS O
, O
it O
is O
important O
to O
pursue O
new O
treatment O
strategies O
that O
have O
fewer O
negative O
side O
effects O
than O
drug O
treatments O
, O
as O
women O
with O
PCOS O
often O
require O
prolonged O
treatment O
. O

Analyzing O
lead O
absorption O
by O
the O
sycamore O
tree O
species O
in O
the O
industrial O
park O
of O
Rasht O
, O
Iran O
. O

In O
this O
study O
, O
the O
subject O
of O
heavy O
metal O
concentration O
in O
soil O
, O
rock O
, O
sediment O
, O
surface O
water O
and O
groundwater O
, O
which O
can O
be O
caused O
by O
natural O
or O
man O
- O
posed O
pollution O
, O
was O
analyzed O
in O
the O
industrial O
park O
of O
Rasht O
. O

These O
concentrations O
were O
compared O
with O
the O
standard O
range O
of O
environmental O
data O
. O

Heavy O
metals O
are O
important O
environmental O
pollutants O
that O
can O
cause O
health O
hazards O
to O
humans O
, O
plants O
and O
microorganisms O
by O
entering O
food O
chain O
. O

This O
study O
aimed O
to O
investigate O
the O
absorption O
of O
lead O
by O
the O
leaves O
of O
sycamore O
tree O
species O
in O
the O
industrial O
park O
of O
Rasht O
. O

For O
this O
purpose O
, O
a O
sample O
of O
32 O
sycamore O
tree O
species O
were O
randomly O
selected O
at O
a O
specified O
time O
, O
and O
the O
concentration O
of O
lead O
were O
measured O
using O
an O
atomic O
absorption O
device O
. O

Results O
showed O
that O
the O
amount O
of O
lead O
absorption O
by O
sycamore O
leaves O
is O
remarkable O
. O

The O
highest O
amount O
of O
lead O
absorption O
by O
sycamore O
leaves O
was O
detected O
at O
station O
1 O
( O
Khazar O
Steel O
) O
and O
the O
lowest O
amount O
at O
station O
2 O
( O
control O
station O
) O
. O

Transcription O
forms O
and O
remodels O
supercoiling O
domains O
unfolding O
large O
- O
scale O
chromatin O
structures O
. O

DNA O
supercoiling O
is O
an O
inherent O
consequence O
of O
twisting O
DNA O
and O
is O
critical O
for O
regulating O
gene O
expression O
and O
DNA O
replication O
. O

However O
, O
DNA O
supercoiling O
at O
a O
genomic O
scale O
in O
human O
cells O
is O
uncharacterized O
. O

To O
map O
supercoiling O
, O
we O
used O
biotinylated B
trimethylpsoralen I
as O
a O
DNA O
structure O
probe O
to O
show O
that O
the O
human O
genome O
is O
organized O
into O
supercoiling O
domains O
. O

Domains O
are O
formed O
and O
remodeled O
by O
RNA O
polymerase O
and O
topoisomerase O
activities O
and O
are O
flanked O
by O
GC O
- O
AT O
boundaries O
and O
CTCF O
insulator O
protein O
- O
binding O
sites O
. O

Underwound O
domains O
are O
transcriptionally O
active O
and O
enriched O
in O
topoisomerase O
I O
, O
' O
open O
' O
chromatin O
fibers O
and O
DNase O
I O
sites O
, O
but O
they O
are O
depleted O
of O
topoisomerase O
II O
. O

Furthermore O
, O
DNA O
supercoiling O
affects O
additional O
levels O
of O
chromatin O
compaction O
as O
underwound O
domains O
are O
cytologically O
decondensed O
, O
topologically O
constrained O
and O
decompacted O
by O
transcription O
of O
short O
RNAs O
. O

We O
suggest O
that O
supercoiling O
domains O
create O
a O
topological O
environment O
that O
facilitates O
gene O
activation O
, O
providing O
an O
evolutionary O
purpose O
for O
clustering O
genes O
along O
chromosomes O
. O

Evolution O
and O
dynamics O
of O
pancreatic O
cancer O
progression O
. O

Efficient O
metastasis O
is O
believed O
as O
the O
result O
of O
multiple O
genetic O
, O
epigenetic O
and O
/ O
or O
post O
- O
translational O
events O
in O
the O
lifetime O
of O
a O
carcinoma O
. O

At O
the O
genetic O
level O
, O
these O
events O
may O
be O
categorized O
into O
those O
that O
occur O
during O
carcinogenesis O
, O
and O
those O
that O
occur O
during O
subclonal O
evolution O
. O

This O
review O
summarizes O
current O
knowledge O
of O
the O
genetics O
of O
pancreatic O
cancer O
from O
its O
initiation O
within O
a O
normal O
cell O
until O
the O
time O
that O
is O
has O
disseminated O
to O
distant O
organs O
, O
many O
features O
of O
which O
can O
be O
extrapolated O
to O
other O
solid O
tumor O
types O
. O

The O
implications O
of O
these O
findings O
to O
personalize O
genome O
analyses O
of O
an O
individual O
patient O
' O
s O
tumor O
are O
also O
discussed O
. O
Oncogene O
advance O
online O
publication O
, O
18 O
February O
2013 O
; O
doi O
: O
10 O
. O
1038 O
/ O
onc O
. O
2013 O
. O
29 O
. O

Hepatic O
growth O
hormone O
resistance O
after O
acute O
injury O
. O

Severe O
injury O
and O
infection O
are O
often O
followed O
by O
accelerated O
protein O
catabolism O
and O
acute O
insulin O
resistance O
. O

This O
results O
in O
several O
effects O
that O
complicate O
and O
prolong O
recovery O
, O
including O
weakness O
, O
immobility O
, O
impaired O
wound O
healing O
, O
and O
organ O
dysfunction O
. O

Recent O
studies O
have O
demonstrated O
the O
development O
of O
GH O
resistance O
during O
severe O
inflammation O
, O
providing O
a O
potential O
mechanism O
for O
the O
protein O
loss O
that O
follows O
injury O
and O
infection O
. O

To O
understand O
this O
GH O
resistance O
, O
we O
recently O
developed O
a O
murine O
model O
of O
acute O
injury O
. O

Mice O
were O
subjected O
to O
soft O
- O
tissue O
injury O
, O
alone O
or O
combined O
with O
hemorrhage O
, O
and O
injected O
iv O
with O
GH O
30 O
, O
60 O
, O
or O
90 O
minutes O
later O
. O

Hepatic O
GH O
signaling O
was O
measured O
via O
Western O
analysis O
. O

GH O
- O
induced O
signal O
transducer O
and O
activator O
of O
transcription O
5 O
phosphorylation O
was O
decreased O
immediately O
after O
completion O
of O
the O
trauma O
procedure O
, O
and O
at O
30 O
and O
60 O
minutes O
, O
but O
further O
decreased O
by O
90 O
minutes O
after O
trauma O
. O

Combined O
trauma O
and O
hemorrhage O
resulted O
in O
severely O
decreased O
GH O
- O
induced O
signal O
transducer O
and O
activator O
of O
transcription O
5 O
phosphorylation O
compared O
with O
trauma O
alone O
, O
and O
this O
was O
true O
at O
all O
time O
points O
studied O
. O

Western O
analysis O
revealed O
an O
apparent O
decrease O
in O
the O
molecular O
weight O
of O
the O
hepatic O
GH O
receptor O
( O
GHR O
) O
after O
trauma O
and O
hemorrhage O
, O
but O
not O
trauma O
alone O
. O

Additional O
studies O
determined O
that O
the O
hemorrhage O
- O
induced O
decrease O
in O
receptor O
size O
was O
not O
due O
to O
changes O
in O
GHR O
N B
- O
linked O
glycosylation O
. O

These O
results O
suggest O
that O
GH O
sensitivity O
is O
rapidly O
impaired O
after O
acute O
injury O
and O
that O
trauma O
combined O
with O
hemorrhage O
results O
in O
a O
more O
severe O
form O
of O
GH O
resistance O
resulting O
from O
alteration O
or O
inactivation O
of O
hepatic O
GHR O
. O

The O
effects O
of O
an O
environmentally O
relevant O
58 O
- O
congener O
polychlorinated B
biphenyl I
( O
PCB B
) O
mixture O
on O
cardiac O
development O
in O
the O
chick O
embryo O
. O

Chicken O
( O
Gallus O
domesticus O
) O
embryonic O
exposure O
in O
ovo O
to O
a O
58 O
- O
congener O
polychlorinated B
biphenyl I
( O
PCB B
) O
mixture O
resulted O
in O
teratogenic O
heart O
defects O
in O
chick O
embryos O
at O
critical O
heart O
developmental O
stages O
Hamburger O
- O
Hamilton O
( O
HH O
) O
stages O
10 O
, O
16 O
, O
and O
20 O
. O

The O
58 O
- O
congener O
mixture O
contained O
relative O
proportions O
of O
primary O
congeners O
measured O
in O
belted O
sandpiper O
( O
Megaceryle O
alcyon O
) O
and O
spotted O
sandpiper O
( O
Actitis O
macularia O
) O
eggs O
collected O
along O
the O
upper O
Hudson O
River O
, O
New O
York O
, O
USA O
, O
and O
chicken O
doses O
were O
well O
below O
observed O
environmental O
exposure O
levels O
. O

Embryos O
were O
injected O
with O
0 O
. O
08 O
micro O
g O
PCBs B
/ O
g O
egg O
weight O
and O
0 O
. O
50 O
micro O
g O
PCBs B
/ O
g O
egg O
weight O
( O
0 O
. O
01 O
and O
0 O
. O
064 O
ng O
toxic O
equivalent O
/ O
g O
, O
respectively O
) O
at O
embryonic O
day O
0 O
, O
prior O
to O
incubation O
. O

Mortality O
of O
exposed O
embryos O
was O
increased O
at O
all O
developmental O
stages O
, O
with O
a O
marked O
rise O
in O
cardiomyopathies O
at O
HH16 O
and O
HH20 O
( O
p O
< O
0 O
. O
05 O
) O
. O

Heart O
abnormalities O
occurred O
across O
all O
treatments O
, O
including O
abnormal O
elongation O
and O
expansion O
of O
the O
heart O
tube O
at O
HH10 O
, O
improper O
looping O
and O
orientation O
, O
indentations O
in O
the O
emerging O
ventricular O
wall O
( O
HH16 O
and O
HH20 O
) O
, O
and O
irregularities O
in O
overall O
heart O
shape O
( O
HH10 O
, O
HH16 O
, O
and O
HH20 O
) O
. O

Histology O
was O
conducted O
on O
2 O
cardiac O
proteins O
critical O
to O
embryonic O
heart O
development O
, O
ventricular O
myosin O
heavy O
chain O
and O
titin O
, O
to O
investigate O
potential O
mechanistic O
effects O
of O
PCBs B
on O
heart O
development O
, O
but O
no O
difference O
was O
observed O
in O
spatiotemporal O
expression O
. O

Similarly O
, O
cellular O
apoptosis O
in O
the O
developing O
heart O
was O
not O
affected O
by O
exposure O
to O
the O
PCB B
mixture O
. O

Conversely O
, O
cardiomyocyte O
proliferation O
rates O
dramatically O
declined O
( O
p O
< O
0 O
. O
01 O
) O
at O
HH16 O
and O
HH20 O
as O
PCB B
exposure O
concentrations O
increased O
. O

Early O
embryonic O
cardiomyocyte O
proliferation O
contributes O
to O
proper O
formation O
of O
the O
morphology O
and O
overall O
thickness O
of O
the O
ventricular O
wall O
. O

Therefore O
, O
in O
ovo O
exposure O
to O
this O
58 O
- O
congener O
PCB B
mixture O
at O
critical O
stages O
adversely O
affects O
embryonic O
heart O
development O
. O

Environ O
Toxicol O
Chem O
2013 O
; O
32 O
: O
1317 O
- O
1324 O
. O

( O
c O
) O
2013 O
SETAC O
. O

Flock O
- O
Based O
Microfluidics O
. O

Flock O
- O
based O
microfluidics O
are O
created O
by O
depositing O
hydrophilic O
microfibers O
on O
an O
adhesive O
- O
coated O
substrate O
using O
an O
electric O
field O
. O

This O
enables O
the O
fabrication O
of O
self O
- O
powered O
microfluidics O
from O
one O
or O
more O
different O
kinds O
of O
fibers O
that O
form O
2D O
and O
3D O
flowpaths O
, O
which O
can O
wick O
40 O
microliters O
of O
liquid O
per O
square O
centimeter O
. O

With O
this O
approach O
, O
large O
areas O
of O
functional O
wicking O
materials O
can O
be O
produced O
at O
extremely O
low O
cost O
. O

Hollow O
Multilayer O
Microcapsules O
for O
pH O
- O
/ O
Thermally O
Responsive O
Drug O
Delivery O
using O
Aliphatic B
Poly I
( I
urethane I
- I
amine I
) I
as O
Smart O
Component O
. O

Hollow O
multilayer O
microcapsules O
made O
of O
aliphatic O
poly B
( I
urethane I
- I
amine I
) I
( O
PUA B
) O
and O
sodium B
poly I
( I
styrene I
sulfonate I
) I
( O
PSS B
) O
, O
templated O
on O
PSS B
- O
doped O
CaCO3 B
particles O
, O
are O
prepared O
for O
pH O
- O
/ O
thermally O
responsive O
drug O
delivery O
. O

The O
electrostatic O
interaction O
and O
hydrogen B
bonding O
under O
weak O
- O
acid O
conditions O
between O
aliphatic O
PUA B
and O
PSS B
contribute O
to O
the O
formation O
of O
multilayer O
microcapsules O
. O

Scanning O
electron O
microscopy O
( O
SEM O
) O
results O
demonstrate O
an O
obvious O
variation O
of O
the O
hollow O
multilayer O
microcapsules O
in O
response O
to O
changes O
in O
temperature O
and O
pH O
value O
. O

Drug O
- O
release O
behaviors O
using O
DOX B
as O
a O
model O
drug O
demonstrate O
that O
the O
drug O
release O
increases O
on O
decreasing O
the O
pH O
value O
because O
of O
the O
interaction O
weakness O
between O
aliphatic O
PUA O
and O
PSS B
in O
acidic O
conditions O
. O

Moreover O
, O
the O
drug O
release O
is O
higher O
at O
55 O
degrees O
C O
than O
that O
at O
37 O
degrees O
C O
for O
the O
sake O
of O
the O
shrinkage O
of O
aliphatic O
PUA O
above O
its O
lower O
critical O
solution O
temperature O
( O
LCST O
) O
. O

BaSnO3 B
perovskite I
nanoparticles O
for O
high O
efficiency O
dye O
- O
sensitized O
solar O
cells O
. O

The O
synthesis O
of O
highly O
crystalline O
perovskite B
BaSnO3 B
nanoparticles O
for O
use O
as O
photoanode O
materials O
in O
dye O
- O
sensitized O
solar O
cells O
( O
DSSCs O
) O
is O
reported O
, O
and O
the O
photovoltaic O
properties O
of O
DSSCs O
based O
on O
BaSnO3 B
nanoparticles O
( O
BaSnO3 B
cells O
) O
are O
demonstrated O
. O

The O
resulting O
DSSCs O
exhibit O
remarkably O
rapid O
charge O
collection O
and O
a O
DSSC O
fabricated O
with O
a O
BaSnO3 B
film O
thickness O
of O
43 O
micro O
m O
leads O
to O
a O
high O
energy O
conversion O
efficiency O
of O
5 O
. O
2 O
% O
, O
which O
is O
one O
of O
the O
highest O
reported O
for O
ternary B
oxide I
- O
based O
DSSCs O
. O

More O
importantly O
, O
the O
BaSnO3 B
cells O
show O
superior O
charge O
collection O
in O
nanoparticle O
films O
compared O
to O
TiO2 B
cells O
and O
could O
offer O
a O
breakthrough O
in O
the O
efficiencies O
of O
DSSCs O
. O

Incorporating O
Graphene B
Oxide I
and O
Gold O
Nanoclusters O
: O
A O
Synergistic O
Catalyst O
with O
Surprisingly O
High O
Peroxidase O
- O
Like O
Activity O
Over O
a O
Broad O
pH O
Range O
and O
its O
Application O
for O
Cancer O
Cell O
Detection O
. O

A O
synergistic O
graphene B
oxide I
- O
gold O
nanocluster O
( O
GO O
- O
AuNC O
) O
hybrid O
has O
been O
constructed O
as O
an O
enzyme O
mimic O
that O
is O
able O
to O
show O
high O
catalytic O
activity O
over O
a O
broad O
pH O
range O
, O
especially O
at O
neutral O
pH O
. O

Importantly O
, O
the O
target O
- O
functionalized O
hybrid O
has O
been O
applied O
as O
a O
robust O
nanoprobe O
for O
selective O
, O
quantitative O
, O
and O
fast O
colorimetric O
detection O
of O
cancer O
cells O
. O

Synthesis O
of O
heterocyclic B
terpenoids I
by O
promiscuous O
squalene B
- O
hopene B
cyclases O
. O

PROMISCUOUS O
ENZYMES O
: O
The O
substrate O
promiscuity O
of O
squalene B
- O
hopene B
cyclases O
has O
been O
explored O
and O
applied O
in O
the O
enzyme O
- O
catalyzed O
synthesis O
of O
heterocyclic O
terpenoids B
. O

Features O
of O
this O
work O
include O
cyclization O
reactions O
without O
pyrophosphate B
activation O
, O
and O
stereospecific O
ring O
closure O
of O
substrates O
of O
varying O
chain O
length O
and O
terminal O
nucleophile O
. O

This O
provides O
a O
biocatalytic O
alternative O
to O
traditional O
chemical O
catalysts O
. O

Engineered O
nanomaterials O
in O
water O
and O
soils O
: O
A O
risk O
quantification O
based O
on O
probabilistic O
exposure O
and O
effect O
modeling O
. O

The O
production O
and O
use O
of O
engineered O
nanomaterials O
( O
ENMs O
) O
are O
increasing O
rapidly O
, O
and O
therefore O
, O
the O
need O
to O
assess O
their O
environmental O
exposure O
and O
associated O
risks O
has O
become O
increasingly O
important O
. O

Only O
a O
handful O
of O
studies O
have O
quantified O
the O
release O
and O
environmental O
concentrations O
of O
ENMs O
, O
but O
much O
work O
has O
been O
done O
to O
investigate O
the O
effects O
of O
these O
materials O
on O
organisms O
. O

The O
aim O
of O
the O
present O
study O
was O
to O
quantify O
probabilistically O
the O
environmental O
risks O
of O
ENMs O
, O
producing O
species O
sensitivity O
distributions O
that O
were O
then O
compared O
with O
probability O
distributions O
of O
predicted O
environmental O
concentrations O
. O

Five O
nanomaterials O
( O
nano O
- O
Ag B
, O
nano O
- O
TiO2 B
, O
nano O
- O
ZnO B
, O
carbon B
nanotubes O
[ O
CNTs O
] O
, O
and O
fullerenes B
) O
and O
4 O
environmental O
compartments O
( O
surface O
water O
, O
sewage O
treatment O
plant O
effluents O
, O
soils O
, O
and O
sludge O
- O
treated O
soils O
) O
were O
considered O
. O

From O
60 O
ecotoxicological O
studies O
, O
the O
authors O
extracted O
112 O
single O
values O
to O
work O
with O
( O
25 O
values O
in O
13 O
studies O
for O
nano O
- O
Ag B
, O
17 O
values O
in O
10 O
studies O
for O
CNTs O
, O
7 O
values O
in O
7 O
studies O
for O
fullerenes B
, O
34 O
values O
in O
23 O
studies O
for O
nano O
- O
TiO2 B
, O
and O
29 O
values O
in O
17 O
studies O
for O
nano O
- O
ZnO B
) O
. O

The O
results O
indicate O
there O
is O
only O
a O
marginal O
risk O
for O
these O
metal O
- O
based O
nanomaterials O
in O
surface O
water O
( O
0 O
. O
7 O
% O
risk O
for O
nano O
- O
Ag B
and O
< O
0 O
. O
1 O
% O
for O
nano O
- O
TiO2 B
) O
and O
some O
risk O
in O
sewage O
treatment O
plant O
effluents O
( O
nano O
- O
Ag B
39 O
. O
7 O
% O
, O
nano O
- O
TiO2 B
18 O
. O
7 O
% O
, O
and O
nano O
- O
ZnO B
1 O
. O
1 O
% O
) O
. O

Apart O
from O
a O
marginal O
value O
of O
< O
0 O
. O
1 O
% O
for O
nano O
- O
TiO2 B
in O
sludge O
- O
treated O
soils O
, O
no O
risk O
from O
the O
other O
evaluated O
ENMs O
in O
terrestrial O
compartments O
is O
currently O
predicted O
. O

The O
discussion O
of O
the O
results O
considers O
the O
influence O
of O
the O
effects O
of O
different O
forms O
of O
1 O
ENM O
( O
coating O
, O
agglomeration O
state O
, O
and O
mineralogy O
) O
, O
the O
test O
conditions O
( O
dissolution O
and O
agglomeration O
) O
, O
and O
transformation O
reactions O
. O

Environ O
Toxicol O
Chem O
2013 O
; O
32 O
: O
1278 O
- O
1287 O
. O

( O
c O
) O
2013 O
SETAC O
. O

The O
Prevalence O
of O
Meeting O
A1C O
, O
Blood O
Pressure O
, O
and O
LDL O
Goals O
Among O
People O
With O
Diabetes O
, O
1988 O
- O
2010 O
. O

OBJECTIVETo O
determine O
the O
prevalence O
of O
people O
with O
diabetes O
who O
meet O
hemoglobin O
A O
( O
1c O
) O
( O
A1C O
) O
, O
blood O
pressure O
( O
BP O
) O
, O
and O
LDL O
cholesterol B
( O
ABC O
) O
recommendations O
, O
and O
their O
current O
statin O
use O
, O
factors O
associated O
with O
goal O
achievement O
, O
and O
changes O
in O
the O
proportion O
achieving O
goals O
between O
1988 O
and O
2010 O
. O
RESEARCH O
AND O
DESIGN O
METHODSData O
were O
cross O
- O
sectional O
from O
the O
National O
Health O
and O
Nutrition O
Examination O
Surveys O
( O
NHANES O
) O
from O
1988 O
- O
1994 O
, O
1999 O
- O
2002 O
, O
2003 O
- O
2006 O
, O
and O
2007 O

- O
2010 O
. O

Participants O
were O
4 O
, O
926 O
adults O
aged O
> O
= O
20 O
years O
who O
self O
- O
reported O
a O
previous O
diagnosis O
of O
diabetes O
and O
completed O
the O
household O
interview O
and O
physical O
examination O
( O
n O
= O
1 O
, O
558 O
for O
valid O
LDL O
levels O
) O
. O

Main O
outcome O
measures O
were O
A1C O
, O
BP O
, O
and O
LDL O
cholesterol B
, O
in O
accordance O
with O
the O
American O
Diabetes O
Association O
recommendations O
, O
and O
current O
use O
of O
statins O
. O
RESULTSIn O
2007 O
- O
2010 O
, O
52 O
. O
5 O
% O
of O
people O
with O
diabetes O
achieved O
A1C O
< O
7 O
. O
0 O
% O
( O
< O
53 O
mmol O
/ O
mol O
) O
, O
51 O
. O
1 O
% O
achieved O
BP O
< O
130 O
/ O
80 O
mmHg O
, O
56 O
. O
2 O
% O
achieved O
LDL O
< O
100 O
mg O
/ O
dL O
, O
and O
18 O
. O
8 O
% O
achieved O
all O
three O
ABCs O
. O

These O
levels O
of O
control O
were O
significant O
improvements O
from O
1988 O
to O
1994 O
( O
all O
P O
< O
0 O
. O
05 O
) O
. O

Statin O
use O
significantly O
increased O
between O
1988 O
- O
1994 O
( O
4 O
. O
2 O
% O
) O
and O
2007 O
- O
2010 O
( O
51 O
. O
4 O
% O
, O
P O
< O
0 O
. O
01 O
) O
. O

Compared O
with O
non O
- O
Hispanic O
whites O
, O
Mexican O
Americans O
were O
less O
likely O
to O
meet O
A1C O
and O
LDL O
goals O
( O
P O
< O
0 O
. O
03 O
) O
, O
and O
non O
- O
Hispanic O
blacks O
were O
less O
likely O
to O
meet O
BP O
and O
LDL O
goals O
( O
P O
< O
0 O
. O
02 O
) O
. O

Compared O
with O
non O
- O
Hispanic O
blacks O
, O
Mexican O
Americans O
were O
less O
likely O
to O
meet O
A1C O
goals O
( O
P O
< O
0 O
. O
01 O
) O
. O

Younger O
individuals O
were O
less O
likely O
to O
meet O
A1C O
and O
LDL O
goals O
. O
CONCLUSIONSDespite O
significant O
improvement O
during O
the O
past O
decade O
, O
achieving O
the O
ABC O
goals O
remains O
suboptimal O
among O
adults O
with O
diabetes O
, O
particularly O
in O
some O
minority O
groups O
. O

Substantial O
opportunity O
exists O
to O
further O
improve O
diabetes O
control O
and O
, O
thus O
, O
to O
reduce O
diabetes O
- O
related O
morbidity O
and O
mortality O
. O

Simultaneous O
determination O
of O
evodiamine B
and O
evodine B
in O
Beagle O
dog O
plasma O
using O
liquid O
chromatography O
tandem O
mass O
spectrometry O
. O

A O
sensitive O
, O
rapid O
, O
and O
specific O
liquid O
chromatography O
/ O
tandem O
mass O
spectrometry O
assay O
has O
been O
established O
and O
validated O
for O
the O
quantitation O
of O
evodiamine B
and O
evodine B
in O
Beagle O
dog O
plasma O
. O

Plasma O
samples O
of O
0 O
. O
2 O
ml O
were O
processed O
by O
liquid O
- O
liquid O
extraction O
with O
n B
- I
hexane I
/ O
ethyl B
acetate I
( O
2 O
: O
1 O
, O
v O
/ O
v O
) O
. O

Chromatographic O
separations O
were O
done O
on O
a O
Symmetry O
C O
( O
18 O
) O
column O
( O
100 O
mm O
x O
4 O
. O
6 O
mm O
, O
ID O
, O
5 O
mu O
m O
) O
at O
35 O
degrees O
C O
with O
a O
linear O
gradient O
of O
methanol B
and O
20 O
mM O
ammonium B
formate I
containing O
0 O
. O
2 O
% O
formic B
acid I
. O

Evodiamine B
, O
evodine B
, O
and O
glibenclamide B
[ O
internal O
standard O
( O
IS O
) O
] O
were O
ionized O
with O
an O
electrospray O
ionization O
source O
operated O
in O
positive O
ion O
mode O
. O

The O
MS O
/ O
MS O
transitions O
were O
m O
/ O
z O
304 O
. O
1 O
- O
- O
> O
161 O
. O
1 O
for O
evodiamine B
, O
m O
/ O
z O
471 O
. O
2 O
- O
- O
> O
425 O
. O
1 O
for O
evodine B
, O
and O
m O
/ O
z O
494 O
. O
1 O
- O
- O
> O
369 O
. O
1 O
for O
IS O
. O

Calibration O
curves O
were O
linear O
over O
the O
concentration O
range O
of O
0 O
. O
1 O
- O
100 O
ng O
/ O
ml O
for O
evodiamine B
and O
0 O
. O
5 O
- O
500 O
ng O
/ O
ml O
for O
evodine B
. O

The O
mean O
extraction O
recoveries O
were O
88 O
. O
10 O
+ O
/ O
- O
3 O
. O
21 O
% O
for O
evodiamine B
and O
81 O
. O
24 O
+ O
/ O
- O
4 O
. O
07 O
% O
for O
evodine B
. O

The O
intra O
- O
and O
inter O
- O
day O
precisions O
were O
less O
than O
11 O
. O
10 O
% O
and O
12 O
. O
81 O
% O
, O
and O
the O
accuracy O
was O
within O
+ O
/ O
- O
11 O
. O
76 O
% O
for O
both O
analytes O
. O

Evodiamine B
and O
evodine B
were O
stable O
during O
storage O
and O
analytical O
periods O
. O

The O
validated O
method O
has O
been O
successfully O
applied O
to O
a O
pharmacokinetic O
study O
of O
evodiamine B
and O
evodine B
in O
beagle O
dogs O
after O
oral O
administration O
. O

New O
alkaloid O
from O
Streptomyces O
koyangensis O
residing O
in O
Odontotermes O
formosanus O
. O

A O
new O
alkaloid O
was O
isolated O
from O
the O
ethyl B
acetate I
extract O
of O
the O
culture O
of O
a O
termite O
- O
associated O
Streptomyces O
koyangensis O
BY O
- O
4 O
. O

The O
structure O
of O
1 O
was O
elucidated O
by O
using O
MS O
, O
NMR O
, O
electronic O
circular O
dichroism O
data O
, O
and O
computational O
approaches O
. O

Compound O
1 O
showed O
weak O
antimicrobial O
activities O
against O
a O
panel O
of O
test O
microbes O
. O

Two O
new O
triterpenoids B
from O
the O
fungus O
Perenniporia O
maackiae O
. O

Two O
new O
triterpenoids B
, O
3 B
beta I
- I
( I
2 I
- I
methoxy I
- I
oxalyloxy I
) I
- I
24 I
- I
methylene I
- I
lanost I
- I
8 I
- I
en I
- I
21 I
- I
oic I
acid I
( O
1 O
) O
and O
3 B
beta I
- I
( I
2 I
- I
methoxy I
- I
oxalyloxy I
) I
- I
15 I
alpha I
- I
hydroxy I
- I
24 I
- I
methylene I
- I
lanost I
- I
8 I
- I
en I
- I
21 I
- I
oic I
acid I
( O
2 O
) O
, O
were O
isolated O
from O
cultures O
of O
the O
fungus O
Perenniporia O
maackiae O
, O
together O
with O
two O
previously O
known O
triterpenoids B
( O
3 O
and O
4 O
) O

. O

Their O
structures O
were O
determined O
by O
spectroscopic O
methods O
, O
including O
1D O
and O
2D O
NMR O
, O
and O
MS O
analyses O
. O

All O
compounds O
were O
evaluated O
for O
their O
cytotoxic O
activities O
on O
five O
tumor O
cell O
lines O
. O

Three O
new O
norlignans B
from O
Glechoma O
longituba O
. O

Three O
new O
norlignans B
, O
glechomols B
A I
- I
C I
( O
1 O
- O
3 O
, O
respectively O
) O
, O
together O
with O
a O
known O
compound O
, O
4 B
- I
ethylcatechol I
( O
4 O
) O
, O
were O
isolated O
from O
the O
ethyl B
acetate I
extract O
of O
Glechoma O
longituba O
( O
NaKai O
) O
Kupr O
. O

Their O
structures O
were O
elucidated O
by O
the O
detailed O
analysis O
of O
1D O
and O
2D O
NMR O
and O
HR O
- O
MS O
data O
. O

Glechomols B
A I
- I
C I
were O
the O
first O
norlignans B
reported O
from O
genus O
Glechoma O
, O
and O
compound O
4 O
was O
also O
isolated O
from O
genus O
Glechoma O
for O
the O
first O
time O
. O

Intracellular O
antioxidant O
assays O
showed O
that O
compounds O
1 O
- O
4 O
displayed O
significant O
protective O
effects O
on O
H B
( I
2 I
) I
O I
( I
2 I
) I
- O
induced O
cardiac O
cell O
injury O
. O

Heterogeneous O
vapor O
bubble O
nucleation O
on O
a O
rough O
surface O
. O

Vapor O
bubble O
nucleation O
on O
a O
microrough O
surface O
wetted O
by O
a O
volatile O
, O
incompressible O
liquid O
has O
been O
analyzed O
. O

The O
work O
of O
formation O
of O
a O
critical O
nucleus O
in O
a O
surface O
cavity O
has O
been O
evaluated O
. O

Concave O
sites O
of O
a O
surface O
with O
negative O
curvature O
can O
decrease O
the O
height O
of O
the O
activation O
barrier O
for O
the O
formation O
of O
a O
critical O
nucleus O
. O

The O
average O
density O
of O
the O
nucleation O
sites O
has O
been O
evaluated O
for O
a O
surface O
whose O
( O
small O
) O
deviation O
from O
a O
plane O
is O
specified O
by O
a O
Gaussian O
random O
function O
. O

Charge O
screening O
between O
anionic O
and O
cationic O
surfactants O
in O
ionic O
liquids O
. O

The O
aggregation O
and O
interfacial O
behavior O
of O
mixtures O
of O
anionic O
( O
sodium B
dodecylsulfate I
, O
SDS B
) O
and O
cationic O
( O
dodecylammonium B
bromide I
, O
DTAB B
) O
surfactants O
were O
investigated O
. O

A O
room O
- O
temperature O
ionic O
liquid O
( O
IL O
) O
was O
explored O
as O
a O
solvent O
for O
the O
SDS B
/ O
DTAB B
system O
and O
compared O
to O
water O
. O

The O
critical O
micelle O
concentration O
( O
cmc O
) O
and O
composition O
in O
mixed O
micelles O
were O
determined O
for O
both O
solvents O
. O

Our O
experiments O
showed O
nearly O
ideal O
mixing O
of O
SDS B
/ O
DTAB B
over O
the O
entire O
composition O
range O
and O
suggest O
that O
charge O
screening O
is O
prominent O
in O
ILs O
. O

This O
behavior O
is O
in O
sharp O
contrast O
to O
the O
strong O
electrostatic O
attraction O
and O
a O
multiphase O
composition O
gap O
in O
water O
. O

Two O
models O
by O
Clint O
and O
Rubingh O
, O
which O
describe O
ideal O
and O
nonideal O
micellar O
behavior O
, O
respectively O
, O
are O
discussed O
on O
the O
basis O
of O
our O
results O
. O

According O
to O
Rubingh O
' O
s O
model O
, O
the O
composition O
of O
mixed O
micelles O
is O
gradually O
changing O
with O
the O
bulk O
composition O
in O
ILs O
but O
tends O
to O
be O
a O
1 O
: O
1 O
ratio O
in O
water O
. O

The O
results O
here O
are O
further O
support O
of O
the O
strong O
charge O
screening O
in O
ionic O
liquids O
. O

Synthesis O
and O
characterization O
of O
hybrid O
hyaluronic O
Acid O
- O
gelatin O
hydrogels O
. O

Biomimetic O
hybrid O
hydrogels O
have O
generated O
broad O
interest O
in O
tissue O
engineering O
and O
regenerative O
medicine O
. O

Hyaluronic O
acid O
( O
HA O
) O
and O
gelatin O
( O
hydrolyzed O
collagen O
) O
are O
naturally O
derived O
polymers O
and O
biodegradable O
under O
physiological O
conditions O
. O

Moreover O
, O
collagen O
and O
HA O
are O
major O
components O
of O
the O
extracellular O
matrix O
( O
ECM O
) O
in O
most O
of O
the O
tissues O
( O
e O
. O
g O
. O
, O
cardiovascular O
, O
cartilage O
, O
neural O
) O
. O

When O
used O
as O
a O
hybrid O
material O
, O
HA O
- O
gelatin O
hydrogels O
may O
enable O
mimicking O
the O
ECM O
of O
native O
tissues O
. O

Although O
HA O
- O
gelatin O
hybrid O
hydrogels O
are O
promising O
biomimetic O
substrates O
, O
their O
material O
properties O
have O
not O
been O
thoroughly O
characterized O
in O
the O
literature O
. O

Herein O
, O
we O
generated O
hybrid O
hydrogels O
with O
tunable O
physical O
and O
biological O
properties O
by O
using O
different O
concentrations O
of O
HA O
and O
gelatin O
. O

The O
physical O
properties O
of O
the O
fabricated O
hydrogels O
including O
swelling O
ratio O
, O
degradation O
, O
and O
mechanical O
properties O
were O
investigated O
. O

In O
addition O
, O
in O
vitro O
cellular O
responses O
in O
both O
two O
and O
three O
- O
dimensional O
culture O
conditions O
were O
assessed O
. O

It O
was O
found O
that O
the O
addition O
of O
gelatin O
methacrylate B
( O
GelMA O
) O
into O
HA O
methacrylate B
( O
HAMA O
) O
promoted O
cell O
spreading O
in O
the O
hybrid O
hydogels O
. O

Moreover O
, O
the O
hybrid O
hydrogels O
showed O
significantly O
improved O
mechanical O
properties O
compared O
to O
their O
single O
component O
analogs O
. O

The O
HAMA O
- O
GelMA O
hydrogels O
exhibited O
remarkable O
tunability O
behavior O
and O
may O
be O
useful O
for O
cardiovascular O
tissue O
engineering O
applications O
. O

Laponite B
nanodisks O
as O
an O
efficient O
platform O
for O
Doxorubicin B
delivery O
to O
cancer O
cells O
. O

We O
report O
a O
facile O
approach O
to O
using O
laponite B
( O
LAP B
) O
nanodisks O
as O
a O
platform O
for O
efficient O
delivery O
of O
doxorubicin B
( O
DOX B
) O
to O
cancer O
cells O
. O

In O
this O
study O
, O
DOX B
was O
encapsulated O
into O
the O
interlayer O
space O
of O
LAP O
through O
an O
ionic O
exchange O
process O
with O
an O
exceptionally O
high O
loading O
efficiency O
of O
98 O
. O
3 O
+ O
/ O
- O
0 O
. O
77 O
% O
. O

The O
successful O
DOX B
loading O
was O
extensively O
characterized O
via O
different O
methods O
. O

In O
vitro O
drug O
release O
study O
shows O
that O
the O
release O
of O
DOX B
from O
LAP O
/ O
DOX B
nanodisks O
is O
pH O
- O
dependent O
, O
and O
DOX B
is O
released O
at O
a O
quicker O
rate O
at O
acidic O
pH O
condition O
( O
pH O
= O
5 O
. O
4 O
) O
than O
at O
physiological O
pH O
condition O
. O

Importantly O
, O
cell O
viability O
assay O
results O
reveal O
that O
LAP O
/ O
DOX B
nanodisks O
display O
a O
much O
higher O
therapeutic O
efficacy O
in O
inhibiting O
the O
growth O
of O
a O
model O
cancer O
cell O
line O
( O
human O
epithelial O
carcinoma O
cells O
, O
KB O
cells O
) O
than O
free O
DOX B
drug O
at O
the O
same O
DOX B
concentration O
. O

The O
enhanced O
antitumor O
efficacy O
is O
primarily O
due O
to O
the O
much O
more O
cellular O
uptake O
of O
the O
LAP O
/ O
DOX B
nanodisks O
than O
that O
of O
free O
DOX B
, O
which O
has O
been O
confirmed O
by O
confocal O
laser O
scanning O
microscope O
and O
flow O
cytometry O
analysis O
. O

The O
high O
DOX B
payload O
and O
enhanced O
antitumor O
efficacy O
render O
LAP O
nanodisks O
as O
a O
robust O
carrier O
system O
for O
different O
biomedical O
applications O
. O

Danshen O
mediates O
through O
estrogen B
receptors O
to O
activate O
Akt O
and O
inhibit O
apoptosis O
effect O
of O
Leu27IGF O
- O
II O
- O
induced O
IGF O
- O
II O
receptor O
signaling O
activation O
in O
cardiomyoblasts O
. O

Post O
- O
menopausal O
women O
show O
dramatically O
increased O
cardiovascular O
disease O
morbidity O
( O
CVD O
) O
. O

Danshen O
is O
used O
widely O
in O
China O
for O
the O
treatment O
of O
cardiovascular O
disorders O
, O
including O
coronary O
heart O
disease O
. O

Danshen O
possesses O
lipid O
- O
soluble O
biologically O
active O
components O
with O
a O
structure O
similar O
to O
17 B
beta I
- I
estrodiol I
( O
E2 O
) O
. O

This O
study O
assesses O
whether O
the O
cardio O
- O
protection O
exerted O
by O
Danshen O
is O
mediated O
through O
the O
ERs O
within O
H9c2 O
cardiomyoblast O
cells O
. O

Cardiomyoblast O
cells O
pretreated O
with O
Fulvestrant B
( O
ICI B
182 I
, I
780 I
) O
, O
an O
estrogen B
receptor O
antagonist O
was O
applied O
to O
investigate O
the O
estrogenic O
activity O
of O
Danshen O
. O

The O
Danshen O
extract O
preventive O
effects O
on O
Leu27IGF O
- O
II O
- O
induced O
IGF O
- O
IIR O
signaling O
activator O
and O
H9c2 O
cell O
apoptosis O
were O
identified O
using O
TUNEL O
assay O
, O
JC O
- O
1 O
staining O
and O
Western O
blot O
assay O
. O

We O
found O
that O
Danshen O
extract O
treatments O
significantly O
enhanced O
phosphorylated O
Akt O
through O
estrogen B
receptor O
activation O
to O
inhibit O
Leu27IGF O
- O
II O
- O
induced O
calcineurin O
activation O
and O
block O
H9c2 O
cell O
apoptosis O
. O

Danshen O
extracts O
suppressed O
the O
IGF O
- O
IIR O
signaling O
proteins O
, O
pro O
- O
apoptotic O
proteins O
and O
reversed O
the O
mitochondrial O
membrane O
instability O
induced O
by O
Leu27IGF O
- O
II O
. O

However O
, O
the O
cardioprotective O
properties O
of O
Danshen O
to O
inhibit O
Leu27IGF O
- O
II O
- O
induced O
cell O
apoptosis O
and O
promote O
cell O
survival O
were O
attenuated O
by O
applying O
ICI B
, O
which O
suggests O
that O
the O
Danshen O
cardioprotective O
effect O
is O
mediated O
through O
estrogen B
receptors O
. O

All O
our O
data O
indicated O
that O
Danshen O
exerts O
strong O
estrogenic O
activity O
which O
can O
be O
considered O
a O
novel O
selective O
estrogen B
receptor O
modulator O
( O
SERM O
) O
against O
IGF2R O
signaling O
that O
blocks O
cardiac O
apoptosis O
. O

Approach O
to O
distribution O
and O
accumulation O
of O
dibutyl B
phthalate I
in O
rats O
by O
immunoassay O
. O

Dibutyl B
phthalate I
( O
DBP B
) O
is O
mainly O
taken O
up O
by O
the O
general O
population O
from O
food O
intake O
. O

To O
estimate O
intake O
of O
phthalates B
, O
determining O
distribution O
and O
accumulation O
of O
DBP B
in O
biological O
materials O
was O
a O
critical O
need O
. O

In O
this O
work O
, O
we O
set O
up O
two O
novel O
approaches O
with O
a O
monoclonal O
antibody O
specific O
to O
DBP O
to O
determine O
the O
distribution O
and O
accumulation O
of O
DBP O
in O
vivo O
. O

The O
contents O
of O
DBP O
in O
liver O
, O
kidney O
, O
stomach O
and O
testes O
were O
detected O
by O
immunofluorescence O
assays O
and O
indirect O
competitive O
ELISA O
. O

This O
data O
give O
directly O
evidence O
that O
indicates O
the O
distribution O
and O
accumulation O
of O
DBP O
in O
vivo O
. O

Double O
- O
label O
immunofluorescence O
assay O
provides O
with O
a O
visual O
approach O
to O
determination O
of O
the O
distribution O
and O
accumulation O
of O
DBP O
. O

It O
indicated O
that O
DBP B
accumulated O
in O
subcutaneous O
tissue O
such O
as O
sweat O
gland O
, O
hair O
follicle O
. O

Both O
of O
immunofluorescence O
assay O
and O
ELISA O
can O
be O
used O
to O
detect O
the O
content O
of O
DBP O
in O
biological O
materials O
. O

Our O
assays O
showed O
that O
DBP B
accumulated O
in O
viscera O
being O
rich O
in O
fat O
, O
such O
as O
liver O
, O
kidney O
and O
could O
overcome O
physiological O
barriers O
to O
penetrate O
testes O
. O

The O
date O
suggested O
that O
the O
accumulations O
of O
DBP B
exposed O
through O
dermal O
route O
were O
less O
than O
that O
of O
oral O
route O
and O
most O
of O
DBP B
was O
metabolized O
in O
2 O
or O
3days O
. O

Integrating O
clinical O
pharmacology O
concepts O
in O
individualized O
therapy O
with O
tyrosine B
kinase O
inhibitors O
. O

Tyrosine B
kinases O
have O
emerged O
as O
important O
tumor O
targets O
for O
the O
design O
of O
potent O
and O
selective O
inhibitors O
. O

Eighteen O
of O
these O
tyrosine B
kinase O
inhibitors O
( O
TKIs O
) O
have O
already O
been O
approved O
for O
the O
treatment O
of O
diseases O
that O
were O
previously O
essentially O
resistant O
to O
standard O
chemotherapy O
. O

Major O
efforts O
are O
ongoing O
that O
focus O
on O
the O
development O
of O
companion O
diagnostics O
for O
investigational O
and O
approved O
TKIs O
, O
as O
well O
as O
on O
integrating O
clinical O
pharmacology O
principles O
in O
clinical O
practice O
to O
decrease O
toxicity O
and O
improve O
efficacy O
. O

The O
state O
of O
clinical O
pharmacology O
today O
. O

It O
has O
been O
more O
than O
40 O
years O
since O
a O
major O
position O
paper O
on O
clinical O
pharmacology O
was O
published O
by O
the O
World O
Health O
Organization O
( O
WHO O
) O
. O

A O
recent O
publication O
, O
Clinical O
Pharmacology O
in O
Health O
Care O
, O
Teaching O
, O
and O
Research O
, O
provides O
a O
current O
vision O
of O
the O
discipline O
suitable O
for O
the O
twenty O
- O
first O
century O
. O

Uptake O
, O
retention O
and O
internalization O
of O
quantum O
dots O
in O
Daphnia O
is O
influenced O
by O
particle O
surface O
functionalization O
. O

Nanomaterials O
are O
a O
diverse O
group O
of O
compounds O
whose O
inevitable O
release O
into O
the O
environment O
warrants O
study O
of O
the O
fundamental O
processes O
that O
govern O
the O
ingestion O
, O
uptake O
and O
accumulation O
in O
aquatic O
organisms O
. O

Nanomaterials O
have O
the O
ability O
to O
transfer O
to O
higher O
trophic O
levels O
in O
aquatic O
ecosystems O
, O
and O
recent O
evidence O
suggests O
that O
the O
surface O
chemistry O
of O
both O
the O
nanoparticle O
and O
biological O
membrane O
can O
influence O
uptake O
kinetics O
. O

Therefore O
, O
our O
study O
investigates O
the O
effect O
of O
surface O
functionalization O
on O
uptake O
, O
internalization O
and O
depuration O
in O
Daphnia O
spp O
. O

Uncharged O
( O
polyethylene B
glycol I
; O
PEG B
) O
, O
positively O
charged O
( O
amino B
- O
terminated O
: O
NH2 B
) O
and O
negatively O
charged O
( O
carboxyl B
- O
modified O
; O
COOH B
) O
cadmium B
selenide I
/ O
zinc B
sulfide I
quantum O
dots O
were O
used O
to O
monitor O
ingestion O
, O
uptake O
and O
depuration O
of O
nanometals O
in O
Daphnia O
magna O
and O
Ceriodaphnia O
dubia O
over O
24h O
of O
exposure O
. O

These O
studies O
demonstrated O
that O
particles O
with O
higher O
negative O
charge O
( O
COOH B
quantum O
dots O
) O
were O
taken O
up O
to O
a O
greater O
extent O
by O
Daphnia O
( O
259 O
. O
17 O
+ O
/ O
- O
17 O
. O
70 O
RFU O
/ O
20 O
Daphnia O
) O
than O
either O
the O
NH2 B
( O
150 O
. O
01 O
+ O
/ O
- O
18 O
. O
91 O
) O
or O
PEG B
quantum O
dots O
( O
95 O
. O
17 O
+ O
/ O
- O
9 O
. O
78 O
) O
, O
however O
this O
is O
likely O
related O
to O
the O
functional O
groups O
attached O
to O
the O
nanoparticles O
as O
there O
were O
no O
real O
differences O
in O
zeta O
potential O
. O

Whole O
body O
fluorescence O
associates O
well O
with O
fluorescent O
microscopic O
images O
obtained O
at O
the O
24h O
timepoint O
. O

Confocal O
and O
electron O
microscopic O
analysis O
clearly O
demonstrated O
that O
all O
three O
types O
of O
quantum O
dots O
could O
cross O
the O
intestinal O
epithelial O
barrier O
and O
be O
translocated O
to O
other O
cells O
. O

Upon O
cessation O
of O
exposure O
, O
elimination O
of O
all O
three O
materials O
was O
biphasic O
with O
rapid O
initial O
clearance O
that O
likely O
represents O
elimination O
of O
material O
remaining O
in O
the O
GI O
tract O
followed O
by O
a O
much O
slower O
elimination O
phase O
that O
likely O
represents O
elimination O
of O
internalized O
material O
. O

These O
studies O
demonstrate O
that O
daphnids O
can O
take O
up O
intact O
nanomaterial O
from O
the O
water O
column O
and O
that O
this O
uptake O
is O
strongly O
influenced O
by O
particle O
surface O
functionalization O
. O

In O
addition O
, O
the O
usefulness O
of O
using O
quantum O
dots O
as O
a O
proxy O
for O
other O
nanometals O
( O
no O
acute O
toxicity O
, O
clear O
visualization O
in O
electron O
microscopy O
) O
, O
in O
conjunction O
with O
several O
different O
imaging O
techniques O
in O
assessing O
uptake O
and O
accumulation O
of O
nanoparticles O
in O
daphnids O
was O
demonstrated O
. O

A O
kavalactone B
derivative O
inhibits O
lipopolysaccharide O
- O
stimulated O
iNOS O
induction O
and O
NO B
production O
through O
activation O
of O
Nrf2 O
signaling O
in O
BV2 O
microglial O
cells O
. O

Neuroinflammation O
and O
oxidative O
stress O
are O
involved O
in O
the O
pathogenesis O
of O
neurodegenerative O
diseases O
such O
as O
Alzheimer O
' O
s O
diseases O
and O
Parkinson O
' O
s O
disease O
. O

Naturally O
derived O
kavalactones B
isolated O
from O
Piper O
methysticum O
( O
Piperaceae O
) O
have O
been O
shown O
to O
exhibit O
neuroprotective O
effects O
. O

We O
have O
previously O
reported O
that O
a O
chemically O
synthesized O
kavalactone B
derivative O
, O
2 B
' I
, I
6 I
' I
- I
dichloro I
- I
5 I
- I
methoxymethyl I
- I
5 I
, I
6 I
- I
dehydrokawain I
( O
compound O
1 O
) O
protects O
against O
oxidative O
stress O
- O
induced O
neuronal O
cell O
death O
through O
activation O
of O
Nrf2 O
signaling O
. O

In O
the O
present O
study O
, O
we O
examined O
the O
effect O
of O
compound O
1 O
on O
neuroinflammation O
. O

In O
BV2 O
microglial O
cells O
, O
compound O
1 O
strongly O
inhibited O
LPS O
- O
stimulated O
iNOS O
induction O
and O
NO B
production O
, O
but O
did O
not O
affect O
LPS O
- O
stimulated O
induction O
of O
COX2 O
. O

At O
6h O
after O
LPS O
challenge O
, O
when O
iNOS O
induction O
was O
not O
clearly O
seen O
, O
treatment O
with O
LPS O
or O
compound O
1 O
alone O
increased O
expression O
of O
heme O
oxygenase O
1 O
( O
HO O
- O
1 O
) O
whose O
transcription O
is O
regulated O
by O
Nrf2 O
. O

When O
treated O
with O
both O
, O
compound O
1 O
enhanced O
LPS O
- O
stimulated O
HO O
- O
1 O
induction O
, O
which O
was O
more O
evident O
at O
24h O
after O
LPS O
treatment O
. O

Furthermore O
, O
LPS O
- O
stimulated O
activation O
of O
Nrf2 O
signaling O
and O
nuclear O
translocation O
of O
Nrf2 O
were O
potentiated O
by O
compound O
1 O
. O

The O
mechanism O
by O
which O
compound O
1 O
activated O
Nrf2 O
signaling O
was O
supposed O
to O
be O
a O
covalent O
modification O
of O
the O
sulfhydryl B
groups O
of O
Keap1 O
by O
an O
alpha B
, I
beta I
- I
unsaturated I
carbonyl I
group O
present O
in O
the O
compound O
1 O
. O

Treatment O
with O
hemin B
, O
a O
HO O
- O
1 O
inducer O
, O
and O
with O
[ B
Ru I
( I
CO I
) I
3Cl2 I
] I
2 I
, O
a O
CO B
donor O
, O
decreased O
LPS O
- O
stimulated O
iNOS O
induction O
and O
NO B
production O
. O

In O
contrast O
, O
siRNA O
- O
mediated O
knockdown O
of O
HO O
- O
1 O
expression O
reduced O
the O
inhibitory O
effect O
of O
compound O
1 O
on O
LPS O
- O
stimulated O
iNOS O
induction O
and O
NO B
production O
. O

The O
compound O
1 O
inhibited O
LPS O
- O
stimulated O
ERK O
phosphorylation O
after O
LPS O
treatment O
. O

Finally O
, O
compound O
1 O
suppressed O
LPS O
/ O
IFN O
- O
gamma O
- O
stimulated O
NO B
production O
in O
primary O
microglial O
cells O
. O

These O
results O
suggest O
that O
compound O
1 O
is O
capable O
of O
inhibiting O
LPS O
- O
stimulated O
iNOS O
induction O
and O
NO B
production O
via O
activation O
of O
Nrf2 O
signaling O
and O
HO O
- O
1 O
induction O
in O
microglial O
cells O
. O

Taken O
together O
, O
compound O
1 O
has O
a O
potential O
to O
reduce O
neuroinflammation O
as O
well O
as O
oxidative O
stress O
in O
neurodegenerative O
diseases O
through O
activation O
of O
Nrf2 O
signaling O
. O

The O
protein O
corona O
mediates O
the O
impact O
of O
nanomaterials O
and O
slows O
amyloid O
beta O
fibrillation O
. O

Put O
your O
coat O
on O
: O
It O
is O
well O
recognized O
that O
the O
surfaces O
of O
nanomaterials O
in O
biological O
media O
are O
covered O
by O
various O
biomolecules O
( O
e O
. O
g O
. O
, O
proteins O
) O
. O

A O
) O
The O
protein O
corona O
creates O
a O
shell O
over O
different O
nanomaterials O
, O
regardless O
of O
their O
physicochemical O
properties O
( O
e O
. O
g O
. O
, O
composition O
and O
shape O
) O
, O
resulting O
in O
reduced O
levels O
of O
amyloid O
beta O
fibril O
formation O
. O

B O
) O
Pristine O
nanomaterials O
might O
have O
acceleratory O
effects O
on O
the O
fibrillation O
of O
amyloid O
beta O
. O

Effects O
of O
phosphate B
buffer O
in O
parenteral O
drugs O
on O
particle O
formation O
from O
glass O
vials O
. O

The O
characteristics O
of O
inorganic O
particles O
generated O
in O
glass O
vials O
filled O
with O
phosphate B
buffer O
solutions O
were O
investigated O
. O

During O
storage O
, O
particles O
were O
visually O
detected O
in O
the O
phosphate B
buffer O
solution O
in O
particular O
glass O
vials O
which O
pass O
compendial O
tests O
of O
containers O
for O
injectable O
drugs O
. O

These O
particles O
were O
considered O
to O
be O
different O
from O
ordinal O
glass O
delamination O
, O
which O
has O
been O
reported O
in O
a O
number O
of O
papers O
because O
the O
particles O
were O
mainly O
composed O
of O
Al B
, O
P B
and O
O B
, O
but O
not O
Si B
. O

The O
formation O
of O
the O
particles O
accelerated O
at O
higher O
storage O
temperatures O
. O

Among O
the O
surface O
treatments O
tested O
for O
the O
glass O
vials O
, O
sulfur B
treatment O
showed O
a O
protective O
effect O
on O
the O
particle O
formation O
in O
the O
vials O
, O
whereas O
the O
SiO2 B
coating O
did O
not O
have O
any O
protective O
effects O
. O

It O
was O
found O
that O
the O
elution O
ratio O
of O
Al B
and O
Si B
in O
the O
solution O
stored O
in O
the O
glass O
vials O
after O
the O
heating O
was O
similar O
to O
the O
ratio O
of O
Al B
and O
Si B
in O
borosilicate B
glass O
. O

However O
, O
the O
Al B
concentration O
decreased O
during O
storage O
( O
5 O
degrees O
C O
, O
6 O
months O
) O
, O
and O
consequently O
, O
particle O
formation O
was O
observed O
in O
the O
solution O
. O

Adding O
citrate B
, O
which O
is O
a O
chelating O
agent O
for O
Al B
, O
effectively O
suppressed O
the O
particle O
formation O
in O
the O
heated O
solution O
. O

When O
50 O
ppb O
and O
higher O
concentrations O
of O
Al B
ion O
were O
added O
to O
the O
phosphate B
buffer O
solution O
, O
the O
formation O
of O
white O
particles O
containing O
Al B
, O
P B
and O
O B
was O
detected O
. O

It O
is O
suggested O
that O
a O
phosphate B
buffer O
solution O
in O
a O
borosilicate B
glass O
vial O
has O
the O
ability O
to O
form O
particles O
due O
to O
interactions O
with O
the O
Al B
that O
is O
eluted O
from O
the O
glass O
during O
storage O
. O

Microengineered O
PEG B
Hydrogels O
: O
3D O
Scaffolds O
for O
Guided O
Cell O
Growth O
. O

Designing O
three O
- O
dimensional O
( O
3D O
) O
scaffolds O
for O
selective O
manipulation O
of O
cell O
growth O
is O
of O
high O
relevance O
for O
applications O
in O
regenerative O
medicine O
. O

Especially O
, O
scaffolds O
with O
oriented O
morphologies O
bear O
high O
potential O
to O
guide O
the O
restoration O
of O
specific O
tissues O
. O

The O
fabrication O
of O
hydrogel O
scaffolds O
that O
support O
long O
- O
term O
survival O
, O
proliferation O
, O
and O
unidirectional O
growth O
of O
embedded O
cells O
is O
presented O
here O
. O

Parallel O
channel O
structures O
are O
introduced O
into O
the O
bulk O
hydrogels O
by O
uniaxial O
freezing O
, O
providing O
stable O
, O
and O
uniform O
porosity O
suitable O
for O
cell O
invasion O
( O
pore O
diameters O
of O
5 O
- O
15 O
micro O
m O
) O
. O

In O
vitro O
assessment O
of O
the O
scaffolds O
with O
murine O
fibroblasts O
( O
NIH O
L929 O
) O
shows O
a O
remarkable O
unidirectional O
movement O
along O
the O
channels O
, O
with O
the O
cells O
traveling O
several O
millimeters O
through O
the O
hydrogel O
. O

Parameterization O
of O
a O
reactive O
force O
field O
using O
a O
monte O
carlo O
algorithm O
. O

Parameterization O
of O
a O
molecular O
dynamics O
force O
field O
is O
essential O
in O
realistically O
modeling O
the O
physicochemical O
processes O
involved O
in O
a O
molecular O
system O
. O

This O
step O
is O
often O
challenging O
when O
the O
equations O
involved O
in O
describing O
the O
force O
field O
are O
complicated O
as O
well O
as O
when O
the O
parameters O
are O
mostly O
empirical O
. O

ReaxFF O
is O
one O
such O
reactive O
force O
field O
which O
uses O
hundreds O
of O
parameters O
to O
describe O
the O
interactions O
between O
atoms O
. O

The O
optimization O
of O
the O
parameters O
in O
ReaxFF O
is O
done O
such O
that O
the O
properties O
predicted O
by O
ReaxFF O
matches O
with O
a O
set O
of O
quantum O
chemical O
or O
experimental O
data O
. O

Usually O
, O
the O
optimization O
of O
the O
parameters O
is O
done O
by O
an O
inefficient O
single O
- O
parameter O
parabolic O
- O
search O
algorithm O
. O

In O
this O
study O
, O
we O
use O
a O
robust O
metropolis O
Monte O
- O
Carlo O
algorithm O
with O
simulated O
annealing O
to O
search O
for O
the O
optimum O
parameters O
for O
the O
ReaxFF O
force O
field O
in O
a O
high O
- O
dimensional O
parameter O
space O
. O

The O
optimization O
is O
done O
against O
a O
set O
of O
quantum O
chemical O
data O
for O
MgSO4 B
hydrates I
. O

The O
optimized O
force O
field O
reproduced O
the O
chemical O
structures O
, O
the O
equations O
of O
state O
, O
and O
the O
water O
binding O
curves O
of O
MgSO4 B
hydrates I
. O

The O
transferability O
test O
of O
the O
ReaxFF O
force O
field O
shows O
the O
extend O
of O
transferability O
for O
a O
particular O
molecular O
system O
. O

This O
study O
points O
out O
that O
the O
ReaxFF O
force O
field O
is O
not O
indefinitely O
transferable O
. O

( O
c O
) O
2013 O
Wiley O
Periodicals O
, O
Inc O
. O

Co O
- O
delivery O
of O
10 B
- I
Hydroxycamptothecin I
with O
Doxorubicin B
Conjugated O
Prodrugs O
for O
Enhanced O
Anticancer O
Efficacy O
. O

Well O
- O
defined O
amphiphilic O
linear O
- O
dendritic O
prodrugs O
( O
MPEG B
- I
b I
- I
PAMAM I
- I
DOX I
) O
are O
synthesized O
by O
conjugating O
doxorubicin B
( O
DOX B
) O
, O
to O
MPEG B
- I
b I
- I
PAMAM I
through O
the O
acid O
- O
labile O
hydrazone B
bond O
. O

The O
amphiphilic O
prodrugs O
form O
self O
- O
assembled O
nanoparticles O
in O
deionized O
water O
and O
encapsulate O
the O
hydrophobic O
anticancer O
drug O
10 B
- I
hydroxycamptothecin I
( O
HCPT B
) O
with O
a O
high O
drug O
loading O
efficiency O
. O

Studies O
on O
drug O
release O
and O
cellular O
uptake O
of O
the O
co O
- O
delivery O
system O
reveal O
that O
both O
drugs O
are O
released O
in O
a O
pH O
- O
dependent O
manner O
and O
effectively O
taken O
up O
by O
MCF O
- O
7 O
cells O
. O

In O
vitro O
methyl B
thiazolyl I
tetrazolium I
( O
MTT B
) O
assays O
and O
drug O
- O
induced O
apoptosis O
tests O
demonstrate O
the O
HCPT B
- O
loaded O
nanoparticles O
suppress O
cancer O
cell O
growth O
more O
efficiently O
than O
the O
MPEG B
- I
b I
- I
PAMAM I
- O
DOX B
prodrugs O
, O
free O
HCPT B
, O
and O
physical O
mixtures O
of O
MPEG B
- I
b I
- I
PAMAM I
- O
DOX B
and O
HCPT B
at O
equivalent O
DOX B
or O
HCPT B
doses O
. O

Rational O
Discovery O
of O
Dengue O
Type O
2 O
Non O
- O
competitive O
Inhibitors O
. O

Various O
works O
have O
been O
carried O
out O
in O
developing O
therapeutics O
against O
dengue O
. O

However O
, O
to O
date O
, O
no O
effective O
vaccine O
or O
anti O
- O
dengue O
agent O
has O
yet O
been O
discovered O
. O

The O
development O
of O
protease O
inhibitors O
is O
considered O
as O
a O
promising O
option O
, O
but O
most O
previous O
works O
have O
involved O
competitive O
inhibition O
. O

In O
this O
study O
, O
we O
focused O
on O
rational O
discovery O
of O
potential O
anti O
- O
dengue O
agents O
based O
on O
non O
- O
competitive O
inhibition O
of O
DEN O
- O
2 O
NS2B O
/ O
NS3 O
protease O
. O

A O
homology O
model O
of O
the O
DEN O
- O
2 O
NS2B O
/ O
NS3 O
protease O
( O
using O
West O
Nile O
Virus O
NS2B O
/ O
NS3 O
protease O
complex O
, O
2FP7 O
, O
as O
the O
template O
) O
was O
used O
as O
the O
target O
and O
pinostrobin B
, O
a O
flavanone B
, O
was O
used O
as O
the O
standard O
ligand O
. O

Virtual O
screening O
was O
performed O
involving O
a O
total O
of O
13 O
, O
341 O
small O
compounds O
, O
with O
the O
backbone O
structures O
of O
chalcone B
, O
flavanone B
and O
flavone B
, O
available O
from O
the O
ZINC O
database O
. O

Ranking O
of O
the O
resulting O
compounds O
yielded O
compounds O
with O
higher O
binding O
affinities O
compared O
to O
the O
standard O
ligand O
. O

Inhibition O
assay O
of O
the O
selected O
top O
ranking O
compounds O
against O
DEN O
- O
2 O
NS2B O
/ O
NS3 O
proteolytic O
activity O
resulted O
in O
significantly O
better O
inhibition O
compared O
to O
the O
standard O
and O
correlated O
well O
with O
in O
silico O
results O
. O

In O
conclusion O
, O
via O
this O
rational O
discovery O
technique O
, O
better O
inhibitors O
were O
identified O
. O

This O
method O
can O
be O
used O
in O
further O
work O
to O
discover O
lead O
compounds O
for O
anti O
- O
dengue O
agents O
. O

( O
c O
) O
2013 O
John O
Wiley O
& O
Sons O
A O
/ O
S O
. O

Potential O
of O
nanocrystalline O
cellulose O
- O
fibrin O
nanocomposites O
for O
artificial O
vascular O
graft O
applications O
. O

The O
potential O
of O
synthesizing O
new O
nanocomposites O
from O
nanocrystalline O
cellulose O
( O
NCC O
) O
and O
fibrin O
for O
small O
- O
diameter O
replacement O
vascular O
graft O
( O
SDRVG O
) O
application O
was O
demonstrated O
. O

Periodate O
oxidation O
of O
NCC O
can O
augment O
reactive O
carbonyl B
groups O
on O
NCC O
and O
facilitate O
its O
cross O
- O
linking O
with O
fibrin O
. O

NCC O
- O
fibrin O
nanocomposites O
were O
synthesized O
, O
composed O
of O
homogeneously O
dispersed O
oxidized O
NCC O
( O
ONCC O
) O
in O
a O
fibrin O
matrix O
, O
with O
fibrin O
providing O
elasticity O
and O
ONCC O
providing O
strength O
. O

The O
maximum O
strength O
and O
elongation O
of O
the O
nanocomposites O
were O
determined O
by O
Atomic O
Force O
Microscopy O
( O
AFM O
) O
and O
compared O
with O
a O
native O
blood O
vessel O
. O

The O
manipulation O
of O
degree O
of O
oxidation O
of O
NCC O
and O
the O
NCC O
- O
to O
- O
fibrin O
ratio O
resulted O
in O
the O
variation O
of O
strength O
and O
elongation O
of O
the O
nanocomposites O
, O
indicating O
that O
the O
nanocomposites O
can O
be O
tailored O
to O
conform O
to O
the O
diverse O
mechanical O
properties O
of O
native O
blood O
vessels O
. O

A O
mechanistic O
understanding O
of O
the O
molecular O
interactions O
of O
ONCC O
and O
fibrin O
was O
illustrated O
. O

This O
study O
established O
fundamental O
information O
to O
utilizing O
NCC O
for O
SDRVG O
applications O
. O

Functional O
interactions O
between O
matrix O
metalloproteinases O
and O
glycosaminoglycans O
. O

Similar O
to O
most O
proteinases O
, O
matrix O
metalloproteinases O
( O
MMP O
) O
do O
not O
recognize O
a O
consensus O
cleavage O
site O
. O

Thus O
, O
it O
is O
not O
surprising O
that O
, O
in O
a O
defined O
in O
vitro O
reaction O
, O
most O
MMPs O
can O
act O
on O
a O
wide O
range O
of O
proteins O
, O
including O
many O
extracellular O
matrix O
proteins O
. O

However O
, O
the O
findings O
obtained O
from O
in O
vivo O
studies O
with O
genetic O
models O
have O
demonstrated O
that O
individual O
MMPs O
act O
on O
just O
a O
few O
extracellular O
protein O
substrates O
, O
typically O
not O
matrix O
proteins O
. O

The O
limited O
, O
precise O
functions O
of O
an O
MMP O
imply O
that O
mechanisms O
have O
evolved O
to O
control O
the O
specificity O
of O
proteinase O
: O
substrate O
interactions O
. O

We O
discuss O
the O
possibility O
that O
interactions O
with O
the O
glycosaminoglycan O
chains O
of O
proteoglycans O
may O
function O
as O
allosteric O
regulators O
or O
accessory O
factors O
directing O
MMP O
catalysis O
to O
specific O
substrates O
. O

We O
propose O
that O
understanding O
how O
the O
activity O
of O
specific O
MMPs O
is O
confined O
to O
discreet O
compartments O
and O
targeted O
to O
defined O
substrates O
via O
interactions O
with O
other O
macromolecules O
may O
provide O
a O
means O
of O
blocking O
potentially O
deleterious O
MMP O
- O
mediated O
processes O
at O
the O
same O
time O
as O
sparing O
any O
beneficial O
functions O
. O

The O
pharmacokinetics O
and O
conversion O
of O
the O
lactone B
to O
the O
carboxylate B
forms O
of O
ginkgolide B
B I
in O
rat O
plasma O
. O

Ginkgolide B
B I
consists O
of O
three O
lactone B
groups O
, O
which O
may O
undergo O
hydrolysis O
, O
and O
lead O
to O
the O
rings O
opening O
in O
aqueous O
solution O
with O
different O
pHs O
. O

From O
mechanisms O
of O
pharmacological O
activity O
in O
vivo O
, O
the O
lactone B
appears O
to O
be O
the O
active O
form O
of O
the O
drug O
. O

Pharmacokinetics O
of O
lactone B
form O
( O
GB O
- O
lac O
) O
and O
the O
total O
of O
the O
lactone B
and O
carboxylate B
form O
( O
GB O
- O
tot O
) O
of O
ginkgolide B
B I
were O
investigated O
after O
intravenous O
administration O
of O
a O
dose O
of O
4 O
mg O
/ O
kg O
ginkgolide B
B I
. O

The O
rate O
of O
lactone B
hydrolysis O
was O
also O
studied O
in O
plasma O
in O
vitro O
. O

After O
intravenous O
administration O
, O
ginkgolide B
B I
in O
the O
original O
form O
was O
converted O
to O
its O
carboxylate B
form O
under O
simulated O
physiological O
conditions O
. O

The O
AUC0 O
- O
infinity O
of O
GB O
- O
lac O
constituted O
63 O
. O
5 O
+ O
/ O
- O
17 O
. O
4 O
% O
of O
the O
AUC0 O
- O
infinity O
of O
GB O
- O
tot O
. O

The O
ratio O
of O
average O
cumulation O
of O
excretion O
of O
lactone B
to O
carboxylate B
reached O
approximately O
1 O
to O
1 O
in O
urine O
. O

From O
the O
equilibrium O
of O
lactone B
hydrolysis O
in O
rat O
plasma O
in O
vitro O
, O
the O
k O
obs O
was O
- O
0 O
. O
0176 O
min O
( O
- O
1 O
) O
and O
t O
1 O
/ O
2 O
was O
39 O
. O
38 O
min O
. O

In O
conclusion O
, O
the O
equilibrium O
existed O
between O
lactone B
of O
ginkgolide B
B I
and O
its O
carboxylate B
form O
in O
vivo O
at O
physiological O
pH O
, O
which O
suggested O
that O
more O
attention O
should O
be O
focused O
on O
the O
original O
and O
the O
ionization O
forms O
of O
ginkgolide B
B I
and O
the O
conversion O
of O
the O
lactone B
into O
carboxylate B
in O
vivo O
. O

Molecular O
orientation O
and O
dynamics O
of O
different O
sized O
organic O
radicals O
included O
in O
organic O
1D O
nanochannels O
. O

The O
molecular O
orientation O
and O
dynamics O
of O
di B
- I
t I
- I
butylnitroxide I
( O
DTBN B
) O
and O
4 B
- I
oxo I
- I
2 I
, I
2 I
, I
6 I
, I
6 I
- I
tetramethyl I
- I
1 I
- I
piperidinyl I
- I
1 I
- I
oxyl I
( O
TEMPONE B
) O
radicals O
in O
the O
organic O
1D O
nanochannels O
of O
tris B
( I
o I
- I
phenylenedioxy I
) I
cyclotriphosphazene I
( O
TPP B
) O
were O
investigated O
by O
examining O
inclusion O
compounds O
( O
ICs O
) O
diluted O
by O
the O
co O
- O
inclusion O
of O
nonradicals O
using O
electron O
spin O
resonance O
( O

ESR O
) O
. O

Spectral O
simulation O
showed O
that O
the O
axial O
rotation O
of O
DTBN B
or O
TEMPONE B
molecules O
is O
excited O
in O
TPP B
nanochannels O
with O
activation O
energies O
of O
3 O
and O
10 O
kJ O
mol O
( O
- O
1 O
) O
, O
respectively O
. O

The O
rotation O
axes O
for O
both O
DTBN B
and O
TEMPONE B
were O
determined O
to O
be O
almost O
parallel O
to O
the O
principal O
y O
- O
axis O
of O
the O
g O
tensor O
, O
which O
agrees O
with O
the O
result O
reported O
for O
2 B
, I
2 I
, I
6 I
, I
6 I
- I
tetramethyl I
- I
1 I
- I
piperidinyl I
- I
1 I
- I
oxyl I
( O
TEMPO B
) O
in O
TPP B
nanochannels O
, O
which O
has O
the O
activation O
energy O
of O
5 O
kJ O
mol O
( O
- O
1 O
) O
. O

These O
results O
indicate O
that O
the O
molecular O
orientations O
of O
guest O
nitroxide B
radicals O
are O
almost O
independent O
of O
the O
molecular O
sizes O
of O
the O
guest O
radicals O
in O
TPP B
nanochannels O
, O
although O
the O
molecular O
dynamics O
are O
dependent O
on O
the O
molecular O
sizes O
. O

Ethnobotanical O
study O
on O
traditional O
use O
of O
medicinal O
plants O
in O
South O
- O
Western O
Serbia O
, O
Zlatibor O
district O
. O

Ethnopharmacological O
relevance O
: O
This O
paper O
provides O
significant O
ethnobotanical O
information O
on O
medicinal O
plant O
uses O
in O
the O
Zlatibor O
district O
, O
South O
- O
Western O
Serbia O
. O

Materials O
and O
methods O
: O
A O
survey O
was O
performed O
using O
questionnaires O
with O
220 O
informants O
( O
mean O
age O
47 O
, O
79 O
% O
female O
, O
21 O
% O
male O
) O
. O

In O
addition O
, O
the O
use O
value O
and O
the O
relative O
importance O
of O
species O
were O
determined O
and O
the O
informant O
consensus O
factor O
was O
calculated O
for O
the O
medicinal O
plants O
included O
in O
the O
study O
. O

Intended O
plants O
usage O
was O
compared O
with O
previous O
ethnobotanical O
literature O
, O
with O
reference O
to O
the O
neighboring O
areas O
of O
Zlatibor O
district O
. O

Results O
: O
The O
informants O
provided O
data O
for O
69 O
medicinal O
plants O
belonging O
to O
36 O
families O
. O

Rosaceae O
, O
Lamiaceae O
and O
Asteraceae O
were O
the O
predominant O
locally O
used O
families O
. O

The O
species O
with O
the O
highest O
use O
value O
were O
Mentha O
piperita O
, O
Matricaria O
chamomilla O
, O
Hypericum O
perforatum O
and O
Achillea O
millefolium O
. O

The O
most O
frequently O
reported O
medicinal O
uses O
were O
ones O
for O
treating O
gastrointestinal O
ailments O
, O
respiratory O
problems O
and O
skin O
diseases O
. O

Usually O
, O
the O
administration O
was O
primarily O
oral O
followed O
by O
topical O
applications O
. O

All O
different O
plant O
parts O
were O
utilized O
, O
however O
leaves O
were O
the O
most O
exploited O
parts O
of O
the O
plants O
. O

Conclusions O
: O
Folk O
medicine O
in O
South O
- O
Western O
Serbia O
, O
Zlatibor O
district O
is O
intended O
mainly O
as O
a O
mode O
of O
primary O
health O
care O
in O
healing O
of O
minor O
illnesses O
. O

The O
results O
indicate O
a O
slight O
reduction O
in O
the O
ethnobotanical O
and O
medical O
knowledge O
in O
this O
area O
, O
when O
compared O
with O
neighboring O
regions O
. O

Recombinant O
streptavidin O
- O
C3bot O
for O
delivery O
of O
proteins O
into O
macrophages O
. O

We O
demonstrated O
previously O
that O
monocytes O
and O
macrophages O
are O
target O
cells O
for O
the O
Rho O
- O
modifying O
Clostridium O
botulinum O
C3 O
ADP B
- O
ribosyltransferase O
. O

Here O
, O
we O
report O
the O
construction O
, O
expression O
and O
characterization O
of O
a O
recombinant O
streptavidin O
- O
C3 O
fusion O
protein O
which O
allows O
for O
delivery O
of O
biotin B
- O
labelled O
molecules O
into O
the O
cytosol O
of O
macrophages O
via O
enzymatically O
inactive O
C3bot1E174Q O
. O

The O
enzyme O
domain O
of O
diphtheria O
toxin O
was O
used O
as O
cargo O
to O
demonstrate O
proof O
of O
principle O
. O

This O
transport O
system O
could O
represent O
an O
attractive O
tool O
for O
experimental O
monocyte O
/ O
macrophage O
pharmacology O
. O

Cardiovascular O
disease O
prevention O
: O
matching O
evidence O
- O
based O
algorithms O
with O
individualized O
care O
. O

The O
appropriate O
use O
of O
statins B
in O
primary O
prevention O
remains O
a O
matter O
of O
debate O
. O

Although O
statins B
reduce O
cardiovascular O
events O
at O
all O
levels O
of O
baseline O
risk O
, O
they O
are O
associated O
with O
rare O
but O
important O
side O
effects O
including O
incident O
diabetes O
. O

Herein O
, O
we O
review O
strategies O
for O
statin O
allocation O
ranging O
from O
strict O
" O
evidence O
- O
based O
" O
adherence O
to O
randomized O
controlled O
clinical O
trial O
( O
RCT O
) O
entry O
criteria O
to O
more O
" O
personalized O
" O
risk O
assessment O
using O
high O
- O
sensitivity O
C O
- O
reactive O
protein O
( O
hsCRP O
) O
, O
coronary O
artery O
calcification O
( O
CAC O
) O
, O
or O
genetic O
testing O
. O

Current O
guidelines O
advocate O
an O
unusual O
middle O
ground O
between O
an O
evidence O
- O
based O
approach O
and O
a O
personalized O
approach O
. O

Hedgehog O
- O
Gli O
Activators O
Direct O
Osteo O
- O
chondrogenic O
Function O
of O
Bone O
Morphogenetic O
Protein O
toward O
Osteogenesis O
in O
the O
Perichondrium O
. O

Specification O
of O
progenitors O
into O
the O
osteoblast O
lineage O
is O
an O
essential O
event O
for O
skeletogenesis O
. O

During O
endochondral O
ossification O
, O
cells O
in O
the O
perichondrium O
give O
rise O
to O
osteoblast O
precursors O
. O

Hedgehog O
( O
Hh O
) O
and O
bone O
morphogenetic O
protein O
( O
BMP O
) O
are O
suggested O
to O
regulate O
the O
commitment O
of O
these O
cells O
. O

However O
, O
properties O
of O
perichondrial O
cells O
and O
regulatory O
mechanisms O
of O
the O
specification O
process O
are O
still O
poorly O
understood O
. O

Here O
, O
we O
investigated O
the O
machineries O
by O
combining O
a O
novel O
organ O
culture O
system O
and O
single O
- O
cell O
expression O
analysis O
with O
mouse O
genetics O
and O
biochemical O
analyses O
. O

In O
a O
metatarsal O
organ O
culture O
reproducing O
bone O
collar O
formation O
, O
activation O
of O
BMP O
signaling O
enhanced O
the O
bone O
collar O
formation O
cooperatively O
with O
Hh O
input O
, O
whereas O
the O
signaling O
induced O
ectopic O
chondrocyte O
formation O
in O
the O
perichondrium O
without O
Hh O
input O
. O

Similar O
phenotypes O
were O
also O
observed O
in O
compound O
mutant O
mice O
, O
where O
signaling O
activities O
of O
Hh O
and O
BMP O
were O
genetically O
manipulated O
. O

Single O
- O
cell O
quantitative O
RT O
- O
PCR O
analyses O
showed O
heterogeneity O
of O
perichondrial O
cells O
in O
terms O
of O
natural O
characteristics O
and O
responsiveness O
to O
Hh O
input O
. O

In O
vitro O
analyses O
revealed O
that O
Hh O
signaling O
suppressed O
BMP O
- O
induced O
chondrogenic O
differentiation O
; O
Gli1 O
inhibited O
the O
expression O
of O
Sox5 O
, O
Sox6 O
, O
and O
Sox9 O
( O
SRY O
box O
- O
containing O
gene O
9 O
) O
as O
well O
as O
transactivation O
by O
Sox9 O
. O

Indeed O
, O
ectopic O
expression O
of O
chondrocyte O
maker O
genes O
were O
observed O
in O
the O
perichondrium O
of O
metatarsals O
in O
Gli1 O
( O
- O
/ O
- O
) O
fetuses O
, O
and O
the O
phenotype O
was O
more O
severe O
in O
Gli1 O
( O
- O
/ O
- O
) O
; O
Gli2 O
( O
- O
/ O
- O
) O
newborns O
. O

These O
data O
suggest O
that O
Hh O
- O
Gli O
activators O
alter O
the O
function O
of O
BMP O
to O
specify O
perichondrial O
cells O
into O
osteoblasts O
; O
the O
timing O
of O
Hh O
input O
and O
its O
target O
populations O
are O
critical O
for O
BMP O
function O
. O

A O
novel O
mechanism O
by O
which O
SDF O
- O
1 O
beta O
protects O
cardiac O
cells O
from O
palmitate B
- O
induced O
ER O
stress O
and O
apoptosis O
via O
CXCR7 O
and O
AMPK O
/ O
p38 O
MAPK O
- O
mediated O
IL O
- O
6 O
generation O
. O

We O
studied O
the O
protective O
effect O
of O
stromal O
cell O
- O
derived O
factor O
- O
1beta O
( O
SDF O
- O
1 O
beta O
) O
on O
cardiac O
cells O
from O
lipotoxicity O
in O
vitro O
and O
diabetes O
in O
vivo O
. O

Exposure O
of O
cardiac O
cells O
to O
palmitate B
increased O
apoptosis O
by O
activating O
NADPH B
oxidase O
- O
associated O
nitrosative O
stress O
and O
endoplasmic O
reticulum O
( O
ER O
) O
stress O
, O
which O
abolished O
by O
pretreatment O
with O
SDF O
- O
1 O
beta O
via O
up O
- O
regulation O
of O
AMPK O
- O
mediated O
p38 O
MAPK O
phosphorylation O
and O
IL O
- O
6 O
production O
. O

The O
SDF O
- O
1 O
beta O
cardiac O
protection O
could O
be O
abolished O
by O
inhibition O
of O
AMPK O
, O
p38 O
MAPK O
or O
IL O
- O
6 O
. O

Activation O
of O
AMPK O
or O
addition O
of O
recombinant O
IL O
- O
6 O
recaptured O
a O
similar O
cardiac O
protection O
. O

SDF O
- O
1 O
beta O
receptor O
CXCR4 O
antagonist O
AMD3100 O
or O
CXCR4 O
siRNA O
could O
not O
, O
but O
CXCR7 O
siRNA O
completely O
abolish O
SDF O
- O
1 O
beta O
' O
s O
protection O
from O
palmitate B
- O
induced O
apoptosis O
and O
activation O
of O
AMPK O
and O
p38 O
MAPK O
. O

Administration O
of O
SDF O
- O
1 O
beta O
to O
diabetic O
rats O
, O
induced O
by O
high O
- O
fat O
- O
diet O
feeding O
with O
a O
small O
dose O
of O
streptozotocin B
, O
could O
significantly O
reduce O
cardiac O
apoptosis O
and O
increase O
in O
AMPK O
phosphorylation O
along O
with O
a O
prevention O
of O
diabetes O
- O
induced O
cardiac O
oxidative O
damage O
, O
inflammation O
, O
hypertrophy O
and O
remodeling O
. O

These O
results O
showed O
that O
SDF O
- O
1 O
beta O
protects O
palmitate B
- O
induced O
cardiac O
apoptosis O
, O
which O
is O
mediated O
by O
NADPH B
oxidase O
- O
activated O
nitrosative O
damage O
and O
ER O
stress O
, O
via O
CXCR7 O
to O
activate O
AMPK O
/ O
p38 O
MAPK O
- O
mediated O
IL O
- O
6 O
generation O
. O

The O
cardiac O
protection O
by O
SDF O
- O
1 O
beta O
from O
diabetes O
- O
induced O
oxidative O
damage O
, O
cell O
death O
and O
remodeling O
was O
also O
associated O
with O
AMPK O
activation O
. O

Modulation O
of O
cytochrome O
P450 O
1 O
( O
Cyp1 O
) O
by O
vanadium B
in O
hepatic O
tissue O
and O
isolated O
hepatocyte O
of O
C57BL O
/ O
6 O
mice O
. O

The O
objective O
of O
the O
current O
study O
was O
to O
investigate O
the O
effect O
of O
vanadium B
( O
V B
( I
5 I
+ I
) I
) O
on O
Cyp1 O
expression O
and O
activity O
in O
C57BL O
/ O
6 O
mice O
liver O
and O
isolated O
hepatocytes O
. O

For O
this O
purpose O
, O
C57BL6 O
mice O
were O
injected O
intraperitoneally O
with O
V O
( O
5 O
+ O
) O
( O
5 O
mg O
/ O
kg O
) O
in O
the O
absence O
and O
presence O
of O
2 B
, I
3 I
, I
7 I
, I
8 I
- I
tetrachlorodibenzo I
- I
p I
- I
dioxin I
( O
TCDD B
) O
( O
15 O
mu O
g O
/ O
kg O
) O
for O
6 O
and O
24 O
h O
. O

Furthermore O
, O
isolated O
hepatocytes O
from O
C57BL6 O
mice O
were O
treated O
with O
V O
( O
5 O
+ O
) O
( O
5 O
, O
10 O
, O
and O
20 O
mu O
M O
) O
in O
the O
absence O
and O
presence O
of O
TCDD B
( O
1 O
nM O
) O
for O
3 O
, O
6 O
, O
12 O
, O
and O
24 O
h O
. O

In O
vivo O
, O
V B
( I
5 I
+ I
) I
alone O
did O
not O
significantly O
alter O
Cyp1a1 O
, O
Cyp1a2 O
, O
or O
Cyp1b1 O
mRNA O
, O
protein O
, O
or O
catalytic O
activity O
levels O
. O

Upon O
co O
- O
exposure O
to O
V B
( I
5 I
+ I
) I
and O
TCDD B
, O
V B
( I
5 I
+ I
) I
significantly O
potentiated O
the O
TCDD B
- O
mediated O
induction O
of O
the O
Cyp1a1 O
, O
Cyp1a2 O
, O
and O
Cyp1b1 O
mRNA O
, O
protein O
, O
and O
catalytic O
activity O
levels O
at O
24 O
h O
. O

In O
vitro O
, O
V B
( I
5 I
+ I
) I
decreased O
the O
TCDD B
- O
mediated O
induction O
of O
Cyp1a1 O
mRNA O
, O
protein O
, O
and O
catalytic O
activity O
levels O
. O

Furthermore O
, O
V B
( I
5 I
+ I
) I
significantly O
inhibited O
the O
TCDD B
- O
induced O
AhR O
- O
dependent O
luciferase O
activity O
. O

V B
( I
5 I
+ I
) I
also O
increased O
serum O
hemoglobin O
( O
Hb O
) O
levels O
in O
animals O
treated O
for O
24 O
h O
. O

Upon O
treatment O
of O
isolated O
hepatocytes O
with O
Hb O
alone O
or O
in O
the O
presence O
of O
TCDD B
, O
there O
was O
an O
increase O
in O
the O
AhR O
- O
dependent O
luciferase O
activity O
. O

When O
isolated O
hepatocytes O
were O
treated O
for O
2 O
h O
with O
V B
( I
5 I
+ I
) I
in O
the O
presence O
of O
TCDD B
, O
followed O
by O
replacement O
of O
the O
medium O
with O
new O
medium O
containing O
Hb O
, O
there O
was O
further O
potentiation O
to O
the O
TCDD B
- O
mediated O
effect O
. O

The O
present O
study O
demonstrates O
that O
there O
is O
a O
differential O
modulation O
of O
Cyp1a1 O
by O
V O
( O
5 O
+ O
) O
in O
C57BL O
/ O
6 O
mice O
livers O
and O
isolated O
hepatocytes O
and O
demonstrates O
Hb O
as O
an O
in O
vivo O
specific O
modulator O
. O

Metabolic O
dephenylation O
of O
the O
rubber O
antioxidant O
N B
- I
phenyl I
- I
2 I
- I
naphthylamine I
to O
carcinogenic O
2 B
- I
naphthylamine I
in O
rats O
. O

N B
- I
Phenyl I
- I
2 I
- I
naphthylamine I
( O
P2NA B
) O
was O
widely O
used O
as O
oxidation O
inhibitor O
, O
particularly O
in O
rubber O
manufacturing O
. O

Technical O
- O
grade O
P2NA O
was O
contaminated O
with O
carcinogenic O
2 B
- I
naphthylamine I
( O
2NA B
) O
, O
and O
bladder O
cancer O
risk O
in O
exposed O
workers O
was O
attributed O
to O
this O
impurity O
. O

Investigations O
in O
humans O
and O
mammalian O
species O
revealed O
that O
small O
amounts O
of O
2NA B
are O
excreted O
into O
urine O
after O
exposure O
to O
P2NA O
. O

However O
, O
since O
2NA B
per O
se O
is O
not O
carcinogenic O
and O
main O
downstream O
metabolites O
of O
2NA B
have O
not O
been O
found O
in O
urine O
so O
far O
, O
it O
remained O
uncertain O
if O
2NA B
derived O
from O
P2NA O
dephenylation O
is O
further O
activated O
to O
carcinogenic O
downstream O
metabolites O
. O

An O
experimental O
animal O
study O
was O
therefore O
designed O
to O
indicate O
if O
, O
and O
if O
yes O
to O
which O
extent O
, O
2NA O
from O
P2NA O
dephenylation O
is O
accessible O
to O
the O
metabolic O
pathway O
that O
is O
held O
responsible O
for O
the O
carcinogenicity O
of O
2NA O
. O

Groups O
of O
5 O
male O
and O
female O
CD O
rats O
were O
dosed O
with O
P2NA O
( O
2 O
- O
550 O
mg O
/ O
kg O
b O
. O
w O
. O
) O
and O
2NA B
( O
0 O
. O
075 O
- O
75 O
mg O
/ O
kg O
b O
. O
w O
. O
) O
; O
2NA B
- O
haemoglobin O
adducts O
and O
urinary O
2NA B
excretion O
were O
determined O
applying O
GC O
- O
MS O
/ O
MS O
. O

2NA B
haemoglobin O
adducts O
originated O
dose O
- O
dependently O
after O
2NA B
and O
P2NA O
dosing O
. O

To O
induce O
identical O
adduct O
concentrations O
, O
an O
approximately O
100 O
- O
200 O
- O
fold O
higher O
dose O
of O
P2NA O
was O
necessary O
compared O
to O
2NA O
. O

Since O
haemoglobin O
adducts O
are O
formed O
by O
the O
same O
pathway O
( O
N B
- O
hydroxylation O
) O
as O
the O
ultimate O
carcinogens O
from O
2NA B
, O
the O
comparison O
of O
adduct O
concentrations O
after O
2NA B
and O
P2NA O
dosage O
permits O
a O
quantitative O
estimate O
of O
the O
carcinogenicity O
of O
P2NA O
. O

The O
results O
show O
that O
2NA B
derived O
from O
dephenylation O
of O
P2NA O
enters O
the O
carcinogenic O
downstream O
pathway O
of O
2NA B
in O
rats O
. O

Hence O
, O
the O
bladder O
cancer O
risk O
after O
human O
exposures O
to O
P2NA O
must O
be O
re O
- O
evaluated O
. O

Effect O
of O
bisphenol B
- I
A I
on O
insulin O
signal O
transduction O
and O
glucose B
oxidation O
in O
skeletal O
muscle O
of O
adult O
male O
albino O
rat O
. O

The O
estrogenic O
monomer O
bisphenol B
- I
A I
( O
BPA B
) O
is O
an O
endocrine O
- O
disrupting O
chemical O
used O
in O
the O
production O
of O
epoxy B
resins O
, O
plastic O
food O
and O
beverage O
containers O
, O
leading O
to O
ubiquitous O
human O
exposure O
. O

Environmentally O
relevant O
doses O
of O
BPA B
have O
profound O
effects O
on O
mice O
endocrine O
pancreas O
. O

It O
increases O
pancreatic O
insulin O
content O
and O
favors O
postprandial O
hyperinsulinemia O
and O
insulin O
resistance O
in O
male O
mice O
. O

Skeletal O
muscle O
plays O
a O
crucial O
role O
in O
maintaining O
systemic O
glucose B
metabolism O
. O

In O
the O
present O
study O
, O
we O
investigated O
the O
possible O
effects O
of O
BPA B
on O
insulin O
- O
signaling O
molecules O
and O
glucose B
oxidation O
in O
skeletal O
muscle O
of O
male O
rat O
. O

Adult O
male O
Wistar O
albino O
rats O
were O
divided O
into O
three O
groups O
. O

Group O
I O
: O
control O
( O
vehicle O
treated O
) O
and O
groups O
II O
and O
III O
were O
administered O
with O
BPA B
orally O
( O
20 O
and O
200 O
mg O
/ O
kg O
bw O
/ O
day O
, O
respectively O
) O
. O

Although O
there O
was O
no O
change O
in O
the O
levels O
of O
insulin O
receptor O
( O
IR O
) O
, O
Akt O
( O
protein O
kinase O
B O
) O
and O
glucose B
transporter O
- O
4 O
( O
GLUT4 O
) O
messenger O
RNA O
, O
BPA B
significantly O
decreased O
the O
IR O
, O
Akt O
and O
GLUT4 O
protein O
levels O
( O
both O
plasma O
membrane O
and O
cytosolic O
fraction O
) O
of O
the O
gastrocnemius O
muscle O
. O

There O
was O
an O
increase O
in O
serum O
insulin O
and O
decrease O
in O
serum O
testosterone B
levels O
but O
fasting O
blood O
glucose B
level O
remained O
unaltered O
. O

In O
conclusion O
, O
BPA B
has O
adverse O
effects O
on O
phosphorylation O
of O
Akt O
, O
GLUT4 O
translocation O
and O
( B
14 I
) I
C I
- I
glucose I
oxidation O
. O

Effects O
of O
the O
combined O
artesunate B
and O
mefloquine B
antimalarial O
drugs O
on O
rat O
embryos O
. O

Artemisinins B
combination O
therapy O
( O
ACT O
) O
is O
the O
first O
choice O
therapy O
for O
falciparum O
malaria O
. O

Data O
on O
the O
safety O
of O
ACTs O
in O
pregnancy O
are O
limited O
and O
controversial O
and O
the O
use O
is O
not O
recommended O
on O
the O
first O
trimester O
. O

To O
evaluate O
the O
effects O
of O
isolated O
and O
combined O
artesunate B
( O
AS O
) O
/ O
mefloquine B
( O
MQ O
) O
on O
embryo O
rats O
, O
pregnant O
rats O
were O
treated O
orally O
with O
AS B
( O
15 O
and O
40 O
mg O
/ O
kg O
body O
weight O
( O
bwt O
) O
/ O
day O
) O
, O
MQ O
( O
30 O
and O
80 O
mg O
/ O
kg O
bwt O
/ O
day O
) O
and O
AS B
/ O
MQ O
( O
15 O
/ O
30 O
and O
40 O
/ O
80 O
mg O
/ O
kg O
bwt O
/ O
day O
) O
on O
days O
9 O
- O
11 O
post O
coitum O
( O
pc O
) O
. O

The O
dams O
were O
euthanized O
on O
day O
12 O
pc O
and O
gestational O
and O
embryos O
histological O
parameters O
were O
evaluated O
. O

Embryolethality O
and O
histopathological O
anomalies O
were O
significant O
when O
AS O
was O
given O
alone O
or O
combined O
with O
MQ O
. O

Combination O
of O
AS B
and O
MQ B
did O
not O
enhance O
their O
toxicity O
compared O
to O
their O
separate O
administrations O
; O
on O
the O
other O
side O
, O
there O
was O
a O
reduction O
in O
the O
toxic O
effects O
of O
the O
AS B
when O
combined O
with O
MQ B
. O

Isolated O
MQ O
did O
not O
induce O
developmental O
toxicity O
. O

Cytotoxic O
, O
genotoxic O
and O
antigenotoxic O
potencies O
of O
oligorutins O
. O

Rutin B
has O
been O
enzymatically O
oligomerized O
by O
laccase O
from O
Trametes O
versicolor O
. O

Five O
fractions O
of O
oligomers O
were O
obtained O
from O
the O
monomers O
having O
high O
solubility O
in O
water O
, O
which O
can O
reach O
351 O
- O
times O
that O
of O
rutin B
. O

Cytotoxicity O
of O
rutin B
and O
oligorutin O
fractions O
was O
evaluated O
towards O
K562 O
cells O
. O

Oligorutin O
fractions O
showed O
a O
lower O
antiproliferative O
effect O
compared O
with O
its O
monomer O
. O

The O
genotoxic O
potential O
of O
rutin B
and O
oligorutin O
fractions O
was O
assessed O
, O
at O
the O
limit O
of O
the O
solubility O
of O
each O
molecule O
, O
using O
the O
comet O
test O
. O

None O
of O
the O
tested O
concentrations O
of O
either O
rutin B
or O
oligorutin O
fractions O
has O
showed O
a O
genotoxic O
effect O
. O

Similarly O
, O
the O
antigenotoxic O
effect O
of O
these O
flavonoids B
was O
tested O
using O
the O
same O
assay O
. O

The O
obtained O
results O
showed O
a O
higher O
ability O
of O
oligorutin O
fractions O
to O
reduce O
the O
genotoxicity O
induced O
by O
hydrogen B
peroxide I
compared O
with O
monomeric O
rutin B
. O

Rheological O
properties O
and O
tunable O
thermoplasticity O
of O
phenolic O
rich O
fraction O
of O
pyrolysis O
bio O
- O
oil O
. O

In O
this O
work O
we O
report O
on O
the O
preparation O
, O
characterization O
, O
and O
properties O
of O
a O
thermally O
treated O
lignin O
- O
derived O
, O
phenolic O
- O
rich O
fraction O
( O
PRF O
) O
of O
wood O
pyrolysis O
bio O
- O
oil O
obtained O
by O
ethyl B
acetate I
extraction O
. O

The O
PRF O
was O
characterized O
for O
viscoelastic O
and O
rheological O
behavior O
using O
dynamic O
mechanical O
analysis O
( O
DMA O
) O
and O
cone O
and O
plate O
rheology O
. O

A O
unique O
thermoplastic O
behavior O
was O
evidenced O
. O

Heat O
- O
treated O
PRFs O
acquire O
high O
modulus O
but O
show O
low O
temperatures O
of O
thermal O
flow O
which O
can O
be O
systematically O
manipulated O
through O
the O
thermal O
pretreatment O
. O

Loss O
of O
volatiles O
, O
changes O
in O
molecular O
weight O
, O
and O
glass O
transition O
temperature O
( O
Tg O
) O
were O
investigated O
using O
thermogravimetric O
analysis O
( O
TGA O
) O
, O
mass O
spectrometry O
( O
MS O
) O
, O
and O
differential O
scanning O
calorimetry O
( O
DSC O
) O
, O
respectively O
. O

Underlying O
mechanisms O
for O
the O
thermal O
and O
rheological O
behavior O
are O
discussed O
with O
regard O
to O
interactions O
between O
pyrolytic O
lignin O
nanoparticles O
present O
in O
the O
system O
and O
the O
role O
of O
volatile O
materials O
on O
determining O
the O
properties O
of O
the O
material O
resembling O
in O
several O
aspects O
to O
colloidal O
suspension O
systems O
. O

Low O
thermal O
flow O
temperatures O
and O
reversible O
thermal O
effects O
can O
be O
attributed O
to O
association O
of O
pyrolytic O
lignin O
particles O
due O
to O
intermolecular O
interactions O
that O
are O
easily O
ruptured O
at O
higher O
temperatures O
. O

The O
thermoplastic O
behavior O
of O
PRF O
and O
its O
low O
Tg O
is O
of O
particular O
interest O
, O
as O
it O
gives O
opportunities O
for O
application O
of O
this O
fraction O
in O
several O
melt O
processing O
and O
adhesive O
technologies O
. O

Accurate O
semiexperimental O
structure O
of O
1 B
, I
3 I
, I
4 I
- I
oxadiazole I
by O
the O
mixed O
estimation O
method O
. O

In O
order O
to O
determine O
an O
accurate O
equilibrium O
structure O
for O
1 B
, I
3 I
, I
4 I
- I
oxadiazole I
, O
microwave O
transitions O
and O
ground O
- O
state O
rotational O
constants O
are O
reported O
for O
the O
parent O
species O
and O
for O
the O
( B
18 I
) I
O I
isotopologue O
measured O
in O
natural O
abundance O
. O

These O
rotational O
constants O
along O
with O
those O
of O
the O
( B
13 I
) I
C I
, O
( B
15 I
) I
N I
, O
and O
D1 O
species O
were O
used O
together O
with O
vibration O
- O
rotation O
constants O
calculated O
from O
a O
cubic O
force O
field O
calculated O
at O
the O
B3LYP O
/ O
6 O
- O
311 O
+ O
G O
( O
3df O
, O
2pd O
) O
level O
of O
theory O
to O
derive O
a O
semiexperimental O
equilibrium O
structure O
. O

However O
, O
the O
results O
of O
this O
fit O
were O
not O
satisfactory O
; O
therefore O
, O
the O
structure O
was O
later O
significantly O
improved O
by O
the O
mixed O
estimation O
method O
. O

In O
this O
method O
, O
internal O
coordinates O
from O
good O
- O
quality O
quantum O
chemical O
calculations O
( O
with O
appropriate O
uncertainties O
) O
are O
fitted O
simultaneously O
with O
moments O
of O
inertia O
of O
the O
full O
set O
of O
isotopologues O
. O

The O
accuracy O
of O
this O
structure O
has O
been O
confirmed O
by O
using O
an O
extrapolation O
technique O
. O

All O
elements O
of O
the O
( B
14 I
) I
N I
nuclear O
quadrupole O
coupling O
tensor O
have O
been O
determined O
. O

Antinociceptive O
effect O
of O
7 B
- I
methoxyflavone I
isolated O
from O
Zornia O
brasiliensis O
. O

In O
this O
study O
, O
we O
investigated O
the O
antinociceptive O
effect O
of O
7 B
- I
methoxyflavone I
( O
7MF B
) O
in O
mice O
using O
the O
following O
tests O
: O
acetic B
acid I
- O
induced O
writhing O
, O
glutamate B
- O
and O
formalin B
- O
induced O
nociception O
and O
hotplate O
. O

7MF B
( O
30 O
, O
50 O
, O
100 O
and O
300 O
mu O
mol O
/ O
kg O
, O
i O
. O
p O
. O
) O
reduced O
the O
number O
of O
writhes O
, O
with O
ID O
( O
50 O
) O
= O
82 O
. O
5 O
+ O
/ O
- O
11 O
. O
7 O
mu O
mol O
/ O
kg O
and O
E O
( O
max O
) O
= O
58 O
. O
4 O
% O
. O

7MF B
treatment O
( O
100 O
mu O
mol O
/ O
kg O
, O
i O
. O
p O
. O
) O
inhibited O
paw O
- O
licking O
time O
in O
the O
neurogenic O
phase O
of O
the O
formalin B
pain O
response O
( O
65 O
. O
6 O
% O
) O
and O
did O
not O
decrease O
the O
nociceptive O
response O
in O
the O
inflammatory O
phase O
. O

In O
addition O
, O
in O
glutamate B
- O
induced O
nociception O
, O
7MF B
inhibited O
26 O
% O
of O
the O
nociceptive O
answer O
. O

On O
the O
other O
hand O
, O
7MF B
did O
not O
increase O
the O
latency O
time O
of O
the O
animals O
in O
the O
hotplate O
test O
. O

These O
results O
suggest O
that O
7MF B
has O
peripheral O
antinociceptive O
activity O
. O

Directed O
organization O
of O
DNA O
filaments O
in O
a O
soft O
matter O
template O
. O

We O
have O
developed O
a O
noninvasive O
, O
all O
- O
optical O
, O
holographic O
technique O
for O
permanently O
aligning O
liquid O
crystalline O
DNA O
filaments O
in O
a O
microperiodic O
template O
realized O
in O
soft O
- O
composite O
( O
polymeric O
) O
materials O
. O

By O
combining O
optical O
intensity O
holography O
with O
a O
selective O
microfluidic O
etching O
process O
, O
a O
channelled O
microstructure O
has O
been O
realized O
which O
enables O
self O
- O
assembly O
of O
DNA O
. O

The O
striking O
chemicophysical O
properties O
of O
the O
structure O
immobilize O
the O
DNA O
filaments O
within O
the O
microchannels O
without O
the O
need O
of O
any O
kind O
of O
surface O
chemistry O
or O
functionalization O
. O

Polarized O
optical O
, O
confocal O
, O
and O
electronic O
microscopies O
have O
been O
used O
for O
characterizing O
the O
DNA O
geometry O
inside O
the O
microchannels O
in O
terms O
of O
birefringence O
, O
fluorescence O
, O
and O
nanoscale O
organization O
properties O
. O

In O
particular O
, O
observation O
of O
a O
far O
- O
field O
diffraction O
pattern O
confirms O
a O
periodic O
organization O
of O
the O
DNA O
filaments O
inside O
the O
polymeric O
template O
. O

Self O
- O
assembly O
of O
morphology O
- O
tunable O
architectures O
from O
tetraarylmethane B
derivatives O
for O
targeted O
drug O
delivery O
. O

Tetraarylmethane B
compounds O
consisting O
of O
two O
pyrogallol B
and O
two O
aniline B
units O
, O
namely O
, O
Ar2CAr B
' I
2 I
{ O
Ar O
= O
3 B
, I
4 I
, I
5 I
- I
C6H2 I
( I
OH I
) I
3 I
and O
Ar O
' O
= O
3 B
, I
5 I
- I
R2 I
- I
4 I
- I
C6H2NH2 I
[ O
R O
= O
Me B
( O
1 O
) O
, O
iPr B
( O
2 O
) O
] O
} O
exhibit O
excellent O
self O
- O
assembly O
behavior O
. O

Compound O
1 O
yields O
size O
- O
tunable O
hollow O
nanospheres O
( O
HNSs O
) O
with O
a O
narrow O
size O
distribution O
, O
and O
2 O
yields O
various O
morphologies O
ranging O
from O
microtubules O
to O
microrods O
via O
self O
- O
assembly O
induced O
by O
hydrogen B
bonding O
and O
pi O
- O
pi O
stacking O
interactions O
. O

On O
the O
basis O
of O
the O
experimental O
results O
, O
a O
plausible O
mechanism O
for O
morphology O
tunability O
was O
proposed O
. O

As O
a O
means O
of O
utilizing O
the O
self O
- O
assembled O
HNSs O
for O
targeting O
controlled O
drug O
delivery O
, O
folic B
acid I
( O
FA O
) O
and O
rhodamine B
6G I
( O
Rh6G B
) O
were O
grafted O
onto O
compound O
1 O
to O
yield O
the O
FA O
- O
Rh6G B
- O
1 O
complex O
. O

The O
HNSs O
fabricated O
with O
FA O
- O
Rh6G O
- O
1 O
showed O
low O
cytotoxicity O
against O
human O
embryonic O
kidney O
293T O
cells O
and O
CT26 O
colon O
carcinoma O
cells O
and O
good O
doxorubicin B
( O
DOX B
) O
loading O
capacity O
( O
9 O
. O
6 O
wt O
% O
) O
. O

The O
FA O
receptor O
- O
mediated O
endocytosis O
of O
FA O
- O
Rh6G O
- O
1 O
HNSs O
examined O
by O
using O
a O
confocal O
laser O
scanning O
microscope O
and O
a O
flow O
cytometer O
revealed O
that O
the O
uptake O
of O
FA O
- O
Rh6G O
- O
1 O
HNSs O
into O
CT26 O
cells O
was O
induced O
by O
FA O
receptor O
- O
mediated O
endocytosis O
. O

In O
vitro O
drug O
delivery O
tests O
showed O
that O
the O
DOX B
molecules O
were O
released O
from O
the O
resulting O
HNSs O
in O
a O
sustainable O
and O
pH O
- O
dependent O
manner O
, O
demonstrating O
a O
potential O
application O
for O
HNSs O
in O
targeted O
drug O
delivery O
for O
cancer O
therapy O
. O

Novel O
microwave O
assisted O
chemical O
synthesis O
of O
Nd B
2 I
Fe I
1 I
4 I
B I
hard O
magnetic O
nanoparticles O
. O

The O
high O
coercivity O
and O
excellent O
energy O
product O
of O
Nd2Fe14B B
hard O
magnets O
have O
led O
to O
a O
large O
number O
of O
high O
value O
added O
industrial O
applications O
. O

Chemical O
synthesis O
of O
Nd2Fe14B B
nanoparticles O
is O
challenging O
due O
to O
the O
large O
reduction O
potential O
of O
Nd B
( I
3 I
+ I
) I
and O
the O
high O
tendency O
for O
Nd2Fe14B B
oxidation O
. O

We O
report O
the O
novel O
synthesis O
of O
Nd2Fe14B B
nanoparticles O
by O
a O
microwave O
assisted O
combustion O
process O
. O

The O
process O
consisted O
of O
Nd B
- I
Fe B
- I
B I
mixed O
oxide B
preparation O
by O
microwave O
assisted O
combustion O
, O
followed O
by O
the O
reduction O
of O
the O
mixed O
oxide B
by O
CaH2 B
. O

This O
combustion O
process O
is O
fast O
, O
energy O
efficient O
and O
offers O
facile O
elemental O
substitution O
. O

The O
coercivity O
of O
the O
resulting O
powders O
was O
~ O
8 O
. O
0 O
kOe O
and O
the O
saturation O
magnetization O
was O
~ O
40 O
emu O
g O
( O
- O
1 O
) O
. O

After O
removal O
of O
CaO B
by O
washing O
, O
saturation O
magnetization O
increased O
and O
an O
energy O
product O
of O
3 O
. O
57 O
MGOe B
was O
obtained O
. O

A O
range O
of O
magnetic O
properties O
was O
obtained O
by O
varying O
the O
microwave O
power O
, O
reduction O
temperature O
and O
Nd O
to O
Fe B
ratio O
. O

A O
transition O
from O
soft O
to O
exchange O
coupled O
to O
hard O
magnetic O
properties O
was O
obtained O
by O
varying O
the O
composition O
of O
NdxFe1 B
- I
xB8 I
( O
x O
varies O
from O
7 O
% O
to O
40 O
% O
) O
. O

This O
synthesis O
procedure O
offers O
an O
inexpensive O
and O
facile O
platform O
to O
produce O
exchange O
coupled O
hard O
magnets O
. O

Acyl B
- I
CoA I
Synthetase O
1 O
Is O
Induced O
by O
Gram O
- O
negative O
Bacteria O
and O
Lipopolysaccharide O
and O
Is O
Required O
for O
Phospholipid O
Turnover O
in O
Stimulated O
Macrophages O
. O

The O
enzyme O
acyl B
- I
CoA I
synthetase O
1 O
( O
ACSL1 O
) O
is O
induced O
by O
peroxisome O
proliferator O
- O
activated O
receptor O
alpha O
( O
PPAR O
alpha O
) O
and O
PPAR O
gamma O
in O
insulin O
target O
tissues O
, O
such O
as O
skeletal O
muscle O
and O
adipose O
tissue O
, O
and O
plays O
an O
important O
role O
in O
beta O
- O
oxidation O
in O
these O
tissues O
. O

In O
macrophages O
, O
however O
, O
ACSL1 O
mediates O
inflammatory O
effects O
without O
significant O
effects O
on O
beta O
- O
oxidation O
. O

Thus O
, O
the O
function O
of O
ACSL1 O
varies O
in O
different O
tissues O
. O

We O
therefore O
investigated O
the O
signals O
and O
signal O
transduction O
pathways O
resulting O
in O
ACSL1 O
induction O
in O
macrophages O
as O
well O
as O
the O
consequences O
of O
ACSL1 O
deficiency O
for O
phospholipid O
turnover O
in O
LPS O
- O
activated O
macrophages O
. O

LPS O
, O
Gram O
- O
negative O
bacteria O
, O
IFN O
- O
gamma O
, O
and O
TNF O
alpha O
all O
induce O
ACSL1 O
expression O
in O
macrophages O
, O
whereas O
PPAR O
agonists O
do O
not O
. O

LPS O
- O
induced O
ACSL1 O
expression O
is O
dependent O
on O
Toll O
- O
like O
receptor O
4 O
( O
TLR4 O
) O
and O
its O
adaptor O
protein O
TRIF O
( O
Toll O
- O
like O
receptor O
adaptor O
molecule O
1 O
) O
but O
does O
not O
require O
the O
MyD88 O
( O
myeloid O
differentiation O
primary O
response O
gene O
88 O
) O
arm O
of O
TLR4 O
signaling O
; O
nor O
does O
it O
require O
STAT1 O
( O
signal O
transducer O
and O
activator O
of O
transcription O
1 O
) O
for O
maximal O
induction O
. O

Furthermore O
, O
ACSL1 O
deletion O
attenuates O
phospholipid O
turnover O
in O
LPS O
- O
stimulated O
macrophages O
. O

Thus O
, O
the O
regulation O
and O
biological O
function O
of O
ACSL1 O
in O
macrophages O
differ O
markedly O
from O
that O
in O
insulin O
target O
tissues O
. O

These O
results O
suggest O
that O
ACSL1 O
may O
have O
an O
important O
role O
in O
the O
innate O
immune O
response O
. O

Further O
, O
these O
findings O
illustrate O
an O
interesting O
paradigm O
in O
which O
the O
same O
enzyme O
, O
ACSL1 O
, O
confers O
distinct O
biological O
effects O
in O
different O
cell O
types O
, O
and O
these O
disparate O
functions O
are O
paralleled O
by O
differences O
in O
the O
pathways O
that O
regulate O
its O
expression O
. O

CYP2C8 O
* O
3 O
polymorphism O
and O
donor O
age O
are O
associated O
with O
allograft O
dysfunction O
in O
kidney O
transplant O
recipients O
treated O
with O
calcineurin O
inhibitors O
. O

Epoxieicosatrienoic B
acids I
( O
EETs B
) O
play O
a O
protective O
role O
against O
damaging O
processes O
in O
the O
kidney O
. O

We O
have O
assessed O
the O
effect O
of O
polymorphisms O
in O
EETs B
- O
producing O
enzymes O
( O
CYP2C8 O
and O
CYP2J2 O
) O
and O
other O
proteins O
involved O
in O
calcineurin O
inhibitors O
( O
CNIs O
) O
disposition O
( O
CYP3A4 O
, O
CYP3A5 O
, O
and O
ABCB1 O
) O
on O
graft O
function O
and O
clinical O
outcome O
in O
166 O
renal O
transplant O
recipients O
treated O
with O
CNIs O
. O

Both O
CYP2C8 O
* O
3 O
and O
donor O
age O
greater O
than O
48 O
years O
were O
associated O
to O
a O
higher O
incidence O
of O
delayed O
graft O
function O
( O
DGF O
) O
[ O
OR O
= O
2 O
. O
01 O
( O
1 O
. O
1 O
- O
4 O
. O
1 O
) O
, O
P O
= O
. O
04 O
and O
5 O
. O
14 O
( O
2 O
. O
4 O
- O
10 O
. O
9 O
) O
, O
P O
< O
. O
0001 O
; O
respectively O
] O
and O
worse O
creatinine B
clearance O
1 O
year O
after O
grafting O
( O
P O
< O
. O
05 O
and O
P O
< O
. O
001 O
, O
respectively O
) O
. O

In O
addition O
, O
carrying O
4 O
- O
6 O
variants O
in O
the O
3 O
ABCB1 O
loci O
and O
older O
donor O
age O
were O
individually O
associated O
to O
higher O
incidence O
of O
calcineurin O
- O
inhibitor O
- O
induced O
nephrotoxicity O
[ O
OR O
= O
2 O
. O
38 O
( O
1 O
. O
1 O
- O
5 O
. O
4 O
) O
, O
P O
= O
. O
03 O
and O
OR O
= O
1 O
. O
03 O
( O
1 O
. O
01 O
- O
1 O
. O
06 O
) O
, O
P O
= O
. O
038 O
] O
. O

Regression O
analyses O
confirmed O
the O
relevant O
effect O
of O
both O
CYP2C8 O
* O
3 O
and O
donor O
age O
on O
graft O
dysfunction O
. O

Carrying O
the O
2C8 O
* O
3 O
allele O
and O
having O
a O
donor O
older O
than O
48 O
years O
was O
defined O
as O
a O
high O
- O
risk O
status O
and O
observed O
to O
be O
highly O
related O
to O
DGF O
[ O
OR O
= O
3 O
. O
91 O
( O
1 O
. O
46 O
- O
10 O
. O
48 O
) O
, O
P O
< O
. O
01 O
] O
and O
worse O
creatinine B
clearance O
( O
P O
= O
. O
033 O
) O
. O

Our O
results O
show O
that O
genetic O
and O
clinical O
parameters O
can O
be O
combined O
to O
identify O
risk O
factors O
for O
allograft O
dysfunction O
in O
renal O
transplant O
recipients O
. O

Dissecting O
the O
roles O
of O
the O
N B
- O
and O
C B
- O
flanking O
residues O
of O
acetyllysine B
substrates O
for O
SIRT1 O
activity O
. O

SIRT1 O
specificity O
: O
The O
multispecific O
SIRT1 O
enzyme O
catalyzes O
the O
deacetylation O
of O
acetyllysine B
residues O
within O
protein O
targets O
. O

However O
, O
little O
is O
known O
regarding O
the O
molecular O
basis O
for O
SIRT1 O
substrate O
recognition O
. O

Kinetic O
analysis O
of O
SIRT1 O
with O
a O
panel O
of O
peptide O
substrates O
shows O
the O
high O
importance O
of O
the O
region O
N B
- O
flanking O
the O
target O
acetyllysine B
and O
its O
high O
conservation O
through O
evolution O
. O

Chromatin O
Remodeling O
by O
Rosuvastatin B
Normalizes O
TSC2 O
- O
/ O
meth O
Cell O
Phenotype O
through O
the O
Expression O
of O
Tuberin O
. O

Tuberous O
sclerosis O
complex O
( O
TSC O
) O
is O
a O
multi O
- O
systemic O
syndrome O
caused O
by O
mutations O
in O
TSC1 O
or O
TSC2 O
gene O
. O

In O
TSC2 O
- O
null O
cells O
, O
Rheb O
, O
a O
member O
of O
the O
Ras O
family O
of O
GTPases O
, O
is O
constitutively O
activated O
. O

Statins O
inhibit O
3 B
- I
hydroxy I
- I
3 I
- I
methylglutaryl I
coenzyme I
A I
reductase O
and O
block O
the O
synthesis O
of O
isoprenoid B
lipids O
with O
inhibition O
of O
Rheb O
farnesylation O
and O
RhoA O
geranylgeranylation O
. O

The O
effects O
of O
rosuvastatin B
on O
the O
function O
of O
human O
TSC2 O
( O
- O
/ O
- O
) O
and O
TSC2 O
( O
- O
/ O
meth O
) O
alpha O
- O
actin O
smooth O
muscle O
( O
ASM O
) O
cells O
have O
been O
investigated O
. O

The O
TSC2 O
( O
- O
/ O
- O
) O
and O
TSC2 O
( O
- O
/ O
meth O
) O
ASM O
cells O
, O
previously O
isolated O
in O
our O
laboratory O
from O
the O
renal O
angiomyolipoma O
of O
two O
TSC O
patients O
, O
do O
not O
express O
tuberin O
and O
bear O
loss O
of O
heterozigosity O
caused O
by O
a O
double O
hit O
on O
TSC2 O
and O
methylation O
of O
TSC2 O
promoter O
, O
respectively O
. O

Exposure O
to O
rosuvastatin B
affected O
TSC2 O
( O
- O
/ O
meth O
) O
ASM O
cell O
growth O
and O
promoted O
tuberin O
expression O
by O
acting O
as O
a O
demethylating O
agent O
. O

This O
occurred O
without O
changes O
in O
interleukin O
release O
. O

Rosuvastatin B
also O
reduced O
RhoA O
activation O
in O
TSC2 O
( O
- O
/ O
meth O
) O
ASM O
cells O
, O
and O
it O
required O
coadministration O
with O
the O
specific O
mTOR O
( O
mammalian O
target O
of O
rapamycin B
) O
inhibitor O
rapamycin B
to O
be O
effective O
in O
TSC2 O
( O
- O
/ O
- O
) O
ASM O
cells O
. O

Rapamycin B
enhanced O
rosuvastatin B
effect O
in O
inhibiting O
cell O
proliferation O
in O
TSC2 O
( O
- O
/ O
- O
) O
and O
TSC2 O
( O
- O
/ O
meth O
) O
ASM O
cells O
. O

Rosuvastatin B
alone O
did O
not O
alter O
phosphorylation O
of O
S6 O
and O
extracellular O
signal O
- O
regulated O
kinase O
( O
ERK O
) O
, O
and O
at O
the O
higher O
concentration O
, O
rosuvastatin B
and O
rapamycin B
slightly O
decreased O
ERK O
phosphorylation O
. O

These O
results O
suggest O
that O
rosuvastatin B
may O
potentially O
represent O
a O
treatment O
adjunct O
to O
the O
therapy O
with O
mTOR O
inhibitors O
now O
in O
clinical O
development O
for O
TSC O
. O

In O
particular O
, O
rosuvastatin B
appears O
useful O
when O
the O
disease O
is O
originated O
by O
epigenetic O
defects O
. O

PtCl2 B
- O
Catalyzed O
Tandem O
Enyne B
Cyclization O
/ O
1 B
, I
2 I
Ester I
Migration O
Reaction O
Controlled O
by O
Substituent O
Effects O
of O
All B
- I
Carbon I
1 I
, I
6 I
- I
Enynyl I
Esters I
. O

On O
the O
move O
: O
A O
novel O
PtCl2 B
- O
catalyzed O
tandem O
1 B
, I
6 I
- I
enyne I
cyclization O
/ O
1 B
, I
2 I
- I
acyloxy I
migration O
reaction O
was O
developed O
, O
which O
was O
shown O
to O
be O
controlled O
by O
substitution O
effects O
. O

Using O
this O
method O
, O
a O
series O
of O
substituted O
enol B
esters I
containing O
the O
cyclopentenyl B
motif O
were O
prepared O
in O
moderate O
to O
high O
yields O
. O

Surface O
Enhanced O
Raman O
Scattering O
on O
Non O
- O
SERS O
Active O
Substrates O
and O
In O
Situ O
Electrochemical O
Study O
based O
on O
a O
Single O
Gold O
Microshell O
. O

A O
single O
gold O
microshell O
, O
which O
was O
elaborately O
fabricated O
to O
carry O
numerous O
hot O
spots O
on O
its O
own O
surface O
, O
enabled O
the O
acquisition O
of O
the O
SERS O
spectra O
from O
the O
molecules O
on O
non O
- O
SERS O
active O
substrates O
such O
as O
Si B
/ O
SiO2 B
, O
ITO B
, O
and O
glass O
. O

A O
self O
- O
assembled O
monolayer O
of O
11 B
- I
mercaptoundecanols I
on O
the O
gold O
microshell O
offered O
an O
easy O
and O
reliable O
way O
to O
electrically O
insulate O
from O
the O
underlying O
flat O
Pt B
electrode O
and O
accomplish O
in O
situ O
monitoring O
the O
electrochemical O
reaction O
with O
minimal O
interference O
. O

Acute O
waterborne O
copper B
toxicity O
to O
the O
euryhaline O
copepod O
Acartia O
tonsa O
at O
different O
salinities O
: O
Influence O
of O
natural O
freshwater O
and O
marine O
dissolved O
organic O
matter O
. O

The O
influence O
of O
natural O
dissolved O
organic O
matter O
( O
DOM O
) O
on O
acute O
waterborne O
Cu B
toxicity O
was O
evaluated O
in O
the O
euryhaline O
copepod O
Acartia O
tonsa O
at O
3 O
different O
water O
salinities O
. O

Three O
sources O
of O
freshwater O
DOM O
( O
extracted O
by O
reverse O
osmosis O
) O
and O
2 O
sources O
of O
marine O
DOM O
( O
extracted O
using O
a O
solid O
- O
phase O
technique O
) O
were O
used O
. O

Artificial O
salt O
water O
was O
used O
to O
prepare O
the O
experimental O
media O
. O

Different O
combinations O
of O
Cu B
concentrations O
and O
DOM B
sources O
and O
concentrations O
were O
tested O
at O
salinities O
of O
5 O
, O
15 O
, O
and O
30 O
ppt O
. O

Toxicity O
data O
( O
48 O
- O
h O
median O
lethal O
concentration O
[ O
LC50 O
] O
values O
) O
were O
calculated O
based O
on O
dissolved O
Cu B
concentrations O
. O

In O
a O
broad O
view O
, O
data O
showed O
that O
increasing O
salinity O
was O
protective O
against O
the O
acute O
waterborne O
Cu B
toxicity O
. O

In O
general O
, O
Cu B
toxicity O
was O
also O
lower O
in O
the O
presence O
than O
in O
the O
absence O
of O
DOM B
. O

Toxicity O
( O
48 O
- O
h O
LC50 O
) O
values O
from O
all O
treatments O
at O
the O
same O
salinity O
showed O
a O
positive O
linear O
relationship O
with O
the O
dissolved O
organic O
carbon B
( O
DOC O
) O
. O

Thus O
, O
the O
protective O
effect O
of O
DOM B
against O
the O
acute O
Cu B
toxicity O
seems O
to O
be O
dependent O
mainly O
on O
the O
DOM B
concentration O
. O

However O
, O
it O
seems O
also O
to O
be O
dependent O
to O
some O
extent O
on O
the O
source O
of O
DOM B
used O
. O

In O
summary O
, O
findings O
reported O
in O
the O
present O
study O
clearly O
indicate O
that O
both O
salinity O
and O
DOM B
( O
source O
and O
concentration O
) O
should O
be O
taken O
into O
account O
in O
the O
development O
of O
an O
estuarine O
version O
of O
the O
biotic O
ligand O
model O
. O

Environ O
Toxicol O
Chem O
2013 O
; O
32 O
: O
1412 O
- O
1419 O
. O

( O
c O
) O
2013 O
SETAC O
. O

Physical O
Properties O
and O
Erosion O
Behavior O
of O
Poly B
( I
trimethylene I
carbonate I
- I
co I
- I
epsilon I
- I
caprolactone I
) I
Networks O
. O

Form O
- O
stable O
resorbable O
networks O
are O
prepared O
by O
gamma O
irradiating O
trimethylene B
carbonate I
( O
TMC B
) O
- O
and O
epsilon B
- I
caprolactone I
( O
CL O
) O
- O
based O
( O
co O
) O
polymer O
films O
. O

To O
evaluate O
their O
suitability O
for O
biomedical O
applications O
, O
their O
physical O
properties O
and O
erosion O
behavior O
are O
investigated O
. O

Homopolymer O
and O
copolymer O
networks O
that O
are O
amorphous O
at O
room O
temperature O
are O
flexible O
and O
rubbery O
with O
elastic O
moduli O
ranging O
from O
1 O
. O
8 O
+ O
/ O
- O
0 O
. O
3 O
to O
5 O
. O
2 O
+ O
/ O
- O
0 O
. O
4 O
MPa O
and O
permanent O
set O
values O
as O
low O
as O
0 O
. O
9 O
% O
strain O
. O

The O
elastic O
moduli O
of O
the O
semicrystalline O
networks O
are O
higher O
and O
range O
from O
61 O
+ O
/ O
- O
3 O
to O
484 O
+ O
/ O
- O
34 O
MPa O
. O

The O
erosion O
behavior O
of O
( O
co O
) O
polymer O
networks O
is O
investigated O
in O
vitro O
using O
macrophage O
cultures O
, O
and O
in O
vivo O
by O
subcutaneous O
implantation O
in O
rats O
. O

In O
macrophage O
cultures O
, O
as O
well O
as O
upon O
implantation O
, O
a O
surface O
erosion O
process O
is O
observed O
for O
the O
amorphous O
( O
co O
) O
polymer O
networks O
, O
while O
an O
abrupt O
decrease O
in O
the O
rate O
and O
a O
change O
in O
the O
nature O
of O
the O
erosion O
process O
are O
observed O
with O
increasing O
crystallinity O
. O

These O
resorbable O
and O
form O
- O
stable O
networks O
with O
tuneable O
properties O
may O
find O
application O
in O
a O
broad O
range O
of O
biomedical O
applications O
. O

Improvement O
of O
nanoprecipitation O
technique O
for O
preparation O
of O
gelatin O
nanoparticles O
and O
potential O
macromolecular O
drug O
loading O
. O

An O
optimum O
nanoprecipitation O
technique O
for O
gelatin O
nanoparticles O
is O
established O
, O
based O
on O
aqueous O
gelatin O
solution O
and O
ethanolic O
solution O
containing O
stabilizer O
. O

Crosslinking O
with O
glutaraldehyde B
results O
in O
stable O
gelatine O
nanoparticles O
. O

Several O
factors O
such O
as O
the O
surfactant O
concentration O
, O
type O
of O
surfactant O
, O
type O
of O
nonsolvent O
and O
gelatin O
concentration O
are O
evaluated O
. O

Gelatin O
nanoparticles O
with O
200 O
- O
300 O
nm O
can O
be O
produced O
using O
20 O
- O
30 O
mg O
mL O
( O
- O
1 O
) O
of O
gelatin O
and O
a O
minimum O
of O
7 O
% O
w O
/ O
v O
stabilizer O
( O
Poloxamer B
407 I
or I
188 I
) O
. O

Furthermore O
, O
methanol B
and O
ethanol B
are O
good O
nonsolvents O
, O
whereas O
other O
nonsolvents O
such O
as O
acetone B
, O
isopropyl B
alcohol I
, O
and O
acetonitrile B
, O
result O
in O
phase O
separation O
and O
visible O
precipitates O
. O

The O
entrapment O
efficiency O
of O
fluorescein B
- I
isothiocyanate I
( O
FITC B
) O
- O
dextran O
as O
model O
drug O
was O
determined O
to O
50 O
% O
with O
no O
substantial O
effect O
on O
particle O
size O
. O

80 O
% O
of O
the O
drug O
is O
only O
released O
after O
enzymatic O
digestion O
. O

Neural O
correlates O
of O
performance O
monitoring O
in O
chronic O
cannabis O
users O
and O
cannabis O
- O
naive O
controls O
. O

Chronic O
cannabis O
use O
is O
associated O
with O
residual O
negative O
effects O
on O
measures O
of O
executive O
functioning O
. O

However O
, O
little O
previous O
work O
has O
focused O
specifically O
on O
executive O
processes O
involved O
in O
performance O
monitoring O
in O
frequent O
cannabis O
users O
. O

The O
present O
study O
investigated O
event O
- O
related O
potential O
( O
ERP O
) O
correlates O
of O
performance O
monitoring O
in O
chronic O
cannabis O
users O
. O

The O
error O
- O
related O
negativity O
( O
ERN O
) O
and O
error O
positivity O
( O
Pe O
) O
, O
ERPs O
sensitive O
to O
performance O
monitoring O
, O
were O
recorded O
from O
30 O
frequent O
cannabis O
users O
( O
mean O
usage O
= O
5 O
. O
52 O
days O
/ O
week O
) O
and O
32 O
cannabis O
- O
na O
i O
ve O
control O
participants O
during O
a O
speeded O
stimulus O
discrimination O
task O
. O

The O
" O
oddball O
" O
P3 O
ERP O
was O
recorded O
as O
well O
. O

Users O
and O
controls O
did O
not O
differ O
on O
the O
amplitude O
or O
latency O
of O
the O
ERN O
; O
however O
, O
Pe O
amplitude O
was O
larger O
among O
users O
. O

Users O
also O
showed O
increased O
amplitude O
and O
reduced O
latency O
of O
the O
P3 O
in O
response O
to O
infrequent O
stimuli O
presented O
during O
the O
task O
. O

Among O
users O
, O
urinary O
cannabinoid O
metabolite O
levels O
at O
testing O
were O
unrelated O
to O
ERP O
outcomes O
. O

However O
, O
total O
years O
of O
cannabis O
use O
correlated O
negatively O
with O
P3 O
latency O
and O
positively O
with O
P3 O
amplitude O
, O
and O
age O
of O
first O
cannabis O
use O
correlated O
negatively O
with O
P3 O
amplitude O
. O

The O
results O
of O
this O
study O
suggest O
that O
chronic O
cannabis O
use O
is O
associated O
with O
alterations O
in O
neural O
activity O
related O
to O
the O
processing O
of O
motivationally O
- O
relevant O
stimuli O
( O
P3 O
) O
and O
errors O
( O
Pe O
) O
. O

Expansion O
of O
Secretin O
- O
Like O
G O
Protein O
- O
Coupled O
Receptors O
and O
Their O
Peptide O
Ligands O
via O
Local O
Duplications O
Before O
and O
After O
Two O
Rounds O
of O
Whole O
- O
Genome O
Duplication O
. O

In O
humans O
, O
the O
secretin O
- O
like O
G O
protein O
- O
coupled O
receptor O
( O
GPCR O
) O
family O
comprises O
15 O
members O
with O
18 O
corresponding O
peptide O
ligand O
genes O
. O

Although O
members O
have O
been O
identified O
in O
a O
large O
variety O
of O
vertebrate O
and O
nonvertebrate O
species O
, O
the O
origin O
and O
relationship O
of O
these O
proteins O
remain O
unresolved O
. O

To O
address O
this O
issue O
, O
we O
employed O
large O
- O
scale O
genome O
comparisons O
to O
identify O
genome O
fragments O
with O
conserved O
synteny O
and O
matched O
these O
fragments O
to O
linkage O
groups O
in O
reconstructed O
early O
gnathostome O
ancestral O
chromosomes O
( O
GAC O
) O
. O

This O
genome O
comparison O
revealed O
that O
most O
receptor O
and O
peptide O
genes O
were O
clustered O
in O
three O
GAC O
linkage O
groups O
and O
suggested O
that O
the O
ancestral O
forms O
of O
five O
peptide O
subfamilies O
( O
corticotropin O
- O
releasing O
hormone O
- O
like O
, O
calcitonin O
- O
like O
, O
parathyroid O
hormone O
- O
like O
, O
glucagon O
- O
like O
, O
and O
growth O
hormone O
- O
releasing O
hormone O
- O
like O
) O
and O
their O
cognate O
receptor O
families O
emerged O
through O
tandem O
local O
gene O
duplications O
before O
two O
rounds O
( O
2R O
) O
of O
whole O
- O
genome O
duplication O
. O

These O
subfamily O
genes O
have O
, O
then O
, O
been O
amplified O
by O
2R O
whole O
- O
genome O
duplication O
, O
followed O
by O
additional O
local O
duplications O
and O
gene O
loss O
prior O
to O
the O
divergence O
of O
land O
vertebrates O
and O
teleosts O
. O

This O
study O
delineates O
a O
possible O
evolutionary O
scenario O
for O
whole O
secretin O
- O
like O
peptide O
and O
receptor O
family O
members O
and O
may O
shed O
light O
on O
evolutionary O
mechanisms O
for O
expansion O
of O
a O
gene O
family O
with O
a O
large O
number O
of O
paralogs O
. O

Decompression O
- O
induced O
crystal O
polymorphism O
in O
a O
room O
- O
temperature O
ionic O
liquid O
, O
N B
, I
N I
- I
diethyl I
- I
N I
- I
methyl I
- I
N I
- I
( I
2 I
- I
methoxyethyl I
) I
ammonium I
tetrafluoroborate I
. O

We O
explore O
the O
phase O
behavior O
of O
room O
- O
temperature O
ionic O
liquids O
( O
RTILs O
) O
compressed O
under O
high O
pressure O
to O
determine O
whether O
they O
crystallize O
or O
hold O
a O
liquid O
state O
. O

RTILs O
have O
attractive O
supercooling O
properties O
compared O
with O
ordinary O
molecular O
liquids O
, O
which O
easily O
become O
a O
glassy O
state O
without O
crystallizing O
at O
ambient O
pressure O
. O

Thus O
, O
phase O
behavior O
under O
extreme O
stress O
, O
such O
as O
pressure O
, O
might O
yield O
interesting O
results O
. O

Here O
, O
we O
show O
that O
N B
, I
N I
- I
diethyl I
- I
N I
- I
methyl I
- I
N I
- I
( I
2 I
- I
methoxyethyl I
) I
ammonium I
tetrafluoroborate I
( O
[ B
DEME I
] I
[ I
BF4 I
] I
) O
could O
be O
crystallized O
upon O
compression O
, O
but O
it O
usually O
formed O
a O
superpressed O
liquid O
. O

Alternatively O
, O
unusual O
crystallization O
could O
be O
induced O
by O
releasing O
the O
pressure O
on O
the O
superpressed O
liquid O
. O

Notably O
, O
crystal O
polymorphism O
was O
observed O
in O
the O
decompression O
process O
. O

These O
facts O
along O
with O
visual O
observations O
indicate O
the O
possibility O
of O
[ B
DEME I
] I
[ I
BF4 I
] I
serving O
as O
a O
superpressurized O
glass O
. O

Our O
findings O
may O
facilitate O
the O
development O
of O
a O
new O
range O
of O
applications O
for O
RTILs O
that O
have O
undergone O
high O
- O
pressure O
recrystallization O
. O

Excitons O
in O
conjugated O
polymers O
: O
a O
tale O
of O
two O
particles O
. O

Since O
the O
discovery O
of O
electroluminescence O
in O
the O
phenyl B
- O
based O
conjugated O
polymers O
in O
1990 O
, O
the O
field O
of O
polymer O
optoelectronics O
has O
matured O
to O
the O
extent O
that O
presently O
a O
wide O
class O
of O
devices O
have O
been O
commercialized O
. O

These O
range O
from O
both O
miniature O
and O
wide O
- O
area O
light O
emitting O
devices O
to O
hybrid O
photovoltaic O
devices O
. O

Similarly O
, O
our O
understanding O
of O
the O
fundamental O
processes O
that O
determine O
these O
optoelectronic O
properties O
has O
also O
progressed O
. O

In O
particular O
, O
owing O
to O
insights O
from O
both O
experimental O
and O
theoretical O
investigations O
, O
the O
role O
of O
the O
primary O
excited O
states O
, O
i O
. O
e O
. O
, O
excitons O
, O
is O
now O
considerably O
clearer O
. O

This O
review O
discusses O
these O
primary O
excited O
states O
and O
explains O
how O
the O
three O
key O
roles O
of O
electron O
- O
electron O
interactions O
, O
electron O
- O
nuclear O
coupling O
, O
and O
disorder O
determine O
their O
properties O
. O

We O
show O
that O
the O
properties O
of O
an O
exciton O
are O
more O
readily O
understood O
by O
decomposing O
it O
into O
two O
effective O
particles O
. O

First O
, O
a O
relative O
particle O
that O
describes O
the O
size O
and O
binding O
energy O
of O
the O
electron O
- O
hole O
pair O
. O

Second O
, O
a O
center O
- O
of O
- O
mass O
particle O
that O
describes O
the O
extent O
of O
the O
delocalization O
of O
the O
electron O
- O
hole O
pair O
. O

Disorder O
and O
coupling O
to O
the O
normal O
modes O
localizes O
the O
center O
- O
of O
- O
mass O
particle O
and O
provides O
a O
quantitative O
definition O
of O
chromophores O
in O
conjugated O
polymers O
, O
paving O
the O
way O
for O
a O
first O
- O
principles O
theory O
of O
exciton O
diffusion O
in O
these O
systems O
. O

Components O
of O
the O
Interleukin O
- O
6 O
transsignalling O
system O
are O
associated O
with O
the O
metabolic O
syndrome O
, O
endothelial O
dysfunction O
and O
arterial O
stiffness O
. O

OBJECTIVE O
: O
The O
metabolic O
syndrome O
( O
MetS O
) O
is O
an O
increasing O
epidemiologic O
challenge O
and O
cardiovascular O
risk O
factor O
. O

Interleukin O
- O
6 O
( O
IL O
- O
6 O
) O
is O
a O
cytokine O
that O
exerts O
its O
biological O
function O
via O
a O
complex O
orchestration O
of O
soluble O
and O
membrane O
bound O
receptors O
. O

We O
have O
investigated O
associations O
between O
IL O
- O
6 O
and O
its O
soluble O
receptors O
, O
soluble O
IL O
- O
6 O
receptor O
( O
sIL O
- O
6r O
) O
and O
soluble O
glycoprotein O
130 O
( O
sGP130 O
) O
and O
the O
metabolic O
syndrome O
. O

Furthermore O
, O
we O
have O
investigated O
possible O
associations O
with O
endothelial O
dysfunction O
and O
arterial O
stiffness O
. O

METHODS O
: O
A O
total O
of O
563 O
subjects O
were O
included O
in O
this O
study O
. O

The O
Adult O
Treatment O
Panel O
III O
criteria O
of O
the O
National O
Cholesterol B
Education O
Program O
were O
used O
for O
the O
definition O
of O
MetS O
. O

We O
used O
commercially O
available O
ELISA O
to O
analyse O
circulating O
levels O
of O
the O
markers O
. O

Pulse O
wave O
propagation O
time O
( O
PWP O
) O
was O
determined O
to O
assess O
arterial O
stiffness O
. O

RESULTS O
: O
The O
criteria O
for O
having O
MetS O
were O
filled O
by O
221 O
subjects O
. O

sGP130 O
, O
sIL O
- O
6r O
and O
IL O
- O
6 O
levels O
were O
elevated O
in O
subjects O
with O
MetS O
( O
p O
< O
0 O
. O
05 O
for O
all O
markers O
) O
, O
and O
are O
associated O
with O
increasing O
components O
of O
MetS O
. O

Particularly O
hypertriglyceridaemi O
, O
hypertension O
and O
fasting O
plasma O
glucose B
( O
FPG O
) O
seem O
to O
carry O
this O
association O
. O

sGP130 O
( O
p O
< O
0 O
. O
01 O
) O
, O
IL O
- O
6 O
( O
p O
< O
0 O
. O
05 O
) O
and O
partially O
sIL O
- O
6r O
( O
p O
< O
0 O
. O
05 O
) O
correlated O
with O
markers O
of O
endothelial O
function O
( O
E O
- O
selectin O
, O
I O
- O
CAM O
- O
1 O
, O
V O
- O
CAM O
- O
1 O
) O
and O
inversely O
with O
PWP O
after O
adjustment O
for O
relevant O
covariates O
. O

CONCLUSION O
: O
sGP130 O
, O
sIL O
- O
6r O
and O
IL O
- O
6 O
were O
significantly O
elevated O
in O
subjects O
with O
MetS O
. O

In O
addition O
, O
sGP130 O
, O
IL O
- O
6 O
and O
partially O
sIL O
- O
6r O
were O
associated O
with O
markers O
of O
endothelial O
function O
and O
arterial O
stiffness O
. O

This O
finding O
sheds O
new O
light O
on O
the O
role O
of O
these O
inflammatory O
cytokines O
in O
subjects O
with O
MetS O
and O
the O
development O
and O
progression O
of O
clinically O
silent O
atherosclerosis O
. O

Atorvastatin B
withdrawal O
elicits O
oxidative O
/ O
nitrosative O
damage O
in O
the O
rat O
cerebral O
cortex O
. O

Statins O
are O
inhibitors O
of O
the O
enzyme O
3 B
- I
hydroxy I
- I
3 I
- I
methylglutaryl I
coenzyme I
A I
reductase O
, O
the O
rate O
- O
limiting O
step O
in O
cholesterol B
biosynthesis O
. O

Statins O
effectively O
prevent O
and O
reduce O
the O
risk O
of O
coronary O
artery O
disease O
through O
lowering O
serum O
cholesterol B
, O
and O
also O
exert O
anti O
- O
thrombotic O
, O
anti O
- O
inflammatory O
and O
antioxidant O
effects O
independently O
of O
changes O
in O
cholesterol B
levels O
. O

On O
the O
other O
hand O
, O
clinical O
and O
experimental O
evidence O
suggests O
that O
abrupt O
cessation O
of O
statin O
treatment O
( O
i O
. O
e O
. O
statin O
withdrawal O
) O
is O
associated O
with O
a O
deleterious O
rebound O
phenomenon O
. O

In O
fact O
, O
statin B
withdrawal O
increases O
the O
risk O
of O
thrombotic O
vascular O
events O
, O
causes O
impairment O
of O
endothelium O
- O
dependent O
relaxation O
and O
facilitates O
experimental O
seizures O
. O

However O
, O
evidence O
for O
statin O
withdrawal O
- O
induced O
detrimental O
effects O
to O
the O
brain O
parenchyma O
is O
still O
lacking O
. O

In O
the O
present O
study O
adult O
male O
Wistar O
rats O
were O
treated O
with O
atorvastatin B
for O
seven O
days O
( O
10mg O
/ O
kg O
/ O
day O
) O
and O
neurochemical O
assays O
were O
performed O
in O
the O
cerebral O
cortex O
30min O
( O
atorvastatin B
treatment O
) O
or O
24h O
( O
atorvastatin B
withdrawal O
) O
after O
the O
last O
atorvastatin B
administration O
. O

We O
found O
that O
atorvastatin B
withdrawal O
decreased O
levels O
of O
nitric B
oxide I
and O
mitochondrial O
superoxide B
dismutase O
activity O
, O
whereas O
increased O
NADPH B
oxidase O
activity O
and O
immunoreactivity O
for O
the O
protein O
nitration O
marker O
3 B
- I
nitrotyrosine I
in O
the O
cerebral O
cortex O
. O

Catalase O
, O
glutathione B
- O
S B
- O
transferase O
and O
xanthine B
oxidase O
activities O
were O
not O
altered O
by O
atorvastatin B
treatment O
or O
withdrawal O
, O
as O
well O
as O
protein O
carbonyl B
and O
4 B
- I
hydroxy I
- I
2 I
- I
nonenal I
immunoreactivity O
. O

Immunoprecipitation O
of O
mitochondrial O
SOD O
followed O
by O
analysis O
of O
3 B
- I
nitrotyrosine I
revealed O
increased O
levels O
of O
nitrated O
mitochondrial O
SOD O
, O
suggesting O
the O
mechanism O
underlying O
the O
atorvastatin B
withdrawal O
- O
induced O
decrease O
in O
enzyme O
activity O
. O

Altogether O
, O
our O
results O
indicate O
the O
atorvastatin B
withdrawal O
elicits O
oxidative O
/ O
nitrosative O
damage O
in O
the O
rat O
cerebral O
cortex O
, O
and O
that O
changes O
in O
NADPH B
oxidase O
activity O
and O
mitochondrial O
superoxide B
dismutase O
activities O
may O
underlie O
such O
harmful O
effects O
. O

Medical O
therapy O
of O
coronary O
artery O
disease O
after O
percutaneous O
intervention O
. O

Medical O
therapy O
following O
percutaneous O
coronary O
intervention O
aims O
at O
preventing O
first O
, O
coronary O
disease O
progression O
and O
its O
clinical O
manifestations O
, O
and O
finally O
, O
the O
two O
main O
complications O
of O
coronary O
stenting O
, O
stent O
thrombosis O
and O
restenosis O
. O

Prevention O
of O
in O
- O
stent O
restenosis O
is O
restricted O
to O
local O
drug O
delivery O
in O
the O
form O
of O
drug O
eluting O
stents O
( O
DES O
) O
. O

Second O
generation O
DES O
have O
improved O
their O
efficacy O
and O
safety O
profile O
by O
innovations O
in O
drug O
coating O
, O
the O
polymer O
drug O
- O
delivery O
system O
and O
stent O
design O
. O

The O
mainstay O
of O
stent O
thrombosis O
prevention O
remains O
dual O
anti O
- O
platelet O
therapy O
with O
acetylsalicylic B
acid I
and O
a O
platelet O
ADP B
- O
receptor O
blocker O
, O
traditionally O
clopidogrel B
. O

Two O
new O
drugs O
, O
prasugrel B
and O
ticagrelor B
, O
provide O
faster O
, O
greater O
, O
and O
more O
consistent O
platelet O
inhibition O
than O
clopidogrel B
, O
and O
have O
been O
shown O
to O
be O
more O
efficacious O
in O
preventing O
ischemic O
events O
after O
PCI O
in O
acute O
coronary O
syndrome O
patients O
. O

Oxysterol B
- O
binding O
proteins O
: O
Functions O
in O
cell O
regulation O
beyond O
lipid O
metabolism O
. O

Oxysterol B
- O
binding O
( O
OSBP O
) O
- O
related O
proteins O
( O
ORPs O
) O
constitute O
a O
family O
of O
sterol B
and O
phosphoinositide B
binding O
/ O
transfer O
proteins O
in O
eukaryotes O
from O
yeast O
to O
man O
. O

While O
their O
functions O
have O
mainly O
been O
addressed O
in O
cellular O
lipid O
metabolism O
or O
sterol B
transport O
, O
increasing O
evidence O
points O
to O
more O
versatile O
regulatory O
roles O
in O
a O
spectrum O
of O
cellular O
regimes O
. O

In O
fact O
ORPs O
do O
not O
appear O
to O
be O
robust O
controllers O
of O
lipid O
homeostasis O
. O

Several O
ORPs O
localize O
at O
membrane O
contacts O
sites O
( O
MCS O
) O
, O
where O
endoplasmic O
reticulum O
( O
ER O
) O
is O
apposed O
with O
other O
organelle O
limiting O
membranes O
. O

Apparently O
, O
ORPs O
have O
the O
capacity O
to O
control O
the O
formation O
of O
MCS O
or O
activity O
of O
enzymatic O
machineries O
at O
these O
sites O
. O

Thereby O
, O
ORPs O
most O
likely O
affect O
organelle O
membrane O
lipid O
compositions O
, O
with O
impacts O
on O
signaling O
and O
vesicle O
transport O
, O
but O
also O
cellular O
lipid O
metabolism O
. O

Moreover O
, O
an O
increasing O
number O
of O
protein O
interaction O
partners O
of O
ORPs O
have O
been O
identified O
, O
connecting O
these O
proteins O
with O
various O
aspects O
of O
cell O
regulation O
. O

Small O
molecular O
anti O
- O
proliferative O
compounds O
, O
ORPphilins B
, O
were O
recently O
found O
to O
target O
two O
members O
of O
the O
ORP O
family O
, O
OSBP O
and O
ORP4 O
, O
revealing O
an O
essential O
function O
of O
ORPs O
in O
cancer O
cell O
proliferation O
and O
survival O
. O

Further O
functions O
assigned O
for O
ORPs O
include O
regulation O
of O
extracellular O
signal O
regulated O
kinase O
( O
ERK O
) O
activity O
( O
OSBP O
) O
, O
control O
of O
ER O
- O
late O
endosome O
MCS O
and O
late O
endosome O
motility O
( O
ORP1L O
) O
, O
regulation O
of O
beta O
1 O
- O
integrin O
activity O
( O
ORP3 O
) O
, O
modulation O
of O
hepatocyte O
insulin O
signaling O
and O
macrophage O
migration O
( O
ORP8 O
) O
, O
as O
well O
as O
post O
- O
Golgi O
vesicle O
transport O
, O
phosphatidylinositol B
- I
4 I
- I
phosphate I
and O
target O
of O
rapamycin B
complex O
1 O
signaling O
and O
nitrogen B

sensing O
( O
Saccharomyces O
cerevisiae O
Osh4p O
) O
. O

These O
and O
other O
recent O
observations O
shed O
light O
on O
the O
ORPs O
as O
integrators O
of O
lipid O
signals O
with O
an O
unforeseen O
variety O
of O
vital O
cellular O
processes O
. O

Inhibitory O
effect O
of O
dihydroartemisinin B
against O
phorbol B
ester I
- O
induced O
cyclooxygenase O
- O
2 O
expression O
in O
macrophages O
. O

Dihydroartemisinin B
( O
DHA B
) O
, O
a O
semi O
- O
synthetic O
derivative O
of O
artemisinin B
isolated O
from O
the O
traditional O
Chinese O
herb O
Artemisia O
annua O
L O
. O
, O
has O
recently O
been O
shown O
to O
possess O
antitumor O
activity O
in O
various O
cancer O
cells O
. O

However O
, O
the O
effect O
of O
anti O
- O
inflammatory O
potentials O
of O
DHA B
in O
murine O
macrophage O
RAW O
264 O
. O
7 O
cells O
has O
not O
been O
studied O
. O

The O
present O
study O
investigated O
the O
effect O
of O
COX O
- O
2 O
and O
molecular O
mechanisms O
by O
DHA B
in O
PMA B
stimulated O
RAW O
264 O
. O
7 O
cells O
. O

DHA B
dose O
- O
dependently O
decreased O
PMA B
- O
induced O
COX O
- O
2 O
expression O
and O
PGE2 B
production O
, O
as O
well O
as O
COX O
- O
2 O
promoter O
- O
driven O
luciferase O
activity O
. O

Additionally O
, O
DHA B
decreased O
luciferase O
activity O
of O
COX O
- O
2 O
regulation O
- O
related O
transcription O
factors O
including O
NF O
- O
kappa O
B O
, O
AP O
- O
1 O
, O
C O
/ O
EBP O
and O
CREB O
. O

DHA B
also O
remarkably O
reduced O
PMA B
- O
induced O
p65 O
, O
C O
/ O
EBP O
beta O
, O
c O
- O
jun O
and O
CREB O
nuclear O
translocation O
. O

Furthermore O
, O
DHA B
evidently O
inhibited O
PMA B
- O
induced O
phosphorylation O
of O
AKT O
and O
the O
MAP O
Kinases O
, O
such O
as O
ERK O
, O
JNK O
and O
p38 O
. O

Taken O
together O
, O
our O
data O
indicated O
that O
DHA B
effectively O
attenuates O
COX O
- O
2 O
production O
via O
down O
- O
regulation O
of O
AKT O
and O
MAPK O
pathway O
, O
revealing O
partial O
molecular O
basis O
for O
the O
anti O
- O
inflammatory O
properties O
of O
DHA B
. O

Low O
- O
dose O
bisphenol B
A I
and O
estrogen B
increase O
ventricular O
arrhythmias O
following O
ischemia O
- O
reperfusion O
in O
female O
rat O
hearts O
. O

Bisphenol B
A I
( O
BPA B
) O
is O
an O
environmental O
estrogenic O
endocrine O
disruptor O
that O
may O
have O
adverse O
health O
impacts O
on O
a O
range O
of O
tissue O
/ O
systems O
. O

In O
previous O
studies O
, O
we O
reported O
that O
BPA B
rapidly O
promoted O
arrhythmias O
in O
female O
rodent O
hearts O
through O
alteration O
of O
myocyte O
calcium B
handling O
. O

In O
the O
present O
study O
we O
investigated O
the O
acute O
effects O
of O
BPA B
on O
ventricular O
arrhythmias O
and O
infarction O
following O
ischemia O
- O
reperfusion O
in O
rat O
hearts O
. O

Rat O
hearts O
were O
subjected O
to O
20min O
of O
global O
ischemia O
followed O
by O
reperfusion O
. O

In O
female O
, O
but O
not O
male O
hearts O
, O
acute O
exposure O
to O
1nM O
BPA B
, O
either O
alone O
or O
combined O
with O
1nM O
17 B
beta I
- I
estradiol I
( O
E2 O
) O
, O
during O
reperfusion O
resulted O
in O
a O
marked O
increase O
in O
the O
duration O
of O
sustained O
ventricular O
arrhythmias O
. O

BPA B
plus O
E2 O
increased O
the O
duration O
ventricular O
fibrillation O
, O
and O
the O
duration O
of O
VF O
as O
a O
fraction O
of O
total O
duration O
of O
sustained O
ventricular O
arrhythmia O
. O

The O
pro O
- O
arrhythmic O
effects O
of O
estrogens B
were O
abolished O
by O
MPP B
combined O
with O
PHTPP B
, O
suggesting O
the O
involvements O
of O
both O
ER O
alpha O
and O
ER O
beta O
signaling O
. O

In O
contrast O
to O
their O
pro O
- O
arrhythmic O
effects O
, O
BPA B
and O
E2 O
reduced O
infarction O
size O
, O
agreeing O
with O
previously O
described O
protective O
effect O
of O
estrogen B
against O
cardiac O
infarction O
. O

In O
conclusion O
, O
rapid O
exposure O
to O
low O
dose O
BPA B
, O
particularly O
when O
combined O
with O
E2 O
, O
exacerbates O
ventricular O
arrhythmia O
following O
IR O
injury O
in O
female O
rat O
hearts O
. O

Effects O
of O
maternally O
exposed O
coloring O
food O
additives O
on O
receptor O
expressions O
related O
to O
learning O
and O
memory O
in O
rats O
. O

Exposure O
to O
artificial O
food O
colors O
and O
additives O
( O
AFCAs O
) O
has O
been O
implicated O
in O
the O
induction O
and O
severity O
of O
some O
childhood O
behavioral O
and O
learning O
disabilities O
. O

N B
- I
methyl I
- I
D I
- I
aspartate I
receptors O
( O
NMDARs O
) O
and O
nicotinic O
acetylcholine B
receptors O
( O
nACHRs O
) O
are O
thought O
to O
be O
effective O
in O
the O
learning O
and O
memory O
- O
generating O
process O
. O

In O
this O
study O
, O
we O
investigated O
the O
effects O
of O
intrauterine O
exposure O
to O
AFCAs B
on O
subunit O
concentrations O
of O
NMDARs O
and O
nAChRs O
isoforms O
in O
rats O
. O

We O
administered O
a O
mixture O
of O
AFCAs O
( O
Eritrosin B
, O
Ponceau B
4R I
, O
Allura B
Red I
AC I
, O
Sunset B
Yellow I
FCF I
, O
Tartrazin B
, O
Amaranth B
, O
Brilliant B
Blue I
, O
Azorubin B
and O
Indigotin B
) O
to O
female O
rats O
before O
and O
during O
gestation O
. O

The O
concentration O
of O
NR2A O
and O
NR2B O
subunits O
and O
nAChR O
alpha O
7 O
, O
alpha O
4 O
beta O
2 O
isoforms O
in O
their O
offspring O
' O
s O
hippocampi O
were O
measured O
by O
Western O
Blotting O
. O

Expressions O
of O
NR2B O
and O
nAChR O
beta O
2 O
were O
significantly O
increased O
( O
17 O
% O
and O
6 O
. O
70 O
% O
, O
respectively O
) O
, O
whereas O
expression O
of O
nAChR O
alpha O
4 O
was O
significantly O
decreased O
( O
5 O
. O
67 O
% O
) O
in O
male O
experimental O
group O
compared O
to O
the O
male O
control O
group O
( O
p O
< O
0 O
. O
05 O
) O
. O

In O
the O
female O
experimental O
group O
, O
AFCAs B
caused O
a O
14 O
% O
decrease O
in O
NR2B O
expression O
when O
compared O
to O
the O
female O
control O
group O
( O
p O
< O
0 O
. O
05 O
) O
. O

Our O
results O
indicate O
that O
exposure O
to O
AFCAs O
during O
the O
fetal O
period O
may O
lead O
to O
alterations O
in O
expressions O
of O
NMDARs O
and O
nAChRs O
in O
adulthood O
. O

These O
alterations O
were O
different O
between O
male O
and O
female O
genders O
. O

Metallothionein O
1A O
polymorphisms O
may O
influence O
urine O
uric B
acid I
and O
N B
- I
acetyl I
- O
beta O
- O
d O
- O
glucosaminidase O
( O
NAG O
) O
excretion O
in O
chronic O
lead O
- O
exposed O
workers O
. O

Lead O
is O
a O
renal O
toxin O
, O
and O
susceptibility O
to O
lead O
varies O
between O
individuals O
. O

Metallothionein O
( O
MT O
) O
is O
known O
for O
its O
metal O
scavenging O
role O
. O

The O
aim O
of O
the O
study O
was O
to O
investigate O
the O
association O
of O
blood O
lead O
levels O
, O
urinary O
uric B
acid I
( O
UA O
) O
and O
N B
- I
acetyl I
- O
beta O
- O
d O
- O
glucosaminidase O
( O
NAG O
) O
in O
chronic O
occupational O
lead O
- O
exposed O
workers O
, O
and O
to O
study O
whether O
the O
association O
was O
influenced O
by O
MT1A O
gene O
polymorphisms O
. O

In O
this O
cross O
- O
sectional O
study O
, O
412 O
lead O
- O
exposed O
workers O
participated O
. O

Their O
annual O
health O
examination O
data O
and O
renal O
function O
markers O
were O
collected O
after O
the O
Institutional O
Review O
Broad O
of O
Kaohsiung O
Medical O
University O
Hospital O
approved O
the O
study O
and O
consent O
letters O
were O
obtained O
. O

From O
the O
blood O
samples O
, O
DNA O
was O
extracted O
and O
used O
for O
real O
- O
time O
PCR O
typing O
of O
2 O
MT1A O
single O
nucleotide O
polymorphisms O
( O
SNPs O
) O
: O
rs11640851 O
and O
rs8052394 O
on O
exons O
2 O
and O
3 O
. O

Descriptive O
analysis O
, O
one O
- O
way O
ANOVA O
, O
and O
multiple O
linear O
regressions O
were O
performed O
. O

There O
was O
a O
significant O
inverted O
relationship O
of O
creatinine B
- O
adjusted O
urine O
UA O
concentrations O
and O
the O
time O
- O
weighted O
index O
of O
cumulative O
blood O
lead O
levels O
( O
TWICL O
) O
that O
may O
be O
significantly O
influenced O
by O
the O
AC O
genotypes O
of O
rs11640851 O
in O
exon O
2 O
and O
rs8052394 O
in O
exon O
3 O
. O

After O
controlling O
for O
potential O
confounding O
factors O
, O
the O
creatinine B
- O
adjusted O
urine O
NAG O
concentrations O
were O
shown O
to O
be O
influenced O
by O
the O
GG O
genotype O
of O
rs8052394 O
in O
exon O
3 O
, O
and O
were O
weakly O
increased O
with O
TWICL O
. O

Therefore O
, O
we O
concluded O
that O
the O
variations O
of O
MT1A O
SNPs O
may O
influence O
urine O
UA O
and O
NAG O
excretion O
in O
chronic O
lead O
- O
exposed O
workers O
, O
and O
urine O
creatinine B
- O
adjusted O
urine O
UA O
as O
a O
biomarker O
of O
lead O
toxicity O
should O
be O
considered O
. O

Reduced O
Acute O
Recovery O
from O
Alcohol B
Impairment O
in O
Adults O
with O
ADHD O
. O

RATIONALE O
: O
Prior O
research O
has O
found O
that O
adults O
with O
attention O
- O
deficit O
/ O
hyperactivity O
disorder O
( O
ADHD O
) O
show O
increased O
sensitivity O
to O
the O
impairing O
effects O
of O
alcohol B
( O
Weafer O
et O
al O
. O
, O
Exp O
Clin O
Psychopharmacol O
17 O
: O
113 O
- O
121 O
, O
2009 O
) O
. O

However O
, O
these O
studies O
have O
focused O
exclusively O
on O
the O
ascending O
limb O
of O
the O
blood O
alcohol B
concentration O
( O
BAC O
) O
curve O
, O
and O
it O
is O
unclear O
whether O
these O
adults O
continue O
to O
show O
increased O
sensitivity O
during O
the O
later O
phase O
of O
the O
dose O
as O
BAC O
is O
declining O
. O

OBJECTIVE O
: O
This O
study O
tested O
the O
hypothesis O
that O
those O
with O
ADHD O
would O
display O
increased O
response O
to O
alcohol B
during O
the O
ascending O
limb O
of O
the O
BAC O
curve O
and O
less O
recovery O
from O
the O
impairing O
effects O
during O
the O
descending O
limb O
. O

METHODS O
: O
Adult O
social O
drinkers O
with O
ADHD O
and O
control O
adults O
completed O
measures O
of O
motor O
coordination O
, O
reaction O
time O
( O
RT O
) O
, O
and O
subjective O
intoxication O
twice O
following O
0 O
. O
64 O
g O
/ O
kg O
alcohol B
and O
placebo O
. O

The O
measures O
were O
administered O
during O
the O
ascending O
limb O
of O
the O
BAC O
curve O
and O
again O
during O
the O
descending O
limb O
. O

RESULTS O
: O
During O
the O
ascending O
limb O
, O
alcohol B
reduced O
motor O
coordination O
, O
slowed O
RT O
, O
and O
increased O
self O
- O
reports O
of O
subjective O
intoxication O
. O

Those O
with O
ADHD O
displayed O
greater O
impairment O
of O
motor O
coordination O
compared O
with O
controls O
. O

During O
the O
descending O
limb O
, O
controls O
reported O
diminished O
subjective O
intoxication O
and O
showed O
recovery O
from O
the O
impairing O
effects O
of O
alcohol B
on O
both O
their O
motor O
coordination O
and O
their O
RT O
. O

Those O
with O
ADHD O
showed O
reduced O
subjective O
intoxication O
and O
faster O
RT O
during O
this O
time O
, O
but O
they O
did O
not O
recover O
motor O
control O
. O

CONCLUSIONS O
: O
The O
protracted O
time O
course O
of O
motor O
impairment O
in O
adults O
with O
ADHD O
despite O
reductions O
in O
subjective O
intoxication O
may O
contribute O
to O
poor O
decision O
making O
and O
diminished O
behavioral O
control O
in O
this O
group O
. O

Effect O
of O
chronic O
ethanol B
treatment O
on O
mu O
- O
opioid O
receptor O
function O
, O
interacting O
proteins O
and O
morphine B
- O
induced O
place O
preference O
. O

RATIONALE O
: O
Both O
the O
acute O
and O
chronic O
consumption O
of O
ethanol B
have O
been O
reported O
to O
modify O
several O
molecular O
events O
in O
the O
central O
nervous O
system O
, O
and O
the O
endogenous O
mu O
- O
opioid O
receptor O
system O
is O
involved O
in O
the O
reinforcing O
/ O
rewarding O
effects O
of O
ethanol B
. O

OBJECTIVES O
: O
The O
present O
study O
was O
designed O
to O
clarify O
the O
effects O
of O
chronic O
ethanol B
treatment O
on O
cellular O
processes O
involving O
mu O
- O
opioid O
receptor O
and O
the O
development O
of O
morphine B
- O
induced O
rewarding O
effects O
. O

METHODS O
: O
Male O
C57BL O
/ O
6J O
mice O
were O
continuously O
treated O
with O
a O
liquid O
diet O
containing O
3 O
. O
0 O
w O
/ O
v O
ethanol B
. O

The O
direct O
involvement O
of O
mu O
- O
opioid O
receptor O
functions O
in O
the O
activation O
of O
G O
- O
proteins O
and O
changes O
in O
protein O
levels O
in O
the O
lower O
midbrain O
of O
mice O
after O
chronic O
treatment O
with O
ethanol B
were O
investigated O
by O
a O
[ B
( I
35 I
) I
S I
] O
GTP I
gamma I
S I
binding O
assay O
and O
Western O
blotting O
, O
respectively O
. O

The O
rewarding O
effects O
of O
morphine B
( O
5 O
mg O
/ O
kg O
) O
under O
treatment O
with O
ethanol B
were O
measured O
by O
the O
conditioned O
place O
preference O
paradigm O
. O

RESULTS O
: O
The O
function O
of O
mu O
- O
opioid O
receptor O
was O
increased O
by O
treatment O
with O
ethanol B
in O
the O
lower O
midbrain O
using O
[ B
( I
35 I
) I
S I
] I
GTP I
gamma I
S I
binding O
assay O
. O

Furthermore O
, O
the O
GRK2 O
protein O
level O
was O
significantly O
increased O
by O
treatment O
with O
ethanol B
. O

Chronic O
treatment O
with O
ethanol B
enhanced O
the O
rewarding O
effects O
of O
morphine B
. O

On O
the O
other O
hand O
, O
this O
enhancement O
of O
the O
rewarding O
effects O
of O
morphine B
by O
ethanol B
treatment O
was O
significantly O
inhibited O
by O
the O
GRK2 O
inhibitor O
beta O
- O
adrenergic O
receptor O
kinase O
1 O
inhibitor O
. O

CONCLUSIONS O
: O
The O
present O
study O
demonstrated O
that O
chronic O
treatment O
with O
ethanol B
enhanced O
the O
rewarding O
effects O
of O
morphine B
by O
up O
- O
regulating O
functional O
changes O
in O
mu O
- O
opioid O
receptor O
, O
mediated O
by O
GRK2 O
. O

Interleukin O
- O
10 O
promoter O
variants O
predict O
HPV O
- O
positive O
tumors O
and O
survival O
of O
squamous O
cell O
carcinoma O
of O
the O
oropharynx O
. O

Interleukin O
- O
10 O
( O
IL O
- O
10 O
) O
plays O
an O
important O
role O
in O
a O
host O
' O
s O
defense O
against O
human O
papillomavirus O
( O
HPV O
) O
infection O
. O

IL O
- O
10 O
promoter O
variants O
may O
affect O
its O
expression O
level O
or O
functional O
efficiency O
and O
, O
subsequently O
, O
susceptibility O
to O
and O
survival O
of O
HPV16 O
- O
associated O
squamous O
cell O
carcinoma O
of O
oropharynx O
( O
SCCOP O
) O
. O

We O
determined O
tumor O
HPV16 O
DNA O
and O
genotyped O
three O
IL O
- O
10 O
promoter O
polymorphisms O
in O
309 O
incident O
patients O
with O
SCCOP O
. O

Compared O
with O
the O
patients O
with O
corresponding O
common O
homozygous O
genotypes O
, O
patients O
carrying O
variant O
genotypes O
of O
IL O
- O
10 O
rs1800871 O
and O
rs1800872 O
were O
~ O
2 O
. O
5 O
times O
more O
likely O
to O
have O
HPV16 O
( O
+ O
) O
tumors O
among O
patients O
with O
SCCOP O
. O

Among O
HPV16 O
( O
+ O
) O
patients O
with O
SCCOP O
only O
, O
compared O
to O
those O
with O
the O
corresponding O
variant O
genotypes O
, O
the O
patients O
with O
IL O
- O
10 O
rs1800871 O
and O
rs1800872 O
CC O
genotypes O
had O
significantly O
better O
survival O
and O
~ O
70 O
- O
80 O
% O
reduced O
risk O
of O
death O
/ O
recurrence O
after O
multivariable O
adjustment O
. O

Additionally O
, O
functional O
relevance O
of O
these O
variants O
was O
characterized O
to O
explore O
the O
genotype O
- O
phenotype O
correlation O
. O

Our O
findings O
indicate O
that O
IL O
- O
10 O
genetic O
variants O
may O
be O
associated O
with O
tumor O
HPV16 O
( O
+ O
) O
SCCOP O
and O
predict O
survival O
of O
HPV16 O
( O
+ O
) O
patients O
with O
SCCOP O
. O

Larger O
studies O
are O
needed O
to O
validate O
our O
findings O
. O
- O
Jin O
, O
L O
. O
, O
Sturgis O
, O
E O
. O

M O
. O
, O
Cao O
, O
X O
. O
, O
Song O
, O
X O
. O
, O
Salahuddin O
, O
T O
. O
, O
Wei O
, O
Q O
. O
, O
Li O
, O
G O
. O

Interleukin O
- O
10 O
promoter O
variants O
predict O
HPV O
- O
positive O
tumors O
and O
survival O
of O
squamous O
cell O
carcinoma O
of O
the O
oropharynx O
. O

Effect O
of O
Ketoconazole B
on O
the O
Pharmacokinetics O
of O
the O
11 B
beta I
- I
Hydroxysteroid I
Dehydrogenase O
Type O
1 O
Inhibitor O
ABT B
- I
384 I
and O
Its O
Two O
Active O
Metabolites O
in O
Healthy O
Volunteers O
: O
Population O
Analysis O
of O
Data O
from O
a O
Drug O
- O
Drug O
Interaction O
Study O
. O

ABT B
- I
384 I
[ O
1 B
- I
piperazineacetamide I
, O
N B
- I
[ I
5 I
- I
( I
aminocarbonyl I
) I
tricyclo I
[ I
3 I
. I
3 I
. I
1 I
. I
13 I
, I
7 I
] I
dec I
- I
2 I
- I
yl I
] I
- I
alpha I
, I
alpha I
- I
dimethyl I
- I
4 I
- I
[ I
5 I
- I
( I
trifluoromethyl I
) I
- I
2 I
- I
pyridinyl I
] I
- O
, O
stereoisomer O
] O
is O
a O
potent O
and O
selective O
inhibitor O
of O
11 B
beta I
- I
hydroxysteroid I
dehydrogenase O
type O
1 O
( O
HSD O
- O
1 O
) O
. O

ABT B
- I
384 I
has O
been O
shown O
to O
be O
safe O
and O
well O
tolerated O
in O
humans O
at O
doses O
up O
to O
100 O
mg O
daily O
, O
and O
to O
fully O
inhibit O
both O
peripheral O
and O
brain O
HSD O
- O
1 O
at O
a O
dose O
of O
2 O
mg O
daily O
. O

The O
effect O
of O
ketoconazole B
on O
the O
pharmacokinetics O
of O
ABT B
- I
384 I
and O
its O
two O
active O
metabolites O
, O
A B
- I
1331480 I
and O
A B
- I
847082 I
, O
was O
investigated O
in O
healthy O
volunteers O
. O

When O
10 O
mg O
of O
ABT B
- I
384 I
was O
coadministered O
with O
ketoconazole B
, O
ABT B
- I
384 I
exposures O
increased O
18 O
- O
fold O
for O
area O
under O
the O
plasma O
concentration O
- O
time O
curve O
from O
time O
0 O
to O
infinity O
and O
3 O
. O
5 O
- O
fold O
for O
Cmax O
. O

The O
results O
suggest O
that O
ABT B
- I
384 I
is O
a O
sensitive O
substrate O
of O
CYP3A O
. O

After O
ketoconazole B
coadministration O
, O
exposures O
of O
A B
- I
1331480 I
and O
A B
- I
847082 I
were O
also O
greatly O
increased O
. O

A O
population O
pharmacokinetic O
model O
was O
constructed O
for O
ABT B
- I
384 I
and O
its O
metabolites O
using O
NonMEM O
. O

A O
two O
- O
compartment O
model O
with O
three O
transit O
absorption O
compartments O
best O
described O
ABT O
- O
384 O
data O
. O

The O
model O
predicted O
a O
69 O
. O
3 O
% O
decrease O
in O
ABT B
- I
384 I
clearance O
and O
91 O
. O
1 O
% O
increase O
in O
the O
volume O
of O
distribution O
of O
ABT B
- I
384 I
in O
the O
presence O
of O
ketoconazole B
. O

A B
- I
1331480 I
was O
shown O
to O
be O
formation O
rate O
- O
limited O
and O
A B
- I
847082 I
was O
elimination O
rate O
- O
limited O
. O

Both O
metabolites O
were O
characterized O
by O
a O
one O
- O
compartment O
model O
with O
first O
- O
order O
rate O
constants O
of O
formation O
and O
elimination O
. O

Overall O
the O
model O
adequately O
captured O
the O
concentration O
- O
time O
profiles O
of O
ABT B
- I
384 I
, O
A B
- I
1331480 I
, O
and O
A B
- I
847082 I
in O
both O
ABT B
- I
384 I
- O
alone O
and O
ketoconazole B
- O
coadministration O
conditions O
. O

Although O
ABT B
- I
384 I
exposures O
were O
greatly O
increased O
in O
the O
presence O
of O
ketoconazole B
, O
coadministration O
of O
ABT B
- I
384 I
with O
ketoconazole B
or O
other O
strong O
/ O
moderate O
CYP3A O
inhibitors O
is O
not O
expected O
to O
contribute O
to O
any O
major O
clinical O
safety O
issues O
considering O
the O
favorable O
safety O
profile O
of O
ABT B
- I
384 I
. O

Two O
new O
sesquiterpenoids B
from O
the O
rhizomes O
of O
Nardostachys O
jatamansi O
. O

Phytochemical O
investigation O
of O
CHCl B
( I
3 I
) I
: O
MeOH B
( O
1 O
: O
1 O
) O
extract O
from O
the O
rhizomes O
of O
Nardostachys O
jatamansi O
led O
to O
the O
isolation O
of O
two O
new O
sesquiterpenoids B
( O
5 O
and O
6 O
) O
, O
along O
with O
six O
known O
compounds O
( O
1 O
- O
4 O
, O
7 O
, O
and O
8 O
) O
. O

The O
structures O
of O
two O
new O
compounds O
were O
established O
using O
IR O
, O
MS O
, O
1D O
, O
and O
2D O
NMR O
techniques O
. O

In O
addition O
, O
all O
the O
isolates O
were O
tested O
for O
their O
cytotoxicities O
against O
the O
A549 O
( O
lung O
cancer O
) O
, O
DU O
- O
145 O
( O
prostate O
cancer O
) O
, O
MCF O
- O
7 O
( O
breast O
cancer O
) O
, O
and O
SK O
- O
N O
- O
SH O
( O
neuroblastoma O
) O
. O

Transient O
Receptor O
Potential O
( O
TRP O
) O
Cation O
Channels O
in O
Diabetes O
. O

Transient O
Receptor O
Potential O
( O
TRP O
) O
proteins O
constitute O
a O
family O
of O
cation O
channels O
with O
very O
diverse O
permeation O
and O
gating O
properties O
. O

Likewise O
they O
have O
a O
very O
diverse O
role O
in O
mammalian O
physiology O
ranging O
from O
sensory O
nerve O
endings O
, O
the O
cardiac O
muscle O
to O
immune O
cells O
. O

Increasing O
evidence O
has O
implicated O
TRP O
channels O
in O
the O
pathology O
of O
diabetes O
, O
both O
on O
the O
level O
of O
insulin O
release O
from O
the O
pancreatic O
beta O
cells O
and O
in O
secondary O
conditions O
such O
as O
diabetic O
neuropathy O
, O
nephropathy O
and O
vasculopathy O
. O

In O
this O
review O
we O
summarize O
these O
recent O
findings O
, O
which O
all O
together O
indicate O
that O
TRP O
channels O
are O
interesting O
drug O
targets O
for O
the O
treatment O
of O
patients O
suffering O
from O
diabetes O
. O

Symmetrical O
Windowing O
for O
Quantum O
States O
in O
Quasi O
- O
Classical O
Trajectory O
Simulations O
. O

A O
microscopically O
reversible O
approach O
toward O
computing O
reaction O
probabilities O
via O
classical O
trajectory O
simulation O
has O
been O
developed O
that O
bins O
trajectories O
symmetrically O
on O
the O
basis O
of O
their O
initial O
and O
final O
classical O
actions O
. O

The O
symmetrical O
quasi O
- O
classical O
( O
SQC O
) O
approach O
involves O
defining O
a O
classical O
action O
window O
function O
centered O
at O
integer O
quantum O
values O
of O
the O
action O
, O
choosing O
a O
width O
parameter O
that O
is O
less O
than O
unit O
quantum O
width O
, O
and O
applying O
the O
window O
function O
to O
both O
initial O
reactant O
and O
final O
product O
vibrational O
states O
. O

Calculations O
were O
performed O
using O
flat O
histogram O
windows O
and O
Gaussian O
windows O
over O
a O
range O
of O
width O
parameters O
. O

Use O
of O
the O
Wigner O
distribution O
function O
was O
also O
investigated O
as O
a O
possible O
choice O
. O

It O
was O
demonstrated O
for O
collinear O
H B
+ O
H2 B
reactive O
scattering O
on O
the O
BKMP2 O
potential O
energy O
surface O
that O
reaction O
probabilities O
computed O
via O
the O
SQC O
methodology O
using O
a O
Gaussian O
window O
function O
of O
1 O
/ O
2 O
unit O
width O
produces O
good O
agreement O
with O
quantum O
mechanical O
results O
over O
the O
0 O
. O
4 O
- O
0 O
. O
6 O
eV O
energy O
range O
relevant O
to O
the O
ground O
vibrational O
state O
to O
the O
ground O
vibrational O
state O
reactive O
transition O
. O

Binding O
of O
Diverse O
Environmental O
Chemicals O
with O
Human O
Cytochromes O
P450 O
2A13 O
, O
2A6 O
, O
and O
1B1 O
and O
Enzyme O
Inhibition O
. O

A O
total O
of O
68 O
chemicals O
including O
derivatives O
of O
naphthalene B
, O
phenanthrene B
, O
fluoranthene B
, O
pyrene B
, O
biphenyl B
, O
and O
flavone B
were O
examined O
for O
their O
abilities O
to O
interact O
with O
human O
P450s O
2A13 O
and O
2A6 O
. O

Fifty O
- O
one O
of O
these O
68 O
chemicals O
induced O
stronger O
Type O
I O
binding O
spectra O
( O
iron B
low O
- O
to O
high O
- O
spin O
state O
shift O
) O
with O
P450 O
2A13 O
than O
those O
seen O
with O
P450 O
2A6 O
, O
i O
. O
e O
. O
, O
the O
spectral O
binding O
intensities O
( O
Delta O
Amax O
/ O
Ks O
ratio O
) O
determined O
with O
these O
chemicals O
were O
always O
higher O
for O
P450 O
2A13 O
. O

In O
addition O
, O
benzo B
[ I
c I
] I
phenanthrene I
, O
fluoranthene B
, O
2 B
, I
3 I
- I
dihydroxy I
- I
2 I
, I
3 I
- I
dihydrofluoranthene I
, O
pyrene B
, O
1 B
- I
hydroxypyrene I
, O
1 B
- I
nitropyrene I
, O
1 B
- I
acetylpyrene I
, O
2 B
- I
acetylpyrene I
, O
2 B
, I
5 I
, I
2 I
' I
, I
5 I
' I
- I
tetrachlorobiphenyl I
, O
7 B
- I
hydroxyflavone I
, O
chrysin B
, O
and O
galangin B
were O
found O
to O
induce O
a O
Type O
I O
spectral O
change O
only O
with O
P450 O

2A13 O
. O

Coumarin B
7 O
- O
hydroxylation O
, O
catalyzed O
by O
P450 O
2A13 O
, O
was O
strongly O
inhibited O
by O
2 B
' I
- I
methoxy I
- I
5 I
, I
7 I
- I
dihydroxyflavone I
, O
2 B
- I
ethynylnaphthalene I
, O
2 B
' I
- I
methoxyflavone I
, O
2 B
- I
naphththalene I
propargyl I
ether I
, O
acenaphthene B
, O
acenaphthylene B
, O
naphthalene B
, O
1 B
- I
acetylpyrene I
, O
flavanone B
, O
chrysin B
, O
3 B
- I
ethynylphenanthrene I
, O

flavone B
, O
and O
7 B
- I
hydroxyflavone I
; O
these O
chemicals O
induced O
Type O
I O
spectral O
changes O
with O
low O
Ks O
values O
. O

On O
the O
basis O
of O
the O
intensities O
of O
the O
spectral O
changes O
and O
inhibition O
of O
P450 O
2A13 O
, O
we O
classified O
the O
68 O
chemicals O
into O
eight O
groups O
based O
on O
the O
order O
of O
affinities O
for O
these O
chemicals O
and O
inhibition O
of O
P450 O
2A13 O
. O

The O
metabolism O
of O
chemicals O
by O
P450 O
2A13 O
during O
the O
assays O
explained O
why O
some O
of O
the O
chemicals O
that O
bound O
well O
were O
poor O
inhibitors O
of O
P450 O
2A13 O
. O

Finally O
, O
we O
compared O
the O
68 O
chemicals O
for O
their O
abilities O
to O
induce O
Type O
I O
spectral O
changes O
of O
P450 O
2A13 O
with O
the O
Reverse O
Type O
I O
binding O
spectra O
observed O
with O
P450 O
1B1 O
: O
45 O
chemicals O
interacted O
with O
both O
P450s O
2A13 O
and O
1B1 O
, O
indicating O
that O
the O
two O
enzymes O
have O
some O
similarty O
of O
structural O
features O
regarding O
these O
chemicals O
. O

Molecular O
docking O
analyses O
suggest O
similarities O
at O
the O
active O
sites O
of O
these O
P450 O
enzymes O
. O

These O
results O
indicate O
that O
P450 O
2A13 O
, O
as O
well O
as O
Family O
1 O
P450 O
enzymes O
, O
is O
able O
to O
catalyze O
many O
detoxication O
and O
activation O
reactions O
with O
chemicals O
of O
environmental O
interest O
. O

ATP B
synthase O
: O
a O
molecular O
therapeutic O
drug O
target O
for O
antimicrobial O
and O
antitumor O
peptides O
. O

In O
this O
review O
we O
discuss O
the O
role O
of O
ATP B
synthase O
as O
a O
molecular O
drug O
target O
for O
natural O
and O
synthetic O
antimicrobial O
/ O
antitumor O
peptides O
. O

We O
start O
with O
an O
introduction O
of O
the O
universal O
nature O
of O
the O
ATP B
synthase O
enzyme O
and O
its O
role O
as O
a O
biological O
nanomotor O
. O

Significant O
structural O
features O
required O
for O
catalytic O
activity O
and O
motor O
functions O
of O
ATP B
synthase O
are O
described O
. O

Relevant O
details O
regarding O
the O
presence O
of O
ATP B
synthase O
on O
the O
surface O
of O
several O
animal O
cell O
types O
, O
where O
it O
is O
associated O
with O
multiple O
cellular O
processes O
making O
it O
a O
potential O
drug O
target O
with O
respect O
to O
antimicrobial O
peptides O
and O
other O
inhibitors O
such O
as O
dietary O
polyphenols B
, O
is O
also O
reviewed O
. O

ATP B
synthase O
is O
known O
to O
have O
about O
twelve O
discrete O
inhibitor O
binding O
sites O
including O
peptides O
and O
other O
inhibitors O
located O
at O
the O
interface O
of O
alpha O
/ O
beta O
subunits O
on O
the O
F1 O
sector O
of O
the O
enzyme O
. O

Molecular O
interaction O
of O
peptides O
at O
the O
beta O
DEELSEED O
site O
on O
ATP B
synthase O
is O
discussed O
with O
specific O
examples O
. O

An O
inhibitory O
effect O
of O
other O
natural O
/ O
synthetic O
inhibitors O
on O
ATP B
is O
highlighted O
to O
explore O
the O
therapeutic O
roles O
played O
by O
peptides O
and O
other O
inhibitors O
. O

Lastly O
, O
the O
effect O
of O
peptides O
on O
the O
inhibition O
of O
the O
Escherichia O
coli O
model O
system O
through O
their O
action O
on O
ATP B
synthase O
is O
presented O
. O

Interlayer O
breathing O
and O
shear O
modes O
in O
few O
- O
trilayer O
MoS2 B
and O
WSe2 B
. O

Two O
- O
dimensional O
( O
2D O
) O
layered O
transition B
metal I
dichalcogenides I
( O
TMDs B
) O
have O
recently O
attracted O
tremendous O
interest O
as O
potential O
valleytronic O
and O
nanoelectronic O
materials O
, O
in O
addition O
to O
being O
well O
- O
known O
as O
excellent O
lubricants O
in O
the O
bulk O
. O

The O
interlayer O
van O
der O
Waals O
( O
vdW O
) O
coupling O
and O
low O
- O
frequency O
phonon O
modes O
and O
how O
they O
evolve O
with O
the O
number O
of O
layers O
are O
important O
for O
both O
the O
mechanical O
and O
the O
electrical O
properties O
of O
2D O
TMDs B
. O

Here O
we O
uncover O
the O
ultralow O
frequency O
interlayer O
breathing O
and O
shear O
modes O
in O
few O
- O
layer O
MoS2 B
and O
WSe2 B
, O
prototypical O
layered O
TMDs B
, O
using O
both O
Raman O
spectroscopy O
and O
first O
principles O
calculations O
. O

Remarkably O
, O
the O
frequencies O
of O
these O
modes O
can O
be O
perfectly O
described O
using O
a O
simple O
linear O
chain O
model O
with O
only O
nearest O
- O
neighbor O
interactions O
. O

We O
show O
that O
the O
derived O
in O
- O
plane O
( O
shear O
) O
and O
out O
- O
of O
- O
plane O
( O
breathing O
) O
force O
constants O
from O
experiment O
remain O
the O
same O
from O
two O
- O
layer O
2D O
crystals O
to O
the O
bulk O
materials O
, O
suggesting O
that O
the O
nanoscale O
interlayer O
frictional O
characteristics O
of O
these O
excellent O
lubricants O
should O
be O
independent O
of O
the O
number O
of O
layers O
. O

Checkpoint O
protein O
Rad9 O
plays O
an O
important O
role O
in O
nucleotide B
excision O
repair O
. O

Rad9 O
, O
an O
evolutionarily O
conserved O
checkpoint O
gene O
with O
multiple O
functions O
for O
preserving O
genomic O
integrity O
, O
has O
been O
shown O
to O
play O
important O
roles O
in O
homologous O
recombination O
repair O
, O
base O
excision O
repair O
and O
mismatch O
repair O
. O

However O
, O
whether O
Rad9 O
has O
an O
impact O
on O
nucleotide B
excision O
repair O
remains O
unknown O
. O

Here O
we O
demonstrated O
that O
Rad9 O
was O
involved O
in O
nucleotide B
excision O
repair O
and O
loss O
of O
Rad9 O
led O
to O
defective O
removal O
of O
the O
UV O
- O
derived O
photoproduct O
6 B
- I
4PP I
( O
6 B
, I
4 I
pyrimidine I
- I
pyrimidone I
) O
and O
the O
BPDE B
( O
anti B
- I
benzo I
( I
a I
) I
pyrene I
- I
trans I
- I
7 I
, I
8 I
- I
dihydrodiol I
- I
9 I
, I
10 I
- I
epoxide I
) O
- O
DNA O
adducts O
in O
mammalian O
cells O
. O

We O
also O
demonstrated O
that O
Rad9 O
could O
co O
- O
localize O
with O
XPC O
in O
response O
to O
local O
UV O
irradiation O
. O

However O
, O
our O
data O
showed O
that O
Rad9 O
was O
not O
required O
for O
the O
photoproducts O
recognition O
step O
of O
nucleotide B
excision O
repair O
. O

Further O
investigation O
revealed O
that O
reduction O
of O
Rad9 O
reduced O
the O
UV O
- O
induced O
transcription O
of O
the O
genes O
of O
the O
nucleotide B
excision O
repair O
factors O
DDB2 O
, O
XPC O
, O
DDB1 O
and O
XPB O
and O
DDB2 O
protein O
levels O
in O
human O
cells O
. O

Interestingly O
, O
knockdown O
of O
one O
subunit O
of O
DNA O
damage O
recognition O
complex O
, O
hHR23B O
impaired O
Rad9 O
- O
loading O
onto O
UV O
- O
damaged O
chromatin O
. O

Based O
on O
these O
results O
, O
we O
suggest O
that O
Rad9 O
plays O
an O
important O
role O
in O
nucleotide B
excision O
repair O
through O
mechanisms O
including O
maintaining O
DDB2 O
protein O
level O
in O
human O
cells O
. O

LOX O
- O
1 O
is O
a O
novel O
marker O
for O
peripheral O
artery O
disease O
in O
patients O
with O
type O
2 O
diabetes O
. O

OBJECTIVE O
: O
The O
aim O
of O
this O
study O
was O
to O
investigate O
whether O
serum O
soluble O
lectin O
- O
like O
oxidized O
low O
- O
density O
lipoprotein O
receptor O
- O
1 O
( O
sLOX O
- O
1 O
) O
, O
which O
mediates O
initiation O
and O
progression O
of O
atherosclerosis O
in O
endothelial O
cells O
, O
could O
be O
a O
novel O
marker O
for O
peripheral O
artery O
disease O
( O
PAD O
) O
in O
patients O
with O
type O
2 O
diabetes O
. O

METHODS O
: O
We O
evaluated O
relationships O
of O
serum O
sLOX O
- O
1 O
to O
ankle O
- O
brachial O
index O
( O
ABI O
) O
and O
examined O
the O
association O
of O
serum O
sLOX O
- O
1 O
with O
PAD O
in O
410 O
patients O
with O
type O
2 O
diabetes O
. O

RESULTS O
: O
Serum O
sLOX O
- O
1 O
was O
inversely O
correlated O
with O
ABI O
( O
r O
= O
- O
0 O
. O
197 O
, O
P O
< O
0 O
. O
0001 O
) O
. O

Stepwise O
regression O
analysis O
demonstrated O
that O
serum O
sLOX O
- O
1 O
( O
beta O
= O
- O
0 O
. O
168 O
, O
F O
= O
5 O
. O
571 O
, O
P O
< O
0 O
. O
05 O
) O
was O
independently O
associated O
with O
ABI O
, O
and O
multiple O
logistic O
regression O
analysis O
demonstrated O
that O
serum O
sLOX O
- O
1 O
( O
16 O
. O
254 O
( O
1 O
. O
237 O
- O
213 O
. O
651 O
) O
, O
P O
= O
0 O
. O
0339 O
) O
was O
independently O
associated O
with O
PAD O
. O

CONCLUSIONS O
: O
Serum O
sLOX O
- O
1 O
is O
associated O
with O
ABI O
and O
it O
could O
be O
a O
novel O
marker O
for O
PAD O
in O
patients O
with O
type O
2 O
diabetes O
. O

Discovery O
of O
biological O
evaluation O
of O
pyrazole B
/ O
imidazole B
amides I
as O
mGlu5 O
receptor O
negative O
allosteric O
modulators O
. O

Development O
of O
SAR O
in O
a O
5 B
- I
aryl I
- I
3 I
- I
acylpyridinyl I
- I
pyrazoles I
and O
1 B
- I
aryl I
- I
4 I
- I
acylpyridinyl I
imidazoles I
series O
of O
mGlu5 O
receptor O
negative O
allosteric O
modulators O
( O
mGluR5 O
NAMs O
) O
using O
a O
functional O
cell O
- O
based O
assay O
is O
described O
in O
this O
Letter O
. O

Analysis O
of O
the O
Ligand O
- O
lipophilic O
efficiency O
( O
LipE O
) O
of O
compounds O
provided O
new O
insight O
for O
the O
design O
of O
potent O
mGluR5 O
negative O
allosteric O
modulators O
with O
anti O
- O
depressant O
activities O
. O

Microwave O
assisted O
nano O
( O
ZnO B
- O
TiO2 B
) O
catalyzed O
synthesis O
of O
some O
new O
4 B
, I
5 I
, I
6 I
, I
7 I
- I
tetrahydro I
- I
6 I
- I
( I
( I
5 I
- I
substituted I
- I
1 I
, I
3 I
, I
4 I
- I
oxadiazol I
- I
2 I
- I
yl I
) I
methyl I
) I
thieno I
[ I
2 I
, I
3 I
- I
c I
] I
pyridine I
as O
antimicrobial O
agents O
. O

Combined O
nano O
zinc B
oxide I
and O
titanium B
dioxide I
[ O
nano O
( O
ZnO B
- O
TiO B
( I
2 I
) I
) O
] O
has O
been O
reported O
first O
time O
for O
the O
synthesis O
of O
novel O
series O
of O
4 B
, I
5 I
, I
6 I
, I
7 I
- I
tetrahydro I
- I
6 I
- I
( I
( I
5 I
- I
substituted I
- I
1 I
, I
3 I
, I
4 I
- I
oxadiazol I
- I
2 I
- I
yl I
) I
methyl I
) I
thieno I
[ I
2 I
, I
3 I
- I
c I
] I
pyridine I
. O

All O
the O
synthesized O
compounds O
( O
7a O
- O
7m O
) O
are O
novel O
and O
were O
screened O
for O
their O
antimicrobial O
activity O
against O
four O
different O
strains O
like O
Escherichia O
coli O
, O
Pseudomonas O
aeruginosa O
, O
Staphylococcus O
aureus O
and O
Bacillus O
subtilis O
and O
antifungal O
activity O
was O
determined O
against O
two O
strains O
Candida O
albicans O
and O
Aspergillus O
niger O
. O

SAR O
for O
the O
newly O
synthesised O
derivatives O
has O
been O
developed O
by O
comparing O
their O
MIC O
values O
with O
ampicillin B
, O
ciprofloxacin B
and O
miconazole B
for O
antibacterial O
and O
antifungal O
activities O
, O
respectively O
. O

Among O
the O
synthesized O
compounds O
, O
2 B
, I
6 I
dichlorophenyl I
analogue O
( O
7f O
) O
, O
4 B
fluorophenyl I
analogue O
( O
7k O
) O
and O
2 B
, I
6 I
dichlorophenyl I
analogue O
( O
7l O
) O
shows O
promising O
antibacterial O
as O
well O
as O
antifungal O
activity O
whereas O
thiophene B
substituted O
compound O
( O
7j O
) O
shows O
promising O
antibacterial O
activity O
. O

Improved O
guanide B
compounds O
which O
bind O
the O
CXCR4 O
co O
- O
receptor O
and O
inhibit O
HIV O
- O
1 O
infection O
. O

The O
G O
- O
protein O
coupled O
receptor O
CXCR4 O
is O
a O
co O
- O
receptor O
for O
HIV O
- O
1 O
infection O
and O
is O
involved O
in O
signaling O
cell O
migration O
and O
proliferation O
. O

In O
a O
previous O
study O
of O
non O
- O
peptide O
, O
guanide B
- O
based O
CXCR4 O
- O
binding O
compounds O
, O
spermine B
and O
spermidine B
phenylguanides B
inhibited O
HIV O
- O
1 O
entry O
at O
low O
micromolar O
concentrations O
. O

Subsequently O
, O
crystal O
structures O
of O
CXCR4 O
were O
used O
to O
dock O
a O
series O
of O
naphthylguanide B
derivatives O
of O
the O
polyamines B
spermidine B
and O
spermine B
. O

Synthesis O
and O
evaluation O
of O
the O
naphthylguanide B
compounds O
identified O
our O
best O
compound O
, O
spermine B
tris I
- I
1 I
- I
naphthylguanide I
, O
which O
bound O
CXCR4 O
with O
an O
IC O
( O
50 O
) O
of O
40 O
nM O
and O
inhibited O
the O
infection O
of O
TZM O
- O
bl O
cells O
with O
X4 O
, O
but O
not O
R5 O
, O
strains O
of O
HIV O
- O
1 O
with O
an O
IC O
( O
50 O
) O
of O
50 O
- O
100 O
nM O
. O

Advances O
in O
the O
discovery O
of O
kinesin O
spindle O
protein O
( O
Eg5 O
) O
inhibitors O
as O
antitumor O
agents O
. O

Cancer O
is O
considered O
as O
one O
of O
the O
most O
serious O
health O
problems O
. O

Despite O
the O
presence O
of O
many O
effective O
chemotherapeutic O
agents O
, O
their O
severe O
side O
effects O
together O
with O
the O
appearance O
of O
mutant O
tumors O
limit O
the O
use O
of O
these O
drugs O
and O
increase O
the O
need O
for O
new O
anticancer O
agents O
. O

Eg5 O
represents O
an O
attractive O
target O
for O
medicinal O
chemists O
since O
Eg5 O
is O
overexpressed O
in O
many O
proliferative O
tissues O
while O
almost O
no O
Eg5 O
is O
detected O
in O
nonproliferative O
tissues O
. O

Many O
Eg5 O
inhibitors O
displayed O
potent O
anticancer O
activity O
against O
some O
of O
the O
mutant O
tumors O
with O
limited O
side O
effects O
. O

The O
present O
review O
provides O
an O
overview O
about O
the O
progress O
in O
the O
discovery O
of O
Eg5 O
inhibitors O
especially O
from O
2009 O
to O
2012 O
as O
well O
as O
the O
clinical O
trials O
conducted O
on O
some O
of O
these O
inhibitors O
. O

Synthesis O
, O
biological O
evaluation O
of O
new O
oxazolidino B
- I
sulfonamides I
as O
potential O
antimicrobial O
agents O
. O

A O
number O
of O
linezolid B
- O
like O
oxazolidino B
- I
sulfonamides I
( O
7a O
- O
y O
and O
8a O
- O
b O
) O
were O
designed O
and O
synthesized O
with O
a O
view O
to O
develop O
antimicrobial O
agents O
with O
improved O
properties O
. O

Most O
of O
the O
synthesized O
compounds O
showed O
good O
to O
moderate O
activity O
against O
a O
panel O
of O
standard O
Gram O
- O
positive O
and O
Gram O
- O
negative O
bacteria O
and O
fungal O
strains O
. O

The O
compounds O
7i O
and O
7v O
exhibited O
significant O
activity O
, O
with O
a O
MIC O
value O
of O
2 O
. O
0 O
- O
6 O
. O
0 O
mu O
g O
/ O
mL O
against O
a O
panel O
of O
Gram O
- O
positive O
and O
Gram O
- O
negative O
bacteria O
. O

These O
compounds O
also O
showed O
activity O
against O
Candida O
albicans O
, O
with O
a O
MIC O
value O
of O
4 O
. O
0 O
mu O
g O
/ O
mL O
. O

A O
correlation O
of O
the O
antimicrobial O
activity O
with O
calculated O
lipophilicity O
values O
( O
C O
log O
P O
) O
is O
also O
presented O
. O

Synthesis O
and O
cytotoxicity O
of O
3 B
- I
aryl I
acrylic I
amide I
derivatives O
of O
the O
simplified O
saframycin B
- O
ecteinascidin B
skeleton O
prepared O
from O
l B
- I
dopa I
. O

Twenty O
four O
compounds O
with O
diversified O
3 B
- I
aryl I
acrylic I
amide I
side O
chains O
of O
the O
simplified O
saframycin B
- O
ecteinascidin I
pentacyclic O
skeleton O
were O
synthesized O
via O
a O
14 O
- O
step O
stereospecific O
route O
starting O
from O
l B
- I
dopa I
. O

The O
cytotoxicities O
of O
these O
compounds O
were O
tested O
against O
eight O
human O
tumor O
cell O
lines O
including O
HCT O
- O
8 O
, O
BEL O
- O
7402 O
, O
BGC O
- O
803 O
, O
A549 O
, O
A2780 O
, O
MCF O
- O
7 O
, O
MX O
- O
1 O
, O
and O
MDA O
- O
MB O
- O
231 O
. O

Most O
of O
these O
compounds O
exhibited O
potent O
antitumor O
activity O
, O
and O
a O
preliminary O
structure O
- O
activity O
relationship O
( O
SAR O
) O
was O
discussed O
. O

Compound O
28 O
with O
3 B
- I
thiophenyl I
acrylic I
amide I
side O
chain O
exhibited O
selective O
cytotoxicity O
against O
MDA O
- O
MB O
- O
231 O
cell O
line O
with O
the O
IC50 O
value O
of O
50 O
nM O
. O

The O
Interaction O
of O
Adrenomedullin O
and O
Macrophages O
Induces O
Ovarian O
Cancer O
Cell O
Migration O
via O
Activation O
of O
RhoA O
Signaling O
Pathway O
. O

Tumor O
- O
associated O
macrophages O
( O
TAMs O
) O
are O
correlated O
with O
poor O
prognosis O
in O
many O
human O
cancers O
; O
however O
, O
the O
mechanism O
by O
which O
TAMs O
facilitate O
ovarian O
cancer O
cell O
migration O
and O
invasion O
remains O
unknown O
. O

This O
study O
was O
aimed O
to O
examine O
the O
function O
of O
adrenomedullin O
( O
ADM O
) O
in O
macrophage O
polarization O
and O
their O
further O
effects O
on O
the O
migration O
of O
ovarian O
cancer O
cells O
. O

Exogenous O
ADM O
antagonist O
and O
small O
interfering O
RNA O
( O
siRNA O
) O
specific O
for O
ADM O
expression O
were O
treated O
to O
macrophages O
and O
EOC O
cell O
line O
HO8910 O
, O
respectively O
. O

Then O
macrophages O
were O
cocultured O
with O
HO8910 O
cells O
without O
direct O
contact O
. O

Flow O
cytometry O
, O
Western O
blot O
and O
real O
- O
time O
PCR O
were O
used O
to O
detect O
macrophage O
phenotype O
and O
cytokine O
production O
. O

The O
migration O
ability O
and O
cytoskeleton O
rearrangement O
of O
ovarian O
cancer O
cells O
were O
determined O
by O
Transwell O
migration O
assay O
and O
phalloidin B
staining O
. O

Western O
blot O
was O
performed O
to O
evaluate O
the O
activity O
status O
of O
signaling O
molecules O
in O
the O
process O
of O
ovarian O
cancer O
cell O
migration O
. O

The O
results O
showed O
that O
ADM O
induced O
macrophage O
phenotype O
and O
cytokine O
production O
similar O
to O
TAMs O
. O

Macrophages O
polarized O
by O
ADM O
promoted O
the O
migration O
and O
cytoskeleton O
rearrangement O
of O
HO8910 O
cells O
. O

The O
expression O
of O
RhoA O
and O
its O
downstream O
effector O
, O
cofilin O
, O
were O
upregulated O
in O
macrophage O
- O
induced O
migration O
of O
HO8910 O
cells O
. O

In O
conclusion O
, O
ADM B
could O
polarize O
macrophages O
similar O
to O
TAMs O
, O
and O
then O
polarized O
macrophages O
promote O
the O
migration O
of O
ovarian O
cancer O
cells O
via O
activation O
of O
RhoA O
signaling O
pathway O
in O
vitro O
. O

Identification O
of O
three O
genes O
encoding O
for O
the O
late O
acyltransferases O
of O
lipid B
A I
in O
Cronobacter O
sakazakii O
. O

Lipid O
A O
, O
the O
hydrophobic O
anchor O
of O
lipopolysaccharide O
, O
is O
an O
essential O
component O
in O
the O
outer O
membrane O
of O
most O
Gram O
- O
negative O
bacteria O
. O

Food O
- O
borne O
pathogen O
Cronobacter O
sakazakii O
synthesizes O
two O
lipid B
A I
species O
, O
differing O
by O
the O
length O
of O
the O
secondary O
acyl B
chain O
. O

In O
this O
work O
, O
we O
identified O
three O
genes O
ESA02293 O
, O
ESA02951 O
and O
ESA01386 O
encoding O
for O
the O
late O
acyltransferases O
of O
lipid O
A O
biosynthesis O
pathway O
in O
C O
. O
sakazakii O
. O

Based O
on O
the O
sequence O
alignment O
, O
proteins O
YP O
_ O
001438378 O
. O
1 O
encoded O
by O
ESA02293 O
, O
YP O
_ O
001439016 O
. O
1 O
encoded O
by O
ESA02951 O
, O
and O
YP O
_ O
001437482 O
. O
1 O
encoded O
by O
ESA01386 O
are O
homologous O
to O
E O
. O
coli O
LpxL O
, O
LpxP O
and O
LpxM O
, O
respectively O
. O

Functions O
of O
the O
three O
acyltransferases O
were O
confirmed O
by O
overexpressing O
the O
genes O
in O
E O
. O
coli O
, O
isolating O
lipid O
As O
and O
analyzing O
their O
structures O
using O
an O
ESI O
/ O
MS O
. O

C O
. O
sakazakii O
LpxL O
and O
LpxM O
transfer O
a O
C14 B
: I
0 I
secondary B
acyl I
chain O
to O
the O
2 O
' O
- O
and O
3 O
' O
- O
position O
of O
lipid B
A I
, O
respectively O
. O

C O
. O
sakazakii O
LpxP O
can O
transfer O
either O
a O
C16 O
: O
1 O
or O
a O
C14 O
: O
0 O
secondary O
acyl B
chains O
to O
the O
2 O
' O
- O
position O
of O
lipid B
A I
. O

A O
35kD O
Phyllanthus O
niruri O
protein O
modulates O
iron B
mediated O
oxidative O
impairment O
to O
hepatocytes O
via O
the O
inhibition O
of O
ERKs O
, O
p38 O
MAPKs O
and O
activation O
of O
PI3k O
/ O
Akt O
pathway O
. O

It O
has O
been O
reported O
that O
the O
herb O
, O
Phyllanthus O
niruri O
, O
possess O
antioxidant O
, O
anti O
- O
infection O
, O
anti O
- O
asthmatic O
, O
anti O
- O
diuretic O
, O
anti O
- O
soresis O
and O
many O
more O
beneficial O
activities O
. O

The O
goal O
of O
our O
present O
study O
was O
to O
evaluate O
the O
protective O
role O
of O
a O
35kD O
protein O
( O
PNP O
) O
isolated O
from O
this O
herb O
against O
iron B
- O
induced O
cytotoxicity O
in O
murine O
hepatocytes O
. O

Exposure O
of O
hepatocytes O
to O
iron B
( O
FeSO4 B
) O
caused O
elevation O
of O
reactive O
oxygen B
species O
( O
ROS O
) O
production O
, O
enhanced O
lipid O
peroxidation O
and O
protein O
carbonylation O
, O
depleted O
glutathione B
levels O
, O
decreased O
the O
antioxidant O
power O
( O
FRAP O
) O
of O
the O
cells O
and O
reduced O
cell O
viability O
. O

Iron B
mediated O
cytotoxicity O
disrupted O
mitochondrial O
membrane O
potential O
( O
Delta O
psi O
m O
) O
and O
thereby O
caused O
apoptosis O
mainly O
by O
the O
intrinsic O
pathway O
via O
the O
down O
- O
regulation O
of O
I O
kappa O
B O
alpha O
with O
a O
concomitant O
up O
- O
regulation O
of O
NF O
- O
kB O
as O
well O
as O
the O
phosphorylation O
of O
ERKs O
and O
p38 O
MAP O
kinases O
. O

In O
addition O
, O
iron B
- O
induced O
cytotoxicity O
disrupted O
the O
normal O
balance O
of O
Bcl O
- O
2 O
family O
proteins O
in O
hepatocytes O
. O

Incubation O
of O
hepatocytes O
with O
PNP B
, O
however O
, O
protected O
the O
cells O
from O
apoptosis O
by O
stabilizing O
the O
mitochondria O
and O
arresting O
the O
release O
of O
cytochrome O
c O
. O

It O
also O
suppressed O
caspase O
activation O
and O
cleavage O
of O
PARP O
. O

Moreover O
, O
this O
protein O
has O
strong O
free O
radical O
scavenging O
activity O
and O
thereby O
scavenged O
ROS O
extensively O
. O

Combining O
all O
, O
results O
suggest O
that O
simultaneous O
treatment O
with O
PNP B
might O
suppress O
the O
iron B
- O
induced O
cytotoxicity O
in O
hepatocytes O
. O

Hepatic O
and O
renal O
Bcrp O
transporter O
expression O
in O
mice O
treated O
with O
perfluorooctanoic B
acid I
. O

The O
breast O
cancer O
resistance O
protein O
( O
Bcrp O
) O
is O
an O
efflux O
transporter O
that O
participates O
in O
the O
biliary O
and O
renal O
excretion O
of O
drugs O
and O
environmental O
chemicals O
. O

Recent O
evidence O
suggests O
that O
pharmacological O
activation O
of O
the O
peroxisome O
proliferator O
activated O
receptor O
alpha O
( O
PPAR O
alpha O
) O
can O
up O
- O
regulate O
the O
hepatic O
expression O
of O
Bcrp O
. O

The O
current O
study O
investigated O
the O
regulation O
of O
hepatic O
and O
renal O
Bcrp O
mRNA O
and O
protein O
in O
mice O
treated O
with O
the O
PPAR O
alpha O
agonist O
perfluorooctanoic B
acid I
( O
PFOA B
) O
and O
the O
ability O
of O
PFOA B
to O
alter O
human O
BCRP O
function O
in O
vitro O
. O

Bcrp O
mRNA O
and O
protein O
expression O
were O
quantified O
in O
the O
livers O
and O
kidneys O
of O
male O
C57BL O
/ O
6 O
mice O
treated O
with O
vehicle O
or O
PFOA B
( O
1 O
or O
3mg O
/ O
kg O
/ O
day O
oral O
gavage O
) O
for O
7 O
days O
. O

PFOA B
treatment O
increased O
liver O
weights O
as O
well O
as O
the O
hepatic O
mRNA O
and O
protein O
expression O
of O
the O
PPAR O
alpha O
target O
gene O
, O
cytochrome O
P450 O
4a14 O
. O

Compared O
to O
vehicle O
- O
treated O
control O
mice O
, O
PFOA B
increased O
hepatic O
Bcrp O
mRNA O
and O
protein O
between O
1 O
. O
5 O
- O
and O
3 O
- O
fold O
. O

Immunofluorescent O
staining O
confirmed O
enhanced O
canalicular O
Bcrp O
staining O
in O
liver O
sections O
from O
PFOA B
- O
treated O
mice O
. O

The O
kidney O
expression O
of O
cytochrome O
P450 O
4a14 O
mRNA O
, O
but O
not O
Bcrp O
, O
was O
increased O
in O
mice O
treated O
with O
PFOA B
. O

Micromolar O
concentrations O
of O
PFOA B
decreased O
human O
BCRP O
ATPase O
activity O
and O
inhibited O
BCRP O
- O
mediated O
transport O
in O
inverted O
membrane O
vesicles O
. O

Together O
, O
these O
studies O
demonstrate O
that O
PFOA B
induces O
hepatic O
Bcrp O
expression O
in O
mice O
and O
may O
inhibit O
human O
BCRP O
transporter O
function O
at O
concentrations O
that O
exceed O
levels O
observed O
in O
humans O
. O

Fluctuating O
charge O
- O
density O
waves O
in O
a O
cuprate O
superconductor O
. O

Cuprate B
materials O
hosting O
high O
- O
temperature O
superconductivity O
( O
HTS O
) O
also O
exhibit O
various O
forms O
of O
charge O
and O
spin O
ordering O
whose O
significance O
is O
not O
fully O
understood O
. O

So O
far O
, O
static O
charge O
- O
density O
waves O
( O
CDWs O
) O
have O
been O
detected O
by O
diffraction O
probes O
only O
at O
particular O
doping O
levels O
or O
in O
an O
applied O
external O
field O
. O

However O
, O
dynamic O
CDWs O
may O
also O
be O
present O
more O
broadly O
and O
their O
detection O
, O
characterization O
and O
relationship O
with O
HTS O
remain O
open O
problems O
. O

Here O
we O
present O
a O
method O
based O
on O
ultrafast O
spectroscopy O
to O
detect O
the O
presence O
and O
measure O
the O
lifetimes O
of O
CDW O
fluctuations O
in O
cuprates B
. O

In O
an O
underdoped O
La1 B
. I
9Sr0 I
. I
1CuO4 I
film O
( O
Tc O
= O
26 O
K O
) O
, O
we O
observe O
collective O
excitations O
of O
CDW O
that O
persist O
up O
to O
100 O
K O
. O

This O
dynamic O
CDW O
fluctuates O
with O
a O
characteristic O
lifetime O
of O
2 O
ps O
at O
T O
= O
5 O
K O
that O
decreases O
to O
0 O
. O
5 O
ps O
at O
T O
= O
100 O
K O
. O

In O
contrast O
, O
in O
an O
optimally O
doped O
La1 B
. I
84Sr0 I
. I
16CuO4 I
film O
( O
Tc O
= O
38 O
. O
5 O
K O
) O
, O
we O
detect O
no O
signatures O
of O
fluctuating O
CDWs O
at O
any O
temperature O
, O
favouring O
the O
competition O
scenario O
. O

This O
work O
forges O
a O
path O
for O
studying O
fluctuating O
order O
parameters O
in O
various O
superconductors O
and O
other O
materials O
. O

Modulation O
of O
A O
- O
type O
K B
( I
+ I
) I
channels O
by O
the O
short O
- O
chain O
cobrotoxin O
through O
the O
protein O
kinase O
C O
- O
delta O
isoform O
decreases O
membrane O
excitability O
in O
dorsal O
root O
ganglion O
neurons O
. O

A O
- O
type O
K B
( I
+ I
) I
channels O
are O
crucial O
in O
controlling O
neuronal O
excitability O
, O
and O
their O
regulation O
in O
sensory O
neurons O
may O
alter O
pain O
sensation O
. O

In O
this O
study O
, O
we O
identified O
the O
functional O
role O
of O
cobrotoxin O
, O
the O
short O
- O
chain O
alpha O
- O
neurotoxin O
isolated O
from O
Naja O
atra O
venom O
, O
which O
acts O
in O
the O
regulation O
of O
the O
transient O
A O
- O
type O
K B
( I
+ I
) I
currents O
( O
IA O
) O
and O
membrane O
excitability O
in O
dorsal O
root O
ganglion O
( O
DRG O
) O
neurons O
via O
the O
activation O
of O
the O
muscarinic O
M3 O
receptor O
( O
M3R O
) O
. O

Our O
results O
showed O
that O
cobrotoxin O
increased O
IA O
in O
a O
concentration O
- O
dependent O
manner O
, O
whereas O
the O
sustained O
delayed O
rectifier O
K B
( I
+ I
) I
currents O
( O
IDR O
) O
were O
not O
affected O
. O

Cobrotoxin O
did O
not O
affect O
the O
activation O
of O
IA O
markedly O
, O
however O
, O
it O
shifted O
the O
inactivation O
curve O
significantly O
in O
the O
depolarizing O
direction O
. O

The O
cobrotoxin O
- O
induced O
IA O
response O
was O
blocked O
by O
the O
M3R O
- O
selective O
antagonists O
DAU B
- I
5884 I
and O
4 B
- I
DAMP I
. O

An O
siRNA O
targeting O
the O
M3R O
in O
small O
DRG O
neurons O
abolished O
the O
cobrotoxin O
- O
induced O
IA O
increase O
. O

In O
addition O
, O
dialysis O
of O
the O
cells O
with O
the O
novel O
protein O
kinase O
C O
- O
delta O
isoform O
( O
PKC O
- O
delta O
) O
inhibitor O
delta O
v1 O
- O
1 O
or O
an O
siRNA O
targeting O
PKC O
- O
delta O
abolished O
the O
cobrotoxin O
- O
induced O
IA O
response O
, O
whereas O
inhibition O
of O
PKA O
or O
classic O
PKC O
activity O
elicited O
no O
such O
effects O
. O

Moreover O
, O
we O
observed O
a O
significant O
decrease O
in O
the O
firing O
rate O
of O
the O
neuronal O
action O
potential O
induced O
by O
M3R O
activation O
. O

Pretreatment O
of O
the O
cells O
with O
4 B
- I
aminopyridine I
, O
a O
selective O
blocker O
of O
IA O
, O
abolished O
this O
effect O
. O

Taken O
together O
, O
these O
results O
suggest O
that O
the O
short O
- O
chain O
cobrotoxin O
selectively O
enhances O
IA O
via O
a O
novel O
PKC O
- O
delta O
- O
dependent O
pathway O
. O

This O
effect O
occurred O
via O
the O
activation O
of O
M3R O
and O
might O
contribute O
to O
its O
neuronal O
hypoexcitability O
in O
small O
DRG O
neurons O
. O

Molecular O
aspects O
of O
cancer O
cell O
resistance O
to O
chemotherapy O
. O

Cancer O
cell O
resistance O
to O
chemotherapy O
is O
still O
a O
heavy O
burden O
that O
impairs O
treatment O
of O
cancer O
patients O
. O

Both O
intrinsic O
and O
acquired O
resistance O
results O
from O
the O
numerous O
genetic O
and O
epigenetic O
changes O
occurring O
in O
cancer O
cells O
. O

Most O
of O
the O
hallmarks O
of O
cancer O
cells O
provide O
general O
mechanisms O
to O
sustain O
stresses O
such O
as O
the O
ones O
induced O
by O
chemotherapeutic O
drugs O
. O

Moreover O
, O
specific O
changes O
in O
the O
target O
bring O
resistance O
to O
specific O
drugs O
like O
modification O
in O
nucleotide B
synthesis O
enzymes O
upon O
anti O
- O
metabolite O
exposure O
, O
in O
microtubule O
composition O
upon O
spindle O
poison O
treatment O
, O
in O
topoisomerase O
activity O
upon O
topoisomerase O
inhibitor O
incubation O
or O
in O
intracellular O
signaling O
pathways O
when O
targeting O
tyrosine B
kinase O
receptors O
. O

Finally O
, O
the O
stemness O
properties O
of O
a O
few O
cancer O
cells O
as O
well O
as O
components O
of O
the O
tumor O
stroma O
, O
like O
fibroblasts O
and O
tumor O
- O
associated O
macrophages O
but O
also O
hypoxia O
, O
also O
help O
tumor O
to O
resist O
to O
anticancer O
agents O
. O

These O
processes O
provide O
an O
additional O
level O
of O
complexity O
to O
the O
understanding O
of O
the O
tumor O
resistance O
phenomenon O
. O

This O
review O
aims O
to O
describe O
the O
different O
general O
mechanisms O
as O
well O
as O
some O
examples O
of O
specific O
on O
target O
modifications O
inducing O
cancer O
cell O
resistance O
to O
chemotherapy O
at O
the O
molecular O
level O
. O

Perspectives O
to O
develop O
more O
efficient O
treatment O
, O
using O
genomic O
signature O
or O
more O
specific O
biomarkers O
to O
characterize O
putative O
resistance O
mechanisms O
in O
patients O
before O
choosing O
the O
more O
appropriate O
treatment O
, O
will O
also O
be O
discussed O
. O

ATM O
kinase O
activity O
modulates O
ITCH O
E3 O
- O
ubiquitin O
ligase O
activity O
. O

Ataxia O
Telangiectasia O
Mutated O
( O
ATM O
) O
kinase O
, O
a O
central O
regulator O
of O
the O
DNA O
damage O
response O
, O
regulates O
the O
activity O
of O
several O
E3 O
- O
ubiquitin O
ligases O
, O
and O
the O
ubiquitination O
- O
proteasome O
system O
is O
a O
consistent O
target O
of O
ATM O
. O

ITCH O
is O
an O
E3 O
- O
ubiquitin O
ligase O
that O
modulates O
the O
ubiquitination O
of O
several O
targets O
, O
therefore O
participating O
to O
the O
regulation O
of O
several O
cellular O
responses O
, O
such O
as O
the O
DNA O
damage O
response O
, O
tumor O
necrosis O
factor O
alpha O
( O
TNF O
alpha O
) O
, O
Notch O
and O
Hedgehog O
signaling O
, O
and O
the O
differentiation O
of O
' O
naive O
' O
lymphocytes O
into O
T O
helper O
type O
2 O
cells O
. O

Here O
we O
uncover O
ATM O
as O
a O
novel O
positive O
modulator O
of O
ITCH O
E3 O
- O
ubiquitin O
ligase O
activity O
. O

A O
single O
residue O
on O
ITCH O
protein O
, O
S161 O
, O
which O
is O
part O
of O
an O
ATM O
SQ O
consensus O
motif O
, O
is O
required O
for O
ATM O
- O
dependent O
activation O
of O
ITCH O
. O

ATM O
activity O
enhances O
ITCH O
enzymatic O
activity O
, O
which O
in O
turn O
drives O
the O
ubiquitination O
and O
degradation O
of O
c O
- O
FLIP O
- O
L O
and O
c O
- O
Jun O
, O
previously O
identified O
as O
ITCH O
substrates O
. O

Importantly O
, O
ATM O
- O
deficient O
mice O
show O
resistance O
to O
hepatocyte O
cell O
death O
, O
similarly O
to O
Itch O
- O
deficient O
animals O
, O
providing O
in O
vivo O
genetic O
evidence O
for O
this O
circuit O
. O

Our O
data O
identify O
ITCH O
as O
a O
novel O
component O
of O
the O
ATM O
- O
dependent O
signaling O
pathway O
and O
suggest O
that O
the O
impairment O
of O
the O
correct O
functionality O
of O
ITCH O
caused O
by O
Atm O
deficiency O
may O
contribute O
to O
the O
complex O
clinical O
features O
linked O
to O
Ataxia O
Telangiectasia O
. O
Oncogene O
advance O
online O
publication O
, O
25 O
February O
2013 O
; O
doi O
: O
10 O
. O
1038 O
/ O
onc O
. O
2013 O
. O
52 O
. O

Allelic O
imbalance O
in O
sporadic O
parathyroid O
carcinoma O
and O
evidence O
for O
its O
de O
novo O
origins O
. O

Parathyroid O
cancer O
is O
a O
rare O
, O
clinically O
aggressive O
cause O
of O
primary O
hyperparathyroidism O
, O
and O
whether O
these O
malignancies O
generally O
evolve O
from O
pre O
- O
existing O
benign O
adenomas O
or O
arise O
de O
novo O
is O
unclear O
. O

Furthermore O
, O
while O
inactivation O
of O
the O
CDC73 O
( O
HRPT2 O
) O
tumor O
suppressor O
gene O
, O
encoding O
parafibromin O
, O
is O
a O
major O
contributor O
, O
other O
genes O
essential O
to O
parathyroid O
carcinogenesis O
remain O
unknown O
. O

We O
sought O
to O
identify O
genomic O
regions O
potentially O
harboring O
such O
oncogenes O
or O
tumor O
suppressor O
genes O
, O
and O
to O
gain O
insight O
into O
the O
origins O
and O
molecular O
relationship O
of O
malignant O
versus O
benign O
parathyroid O
tumors O
. O

We O
performed O
genome O
- O
wide O
copy O
- O
number O
and O
loss O
of O
heterozygosity O
analysis O
using O
Affymetrix O
50K O
SNP O
mapping O
arrays O
and O
/ O
or O
comparative O
genomic O
hybridization O
on O
16 O
primary O
parathyroid O
carcinomas O
, O
local O
recurrences O
or O
distant O
metastases O
, O
and O
matched O
normal O
controls O
, O
from O
10 O
individuals O
. O

Recurrent O
regions O
of O
allelic O
loss O
were O
observed O
on O
chromosomes O
1p O
, O
3 O
, O
and O
13q O
suggesting O
that O
key O
parathyroid O
tumor O
suppressor O
genes O
are O
located O
in O
these O
chromosomal O
locations O
. O

Recurrent O
allelic O
gains O
were O
seen O
on O
chromosomes O
1q O
and O
16 O
, O
suggesting O
the O
presence O
of O
parathyroid O
oncogenes O
on O
these O
chromosomes O
. O

Importantly O
, O
the O
most O
common O
alteration O
in O
benign O
parathyroid O
adenomas O
, O
loss O
of O
11q O
, O
was O
not O
found O
as O
a O
recurrent O
change O
in O
the O
malignant O
parathyroid O
tissues O
. O

Molecular O
allelotyping O
using O
highly O
polymorphic O
microsatellite O
markers O
provided O
further O
confirmation O
that O
the O
prevalence O
of O
11q O
loss O
is O
markedly O
and O
significantly O
lower O
in O
carcinomas O
as O
compared O
with O
adenomas O
. O

Our O
observations O
provide O
molecular O
support O
for O
the O
concept O
that O
sporadic O
parathyroid O
cancer O
usually O
arises O
de O
novo O
, O
rather O
than O
evolving O
from O
a O
pre O
- O
existing O
typical O
benign O
adenoma O
. O

Furthermore O
, O
these O
results O
help O
direct O
future O
investigation O
to O
ultimately O
determine O
which O
of O
the O
candidate O
genes O
in O
these O
chromosomal O
locations O
make O
significant O
contributions O
to O
the O
molecular O
pathogenesis O
of O
parathyroid O
cancer O
. O

Fluorescence O
spectroscopy O
of O
PTCDA B
molecules O
on O
the O
KCl B
( O
100 O
) O
surface O
in O
the O
limit O
of O
low O
coverages O
: O
site O
selection O
and O
diffusion O
. O

We O
performed O
fluorescence O
( O
FL O
) O
and O
fluorescence O
excitation O
( O
FLE O
) O
spectroscopy O
on O
the O
model O
molecule O
perylene B
- I
3 I
, I
4 I
, I
9 I
, I
10 I
- I
tetracarboxyl I
acid I
dianhydride I
( O
PTCDA B
) O
for O
very O
low O
coverages O
( O
below O
1 O
% O
of O
a O
monolayer O
) O
on O
thin O
( O
100 O
) O
oriented O
KCl B
films O
. O

Two O
different O
states O
of O
PTCDA B
molecules O
can O
be O
distinguished O
in O
the O
spectra O
: O
an O
initial O
state O
, O
which O
is O
observed O
directly O
after O
deposition O
of O
the O
molecules O
onto O
the O
cold O
sample O
at O
20 O
K O
, O
and O
a O
final O
state O
, O
which O
is O
found O
after O
intensive O
optical O
excitation O
or O
thermal O
annealing O
of O
the O
sample O
. O

The O
spectrum O
of O
the O
final O
state O
is O
blue O
- O
shifted O
with O
respect O
to O
that O
of O
the O
initial O
state O
by O
130 O
+ O
/ O
- O
15 O
cm O
( O
- O
1 O
) O
and O
exhibits O
lines O
with O
significantly O
reduced O
widths O
. O

This O
can O
be O
explained O
by O
diffusion O
of O
molecules O
from O
initially O
populated O
terrace O
sites O
to O
energetically O
favoured O
step O
edge O
sites O
. O

Polarization O
dependent O
spectroscopy O
reveals O
the O
same O
azimuthal O
orientation O
of O
the O
molecules O
on O
both O
adsorption O
sites O
and O
leads O
to O
a O
model O
of O
the O
adsorption O
geometry O
of O
PTCDA B
at O
the O
KCl B
step O
sites O
. O

Our O
experiment O
demonstrates O
how O
optical O
spectroscopy O
can O
be O
used O
to O
investigate O
kinetic O
processes O
of O
fluorescent O
molecules O
on O
surfaces O
. O

Avoidance O
behaviour O
response O
and O
esterase O
inhibition O
in O
the O
earthworm O
, O
Lumbricus O
terrestris O
, O
after O
exposure O
to O
chlorpyrifos B
. O

The O
avoidance O
response O
of O
earthworms O
to O
polluted O
soils O
has O
been O
standardised O
using O
a O
simple O
and O
low O
- O
cost O
test O
, O
which O
facilitates O
soil O
toxicity O
screening O
. O

In O
this O
study O
, O
the O
avoidance O
response O
of O
Lumbricus O
terrestris O
was O
quantified O
in O
chlorpyrifos B
- O
spiked O
soils O
, O
depending O
on O
the O
pesticide O
concentration O
and O
exposure O
duration O
. O

The O
inhibition O
of O
acetylcholinesterase O
( O
AChE O
) O
and O
carboxylesterase O
( O
CbE O
) O
activities O
was O
also O
determined O
as O
indirect O
measures O
of O
pesticide O
bioavailability O
. O

The O
effects O
of O
different O
chlorpyrifos B
concentrations O
were O
examined O
in O
a O
standardised O
test O
( O
two O
- O
chamber O
system O
) O
with O
0 O
. O
6 O
, O
3 O
and O
15 O
mg O
/ O
kg O
chlorpyrifos B
. O

A O
modification O
of O
the O
test O
involved O
a O
pre O
- O
exposure O
step O
( O
24 O
, O
48 O
or O
72 O
h O
) O
in O
soils O
spiked O
with O
15 O
mg O
/ O
kg O
. O

In O
both O
protocols O
, O
earthworms O
were O
unable O
to O
avoid O
the O
contaminated O
soils O
. O

However O
, O
the O
esterase O
activities O
showed O
that O
all O
earthworms O
were O
exposed O
to O
chlorpyrifos B
. O

Acetylcholinesterase O
activity O
did O
not O
change O
in O
earthworms O
in O
the O
standardised O
behavioural O
test O
( O
0 O
. O
58 O
+ O
/ O
- O
0 O
. O
20 O
U O
/ O
mg O
protein O
, O
mean O
+ O
/ O
- O
SD O
; O
n O
= O
72 O
) O
, O
whereas O
the O
CbE O
activity O
was O
significantly O
inhibited O
( O
62 O
- O
87 O
% O
inhibition O
) O
in O
earthworms O
exposed O
to O
3 O
and O
15 O
mg O
/ O
kg O
. O

In O
the O
modified O
test O
, O
earthworms O
had O
greatly O
inhibited O
AChE O
activity O
( O
0 O
. O
088 O
+ O
/ O
- O
0 O
. O
034 O
U O
/ O
mg O
protein O
, O
n O
= O
72 O
) O
, O
which O
was O
supported O
by O
reactivation O
of O
the O
inhibited O
enzyme O
activity O
in O
the O
presence O
of O
pralidoxime B
( O
2 B
- I
PAM I
) O
. O

Similarly O
, O
the O
CbE O
activity O
was O
significantly O
inhibited O
in O
earthworms O
with O
all O
treatments O
. O

This O
study O
suggests O
that O
the O
avoidance O
behaviour O
test O
for O
organophosphorus B
- O
contaminated O
soils O
could O
be O
supported O
by O
specific O
biomarkers O
to O
facilitate O
a O
better O
understanding O
of O
pesticide O
exposure O
and O
toxicity O
during O
this O
test O
. O

Impact O
of O
childhood O
- O
onset O
type O
1 O
diabetes O
on O
schooling O
: O
a O
population O
- O
based O
register O
study O
. O

AIMS O
/ O
HYPOTHESIS O
: O
We O
investigated O
the O
impact O
of O
type O
1 O
diabetes O
on O
educational O
achievements O
in O
compulsory O
and O
upper O
secondary O
school O
, O
as O
well O
as O
potential O
long O
- O
lasting O
effects O
. O

METHODS O
: O
Altogether O
2 O
, O
485 O
individuals O
with O
type O
1 O
diabetes O
, O
diagnosed O
at O
the O
age O
of O
< O
15 O
years O
and O
born O
in O
1972 O
- O
1978 O
, O
were O
selected O
from O
the O
Swedish O
Childhood O
Diabetes O
Register O
, O
which O
was O
linked O
to O
national O
population O
registers O
including O
the O
Swedish O
Education O
Register O
. O

For O
each O
individual O
, O
four O
controls O
from O
the O
general O
population O
, O
matched O
for O
year O
of O
birth O
and O
residence O
at O
the O
time O
of O
diagnosis O
, O
were O
selected O
by O
Statistics O
Sweden O
( O
n O
= O
9 O
, O
940 O
) O
. O

We O
analysed O
the O
impact O
of O
diabetes O
on O
final O
school O
grades O
at O
16 O
years O
( O
compulsory O
school O
) O
and O
19 O
years O
( O
upper O
secondary O
school O
) O
and O
on O
participation O
in O
the O
labour O
market O
at O
29 O
years O
using O
linear O
, O
logistic O
, O
ordered O
logistic O
and O
quantile O
regression O
analyses O
, O
controlling O
for O
demographics O
and O
socioeconomic O
background O
. O

RESULTS O
: O
Diabetes O
had O
a O
negative O
effect O
on O
mean O
final O
grades O
( O
scale O
of O
1 O
- O
5 O
) O
in O
compulsory O
school O
( O
- O
0 O
. O
07 O
, O
p O
< O
0 O
. O
001 O
) O
and O
theoretical O
programmes O
in O
upper O
secondary O
school O
( O
- O
0 O
. O
07 O
, O
p O
= O
0 O
. O
001 O
) O
. O

Children O
with O
early O
- O
onset O
diabetes O
( O
0 O
- O
4 O
years O
) O
suffered O
a O
greater O
disadvantage O
as O
a O
result O
of O
the O
disease O
( O
- O
0 O
. O
15 O
, O
p O
= O
0 O
. O
001 O
in O
compulsory O
school O
) O
. O

The O
strongest O
effect O
was O
seen O
in O
the O
lowest O
deciles O
of O
the O
conditional O
distribution O
on O
mean O
final O
grades O
. O

At O
age O
29 O
, O
individuals O
with O
diabetes O
were O
less O
likely O
to O
be O
gainfully O
employed O
( O
OR O
0 O
. O
82 O
, O
95 O
% O
CI O
0 O
. O
73 O
, O
0 O
. O
91 O
) O
. O

CONCLUSIONS O
/ O
INTERPRETATION O
: O
The O
small O
but O
significant O
negative O
effect O
of O
type O
1 O
diabetes O
on O
schooling O
could O
affect O
opportunities O
for O
further O
education O
and O
career O
development O
. O

Attention O
must O
be O
paid O
in O
school O
to O
the O
special O
needs O
of O
children O
with O
diabetes O
. O

Multiple O
biological O
properties O
of O
macelignan B
and O
its O
pharmacological O
implications O
. O

Macelignan B
found O
in O
the O
nutmeg O
mace O
of O
Myristica O
fragrans O
obtains O
increasing O
attention O
as O
a O
new O
avenue O
in O
treating O
various O
diseases O
. O

Macelignan B
has O
been O
shown O
to O
possess O
a O
spectrum O
of O
pharmacological O
activities O
, O
including O
anti O
- O
bacterial O
, O
anti O
- O
inflammatory O
, O
anti O
- O
cancer O
, O
anti O
- O
diabetes O
, O
and O
hepatoprotective O
activities O
; O
recently O
, O
it O
has O
also O
been O
shown O
to O
have O
neuroprotective O
activities O
. O

This O
review O
summarizes O
the O
current O
research O
on O
the O
biological O
effects O
of O
macelignan B
derived O
from O
M O
. O
fragrans O
, O
with O
emphasis O
on O
the O
importance O
in O
understanding O
and O
treating O
complex O
diseases O
such O
as O
cancer O
and O
Alzheimer O
' O
s O
disease O
. O

Induction O
of O
heme B
oxygenase O
- O
1 O
protects O
mouse O
liver O
from O
apoptotic O
ischemia O
/ O
reperfusion O
injury O
. O

Ischemia O
/ O
reperfusion O
( O
I O
/ O
R O
) O
injury O
is O
the O
main O
cause O
of O
primary O
graft O
dysfunction O
of O
liver O
allografts O
. O

Cobalt B
- I
protoporphyrin I
( O
CoPP B
) O
- O
dependent O
induction O
of O
heme B
oxygenase O
( O
HO O
) O
- O
1 O
has O
been O
shown O
to O
protect O
the O
liver O
from O
I O
/ O
R O
injury O
. O

This O
study O
analyzes O
the O
apoptotic O
mechanisms O
of O
HO O
- O
1 O
- O
mediated O
cytoprotection O
in O
mouse O
liver O
exposed O
to O
I O
/ O
R O
injury O
. O

HO O
- O
1 O
induction O
was O
achieved O
by O
the O
administration O
of O
CoPP B
( O
1 O
. O
5 O
mg O
/ O
kg O
body O
weight O
i O
. O
p O
. O
) O
. O

Mice O
were O
studied O
in O
in O
vivo O
model O
of O
hepatic O
segmental O
( O
70 O
% O
) O
ischemia O
for O
60 O
min O
and O
reperfusion O
injury O
. O

Mice O
were O
randomly O
allocated O
to O
four O
main O
experimental O
groups O
( O
n O
= O
10 O
each O
) O
: O
( O
1 O
) O
A O
control O
group O
undergoing O
sham O
operation O
. O

( O
2 O
) O
Similar O
to O
group O
1 O
but O
with O
the O
administration O
of O
CoPP O
72 O
h O
before O
the O
operation O
. O

( O
3 O
) O
Mice O
undergoing O
in O
vivo O
hepatic O
I O
/ O
R O
. O

( O
4 O
) O
Similar O
to O
group O
3 O
but O
with O
the O
administration O
of O
CoPP O
72 O
h O
before O
ischemia O
induction O
. O

When O
compared O
with O
the O
I O
/ O
R O
mice O
group O
, O
in O
the O
I O
/ O
R O
+ O
CoPP O
mice O
group O
, O
the O
increased O
hepatic O
expression O
of O
HO O
- O
1 O
was O
associated O
with O
a O
significant O
reduction O
in O
liver O
enzyme O
levels O
, O
fewer O
apoptotic O
hepatocytes O
cells O
were O
identified O
by O
morphological O
criteria O
and O
by O
immunohistochemistry O
for O
caspase O
- O
3 O
, O
there O
was O
a O
decreased O
mean O
number O
of O
proliferating O
cells O
( O
positively O
stained O
for O
Ki67 O
) O
, O
and O
a O
reduced O
hepatic O
expression O
of O
: O
C O
/ O
EBP O
homologous O
protein O
( O
an O
index O
of O
endoplasmic O
reticulum O

stress O
) O
, O
the O
NF O
- O
kappa O
B O
' O
s O
regulated O
genes O
( O
CIAP2 O
, O
MCP O
- O
1 O
and O
IL O
- O
6 O
) O
, O
and O
increased O
hepatic O
expression O
of O
I O
kappa O
Ba O
( O
the O
inhibitory O
protein O
of O
NF O
- O
kappa O
B O
) O
. O

HO O
- O
1 O
over O
- O
expression O
plays O
a O
pivotal O
role O
in O
reducing O
the O
hepatic O
apoptotic O
IR O
injury O
. O

HO O
- O
1 O
may O
serve O
as O
a O
potential O
target O
for O
therapeutic O
intervention O
in O
hepatic O
I O
/ O
R O
injury O
during O
liver O
transplantation O
. O

Myeloperoxidase O
Activity O
and O
Its O
Corresponding O
mRNA O
Expression O
as O
well O
as O
Gene O
Polymorphism O
in O
the O
Population O
Living O
in O
the O
Coal B
- O
Burning O
Endemic O
Fluorosis O
Area O
in O
Guizhou O
of O
China O
. O

The O
myeloperoxidase O
( O
MPO O
) O
activity O
and O
its O
corresponding O
mRNA O
expression O
as O
well O
as O
gene O
polymorphism O
were O
investigated O
in O
the O
population O
who O
live O
in O
the O
endemic O
fluorosis O
area O
. O

In O
the O
study O
, O
150 O
people O
were O
selected O
from O
the O
coal B
- O
burning O
endemic O
fluorosis O
area O
and O
150 O
normal O
persons O
from O
the O
non O
- O
fluorosis O
area O
in O
Guizhou O
province O
of O
China O
. O

The O
blood O
samples O
were O
collected O
from O
these O
people O
. O

The O
activity O
of O
MPO O
in O
the O
plasma O
was O
determined O
by O
spectrophotometer O
; O
the O
expression O
of O
MPO O
mRNA O
was O
measured O
by O
employing O
real O
- O
time O
polymerase O
chain O
reaction O
; O
DNAs O
were O
extracted O
from O
the O
leucocytes O
in O
blood O
and O
five O
SNP O
genotypes O
of O
MPO O
promoter O
gene O
detected O
by O
a O
multiplex O
genotyping O
method O
, O
adapter O
- O
ligation O
- O
mediated O
allele O
- O
specific O
amplification O
. O

The O
results O
showed O
that O
the O
MPO O
activity O
and O
its O
corresponding O
mRNA O
in O
blood O
were O
significantly O
increased O
in O
the O
population O
living O
in O
the O
area O
of O
fluorosis O
. O

The O
different O
genotype O
frequencies O
of O
MPO O
, O
including O
- O
1228G O
/ O
A O
, O
- O
585T O
/ O
C O
, O
- O
463G O
/ O
A O
, O
and O
- O
163C O
/ O
T O
, O
and O
the O
three O
haplotypes O
with O
higher O
frequencies O
, O
including O
- O
163C O
- O
463G O
- O
585T O
- O
1228G O
- O
1276T O
, O
- O
163C O
- O
463G O
- O
585T O
- O
1228G O
- O
1276C O
, O
and O
- O
163C O
- O
463G O
- O
585T O
- O
1228A O
- O
1276T O
, O
were O
significantly O
associated O
with O
fluorosis O
. O

The O
results O
indicated O
that O
the O
elevated O
activity O
of O
MPO O
induced O
by O
endemic O
fluorosis O
may O
be O
connected O
in O
mechanism O
to O
the O
stimulated O
expression O
of O
MPO O
mRNA O
and O
the O
changed O
gene O
polymorphism O
. O

Microporous O
carbon B
nanoplates O
from O
regenerated O
silk O
proteins O
for O
supercapacitors O
. O

Novel O
carbon B
- O
based O
microporous O
nanoplates O
containing O
numerous O
heteroatoms O
( O
H O
- O
CMNs O
) O
are O
fabricated O
from O
regenerated O
silk O
fibroin O
by O
the O
carbonization O
and O
activation O
of O
KOH B
. O

The O
H B
- O
CMNs O
exhibit O
superior O
electrochemical O
performance O
, O
displaying O
a O
specific O
capacitance O
of O
264 O
F O
/ O
g O
in O
aqueous O
electrolytes O
, O
a O
specific O
energy O
of O
133 O
Wh O
/ O
kg O
, O
a O
specific O
power O
of O
217 O
kW O
/ O
kg O
, O
and O
a O
stable O
cycle O
life O
over O
10000 O
cycles O
. O

Pharmacokinetic O
properties O
of O
anti O
- O
influenza O
neuraminidase O
inhibitors O
. O

Neuraminidase O
inhibitors O
are O
the O
mainstay O
of O
anti O
- O
influenza O
treatment O
. O

Oseltamivir B
is O
the O
most O
widely O
used O
drug O
but O
is O
currently O
available O
only O
as O
an O
oral O
formulation O
. O

Resistance O
spreads O
rapidly O
in O
seasonal O
H1N1 O
influenza O
A O
viruses O
, O
which O
were O
universally O
resistant O
in O
2008 O
, O
because O
of O
the O
H275Y O
mutation O
in O
the O
neuraminidase O
( O
NA O
) O
gene O
. O

Oseltamivir B
is O
a O
prodrug O
for O
the O
active O
carboxylate B
metabolite O
. O

Ex O
vivo O
conversion O
in O
blood O
samples O
may O
have O
confounded O
early O
pharmacokinetic O
studies O
. O

Oseltamivir B
shows O
dose O
linear O
kinetics O
, O
and O
oseltamivir B
carboxylate I
has O
an O
elimination O
half O
- O
life O
( O
t O
( O
1 O
/ O
2 O
) O
beta O
) O
after O
oral O
administration O
in O
healthy O
individuals O
of O
approximately O
7 O
. O
7 O
hours O
. O

Oseltamivir B
carboxylate I
is O
eliminated O
primarily O
by O
tubular O
secretion O
, O
and O
both O
clearance O
and O
tissue O
distribution O
are O
reduced O
by O
probenecid B
. O

The O
H275Y O
mutation O
in O
NA O
confers O
high O
- O
level O
oseltamivir B
resistance O
and O
intermediate O
peramivir B
resistance O
but O
does O
not O
alter O
zanamivir B
susceptibility O
. O

Zanamivir B
is O
available O
as O
a O
powder O
for O
inhalation O
, O
and O
a O
parenteral O
form O
is O
under O
development O
. O

Zanamivir B
distributes O
in O
an O
apparent O
volume O
of O
distribution O
approximating O
that O
of O
extracellular O
water O
and O
is O
rapidly O
eliminated O
( O
t O
( O
1 O
/ O
2 O
) O
beta O
of O
approximately O
3 O
. O
0 O
hours O
) O
. O

Peramivir B
is O
slowly O
eliminated O
( O
t O
( O
1 O
/ O
2 O
) O
beta O
of O
7 O
. O
7 O
- O
20 O
. O
8 O
hours O
) O
and O
is O
prescribed O
as O
either O
a O
once O
- O
daily O
injection O
or O
as O
a O
single O
infusion O
. O

Laninamivir B
is O
a O
recently O
developed O
slowly O
eliminated O
compound O
for O
administration O
by O
inhalation O
. O

Comparison O
of O
subcutaneous O
and O
intravenous O
administration O
of O
trastuzumab O
: O
a O
phase O
I O
/ O
Ib O
trial O
in O
healthy O
male O
volunteers O
and O
patients O
with O
HER2 O
- O
positive O
breast O
cancer O
. O

Trastuzumab O
is O
a O
key O
component O
of O
treatment O
for O
human O
epidermal O
growth O
factor O
receptor O
2 O
( O
HER2 O
) O
- O
positive O
breast O
cancer O
in O
both O
the O
early O
and O
metastatic O
settings O
. O

It O
is O
administered O
intravenously O
, O
with O
between O
17 O
and O
52 O
infusions O
in O
standard O
regimens O
over O
1 O
year O
. O

Intravenous O
administration O
of O
trastuzumab O
requires O
substantial O
time O
commitments O
for O
patients O
and O
health O
care O
professionals O
and O
can O
result O
in O
patient O
discomfort O
. O

A O
subcutaneous O
formulation O
of O
trastuzumab O
, O
containing O
recombinant O
human O
hyaluronidase O
to O
overcome O
subcutaneous O
absorption O
barriers O
, O
would O
reduce O
the O
administration O
duration O
and O
remove O
the O
need O
to O
establish O
intravenous O
access O
, O
thus O
improving O
the O
overall O
convenience O
of O
trastuzumab O
administration O
. O

This O
open O
- O
label O
, O
2 O
- O
part O
, O
phase O
I O
/ O
Ib O
study O
( O
NCT00800436 O
) O
was O
undertaken O
in O
healthy O
male O
volunteers O
and O
female O
patients O
with O
HER2 O
- O
positive O
early O
breast O
cancer O
to O
identify O
the O
dose O
of O
subcutaneous O
trastuzumab O
that O
resulted O
in O
exposure O
comparable O
with O
the O
approved O
intravenous O
trastuzumab O
dose O
. O

A O
subcutaneous O
trastuzumab O
dose O
of O
8 O
mg O
/ O
kg O
was O
found O
to O
result O
in O
exposure O
comparable O
with O
the O
intravenous O
trastuzumab O
dose O
of O
6 O
mg O
/ O
kg O
. O

The O
subcutaneous O
formulation O
was O
well O
tolerated O
, O
with O
a O
trend O
toward O
fewer O
adverse O
events O
versus O
intravenous O
administration O
; O
most O
adverse O
events O
were O
mild O
in O
intensity O
. O

These O
results O
support O
an O
ongoing O
phase O
III O
efficacy O
and O
safety O
study O
comparing O
a O
fixed O
subcutaneous O
trastuzumab O
dose O
with O
intravenous O
trastuzumab O
administration O
. O

Inhibitory O
effect O
of O
ketoconazole B
on O
the O
pharmacokinetics O
of O
a O
multireceptor O
tyrosine B
kinase O
inhibitor O
BMS B
- I
690514 I
in O
healthy O
participants O
: O
assessing O
the O
mechanism O
of O
the O
interaction O
with O
physiologically O
- O
based O
pharmacokinetic O
simulations O
. O

BMS B
- I
690514 I
, O
a O
selective O
inhibitor O
of O
the O
ErbB O
and O
vascular O
endothelial O
growth O
factor O
receptors O
, O
has O
shown O
antitumor O
activity O
in O
early O
clinical O
development O
. O

The O
compound O
is O
metabolized O
by O
multiple O
enzymes O
, O
with O
CYP3A4 O
responsible O
for O
the O
largest O
fraction O
( O
34 O
% O
) O
of O
metabolism O
. O

It O
is O
also O
a O
substrate O
of O
P O
- O
glycoprotein O
( O
P O
- O
gp O
) O
in O
vitro O
. O

To O
assess O
the O
effect O
of O
ketoconazole B
on O
BMS B
- I
690514 I
pharmacokinetics O
, O
17 O
healthy O
volunteers O
received O
200 O
mg O
BMS B
- I
690514 I
alone O
followed O
by O
100 O
mg O
BMS B
- I
690514 I
with O
ketoconazole B
( O
400 O
mg O
once O
daily O
for O
4 O
days O
) O
. O

The O
AUC O
( O
infinity O
) O
of O
100 O
mg O
BMS B
- I
690514 I
concomitantly O
administered O
with O
ketoconazole B
was O
similar O
to O
that O
of O
200 O
mg O
BMS B
- I
690514 I
alone O
. O

The O
dose O
- O
normalized O
C O
( O
max O
) O
and O
AUC O
( O
infinity O
) O
of O
BMS B
- I
690514 I
from O
the O
100 O
- O
mg O
BMS B
- I
690514 I
/ O
400 O
- O
mg O
ketoconazole B
treatment O
increased O
by O
55 O
% O
and O
127 O
% O
, O
respectively O
, O
relative O
to O
those O
from O
200 O
mg O
BMS B
- I
690514 I
alone O
. O

Prediction O
of O
the O
drug O
- O
drug O
interaction O
( O
DDI O
) O
using O
a O
population O
- O
based O
simulator O
( O
Simcyp O
) O
indicated O
that O
, O
in O
addition O
to O
CYP3A4 O
inhibition O
, O
the O
inhibition O
of O
P O
- O
gp O
by O
ketoconazole B
in O
the O
intestine O
, O
liver O
, O
and O
kidneys O
must O
be O
invoked O
to O
fully O
account O
for O
the O
DDI O
observed O
. O

This O
finding O
suggests O
that O
the O
inhibition O
of O
P O
- O
gp O
by O
ketoconazole B
, O
along O
with O
its O
effect O
on O
CYP3A4 O
, O
needs O
to O
be O
considered O
when O
designing O
a O
DDI O
study O
of O
ketoconazole B
with O
a O
victim O
drug O
that O
is O
a O
dual O
substrate O
. O

Construction O
of O
robust O
enzyme O
nanocapsules O
for O
effective O
organophosphate B
decontamination O
, O
detoxification O
, O
and O
protection O
. O

Nanocapsules O
of O
organophosphorous B
hydrolase O
with O
enhanced O
enzyme O
activity O
and O
stability O
are O
prepared O
via O
in O
situ O
polymerization O
, O
providing O
a O
novel O
class O
of O
nanoparticles O
for O
the O
decontamination O
and O
detoxification O
of O
organophosphates B
such O
as O
chemical O
warfare O
agents O
and O
pesticides O
. O

Using O
the O
nanocapsules O
as O
building O
blocks O
, O
bioactive O
nanocomposites O
are O
also O
fabricated O
, O
enabling O
their O
use O
for O
organophosphate B
protection O
. O

Bioactive O
formulations O
with O
sugar B
- O
derived O
surfactants O
: O
a O
new O
approach O
for O
photoprotection O
and O
controlled O
release O
of O
promethazine B
. O

Skin O
deep O
: O
A O
bioactive O
formulation O
for O
dermal O
delivery O
of O
antihistamines O
is O
obtained O
by O
using O
the O
original O
properties O
of O
catanionic O
associations O
towards O
self O
- O
assembly O
in O
water O
. O

The O
drug O
, O
which O
participates O
in O
its O
own O
transport O
, O
is O
preserved O
from O
photodegradation O
when O
solubilised O
in O
the O
bioactive O
formulation O
. O

The O
drug O
release O
through O
the O
skin O
is O
also O
delayed O
. O

A O
simple O
method O
for O
fabricating O
patterned O
curvilinear O
microstructures O
in O
poly B
( I
dimethylsiloxane I
) I
by O
selective O
wetting O
. O

The O
fabrication O
of O
patterned O
microstructures O
in O
poly B
( I
dimethylsiloxane I
) I
( O
PDMS B
) O
is O
a O
prerequisite O
for O
soft O
lithography O
. O

Herein O
, O
curvilinear O
surface O
relief O
microstructures O
in O
PDMS B
are O
fabricated O
through O
a O
simple O
three O
- O
stage O
approach O
combining O
microcontact O
printing O
( O
mu O
CP O
) O
, O
selective O
surface O
wetting O
/ O
dewetting O
and O
replica O
molding O
( O
REM O
) O
. O

First O
, O
using O
an O
original O
PDMS B
stamp O
( O
first O
- O
generation O
stamp O
) O
with O
linear O
relief O
features O
, O
a O
chemical O
pattern O
on O
gold O
substrate O
is O
generated O
by O
mu O
CP O
using O
hexadecanethiol B
( O
HDT B
) O
as O
an O
ink O
. O

Then O
, O
by O
a O
dip O
- O
coating O
process O
, O
an O
ordered O
polyethylene B
glycol I
( O
PEG B
) O
polymer O
- O
dot O
array O
forms O
on O
the O
HDT O
- O
patterned O
gold O
substrate O
. O

Finally O
, O
based O
on O
a O
REM O
process O
, O
the O
PEG B
- O
dot O
array O
on O
gold O
substrate O
is O
used O
to O
fabricate O
a O
second O
- O
generation O
PDMS B
stamp O
with O
microcavity O
array O
, O
and O
the O
second O
- O
generation O
PDMS B
stamp O
is O
used O
to O
generate O
third O
- O
generation O
PDMS B
stamp O
with O
microbump O
array O
. O

These O
fabricated O
new O
- O
generation O
stamps O
are O
utilized O
in O
mu O
CP O
and O
in O
micromolding O
in O
capillaries O
( O
MIMIC O
) O
, O
allowing O
the O
generation O
of O
surface O
micropatterns O
which O
cannot O
be O
obtained O
using O
the O
original O
PDMS B
stamp O
. O

The O
method O
will O
be O
useful O
in O
producing O
new O
- O
generation O
PDMS B
stamps O
, O
especially O
for O
those O
who O
want O
to O
use O
soft O
lithography O
in O
their O
studies O
but O
have O
no O
access O
to O
the O
microfabrication O
facilities O
. O

The O
discovery O
of O
novel O
human O
androgen B
receptor O
antagonist O
chemotypes O
using O
a O
combined O
pharmacophore O
screening O
procedure O
. O

Unraveling O
the O
mechanisms O
involved O
in O
castration O
- O
and O
therapy O
- O
resistant O
prostate O
cancer O
has O
led O
to O
a O
renewed O
interest O
in O
androgen B
receptor O
( O
AR O
) O
- O
targeted O
therapeutics O
. O

Anti O
- O
androgens B
that O
block O
the O
activity O
of O
the O
AR O
therefore O
remain O
a O
valid O
therapeutic O
option O
. O

However O
, O
they O
must O
be O
more O
effective O
than O
, O
or O
display O
a O
distinct O
mechanism O
of O
action O
or O
binding O
mode O
from O
those O
of O
bicalutamide B
and O
hydroxyflutamide B
, O
which O
are O
currently O
in O
clinical O
use O
. O

For O
that O
reason O
, O
the O
second O
- O
generation O
anti O
- O
androgen B
MDV3100 B
was O
developed O
. O

MDV3100 B
, O
however O
, O
shares O
its O
4 B
- I
cyano I
- I
3 I
- I
( I
trifluoromethyl I
) I
phenyl I
group O
with O
bicalutamide B
and O
hydroxyflutamide B
required O
for O
binding O
to O
the O
AR O
. O

In O
this O
work O
, O
we O
used O
a O
combined O
strategy O
to O
find O
new O
antagonist O
structures O
distinct O
from O
the O
4 B
- I
cyano I
- I
3 I
- I
( I
trifluoromethyl I
) I
phenyl I
group O
to O
avoid O
cross O
- O
resistance O
for O
these O
compounds O
and O
to O
find O
structures O
without O
agonist O
activity O
on O
mutant O
ARs O
( O
AR O
W741C O
and O
AR O
T877A O
) O
. O

We O
found O
two O
novel O
chemotypes O
with O
AR O
- O
antagonistic O
activity O
( O
IC O
( O
50 O
) O
: O
3 O
- O
6 O
mu O
M O
) O
by O
virtual O
screening O
and O
confirmed O
their O
biological O
activity O
in O
an O
androgen B
- O
responsive O
reporter O
assay O
. O

The O
design O
of O
our O
computational O
approach O
was O
validated O
by O
the O
observation O
of O
strongly O
decreased O
or O
absence O
of O
agonistic O
activity O
on O
the O
two O
mutant O
ARs O
. O

Further O
structural O
derivatization O
to O
optimize O
the O
potency O
of O
these O
compounds O
can O
render O
these O
chemotypes O
into O
very O
promising O
, O
alternative O
AR O
antagonists O
for O
prostate O
cancer O
therapy O
. O

The O
Overexpression O
of O
Hypomethylated O
miR O
- O
663 O
Induces O
Chemotherapy O
Resistance O
in O
Human O
Breast O
Cancer O
Cells O
by O
Targeting O
Heparin O
Sulfate O
Proteoglycan O
2 O
( O
HSPG2 O
) O
. O

MicroRNAs O
are O
involved O
in O
regulating O
the O
biology O
of O
cancer O
cells O
, O
but O
their O
involvement O
in O
chemoresistance O
is O
not O
fully O
understood O
. O

We O
found O
that O
miR O
- O
663 O
was O
up O
- O
regulated O
in O
our O
induced O
multidrug O
- O
resistant O
MDA O
- O
MB O
- O
231 O
/ O
ADM O
cell O
line O
and O
that O
this O
up O
- O
regulation O
was O
closely O
related O
to O
chemosensitivity O
. O

In O
the O
present O
study O
, O
we O
aimed O
to O
clarify O
the O
role O
of O
miR O
- O
663 O
in O
regulating O
the O
chemoresistance O
of O
breast O
cancer O
. O

MicroRNA O
microarray O
and O
quantitative O
RT O
- O
PCR O
assays O
were O
used O
to O
identify O
differentially O
expressed O
microRNAs O
. O

Cell O
apoptosis O
was O
evaluated O
by O
annexin O
V O
/ O
propidium B
iodide I
staining O
, O
TUNEL O
, O
and O
reactive O
oxygen B
species O
generation O
analysis O
. O

The O
expression O
of O
miR O
- O
663 O
and O
HSPG2 O
in O
breast O
cancer O
tissues O
was O
detected O
by O
in O
situ O
hybridization O
and O
immunohistochemistry O
. O

The O
potential O
targets O
of O
miR O
- O
663 O
were O
defined O
by O
a O
luciferase O
reporter O
assay O
. O

Bisulfite B
sequencing O
PCR O
was O
used O
to O
analyze O
the O
methylation O
status O
. O

We O
found O
that O
miR O
- O
663 O
was O
significantly O
elevated O
in O
MDA O
- O
MB O
- O
231 O
/ O
ADM O
cells O
, O
and O
the O
down O
- O
regulation O
of O
miR O
- O
663 O
sensitized O
MDA O
- O
MB O
- O
231 O
/ O
ADM O
cells O
to O
both O
cyclophosphamide B
and O
docetaxel B
. O

The O
overexpression O
of O
miR O
- O
663 O
in O
breast O
tumor O
tissues O
was O
associated O
with O
chemoresistance O
; O
in O
MDA O
- O
MB O
- O
231 O
cells O
, O
this O
chemoresistance O
was O
accompanied O
by O
the O
down O
- O
regulation O
of O
HSPG2 O
, O
which O
was O
identified O
as O
a O
target O
of O
miR O
- O
663 O
. O

MDA O
- O
MB O
- O
231 O
/ O
ADM O
contained O
fewer O
methylated O
CpG B
sites O
than O
its O
parental O
cell O
line O
, O
and O
miR O
- O
663 O
expression O
in O
MDA O
- O
MB O
- O
231 O
cells O
was O
reactivated O
by O
5 B
- I
aza I
- I
29 I
- I
deoxycytidine I
treatment O
, O
indicating O
that O
DNA O
methylation O
may O
play O
a O
functional O
role O
in O
the O
expression O
of O
miR O
- O
663 O
. O

Our O
findings O
suggest O
that O
the O
overexpression O
of O
hypomethylated O
miR O
- O
663 O
induced O
chemoresistance O
in O
breast O
cancer O
cells O
by O
down O
- O
regulating O
HSPG2 O
, O
thus O
providing O
a O
potential O
target O
for O
the O
development O
of O
an O
microRNA O
- O
based O
approach O
for O
breast O
cancer O
therapy O
. O

A O
concise O
synthesis O
of O
pyrazole B
analogues O
of O
combretastatin B
A1 I
as O
potent O
anti O
- O
tubulin O
agents O
. O

Combretastatin B
A1 I
( O
CA1 O
) O
binds O
to O
the O
beta O
- O
subunit O
at O
the O
colchicine B
binding O
site O
of O
tubulin O
and O
inhibits O
polymerization O
. O

As O
such O
, O
it O
is O
both O
an O
antitumor O
agent O
and O
a O
vascular O
disrupting O
agent O
. O

It O
has O
been O
shown O
to O
be O
at O
least O
tenfold O
more O
potent O
than O
combretastatin B
A4 I
( O
CA4 B
) O
in O
terms O
of O
vascular O
shutdown O
, O
which O
correlates O
with O
its O
metabolism O
to O
reactive O
ortho B
- I
quinone I
species O
that O
are O
assumed O
to O
be O
directly O
cytotoxic O
in O
tumor O
cells O
. O

A O
series O
of O
3 B
, I
4 I
- I
diarylpyrazoles I
were O
concisely O
synthesized O
, O
one O
of O
which O
, O
3 B
- I
methoxy I
- I
6 I
- I
[ I
4 I
- I
( I
3 I
, I
4 I
, I
5 I
- I
trimethoxyphenyl I
) I
- I
1H I
- I
pyrazol I
- I
3 I
- I
yl I
] I
benzene I
- I
1 I
, I
2 I
- I
diol I
( O
27 O
) O
, O
proved O
to O
be O
a O
cytotoxic O
anti O
- O
tubulin O
agent O
with O
low O
nanomolar O
potency O
. O

We O
also O
report O
that O
combretastatins B
, O
including O
CA1 O
, O
CA4 O
, O
and O
27 O
, O
are O
effective O
against O
mesothelioma O
cell O
lines O
and O
therefore O
have O
significant O
clinical O
promise O
. O

Metabolism O
experiments O
demonstrate O
that O
27 O
retains O
the O
ability O
to O
form O
ortho B
- I
quinone I
species O
, O
while O
the O
pyrazole B
ring O
shows O
high O
metabolic O
stability O
, O
suggesting O
that O
this O
compound O
might O
result O
in O
better O
pharmacokinetic O
profiles O
than O
CA1 O
, O
with O
similar O
pharmacodynamic O
properties O
and O
clinical O
potential O
. O

Understanding O
quantitative O
structure O
- O
property O
relationships O
uncertainty O
in O
environmental O
fate O
modeling O
. O

In O
cases O
in O
which O
experimental O
data O
on O
chemical O
- O
specific O
input O
parameters O
are O
lacking O
, O
chemical O
regulations O
allow O
the O
use O
of O
alternatives O
to O
testing O
, O
such O
as O
in O
silico O
predictions O
based O
on O
quantitative O
structure O
- O
property O
relationships O
( O
QSPRs O
) O
. O

Such O
predictions O
are O
often O
given O
as O
point O
estimates O
; O
however O
, O
little O
is O
known O
about O
the O
extent O
to O
which O
uncertainties O
associated O
with O
QSPR O
predictions O
contribute O
to O
uncertainty O
in O
fate O
assessments O
. O

In O
the O
present O
study O
, O
QSPR O
- O
induced O
uncertainty O
in O
overall O
persistence O
( O
POV O
) O
and O
long O
- O
range O
transport O
potential O
( O
LRTP O
) O
was O
studied O
by O
integrating O
QSPRs O
into O
probabilistic O
assessments O
of O
five O
polybrominated B
diphenyl I
ethers I
( O
PBDEs B
) O
, O
using O
the O
multimedia O
fate O
model O
Simplebox O
. O

The O
uncertainty O
analysis O
considered O
QSPR O
predictions O
of O
the O
fate O
input O
parameters O
' O
melting O
point O
, O
water O
solubility O
, O
vapor O
pressure O
, O
organic O
carbon B
- O
water O
partition O
coefficient O
, O
hydroxyl B
radical O
degradation O
, O
biodegradation O
, O
and O
photolytic O
degradation O
. O

Uncertainty O
in O
POV O
and O
LRTP O
was O
dominated O
by O
the O
uncertainty O
in O
direct O
photolysis O
and O
the O
biodegradation O
half O
- O
life O
in O
water O
. O

However O
, O
the O
QSPRs O
developed O
specifically O
for O
PBDEs B
had O
a O
relatively O
low O
contribution O
to O
uncertainty O
. O

These O
findings O
suggest O
that O
the O
reliability O
of O
the O
ranking O
of O
PBDEs B
on O
the O
basis O
of O
POV O
and O
LRTP O
can O
be O
substantially O
improved O
by O
developing O
better O
QSPRs O
to O
estimate O
degradation O
properties O
. O

The O
present O
study O
demonstrates O
the O
use O
of O
uncertainty O
and O
sensitivity O
analyses O
in O
nontesting O
strategies O
and O
highlights O
the O
need O
for O
guidance O
when O
compounds O
fall O
outside O
the O
applicability O
domain O
of O
a O
QSPR O
. O

Environ O
. O

Toxicol O
. O

Chem O
. O

2013 O
; O
32 O
: O
1069 O
- O
1076 O
. O

( O
c O
) O
2013 O
SETAC O
. O

Balance O
of O
coordination O
and O
hydrophobic O
interaction O
in O
the O
formation O
of O
bilayers O
in O
metal O
- O
coordinated O
surfactant O
mixtures O
. O

Metal O
- O
ligand O
coordination O
and O
hydrophobic O
interaction O
are O
two O
significant O
driving O
forces O
in O
the O
aggregation O
of O
mixtures O
of O
M O
( O
n O
+ O
) O
surfactants O
and O
alkyldimethylamine B
oxide I
( O
CnDMAO B
) O
in O
aqueous O
solutions O
. O

The O
coordinated O
systems O
exhibit O
rich O
aggregation O
behavior O
. O

This O
study O
investigated O
the O
effect O
of O
M O
( O
n O
+ O
) O
ions O
( O
Zn B
( I
2 I
+ I
) I
, O
Ca B
( I
2 I
+ I
) I
, O
Ba B
( I
2 I
+ I
) I
, O
Al B
( I
3 I
+ I
) I
, O
Fe B
( I
3 I
+ I
) I
, O
La B
( I
3 I
+ I
) I
, O
Eu B
( I
3 I
+ I
) I
, O
and O
Tb B
( I
3 I
+ I
) I
) O
and O
hydrophobic O
chains O
( O
hydrocarbon B
and O
fluorocarbon B
) O
on O
the O
formation O
of O
metal O
- O
coordinated O
bilayers O
. O

We O
found O
that O
fluorocarbon B
chains O
and O
branched O
hydrocarbon B
chains O
are O
preferable O
to O
the O
corresponding O
linear O
hydrocarbon B
chains O
for O
the O
formation O
of O
an O
L O
alpha O
phase O
. O

Moreover O
, O
L O
alpha O
phases O
formed O
by O
fluorocarbon B
chains O
exhibited O
higher O
viscoelasticity O
than O
ones O
formed O
by O
the O
hydrocarbons B
, O
and O
the O
bilayers O
formed O
by O
branched O
chains O
were O
rather O
flexible O
, O
revealing O
obvious O
undulation O
. O

The O
construction O
of O
bilayers O
was O
also O
strongly O
affected O
by O
metal O
ions O
due O
to O
their O
variable O
coordination O
ability O
with O
CnDMAO O
. O

Our O
results O
contribute O
to O
the O
understanding O
of O
the O
formation O
of O
metal O
- O
coordinated O
bilayers O
, O
which O
is O
driven O
by O
the O
interplay O
of O
noncovalent O
forces O
. O

A O
natural O
topological O
insulator O
. O

The O
earth O
' O
s O
crust O
and O
outer O
space O
are O
rich O
sources O
of O
technologically O
relevant O
materials O
which O
have O
found O
application O
in O
a O
wide O
range O
of O
fields O
. O

Well O
- O
established O
examples O
are O
diamond B
, O
one O
of O
the O
hardest O
known O
materials O
, O
or O
graphite B
as O
a O
suitable O
precursor O
of O
graphene B
. O

The O
ongoing O
drive O
to O
discover O
novel O
materials O
useful O
for O
( O
opto O
) O
electronic O
applications O
has O
recently O
drawn O
strong O
attention O
to O
topological O
insulators O
. O

Here O
, O
we O
report O
that O
Kawazulite B
, O
a O
mineral O
with O
the O
approximate O
composition O
Bi2 B
( I
Te I
, I
Se I
) I
2 I
( O
Se B
, O
S B
) O
, O
represents O
a O
naturally O
occurring O
topological O
insulator O
whose O
electronic O
properties O
compete O
well O
with O
those O
of O
its O
synthetic O
counterparts O
. O

Kawazulite O
flakes O
with O
a O
thickness O
of O
a O
few O
tens O
of O
nanometers O
were O
prepared O
by O
mechanical O
exfoliation O
. O

They O
exhibit O
a O
low O
intrinsic O
bulk O
doping O
level O
and O
correspondingly O
a O
sizable O
mobility O
of O
surface O
state O
carriers O
of O
more O
than O
1000 O
cm O
( O
2 O
) O
/ O
( O
V O
s O
) O
at O
low O
temperature O
. O

Based O
on O
these O
findings O
, O
further O
minerals O
which O
due O
to O
their O
minimized O
defect O
densities O
display O
even O
better O
electronic O
characteristics O
may O
be O
identified O
in O
the O
future O
. O

Robust O
ordered O
cubic O
mesostructured O
polymer O
/ O
silica B
composite O
films O
grown O
at O
the O
air O
/ O
water O
interface O
. O

Polymer O
/ O
silica B
composite O
films O
, O
stable O
to O
calcination O
, O
were O
produced O
using O
catanionic O
surfactant O
mixtures O
( O
hexadecyltrimethylam B
bromide I
( O
CTAB B
) O
and O
sodium B
dodecyl I
sulfate I
( O
SDS B
) O
) O
and O
polymers O
( O
polyethylenimine B
( O
PEI B
) O
or O
polyacrylamide B
( O
PAAm B
) O
) O
at O
the O
air O
/ O
water O
interface O
. O

Film O
formation O
processes O
were O
probed O
by O
time O
- O
resolved O
neutron O
reflectivity O
measurements O
. O

Grazing O
incidence O
X O
- O
ray O
diffraction O
( O
GID O
) O
measurements O
indicate O
that O
the O
mesophase O
geometry O
of O
the O
interfacial O
films O
could O
be O
controlled O
to O
give O
lamellar O
, O
2D O
hexagonal O
, O
and O
several O
cubic O
phases O
( O
Pn3 O
m O
, O
Fm3 O
m O
, O
and O
Im3 O
m O
) O
by O
varying O
the O
polyelectrolyte O
molecular O
weight O
, O
polyelectrolyte O
chemical O
nature O
, O
or O
the O
cationic O
: O
anionic O
surfactant O
molar O
ratio O
. O

On O
the O
basis O
of O
GID O
results O
, O
a O
phase O
diagram O
for O
the O
catanionic O
surfactant O
/ O
polyelectrolyte O
/ O
TMOS O
film O
system O
was O
drawn O
. O

These O
films O
can O
be O
easily O
removed O
from O
the O
interface O
and O
mesoporous O
silica B
films O
which O
retain O
the O
film O
geometry O
can O
be O
obtained O
after O
calcination O
; O
moreover O
, O
this O
film O
preparation O
method O
provides O
a O
simple O
way O
to O
impart O
polymer O
functionality O
into O
the O
mesostructured O
silica B
wall O
, O
which O
means O
these O
films O
have O
potential O
applications O
in O
a O
variety O
of O
fields O
such O
as O
catalysis O
, O
molecular O
separation O
, O
and O
drug O
delivery O
. O

The O
circadian O
clock O
circuitry O
and O
the O
AHR O
signaling O
pathway O
in O
physiology O
and O
pathology O
. O

Life O
forms O
populating O
the O
Earth O
must O
face O
environmental O
challenges O
to O
assure O
individual O
and O
species O
survival O
. O

The O
strategies O
predisposed O
to O
maintain O
organismal O
homeostasis O
and O
grant O
selective O
advantage O
rely O
on O
anticipatory O
phenomena O
facing O
periodic O
modifications O
, O
and O
compensatory O
phenomena O
facing O
unpredictable O
changes O
. O

Biological O
processes O
bringing O
about O
these O
responses O
are O
respectively O
driven O
by O
the O
circadian O
timing O
system O
, O
a O
complex O
of O
biological O
oscillators O
entrained O
to O
the O
environmental O
light O
/ O
dark O
cycle O
, O
and O
by O
regulatory O
and O
metabolic O
networks O
that O
precisely O
direct O
the O
body O
' O
s O
adjustments O
to O
variations O
of O
external O
conditions O
and O
internal O
milieu O
. O

A O
critical O
role O
in O
organismal O
homeostatic O
functions O
is O
played O
by O
the O
aryl B
hydrocarbon I
receptor O
( O
AHR O
) O
complex O
, O
which O
senses O
environmental O
and O
endogenous O
compounds O
, O
influences O
metabolic O
responses O
controlling O
phase O
I O
/ O
II O
gene O
expression O
, O
and O
modulates O
vital O
phenomena O
such O
as O
development O
, O
inflammation O
and O
adaptive O
immunity O
. O

A O
physiological O
cross O
- O
talk O
between O
circadian O
and O
AHR O
signaling O
pathways O
has O
been O
evidenced O
. O

The O
alteration O
of O
AHR O
signaling O
pathway O
deriving O
from O
genetic O
damage O
with O
polymorphisms O
or O
mutations O
, O
or O
produced O
by O
exogenous O
or O
endogenous O
AHR O
activation O
, O
and O
chronodisruption O
caused O
by O
mismatch O
between O
the O
body O
' O
s O
internal O
clock O
and O
geophysical O
time O
/ O
social O
schedules O
, O
are O
capable O
of O
triggering O
pathological O
mechanisms O
involved O
in O
metabolic O
, O
immune O
- O
related O
and O
neoplastic O
diseases O
. O

On O
the O
other O
hand O
, O
the O
molecular O
components O
of O
the O
circadian O
clock O
circuitry O
and O
AHR O
signaling O
pathway O
may O
represent O
useful O
tools O
for O
preventive O
interventions O
and O
valuable O
targets O
of O
therapeutic O
approaches O
. O

Deficient O
fear O
recognition O
in O
regular O
cocaine B
users O
is O
not O
attributable O
to O
elevated O
impulsivity O
or O
conduct O
disorder O
prior O
to O
cocaine B
use O
. O

We O
previously O
reported O
that O
regular O
recreational O
intranasal O
cocaine B
users O
exhibit O
impaired O
recognition O
of O
facial O
expressions O
of O
fear O
compared O
to O
occasional O
cocaine B
users O
and O
cocaine B
- O
na O
i O
ve O
controls O
. O

The O
aim O
of O
the O
present O
study O
was O
to O
re O
- O
investigate O
this O
phenomenon O
after O
controlling O
for O
impulsivity O
, O
conduct O
disorder O
( O
CD O
) O
and O
anti O
- O
social O
personality O
disorder O
( O
ASPD O
) O
. O

We O
employed O
a O
cross O
- O
sectional O
design O
to O
compare O
31 O
cocaine B
- O
na O
i O
ve O
participants O
, O
35 O
occasional O
cocaine B
users O
and O
20 O
regular O
recreational O
cocaine B
users O
. O

An O
emotional O
facial O
expression O
( O
EFE O
) O
task O
which O
comprised O
a O
male O
and O
a O
female O
face O
expressing O
six O
basic O
emotions O
morphed O
to O
differing O
degrees O
of O
emotional O
intensity O
was O
administered O
together O
with O
questionnaires O
to O
assess O
: O
CD O
, O
ASPD O
and O
impulsiveness O
. O

ASPD O
was O
not O
a O
significant O
covariate O
for O
EFE O
performance O
but O
impulsiveness O
and O
CD O
were O
significant O
covariates O
. O

After O
treating O
impulsiveness O
and O
CD O
as O
covariates O
we O
again O
observed O
a O
group O
difference O
in O
fear O
recognition O
ability O
attributable O
to O
the O
particularly O
impaired O
performance O
of O
regular O
cocaine B
users O
. O

This O
suggests O
that O
, O
although O
elevated O
impulsiveness O
and O
CD O
before O
the O
age O
of O
15 O
years O
, O
may O
predispose O
a O
relative O
inability O
to O
recognize O
facial O
expressions O
of O
fear O
in O
adulthood O
, O
subsequent O
regular O
recreational O
use O
of O
cocaine B
represents O
an O
additional O
factor O
that O
is O
specifically O
associated O
with O
a O
selective O
deficit O
in O
fear O
recognition O
. O

Painting O
by O
numbers O
: O
increasing O
the O
parts O
list O
for O
chromatin O
domains O
. O

In O
this O
issue O
of O
Molecular O
Cell O
, O
van O
Bemmel O
and O
colleagues O
( O
2013 O
) O
report O
the O
genome O
- O
wide O
mapping O
of O
42 O
novel O
chromatin O
factors O
, O
systematically O
identifying O
new O
components O
of O
the O
various O
chromatin O
domains O
present O
in O
fly O
cells O
. O

Isolation O
, O
identification O
and O
antimicrobial O
activity O
of O
propolis O
- O
associated O
fungi O
. O

Propolis O
is O
a O
natural O
product O
widely O
known O
for O
its O
medicinal O
properties O
. O

In O
this O
work O
, O
fungi O
present O
on O
propolis O
samples O
were O
isolated O
, O
identified O
and O
tested O
for O
the O
production O
of O
antimicrobial O
metabolites O
. O

Twenty O
- O
two O
fungal O
isolates O
were O
obtained O
, O
some O
of O
which O
were O
identified O
as O
Alternaria O
alternata O
, O
Aspergillus O
flavus O
, O
Bipolaris O
hawaiiensis O
, O
Fusarium O
merismoides O
, O
Lasiodiplodia O
theobromae O
, O
Penicillium O
citrinum O
, O
Penicillium O
crustosum O
, O
Penicillium O
janthinellum O
, O
Penicillium O
purpurogenum O
, O
Pestalotiopsis O
palustris O
, O
Tetracoccosporium O
paxianum O
and O
Trichoderma O
koningii O
. O

These O
fungi O
were O
grown O
in O
liquid O
media O
to O
obtain O
crude O
extracts O
that O
were O
evaluated O
for O
their O
antibiotic O
activity O
against O
pathogenic O
bacteria O
, O
yeast O
and O
Cladosporium O
cladosporioides O
and O
A O
. O
flavus O
. O

The O
most O
active O
extract O
was O
obtained O
from O
L O
. O
theobromae O
( O
minimum O
inhibitory O
concentration O
= O
64 O
mu O
g O
/ O
mL O
against O
Listeria O
monocitogenes O
) O
. O

Some O
extracts O
showed O
to O
be O
more O
active O
than O
the O
positive O
control O
in O
the O
inhibition O
of O
Staphylococcus O
aureus O
and O
L O
. O
monocitogenes O
. O

Therefore O
, O
propolis O
is O
a O
promising O
source O
of O
fungi O
, O
which O
produces O
active O
agents O
against O
relevant O
food O
poisoning O
bacteria O
and O
crop O
- O
associated O
fungi O
. O

Long O
- O
term O
potentiation O
: O
Peeling O
the O
onion O
. O

Since O
the O
discovery O
of O
long O
- O
term O
potentiation O
( O
LTP O
) O
, O
thousands O
of O
papers O
have O
been O
published O
on O
this O
phenomenon O
. O

With O
this O
massive O
amount O
of O
information O
, O
it O
is O
often O
difficult O
, O
especially O
for O
someone O
not O
directly O
involved O
in O
the O
field O
, O
not O
to O
be O
overwhelmed O
. O

The O
goal O
of O
this O
review O
is O
to O
peel O
away O
as O
many O
layers O
as O
possible O
, O
and O
probe O
the O
core O
properties O
of O
LTP O
. O

We O
would O
argue O
that O
the O
many O
dozens O
of O
proteins O
that O
have O
been O
implicated O
in O
the O
phenomenon O
are O
not O
essential O
, O
but O
rather O
modulate O
, O
often O
in O
indirect O
ways O
, O
the O
threshold O
and O
/ O
or O
magnitude O
of O
LTP O
. O

What O
is O
required O
is O
NMDA B
receptor O
activation O
followed O
by O
CaMKII O
activation O
. O

The O
consequence O
of O
CaMKII O
activation O
is O
the O
rapid O
recruitment O
of O
AMPA B
receptors O
to O
the O
synapse O
. O

This O
recruitment O
is O
independent O
of O
AMPA B
receptor O
subunit O
type O
, O
but O
absolutely O
requires O
an O
adequate O
pool O
of O
surface O
receptors O
. O

An O
important O
unresolved O
issue O
is O
how O
exactly O
CaMKII O
activation O
leads O
to O
modifications O
in O
the O
PSD O
to O
allow O
rapid O
enrichment O
. O

This O
article O
is O
part O
of O
a O
Special O
Issue O
entitled O
' O
GluR O
- O
dep O
synaptic O
plasticity O
' O
. O

Disposition O
and O
Metabolism O
of O
GSK2251052 B
in O
Humans O
: O
A O
Novel O
Boron B
- O
Containing O
Antibiotic O
. O

( B
S I
) I
- I
3 I
- I
( I
Aminomethyl I
) I
- I
7 I
- I
( I
3 I
- I
hydroxypropoxy I
) I
- I
1 I
- I
hydroxy I
- I
1 I
, I
3 I
- I
dihydro I
- I
2 I
, I
1 I
- I
benzoxaborole I
( O
GSK2251052 B
) O
is O
a O
novel O
boron B
- O
containing O
antibiotic O
that O
inhibits O
bacterial O
leucyl B
tRNA O
synthetase O
, O
and O
that O
has O
been O
in O
development O
for O
the O
treatment O
of O
serious O
Gram O
- O
negative O
infections O
. O

In O
this O
study O
, O
six O
healthy O
adult O
male O
subjects O
received O
a O
single O
i O
. O
v O
. O
dose O
of O
[ B
( I
14 I
) I
C I
] I
GSK2251052 I
, O
1500 O
mg O
infused O
over O
1 O
hour O
. O

Blood O
, O
urine O
, O
and O
feces O
were O
collected O
over O
an O
extended O
period O
of O
14 O
days O
, O
and O
accelerator O
mass O
spectrometry O
was O
used O
to O
quantify O
low O
levels O
of O
radioactivity O
in O
plasma O
at O
later O
time O
points O
to O
supplement O
the O
less O
- O
sensitive O
liquid O
scintillation O
counting O
technique O
. O

An O
excellent O
mass O
balance O
recovery O
was O
achieved O
representing O
a O
mean O
total O
of O
98 O
. O
2 O
% O
of O
the O
dose O
, O
including O
90 O
. O
5 O
% O
recovered O
in O
the O
urine O
. O

Pharmacokinetic O
analysis O
demonstrated O
that O
radioactivity O
was O
moderately O
associated O
with O
the O
blood O
cellular O
components O
, O
and O
together O
with O
GSK2251052 B
, O
both O
were O
highly O
distributed O
into O
tissues O
. O

The O
parent O
compound O
had O
a O
much O
shorter O
half O
- O
life O
than O
total O
radioactivity O
in O
plasma O
, O
approximately O
11 O
. O
6 O
hours O
compared O
with O
96 O
hours O
. O

GSK2251052 B
and O
its O
major O
metabolite O
M3 O
, O
which O
resulted O
from O
oxidation O
of O
the O
propanol B
side O
chain O
to O
the O
corresponding O
carboxylic B
acid I
, O
comprised O
the O
majority O
of O
the O
plasma O
radioactivity O
, O
37 O
and O
53 O
% O
of O
the O
area O
under O
the O
plasma O
versus O
time O
concentration O
curve O
from O
time O
zero O
to O
infinity O
, O
respectively O
. O

Additionally O
, O
M3 O
was O
eliminated O
renally O
, O
and O
was O
demonstrated O
to O
be O
responsible O
for O
the O
long O
plasma O
radioactivity O
elimination O
half O
- O
life O
. O

A O
combination O
of O
in O
vitro O
metabolism O
experiments O
and O
a O
pharmacokinetic O
study O
in O
monkeys O
with O
the O
inhibitor O
4 B
- I
methylpyrazole I
provided O
strong O
evidence O
that O
alcohol B
dehydrogenase O
, O
potentially O
in O
association O
with O
aldehyde B
dehydrogenase O
, O
is O
the O
primary O
enzyme O
involved O
in O
the O
formation O
of O
the O
M3 O
metabolite O
. O

Strain O
- O
dependent O
dysregulation O
of O
one B
- I
carbon B
metabolism O
in O
male O
mice O
is O
associated O
with O
choline B
- O
and O
folate B
- O
deficient O
diet O
- O
induced O
liver O
injury O
. O

Dysregulation O
of O
one B
- I
carbon I
metabolism O
- O
related O
metabolic O
processes O
is O
a O
major O
contributor O
to O
the O
pathogenesis O
of O
nonalcoholic O
fatty O
liver O
disease O
( O
NAFLD O
) O
. O

It O
is O
well O
established O
that O
genetic O
and O
gender O
- O
specific O
variations O
in O
one B
- I
carbon I
metabolism O
contribute O
to O
the O
vulnerability O
to O
NAFLD O
in O
humans O
. O

To O
examine O
the O
role O
of O
one B
- I
carbon I
metabolism O
dysregulation O
in O
the O
pathogenesis O
and O
individual O
susceptibility O
to O
NAFLD O
, O
we O
used O
a O
" O
population O
- O
based O
" O
mouse O
model O
where O
male O
mice O
from O
7 O
inbred O
were O
fed O
a O
choline B
- O
and O
folate B
- O
deficient O
( O
CFD O
) O
diet O
for O
12 O
wk O
. O

Strain O
- O
dependent O
down O
- O
regulation O
of O
several O
key O
one O
- O
carbon B
metabolism O
genes O
, O
including O
methionine B
adenosyltransferase O
1 O
alpha O
( O
Mat1a O
) O
, O
cystathionine B
- O
beta O
- O
synthase O
( O
Cbs O
) O
, O
methylenetetrahydrof B
reductase O
( O
Mthfr O
) O
, O
adenosyl B
- O
homocysteinase O
( O
Ahcy O
) O
, O
and O
methylenetetrahydrof B
dehydrogenase O
1 O
( O
Mthfd1 O
) O
, O
was O
observed O
. O

These O
changes O
were O
strongly O
associated O
with O
interstrain O
variability O
in O
liver O
injury O
( O
steatosis O
, O
necrosis O
, O
inflammation O
, O
and O
activation O
of O
fibrogenesis O
) O
and O
hyperhomocysteinemia O
. O

Mechanistically O
, O
the O
decreased O
expression O
of O
Mat1a O
, O
Ahcy O
, O
and O
Mthfd1 O
was O
linked O
to O
a O
reduced O
level O
and O
promoter O
binding O
of O
transcription O
factor O
CCAAT O
/ O
enhancer O
binding O
protein O
beta O
( O
CEBP O
beta O
) O
, O
which O
directly O
regulates O
their O
transcription O
. O

The O
strain O
specificity O
of O
diet O
- O
induced O
dysregulation O
of O
one B
- I
carbon I
metabolism O
suggests O
that O
interstrain O
variation O
in O
the O
regulation O
of O
one B
- I
carbon I
metabolism O
may O
contribute O
to O
the O
differential O
vulnerability O
to O
NFLD O
and O
that O
correcting O
the O
imbalance O
may O
be O
considered O
as O
preventive O
and O
treatment O
strategies O
for O
NAFLD O
. O
- O
Pogribny O
, O
I O
. O

P O
. O
, O
Kutanzi O
, O
K O
. O
, O
Melnyk O
, O
S O
. O
, O
de O
Conti O
, O
A O
. O
, O
Tryndyak O
, O
V O
. O
, O
Montgomery O
, O
B O
. O
, O
Pogribna O
, O
M O
. O
, O
Muskhelishvili O
, O
L O
. O
, O
Latendresse O
, O
J O
. O

R O
. O
, O
James O
, O
S O
. O

J O
. O
, O
Beland O
, O
F O
. O

A O
. O
, O
Rusyn O
, O
I O
. O

Strain O
- O
dependent O
dysregulation O
of O
one B
- I
carbon B
metabolism O
in O
male O
mice O
is O
associated O
with O
choline B
- O
and O
folate B
- O
deficient O
diet O
- O
induced O
liver O
injury O
. O

Post O
- O
synthesis O
, O
characterization O
and O
catalytic O
properties O
of O
fluorine B
- O
planted O
MWW O
- O
type O
titanosilicate B
. O

F B
- O
Ti B
- O
MWW O
was O
post O
- O
synthesized O
by O
implanting O
fluorine B
species O
into O
a O
Ti B
- O
MWW O
framework O
through O
an O
acid O
treatment O
process O
in O
the O
presence O
of O
ammonium B
fluoride I
. O

The O
effects O
of O
NH4F B
addition O
amount O
, O
acid O
treatment O
temperature O
and O
precursor O
Ti B
content O
were O
investigated O
on O
the O
incorporation O
of O
F B
species O
, O
the O
zeolite B
structure O
and O
the O
coordination O
sites O
of O
Ti B
. O

Fluorine B
- O
implanting O
improved O
the O
surface O
hydrophobicity O
of O
the O
zeolite B
and O
altered O
the O
electropositivity O
nearby O
the O
tetrahedral O
Ti B
sites O
through O
forming O
the O
SiO3 B
/ O
2F O
and O
SiO4 B
/ O
2F O
( I
- I
) I
units O
. O

The O
negative O
effect O
of O
SiO4 B
/ O
2F B
( I
- I
) I
units O
in O
F B
- O
Ti B
- O
MWW O
was O
eliminated O
selectively O
by O
convenient O
anion O
- O
exchange O
with O
various O
alkali O
chlorides B
. O

F O
- O
Ti B
- O
MWW O
containing O
the O
SiO3 B
/ O
2F O
units O
possessed O
better O
catalytic O
activity O
and O
reusability O
, O
and O
a O
longer O
catalyst O
lifetime O
than O
conventional O
Ti B
- O
MWW O
. O

Mechanism O
of O
morphology O
transformation O
during O
annealing O
of O
nanostructured O
gold O
films O
on O
glass O
. O

Nanostructured O
, O
just O
- O
percolated O
gold O
films O
were O
prepared O
by O
evaporation O
on O
bare O
glass O
. O

Annealing O
of O
the O
films O
at O
temperatures O
close O
to O
or O
higher O
than O
the O
softening O
temperature O
of O
the O
glass O
substrate O
induces O
morphological O
transformation O
to O
discrete O
Au B
islands O
and O
gradual O
embedding O
of O
the O
formed O
islands O
in O
the O
glass O
. O

The O
mechanism O
and O
kinetics O
of O
these O
processes O
are O
studied O
here O
using O
a O
combination O
of O
in O
situ O
high O
- O
temperature O
optical O
spectroscopy O
; O
ex O
situ O
characterization O
of O
the O
island O
shape O
by O
high O
- O
resolution O
scanning O
electron O
microscopy O
( O
HRSEM O
) O
, O
atomic O
force O
microcopy O
( O
AFM O
) O
and O
cross O
- O
sectional O
transmission O
electron O
microscopy O
( O
TEM O
) O
; O
and O
numerical O
simulations O
of O
transmission O
spectra O
using O
the O
Multiple O
Multipole O
Program O
( O
MMP O
) O
approach O
. O

It O
is O
shown O
that O
the O
morphological O
transformation O
of O
just O
- O
percolated O
, O
10 O
nm O
( O
nominal O
thickness O
) O
Au B
films O
evaporated O
on O
glass O
and O
annealed O
at O
600 O
degrees O
C O
, O
i O
. O
e O
. O
, O
in O
the O
vicinity O
of O
the O
substrate O
glass O
transition O
temperature O
( O
Tg O
= O
557 O
degrees O
C O
) O
, O
proceeds O
via O
three O
processes O
exhibiting O
different O
time O
scales O
: O
( O
i O
) O
fast O
recrystallization O
and O
dewetting O
, O
leading O
to O
formation O
of O
single O
- O
crystalline O
islands O
( O
minutes O
) O
; O
the O
initial O
spectrum O
characteristic O
of O
a O
continuous O
Au B
film O
is O
transformed O
to O
that O
of O
an O
island O
film O
, O
displaying O
a O
surface O
plasmon O
( O
SP O
) O

absorption O
band O
. O

( O
ii O
) O
Reshaping O
and O
faceting O
of O
the O
single O
- O
crystalline O
islands O
accompanied O
by O
formation O
of O
circumferential O
glass O
rims O
around O
them O
( O
first O
few O
hours O
) O
; O
the O
overall O
optical O
response O
shows O
a O
blue O
shift O
of O
the O
SP O
band O
. O

( O
iii O
) O
Gradual O
island O
embedding O
in O
the O
glass O
substrate O
( O
tens O
of O
hours O
) O
, O
seen O
as O
a O
characteristic O
red O
shift O
of O
the O
SP O
band O
. O

The O
influence O
of O
the O
annealing O
atmosphere O
( O
air O
, O
vacuum O
) O
on O
the O
embedding O
process O
is O
found O
to O
be O
minor O
. O

Numerical O
modeling O
of O
the O
extinction O
cross O
- O
section O
corresponding O
to O
the O
morphological O
transformations O
during O
island O
recrystallization O
and O
embedding O
is O
in O
qualitative O
agreement O
with O
the O
experimental O
data O
. O

Quality O
assessment O
and O
discrimination O
of O
the O
roots O
of O
Cynanchum O
auriculatum O
and O
Cynanchum O
wilfordii O
by O
HPLC O
- O
UV O
analysis O
. O

Cynanchum O
auriculatum O
and O
Cynanchum O
wilfordii O
are O
widely O
used O
as O
folk O
medicine O
in O
Eastern O
Asia O
. O

However O
, O
the O
indeterminacy O
in O
the O
authentic O
original O
plant O
material O
has O
resulted O
in O
the O
same O
appellative O
name O
being O
given O
to O
the O
two O
plants O
, O
and O
they O
are O
commonly O
misused O
. O

Therefore O
, O
it O
is O
necessary O
to O
establish O
an O
analytical O
method O
for O
discrimination O
as O
well O
as O
quality O
control O
of O
the O
two O
species O
. O

This O
study O
was O
to O
develop O
HPLC O
- O
UV O
methods O
for O
quality O
assessment O
of O
C O
. O
auriculatum O
and O
C O
. O
wilfordii O
and O
discrimination O
between O
the O
two O
species O
. O

Two O
HPLC O
methods O
to O
analyze O
eight O
marker O
compounds O
were O
established O
and O
validated O
. O

The O
first O
method O
analyzed O
seven O
marker O
compounds O
simultaneously O
on O
a O
reversed O
- O
phase O
column O
, O
while O
the O
second O
method O
analyzed O
a O
single O
marker O
compound O
, O
conduritol B
F I
, O
which O
exists O
only O
in O
C O
. O
wilfordii O
, O
on O
a O
Si O
- O
column O
. O

Thirty O
- O
nine O
batches O
of O
C O
. O
auriculatum O
and O
nineteen O
batches O
of O
C O
. O
wilfordii O
that O
were O
collected O
from O
different O
geographical O
regions O
of O
South O
Korea O
were O
analyzed O
by O
these O
methods O
. O

The O
constructed O
data O
matrix O
was O
subjected O
to O
principal O
components O
analysis O
and O
hierarchical O
cluster O
analysis O
in O
order O
to O
classify O
the O
samples O
. O

The O
established O
methods O
offer O
a O
potential O
strategy O
for O
authentication O
and O
differentiation O
of O
the O
two O
species O
. O

Promising O
new O
molecular O
targeted O
therapies O
in O
head O
and O
neck O
cancer O
. O

Despite O
advances O
in O
multimodality O
therapies O
for O
the O
treatment O
of O
squamous O
cell O
carcinoma O
of O
the O
head O
and O
neck O
( O
SCCHN O
) O
, O
survival O
rates O
, O
functional O
outcomes O
and O
toxicities O
of O
therapy O
remain O
poor O
. O

The O
recognition O
of O
the O
prognostic O
value O
of O
human O
papillomavirus O
( O
HPV O
) O
status O
, O
and O
the O
advent O
of O
biologically O
targeted O
therapies O
with O
potential O
for O
decreased O
toxicities O
and O
increased O
selectivity O
, O
represent O
significant O
developments O
in O
our O
understanding O
of O
SCCHN O
. O

Targeted O
agents O
currently O
approved O
or O
under O
investigation O
for O
SCCHN O
include O
epidermal O
growth O
factor O
receptor O
( O
EGFR O
) O
monoclonal O
antibodies O
( O
cetuximab O
, O
panitumumab O
, O
zalutumumab O
, O
nimotuzumab O
) O
, O
EGFR O
tyrosine B
kinase O
inhibitors O
( O
gefitinib B
, O
erlotinib B
, O
lapatinib B
, O
afatanib B
, O
dacomitinib B
) O
, O
vascular O
endothelial O
growth O
factor O
receptor O
( O
VEGFR O
) O
inhibitors O
( O
bevacizumab O
, O
sorafenib B

, O
sunitinib B
, O
vandetanib B
) O
and O
various O
inhibitors O
of O
other O
pathways O
and O
targets O
, O
including O
phosphatidylinositol B
3 O
' O
kinase O
( O
PI3K O
) O
/ O
AKT O
/ O
mammalian O
target O
of O
rapamycin B
( O
mTOR O
) O
, O
MET O
and O
insulin O
- O
like O
growth O
factor O
receptor O
( O
IGF O
- O
1R O
) O
. O

On O
- O
going O
clinical O
trials O
are O
evaluating O
these O
emerging O
agents O
and O
their O
combinations O
in O
the O
treatment O
of O
SCCHN O
. O

Fluorescent O
probes O
for O
G O
- O
quadruplex O
structures O
. O

Mounting O
evidence O
supports O
the O
presence O
of O
biologically O
relevant O
G O
- O
quadruplexes O
in O
single O
- O
cell O
organisms O
, O
but O
the O
existence O
of O
endogenous O
G O
- O
quadruplex O
structures O
in O
mammalian O
cells O
remains O
highly O
controversial O
. O

This O
is O
due O
, O
in O
part O
, O
to O
the O
common O
misconception O
that O
DNA O
and O
RNA O
molecules O
are O
passive O
information O
carriers O
with O
relatively O
little O
structural O
or O
functional O
complexity O
. O

For O
those O
working O
in O
the O
field O
, O
however O
, O
the O
lack O
of O
available O
tools O
for O
characterizing O
DNA O
structures O
in O
vivo O
remains O
a O
major O
limitation O
to O
addressing O
fundamental O
questions O
about O
structure O
- O
function O
relationships O
of O
nucleic O
acids O
. O

In O
this O
review O
, O
we O
present O
progress O
towards O
the O
direct O
detection O
of O
G O
- O
quadruplex O
structures O
by O
using O
small O
molecules O
and O
modified O
oligonucleotides O
as O
fluorescent O
probes O
. O

While O
most O
development O
has O
focused O
on O
cell O
- O
permeable O
probes O
that O
selectively O
bind O
to O
G O
- O
quadruplex O
structures O
with O
high O
affinity O
, O
these O
same O
probes O
can O
induce O
G O
- O
quadruplex O
folding O
, O
thereby O
making O
the O
native O
conformation O
of O
the O
DNA O
or O
RNA O
molecule O
( O
i O
. O
e O
. O
, O
in O
the O
absence O
of O
probe O
) O
uncertain O
. O

For O
this O
reason O
, O
modified O
oligonucleotides O
and O
fluorescent O
base O
analogues O
that O
serve O
as O
" O
internal O
" O
fluorescent O
probes O
are O
presented O
as O
an O
orthogonal O
means O
for O
detecting O
conformational O
changes O
, O
without O
necessarily O
perturbing O
the O
equilibria O
between O
G O
- O
quadruplex O
, O
single O
- O
stranded O
, O
and O
duplex O
DNA O
. O

The O
major O
challenges O
and O
motivation O
for O
the O
development O
of O
fluorescent O
probes O
for O
G O
- O
quadruplex O
structures O
are O
presented O
, O
along O
with O
a O
summary O
of O
the O
key O
photophysical O
, O
biophysical O
, O
and O
biological O
properties O
of O
reported O
examples O
. O

The O
C B
- O
terminal O
extended O
serine B
residue O
is O
absolutely O
required O
in O
nosiheptide O
maturation O
. O

Serine B
qua O
non O
: O
Substitution O
of O
the O
extended O
Ser13 B
in O
the O
core O
peptide O
of O
nosiheptide O
by O
analogous O
amino B
acids I
prevented O
enamide B
dealkylation O
of O
the O
terminal O
residue O
for O
nosiheptide O
maturation O
. O

Carnosine B
inhibits O
A O
beta O
( O
42 O
) O
aggregation O
by O
perturbing O
the O
H B
- O
bond O
network O
in O
and O
around O
the O
central O
hydrophobic O
cluster O
. O

Aggregation O
of O
the O
amyloid O
- O
beta O
peptide O
( O
A O
beta O
) O
into O
fibrillar O
structures O
is O
a O
hallmark O
of O
Alzheimer O
' O
s O
disease O
. O

Thus O
, O
preventing O
self O
- O
assembly O
of O
the O
A O
beta O
peptide O
is O
an O
attractive O
therapeutic O
strategy O
. O

Here O
, O
we O
used O
experimental O
techniques O
and O
atomistic O
simulations O
to O
investigate O
the O
influence O
of O
carnosine B
, O
a O
dipeptide B
naturally O
occurring O
in O
the O
brain O
, O
on O
A O
beta O
aggregation O
. O

Scanning O
force O
microscopy O
, O
circular O
dichroism O
and O
thioflavin B
T I
fluorescence O
experiments O
showed O
that O
carnosine B
does O
not O
modify O
the O
conformational O
features O
of O
A O
beta O
42 O
but O
nonetheless O
inhibits O
amyloid O
growth O
. O

Molecular O
dynamics O
( O
MD O
) O
simulations O
indicated O
that O
carnosine B
interacts O
transiently O
with O
monomeric O
A O
beta O
42 O
by O
salt O
bridges O
with O
charged O
side O
chains O
, O
and O
van O
der O
Waals O
contacts O
with O
residues O
in O
and O
around O
the O
central O
hydrophobic O
cluster O
( O
( B
17 I
) I
LVFFA I
( I
21 I
) O
) O
. O

NMR O
experiments O
on O
the O
nonaggregative O
fragment O
A O
beta O
12 O
- O
28 O
did O
not O
evidence O
specific O
intermolecular O
interactions O
between O
the O
peptide O
and O
carnosine B
, O
in O
agreement O
with O
MD O
simulations O
. O

However O
, O
a O
close O
inspection O
of O
the O
spectra O
revealed O
that O
carnosine B
interferes O
with O
the O
local O
propensity O
of O
the O
peptide O
to O
form O
backbone O
hydrogen B
bonds O
close O
to O
the O
central O
hydrophobic O
cluster O
( O
residues O
E22 O
, O
S26 O
and O
N27 O
) O
. O

Finally O
, O
MD O
simulations O
of O
aggregation O
- O
prone O
A O
beta B
heptapeptide I
segments O
show O
that O
carnosine B
reduces O
the O
propensity O
to O
form O
intermolecular O
backbone O
hydrogen B
bonds O
in O
the O
region O
18 O
- O
24 O
. O

Taken O
together O
, O
the O
experimental O
and O
simulation O
results O
( O
cumulative O
MD O
sampling O
of O
0 O
. O
2 O
ms O
) O
suggest O
that O
, O
despite O
the O
inability O
of O
carnosine B
to O
form O
stable O
contacts O
with O
A O
beta O
, O
it O
might O
block O
the O
pathway O
toward O
toxic O
aggregates O
by O
perturbing O
the O
hydrogen B
bond O
network O
near O
residues O
with O
key O
roles O
in O
fibrillogenesis O
. O

Highly O
Ordered O
Hollow O
Oxide B
Nanostructures O
: O
The O
Kirkendall O
Effect O
at O
the O
Nanoscale O
. O

Highly O
ordered O
ultra O
- O
long O
oxide B
nanotubes O
are O
fabricated O
by O
a O
simple O
two O
- O
step O
strategy O
involving O
the O
growth O
of O
copper B
nanowires O
on O
nanopatterned O
template O
substrates O
by O
magnetron O
sputtering O
, O
followed O
by O
thermal O
annealing O
in O
air O
. O

The O
formation O
of O
such O
tubular O
nanostructures O
is O
explained O
according O
to O
the O
nanoscale O
Kirkendall O
effect O
. O

The O
concept O
of O
this O
new O
fabrication O
route O
is O
also O
extendable O
to O
create O
periodic O
zero O
- O
dimensional O
hollow O
nanostructures O
. O

Solvatochromic O
Effect O
on O
the O
Photoluminescence O
of O
MoS2 B
Monolayers O
. O

The O
effect O
of O
surrounding O
solvents O
on O
the O
photoluminescence O
( O
PL O
) O
of O
MoS2 B
monolayers O
on O
Si B
/ O
SiO2 B
substrates O
is O
studied O
. O

A O
redshift O
( O
up O
to O
- O
60 O
meV O
) O
is O
observed O
for O
MoS2 B
monolayers O
with O
nonhalogenated O
solvent O
surroundings O
. O

A O
blueshift O
( O
up O
to O
60 O
meV O
) O
and O
intensity O
increase O
( O
2 O
- O
50 O
times O
) O
are O
observed O
for O
monolayers O
with O
halogenated O
solvent O
surroundings O
. O

Regio O
- O
and O
Stereocontrolled O
Synthesis O
of O
Oligostilbenoids B
: O
Theoretical O
Highlights O
at O
the O
Supramolecular O
Level O
. O

Oligostilbenoids O
( O
e O
. O
g O
. O
, O
ampelopsin B
F I
, O
viniferin B
, O
pallidol B
) O
result O
from O
homogeneous O
or O
heterogeneous O
coupling O
of O
monomeric O
stilbenoid B
units O
, O
leading O
to O
various O
chemical O
structures O
. O

Oligostilbenoid O
synthesis O
is O
regio O
- O
and O
stereocontrolled O
. O

To O
tackle O
this O
regio O
- O
and O
stereocontrol O
, O
a O
supramolecular O
chemistry O
approach O
is O
required O
that O
can O
be O
achieved O
by O
quantum O
chemistry O
. O

The O
stability O
of O
noncovalent O
pi O
- O
stacks O
, O
formed O
between O
two O
stilbenoid B
units O
prior O
to O
oxidation O
, O
is O
accurately O
evaluated O
with O
density O
functional O
theory O
( O
DFT O
) O
including O
dispersive O
effects O
( O
within O
the O
DFT O
- O
D O
formalism O
) O
. O

These O
noncovalent O
arrangements O
drive O
the O
regiocontrol O
. O

The O
rest O
of O
the O
chemical O
pathway O
is O
a O
succession O
of O
dearomatization O
and O
rearomatization O
stages O
. O

The O
thermodynamics O
and O
kinetics O
of O
the O
processes O
are O
calculated O
with O
classical O
hybrid O
functionals O
. O

This O
study O
allows O
discrimination O
between O
the O
two O
main O
possible O
chemical O
pathways O
, O
namely O
, O
radical O
- O
neutral O
and O
radical O
- O
radical O
reactions O
. O

The O
former O
appears O
more O
likely O
, O
thermodynamics O
and O
kinetics O
being O
in O
perfect O
agreement O
with O
the O
experimental O
1 O
: O
2 O
ratio O
obtained O
for O
ampelopsin B
F I
: O
pallidol B
analogues O
, O
respectively O
. O

Molecular O
interactions O
between O
lecithin O
and O
bile B
salts I
/ I
acids I
in O
oils O
and O
their O
effects O
on O
reverse O
micellization O
. O

It O
has O
been O
known O
that O
the O
addition O
of O
bile B
salts I
to O
lecithin O
organosols B
induces O
the O
formation O
of O
reverse O
wormlike O
micelles O
and O
that O
the O
worms O
are O
similar O
to O
long O
polymer O
chains O
that O
entangle O
each O
other O
to O
form O
viscoelastic O
solutions O
. O

In O
this O
study O
, O
we O
further O
investigated O
the O
effects O
of O
different O
bile B
salts I
and O
bile B
acids I
on O
the O
growth O
of O
lecithin O
reverse O
worms O
in O
cyclohexane B
and O
n B
- I
decane I
. O

We O
utilized O
rheological O
and O
small O
- O
angle O
scattering O
techniques O
to O
analyze O
the O
properties O
and O
structures O
of O
the O
reverse O
micelles O
. O

All O
of O
the O
bile B
salts I
can O
transform O
the O
originally O
spherical O
lecithin O
reverse O
micelles O
into O
wormlike O
micelles O
and O
their O
rheological O
behaviors O
can O
be O
described O
by O
the O
single O
- O
relaxation O
- O
time O
Maxwell O
model O
. O

However O
, O
their O
efficiencies O
to O
induce O
the O
worms O
are O
different O
. O

In O
contrast O
, O
before O
phase O
separation O
, O
bile B
acids I
can O
induce O
only O
short O
cylindrical O
micelles O
that O
are O
not O
long O
enough O
to O
impart O
viscoelasticity O
. O

We O
used O
Fourier O
transform O
infrared O
spectroscopy O
to O
investigate O
the O
interactions O
between O
lecithin O
and O
bile B
salts I
/ I
acids I
and O
found O
that O
different O
bile B
salts I
/ I
acids I
employ O
different O
functional O
groups O
to O
form O
hydrogen B
bonds O
with O
lecithin O
. O

Such O
effects O
determine O
the O
relative O
positions O
of O
the O
bile B
salts I
/ I
acids I
in O
the O
headgroups O
of O
lecithin O
, O
thus O
resulting O
in O
varying O
efficiencies O
to O
alter O
the O
effective O
critical O
packing O
parameter O
for O
the O
formation O
of O
wormlike O
micelles O
. O

This O
work O
highlights O
the O
importance O
of O
intermolecular O
interactions O
in O
molecular O
self O
- O
assembly O
. O

Marine O
drugs O
best O
paper O
award O
2013 O
. O

To O
recognize O
the O
most O
outstanding O
papers O
in O
the O
area O
of O
research O
, O
development O
and O
production O
of O
drugs O
from O
the O
sea O
, O
including O
marine O
natural O
product O
chemistry O
, O
that O
have O
been O
published O
in O
Marine O
Drugs O
, O
we O
would O
like O
to O
start O
an O
annual O
" O
Best O
Paper O
Award O
" O
. O

Cellular O
imaging O
demonstrates O
genetic O
mosaicism O
in O
heterozygous O
carriers O
of O
an O
X O
- O
linked O
ciliopathy O
gene O
. O

X O
- O
linked O
retinitis O
pigmentosa O
( O
XLRP O
) O
is O
the O
least O
common O
genetic O
type O
of O
retinitis O
pigmentosa O
; O
however O
, O
it O
has O
extremely O
devastating O
consequences O
to O
patients O
' O
activities O
of O
daily O
living O
. O

RPGR O
and O
RP2 O
genes O
expressed O
in O
the O
photoreceptor O
sensory O
cilia O
are O
predominantly O
implicated O
in O
XLRP O
; O
however O
, O
the O
interpretation O
of O
genetic O
mutations O
and O
their O
correlation O
with O
clinical O
phenotypes O
remain O
unknown O
, O
and O
the O
role O
of O
these O
genes O
in O
photoreceptor O
cilia O
function O
is O
not O
completely O
elucidated O
. O

Therefore O
, O
we O
evaluated O
structural O
characteristics O
in O
five O
female O
obligate O
carriers O
of O
XLRP O
by O
using O
state O
- O
of O
- O
the O
- O
art O
non O
- O
invasive O
imaging O
methods O
, O
including O
adaptive O
optics O
( O
AO O
) O
scanning O
laser O
ophthalmoscopy O
( O
SLO O
) O
. O

In O
all O
five O
carriers O
examined O
, O
qualitative O
and O
quantitative O
analyses O
by O
AO O
SLO O
imaging O
revealed O
a O
mosaic O
pattern O
of O
cone O
disruption O
, O
even O
in O
the O
absence O
of O
visual O
symptoms O
, O
normal O
visual O
acuity O
and O
normal O
macular O
thickness O
, O
on O
optical O
coherence O
tomography O
and O
mildly O
subnormal O
full O
- O
field O
cone O
electroretinographic O
findings O
. O

As O
the O
technique O
is O
sensitive O
to O
the O
level O
of O
a O
single O
cone O
, O
the O
ability O
to O
visualize O
the O
cone O
cells O
in O
vivo O
should O
be O
especially O
useful O
in O
other O
retinal O
diseases O
. O

In O
addition O
, O
further O
investigation O
of O
XLRP O
carriers O
may O
yield O
insight O
into O
how O
cone O
structures O
change O
over O
time O
and O
ultimately O
enable O
understanding O
of O
the O
role O
of O
RPGR O
and O
RP2 O
in O
cone O
cell O
survival O
. O
European O
Journal O
of O
Human O
Genetics O
advance O
online O
publication O
, O
27 O
February O
2013 O
; O
doi O
: O
10 O
. O
1038 O
/ O
ejhg O
. O
2013 O
. O
21 O
. O

Control O
of O
10 O
nm O
scale O
cylinder O
orientation O
in O
self O
- O
organized O
sugar B
- O
based O
block O
copolymer O
thin O
films O
. O

The O
present O
paper O
describes O
the O
orientational O
control O
of O
10 O
nm O
scale O
cylinders O
in O
sugar B
- O
based O
block O
copolymer O
thin O
films O
by O
simply O
varying O
the O
composition O
of O
the O
annealing O
co O
- O
solvent O
. O

The O
affinity O
of O
the O
block O
copolymer O
to O
the O
solvent O
vapor O
could O
be O
systematically O
adjusted O
in O
this O
way O
. O

Multiphase O
chemistry O
of O
atmospheric O
amines B
. O

Heterogeneous O
reactions O
of O
amines B
have O
been O
recently O
shown O
to O
play O
an O
important O
role O
in O
the O
formation O
and O
transformation O
of O
atmospheric O
aerosols O
. O

This O
perspective O
summarizes O
the O
latest O
laboratory O
progress O
in O
the O
multiphase O
chemistry O
of O
amines B
. O

Particular O
emphasis O
is O
given O
to O
the O
contributions O
of O
amines B
to O
new O
particle O
formation O
, O
growth O
of O
submicron O
particles O
, O
and O
alteration O
in O
the O
physiochemical O
properties O
of O
pre O
- O
existing O
particles O
, O
including O
hygroscopicity O
, O
thermostability O
, O
density O
, O
phase O
, O
and O
optical O
properties O
, O
from O
exposure O
to O
gaseous O
amines B
. O

The O
atmospheric O
implications O
of O
the O
multiphase O
reactions O
of O
amines B
, O
including O
the O
potential O
impact O
on O
direct O
and O
indirect O
climate O
forcing O
of O
aerosols O
, O
and O
future O
research O
directions O
are O
discussed O
. O

When O
direct O
health O
- O
care O
professional O
communications O
have O
an O
impact O
on O
inappropriate O
and O
unsafe O
use O
of O
medicines O
. O

Serious O
safety O
issues O
relating O
to O
drugs O
are O
communicated O
to O
health O
- O
care O
professionals O
via O
Direct O
Health O
- O
Care O
Professional O
Communications O
( O
DHPCs O
) O
. O

We O
explored O
which O
characteristics O
determined O
the O
impact O
of O
DHPCs O
issued O
in O
the O
Netherlands O
for O
ambulatory O
- O
care O
drugs O
( O
2001 O
- O
2008 O
) O
. O

With O
multiple O
linear O
regression O
, O
we O
examined O
the O
impact O
on O
the O
relative O
change O
in O
new O
drug O
use O
post O
- O
DHPC B
of O
the O
following O
: O
time O
to O
DHPC B
, O
trend O
in O
use O
, O
degree O
of O
innovation O
, O
specialist O
drug O
, O
first O
/ O
repeated O
DHPC B
, O
DHPC B
template O
, O
and O
type O
of O
safety O
issue O
. O

DHPCs B
have O
less O
impact O
on O
use O
of O
specialist O
drugs O
than O
nonspecialist O
drugs O
( O
P O
< O
0 O
. O
05 O
) O
. O

The O
DHPCs O
' O
impact O
increased O
after O
availability O
of O
a O
template O
emphasizing O
the O
main O
problem O
( O
P O
< O
0 O
. O
05 O
) O
, O
and O
for O
safety O
issues O
with O
a O
risk O
of O
death O
and O
/ O
or O
disability O
( O
both O
P O
< O
0 O
. O
05 O
) O
( O
adjusted O
R O
( O
2 O
) O
= O
0 O
. O
392 O
) O
. O

Risk O
communication O
can O
be O
effective O
, O
specifically O
in O
case O
of O
well O
- O
structured O
information O
, O
and O
very O
serious O
safety O
issues O
. O

Effectiveness O
may O
improve O
by O
tailoring O
DHPCs O
and O
adding O
other O
communication O
channels O
, O
for O
example O
for O
drugs O
that O
are O
increasingly O
being O
used O
. O

Estimation O
of O
renal O
cell O
carcinoma O
treatment O
effects O
from O
disease O
progression O
modeling O
. O

To O
improve O
future O
drug O
development O
efficiency O
in O
renal O
cell O
carcinoma O
( O
RCC O
) O
, O
a O
disease O
- O
progression O
model O
was O
developed O
with O
longitudinal O
tumor O
size O
data O
from O
a O
phase O
III O
trial O
of O
sorafenib B
in O
RCC O
. O

The O
best O
- O
fit O
model O
was O
externally O
evaluated O
on O
145 O
placebo O
- O
treated O
patients O
in O
a O
phase O
III O
trial O
of O
pazopanib B
; O
the O
model O
incorporated O
baseline O
tumor O
size O
, O
a O
linear O
disease O
- O
progression O
component O
, O
and O
an O
exponential O
drug O
effect O
( O
DE O
) O
parameter O
. O

With O
the O
model O
- O
estimated O
effect O
of O
sorafenib B
on O
RCC O
growth O
, O
we O
calculated O
the O
power O
of O
randomized O
phase O
II O
trials O
between O
sorafenib B
and O
hypothetical O
comparators O
over O
a O
range O
of O
effects O
. O

A O
hypothetical O
comparator O
with O
80 O
% O
greater O
DE O
than O
sorafenib B
would O
have O
82 O
% O
power O
( O
one O
- O
sided O
alpha O
= O
0 O
. O
1 O
) O
with O
50 O
patients O
per O
arm O
. O

Model O
- O
based O
quantitation O
of O
treatment O
effect O
with O
computed O
tomography O
( O
CT O
) O
imaging O
offers O
a O
scaffold O
on O
which O
to O
develop O
new O
, O
more O
efficient O
, O
phase O
II O
trial O
end O
points O
and O
analytic O
strategies O
for O
RCC O
. O

Effect O
of O
miR O
- O
21 O
on O
Renal O
Fibrosis O
by O
Regulating O
MMP O
- O
9 O
and O
TIMP1 O
in O
kk O
- O
ay O
Diabetic O
Nephropathy O
Mice O
. O

MicroRNAs O
( O
miRs O
) O
play O
important O
roles O
in O
initiation O
and O
progression O
of O
many O
pathologic O
processes O
. O

However O
, O
the O
roles O
of O
miRs O
in O
diabetic O
nephropathy O
remain O
unclear O
. O

This O
study O
was O
to O
determine O
whether O
miR O
- O
21 O
was O
involved O
in O
diabetic O
nephropathy O
and O
to O
explore O
the O
relationship O
between O
miR O
- O
21 O
and O
MMP9 O
/ O
TIMP1 O
expression O
in O
diabetic O
nephropathy O
. O

In O
situ O
hybridization O
studies O
showed O
that O
miR O
- O
21 O
was O
primarily O
localized O
and O
distributed O
in O
cortical O
glomerular O
and O
renal O
tubular O
cells O
in O
diabetic O
kk O
- O
ay O
kidney O
. O

Real O
- O
time O
quantitative O
RT O
- O
PCR O
demonstrated O
that O
the O
expression O
of O
miR O
- O
21 O
was O
significantly O
increased O
in O
kk O
- O
ay O
mice O
, O
compared O
with O
control O
C57BL O
mice O
. O

Interestingly O
, O
miR O
- O
21 O
expression O
positively O
correlated O
with O
urine O
albumin O
creatine B
ratio O
( O
ACR O
) O
, O
TIMP1 O
, O
collagen O
IV O
( O
ColIV O
) O
, O
and O
fibronectin O
( O
FN O
) O
; O
while O
negatively O
correlated O
with O
creatine B
clearance O
ratio O
( O
Ccr O
) O
and O
MMP O
- O
9 O
protein O
. O

Importantly O
, O
antagomir O
- O
21 O
not O
only O
ameliorated O
Ccr O
and O
ACR O
but O
also O
decreased O
TIMP1 O
, O
ColIV O
, O
and O
FN O
proteins O
. O

In O
conclusion O
, O
our O
data O
demonstrate O
that O
miR O
- O
21 O
contributes O
to O
renal O
fibrosis O
by O
mediating O
MMP9 O
/ O
TIMP1 O
and O
that O
inhibition O
of O
miR O
- O
21 O
may O
be O
a O
novel O
target O
for O
diabetic O
nephropathy O
. O

Probing O
the O
Metabotropic O
Glutamate B
Receptor O
5 O
( O
mGlu5 O
) O
Positive O
Allosteric O
Modulator O
( O
PAM O
) O
Binding O
Pocket O
: O
Discovery O
of O
Point O
Mutations O
That O
Engender O
a O
" O
Molecular O
Switch O
" O
in O
PAM O
Pharmacology O
. O

Positive O
allosteric O
modulation O
of O
metabotropic O
glutamate B
receptor O
subtype O
5 O
( O
mGlu5 O
) O
is O
a O
promising O
novel O
approach O
for O
the O
treatment O
of O
schizophrenia O
and O
cognitive O
disorders O
. O

Allosteric O
binding O
sites O
are O
topographically O
distinct O
from O
the O
endogenous O
ligand O
( O
orthosteric O
) O
binding O
site O
, O
allowing O
for O
co O
- O
occupation O
of O
a O
single O
receptor O
with O
the O
endogenous O
ligand O
and O
an O
allosteric O
modulator O
. O

Negative O
allosteric O
modulators O
( O
NAMs O
) O
inhibit O
and O
positive O
allosteric O
modulators O
( O
PAMs O
) O
enhance O
the O
affinity O
and O
/ O
or O
efficacy O
of O
the O
orthosteric O
agonist O
. O

The O
molecular O
determinants O
that O
govern O
mGlu5 O
modulator O
affinity O
versus O
cooperativity O
are O
not O
well O
understood O
. O

Focusing O
on O
the O
modulators O
based O
on O
the O
acetylene B
scaffold O
, O
we O
sought O
to O
determine O
the O
molecular O
interactions O
that O
contribute O
to O
PAM O
versus O
NAM O
pharmacology O
. O

Generation O
of O
a O
comparative O
model O
of O
the O
transmembrane O
- O
spanning O
region O
of O
mGlu5 O
served O
as O
a O
tool O
to O
predict O
and O
interpret O
the O
impact O
of O
mutations O
in O
this O
region O
. O

Application O
of O
an O
operational O
model O
of O
allosterism O
allowed O
for O
determination O
of O
PAM O
and O
NAM O
affinity O
estimates O
at O
receptor O
constructs O
that O
possessed O
no O
detectable O
radioligand O
binding O
as O
well O
as O
delineation O
of O
effects O
on O
affinity O
versus O
cooperativity O
. O

Novel O
mutations O
within O
the O
transmembrane O
domain O
( O
TM O
) O
regions O
were O
identified O
that O
had O
differential O
effects O
on O
acetylene B
PAMs O
versus O
2 B
- I
methyl I
- I
6 I
- I
( I
phenylethynyl I
) I
- I
pyridine I
, O
a O
prototypical O
NAM O
. O

Three O
conserved O
amino B
acids I
( O
Y658 O
, O
T780 O
, O
and O
S808 O
) O
and O
two O
nonconserved O
residues O
( O
P654 O
and O
A809 O
) O
were O
identified O
as O
key O
determinants O
of O
PAM O
activity O
. O

Interestingly O
, O
we O
identified O
two O
point O
mutations O
in O
TMs O
6 O
and O
7 O
that O
, O
when O
mutated O
, O
engender O
a O
mode O
switch O
in O
the O
pharmacology O
of O
certain O
PAMs O
. O

Coactivators O
enable O
glucocorticoid O
receptor O
recruitment O
to O
fine O
- O
tune O
estrogen B
receptor O
transcriptional O
responses O
. O

Nuclear O
receptors O
( O
NRs O
) O
are O
central O
regulators O
of O
pathophysiological O
processes O
; O
however O
, O
how O
their O
responses O
intertwine O
is O
still O
not O
fully O
understood O
. O

The O
aim O
of O
this O
study O
was O
to O
determine O
whether O
and O
how O
steroid B
NRs O
can O
influence O
each O
other O
' O
s O
activity O
under O
co O
- O
agonist O
treatment O
. O

We O
used O
a O
unique O
system O
consisting O
of O
a O
multicopy O
integration O
of O
an O
estrogen B
receptor O
responsive O
unit O
that O
allows O
direct O
visualization O
and O
quantification O
of O
estrogen B
receptor O
alpha O
( O
ER O
alpha O
) O
DNA O
binding O
, O
co O
- O
regulator O
recruitment O
and O
transcriptional O
readout O
. O

We O
find O
that O
ER O
alpha O
DNA O
loading O
is O
required O
for O
other O
type O
I O
nuclear O
receptors O
to O
be O
co O
- O
recruited O
after O
dual O
agonist O
treatment O
. O

We O
focused O
on O
ER O
alpha O
/ O
glucocorticoid O
receptor O
interplay O
and O
demonstrated O
that O
it O
requires O
steroid B
receptor O
coactivators O
( O
SRC O
- O
2 O
, O
SRC O
- O
3 O
) O
and O
the O
mediator O
component O
MED14 O
. O

We O
then O
validated O
this O
cooperative O
interplay O
on O
endogenous O
target O
genes O
in O
breast O
cancer O
cells O
. O

Taken O
together O
, O
this O
work O
highlights O
another O
layer O
of O
mechanistic O
complexity O
through O
which O
NRs O
cross O
- O
talk O
with O
each O
other O
on O
chromatin O
under O
multiple O
hormonal O
stimuli O
. O

Variation O
in O
prescribing O
patterns O
and O
therapeutic O
drug O
monitoring O
of O
intravenous O
busulfan B
in O
pediatric O
hematopoietic O
cell O
transplant O
recipients O
. O

Personalizing O
intravenous O
( O
IV O
) O
busulfan B
doses O
in O
children O
using O
therapeutic O
drug O
monitoring O
( O
TDM O
) O
is O
an O
integral O
component O
of O
hematopoietic O
cell O
transplant O
. O

The O
authors O
sought O
to O
characterize O
initial O
dosing O
and O
TDM O
of O
IV O
busulfan B
, O
along O
with O
factors O
associated O
with O
busulfan B
clearance O
, O
in O
729 O
children O
who O
underwent O
busulfan B
TDM O
from O
December O
2005 O
to O
December O
2008 O
. O

The O
initial O
IV O
busulfan B
dose O
in O
children O
weighing O
< O
= O
12 O
kg O
ranged O
4 O
. O
8 O
- O
fold O
, O
with O
only O
19 O
% O
prescribed O
the O
package O
insert O
dose O
of O
1 O
. O
1 O
mg O
/ O
kg O
. O

In O
those O
children O
weighing O
> O
12 O
kg O
, O
the O
initial O
dose O
ranged O
5 O
. O
4 O
- O
fold O
, O
and O
79 O
% O
were O
prescribed O
the O
package O
insert O
dose O
. O

The O
initial O
busulfan B
dose O
achieved O
the O
target O
exposure O
in O
only O
24 O
. O
3 O
% O
of O
children O
. O

A O
wide O
range O
of O
busulfan B
exposures O
were O
targeted O
for O
children O
with O
the O
same O
disease O
( O
eg O
, O
39 O
target O
busulfan B
exposures O
for O
the O
264 O
children O
diagnosed O
with O
acute O
myeloid O
leukemia O
) O
. O

Considerable O
heterogeneity O
exists O
regarding O
when O
TDM O
is O
conducted O
and O
the O
number O
of O
pharmacokinetic O
samples O
obtained O
. O

Busulfan B
clearance O
varied O
by O
age O
and O
dosing O
frequency O
but O
not O
by O
underlying O
disease O
. O

The O
authors O
- O
group O
is O
currently O
evaluating O
how O
using O
population O
pharmacokinetics O
to O
optimize O
initial O
busulfan B
dose O
and O
TDM O
( O
eg O
, O
limited O
sampling O
schedule O
in O
conjunction O
with O
maximum O
a O
posteriori O
Bayesian O
estimation O
) O
may O
affect O
clinical O
outcomes O
in O
children O
. O

Comparing O
the O
pharmacokinetics O
of O
doxylamine B
/ O
pyridoxine B
delayed O
- O
release O
combination O
in O
nonpregnant O
women O
of O
reproductive O
age O
and O
women O
in O
the O
first O
trimester O
of O
pregnancy O
. O

Although O
Diclectin B
( O
doxylamine B
/ O
pyridoxine B
delayed O
- O
released O
combination O
) O
is O
widely O
used O
in O
Canada O
, O
its O
pharmacokinetics O
( O
PK O
) O
during O
pregnancy O
has O
never O
been O
described O
. O

The O
objective O
of O
this O
study O
was O
to O
compare O
the O
PK O
of O
doxylamine B
/ O
pyridoxine B
delayed O
- O
released O
combination O
in O
pregnant O
versus O
nonpregnant O
women O
. O

The O
apparent O
clearances O
( O
CL O
) O
of O
doxylamine B
and O
pyridoxal B
5 I
' I
- I
phosphate I
( O
PLP B
; O
the O
active O
metabolite O
of O
vitamin B
B I
( I
6 I
) I
) O
during O
the O
first O
- O
trimester O
pregnancy O
in O
women O
who O
participated O
in O
a O
Diclectin B
randomized O
trial O
were O
compared O
with O
those O
of O
healthy O
, O
adult O
, O
nonpregnant O
women O
who O
participated O
in O
a O
voluntary O
PK O
trial O
. O

Eighteen O
nonpregnant O
women O
were O
compared O
with O
50 O
pregnant O
women O
who O
were O
treated O
with O
Diclectin B
. O

There O
was O
no O
difference O
in O
the O
apparent O
CL O
of O
doxylamine B
in O
women O
in O
their O
first O
trimester O
of O
pregnancy O
when O
compared O
with O
nonpregnant O
women O
on O
day O
4 O
( O
median O
= O
196 O
. O
7 O
vs O
249 O
. O
5 O
mL O
/ O
h O
/ O
kg O
, O
respectively O
, O
P O
= O
. O
065 O
) O
, O
day O
8 O
( O
median O
= O
248 O
. O
4 O
vs O
249 O
. O
5 O
mL O
/ O
h O
/ O
kg O
, O
respectively O
, O
P O
= O
. O
82 O
) O
, O
and O
day O
15 O
( O
median O
= O
200 O
. O
9 O
vs O
249 O
. O
5 O
mL O
/ O
h O
/ O
kg O
, O
respectively O
, O
P O
= O
. O
55 O
) O
. O

No O
difference O
was O
found O
in O
the O
apparent O
CL O
of O
PLP B
on O
day O
15 O
( O
median O
= O
342 O
. O
3 O
vs O
314 O
. O
7 O
mL O
/ O
h O
/ O
kg O
, O
respectively O
, O
P O
= O
. O
92 O
) O
. O

There O
was O
no O
pregnancy O
- O
induced O
effect O
in O
the O
apparent O
CL O
of O
either O
doxylamine B
or O
PLP B
in O
women O
during O
the O
first O
trimester O
of O
pregnancy O
despite O
the O
existence O
of O
morning O
sickness O
. O

Light O
energy O
collection O
in O
a O
porphyrin B
- O
imide B
- O
corrole B
ensemble O
. O

An O
assembly O
consisting O
of O
three O
units O
, O
that O
is O
, O
a O
meso B
- I
substituted I
corrole I
( O
) O
, O
1 B
, I
8 I
naphthaleneimide I
( O
) O
, O
and O
a O
Zn B
porphyrin I
( O
) O
, O
has O
been O
synthesized O
. O

NIE B
is O
connected O
to O
C3 O
through O
a O
1 B
, I
3 I
- I
phenylene I
bridge O
and O
to O
the O
ZnP B
unit O
through O
a O
direct O
C B
< I
F8FF I
> I
C I
bond O
. O

The O
convergent O
synthetic O
strategy O
includes O
the O
preparation O
of O
a O
trans O
- O
A2 O
B O
- O
corrole B
possessing O
the O
imide O
unit O
, O
followed O
by O
Sonogashira O
coupling O
with O
a O
meso B
- I
substituted I
A3 O
B O
- O
porphyrin B
. O

The O
photophysical O
processes O
in O
the O
resulting O
triad O
are O
examined O
and O
compared O
with O
those O
of O
the O
corresponding O
dyad O
and O
the O
constituent O
reference O
models O
, O
, O
and O
. O

Excitation O
of O
the O
NIE B
unit O
in O
leads O
to O
a O
fast O
energy O
transfer O
of O
98 O
% O
efficiency O
to O
C3 O
with O
a O
rate O
ken O
= O
7 O
. O
5 O
x O
10 O
( O
10 O
) O
s O
( O
- O
1 O
) O
, O
whereas O
excitation O
of O
the O
corrole B
unit O
leads O
to O
a O
reactivity O
of O
the O
excited O
state O
identical O
to O
that O
of O
the O
model O
, O
with O
a O
deactivation O
rate O
to O
the O
ground O
state O
k O
= O
2 O
. O
5 O
x O
10 O
( O
8 O
) O
s O
( O
- O
1 O
) O
. O

Energy O
transfer O
to O
C3 O
and O
to O
ZnP B
moieties O
follows O
excitation O
of O
NIE B
in O
the O
triad O
. O

The O
rates O
are O
ken O
= O
7 O
. O
5 O
x O
10 O
( O
10 O
) O
s O
( O
- O
1 O
) O
and O
ken O
= O
2 O
. O
5 O
x O
10 O
( O
10 O
) O
s O
( O
- O
1 O
) O
for O
the O
sensitization O
of O
the O
C3 O
and O
ZnP O
unit O
, O
respectively O
. O

The O
light O
energy O
transferred O
from O
NIE B
to O
Zn B
porphyrin B
unit O
is O
ultimately O
funneled O
to O
the O
corrole B
component O
, O
which O
is O
the O
final O
recipient O
of O
the O
excitation O
energy O
absorbed O
by O
the O
different O
components O
of O
the O
array O
. O

The O
latter O
process O
occurs O
with O
a O
rate O
ken O
= O
3 O
. O
4 O
x O
10 O
( O
9 O
) O
s O
( O
- O
1 O
) O
and O
89 O
% O
efficiency O
. O

Energy O
transfer O
processes O
take O
place O
in O
all O
cases O
by O
a O
F O
o O
rster O
( O
dipole O
- O
dipole O
) O
mechanism O
. O

The O
theory O
predicts O
quite O
satisfactorily O
the O
rate O
for O
the O
ZnP B
/ O
C3 O
couple O
, O
where O
components O
are O
separated O
by O
about O
23 O
A O
, O
but O
results O
in O
calculated O
rates O
that O
are O
one O
to O
two O
orders O
of O
magnitude O
higher O
for O
the O
couples O
NIE B
/ O
ZnP B
( O
D O
/ O
A O
) O
and O
NIE B
/ O
C3 O
, O
which O
are O
separated O
by O
distances O
of O
about O
14 O
and O
10 O
A O
, O
respectively O
. O

Protective O
effect O
of O
butylated B
hydroxytoluene I
on O
ferric B
nitrilotriacetate I
induced O
hepatotoxicity O
and O
oxidative O
stress O
in O
mice O
. O

The O
present O
study O
was O
undertaken O
to O
evaluate O
the O
possible O
ameliorating O
effect O
of O
butylated B
hydroxyl I
toluene I
( O
BHT B
) O
, O
associated O
with O
ferric B
nitrilotriacetate I
( O
Fe B
- I
NTA I
) O
- O
induced O
oxidative O
stress O
and O
liver O
injury O
in O
mice O
. O

The O
treatment O
of O
mice O
with O
Fe B
- I
NTA I
alone O
enhances O
ornithine B
decarboxylase O
activity O
to O
4 O
. O
6 O
folds O
, O
protein O
carbonyl B
formation O
increased O
up O
to O
2 O
. O
9 O
folds O
and O
DNA O
synthesis O
expressed O
in O
terms O
of O
[ B
( I
3 I
) I
H I
] I
thymidine I
incorporation O
increased O
to O
3 O
. O
2 O
folds O
, O
and O
antioxidants O
and O
antioxidant O
enzymes O
decreased O
to O
1 O
. O
8 O
- O
2 O
. O
5 O
folds O
, O
compared O
with O
the O
corresponding O
saline O
- O
treated O
controls O
. O

These O
changes O
were O
reversed O
significantly O
( O
p O
< O
0 O
. O
001 O
) O
in O
animals O
receiving O
a O
pretreatment O
of O
BHT B
. O

Our O
data O
show O
that O
BHT B
can O
reciprocate O
the O
toxic O
effects O
of O
Fe B
- I
NTA I
and O
can O
serve O
as O
a O
potent O
chemopreventive O
agent O
. O

Cytotoxicity O
and O
uptake O
of O
archaeosomes O
prepared O
from O
Aeropyrum O
pernix O
lipids O
. O

Archaeon O
Aeropyrum O
pernix O
K1 O
is O
an O
obligate O
aerobic O
hyperthermophilic O
organism O
with O
C B
( I
25 I
, I
25 I
) I
- I
archeol I
membrane O
lipids O
with O
head O
groups O
containing O
inositol B
. O

Interactions O
of O
archaeosomes O
, O
liposomes O
prepared O
from O
lipids O
of O
A O
. O
pernix O
, O
with O
mammalian O
cells O
in O
vitro O
were O
studied O
. O

In O
vitro O
cytotoxicity O
was O
tested O
on O
five O
different O
cell O
lines O
: O
rodent O
mouse O
melanoma O
cells O
( O
B16 O
- O
F1 O
) O
and O
Chinese O
hamster O
ovary O
( O
CHO O
) O
cells O
, O
and O
three O
human O
cell O
lines O
- O
epithelial O
colorectal O
adenocarcinoma O
cells O
( O
CACO O
- O
2 O
) O
, O
liver O
hepatocellular O
carcinoma O
cell O
line O
( O
Hep O
G2 O
) O
and O
endothelial O
umbilical O
vein O
cell O
line O
( O
EA O
. O
hy926 O
) O
. O

Archaeosomes O
were O
nontoxic O
to O
human O
Hep O
G2 O
, O
CACO O
- O
2 O
and O
mildly O
toxic O
to O
rodent O
CHO O
and O
B16 O
- O
F1 O
cells O
but O
showed O
strong O
cytotoxic O
effect O
on O
EA O
. O
hy926 O
cells O
. O

Confocal O
microscopy O
revealed O
that O
archaeosomes O
are O
taken O
up O
by O
endocytosis O
. O

The O
uptake O
of O
archaeosomes O
and O
the O
release O
of O
loaded O
calcein B
are O
more O
prominent O
in O
EA O
. O
hy926 O
cells O
, O
which O
is O
in O
line O
with O
high O
toxicity O
toward O
these O
cells O
. O

The O
mechanisms O
of O
uptake O
, O
release O
and O
action O
in O
these O
cells O
as O
well O
as O
in O
vivo O
functioning O
have O
to O
be O
further O
studied O
for O
possible O
targeted O
drug O
delivery O
. O

A O
90 O
- O
day O
subchronic O
toxicity O
study O
of O
neem O
oil O
, O
a O
Azadirachta O
indica O
oil O
, O
in O
mice O
. O

To O
determine O
the O
no O
- O
observed O
- O
adverse O
- O
effect O
level O
( O
NOAEL O
) O
of O
exposure O
and O
target O
organs O
of O
neem O
oil O
for O
establishing O
safety O
criteria O
for O
human O
exposure O
, O
the O
subchronic O
toxicity O
study O
with O
neem O
oil O
in O
mice O
was O
evaluated O
. O

The O
mice O
( O
10 O
per O
sex O
for O
each O
dose O
) O
was O
orally O
administered O
with O
neem O
oil O
with O
the O
doses O
of O
0 O
( O
to O
serve O
as O
a O
control O
) O
, O
177 O
, O
533 O
and O
1600 O
mg O
/ O
kg O
/ O
day O
for O
90 O
days O
. O

After O
the O
treatment O
period O
, O
observation O
of O
reversibility O
or O
persistence O
of O
any O
toxic O
effects O
, O
mice O
were O
continuously O
fed O
without O
treatment O
for O
the O
following O
30 O
days O
. O

During O
the O
two O
test O
periods O
, O
the O
serum O
biochemistry O
, O
organ O
weight O
and O
histopathology O
were O
examined O
. O

The O
results O
showed O
that O
the O
serum O
biochemistry O
and O
organ O
coefficient O
in O
experimental O
groups O
had O
no O
statistical O
difference O
compared O
with O
those O
of O
the O
control O
group O
. O

At O
the O
90th O
day O
, O
the O
histopathological O
examinations O
showed O
that O
the O
1600 O
mg O
/ O
kg O
/ O
day O
dose O
of O
neem O
oil O
had O
varying O
degrees O
of O
damage O
on O
each O
organ O
except O
heart O
, O
uterus O
and O
ovarian O
. O

After O
30 O
- O
day O
recovery O
, O
the O
degree O
of O
lesions O
to O
the O
tissues O
was O
lessened O
or O
even O
restored O
. O

The O
NOAEL O
of O
neem O
oil O
was O
177 O
mg O
/ O
kg O
/ O
day O
for O
mice O
and O
the O
target O
organs O
of O
neem O
oil O
were O
determined O
to O
be O
testicle O
, O
liver O
and O
kidneys O
. O

Simultaneous O
high O
- O
performance O
liquid O
chromatographic O
determination O
of O
a O
rhein B
- O
diclofenac B
prodrug O
and O
its O
active O
compounds O
. O

In O
order O
to O
study O
the O
hydrolytic O
characterization O
of O
an O
anti O
- O
inflammatory O
prodrug O
( O
RD O
- O
1 O
) O
in O
vitro O
, O
a O
simple O
, O
specific O
, O
precise O
and O
accurate O
method O
for O
the O
simultaneous O
determination O
of O
prodrug O
and O
its O
two O
hydrolytic O
active O
compounds O
was O
development O
using O
reverse O
phase O
high O
- O
performance O
liquid O
chromatography O
( O
RP O
- O
HPLC O
) O
. O

The O
chromatographic O
separation O
was O
performed O
on O
an O
ODS O
- O
2 O
C18 O
column O
( O
250 O
mm O
x O
4 O
. O
6 O
mm O
, O
5 O
. O
0 O
microm O
particle O
size O
) O
with O
a O
simple O
elution O
programme O
. O

The O
mobile O
phase O
was O
methanol B
- O
0 O
. O
1 O
% O
phosphoric B
acid I
solution O
( O
adjusted O
pH O
to O
2 O
. O
3 O
) O
( O
80 O
: O
20 O
, O
v O
/ O
v O
) O
; O
wavelength O
of O
257nm O
and O
mobile O
phase O
flow O
rate O
of O
1 O
. O
0 O
mL O
/ O
min O
was O
utilized O
for O
the O
quantitative O
analysis O
. O

Excellent O
linear O
behaviors O
over O
the O
investigated O
concentration O
ranges O
were O
observed O
with O
the O
values O
of O
R2 O
higher O
than O
0 O
. O
999 O
for O
all O
the O
analytes O
. O

The O
validated O
method O
was O
successfully O
applied O
to O
the O
simultaneous O
determination O
of O
prodrug O
and O
its O
active O
components O
. O

Rapid O
identification O
of O
sibutramine B
in O
dietary O
supplements O
using O
a O
stepwise O
approach O
. O

Adulteration O
of O
botanical O
food O
supplements O
with O
undeclared O
synthetic O
drugs O
is O
a O
common O
problem O
. O

One O
of O
the O
most O
affected O
product O
groups O
are O
the O
slimming O
agents O
. O

There O
are O
no O
analytical O
protocols O
for O
the O
detection O
of O
synthetic O
adulterants O
from O
these O
products O
. O

The O
present O
study O
aimed O
at O
the O
development O
of O
a O
multistep O
analytical O
method O
for O
the O
quick O
and O
reliable O
determination O
of O
sibutramine B
, O
one O
of O
the O
most O
common O
adulterants O
among O
botanical O
food O
supplements O
. O

The O
extract O
of O
a O
sibutramine B
- O
containing O
slimming O
formula O
was O
analysed O
by O
colour O
tests O
, O
TLC O
, O
HPLC O
- O
DAD O
, O
MS O
and O
NMR O
. O

The O
multistep O
method O
proposed O
by O
the O
authors O
allows O
the O
quick O
identification O
of O
sibutramine B
in O
counterfeit O
samples O
in O
laboratories O
with O
different O
instrumentation O
. O

Development O
and O
validation O
of O
a O
simple O
LC O
method O
for O
the O
determination O
of O
phenacetin B
, O
coumarin B
, O
tolbutamide B
, O
chlorzoxazone B
, O
testosterone B
and O
their O
metabolites O
as O
markers O
of O
cytochromes O
1A2 O
, O
2A6 O
, O
2C11 O
, O
2E1 O
and O
3A2 O
in O
rat O
microsomal O
medium O
. O

Cytochrome O
P450 O
enzymes O
are O
responsible O
for O
the O
oxidative O
metabolism O
of O
most O
pharmaceutical O
compounds O
. O

A O
" O
cocktail O
" O
approach O
which O
employs O
simultaneous O
administration O
of O
a O
mixture O
of O
substrates O
of O
CYP O
enzymes O
was O
often O
used O
to O
assess O
the O
metabolic O
activity O
of O
multiple O
P450 O
forms O
in O
one O
experiment O
. O

Phenacetin B
, O
coumarin B
, O
tolbutamide B
, O
chlorzoxazone B
and O
testosterone B
are O
commonly O
used O
as O
probe O
substrates O
to O
evaluate O
cytochrome O
P450 O
function O
. O

An O
analytical O
strategy O
to O
simultaneously O
extract O
and O
analyze O
the O
five O
probe O
substrates O
and O
their O
major O
metabolites O
by O
HPLC O
- O
DAD O
was O
developed O
. O

The O
incubation O
was O
done O
with O
all O
the O
substrates O
in O
one O
step O
. O

The O
ten O
analytes O
were O
extracted O
simultaneously O
by O
solid O
- O
phase O
extraction O
( O
SPE O
) O
from O
rat O
liver O
microsomes O
. O

A O
C18 O
analytical O
column O
and O
mobile O
phase O
composed O
of O
acetonitrile B
and O
0 O
. O
02 O
% O
aqueous O
phosphoric B
acid I
were O
used O
for O
the O
chromatographic O
separation O
with O
DAD O
detection O
. O

Limits O
of O
quantification O
varied O
between O
0 O
. O
02378 O
and O
0 O
. O
2361 O
microg O
/ O
mL O
which O
contributed O
to O
quantify O
all O
these O
drugs O
and O
metabolites O
with O
UV O
detection O
. O

The O
method O
is O
applicable O
for O
the O
modeling O
and O
description O
of O
pharmacological O
interactions O
on O
rat O
cytochromes O
P450 O
or O
can O
be O
used O
for O
in O
vitro O
evaluation O
of O
cytochromes O
1A2 O
, O
2A6 O
, O
2C11 O
, O
2E1 O
and O
3A2 O
. O

Synergistic O
antitumor O
activity O
from O
two O
- O
stage O
delivery O
of O
targeted O
toxins O
and O
endosome O
- O
disrupting O
nanoparticles O
. O

Plant O
- O
derived O
Type O
I O
toxins O
are O
candidate O
anticancer O
therapeutics O
requiring O
cytosolic O
delivery O
into O
tumor O
cells O
. O

We O
tested O
a O
concept O
for O
two O
- O
stage O
delivery O
, O
whereby O
tumor O
cells O
precoated O
with O
an O
antibody O
- O
targeted O
gelonin O
toxin O
were O
killed O
by O
exposure O
to O
endosome O
- O
disrupting O
polymer O
nanoparticles O
. O

Co O
- O
internalization O
of O
particles O
and O
tumor O
cell O
- O
bound O
gelonin B
led O
to O
cytosolic O
delivery O
and O
> O
50 O
- O
fold O
enhancement O
of O
toxin O
efficacy O
. O

This O
approach O
allows O
the O
extreme O
potency O
of O
gelonin B
to O
be O
focused O
on O
tumors O
with O
significantly O
reduced O
potential O
for O
off O
- O
target O
toxicity O
. O

Temperature O
dependence O
of O
transport O
properties O
of O
spiro B
- I
MeOTAD I
as O
a O
hole O
transport O
material O
in O
solid O
- O
state O
dye O
- O
sensitized O
solar O
cells O
. O

The O
internal O
transport O
and O
recombination O
parameters O
of O
solid O
- O
state O
dye O
- O
sensitized O
solar O
cells O
( O
ssDSCs O
) O
using O
the O
amorphous O
organic O
semiconductor O
2 B
, I
2 I
' I
, I
7 I
, I
7 I
' I
- I
tetrakis I
( I
N I
, I
N I
- I
di I
- I
p I
- I
methoxyphenylamine I
) I
- I
9 I
, I
9 I
' I
- I
spirobifluorene I
( O
spiro B
- I
MeOTAD I
) O
as O
a O
hole O
transport O
material O
( O
HTM O
) O
are O
investigated O
using O
electrical O
impedance O
spectroscopy O
. O

Devices O
were O
fabricated O
using O
flat O
and O
nanostructured O
TiO2 B
and O
compared O
to O
systems O
using O
nanostructured O
ZrO2 B
to O
differentiate O
between O
the O
transport O
processes O
within O
the O
different O
components O
of O
the O
ssDSC O
. O

The O
effect O
of O
chemically O
p O
- O
doping O
the O
HTM O
on O
its O
transport O
was O
investigated O
, O
and O
its O
temperature O
dependence O
was O
examined O
and O
analyzed O
using O
the O
Arrhenius O
equation O
. O

Using O
this O
approach O
the O
activation O
energy O
of O
the O
hole O
hopping O
transport O
within O
the O
undoped O
spiro B
- I
MeOTAD I
film O
was O
determined O
to O
be O
0 O
. O
34 O
+ O
/ O
- O
0 O
. O
02 O
and O
0 O
. O
40 O
+ O
/ O
- O
0 O
. O
02 O
eV O
for O
the O
mesoporous O
TiO2 B
and O
ZrO2 B
systems O
, O
respectively O
. O

In O
vivo O
genotoxicity O
and O
oxidative O
stress O
evaluation O
of O
an O
ethanolic O
extract O
from O
piqui O
a O
( O
Caryocar O
villosum O
) O
pulp O
. O

In O
this O
study O
, O
the O
ethanolic O
extract O
obtained O
from O
piqui O
a O
pulp O
was O
assessed O
for O
genotoxicity O
and O
oxidative O
stress O
by O
employing O
the O
micronucleus O
test O
in O
bone O
marrow O
and O
peripheral O
blood O
cells O
in O
addition O
to O
comet O
, O
thiobarbituric B
- I
acid I
- O
reactive O
substances O
( O
TBARS O
) O
, O
and O
reduced B
glutathione I
assays O
in O
the O
liver O
, O
kidney O
, O
and O
heart O
. O

Additionally O
, O
phytochemical O
analyses O
were O
performed O
to O
identify O
and O
quantify O
the O
chemical O
constituents O
of O
the O
piqui O
a O
extract O
. O

Wistar O
rats O
were O
treated O
by O
gavage O
with O
an O
ethanolic O
extract O
from O
piqui O
a O
pulp O
( O
75 O
mg O
/ O
kg O
body O
weight O
) O
for O
14 O
days O
, O
and O
24 O
h O
prior O
to O
euthanasia O
, O
they O
received O
an O
injection O
of O
saline O
or O
doxorubicin B
( O
15 O
mg O
/ O
kg O
body O
weight O
, O
intraperoneally O
) O
. O

The O
results O
demonstrated O
that O
piqui O
a O
extract O
at O
the O
tested O
dose O
was O
genotoxic O
but O
not O
mutagenic O
, O
and O
it O
increased O
the O
TBARS O
levels O
in O
the O
heart O
. O

Further O
studies O
are O
required O
to O
fully O
elucidate O
how O
the O
properties O
of O
ethanolic O
extract O
of O
piqui O
a O
pulp O
can O
affect O
human O
health O
. O

Kimchi O
, O
a O
fermented O
vegetable O
, O
improves O
serum O
lipid O
profiles O
in O
healthy O
young O
adults O
: O
randomized O
clinical O
trial O
. O

Abstract O
Vegetable O
- O
based O
diets O
have O
generally O
focused O
on O
their O
health O
benefits O
including O
negative O
associations O
with O
the O
serum O
cholesterol B
concentrations O
. O

The O
aim O
of O
this O
study O
was O
to O
investigate O
whether O
serum O
lipid O
concentrations O
are O
influenced O
by O
the O
amount O
of O
kimchi O
intake O
. O

For O
the O
study O
, O
100 O
volunteers O
were O
assigned O
to O
2 O
dietary O
groups O
, O
low O
( O
15 O
g O
/ O
day O
, O
n O
= O
50 O
) O
and O
high O
( O
210 O
g O
/ O
day O
, O
n O
= O
50 O
) O
kimchi O
intake O
, O
and O
were O
housed O
together O
in O
a O
dormitory O
for O
7 O
days O
. O

Identical O
meals O
except O
with O
different O
amount O
of O
kimchi O
were O
provided O
and O
subjects O
were O
instructed O
to O
maintain O
their O
normal O
physical O
activity O
. O

Concentrations O
of O
fasting O
blood O
glucose B
( O
FBG O
) O
, O
total O
glucose B
, O
total O
cholesterol B
and O
low O
density O
lipoprotein O
( O
LDL O
) O
- O
C O
significantly O
decreased O
in O
both O
groups O
after O
7 O
days O
of O
kimchi O
intake O
, O
but O
the O
effects O
were O
dose O
dependent O
. O

Lipid O
lowering O
effects O
of O
kimchi O
were O
more O
profound O
in O
the O
subjects O
with O
total O
cholesterol B
and O
LDL O
- O
C O
level O
over O
190 O
and O
130 O
mg O
/ O
dL O
, O
respectively O
, O
in O
both O
groups O
. O

FBG O
was O
significantly O
decreased O
in O
the O
high O
kimchi O
intake O
as O
compared O
to O
the O
low O
intake O
group O
( O
P O
= O
. O
003 O
) O
. O

In O
conclusion O
, O
greater O
consumption O
of O
kimchi O
improved O
FBG O
and O
serum O
total O
cholesterol B
in O
young O
healthy O
adults O
. O

Chronic O
food O
administration O
of O
Salvia O
sclarea O
oil O
reduces O
animals O
' O
anxious O
and O
dominant O
behavior O
. O

Recent O
studies O
indicate O
that O
an O
oil O
extract O
from O
Salvia O
sclarea O
may O
provide O
clinical O
benefits O
in O
various O
pathological O
conditions O
. O

In O
comparison O
to O
extracts O
from O
other O
Salvia O
species O
, O
S O
. O
sclarea O
oil O
contains O
twice O
as O
much O
omega B
- I
3 I
fatty I
acids I
, O
which O
are O
involved O
in O
eicosanoid B
synthesis O
pathways O
, O
and O
has O
been O
found O
to O
contain O
significant O
levels O
of O
the O
psychoactive O
monoterpane B
linalool B
. O

In O
the O
present O
study O
, O
we O
examined O
the O
mood O
stabilizing O
and O
anxiolytic O
- O
like O
effects O
of O
chronic O
food O
administration O
of O
S O
. O
sclarea O
oil O
extract O
on O
behavioral O
and O
physiological O
parameters O
of O
mice O
with O
prominent O
dominant O
and O
submissive O
features O
in O
behavioral O
assays O
used O
to O
test O
mood O
stabilizing O
and O
antidepressant O
drugs O
. O

Experimental O
animals O
received O
oil O
supplemented O
food O
from O
the O
age O
of O
4 O
weeks O
or O
from O
conception O
via O
their O
pregnant O
dams O
. O

Each O
age O
group O
received O
either O
S O
. O
sclarea O
oil O
- O
or O
sunflower O
oil O
- O
enriched O
feed O
. O

Dominant O
animals O
, O
whose O
pregnant O
mothers O
received O
S O
. O
sclarea O
oil O
- O
enriched O
feed O
from O
the O
date O
of O
conception O
, O
showed O
a O
significant O
reduction O
of O
dominant O
and O
anxiety O
- O
like O
behavior O
, O
in O
comparison O
to O
their O
sunflower O
oil O
- O
treated O
counterparts O
. O

S O
. O
sclarea O
oil O
- O
treated O
submissive O
animals O
exhibited O
a O
similar O
tendency O
, O
and O
showed O
a O
significant O
reduction O
in O
blood O
corticosterone B
levels O
. O

These O
findings O
enforce O
the O
hypothesis O
that O
S O
. O
sclarea O
oil O
possesses O
anxiolytic O
properties O
. O

Development O
of O
an O
in O
vitro O
dendritic O
cell O
- O
based O
test O
for O
skin O
sensitizer O
identification O
. O

The O
sensitizing O
potential O
of O
chemicals O
is O
currently O
assessed O
using O
animal O
models O
. O

However O
, O
ethical O
and O
economic O
concerns O
and O
the O
recent O
European O
legislative O
framework O
triggered O
intensive O
research O
efforts O
in O
the O
development O
and O
validation O
of O
alternative O
methods O
. O

Therefore O
, O
the O
aim O
of O
this O
study O
was O
to O
develop O
an O
in O
vitro O
predictive O
test O
based O
on O
the O
analysis O
and O
integration O
of O
gene O
expression O
and O
intracellular O
signaling O
profiles O
of O
chemical O
- O
exposed O
skin O
- O
derived O
dendritic O
cells O
. O

Cells O
were O
treated O
with O
four O
known O
sensitizers O
and O
two O
nonsensitizers O
, O
and O
the O
effects O
on O
the O
expression O
of O
20 O
candidate O
genes O
and O
the O
activation O
of O
MAPK O
, O
PI3K O
/ O
Akt O
, O
and O
NF O
- O
kappa O
B O
signaling O
pathways O
were O
analyzed O
by O
real O
- O
time O
reverse O
transcription O
polymerase O
chain O
reaction O
and O
Western O
blotting O
, O
respectively O
. O

Genes O
Trxr1 O
, O
Hmox1 O
, O
Nqo1 O
, O
and O
Cxcl10 O
and O
the O
p38 O
MAPK O
and O
JNK O
signaling O
pathways O
were O
identified O
as O
good O
predictor O
variables O
and O
used O
to O
construct O
a O
dichotomous O
classifier O
. O

For O
validation O
of O
the O
model O
, O
12 O
new O
chemicals O
were O
then O
analyzed O
in O
a O
blind O
assay O
, O
and O
from O
these O
, O
11 O
were O
correctly O
classified O
. O

Considering O
the O
total O
of O
18 O
compounds O
tested O
here O
, O
17 O
were O
correctly O
classified O
, O
representing O
a O
concordance O
of O
94 O
% O
, O
with O
a O
sensitivity O
of O
92 O
% O
( O
12 O
of O
13 O
sensitizers O
identified O
) O
and O
a O
specificity O
of O
100 O
% O
( O
5 O
of O
5 O
nonsensitizers O
identified O
) O
. O

Additionally O
, O
we O
tested O
the O
ability O
of O
our O
model O
to O
discriminate O
sensitizers O
from O
nonallergenic O
but O
immunogenic O
compounds O
such O
as O
lipopolysaccharide O
( O
LPS O
) O
. O

LPS O
was O
correctly O
classified O
as O
a O
nonsensitizer O
. O

Overall O
, O
our O
results O
indicate O
that O
the O
analysis O
of O
proposed O
gene O
and O
signaling O
pathway O
signatures O
in O
a O
mouse O
fetal O
skin O
- O
derived O
dendritic O
cell O
line O
represents O
a O
valuable O
model O
to O
be O
integrated O
in O
a O
future O
in O
vitro O
test O
platform O
. O

Single O
- O
molecule O
spectroscopy O
on O
RC O
- O
LH1 O
complexes O
of O
Rhodopseudomonas O
acidophila O
strain O
10050 O
. O

We O
have O
revisited O
the O
RC O
- O
LH1 O
complex O
from O
Rhodopseudomonas O
( O
Rps O
. O
) O
acidophila O
for O
single O
- O
molecule O
spectroscopy O
. O

For O
the O
current O
study O
the O
pigment O
- O
protein O
complexes O
were O
stabilized O
in O
the O
detergent O
buffer O
solution O
using O
a O
relatively O
mild O
detergent O
( O
dodecyl B
- I
beta I
- I
D I
- I
maltoside I
( O
DDM B
) O
instead O
of O
lauryldimethylamine B
N I
- I
oxide I
( O
LDAO B
) O
) O
. O

This O
leads O
to O
a O
significant O
reduction O
of O
the O
fraction O
of O
broken O
/ O
dissociated O
RC O
- O
LH1 O
complexes O
with O
respect O
to O
previous O
studies O
and O
has O
allowed O
us O
to O
investigate O
a O
sufficiently O
large O
sample O
of O
individual O
RC O
- O
LH1 O
complexes O
. O

For O
most O
of O
the O
complexes O
the O
fluorescence O
- O
excitation O
spectra O
exhibit O
a O
narrow O
spectral O
feature O
at O
the O
red O
end O
of O
the O
spectrum O
. O

Analysis O
of O
the O
statistics O
of O
the O
spectral O
properties O
yields O
a O
close O
resemblance O
with O
the O
results O
obtained O
on O
RC O
- O
LH1 O
complexes O
from O
Rps O
. O
palustris O
for O
which O
a O
low O
- O
resolution O
X O
- O
ray O
structure O
is O
available O
. O

Based O
on O
this O
comparison O
we O
come O
to O
the O
conclusion O
that O
for O
both O
species O
the O
RC O
- O
LH1 O
complex O
can O
be O
described O
by O
the O
same O
structural O
model O
, O
that O
is O
, O
an O
overall O
elliptical O
assembly O
of O
pigments O
that O
features O
a O
gap O
. O

Examination O
of O
the O
Mode O
of O
Action O
of O
the O
Almiramide B
Family O
of O
Natural O
Products O
against O
the O
Kinetoplastid O
Parasite O
Trypanosoma O
brucei O
. O

Almiramide B
C I
is O
a O
marine O
natural O
product O
with O
low O
micromolar O
activity O
against O
Leishmania O
donovani O
, O
the O
causative O
agent O
of O
leishmaniasis O
. O

We O
have O
now O
shown O
that O
almiramide B
C I
is O
also O
active O
against O
the O
related O
parasite O
Trypanosoma O
brucei O
, O
the O
causative O
agent O
of O
human O
African O
trypanosomiasis O
. O

A O
series O
of O
activity O
- O
based O
probes O
have O
been O
synthesized O
to O
explore O
both O
the O
molecular O
target O
of O
this O
compound O
series O
in O
T O
. O
brucei O
lysates O
and O
site O
localization O
through O
epifluorescence O
microscopy O
. O

These O
target O
identification O
studies O
indicate O
that O
the O
almiramides B
likely O
perturb O
glycosomal O
function O
through O
disruption O
of O
membrane O
assembly O
machinery O
. O

Glycosomes O
, O
which O
are O
organelles O
specific O
to O
kinetoplastid O
parasites O
, O
house O
the O
first O
seven O
steps O
of O
glycolysis O
and O
have O
been O
shown O
to O
be O
essential O
for O
parasite O
survival O
in O
the O
bloodstream O
stage O
. O

There O
are O
currently O
no O
reported O
small O
- O
molecule O
disruptors O
of O
glycosome O
function O
, O
making O
the O
almiramides O
unique O
molecular O
probes O
for O
this O
understudied O
parasite O
- O
specific O
organelle O
. O

Additionally O
, O
examination O
of O
toxicity O
in O
an O
in O
vivo O
zebrafish O
model O
has O
shown O
that O
these O
compounds O
have O
little O
effect O
on O
organism O
development O
, O
even O
at O
high O
concentrations O
, O
and O
has O
uncovered O
a O
potential O
side O
effect O
through O
localization O
of O
fluorescent O
derivatives O
to O
zebrafish O
neuromast O
cells O
. O

Combined O
, O
these O
results O
further O
our O
understanding O
of O
the O
potential O
value O
of O
this O
lead O
series O
as O
development O
candidates O
against O
T O
. O
brucei O
. O

Achievement O
of O
pregnancies O
in O
women O
with O
primary O
ovarian O
insufficiency O
using O
close O
monitoring O
of O
follicle O
development O
: O
case O
reports O
. O

Women O
with O
primary O
ovarian O
insufficiency O
( O
POI O
) O
/ O
premature O
ovarian O
failure O
exhibit O
hypergonadotropic O
hypogonadism O
due O
to O
follicle O
dysfunction O
and O
depletion O
before O
the O
age O
of O
40 O
years O
. O

Because O
ovulation O
is O
extremely O
rare O
and O
thought O
to O
be O
unpredictable O
in O
women O
with O
POI O
and O
because O
no O
ovulation O
induction O
regimens O
have O
been O
shown O
to O
be O
efficacious O
, O
oocyte O
donation O
is O
the O
only O
evidence O
- O
based O
treatment O
for O
women O
with O
POI O
with O
desired O
fertility O
. O

Oocyte O
donation O
is O
, O
however O
, O
extremely O
limited O
in O
several O
countries O
including O
Japan O
. O

Here O
, O
we O
report O
four O
women O
with O
POI O
who O
achieved O
pregnancies O
resulting O
from O
timed O
intercourse O
or O
intrauterine O
insemination O
in O
combination O
with O
cyclic O
estrogen B
/ O
progesterone B
therapy O
and O
close O
monitoring O
of O
follicle O
development O
. O

These O
four O
patients O
were O
diagnosed O
with O
POI O
at O
the O
mean O
age O
of O
27 O
. O
5 O
+ O
/ O
- O
8 O
. O
5 O
( O
mean O
+ O
/ O
- O
SD O
; O
range O
, O
19 O
- O
35 O
) O
, O
subjected O
to O
follicle O
monitoring O
at O
the O
mean O
age O
of O
29 O
. O
8 O
+ O
/ O
- O
5 O
. O
7 O
( O
23 O
- O
35 O
) O
, O
and O
conceived O
at O
the O
mean O
age O
of O
34 O
. O
5 O
+ O
/ O
- O
3 O
. O
9 O
( O
29 O
- O
38 O
) O
. O

The O
interval O
between O
the O
initiation O
of O
follicle O
monitoring O
and O
pregnancy O
was O
4 O
. O
8 O
+ O
/ O
- O
2 O
. O
8 O
( O
2 O
- O
8 O
) O
years O
. O

In O
one O
of O
the O
patients O
, O
her O
most O
recent O
ovulation O
occurred O
after O
a O
three O
- O
year O
interval O
. O

All O
four O
patients O
had O
uncomplicated O
pregnancies O
with O
term O
deliveries O
. O

In O
the O
event O
that O
oocyte O
donation O
and O
adoption O
are O
not O
available O
and O
/ O
or O
various O
treatments O
with O
intensive O
ovulation O
induction O
have O
been O
unsuccessful O
, O
close O
and O
continuous O
monitoring O
of O
follicle O
growth O
to O
identify O
very O
rare O
ovulatory O
events O
might O
be O
considered O
for O
patients O
with O
POI O
and O
desired O
fertility O
. O

Artificial O
leaf O
structures O
as O
a O
UV O
detector O
formed O
by O
the O
self O
- O
assembly O
of O
ZnO B
nanoparticles O
. O

Artificial O
leaf O
structures O
have O
been O
fabricated O
by O
the O
self O
- O
assembly O
of O
ZnO B
nanoparticles O
. O

A O
hydrothermal O
method O
was O
used O
to O
synthesize O
the O
nanoparticles O
. O

The O
self O
- O
assembly O
patterns O
showed O
asymmetric O
dendritic O
morphologies O
, O
larger O
surface O
- O
to O
- O
volume O
ratios O
, O
a O
broad O
absorption O
band O
and O
high O
resistance O
. O

A O
non O
- O
equilibrium O
two O
- O
stage O
- O
formation O
process O
included O
diffusion O
limited O
aggregation O
, O
and O
the O
phase O
- O
field O
model O
was O
introduced O
to O
explain O
the O
formation O
mechanism O
of O
the O
pattern O
. O

A O
high O
- O
performance O
ultraviolet O
detector O
was O
fabricated O
on O
the O
artificial O
leaf O
structures O
, O
which O
showed O
that O
the O
current O
under O
the O
irradiation O
of O
a O
UV O
lamp O
( O
1 O
. O
21 O
mW O
cm O
( O
- O
2 O
) O
) O
was O
about O
10 O
( O
4 O
) O
times O
greater O
than O
in O
the O
dark O
. O

The O
various O
and O
functional O
properties O
of O
the O
pattern O
show O
us O
the O
vast O
prospects O
of O
potential O
applications O
for O
light O
harvesting O
systems O
and O
other O
optical O
- O
electric O
devices O
. O

Synthesis O
of O
pyrido B
[ I
2 I
, I
3 I
- I
d I
] I
[ I
1 I
, I
2 I
, I
4 I
] I
triazolo I
[ I
4 I
, I
3 I
- I
a I
] I
pyrimidin I
- I
5 I
- I
ones I
as O
potential O
antimicrobial O
agents O
. O

Synthesis O
of O
new O
derivatives O
of O
pyrido B
[ I
2 I
, I
3 I
- I
d I
] I
[ I
1 I
, I
2 I
, I
4 I
] I
triazolo I
[ I
4 I
, I
3 I
- I
a I
] I
pyrimidin I
- I
5 I
- I
one I
via O
reaction O
of O
7 B
- I
( I
4 I
- I
bromophenyl I
) I
- I
1 I
, I
2 I
- I
dihydro I
- I
5 I
- I
( I
4 I
- I
fluorophenyl I
) I
- I
2 I
- I
thioxopyrido I
[ I
2 I
, I
3 I
- I
d I
] I
pyrimidin I
- I
4 I
( I
3H I
) I
- I
one I
with O
hydrazonoyl B
chlorides I
or O
reaction O
of O
2 B
- I
hydrazino I
- I

pyrido I
[ I
2 I
, I
3 I
- I
d I
] I
pyrimidin I
- I
4 I
( I
3H I
) I
- I
one I
with O
different O
aldehydes B
followed O
by O
cyclization O
of O
the O
products O
. O

All O
the O
newly O
synthesized O
compounds O
were O
evaluated O
for O
their O
antimicrobial O
activities O
and O
also O
their O
minimum O
inhibitory O
concentration O
against O
most O
of O
test O
organisms O
was O
performed O
. O

Amongst O
the O
tested O
compounds O
displayed O
excellent O
activity O
against O
all O
the O
tested O
microorganisms O
except O
SR O
and O
PA O
. O

Glutathione B
dimerization O
- O
based O
plasmonic O
nanoswitch O
for O
biodetection O
of O
reactive O
oxygen B
and O
nitrogen B
species O
. O

Reactive O
oxygen B
and O
nitrogen B
species O
( O
ROS O
and O
RNS O
) O
are O
continuously O
produced O
in O
the O
cellular O
systems O
and O
are O
controlled O
by O
several O
antioxidant O
mechanisms O
. O

Here O
, O
we O
developed O
a O
straightforward O
, O
sensitive O
, O
and O
quantitative O
assay O
for O
the O
colorimetric O
and O
spectroscopic O
detection O
of O
various O
ROS O
and O
RNS O
such O
as O
H2O2 B
, O
. B
OH I
, O
( B
- I
) I
OCl I
, O
NO B
. I
, O
and O
O2 B
( I
- I
) I
using O
glutathione B
- O
modified O
gold O
nanoparticles O
( O
GSH B
- O
AuNPs O
) O
. O

A O
basic O
principle O
here O
is O
that O
the O
GSHs B
on O
the O
AuNP O
surface O
can O
be O
readily O
detached O
via O
the O
formation O
of O
glutathione B
disulfides I
upon O
the O
addition O
of O
ROS O
and O
RNS O
, O
and O
destabilized O
particles O
can O
aggregate O
to O
generate O
the O
plasmonic O
couplings O
between O
plasmonic O
AuNPs O
that O
trigger O
the O
red O
shift O
in O
UV O
- O
vis O
spectrum O
and O
solution O
color O
change O
. O

For O
nonradical O
species O
such O
as O
H2O2 B
, O
this O
process O
can O
be O
more O
efficiently O
achieved O
by O
converting O
them O
into O
radical O
species O
via O
the O
Fenton O
reaction O
. O

Using O
this O
strategy O
, O
we O
were O
able O
to O
rapidly O
and O
quantitatively O
distinguish O
among O
cancerous O
and O
normal O
cells O
based O
on O
ROS O
and O
RNS O
production O
. O

Twisting O
bilayer O
graphene B
superlattices O
. O

Bilayer O
graphene B
is O
an O
intriguing O
material O
in O
that O
its O
electronic O
structure O
can O
be O
altered O
by O
changing O
the O
stacking O
order O
or O
the O
relative O
twist O
angle O
, O
yielding O
a O
new O
class O
of O
low O
- O
dimensional O
carbon B
system O
. O

Twisted O
bilayer O
graphene B
can O
be O
obtained O
by O
( O
i O
) O
thermal O
decomposition O
of O
SiC B
; O
( O
ii O
) O
chemical O
vapor O
deposition O
( O
CVD O
) O
on O
metal O
catalysts O
; O
( O
iii O
) O
folding O
graphene B
; O
or O
( O
iv O
) O
stacking O
graphene B
layers O
one O
atop O
the O
other O
, O
the O
latter O
of O
which O
suffers O
from O
interlayer O
contamination O
. O

Existing O
synthesis O
protocols O
, O
however O
, O
usually O
result O
in O
graphene B
with O
polycrystalline O
structures O
. O

The O
present O
study O
investigates O
bilayer O
graphene B
grown O
by O
ambient O
pressure O
CVD O
on O
polycrystalline O
Cu B
. O

Controlling O
the O
nucleation O
in O
early O
stage O
growth O
allows O
the O
constituent O
layers O
to O
form O
single O
hexagonal O
crystals O
. O

New O
Raman O
active O
modes O
are O
shown O
to O
result O
from O
the O
twist O
, O
with O
the O
angle O
determined O
by O
transmission O
electron O
microscopy O
. O

The O
successful O
growth O
of O
single O
- O
crystal O
bilayer O
graphene B
provides O
an O
attractive O
jumping O
- O
off O
point O
for O
systematic O
studies O
of O
interlayer O
coupling O
in O
misoriented O
few O
- O
layer O
graphene B
systems O
with O
well O
- O
defined O
geometry O
. O

Acyclic B
nucleoside I
phosphonates I
containing O
a O
second O
phosphonate B
group O
are O
potent O
inhibitors O
of O
6 B
- I
oxopurine I
phosphoribosyltransf O
and O
have O
antimalarial O
activity O
. O

Acyclic B
nucleoside I
phosphonates I
( O
ANPs B
) O
that O
contain O
a O
6 B
- I
oxopurine I
base O
are O
good O
inhibitors O
of O
the O
Plasmodium O
falciparum O
( O
Pf O
) O
and O
Plasmodium O
vivax O
( O
Pv O
) O
6 B
- I
oxopurine I
phosphoribosyltransf O
( O
PRTs O
) O
. O

Chemical O
modifications O
based O
on O
the O
crystal O
structure O
of O
2 B
- I
( I
phosphonoethoxy I
) I
ethylguanine I
( O
PEEG B
) O
in O
complex O
with O
human O
HGPRT O
have O
led O
to O
the O
design O
of O
new O
ANPs O
. O

These O
novel O
compounds O
contain O
a O
second O
phosphonate B
group O
attached O
to O
the O
ANP O
scaffold O
. O

{ B
[ I
( I
2 I
- I
[ I
( I
Guanine I
- I
9H I
- I
yl I
) I
methyl I
] I
propane I
- I
1 I
, I
3 I
- I
diyl I
) I
bis I
( I
oxy I
) I
] I
bis I
( I
methylene I
) I
} I
diphosphonic I
acid I
( O
compound O
17 O
) O
exhibited O
a O
Ki O
value O
of O
30 O
nM O
for O
human O
HGPRT O
and O
70 O
nM O
for O
Pf O
HGXPRT O
. O

The O
crystal O
structure O
of O
this O
compound O
in O
complex O
with O
human O
HGPRT O
shows O
that O
it O
fills O
or O
partially O
fills O
three O
critical O
locations O
in O
the O
active O
site O
: O
the O
binding O
sites O
of O
the O
purine B
base O
, O
the O
5 B
' I
- I
phosphate I
group O
, O
and O
pyrophosphate B
. O

This O
is O
the O
first O
HG B
( O
X O
) O
PRT O
inhibitor O
that O
has O
been O
able O
to O
achieve O
this O
result O
. O

Prodrugs O
have O
been O
synthesized O
resulting O
in O
IC50 O
values O
as O
low O
as O
3 O
. O
8 O
mu O
M O
for O
Pf O
grown O
in O
cell O
culture O
, O
up O
to O
25 O
- O
fold O
lower O
compared O
to O
the O
parent O
compounds O
. O

Synthesis O
of O
novel O
estrogen B
receptor O
antagonists O
using O
metal O
- O
catalyzed O
coupling O
reactions O
and O
characterization O
of O
their O
biological O
activity O
. O

Estrogen B
receptor O
( O
ER O
) O
antagonists O
are O
valuable O
in O
the O
treatment O
of O
ER O
- O
positive O
human O
breast O
cancer O
. O

In O
this O
study O
, O
we O
designed O
and O
synthesized O
nine O
new O
derivatives O
of O
17 B
beta I
- I
estradiol I
( O
E2 O
) O
with O
a O
bulky O
side O
chain O
attached O
to O
its O
C O
- O
7 O
alpha O
position O
, O
and O
determined O
their O
ER O
antagonistic O
activity O
using O
in O
vitro O
bioassays O
. O

Four O
of O
the O
derivatives O
showed O
a O
strong O
inhibition O
of O
ER O
alpha O
transactivation O
activity O
in O
a O
luciferase O
reporter O
assay O
and O
blocked O
ER O
alpha O
interactions O
with O
coactivators O
. O

Similarly O
, O
these O
derivatives O
also O
strongly O
inhibited O
the O
growth O
of O
the O
ER O
alpha O
- O
positive O
human O
breast O
cancer O
cells O
. O

Computational O
docking O
analysis O
was O
conducted O
to O
model O
the O
interaction O
of O
these O
antagonists O
with O
the O
human O
ER O
alpha O
and O
showed O
that O
they O
could O
tightly O
bind O
to O
the O
ER O
alpha O
in O
a O
manner O
similar O
to O
that O
of O
ICI B
- I
182 I
, I
780 I
, O
a O
pure O
ER O
antagonist O
. O

These O
results O
provide O
an O
example O
that O
attachment O
of O
a O
bulky O
side O
chain O
to O
the O
C O
- O
7 O
alpha O
position O
of O
E2 O
can O
produce O
ER O
antagonists O
with O
ER O
affinity O
comparable O
to O
that O
of O
ICI B
- I
182 I
, I
780 I
. O

Device O
physics O
and O
operation O
of O
lateral O
bulk O
heterojunction O
devices O
. O

Measurements O
of O
lateral O
bulk O
heterojunction O
( O
BHJ O
) O
devices O
have O
recently O
been O
reported O
as O
a O
means O
to O
characterize O
charge O
transport O
and O
recombination O
properties O
within O
organic O
photovoltaic O
( O
OPV O
) O
materials O
. O

These O
structures O
allow O
for O
the O
direct O
measurement O
of O
the O
lateral O
extents O
of O
the O
space O
charge O
regions O
, O
potential O
and O
electric O
field O
profiles O
, O
current O
versus O
voltage O
characteristics O
, O
and O
other O
physical O
and O
chemical O
properties O
. O

This O
article O
describes O
numerical O
simulations O
that O
show O
three O
different O
transport O
regimes O
present O
within O
lateral O
BHJ O
devices O
and O
two O
different O
experimental O
methods O
, O
which O
verify O
those O
findings O
. O

These O
measurement O
techniques O
utilize O
typical O
confocal O
microscopy O
tools O
as O
well O
as O
steady O
- O
state O
current O
versus O
voltage O
measurements O
on O
high O
aspect O
ratio O
nanofabricated O
structures O
in O
order O
to O
probe O
the O
material O
properties O
between O
the O
electrodes O
. O

Experimental O
results O
show O
that O
the O
lateral O
extents O
of O
space O
charge O
regions O
within O
these O
devices O
are O
approximately O
1 O
- O
5 O
mu O
m O
, O
which O
are O
related O
to O
the O
drift O
lengths O
of O
the O
charge O
carriers O
, O
and O
that O
the O
mechanism O
of O
bimolecular O
recombination O
is O
shown O
to O
be O
a O
bulk O
material O
property O
. O

The O
results O
within O
this O
article O
describe O
a O
series O
of O
methods O
to O
evaluate O
charge O
transport O
and O
recombination O
along O
the O
in O
- O
plane O
direction O
in O
BHJ O
films O
and O
provide O
complementary O
insights O
to O
those O
obtained O
from O
vertical O
- O
device O
- O
based O
measurements O
. O

Practical O
approach O
for O
measuring O
heat O
capacity O
of O
pharmaceutical O
crystals O
/ O
glasses O
by O
modulated O
- O
temperature O
differential O
scanning O
calorimetry O
. O

A O
practical O
protocol O
to O
obtain O
accurate O
heat O
capacity O
values O
of O
pharmaceutical O
compounds O
using O
modulated O
- O
temperature O
differential O
scanning O
calorimetry O
was O
established O
. O

Three O
pharmaceutical O
compounds O
, O
acetaminophen B
, O
indomethacin B
, O
and O
tri B
- I
O I
- I
methyl I
- I
beta I
- I
cyclodextrin I
were O
used O
as O
model O
compounds O
. O

Powder O
samples O
did O
not O
produce O
reproducible O
results O
, O
presumably O
due O
to O
inclusion O
of O
gas O
in O
gap O
of O
powders O
that O
influenced O
the O
measured O
heat O
capacity O
and O
thermal O
homogeneity O
in O
the O
sample O
. O

Thus O
, O
the O
amorphous O
characteristics O
were O
evaluated O
using O
quench O
- O
cooled O
samples O
. O

Crystalline O
samples O
were O
obtained O
by O
partially O
melting O
the O
sample O
to O
allow O
recrystallization O
using O
the O
residual O
crystal O
as O
a O
template O
. O

Optimum O
sample O
mass O
was O
about O
10 O
mg O
. O

Use O
of O
too O
small O
sample O
size O
resulted O
in O
poor O
reproducibility O
due O
to O
localization O
of O
the O
sample O
in O
the O
pan O
, O
while O
too O
large O
size O
resulted O
in O
low O
heat O
capacity O
values O
probably O
because O
of O
heterogeneity O
of O
the O
sample O
temperature O
. O

The O
optimum O
modulation O
period O
was O
in O
the O
range O
of O
60 O
s O
and O
90 O
s O
, O
to O
which O
the O
ramp O
rates O
of O
2 O
degrees O
C O
/ O
min O
and O
1 O
degrees O
C O
/ O
min O
, O
respectively O
, O
were O
applied O
. O

The O
ramp O
amplitude O
was O
less O
significant O
in O
the O
evaluation O
. O

This O
information O
should O
help O
in O
comprehending O
basic O
characteristics O
of O
pharmaceutical O
compounds O
. O

Particle O
condition O
change O
in O
emulsion O
admixture O
evaluated O
by O
in O
situ O
flow O
particle O
imaging O
analysis O
. O

We O
evaluated O
the O
particle O
state O
change O
in O
emulsion O
admixtures O
using O
in O
situ O
flow O
particle O
imaging O
analysis O
( O
FPIA O
) O
. O

Ropion B
( O
R O
) O
intravenous O
( O
flurbiprofen B
axetil I
: O
Ropion B
( O
R O
) O
) O
served O
as O
the O
model O
emulsion O
formulation O
. O

A O
binary O
mixture O
of O
Ropion O
( O
R O
) O
and O
normal O
saline O
( O
NS O
) O
, O
and O
a O
ternary O
admixture O
of O
Ropion O
( O
R O
) O
, O
NS O
, O
and O
Gaster O
( O
R O
) O
injection O
( O
famotidine B
: O
Gaster O
( O
R O
) O
) O
or O
Primperan B
( O
R O
) O
injection O
( O
metoclopramide B
hydrochloride I
: O
Primperan B
( O
R O
) O
) O
were O
prepared O
and O
the O
change O
in O
emulsion O
particle O
state O
was O
analyzed O
using O
FPIA O
under O
in O
situ O
condition O
. O

The O
effect O
of O
storage O
on O
pH O
change O
and O
the O
chemical O
stability O
of O
flurbiprofen B
axetil I
were O
also O
investigated O
. O

In O
Ropion O
( O
R O
) O
, O
various O
particle O
images O
( O
mean O
diameter O
: O
2 O
. O
4 O
micro O
m O
) O
were O
obtained O
. O

From O
our O
analysis O
of O
changes O
in O
scattergrams O
and O
particle O
images O
, O
changing O
behaviors O
of O
emulsion O
particles O
as O
a O
function O
of O
storage O
time O
depended O
on O
the O
systems O
of O
admixture O
samples O
. O

In O
Ropion O
( O
R O
) O
/ O
NS O
and O
Ropion O
( O
R O
) O
/ O
Gaster O
( O
R O
) O
/ O
NS O
systems O
, O
mean O
particle O
size O
and O
particle O
number O
increased O
with O
lengthening O
storage O
time O
; O
however O
, O
these O
values O
were O
dramatically O
increased O
beyond O
6 O
h O
in O
the O
Ropion O
( O
R O
) O
/ O
Primperan O
( O
R O
) O
/ O
NS O
system O
, O
corresponding O
to O
a O
decrease O
in O
measured O
pH O
. O

The O
decomposition O
of O
flurbiprofen B
axetil I
due O
to O
incompatibility O
was O
not O
observed O
in O
all O
systems O
. O

Detailed O
information O
on O
the O
change O
in O
emulsion O
particle O
state O
was O
obtained O
using O
FPIA O
, O
indicating O
that O
this O
method O
is O
useful O
to O
evaluate O
state O
changes O
in O
emulsion O
admixtures O
under O
in O
situ O
condition O
. O

Ca2 B
+ I
- O
dependent O
protein O
kinase11 O
and O
24 O
modulate O
the O
activity O
of O
the O
inward O
rectifying O
K B
+ I
channels O
in O
Arabidopsis O
pollen O
tubes O
. O

Potassium B
( O
K B
( I
+ I
) I
) O
influx O
into O
pollen O
tubes O
via O
K B
( I
+ I
) I
transporters O
is O
essential O
for O
pollen O
tube O
growth O
; O
however O
, O
the O
mechanism O
by O
which O
K B
( I
+ I
) I
transporters O
are O
regulated O
in O
pollen O
tubes O
remains O
unknown O
. O

Here O
, O
we O
report O
that O
Arabidopsis O
thaliana O
Ca B
( I
2 I
+ I
) I
- O
dependent O
protein O
kinase11 O
( O
CPK11 O
) O
and O
CPK24 O
are O
involved O
in O
Ca B
( I
2 I
+ I
) I
- O
dependent O
regulation O
of O
the O
inward O
K B
( I
+ I
) I
( O
K B
( I
+ I
) I
in O
) O
channels O
in O
pollen O
tubes O
. O

Using O
patch O
- O
clamp O
analysis O
, O
we O
demonstrated O
that O
K B
( I
+ I
) I
in O
currents O
of O
pollen O
tube O
protoplasts O
were O
inhibited O
by O
elevated O
[ O
Ca B
( I
2 I
+ I
) I
] O
cyt B
. O

However O
, O
disruption O
of O
CPK11 O
or O
CPK24 O
completely O
impaired O
the O
Ca B
( I
2 I
+ I
) I
- O
dependent O
inhibition O
of O
K B
( I
+ I
) I
in O
currents O
and O
enhanced O
pollen O
tube O
growth O
. O

Moreover O
, O
the O
cpk11 O
cpk24 O
double O
mutant O
exhibited O
similar O
phenotypes O
as O
the O
corresponding O
single O
mutants O
, O
suggesting O
that O
these O
two O
CDPKs O
function O
in O
the O
same O
signaling O
pathway O
. O

Bimolecular O
fluorescence O
complementation O
and O
coimmunoprecipitatio O
experiments O
showed O
that O
CPK11 O
could O
interact O
with O
CPK24 O
in O
vivo O
. O

Furthermore O
, O
CPK11 O
phosphorylated O
the O
N B
terminus O
of O
CPK24 O
in O
vitro O
, O
suggesting O
that O
these O
two O
CDPKs O
work O
together O
as O
part O
of O
a O
kinase O
cascade O
. O

Electrophysiological O
assays O
demonstrated O
that O
the O
Shaker O
pollen O
K B
( I
+ I
) I
in O
channel O
is O
the O
main O
contributor O
to O
pollen O
tube O
K B
( I
+ I
) I
in O
currents O
and O
acts O
as O
the O
downstream O
target O
of O
the O
CPK11 O
- O
CPK24 O
pathway O
. O

We O
conclude O
that O
CPK11 O
and O
CPK24 O
together O
mediate O
the O
Ca B
( I
2 I
+ I
) I
- O
dependent O
inhibition O
of O
K B
( I
+ I
) I
in O
channels O
and O
participate O
in O
the O
regulation O
of O
pollen O
tube O
growth O
in O
Arabidopsis O
. O

Overdosage O
of O
Hand2 O
causes O
limb O
and O
heart O
defects O
in O
the O
human O
chromosomal O
disorder O
partial O
trisomy O
distal O
4q O
. O

Partial O
trisomy O
distal O
4q O
( O
denoted O
4q O
+ O
) O
is O
a O
human O
chromosomal O
disorder O
caused O
by O
duplication O
of O
the O
distal O
end O
of O
the O
long O
arm O
of O
chromosome O
4 O
( O
Chr4 O
) O
. O

This O
disorder O
manifests O
typical O
phenotypes O
, O
including O
craniofacial O
, O
renal O
, O
heart O
and O
thumb O
developmental O
defects O
. O

Although O
these O
clinical O
features O
are O
likely O
caused O
by O
a O
dosage O
imbalance O
in O
the O
gene O
network O
involving O
the O
trisomic O
region O
, O
the O
causative O
gene O
or O
genes O
and O
the O
molecular O
bases O
are O
largely O
unknown O
. O

Here O
, O
we O
report O
mouse O
Recombination O
- O
induced O
mutation O
4 O
( O
Rim4 O
) O
as O
a O
model O
animal O
of O
4q O
+ O
. O

The O
Rim4 O
genome O
contains O
an O
insertion O
of O
a O
6 O
. O
5 O
Mb O
fragment O
from O
mouse O
chromosome O
8 O
into O
chromosome O
6 O
. O

This O
insertion O
fragment O
contains O
17 O
genes O
, O
including O
Hand2 O
, O
that O
encode O
the O
basic O
helix O
- O
loop O
- O
helix O
transcription O
factor O
and O
is O
syntenic O
to O
the O
distal O
end O
of O
human O
Chr4 O
, O
4q32 O
. O
3 O
to O
4q34 O
. O
1 O
, O
which O
is O
responsible O
for O
4q O
+ O
. O

A O
comparison O
of O
phenotypes O
between O
patients O
with O
Rim4 O
and O
4q O
+ O
revealed O
that O
Rim4 O
shows O
direct O
parallels O
with O
many O
phenotypes O
of O
4q O
+ O
such O
as O
craniofacial O
, O
heart O
, O
cervical O
vertebra O
and O
limb O
deformities O
. O

Rebalancing O
the O
gene O
dosage O
by O
a O
genetic O
cross O
with O
Hand2 O
knockout O
mice O
ameliorated O
symptoms O
of O
the O
heart O
and O
limb O
deformities O
of O
Rim4 O
. O

Conversely O
, O
an O
increase O
in O
copy O
number O
of O
Hand2 O
in O
wild O
- O
type O
mice O
recaptures O
the O
heart O
and O
limb O
deformities O
of O
Rim4 O
. O

Our O
results O
collectively O
demonstrate O
that O
overdosage O
of O
Hand2 O
is O
a O
major O
cause O
for O
at O
least O
the O
limb O
and O
heart O
phenotypes O
of O
4q O
+ O
and O
that O
mouse O
Rim4 O
provides O
a O
unique O
animal O
model O
for O
understanding O
the O
molecular O
bases O
underlying O
the O
complex O
phenotypes O
of O
4q O
+ O
. O

Ultrasensitive O
non O
- O
resonant O
detection O
of O
ultrasound O
with O
plasmonic O
metamaterials O
. O

Optical O
sensors O
for O
ultrasound O
detection O
provide O
high O
sensitivity O
and O
bandwidth O
, O
essential O
for O
photoacoustic O
imaging O
in O
clinical O
diagnostics O
and O
biomedical O
research O
. O

Implementing O
plasmonic O
metamaterials O
in O
a O
non O
- O
resonant O
regime O
facilitates O
sub O
- O
nanosecond O
, O
highly O
sensitive O
detectors O
while O
eliminating O
cumbersome O
optical O
alignment O
necessary O
for O
resonant O
sensors O
. O

Luminescent O
conjugated O
oligothiophenes O
for O
sensitive O
fluorescent O
assignment O
of O
protein O
inclusion O
bodies O
. O

Small O
hydrophobic O
ligands O
identifying O
intracellular O
protein O
deposits O
are O
of O
great O
interest O
, O
as O
protein O
inclusion O
bodies O
are O
the O
pathological O
hallmark O
of O
several O
degenerative O
diseases O
. O

Here O
we O
report O
that O
fluorescent O
amyloid O
ligands O
, O
termed O
luminescent O
conjugated O
oligothiophenes O
( O
LCOs O
) O
, O
rapidly O
and O
with O
high O
sensitivity O
detect O
protein O
inclusion O
bodies O
in O
skeletal O
muscle O
tissue O
from O
patients O
with O
sporadic O
inclusion O
body O
myositis O
( O
s O
- O
IBM O
) O
. O

LCOs O
having O
a O
conjugated O
backbone O
of O
at O
least O
five O
thiophene B
units O
emitted O
strong O
fluorescence O
upon O
binding O
, O
and O
showed O
co O
- O
localization O
with O
proteins O
reported O
to O
accumulate O
in O
s O
- O
IBM O
protein O
inclusion O
bodies O
. O

Compared O
with O
conventional O
amyloid O
ligands O
, O
LCOs O
identified O
a O
larger O
fraction O
of O
immunopositive O
inclusion O
bodies O
. O

When O
the O
conjugated O
thiophene B
backbone O
was O
extended O
with O
terminal O
carboxyl B
groups O
, O
the O
LCO O
revealed O
striking O
spectral O
differences O
between O
distinct O
protein O
inclusion O
bodies O
. O

We O
conclude O
that O
1 O
) O
LCOs O
are O
sensitive O
, O
rapid O
and O
powerful O
tools O
for O
identifying O
protein O
inclusion O
bodies O
and O
2 O
) O
LCOs O
identify O
a O
wider O
range O
of O
protein O
inclusion O
bodies O
than O
conventional O
amyloid O
ligands O
. O

Comparative O
Binding O
Energy O
( O
COMBINE O
) O
Analysis O
for O
Understanding O
the O
Binding O
Determinants O
of O
Type O
II O
Dehydroquinase O
Inhibitors O
. O

Herein O
we O
report O
comparative O
binding O
energy O
( O
COMBINE O
) O
analyses O
to O
derive O
quantitative O
structure O
- O
activity O
relationship O
( O
QSAR O
) O
models O
that O
help O
rationalize O
the O
determinants O
of O
binding O
affinity O
for O
inhibitors O
of O
type O
II O
dehydroquinase O
( O
DHQ2 O
) O
, O
the O
third O
enzyme O
of O
the O
shikimic B
acid I
pathway O
. O

Independent O
COMBINE O
models O
were O
derived O
for O
Helicobacter O
pylori O
and O
Mycobacterium O
tuberculosis O
DHQ2 O
, O
which O
is O
an O
essential O
enzyme O
in O
both O
these O
pathogenic O
bacteria O
that O
has O
no O
counterpart O
in O
human O
cells O
. O

These O
studies O
quantify O
the O
importance O
of O
the O
hydrogen B
bonding O
interactions O
between O
the O
ligands O
and O
the O
water O
molecule O
involved O
in O
the O
DHQ2 B
reaction O
mechanism O
. O

They O
also O
highlight O
important O
differences O
in O
the O
ligand O
interactions O
with O
the O
interface O
pocket O
close O
to O
the O
active O
site O
that O
could O
provide O
guides O
for O
future O
inhibitor O
design O
. O

Over O
- O
the O
- O
Counter O
Access O
to O
Emergency O
Contraception O
without O
Age O
Restriction O
: O
An O
Opinion O
of O
the O
Women O
' O
s O
Health O
Practice O
and O
Research O
Network O
of O
the O
American O
College O
of O
Clinical O
Pharmacy O
. O

Family O
planning O
remains O
a O
high O
priority O
area O
for O
the O
United O
States O
, O
with O
goals O
to O
increase O
the O
proportion O
of O
pregnancies O
that O
are O
intended O
, O
reduce O
pregnancy O
rates O
among O
adolescents O
, O
and O
increase O
contraceptive O
use O
prioritized O
in O
the O
Healthy O
People O
2020 O
objectives O
. O

Contraception O
intended O
for O
use O
after O
unprotected O
intercourse O
, O
known O
as O
emergency O
contraception O
, O
remains O
underutilized O
. O

Levonorgestrel B
is O
one O
method O
of O
oral O
emergency O
contraception O
, O
which O
prevents O
fertilization O
and O
does O
not O
disrupt O
an O
already O
established O
pregnancy O
; O
thus O
, O
timing O
of O
administration O
is O
critical O
. O

Despite O
data O
demonstrating O
safety O
and O
efficacy O
, O
evidence O
- O
based O
decision O
making O
has O
been O
overshadowed O
by O
politically O
charged O
actions O
involving O
levonorgestrel B
emergency O
contraception O
for O
over O
a O
decade O
. O

The O
Women O
' O
s O
Health O
Practice O
and O
Research O
Network O
of O
the O
American O
College O
of O
Clinical O
Pharmacy O
supports O
expanded O
access O
to O
levonorgestrel B
emergency O
contraception O
and O
removal O
of O
barriers O
such O
as O
age O
restrictions O
on O
the O
nonprescription O
drug O
product O
. O

Pharmacists O
remain O
a O
key O
provider O
of O
emergency O
contraceptive O
services O
and O
can O
help O
ensure O
timely O
access O
. O

In O
states O
where O
direct O
pharmacy O
access O
to O
emergency O
contraception O
is O
available O
, O
pharmacists O
are O
encouraged O
to O
participate O
. O

Education O
, O
research O
, O
and O
advocacy O
are O
other O
important O
responsibilities O
for O
pharmacists O
in O
this O
arena O
. O

Selective O
functionalization O
of O
the O
internal O
and O
the O
external O
surfaces O
of O
mesoporous O
silicon B
by O
liquid O
masking O
. O

A O
general O
approach O
for O
selective O
, O
differential O
functionalization O
of O
the O
interior O
and O
exterior O
surfaces O
of O
mesoporous O
Si B
is O
reported O
. O

The O
method O
employs O
two O
immiscible O
liquids O
, O
one O
inert O
and O
the O
other O
chemically O
reactive O
with O
the O
porous O
Si B
nanostructure O
. O

First O
, O
a O
porous O
Si B
sample O
is O
prepared O
by O
electrochemical O
etch O
and O
then O
it O
is O
mildly O
oxidized O
, O
which O
places O
a O
thin O
layer O
of O
silicon B
oxide I
at O
the O
surface O
. O

The O
inner O
pore O
walls O
of O
the O
partially O
oxidized O
porous O
Si B
film O
are O
then O
infiltrated O
with O
an O
inert O
liquid O
( O
octane B
) O
. O

The O
sample O
is O
then O
immersed O
in O
aqueous O
solution O
containing O
hydrogen B
fluoride I
( O
HF B
) O
, O
which O
serves O
as O
the O
reactive O
liquid O
. O

The O
hydrophobic O
phase O
is O
retained O
in O
the O
interior O
of O
the O
porous O
nanostructure O
, O
and O
HF B
( O
aq O
) O
attacks O
only O
the O
exposed O
surfaces O
of O
the O
oxidized O
porous O
Si B
sample O
, O
generating O
a O
hydrophobic O
, O
hydrogen B
- O
terminated O
( O
Si B
- I
H I
) O
outer O
layer O
. O

The O
reaction O
is O
self O
- O
limiting O
due O
to O
the O
immiscibility O
of O
octane B
and O
water O
, O
and O
the O
extent O
of O
penetration O
of O
the O
Si B
- I
H I
surface O
into O
the O
porous O
layer O
is O
dependent O
on O
the O
time O
of O
exposure O
to O
HF B
( O
aq O
) O
. O

The O
Si B
- O
H B
surface O
can O
then O
be O
modified O
by O
thermal O
hydrosilylation O
( O
1 B
- I
dodecene I
or O
10 B
- I
bromo I
- I
1 I
- I
decene I
) O
in O
a O
subsequent O
step O
, O
resulting O
in O
a O
bifunctional O
porous O
Si B
film O
containing O
hydrophobic O
pore O
entrances O
to O
hydrophilic O
inner O
pores O
. O

The O
hydrophobic O
dodecyl B
species O
at O
the O
mouths O
of O
the O
pores O
is O
found O
to O
form O
a O
barrier O
for O
molecular O
transport O
; O
it O
decreases O
the O
rate O
of O
leaching O
( O
into O
water O
) O
of O
a O
rhodamine B
test O
molecule O
that O
is O
preloaded O
into O
the O
sample O
by O
> O
8 O
fold O
. O

What O
Can O
We O
Learn O
about O
Dispersion O
from O
the O
Conformer O
Surface O
of O
n B
- I
Pentane I
? O

In O
earlier O
work O
[ O
Gruzman O
, O
D O
. O
; O
Karton O
, O
A O
. O
; O
Martin O
, O
J O
. O
M O
. O
L O
. O
J O
. O
Phys O
. O
Chem O
. O
A O
2009 O
, O
113 O
, O
11974 O
] O
, O
we O
showed O
that O
conformer O
energies O
in O
alkanes B
( O
and O
other O
systems O
) O
are O
highly O
dispersion O
- O
driven O
and O
that O
uncorrected O
DFT O
functionals O
fail O
badly O
at O
reproducing O
them O
, O
while O
simple O
empirical O
dispersion O
corrections O
tend O
to O
overcorrect O
. O

To O
gain O
greater O
insight O
into O
the O
nature O
of O
the O
phenomenon O
, O
we O
have O
mapped O
the O
torsional O
surface O
of O
n B
- I
pentane I
to O
10 O
- O
degree O
resolution O
at O
the O
CCSD O
( O
T O
) O
- O
F12 O
level O
near O
the O
basis O
set O
limit O
. O

The O
data O
obtained O
have O
been O
decomposed O
by O
order O
of O
perturbation O
theory O
, O
excitation O
level O
, O
and O
same O
- O
spin O
vs O
opposite O
- O
spin O
character O
. O

A O
large O
number O
of O
approximate O
electronic O
structure O
methods O
have O
been O
considered O
, O
as O
well O
as O
several O
empirical O
dispersion O
corrections O
. O

Our O
chief O
conclusions O
are O
as O
follows O
: O
( O
a O
) O
the O
effect O
of O
dispersion O
is O
dominated O
by O
same O
- O
spin O
correlation O
( O
or O
triplet O
- O
pair O
correlation O
, O
from O
a O
different O
perspective O
) O
; O
( O
b O
) O
singlet O
- O
pair O
correlation O
is O
important O
for O
the O
surface O
, O
but O
qualitatively O
very O
dissimilar O
to O
the O
dispersion O
component O
; O
( O
c O
) O
single O
and O
double O
excitations O
beyond O
third O
order O
are O
essentially O
unimportant O
for O
this O
surface O
; O
( O
d O
) O
connected O
triple O
excitations O
do O
play O
a O
role O
but O
are O
statistically O
very O
similar O
to O
the O
MP2 O
singlet O
- O
pair O
correlation O
; O
( O
e O
) O
the O
form O
of O
the O

damping O
function O
is O
crucial O
for O
good O
performance O
of O
empirical O
dispersion O
corrections O
; O
( O
f O
) O
at O
least O
in O
the O
lower O
- O
energy O
regions O
, O
SCS O
- O
MP2 O
and O
especially O
MP2 O
. O
5 O
perform O
very O
well O
; O
( O
g O
) O
novel O
spin O
- O
component O
scaled O
double O
hybrid O
functionals O
such O
as O
DSD O
- O
PBEP86 O
- O
D2 O
acquit O
themselves O
very O
well O
for O
this O
problem O
. O

Adhesion O
of O
Mussel O
Foot O
Protein O
- O
3 O
to O
TiO2 B
Surfaces O
: O
the O
Effect O
of O
pH O
. O

The O
underwater O
adhesion O
of O
marine O
mussels O
relies O
on O
mussel O
foot O
proteins O
( O
mfps O
) O
rich O
in O
the O
catecholic B
amino I
acid I
3 B
, I
4 I
- I
dihydroxyphenylalani I
( O
Dopa B
) O
. O

As O
a O
side O
chain O
, O
Dopa B
is O
capable O
of O
strong O
bidentate O
interactions O
with O
a O
variety O
of O
surfaces O
, O
including O
many O
minerals O
and O
metal B
oxides I
. O

Titanium B
is O
among O
the O
most O
widely O
used O
medical O
implant O
material O
and O
quickly O
forms O
a O
TiO2 B
passivation O
layer O
under O
physiological O
conditions O
. O

Understanding O
the O
binding O
mechanism O
of O
Dopa B
to O
TiO2 B
surfaces O
is O
therefore O
of O
considerable O
theoretical O
and O
practical O
interest O
. O

Using O
a O
surface O
forces O
apparatus O
, O
we O
explored O
the O
force O
- O
distance O
profiles O
and O
adhesion O
energies O
of O
mussel O
foot O
protein O
3 O
( O
mfp O
- O
3 O
) O
to O
TiO2 B
surfaces O
at O
three O
different O
pHs O
( O
pH O
3 O
, O
5 O
. O
5 O
and O
7 O
. O
5 O
) O
. O

At O
pH O
3 O
, O
mfp O
- O
3 O
showed O
the O
strongest O
adhesion O
force O
on O
TiO2 B
, O
with O
an O
adhesion O
energy O
of O
~ O
- O
7 O
. O
0 O
mJ O
/ O
m O
( O
2 O
) O
. O

Increasing O
the O
pH O
gives O
rise O
to O
two O
opposing O
effects O
: O
( O
1 O
) O
increased O
oxidation O
of O
Dopa B
, O
thus O
, O
decreasing O
availability O
for O
the O
Dopa B
- O
mediated O
adhesion O
, O
and O
( O
2 O
) O
increased O
bidentate O
Dopa B
- I
Ti I
coordination O
, O
leading O
to O
the O
further O
stabilization O
of O
the O
Dopa B
group O
and O
, O
thus O
, O
an O
increase O
in O
adhesion O
force O
. O

Both O
effects O
were O
reflected O
in O
the O
resonance O
- O
enhanced O
Raman O
spectra O
obtained O
at O
the O
three O
deposition O
pHs O
. O

The O
two O
competing O
effects O
give O
rise O
to O
a O
higher O
adhesion O
force O
of O
mfp O
- O
3 O
on O
the O
TiO2 B
surface O
at O
pH O
7 O
. O
5 O
than O
at O
pH O
5 O
. O
5 O
. O

Our O
results O
suggest O
that O
Dopa B
- O
containing O
proteins O
and O
synthetic O
polymers O
have O
great O
potential O
as O
coating O
materials O
for O
medical O
implant O
materials O
, O
particularly O
if O
redox O
activity O
can O
be O
controlled O
. O

Synthetic O
Approaches O
to O
RBC O
Mimicry O
and O
Oxygen B
Carrier O
Systems O
. O

Whole O
blood O
or O
red O
blood O
cell O
( O
RBC O
) O
transfusions O
are O
highly O
significant O
, O
clinically O
, O
for O
blood O
replacement O
therapies O
in O
traumatic O
injuries O
, O
presurgical O
conditions O
, O
and O
anemias O
. O

However O
, O
natural O
RBC O
- O
based O
products O
suffer O
from O
limited O
shelf O
life O
due O
to O
pathological O
contamination O
and O
also O
present O
risks O
of O
refractoriness O
, O
graft O
- O
versus O
- O
host O
disease O
, O
immunosuppression O
, O
and O
acute O
lung O
injury O
. O

These O
issues O
can O
be O
only O
partially O
resolved O
by O
pathogen O
reduction O
technologies O
, O
serological O
blood O
testing O
, O
leukoreduction O
, O
and O
specialized O
storage O
; O
hence O
, O
they O
severely O
affect O
the O
efficacy O
and O
safety O
of O
the O
blood O
products O
. O

Consequently O
, O
there O
is O
a O
significant O
interest O
in O
synthetic O
RBC O
analogues O
that O
can O
mimic O
its O
oxygen B
- O
transport O
properties O
while O
allowing O
convenient O
manufacture O
, O
reproducibility O
, O
long O
shelf O
life O
, O
and O
reduced O
biological O
risks O
. O

To O
this O
end O
, O
the O
current O
Review O
provides O
a O
comprehensive O
description O
and O
discussion O
of O
the O
various O
research O
approaches O
and O
current O
state O
- O
of O
- O
the O
- O
art O
in O
synthetically O
mimicking O
RBC O
' O
s O
oxygen B
- O
carrying O
biochemical O
properties O
, O
as O
well O
as O
the O
biophysical O
parameters O
( O
shape O
, O
size O
and O
mechanical O
modulus O
) O
that O
influence O
RBCs O
' O
hemodynamic O
transport O
properties O
in O
blood O
flow O
. O

Diabetes O
, O
perioperative O
ischaemia O
and O
volatile O
anaesthetics O
: O
consequences O
of O
derangements O
in O
myocardial O
substrate O
metabolism O
. O

Volatile O
anaesthetics O
exert O
protective O
effects O
on O
the O
heart O
against O
perioperative O
ischaemic O
injury O
. O

However O
, O
there O
is O
growing O
evidence O
that O
these O
cardioprotective O
properties O
are O
reduced O
in O
case O
of O
type O
2 O
diabetes O
mellitus O
. O

A O
strong O
predictor O
of O
postoperative O
cardiac O
function O
is O
myocardial O
substrate O
metabolism O
. O

In O
the O
type O
2 O
diabetic O
heart O
, O
substrate O
metabolism O
is O
shifted O
from O
glucose B
utilisation O
to O
fatty B
acid I
oxidation O
, O
resulting O
in O
metabolic O
inflexibility O
and O
cardiac O
dysfunction O
. O

The O
ischaemic O
heart O
also O
loses O
its O
metabolic O
flexibility O
and O
can O
switch O
to O
glucose B
or O
fatty B
acid I
oxidation O
as O
its O
preferential O
state O
, O
which O
may O
deteriorate O
cardiac O
function O
even O
further O
in O
case O
of O
type O
2 O
diabetes O
mellitus O
. O
Recent O
experimental O
studies O
suggest O
that O
the O
cardioprotective O
properties O
of O
volatile O
anaesthetics O
partly O
rely O
on O
changing O
myocardial O
substrate O
metabolism O
. O

Interventions O
that O
target O
at O
restoration O
of O
metabolic O
derangements O
, O
like O
lifestyle O
and O
pharmacological O
interventions O
, O
may O
therefore O
be O
an O
interesting O
candidate O
to O
reduce O
perioperative O
complications O
. O

This O
review O
will O
focus O
on O
the O
current O
knowledge O
regarding O
myocardial O
substrate O
metabolism O
during O
volatile O
anaesthesia O
in O
the O
obese O
and O
type O
2 O
diabetic O
heart O
during O
perioperative O
ischaemia O
. O

Repurposing O
CRISPR O
as O
an O
RNA O
- O
guided O
platform O
for O
sequence O
- O
specific O
control O
of O
gene O
expression O
. O

Targeted O
gene O
regulation O
on O
a O
genome O
- O
wide O
scale O
is O
a O
powerful O
strategy O
for O
interrogating O
, O
perturbing O
, O
and O
engineering O
cellular O
systems O
. O

Here O
, O
we O
develop O
a O
method O
for O
controlling O
gene O
expression O
based O
on O
Cas9 O
, O
an O
RNA O
- O
guided O
DNA O
endonuclease O
from O
a O
type O
II O
CRISPR O
system O
. O

We O
show O
that O
a O
catalytically O
dead O
Cas9 O
lacking O
endonuclease O
activity O
, O
when O
coexpressed O
with O
a O
guide O
RNA O
, O
generates O
a O
DNA O
recognition O
complex O
that O
can O
specifically O
interfere O
with O
transcriptional O
elongation O
, O
RNA O
polymerase O
binding O
, O
or O
transcription O
factor O
binding O
. O

This O
system O
, O
which O
we O
call O
CRISPR O
interference O
( O
CRISPRi O
) O
, O
can O
efficiently O
repress O
expression O
of O
targeted O
genes O
in O
Escherichia O
coli O
, O
with O
no O
detectable O
off O
- O
target O
effects O
. O

CRISPRi O
can O
be O
used O
to O
repress O
multiple O
target O
genes O
simultaneously O
, O
and O
its O
effects O
are O
reversible O
. O

We O
also O
show O
evidence O
that O
the O
system O
can O
be O
adapted O
for O
gene O
repression O
in O
mammalian O
cells O
. O

This O
RNA O
- O
guided O
DNA O
recognition O
platform O
provides O
a O
simple O
approach O
for O
selectively O
perturbing O
gene O
expression O
on O
a O
genome O
- O
wide O
scale O
. O

Novel O
effects O
of O
ectoine B
, O
a O
bacteria O
- O
derived O
natural O
tetrahydropyrimidine B
, O
in O
experimental O
colitis O
. O

Evidence O
suggests O
an O
important O
role O
of O
intestinal O
barrier O
dysfunction O
in O
the O
etiology O
of O
inflammatory O
bowel O
disease O
( O
IBD O
) O
. O

Therefore O
stabilizing O
mucosal O
barrier O
function O
constitutes O
a O
new O
therapeutic O
approach O
in O
its O
management O
. O

Ectoine B
is O
a O
compatible O
solute O
produced O
by O
aerobic O
chemoheterotrophic O
and O
halophilic O
/ O
halotolerant O
bacteria O
, O
where O
it O
acts O
as O
osmoprotectant O
and O
effective O
biomembrane O
stabilizer O
, O
protecting O
the O
producing O
cells O
from O
extreme O
environmental O
stress O
. O

Since O
this O
natural O
compound O
was O
also O
shown O
to O
prevent O
inflammatory O
responses O
associated O
with O
IBD O
, O
its O
potential O
usefulness O
was O
studied O
in O
a O
model O
of O
colitis O
. O

Groups O
of O
rats O
were O
treated O
orally O
with O
different O
doses O
of O
ectoine B
( O
30 O
- O
300mg O
/ O
kg O
) O
or O
sulfasalazine B
( O
reference O
drug O
) O
daily O
for O
11 O
days O
. O

On O
day O
8 O
colitis O
was O
induced O
by O
intracolonic O
instillation O
of O
2 B
, I
4 I
, I
6 I
- I
trinitrobenzenesulfo I
acid I
, O
when O
overt O
signs O
of O
lesions O
develop O
within O
the O
next O
3 O
days O
. O

On O
day O
12 O
, O
blood O
was O
withdrawn O
from O
the O
retro O
- O
orbital O
plexus O
of O
the O
rats O
and O
the O
animals O
were O
sacrificed O
. O

The O
colon O
was O
excised O
and O
examined O
macroscopically O
and O
microscopically O
. O

Relevant O
parameters O
of O
oxidative O
stress O
and O
inflammation O
were O
measured O
in O
serum O
and O
colon O
homogenates O
. O

Induction O
of O
colitis O
led O
to O
marked O
weight O
loss O
, O
significant O
histopathological O
changes O
of O
the O
colon O
, O
and O
variable O
changes O
in O
levels O
of O
myeloperoxidase O
, O
reduced B
glutathione I
, O
malondialdehyde B
, O
and O
all O
inflammatory O
markers O
tested O
. O

Treatment O
with O
ectoine B
ameliorated O
the O
inflammatory O
changes O
in O
TNBS O
- O
induced O
colitis O
. O

This O
effect O
was O
associated O
with O
reduction O
in O
the O
levels O
of O
TNF O
- O
alpha O
, O
IL O
- O
1 O
beta O
, O
ICAM O
- O
1 O
, O
PGE2 B
and O
LTB4 B
. O

The O
findings O
suggest O
that O
intestinal O
barrier O
stabilizers O
from O
natural O
sources O
could O
offer O
new O
therapeutic O
measures O
for O
the O
management O
of O
IBD O
. O

Cytotoxic O
effect O
of O
leaf O
essential O
oil O
of O
Lippia O
gracilis O
Schauer O
( O
Verbenaceae O
) O
. O

Medicinal O
plants O
are O
one O
of O
the O
most O
important O
sources O
of O
drugs O
used O
in O
the O
pharmaceutical O
industry O
. O

Among O
traditional O
medicinal O
plants O
, O
Lippia O
gracilis O
Schauer O
( O
Verbenaceae O
) O
had O
been O
used O
for O
several O
medicinal O
purposes O
in O
Brazilian O
northeastern O
. O

In O
this O
study O
, O
leaf O
essential O
oil O
( O
EO O
) O
of O
L O
. O
gracilis O
was O
prepared O
using O
hydrodistillation O
. O

Followed O
by O
GC O
- O
MS O
analysis O
, O
its O
composition O
was O
characterized O
by O
the O
presence O
of O
thymol B
( O
55 O
. O
50 O
% O
) O
, O
as O
major O
constituent O
. O

The O
effects O
of O
EO O
on O
cell O
proliferation O
and O
apoptosis O
induction O
were O
investigated O
in O
HepG2 O
cells O
. O

Furthermore O
, O
mice O
bearing O
Sarcoma O
180 O
tumor O
cells O
were O
used O
to O
confirm O
its O
in O
vivo O
effectiveness O
. O

EO O
and O
its O
constituents O
( O
thymol B
, O
p B
- I
cymene I
, O
gamma B
- I
terpinene I
and O
myrcene B
) O
displayed O
cytotoxicity O
to O
different O
tumor O
cell O
lines O
. O

EO O
treatment O
caused O
G1 O
arrest O
in O
HepG2 O
cells O
accompanied O
by O
the O
induction O
of O
DNA O
fragmentation O
without O
affecting O
cell O
membrane O
integrity O
. O

Cell O
morphology O
consistent O
with O
apoptosis O
and O
a O
remarkable O
activation O
of O
caspase O
- O
3 O
were O
also O
observed O
, O
suggesting O
induction O
of O
caspase O
- O
dependent O
apoptotic O
cell O
death O
. O

In O
vivo O
antitumor O
study O
showed O
tumor O
growth O
inhibition O
rates O
of O
38 O
. O
5 O
- O
41 O
. O
9 O
% O
. O

In O
conclusion O
, O
the O
tested O
essential O
oil O
of O
L O
. O
gracilis O
leaves O
, O
which O
has O
thymol B
as O
its O
major O
constituent O
, O
possesses O
significant O
in O
vitro O
and O
in O
vivo O
antitumor O
activity O
. O

These O
data O
suggest O
that O
leaf O
essential O
oil O
of O
L O
. O
gracilis O
is O
a O
potential O
medicinal O
resource O
. O

A O
mitochondrial O
ribosomal O
and O
RNA O
decay O
pathway O
blocks O
cell O
proliferation O
. O

Proliferating O
cells O
require O
coordinated O
gene O
expression O
between O
the O
nucleus O
and O
mitochondria O
in O
order O
to O
divide O
, O
ensuring O
sufficient O
organelle O
number O
in O
daughter O
cells O
[ O
1 O
] O
. O

However O
, O
the O
machinery O
and O
mechanisms O
whereby O
proliferating O
cells O
monitor O
mitochondria O
and O
coordinate O
organelle O
biosynthesis O
remain O
poorly O
understood O
. O

Antibiotics O
inhibiting O
mitochondrial O
translation O
have O
emerged O
as O
therapeutics O
for O
human O
cancers O
because O
they O
block O
cell O
proliferation O
[ O
2 O
, O
3 O
] O
. O

These O
proliferative O
defects O
were O
attributable O
to O
modest O
decreases O
in O
mitochondrial O
respiration O
[ O
3 O
, O
4 O
] O
, O
even O
though O
tumors O
are O
mainly O
glycolytic O
[ O
5 O
] O
and O
mitochondrial O
respiratory O
chain O
function O
appears O
to O
play O
a O
minor O
role O
in O
cell O
proliferation O
in O
vivo O
[ O
6 O
] O
. O

Here O
we O
challenge O
this O
interpretation O
by O
demonstrating O
that O
one O
class O
of O
antiproliferative O
antibiotic O
induces O
stalled O
mitochondrial O
ribosomes O
, O
which O
triggers O
a O
mitochondrial O
ribosome O
and O
RNA O
decay O
pathway O
. O

Rescue O
of O
the O
stalled O
mitochondrial O
ribosomes O
initiates O
a O
retrograde O
signaling O
response O
to O
block O
cell O
proliferation O
and O
occurs O
prior O
to O
any O
loss O
of O
mitochondrial O
respiration O
. O

The O
loss O
of O
respiratory O
chain O
function O
is O
simply O
a O
downstream O
effect O
of O
impaired O
mitochondrial O
translation O
and O
not O
the O
antiproliferative O
signal O
. O

This O
mitochondrial O
ribosome O
quality O
- O
control O
pathway O
is O
actively O
monitored O
in O
cells O
and O
constitutes O
an O
important O
organelle O
checkpoint O
for O
cell O
division O
. O

High O
rates O
of O
pregnancy O
loss O
by O
subordinates O
leads O
to O
high O
reproductive O
skew O
in O
wild O
golden O
lion O
tamarins O
( O
Leontopithecus O
rosalia O
) O
. O

Across O
taxa O
, O
cooperative O
breeding O
has O
been O
associated O
with O
high O
reproductive O
skew O
. O

Cooperatively O
breeding O
golden O
lion O
tamarins O
( O
Leontopithecus O
rosalia O
) O
were O
long O
thought O
to O
have O
a O
monogynous O
mating O
system O
in O
which O
reproduction O
was O
limited O
to O
a O
single O
dominant O
female O
. O

Subordinates O
with O
few O
reproductive O
opportunities O
delayed O
dispersal O
and O
remained O
in O
the O
natal O
group O
to O
provide O
alloparental O
care O
to O
siblings O
, O
thus O
allowing O
dominant O
reproductive O
females O
to O
meet O
the O
energetic O
needs O
associated O
with O
high O
rates O
of O
reproduction O
and O
successful O
infant O
rearing O
. O

The O
goal O
of O
this O
study O
was O
to O
re O
- O
assess O
monogyny O
in O
wild O
golden O
lion O
tamarin O
groups O
based O
upon O
pregnancy O
diagnoses O
that O
used O
non O
- O
invasive O
enzyme O
immunoassay O
for O
progesterone B
and O
cortisol B
, O
combined O
with O
weekly O
data O
on O
individual O
weight O
gain O
, O
bi O
- O
annual O
physical O
examinations O
noting O
pregnancy O
and O
lactation O
status O
and O
daily O
behavioral O
observations O
. O

We O
established O
quantitative O
and O
qualitative O
criteria O
to O
detect O
and O
determine O
the O
timing O
of O
pregnancies O
that O
did O
not O
result O
in O
the O
birth O
of O
infants O
. O

Pregnancy O
polygyny O
occurred O
in O
83 O
% O
of O
golden O
lion O
tamarin O
groups O
studied O
. O

The O
loss O
of O
64 O
% O
of O
subordinate O
pregnancies O
compared O
to O
only O
15 O
% O
by O
dominant O
females O
limited O
reproductive O
success O
mainly O
to O
dominant O
females O
, O
thus O
maintaining O
high O
reproductive O
skew O
in O
female O
golden O
lion O
tamarins O
. O

Pregnancy O
loss O
by O
subordinate O
adults O
did O
not O
appear O
to O
result O
from O
dominant O
interference O
in O
subordinate O
hormonal O
mechanisms O
, O
but O
more O
likely O
resulted O
from O
subordinate O
abandonment O
of O
newborn O
infants O
to O
mitigate O
dominant O
aggression O
. O

Synthesis O
of O
novel O
2 B
- I
amino I
- I
4 I
- I
( I
5 I
' I
- I
substituted I
2 I
' I
- I
phenyl I
- I
1H I
- I
indol I
- I
3 I
' I
- I
yl I
) I
- I
6 I
- I
aryl I
- I
4H I
- I
pyran I
- I
3 I
- I
carbonitrile I
derivatives O
as O
antimicrobial O
and O
antioxidant O
agents O
. O

As O
a O
part O
of O
systematic O
investigation O
of O
synthesis O
and O
biological O
activities O
of O
indole B
analogues O
linked O
to O
various O
heterocyclic O
systems O
, O
we O
have O
synthesized O
new O
compounds O
viz O
. O
, O
2 B
- I
amino I
- I
4 I
- I
( I
5 I
' I
- I
substituted I
2 I
' I
- I
phenyl I
- I
1H I
- I
indol I
- I
3 I
' I
- I
yl I
) I
- I
6 I
- I
aryl I
- I
4H I
- I
pyran I
- I
3 I
- I
carbonitriles I
( O
2a O
- O
i O
) O
, O
4 B
, I
5 I
- I
diamino I
- I
6 I
- I
( I
5 I
' I
- I
substituted I
2 I
' I
- I
phenyl I
- I
1H I
- I
indol I
- I
3 I
' I
- I

yl I
) I
- I
8 I
- I
aryl I
- I
2 I
- I
oxo I
- I
2 I
, I
6 I
- I
dihydrodipyrano I
[ I
2 I
, I
3 I
- I
b I
: I
3 I
, I
2 I
- I
e I
] I
pyridine I
- I
3 I
- I
carbonitriles I
( O
3a O
- O
i O
) O
, O
4 B
- I
amino I
- I
5 I
- I
( I
5 I
' I
- I
substituted I
2 I
' I
- I
phenyl I
- I
1H I
- I
indol I
- I
3 I
- I
yl I
) I
- I
7 I
- I
aryl I
- I
1H I
- I
pyrano I
[ I
2 I
, I
3 I
- I
d I
] I
pyrimidin I
- I
2 I
( I
5H I
) I
- I
ones I
( O
4a O
- O
i O
) O
, O

4 B
- I
amino I
- I
5 I
- I
( I
5 I
' I
- I
substituted I
2 I
' I
- I
phenyl I
- I
1H I
- I
indol I
- I
3 I
' I
- I
yl I
) I
- I
7 I
- I
aryl I
- I
1H I
- I
pyrano I
[ I
2 I
, I
3 I
- I
d I
] I
pyrimidin I
- I
2 I
( I
5H I
) I
- I
thiones I
( O
5a O
- O
i O
) O
, O
4 B
- I
( I
5 I
' I
- I
subtituted I
2 I
' I
- I
phenyl I
- I
1H I
- I
indol I
- I
3 I
' I
- I
yl I
) I
- I
6 I
- I
aryl I
- I
1 I
, I
4 I
- I
dihydropyrano I
[ I
2 I
, I
3 I
- I
c I
] I

pyrazol I
- I
3 I
- I
amines I
( O
6a O
- O
i O
) O
and O
5 B
- I
( I
5 I
' I
- I
substituted I
2 I
' I
- I
phenyl I
- I
1H I
- I
indol I
- I
3 I
' I
- I
yl I
) I
- I
7 I
- I
aryl I
- I
3H I
- I
pyrano I
[ I
2 I
, I
3 I
- I
d I
] I
pyrimidin I
- I
4 I
( I
5H I
) I
- I
ones I
( O
7a O
- O
i O
) O
. O

Antibacterial O
activity O
results O
revealed O
that O
, O
compound O
6a O
showed O
promising O
activity O
versus O
Escherichia O
coli O
, O
Staphylococcus O
aureus O
and O
Klebsiella O
pneumoniae O
. O

Compound O
6d O
exhibited O
good O
activity O
against O
S O
. O
aureus O
, O
K O
. O
pneumoniae O
and O
Pseudomonas O
aeruginosa O
. O

Antifungal O
activity O
results O
indicated O
that O
, O
compound O
4d O
exhibited O
maximum O
zone O
of O
inhibition O
against O
Aspergillus O
oryzae O
and O
Aspergillus O
flavus O
. O

In O
case O
of O
antioxidant O
activity O
, O
compound O
4a O
showed O
promising O
radical O
scavenging O
activity O
, O
ferric B
ions O
( O
Fe B
( I
3 I
+ I
) I
) O
reducing O
antioxidant O
power O
( O
FRAP O
) O
and O
metal O
chelating O
activity O
. O

Antiproliferative O
effect O
of O
two O
novel O
COX O
- O
2 O
inhibitors O
on O
human O
keratinocytes O
. O

Selective O
COX O
- O
2 O
inhibitors O
( O
COXib O
) O
belonging O
to O
the O
class O
of O
diaryl B
heterocycles O
( O
e O
. O
g O
. O
, O
celecoxib B
, O
rofecoxib B
, O
etc O
. O
) O
, O
are O
devoid O
of O
the O
undesirable O
effects O
due O
to O
their O
capacity O
to O
inhibit O
selectively O
inducible O
( O
COX O
- O
2 O
) O
, O
responsible O
for O
inflammatory O
effects O
but O
not O
constitutive O
cyclooxygenase O
- O
1 O
( O
COX O
- O
1 O
) O
( O
COX O
) O
; O
responsible O
for O
cytoprotective O
effects O
on O
gastric O
mucosa O
. O

In O
addition O
, O
several O
reports O
have O
identified O
an O
increased O
risk O
of O
cardiovascular O
events O
associated O
with O
the O
use O
of O
COXib O
. O

We O
have O
developed O
a O
new O
series O
of O
anti O
- O
inflammatory O
agents O
( O
1 B
, I
5 I
- I
diarylpyrrole I
- I
3 I
- I
alkoxyethyl I
esters I
and I
ethers I
) O
. O

To O
evaluate O
the O
effect O
of O
two O
1 B
, I
5 I
- I
diarylpyrrole I
- I
3 I
- I
alkoxyethyl I
ethers I
, O
VA441 B
and O
VA428 B
( O
up O
to O
100 O
mu O
M O
) O
, O
respectively O
, O
in O
comparison O
with O
two O
well O
known O
COXib B
, O
celecoxib B
and O
rofecoxib B
, O
on O
HaCaT O
cell O
( O
keratinocytes O
) O
proliferation O
and O
toxicity O
. O

Crucial O
molecules O
in O
cell O
cycle O
progression O
, O
i O
. O
e O
. O
NF O
kappa O
B O
and O
ERK O
as O
targets O
/ O
mediators O
and O
cyclin O
D1 O
and O
p21 O
Cip1 O
/ O
Kip O
as O
final O
effectors O
were O
evaluated O
by O
Western O
blot O
, O
immunohystochemistry O
and O
q O
- O
PCR O
analysis O
. O

Both O
compounds O
, O
VA441 B
and O
VA428 B
, O
showed O
a O
strong O
inhibition O
of O
cell O
proliferation O
, O
and O
did O
not O
exhibit O
cytotoxicity O
. O

The O
anti O
- O
proliferative O
effect O
was O
accompanied O
by O
a O
strong O
activation O
of O
ERK O
and O
induction O
of O
the O
cell O
cycle O
inhibitor O
p21 O
. O

In O
addition O
, O
there O
was O
a O
clear O
inhibition O
of O
the O
transcription O
factor O
NF O
- O
kappa O
B O
and O
downregulation O
of O
cyclin O
D1 O
, O
with O
enforced O
inhibition O
of O
the O
HaCaT O
cell O
cycle O
progression O
. O

These O
data O
suggest O
that O
compounds O
VA441 B
and O
VA428 B
, O
along O
with O
their O
role O
in O
inhibiting O
COX O
- O
2 O
and O
inflammation O
, O
could O
have O
a O
possible O
therapeutic O
( O
topical O
and O
systemic O
) O
use O
against O
skin O
proliferative O
disorders O
, O
such O
as O
psoriasis O
. O

Role O
of O
oxidative O
stress O
in O
chemical O
allergens O
induced O
skin O
cells O
activation O
. O

Allergic O
contact O
dermatitis O
( O
ACD O
) O
is O
an O
important O
occupational O
and O
environmental O
disease O
caused O
by O
topical O
exposure O
to O
chemical O
allergens O
. O

It O
describes O
the O
adverse O
effects O
that O
may O
results O
when O
exposure O
to O
a O
chemical O
elicits O
a O
T O
cell O
- O
mediated O
inflammatory O
skin O
disease O
. O

The O
ability O
of O
contact O
sensitizers O
to O
induce O
the O
oxidative O
stress O
pathway O
in O
keratinocytes O
and O
dendritic O
cells O
has O
been O
confirmed O
by O
several O
authors O
. O

Reactive O
oxygen B
species O
( O
ROS O
) O
can O
serve O
as O
essential O
second O
messengers O
mediating O
cellular O
responses O
resulting O
in O
immune O
cells O
activation O
. O

Oxidative O
stress O
may O
be O
the O
starter O
point O
, O
as O
it O
leads O
to O
the O
activation O
of O
transcription O
factors O
and O
signaling O
pathways O
, O
including O
NF O
- O
kB O
and O
p38 O
MAPK O
, O
which O
leads O
to O
the O
release O
of O
cytokines O
and O
chemokines O
. O

ROS O
are O
also O
involved O
in O
the O
activation O
of O
the O
NLRP3 O
/ O
NALP3 O
inflammasome O
, O
which O
is O
required O
to O
direct O
the O
proteolytic O
maturation O
of O
inflammatory O
cytokines O
such O
as O
IL O
- O
1 O
beta O
and O
IL O
- O
18 O
, O
which O
are O
all O
integral O
to O
the O
process O
of O
dendritic O
cells O
mobilization O
, O
migration O
and O
functional O
maturation O
. O

Moreover O
, O
emerging O
evidence O
correlates O
ROS O
to O
changes O
in O
the O
constitution O
of O
the O
extracellular O
microenvironment O
found O
to O
facilitate O
ACD O
. O

The O
purpose O
of O
this O
review O
is O
to O
provide O
both O
conceptual O
and O
technical O
frameworks O
on O
the O
role O
of O
oxidative O
stress O
in O
chemical O
allergy O
. O

Relative O
expression O
of O
cholesterol B
transport O
- O
related O
proteins O
and O
inflammation O
markers O
through O
the O
induction O
of O
7 B
- I
ketosterol I
- O
mediated O
stress O
in O
Caco O
- O
2 O
cells O
. O

Human O
diets O
contain O
sterol B
oxidation O
products O
that O
can O
induce O
cytotoxic O
effects O
, O
mainly O
caused O
by O
cholesterol B
oxides I
. O

However O
, O
phytosterol B
oxides I
effects O
have O
been O
less O
extensively O
investigated O
. O

This O
study O
evaluates O
the O
production O
of O
inflammatory O
biomarkers O
( O
IL O
- O
1 O
beta O
, O
IL O
- O
8 O
, O
IL O
- O
10 O
, O
TNF O
alpha O
) O
and O
the O
influence O
of O
gene O
expression O
transporters O
and O
enzymes O
related O
to O
cholesterol B
absorption O
and O
metabolism O
( O
NPC1L1 O
, O
ABCG5 O
/ O
8 O
, O
HMGCoA O
, O
ACAT O
) O
produced O
by O
7 B
- I
ketosterols I
( O
stigmasterol B
/ O
cholesterol B
) O
in O
Caco O
- O
2 O
cells O
. O

These O
effects O
were O
linked O
to O
intracellular O
signaling O
pathways O
by O
using O
several O
inhibitors O
. O

Results O
showed O
7 B
- I
ketostigmasterol I
to O
have O
a O
greater O
proinflammatory O
potential O
than O
7 B
- I
ketocholesterol I
. O

In O
non O
- O
pre O
- O
treated O
cells O
, O
only O
efflux O
transporters O
were O
down O
- O
regulated O
by O
7 B
- I
ketosterols I
, O
showing O
a O
greater O
influence O
upon O
ABCG5 O
expression O
. O

Cell O
- O
pre O
- O
incubation O
with O
bradykinin B
induced O
changes O
in O
ABCG O
expression O
levels O
after O
7 B
- I
ketostigmasterol I
- O
incubation O
; O
however O
, O
the O
energetic O
metabolism O
inhibition O
reduced O
NPC1L1 O
expression O
only O
in O
7 B
- I
ketocholesterol I
- O
incubated O
cells O
. O

In O
non O
- O
pre O
- O
treated O
cells O
, O
HMG B
- I
CoA I
was O
up O
- O
regulated O
by O
both O
7 B
- I
ketosterols I
. O

However O
, O
exposure O
to O
inhibitors O
down O
- O
regulated O
the O
expression O
levels O
, O
mainly O
in O
7 B
- I
ketocholesterol I
- O
incubated O
cells O
. O

While O
ACAT O
expression O
values O
in O
non O
- O
pre O
- O
treated O
cells O
were O
unchanged O
, O
exposure O
to O
inhibitors O
caused O
down O
- O
regulation O
of O
mRNA O
levels O
. O

These O
results O
suggest O
that O
internalization O
and O
excretion O
of O
7 B
- I
ketostigmasterol I
is O
probably O
influenced O
by O
[ O
Ca B
] O
i O
, O
which O
also O
could O
mediate O
HMGCoA O
activity O
in O
POPs O
metabolism O
. O

However O
, O
energetic O
metabolism O
and O
reducing O
equivalents O
exert O
different O
influences O
upon O
the O
7 B
- I
ketosterol I
internalization O
. O

Neuroprotective O
effects O
of O
neolignans B
isolated O
from O
Magnoliae O
Cortex O
against O
glutamate B
- O
induced O
apoptotic O
stimuli O
in O
HT22 O
cells O
. O

In O
the O
course O
of O
screening O
for O
neuroprotective O
natural O
products O
, O
Magnoliae O
Cortex O
showed O
potent O
inhibition O
of O
hippocampal O
neuronal O
HT22 O
cell O
death O
. O

Obovatol B
, O
honokiol B
, O
and O
magnolol B
were O
isolated O
from O
the O
ethanolic O
extract O
of O
Magnoliae O
Cortex O
. O

Isolated O
compounds O
obovatol B
, O
honokiol B
, O
and O
magnolol B
were O
protective O
against O
5mM O
glutamate B
- O
induced O
cell O
death O
. O

When O
cells O
were O
stressed O
using O
glutamate B
, O
cell O
viability O
decreased O
to O
16 O
. O
98 O
+ O
/ O
- O
4 O
. O
58 O
% O
over O
the O
control O
( O
100 O
. O
00 O
+ O
/ O
- O
10 O
. O
15 O
% O
) O
. O

In O
contrast O
, O
10 O
mu O
M O
obovatol B
, O
10 O
mu O
M O
honokiol B
, O
and O
50 O
mu O
M O
magnolol B
increased O
cell O
viability O
to O
91 O
. O
80 O
+ O
/ O
- O
1 O
. O
70 O
% O
, O
93 O
. O
59 O
+ O
/ O
- O
1 O
. O
93 O
% O
, O
and O
85 O
. O
36 O
+ O
/ O
- O
7 O
. O
40 O
% O
, O
respectively O
. O

The O
neuroprotective O
effects O
of O
obovatol B
and O
honokiol B
were O
attributable O
to O
the O
inhibition O
of O
intracellular O
reactive O
oxygen B
species O
production O
, O
followed O
by O
protection O
of O
the O
mitochondrial O
membrane O
potential O
( O
Delta O
Psi O
m O
) O
, O
recovery O
of O
Bcl O
- O
2 O
and O
Bid O
levels O
, O
inhibition O
of O
apoptosis O
- O
inducing O
factor O
expression O
, O
and O
phosphorylation O
of O
mitogen O
- O
activated O
protein O
kinases O
such O
as O
p38 O
kinases O
, O
extracellular O
signal O
- O
regulated O
kinases O
, O
and O
c O
- O
Jun O
N B
- O
terminal O
kinases O
. O

On O
the O
contrary O
, O
magnolol B
did O
not O
show O
any O
significant O
effect O
on O
the O
Delta O
Psi O
m O
and O
apoptotic O
factors O
. O

Among O
three O
compounds O
, O
obovatol B
most O
strongly O
scavenged O
2 B
, I
2 I
- I
diphenyl I
- I
1 I
- I
picrylhydrazyl I
radicals O
and O
inhibited O
the O
elevation O
of O
intracellular O
reactive O
oxygen B
species O
levels O
in O
glutamate B
- O
stressed O
HT22 O
cells O
. O

These O
data O
suggest O
that O
obovatol B
and O
honokiol B
may O
have O
clinical O
applications O
for O
preventing O
neurodegenerative O
disorders O
. O

Inhibition O
of O
angiogenesis O
and O
invasion O
by O
DMBT B
is O
mediated O
by O
downregulation O
of O
VEGF O
and O
MMP O
- O
9 O
through O
Akt O
pathway O
in O
MDA O
- O
MB O
- O
231 O
breast O
cancer O
cells O
. O

Invasion O
, O
either O
directly O
or O
via O
metastasis O
formation O
, O
is O
the O
main O
cause O
of O
death O
in O
cancer O
patients O
, O
development O
of O
efficient O
anti O
- O
invasive O
agents O
is O
an O
important O
research O
challenge O
. O

In O
order O
to O
obtain O
more O
potent O
inhibitors O
, O
a O
series O
of O
brartemicin B
analogs O
were O
synthesized O
and O
evaluated O
for O
their O
inhibitory O
activity O
against O
invasion O
. O

Among O
the O
synthetic O
analogs O
tested O
, O
DMBT B
, O
6 B
, I
6 I
' I
- I
bis I
( I
2 I
, I
3 I
- I
dimethoxybenzoyl I
) I
- I
a I
, I
a I
- I
d I
- I
trehalose I
, O
was O
found O
to O
be O
the O
most O
potent O
anti O
- O
invasive O
agent O
. O

But O
the O
effects O
of O
DMBT B
on O
breast O
cancer O
cells O
were O
not O
known O
. O

In O
this O
study O
, O
the O
effects O
of O
DMBT B
on O
invasion O
and O
metastasis O
in O
MDA O
- O
MB O
- O
231 O
cells O
were O
investigated O
. O

MTT B
assay O
showed O
that O
no O
obvious O
inhibitory O
or O
cytotoxic O
effect O
of O
DMBT B
was O
found O
. O

DMBT B
could O
inhibit O
invasion O
, O
migration O
and O
tube O
formation O
of O
HUVECs O
. O

Gelatin O
zymography O
showed O
that O
DMBT O
inhibited O
secretion O
and O
activity O
of O
MMP O
- O
9 O
. O

Western O
blotting O
demonstrated O
that O
DMBT B
effectively O
suppressed O
the O
expression O
of O
VEGF O
, O
p O
- O
VEGFR O
- O
2 O
, O
p O
- O
EGFR O
, O
and O
p O
- O
Akt O
. O

These O
results O
suggested O
that O
DMBT O
could O
inhibit O
invasion O
and O
angiogenesis O
by O
downregulation O
of O
VEGFand O
MMP O
- O
9 O
, O
resulting O
from O
the O
inhibition O
of O
Akt O
pathway O
. O

DMBT B
might O
be O
a O
promising O
lead O
molecule O
for O
the O
anti O
- O
metastasis O
and O
serve O
as O
a O
therapeutic O
agent O
to O
inhibit O
breast O
cancer O
cell O
invasion O
and O
metastasis O
. O

Curcumin B
loaded O
solid O
lipid O
nanoparticles O
: O
An O
efficient O
formulation O
approach O
for O
cerebral O
ischemic O
reperfusion O
injury O
in O
rats O
. O

SCOPE O
: O
To O
evaluate O
curcumin B
loaded O
solid O
lipid O
nanoparticles O
( O
C O
- O
SLNs O
) O
in O
the O
experimental O
paradigm O
of O
cerebral O
ischemia O
( O
BCCAO O
model O
) O
in O
rats O
. O

METHODS O
AND O
RESULTS O
: O
Oral O
administration O
of O
free O
curcumin B
and O
C O
- O
SLNs O
( O
25 O
and O
50mg O
/ O
kg O
) O
was O
started O
5days O
prior O
and O
continued O
for O
3days O
after O
BCCAO O
. O

Alleviation O
in O
behavioral O
, O
oxidative O
and O
nitrosative O
stress O
, O
acetylcholinesterase O
, O
mitochondrial O
enzyme O
complexes O
, O
and O
physiological O
parameters O
were O
assessed O
. O

Confirmation O
of O
effective O
brain O
delivery O
of O
C O
- O
SLNs O
( O
p O
. O
o O
) O
was O
done O
using O
biodistribution O
studies O
in O
mice O
and O
confocal O
microscopy O
of O
rat O
brain O
section O
. O

There O
was O
an O
improvement O
of O
90 O
% O
in O
cognition O
and O
52 O
% O
inhibition O
of O
acetylcholinesterase O
versus O
cerebral O
ischemic O
group O
( O
I O
/ O
R O
) O
. O

Neurological O
scoring O
improved O
by O
79 O
% O
. O

Levels O
of O
superoxide B
dismutase O
, O
catalase O
, O
glutathione B
, O
and O
mitochondrial O
complex O
enzyme O
activities O
were O
significantly O
increased O
, O
while O
lipid O
peroxidation O
, O
nitrite B
, O
and O
acetylcholinesterase O
levels O
decreased O
( O
p O
< O
0 O
. O
05 O
) O
after O
C O
- O
SLNs O
administration O
. O

It O
is O
noteworthy O
to O
report O
the O
restoration O
of O
SOD O
, O
GSH B
, O
catalase O
, O
and O
mitochondrial O
complex O
enzyme O
levels O
equivalent O
to O
sham O
control O
values O
. O

Gamma O
- O
scintigraphic O
studies O
show O
16 O
. O
4 O
and O
30 O
times O
improvement O
in O
brain O
bioavailability O
( O
AUC O
) O
upon O
oral O
and O
i O
. O
v O
administration O
of O
C O
- O
SLNs O
versus O
solubilized O
curcumin B
( O
C O
- O
S O
) O
. O

CONCLUSIONS O
: O
Study O
indicates O
protective O
role O
of O
curcumin B
against O
cerebral O
ischemic O
insult O
; O
provided O
it O
is O
packaged O
suitably O
for O
improved O
brain O
delivery O
. O

Steroids B
excreted O
in O
urine O
by O
neonates O
with O
21 O
- O
hydroxylase O
deficiency O
. O

4 O
. O

Characterization O
, O
using O
GC O
- O
MS O
and O
GC O
- O
MS O
/ O
MS O
, O
of O
11oxo B
- I
pregnanes I
and O
11oxo B
- I
pregnenes I
. O

In O
21 O
- O
hydroxylase O
deficiency O
, O
urinary O
metabolites O
of O
21 B
- I
deoxycortisol I
, O
mainly O
derived O
from O
its O
11oxo O
form O
21 B
- I
deoxycortisone I
, O
are O
indicators O
of O
intra O
- O
adrenal O
overproduction O
of O
17 B
- I
hydroxyprogesterone I
. O

In O
affected O
neonates O
these O
metabolites O
are O
numerous O
and O
most O
have O
not O
been O
previously O
described O
. O

This O
work O
forms O
the O
concluding O
part O
of O
a O
comprehensive O
study O
of O
urinary O
steroids B
, O
aiming O
to O
enhance O
the O
diagnosis O
of O
this O
disorder O
and O
to O
further O
elucidate O
steroid B
metabolism O
in O
neonates O
. O

Cortisol B
metabolites O
found O
in O
untreated O
patients O
, O
similarly O
almost O
exclusively O
present O
in O
their O
11oxo O
form O
in O
neonates O
, O
have O
been O
included O
for O
completeness O
. O

Steroids B
were O
analyzed O
, O
after O
extraction O
and O
enzymatic O
conjugate O
hydrolysis O
, O
as O
methyloxime B
- O
trimethylsilyl B
ether I
derivatives O
on O
gas O
- O
chromatographs O
coupled O
to O
quadrupole O
and O
ion O
- O
trap O
mass O
- O
spectrometers O
. O

GC O
- O
MS O
and O
GC O
- O
MS O
/ O
MS O
spectra O
were O
used O
together O
to O
determine O
the O
structure O
of O
hitherto O
undescribed O
11oxo B
- I
pregnane I
( O
enes B
) O
. O

Few O
GC O
- O
MS O
features O
were O
associated O
with O
the O
presence O
of O
the O
non O
- O
derivatizeable O
11oxo B
group O
in O
pregnane B
( I
ene I
) I
s I
. O

GC O
- O
MS O
/ O
MS O
contributed O
only O
to O
the O
characterization O
of O
structures O
outside O
the O
C O
- O
ring O
, O
as O
described O
in O
the O
preceding O
parts O
of O
this O
study O
. O

Parallels O
were O
found O
between O
the O
metabolism O
of O
21 B
- I
deoxycortisone I
and O
cortisone B
. O

The O
major O
metabolic O
pathway O
was O
that O
of O
classical O
3 O
alpha O
, O
5 O
beta O
- O
reduction O
with O
a O
prominent O
further O
hydroxylation O
, O
predominantly O
at O
C6 O
. O

Oxidation O
of O
the O
6 B
- I
hydroxyl I
was O
also O
common O
. O

We O
conclude O
that O
further O
oxygenated O
metabolites O
of O
21 B
- I
deoxycortisone I
have O
potential O
as O
more O
reliable O
markers O
of O
21 O
- O
hydroxylase O
deficiency O
in O
the O
early O
neonatal O
period O
, O
because O
their O
levels O
are O
higher O
during O
that O
period O
of O
life O
than O
for O
the O
classical O
marker O
11oxo B
- I
pregnanetriol I
. O

In O
vivo O
assessment O
of O
specific O
cytotoxic O
T O
lymphocyte O
killing O
. O

The O
direct O
killing O
of O
target O
cells O
by O
cytotoxic O
T O
lymphocytes O
( O
CTLs O
) O
plays O
a O
fundamental O
role O
in O
protective O
immunity O
to O
viral O
, O
bacterial O
, O
protozoan O
and O
fungi O
infections O
, O
as O
well O
as O
to O
tumor O
cells O
. O

In O
vivo O
cytotoxic O
assays O
take O
into O
account O
the O
interaction O
of O
target O
and O
effector O
cells O
in O
the O
context O
of O
the O
proper O
microenvironment O
making O
the O
analysis O
biologically O
more O
relevant O
than O
in O
vitro O
cytotoxic O
assays O
. O

Thus O
, O
the O
development O
, O
improvement O
and O
validation O
of O
in O
vivo O
methods O
are O
necessary O
in O
view O
of O
the O
importance O
of O
the O
results O
they O
may O
provide O
. O

We O
describe O
and O
discuss O
in O
this O
manuscript O
a O
method O
to O
evaluate O
in O
vivo O
specific O
cytotoxic O
T O
lymphocyte O
killing O
. O

We O
used O
as O
model O
system O
mice O
immunized O
with O
human O
recombinant O
replication O
- O
deficient O
adenovirus O
5 O
( O
HAd5 O
) O
containing O
different O
transgenes O
as O
the O
trigger O
of O
a O
CTL O
- O
mediated O
immune O
response O
. O

To O
these O
mice O
, O
we O
adoptively O
transferred O
syngeneic O
cells O
labeled O
with O
different O
vital O
fluorescent O
dyes O
. O

Donor O
cells O
were O
pulsed O
( O
target O
) O
or O
not O
( O
control O
non O
- O
target O
) O
with O
distinct O
CD8 O
T O
- O
cell O
epitopes O
, O
mixed O
in O
a O
1 O
: O
1 O
ratio O
and O
injected O
i O
. O
v O
. O
into O
immunized O
or O
non O
- O
immunized O
recipient O
mice O
. O

After O
18 O
- O
24h O
, O
spleen O
cells O
are O
collected O
and O
analysed O
by O
flow O
cytometry O
. O

A O
deviation O
from O
the O
1 O
: O
1 O
ratio O
of O
control O
and O
target O
cell O
populations O
indicates O
antigen O
specific O
lysis O
of O
target O
cells O
. O

Protein O
nitration O
promotes O
inducible O
nitric B
oxide I
synthase O
transcription O
mediated O
by O
NF O
- O
kappa O
B O
in O
high O
glucose B
- O
stimulated O
human O
lens O
epithelial O
cells O
. O

Although O
an O
important O
event O
in O
hyperglycaemia O
- O
induced O
oxidative O
stress O
is O
the O
nuclear O
factor O
- O
kappa O
b O
( O
NF O
- O
kappa O
B O
) O
- O
activated O
inducible O
nitric B
oxide I
synthase O
( O
iNOS O
) O
expression O
, O
the O
underlying O
mechanism O
is O
not O
fully O
characterized O
. O

Peroxynitrite B
, O
formed O
from O
NO B
and O
superoxide B
, O
can O
induce O
multiple O
proteins O
nitration O
, O
even O
including O
NF O
- O
kappa O
B O
and O
iNOS O
, O
to O
alter O
their O
functions O
. O

In O
this O
study O
, O
we O
found O
high O
glucose B
caused O
conspicuous O
nitration O
of O
nuclear O
NF O
- O
kappa O
B O
p65 O
and O
its O
co O
- O
activator O
p300 O
in O
human O
lens O
epithelial O
cells O
. O

The O
nitration O
of O
NF O
- O
kappa O
B O
and O
p300 O
promoted O
their O
co O
- O
localization O
and O
binding O
to O
ensure O
the O
activation O
of O
the O
iNOS O
gene O
transcription O
. O

Moreover O
, O
nearly O
all O
predicted O
NF O
- O
kappa O
B O
binding O
sites O
in O
the O
human O
iNOS O
gene O
promoter O
were O
responsive O
to O
high O
glucose B
stimulation O
, O
might O
for O
a O
synergistic O
role O
. O

While O
, O
only O
the O
NF O
- O
kappa O
B O
binding O
site O
- O
5212 O
showed O
significant O
alterations O
by O
high O
glucose B
and O
peroxynitrite B
stimulations O
, O
indicating O
it O
a O
more O
important O
role O
in O
the O
protein O
nitration O
promoted O
iNOS O
gene O
transcription O
. O

Our O
results O
demonstrated O
that O
protein O
nitration O
can O
promote O
the O
NF O
- O
kappa O
B O
- O
activated O
iNOS O
gene O
transcription O
in O
human O
lens O
epithelial O
cells O
by O
high O
glucose B
stimulation O
. O

Effect O
of O
serum O
on O
diesel O
exhaust O
particles O
( O
DEP O
) O
- O
induced O
apoptosis O
of O
airway O
epithelial O
cells O
in O
vitro O
. O

Patients O
with O
chronic O
airway O
diseases O
may O
be O
more O
susceptible O
to O
adverse O
effects O
of O
air O
pollutants O
including O
diesel O
exhaust O
particles O
( O
DEP O
) O
. O

We O
investigated O
effects O
of O
foetal O
calf O
serum O
( O
FCS O
) O
on O
DEP O
- O
induced O
changes O
in O
airway O
epithelial O
cell O
apoptosis O
and O
inflammation O
. O

DEP O
( O
50 O
- O
200 O
mu O
g O
/ O
ml O
) O
increased O
A549 O
cell O
viability O
in O
the O
absence O
of O
FCS O
. O

In O
the O
presence O
of O
3 O
. O
3 O
% O
FCS O
, O
DEP O
( O
50 O
- O
400 O
mu O
g O
/ O
ml O
) O
decreased O
A549 O
cell O
viability O
. O

N B
- I
acetylcysteine I
( O
NAC B
, O
33 O
mM O
) O
and O
the O
c O
- O
jun O
N B
- O
terminal O
kinase O
( O
JNK O
) O
inhibitor O
( O
SP600125 B
, O
33 O
mu O
M O
) O
further O
decreased O
the O
viability O
in O
the O
presence O
of O
DEP O
( O
200 O
mu O
g O
/ O
ml O
) O
and O
3 O
. O
3 O
% O
FCS O
. O

Under O
serum O
- O
free O
( O
SF O
) O
condition O
, O
DEP O
( O
50 O
mu O
g O
/ O
ml O
) O
reduced O
apoptotic O
cells O
; O
however O
, O
when O
3 O
. O
3 O
% O
FCS O
added O
to O
the O
culture O
medium O
, O
this O
effect O
was O
abolished O
. O

DEP O
( O
200 O
mu O
g O
/ O
ml O
) O
induced O
mRNA O
expression O
of O
p21 O
( O
CIP1 O
/ O
WAF1 O
) O
both O
in O
absence O
or O
presence O
of O
3 O
. O
3 O
% O
FCS O
and O
enhanced O
JNK2 O
mRNA O
expression O
only O
in O
the O
presence O
of O
3 O
. O
3 O
% O
FCS O
. O

Under O
SF O
condition O
, O
DEP O
( O
50 O
mu O
g O
/ O
ml O
) O
induced O
mRNA O
expression O
for O
p27 O
and O
p53 O
, O
whereas O
cyclin O
E O
mRNA O
expression O
was O
inhibited O
by O
DEP O
( O
50 O
and O
200 O
mu O
g O
/ O
ml O
) O
. O

Furthermore O
, O
DEP O
( O
200 O
mu O
g O
/ O
ml O
) O
decreased O
the O
release O
of O
interleukin O
( O
IL O
) O
- O
8 O
in O
the O
absence O
of O
FCS O
. O

In O
conclusion O
, O
FCS O
modulates O
effects O
of O
DEP O
on O
cell O
death O
, O
cell O
cycle O
and O
apoptosis O
regulating O
proteins O
, O
and O
IL O
- O
8 O
release O
by O
activating O
oxidant O
stress O
pathways O
, O
JNK O
and O
NF O
- O
kappa O
B O
. O

Extravasation O
of O
serum O
, O
as O
occurs O
in O
the O
inflamed O
airways O
of O
patients O
with O
chronic O
airway O
diseases O
such O
as O
asthma O
and O
COPD O
, O
may O
render O
airway O
epithelial O
cells O
more O
susceptible O
to O
the O
deleterious O
effects O
of O
DEP O
. O

Neuropeptide O
S O
enhances O
memory O
and O
mitigates O
memory O
impairment O
induced O
by O
MK801 B
, O
scopolamine B
or O
A O
beta O
1 O
- O
42 O
in O
mice O
novel O
object O
and O
object O
location O
recognition O
tasks O
. O

Neuropeptide O
S O
( O
NPS O
) O
, O
the O
endogenous O
ligand O
of O
NPSR O
, O
has O
been O
shown O
to O
promote O
arousal O
and O
anxiolytic O
- O
like O
effects O
. O

According O
to O
the O
predominant O
distribution O
of O
NPSR O
in O
brain O
tissues O
associated O
with O
learning O
and O
memory O
, O
NPS O
has O
been O
reported O
to O
modulate O
cognitive O
function O
in O
rodents O
. O

Here O
, O
we O
investigated O
the O
role O
of O
NPS O
in O
memory O
formation O
, O
and O
determined O
whether O
NPS O
could O
mitigate O
memory O
impairment O
induced O
by O
selective O
N B
- I
methyl I
- I
d I
- I
aspartate I
receptor O
antagonist O
MK801 B
, O
muscarinic O
cholinergic O
receptor O
antagonist O
scopolamine B
or O
A O
beta O
1 O
- O
42 O
in O
mice O
, O
using O
novel O
object O
and O
object O
location O
recognition O
tasks O
. O

Intracerebroventricu O
( O
i O
. O
c O
. O
v O
. O
) O
injection O
of O
1 O
nmol O
NPS B
5 O
min O
after O
training O
not O
only O
facilitated O
object O
recognition O
memory O
formation O
, O
but O
also O
prolonged O
memory O
retention O
in O
both O
tasks O
. O

The O
improvement O
of O
object O
recognition O
memory O
induced O
by O
NPS O
could O
be O
blocked O
by O
the O
selective O
NPSR O
antagonist O
SHA B
68 I
, O
indicating O
pharmacological O
specificity O
. O

Then O
, O
we O
found O
that O
i O
. O
c O
. O
v O
. O
injection O
of O
NPS O
reversed O
memory O
disruption O
induced O
by O
MK801 B
, O
scopolamine B
or O
A O
beta O
1 O
- O
42 O
in O
both O
tasks O
. O

In O
summary O
, O
our O
results O
indicate O
that O
NPS O
facilitates O
memory O
formation O
and O
prolongs O
the O
retention O
of O
memory O
through O
activation O
of O
the O
NPSR O
, O
and O
mitigates O
amnesia O
induced O
by O
blockage O
of O
glutamatergic O
or O
cholinergic O
system O
or O
by O
A O
beta O
1 O
- O
42 O
, O
suggesting O
that O
NPS O
/ O
NPSR O
system O
may O
be O
a O
new O
target O
for O
enhancing O
memory O
and O
treating O
amnesia O
. O

Antivenom O
for O
snakebite O
envenoming O
in O
Sri O
Lanka O
: O
The O
need O
for O
geographically O
specific O
antivenom O
and O
improved O
efficacy O
. O

Sri O
Lanka O
is O
a O
tropical O
developing O
island O
nation O
that O
endures O
significant O
economic O
and O
medical O
burden O
as O
a O
result O
of O
snakebite O
envenomation O
, O
having O
not O
only O
a O
high O
prevalence O
of O
envenomations O
, O
but O
also O
one O
of O
the O
highest O
incidence O
rates O
( O
200 O
snakebites O
/ O
100 O
, O
000 O
people O
/ O
year O
) O
of O
venomous O
snakebite O
in O
the O
world O
( O
Kasturiratne O
et O
al O
. O
, O
2005 O
) O
. O

Ironically O
, O
the O
very O
snakes O
responsible O
for O
this O
human O
morbidity O
and O
mortality O
are O
a O
valuable O
a O
biomedical O
and O
ecological O
national O
resource O
, O
despite O
the O
medical O
and O
economic O
consequences O
of O
envenomation O
. O

Currently O
, O
no O
snake O
antivenom O
is O
produced O
using O
venoms O
from O
native O
Sri O
Lankan O
snakes O
as O
immunogens O
, O
and O
there O
is O
a O
true O
need O
for O
an O
efficacious O
Sri O
Lanka O
, O
poly O
- O
specific O
snake O
antivenom O
. O

An O
approach O
to O
fulfilling O
this O
need O
via O
combining O
the O
scientific O
, O
technological O
and O
economical O
resources O
from O
Costa O
Rica O
and O
the O
United O
States O
with O
the O
knowledge O
and O
talent O
of O
Sri O
Lankan O
official O
governmental O
agencies O
, O
legal O
counsels O
, O
environmental O
, O
medical O
and O
veterinary O
academic O
institutions O
, O
and O
religious O
and O
cultural O
leaders O
has O
been O
initiated O
, O
coordinated O
and O
funded O
by O
Animal O
Venom O
Research O
International O
( O
AVRI O
) O
, O
a O
nonprofit O
charity O
. O

This O
bridging O
of O
nations O
and O
the O
cooperative O
pooling O
of O
their O
resources O
represents O
a O
potential O
avenue O
for O
antivenom O
development O
in O
a O
developing O
country O
that O
suffers O
the O
consequences O
of O
few O
specific O
resources O
for O
the O
medical O
management O
of O
venomous O
snakebite O
. O

The O
desired O
final O
outcome O
of O
such O
an O
endeavor O
for O
Sri O
Lanka O
is O
, O
most O
importantly O
, O
improved O
medical O
outcomes O
for O
snakebite O
patients O
, O
with O
enhanced O
and O
expanded O
science O
and O
technology O
relating O
to O
snake O
venoms O
and O
antivenoms O
, O
and O
the O
collateral O
benefits O
of O
reduced O
economic O
cost O
for O
the O
country O
. O

In O
chemico O
evaluation O
of O
prohapten O
skin O
sensitizers O
: O
behavior O
of O
2 B
- I
methoxy I
- I
4 I
- I
( I
( I
1 I
) I
( I
3 I
) I
C I
) I
methylphenol I
in O
the O
peroxidase O
peptide O
reactivity O
assay O
( O
PPRA O
) O
as O
an O
alternative O
to O
animal O
testing O
. O

In O
chemico O
methods O
, O
based O
on O
the O
assessment O
of O
a O
hapten O
' O
s O
reactivity O
toward O
peptides O
, O
have O
been O
proposed O
as O
alternative O
methods O
for O
the O
assessment O
of O
the O
skin O
sensitizing O
potential O
of O
chemicals O
. O

However O
, O
even O
with O
these O
approaches O
showing O
promise O
, O
a O
major O
drawback O
is O
the O
activation O
of O
prohaptens O
, O
i O
. O
e O
. O
molecules O
needing O
a O
metabolic O
activation O
to O
become O
reactive O
and O
therefore O
sensitizing O
. O

Recently O
, O
it O
has O
been O
proposed O
to O
couple O
an O
enzymatic O
activation O
step O
based O
on O
horseradish O
peroxidase O
( O
HRP O
) O
/ O
hydrogen B
peroxide I
to O
such O
peptide O
reactivity O
assays O
. O

To O
evaluate O
this O
approach O
, O
the O
behavior O
of O
2 B
- I
methoxy I
- I
4 I
- I
methylphenol I
( O
2M4MP B
) O
, O
reported O
as O
a O
moderate O
sensitizer O
according O
to O
the O
Local O
Lymph O
Node O
Assay O
( O
LLNA O
) O
, O
has O
been O
investigated O
in O
this O
assay O
. O

To O
follow O
the O
reaction O
with O
the O
peptides O
and O
characterize O
more O
easily O
intermediates O
and O
adducts O
, O
the O
molecule O
was O
first O
( B
13 I
) I
C I
isotopically O
substituted O
at O
the O
most O
probable O
reactive O
position O
. O

When O
2M4MP O
was O
incubated O
with O
HRP O
/ O
H2O2 B
in O
a O
mixture O
PBS O
( O
pH O
7 O
. O
4 O
, O
0 O
. O
1M O
) O
/ O
acetonitrile B
2 O
: O
1 O
, O
two O
main O
products O
were O
formed O
deriving O
from O
the O
formation O
of O
a O
quinone B
methide I
2M4MQ O
subsequently O
trapped O
by O
either O
H2O2 B
or O
H2O B
to O
form O
a O
benzylic B
hydroperoxide I
or I
alcohol I
, O
respectively O
. O

When O
nucleophiles O
such O
as O
GSH B
or O
a O
peptide O
containing O
a O
cysteine B
residue O
( O
Pep O
- O
Cys B
) O
were O
present O
in O
the O
reaction O
medium O
, O
the O
quinone B
methide I
2M4MQ O
was O
trapped O
by O
the O
more O
nucleophilic O
thiol B
function O
to O
form O
thio B
- O
adducts O
. O

No O
modifications O
of O
2M4MP O
were O
observed O
when O
the O
same O
reactions O
were O
carried O
out O
without O
HRP O
confirming O
that O
the O
activation O
of O
the O
molecule O
was O
enzyme O
related O
. O

Amino B
nucleophiles O
were O
shown O
to O
be O
far O
less O
reactive O
towards O
the O
quinone B
methide I
2M4MQ O
with O
only O
tiny O
formation O
of O
adducts O
with O
lysine B
or O
arginine B
side O
chains O
. O

In O
addition O
we O
demonstrated O
that O
the O
same O
enzymatic O
activation O
could O
also O
take O
place O
in O
a O
microemulsion O
based O
on O
sodium B
dodecyl I
sulfate I
/ O
tert B
- I
butanol I
/ O
chloroform B
/ O
buffer O
. O

Which O
metabolites O
circulate O
? O

Characterization O
of O
the O
circulating O
metabolites O
for O
a O
new O
chemical O
entity O
in O
humans O
is O
essential O
for O
safety O
assessment O
, O
an O
understanding O
of O
their O
contributions O
to O
pharmacologic O
activities O
, O
and O
their O
potential O
involvement O
in O
drug O
- O
drug O
interactions O
. O

This O
review O
examines O
the O
abundance O
of O
metabolites O
relative O
to O
the O
total O
parent O
drug O
[ O
metabolite O
- O
to O
- O
parent O
( O
M O
/ O
P O
) O
ratio O
] O
from O
125 O
drugs O
in O
relation O
to O
their O
structural O
and O
physicochemical O
characteristics O
, O
lipoidal O
permeability O
, O
protein O
binding O
, O
and O
fractional O
formation O
from O
parent O
( O
fm O
) O
. O

Our O
analysis O
suggests O
that O
fm O
is O
the O
major O
determinant O
of O
total O
drug O
M O
/ O
P O
ratio O
for O
amine B
, O
alcohol B
, O
N B
- I
and I
S I
- I
oxide I
, O
and O
carboxylic B
acid I
metabolites O
. O

Passage O
from O
the O
hepatocyte O
to O
systemic O
circulation O
does O
not O
appear O
to O
be O
limiting O
owing O
to O
the O
vast O
majority O
of O
metabolites O
formed O
being O
relatively O
lipid O
permeable O
. O

In O
some O
cases O
, O
active O
transport O
plays O
an O
important O
role O
in O
this O
process O
( O
e O
. O
g O
. O
, O
carboxylic B
acid I
metabolites O
) O
. O

Differences O
in O
total O
parent O
drug O
clearance O
and O
metabolite O
clearance O
are O
attenuated O
by O
the O
reduction O
in O
lipophilicity O
introduced O
by O
the O
metabolic O
step O
and O
resultant O
compensatory O
changes O
in O
unbound O
clearance O
and O
protein O
binding O
. O

A O
small O
subclass O
of O
these O
drugs O
( O
e O
. O
g O
. O
, O
terfenadine B
) O
is O
unintentional O
prodrugs O
with O
very O
high O
parent O
drug O
clearance O
, O
resulting O
in O
very O
high O
M O
/ O
P O
ratios O
. O

In O
contrast O
, O
arenol B
metabolites O
show O
a O
more O
complex O
relationship O
with O
fm O
due O
largely O
to O
the O
new O
metabolic O
routes O
( O
conjugation O
) O
available O
to O
the O
metabolite O
compared O
with O
the O
parent O
drug O
molecule O
. O

For O
these O
metabolites O
, O
a O
more O
thorough O
understanding O
of O
the O
elimination O
clearance O
of O
the O
metabolite O
is O
critical O
to O
discern O
the O
likelihood O
of O
whether O
the O
phenol B
will O
constitute O
a O
major O
circulating O
metabolite O
. O

Alternariol B
induces O
abnormal O
nuclear O
morphology O
and O
cell O
cycle O
arrest O
in O
murine O
RAW O
264 O
. O
7 O
macrophages O
. O

The O
mycotoxin O
alternariol B
( O
AOH B
) O
, O
a O
frequent O
contaminant O
in O
fruit O
and O
cereal O
products O
, O
is O
known O
to O
induce O
DNA O
damage O
with O
subsequent O
cell O
cycle O
arrest O
. O

Here O
we O
elucidated O
the O
effects O
of O
AOH B
on O
stages O
of O
cell O
cycle O
progression O
using O
the O
RAW O
264 O
. O
7 O
macrophage O
model O
. O

AOH B
resulted O
in O
an O
accumulation O
of O
cells O
in O
the O
G2 O
/ O
M O
- O
phase O
( O
4N O
) O
. O

Most O
cells O
exhibited O
a O
large O
G2 O
nucleus O
whereas O
numbers O
of O
true O
mitotic O
cells O
were O
reduced O
relative O
to O
control O
. O

Both O
cyclin O
B1 O
and O
p O
- O
cdc2 O
levels O
increased O
, O
while O
cyclin O
B1 O
remained O
in O
the O
cytoplasm O
; O
suggesting O
arrest O
in O
the O
G2 O
/ O
M O
transition O
point O
. O

Remarkably O
, O
after O
exposure O
to O
AOH B
for O
24h O
, O
most O
of O
the O
cells O
exhibited O
abnormally O
shaped O
nuclei O
, O
as O
evidenced O
by O
partly O
divided O
nuclei O
, O
nuclear O
blebs O
, O
polyploidy O
and O
micronuclei O
( O
MN O
) O
. O

AOH B
treatment O
also O
induced O
abnormal O
Aurora O
B O
bridges O
, O
suggesting O
that O
cytokinesis O
was O
interfered O
within O
cells O
undergoing O
karyokinesis O
. O

A O
minor O
part O
of O
the O
resultant O
G1 O
tetraploid O
( O
4N O
) O
cells O
re O
- O
entered O
the O
S O
- O
phase O
and O
progressed O
to O
8N O
cells O
. O

pH O
- O
sensitive O
nanocargo O
based O
on O
smart O
polymer O
functionalized O
graphene B
oxide I
for O
site O
- O
specific O
drug O
delivery O
. O

Graphene B
oxide I
( O
GO O
) O
was O
functionalized O
covalently O
with O
pH O
- O
sensitive O
poly B
( I
2 I
- I
( I
diethylamino I
) I
ethyl I
methacrylate I
) I
( O
PDEA B
) O
by O
surface O
- O
initiated O
in O
situ O
atom O
transfer O
radical O
polymerization O
. O

The O
structure O
of O
the O
PDEA B
- O
grafted O
GO O
( O
GO O
- O
PDEA B
) O
were O
examined O
by O
Fourier O
- O
transform O
infrared O
spectroscopy O
, O
proton O
nuclear O
magnetic O
resonance O
spectroscopy O
, O
X O
- O
ray O
photoelectron O
spectroscopy O
, O
thermogravimetric O
analysis O
and O
atomic O
force O
microscopy O
. O

The O
grafted O
PDEA B
endowed O
the O
GO O
sheets O
with O
good O
solubility O
and O
stability O
in O
physiological O
solutions O
. O

Simple O
physisorption O
by O
pi O
- O
pi O
stacking O
and O
hydrophobic O
interactions O
on O
GO O
- O
PDEA O
can O
be O
used O
to O
load O
camptothecin B
( O
CPT B
) O
, O
a O
widely O
used O
water O
- O
insoluble O
cancer O
drug O
. O

The O
loaded O
CPT B
was O
released O
only O
at O
the O
lower O
( O
acidic O
) O
pH O
normally O
found O
in O
a O
tumor O
environment O
but O
not O
in O
basic O
and O
neutral O
pH O
. O

GO O
- O
PDEA O
did O
not O
show O
practical O
toxicity O
to O
N2a O
cancer O
cells O
but O
the O
GO O
- O
PDEA O
- O
CPT B
complex O
exhibited O
high O
potency O
in O
killing O
N2a O
cancer O
cells O
in O
vitro O
. O

These O
results O
suggest O
that O
the O
GO O
- O
PDEA B
nanocargo O
carrier O
might O
be O
a O
promising O
material O
for O
site O
- O
specific O
anticancer O
drug O
delivery O
and O
controlled O
release O
. O

Revised O
conformational O
assignments O
and O
conformational O
evolution O
of O
tyrosine B
by O
laser O
desorption O
supersonic O
jet O
laser O
spectroscopy O
. O

The O
number O
of O
conformers O
and O
their O
structures O
of O
tyrosine B
are O
reassigned O
on O
the O
basis O
of O
resonance O
enhanced O
multiphoton O
ionization O
( O
REMPI O
) O
, O
ultraviolet O
- O
ultraviolet O
hole O
burning O
( O
UV O
- O
UV O
HB O
) O
, O
infrared O
( O
IR O
) O
dip O
spectra O
, O
and O
quantum O
chemical O
calculations O
. O

From O
comparison O
between O
REMPI O
and O
UV O
- O
UV O
HB O
spectra O
, O
it O
was O
found O
that O
12 O
conformers O
coexist O
in O
the O
supersonic O
jet O
. O

The O
structures O
of O
these O
conformers O
are O
determined O
by O
the O
IR O
spectra O
and O
theoretical O
calculations O
. O

The O
number O
of O
conformers O
is O
more O
than O
that O
reported O
in O
the O
previous O
reports O
( O
8 O
conformers O
) O
, O
and O
is O
rationalized O
by O
the O
systematic O
formation O
of O
conformers O
from O
simpler O
molecules O
without O
substituents O
, O
just O
like O
evolution O
. O

The O
importance O
of O
dipole O
- O
dipole O
interaction O
between O
an O
amino B
- I
acid I
chain O
and O
hydroxyl B
group O
at O
the O
benzene B
ring O
was O
also O
discussed O
. O

Mutant O
B O
- O
RAF O
- O
Mcl O
- O
1 O
survival O
signaling O
depends O
on O
the O
STAT3 O
transcription O
factor O
. O

Approximately O
50 O
% O
of O
melanomas O
depend O
on O
mutant O
B O
- O
RAF O
for O
proliferation O
, O
metastasis O
and O
survival O
. O

The O
inhibition O
of O
oncogenic O
B O
- O
RAF O
with O
highly O
targeted O
compounds O
has O
produced O
remarkable O
albeit O
short O
- O
lived O
clinical O
responses O
in O
B O
- O
RAF O
mutant O
melanoma O
patients O
. O

Reactivation O
of O
signaling O
downstream O
of O
B O
- O
RAF O
is O
frequently O
associated O
with O
acquired O
resistance O
to O
B O
- O
RAF O
inhibitors O
, O
and O
the O
identification O
of O
B O
- O
RAF O
targets O
may O
provide O
new O
strategies O
for O
managing O
melanoma O
. O

Oncogenic O
B O
- O
RAF O
( O
V600E O
) O
is O
known O
to O
promote O
the O
stabilizing O
phosphorylation O
of O
the O
anti O
- O
apoptotic O
protein O
Mcl O
- O
1 O
, O
implicated O
in O
melanoma O
survival O
and O
chemoresistance O
. O

We O
now O
show O
that O
B O
- O
RAF O
( O
V600E O
) O
signaling O
also O
induces O
the O
transcription O
of O
Mcl O
- O
1 O
in O
melanocytes O
and O
melanoma O
. O

We O
demonstrate O
that O
activation O
of O
STAT3 O
serine B
- O
727 O
and O
tyrosine B
- O
705 O
phosphorylations O
is O
promoted O
by O
B O
- O
RAF O
( O
V600E O
) O
activity O
and O
that O
the O
Mcl O
- O
1 O
promoter O
is O
dependent O
on O
a O
STAT O
consensus O
- O
site O
for O
B O
- O
RAF O
- O
mediated O
activation O
. O

Consequently O
, O
suppression O
of O
STAT3 O
activity O
disrupted O
B O
- O
RAF O
( O
V600E O
) O
- O
mediated O
induction O
of O
Mcl O
- O
1 O
and O
reduced O
melanoma O
cell O
survival O
. O

We O
propose O
that O
STAT3 O
has O
a O
central O
role O
in O
the O
survival O
and O
contributes O
to O
chemoresistance O
of O
B O
- O
RAF O
( O
V600E O
) O
melanoma O
. O
Oncogene O
advance O
online O
publication O
, O
4 O
March O
2013 O
; O
doi O
: O
10 O
. O
1038 O
/ O
onc O
. O
2013 O
. O
45 O
. O

Active O
silver B
nanoparticles O
for O
wound O
healing O
. O

In O
this O
preliminary O
study O
, O
the O
silver B
nanoparticle O
( O
Ag B
NP O
) O
- O
based O
dressing O
, O
Acticoat B
( O
TM O
) O
Flex O
3 O
, O
has O
been O
applied O
to O
a O
3D O
fibroblast O
cell O
culture O
in O
vitro O
and O
to O
a O
real O
partial O
thickness O
burn O
patient O
. O

The O
in O
vitro O
results O
show O
that O
Ag B
NPs O
greatly O
reduce O
mitochondrial O
activity O
, O
while O
cellular O
staining O
techniques O
show O
that O
nuclear O
integrity O
is O
maintained O
, O
with O
no O
signs O
of O
cell O
death O
. O

For O
the O
first O
time O
, O
transmission O
electron O
microscopy O
( O
TEM O
) O
and O
inductively O
coupled O
plasma O
mass O
spectrometry O
( O
ICP O
- O
MS O
) O
analyses O
were O
carried O
out O
on O
skin O
biopsies O
taken O
from O
a O
single O
patient O
during O
treatment O
. O

The O
results O
show O
that O
Ag B
NPs O
are O
released O
as O
aggregates O
and O
are O
localized O
in O
the O
cytoplasm O
of O
fibroblasts O
. O

No O
signs O
of O
cell O
death O
were O
observed O
, O
and O
the O
nanoparticles O
had O
different O
distributions O
within O
the O
cells O
of O
the O
upper O
and O
lower O
dermis O
. O

Depth O
profiles O
of O
the O
Ag B
concentrations O
were O
determined O
along O
the O
skin O
biopsies O
. O

In O
the O
healed O
sample O
, O
most O
of O
the O
silver B
remained O
in O
the O
surface O
layers O
, O
whereas O
in O
the O
unhealed O
sample O
, O
the O
silver B
penetrated O
more O
deeply O
. O

The O
Ag B
concentrations O
in O
the O
cell O
cultures O
were O
also O
determined O
. O

Clinical O
observations O
and O
experimental O
data O
collected O
here O
are O
consistent O
with O
previously O
published O
articles O
and O
support O
the O
safety O
of O
Ag O
NP O
- O
based O
dressing O
in O
wound O
treatment O
. O

Assessment O
of O
the O
abuse O
liability O
of O
ABT B
- I
288 I
, O
a O
novel O
histamine B
H3 O
receptor O
antagonist O
. O

RATIONALE O
: O
Histamine B
H3 O
receptor O
antagonists O
, O
such O
as O
ABT B
- I
288 I
, O
have O
been O
shown O
to O
possess O
cognitive O
- O
enhancing O
and O
wakefulness O
- O
promoting O
effects O
. O

On O
the O
surface O
, O
this O
might O
suggest O
that O
H3 O
antagonists O
possess O
psychomotor O
stimulant O
- O
like O
effects O
and O
, O
as O
such O
, O
may O
have O
the O
potential O
for O
abuse O
. O

OBJECTIVES O
: O
The O
aim O
of O
the O
present O
study O
was O
to O
further O
characterize O
whether O
ABT B
- I
288 I
possesses O
stimulant O
- O
like O
properties O
and O
whether O
its O
pharmacology O
gives O
rise O
to O
abuse O
liability O
. O

METHODS O
: O
The O
locomotor O
- O
stimulant O
effects O
of O
ABT B
- I
288 I
were O
measured O
in O
mice O
and O
rats O
, O
and O
potential O
development O
of O
sensitization O
was O
addressed O
. O

Drug O
discrimination O
was O
used O
to O
assess O
amphetamine B
- O
like O
stimulus O
properties O
, O
and O
drug O
self O
- O
administration O
was O
used O
to O
evaluate O
reinforcing O
effects O
of O
ABT B
- I
288 I
. O

The O
potential O
development O
of O
physical O
dependence O
was O
also O
studied O
. O

RESULTS O
: O
ABT B
- I
288 I
lacked O
locomotor O
- O
stimulant O
effects O
in O
both O
rats O
and O
mice O
. O

Repeated O
administration O
of O
ABT B
- I
288 I
did O
not O
result O
in O
cross O
- O
sensitization O
to O
the O
stimulant O
effects O
of O
d B
- I
amphetamine I
in O
mice O
, O
suggesting O
that O
there O
is O
little O
overlap O
in O
circuitries O
upon O
which O
the O
two O
drugs O
interact O
for O
motor O
activity O
. O

ABT B
- I
288 I
did O
not O
produce O
amphetamine B
- O
like O
discriminative O
stimulus O
effects O
in O
drug O
discrimination O
studies O
nor O
was O
it O
self O
- O
administered O
by O
rats O
trained O
to O
self O
- O
administer O
cocaine B
. O

There O
were O
no O
signs O
of O
physical O
dependence O
upon O
termination O
of O
repeated O
administration O
of O
ABT B
- I
288 I
for O
30 O
days O
. O

CONCLUSIONS O
: O
The O
sum O
of O
these O
preclinical O
data O
, O
the O
first O
of O
their O
kind O
applied O
to O
H3 O
antagonists O
, O
indicates O
that O
ABT B
- I
288 I
is O
unlikely O
to O
possess O
a O
high O
potential O
for O
abuse O
in O
the O
human O
population O
and O
suggests O
that O
H3 O
antagonists O
, O
as O
a O
class O
, O
are O
similar O
in O
this O
regard O
. O

Optimized O
templates O
for O
bottom O
- O
up O
growth O
of O
high O
- O
performance O
integrated O
biomolecular O
detectors O
. O

Electrochemical O
deposition O
of O
metals O
represents O
an O
important O
approach O
in O
the O
bottom O
- O
up O
fabrication O
of O
nanostructures O
and O
microstructures O
. O

We O
have O
used O
this O
approach O
to O
generate O
high O
- O
performance O
chip O
- O
based O
biosensors O
using O
silicon B
as O
a O
platform O
for O
the O
generation O
of O
sensor O
arrays O
. O

Here O
, O
we O
explore O
the O
applicability O
of O
different O
materials O
to O
support O
the O
electrodeposition O
and O
identify O
the O
parameters O
that O
are O
essential O
for O
robust O
sensor O
growth O
. O

We O
show O
that O
inexpensive O
materials O
can O
be O
used O
as O
templates O
for O
electrodeposition O
, O
and O
demonstrate O
that O
these O
low O
- O
cost O
sensors O
exhibit O
clinically O
- O
relevant O
levels O
of O
sensitivity O
and O
specificity O
. O

In O
particular O
, O
we O
prove O
herein O
that O
the O
glass O
- O
based O
sensors O
successfully O
detect O
E O
. O
coli O
in O
urine O
, O
when O
present O
at O
the O
100 O
cfu O
mu O
L O
( O
- O
1 O
) O
levels O
found O
typically O
in O
samples O
of O
patients O
with O
urinary O
tract O
infections O
. O

Current O
self O
- O
complianced O
and O
self O
- O
rectifying O
resistive O
switching O
in O
Ag B
- O
electroded O
single O
Na B
- O
doped O
ZnO I
nanowires O
. O

We O
demonstrate O
current O
self O
- O
complianced O
and O
self O
- O
rectifying O
bipolar O
resistive O
switching O
in O
an O
Ag B
- O
electroded O
Na B
- O
doped O
ZnO B
nanowire O
device O
. O

The O
resistive O
switching O
is O
controlled O
by O
the O
formation O
and O
rupture O
of O
an O
Ag B
nanoisland O
chain O
on O
the O
surface O
along O
the O
Na B
- O
doped O
ZnO B
nanowire O
. O

Na B
- O
doping O
plays O
important O
roles O
in O
both O
the O
self O
- O
compliance O
and O
self O
- O
rectifying O
properties O
. O

Mesenchymal O
stem O
cells O
secretome O
: O
a O
new O
paradigm O
for O
central O
nervous O
system O
regeneration O
? O

The O
low O
regeneration O
potential O
of O
the O
central O
nervous O
system O
( O
CNS O
) O
represents O
a O
challenge O
for O
the O
development O
of O
new O
therapeutic O
strategies O
. O

Mesenchymal O
stem O
cells O
( O
MSCs O
) O
have O
been O
proposed O
as O
a O
possible O
therapeutic O
tool O
for O
CNS O
disorders O
. O

In O
addition O
to O
their O
differentiation O
potential O
, O
it O
is O
well O
accepted O
nowadays O
that O
their O
beneficial O
actions O
can O
also O
be O
mediated O
by O
their O
secretome O
. O

Indeed O
, O
it O
was O
already O
demonstrated O
, O
both O
in O
vitro O
and O
in O
vivo O
, O
that O
MSCs O
are O
able O
to O
secrete O
a O
broad O
range O
of O
neuroregulatory O
factors O
that O
promote O
an O
increase O
in O
neurogenesis O
, O
inhibition O
of O
apoptosis O
and O
glial O
scar O
formation O
, O
immunomodulation O
, O
angiogenesis O
, O
neuronal O
and O
glial O
cell O
survival O
, O
as O
well O
as O
relevant O
neuroprotective O
actions O
on O
different O
pathophysiological O
contexts O
. O

Considering O
their O
protective O
action O
in O
lesioned O
sites O
, O
MSCs O
' O
secretome O
might O
also O
improve O
the O
integration O
of O
local O
progenitor O
cells O
in O
neuroregeneration O
processes O
, O
opening O
a O
door O
for O
their O
future O
use O
as O
therapeutical O
strategies O
in O
human O
clinical O
trials O
. O

Thus O
, O
in O
this O
review O
we O
analyze O
the O
current O
understanding O
of O
MSCs O
secretome O
as O
a O
new O
paradigm O
for O
the O
treatment O
of O
CNS O
neurodegenerative O
diseases O
. O

The O
hazardous O
effects O
of O
the O
three O
natural O
food O
dyes O
on O
developmental O
stages O
and O
longevity O
of O
Drosophila O
melanogaster O
. O

Nowadays O
, O
food O
dyes O
obtained O
from O
herbal O
, O
animal O
, O
microbial O
and O
mineral O
sources O
are O
widely O
used O
as O
food O
additives O
. O

In O
this O
study O
, O
the O
toxic O
effects O
of O
three O
different O
natural O
food O
dyes O
( O
carmine B
, O
turmeric O
and O
annatto B
) O
on O
72 O
+ O
/ O
- O
4 O
h O
larvae O
of O
Oregon O
- O
R O
wild O
type O
of O
Drosophila O
melanogaster O
were O
investigated O
. O

For O
this O
purpose O
, O
four O
different O
application O
doses O
( O
50 O
, O
75 O
, O
100 O
, O
125 O
mg O
mL O
( O
- O
1 O
) O
) O
were O
chosen O
by O
means O
of O
preliminary O
studies O
. O

It O
was O
determined O
that O
larval O
mortality O
increased O
with O
increasing O
concentration O
in O
the O
application O
groups O
and O
the O
toxicity O
order O
was O
carmine B
> O
turmeric B
> O
annatto B
. O

It O
was O
observed O
that O
the O
survival O
rate O
was O
highest O
in O
the O
control O
with O
98 O
% O
and O
lowest O
in O
125 O
mg O
mL O
( O
- O
1 O
) O
carmine B
with O
16 O
% O
. O

In O
addition O
, O
the O
average O
lifespan O
of O
the O
adult O
individuals O
obtained O
from O
third O
instar O
larvae O
was O
also O
studied O
. O

While O
the O
average O
lifespan O
was O
40 O
. O
88 O
+ O
/ O
- O
1 O
. O
44 O
days O
in O
the O
control O
group O
, O
these O
values O
were O
10 O
. O
81 O
+ O
/ O
- O
0 O
. O
55 O
- O
23 O
. O
90 O
+ O
/ O
- O
1 O
. O
27 O
days O
in O
the O
carmine B
group O
, O
15 O
. O
00 O
+ O
/ O
- O
0 O
. O
80 O
- O
22 O
. O
42 O
+ O
/ O
- O
1 O
. O
43 O
days O
in O
the O
turmeric O
group O
and O
10 O
. O
33 O
+ O
/ O
- O
1 O
. O
03 O
- O
35 O
. O
68 O
+ O
/ O
- O
1 O
. O
54 O
days O
in O
the O
annatto B
group O
, O
respectively O
. O

According O
to O
the O
obtained O
results O
, O
when O
both O
the O
developmental O
period O
from O
larvae O
into O
adults O
and O
the O
lifespan O
of O
the O
developing O
adults O
were O
compared O
with O
the O
control O
group O
, O
the O
food O
dyes O
were O
found O
to O
be O
toxic O
and O
the O
toxicity O
order O
of O
carmine B
> O
turmeric B
> O
annatto B
was O
identified O
. O

Which O
density O
functional O
is O
close O
to O
CCSD O
accuracy O
to O
describe O
geometry O
and O
interaction O
energy O
of O
small O
non O
- O
covalent O
dimers O
? O

A O
benchmark O
study O
using O
gaussian09 O
. O

A O
benchmark O
study O
on O
all O
possible O
density O
functional O
theory O
( O
DFT O
) O
methods O
in O
Gaussian09 O
is O
done O
to O
locate O
functionals O
that O
agree O
well O
with O
CCSD O
/ O
aug O
- O
cc O
- O
pVTZ O
geometry O
and O
Ave O
- O
CCSD O
( O
T O
) O
/ O
( O
Q O
- O
T O
) O
interaction O
energy O
( O
Eint O
) O
for O
small O
non O
- O
covalently O
interacting O
molecular O
dimers O
in O
" O
dispersion O
- O
dominated O
" O
( O
class O
1 O
) O
, O
" O
dipole O
- O
induced O
dipole O
" O
( O
class O
2 O
) O
, O
and O
" O
dipole O
- O
dipole O
" O
( O
class O
3 O
) O
classes O
. O

A O
DFT O
method O
is O
recommended O
acceptable O
if O
the O
geometry O
showed O
close O
agreement O
to O
CCSD O
result O
( O
RMSD O
< O
0 O
. O
045 O
) O
and O
Eint O
was O
within O
80 O
- O
120 O
% O
accuracy O
. O

Among O
382 O
tested O
functionals O
, O
1 O
- O
46 O
% O
gave O
good O
geometry O
, O
13 O
- O
44 O
% O
gave O
good O
Eint O
, O
while O
1 O
- O
33 O
% O
satisfied O
geometry O
and O
energy O
criteria O
. O

Further O
screening O
to O
locate O
the O
best O
performing O
functionals O
for O
all O
the O
three O
classes O
was O
made O
by O
counting O
the O
acceptable O
values O
of O
energy O
and O
geometry O
given O
by O
each O
functionals O
. O

The O
meta O
- O
generalized O
gradient O
approximation O
( O
GGA O
) O
functional O
M06L O
was O
the O
best O
performer O
with O
total O
14 O
hits O
; O
seven O
acceptable O
energies O
and O
seven O
acceptable O
geometries O
. O

This O
was O
the O
only O
functional O
" O
recommended O
" O
for O
at O
least O
two O
dimers O
in O
each O
class O
. O

The O
functionals O
M05 O
, O
B2PLYPD O
, O
B971 O
, O
mPW2PLYPD O
, O
PBEB95 O
, O
and O
CAM O
- O
B3LYP O
gave O
11 O
hits O
while O
PBEhB95 O
, O
PW91B95 O
, O
Wb97x O
, O
BRxVP86 O
, O
BRxP86 O
, O
HSE2PBE O
, O
HSEh1PBE O
, O
PBE1PBE O
, O
PBEh1PBE O
, O
and O
PW91TPSS O
gave O
10 O
hits O
. O

Among O
these O
, O
M05 O
, O
B971 O
, O
mPW2PLYPD O
, O
Wb97x O
, O
and O
PW91TPSS O
were O
among O
the O
" O
recommended O
" O
list O
of O
at O
least O
one O
dimer O
from O
each O
class O
. O

Long O
- O
range O
correction O
( O
LC O
) O
of O
Hirao O
and O
coworkers O
to O
exchange O
- O
correlation O
functionals O
showed O
massive O
improvement O
in O
geometry O
and O
Eint O
. O

The O
best O
performing O
LC O
- O
functionals O
were O
LC O
- O
G96KCIS O
and O
LC O
- O
PKZBPKZB O
. O

Our O
results O
predict O
that O
M06L O
is O
the O
most O
trustworthy O
DFT O
method O
in O
Gaussian09 O
to O
study O
small O
non O
- O
covalently O
interacting O
systems O
. O

( O
c O
) O
2013 O
Wiley O
Periodicals O
, O
Inc O
. O

Unusual O
amino B
acids I
and O
monofluoroacetate B
from O
Dichapetalum O
michelsonii O
( O
Umutambasha O
) O
, O
a O
toxic O
plant O
from O
Rwanda O
. O

In O
the O
course O
of O
our O
investigations O
on O
Umutambasha O
in O
order O
to O
identify O
its O
convulsant O
principles O
, O
small O
quantities O
of O
monofluoroacetate B
were O
observed O
in O
stem O
bark O
, O
leaves O
, O
and O
fruits O
of O
this O
plant O
newly O
identified O
as O
Dichapetalum O
michelsonii O
Hauman O
. O

Conclusive O
evidence O
for O
a O
monofluoroacetate B
presence O
came O
from O
its O
isolation O
from O
the O
freeze O
- O
dried O
extract O
of O
stem O
bark O
. O

Three O
free O
unusual O
amino B
acids I
, O
named O
N B
- I
methyl I
- I
alpha I
- I
alanine I
, O
N B
- I
methyl I
- I
beta I
- I
alanine I
, O
and O
2 B
, I
7 I
- I
diaminooctan I
- I
1 I
, I
8 I
- I
dioic I
acid I
, O
described O
for O
the O
first O
time O
in O
a O
plant O
, O
and O
known O
trigonelline B
were O
also O
isolated O
from O
the O
stem O
bark O
of O
D O
. O
michelsonii O
. O

Structure O
elucidations O
were O
mainly O
achieved O
by O
spectroscopic O
methods O
( O
1H B
- O
NMR O
, O
2D O
- O
NMR O
, O
MS O
) O
and O
by O
comparison O
with O
authentic O
references O
. O

These O
unusual O
amino B
acids I
were O
detected O
by O
a O
fast O
, O
reliable O
TLC O
analysis O
in O
all O
our O
batches O
of O
Umutambasha O
, O
suggesting O
that O
they O
could O
be O
used O
for O
identification O
purposes O
in O
case O
of O
human O
or O
livestock O
intoxications O
. O

Finally O
, O
EEG O
recordings O
and O
behavioural O
observations O
performed O
in O
mice O
suggested O
that O
the O
convulsive O
patterns O
produced O
by O
Umutambasha O
are O
the O
consequence O
of O
monofluoroacetate B
presence O
in O
D O
. O
michelsonii O
. O

Robust O
Synthesis O
of O
Gold O
Cubic O
Nanoframes O
through O
a O
Combination O
of O
Galvanic O
Replacement O
, O
Gold O
Deposition O
, O
and O
Silver B
Dealloying O
. O

A O
facile O
, O
robust O
approach O
to O
the O
synthesis O
of O
Au B
cubic O
nanoframes O
is O
described O
. O

The O
synthesis O
involves O
three O
major O
steps O
: O
1 O
) O
preparation O
of O
Au B
- I
Ag I
alloyed O
nanocages O
using O
a O
galvanic O
replacement O
reaction O
between O
Ag B
nanocubes O
and O
HAuCl4 B
; O
2 O
) O
deposition O
of O
thin O
layers O
of O
pure O
Au B
onto O
the O
surfaces O
of O
the O
nanocages O
by O
reducing O
HAuCl4 B
with O
ascorbic B
acid I
, O
and O
; O
3 O
) O
formation O
of O
Au B
cubic O
nanoframes O
through O
a O
dealloying O
process O
with O
HAuCl4 B
. O

The O
key O
to O
the O
formation O
of O
Au B
cubic O
nanoframes O
is O
to O
coat O
the O
surfaces O
of O
the O
Au B
- I
Ag I
nanocages O
with O
sufficiently O
thick O
layers O
of O
Au B
before O
they O
are O
dealloyed O
. O

The O
Au B
layer O
could O
prevent O
the O
skeleton O
of O
a O
nanocage O
from O
being O
fragmented O
during O
the O
dealloying O
step O
. O

The O
as O
- O
prepared O
Au B
cubic O
nanoframes O
exhibit O
tunable O
localized O
surface O
plasmon O
resonance O
peaks O
in O
the O
near O
- O
infrared O
region O
, O
but O
with O
much O
lower O
Ag B
content O
as O
compared O
with O
the O
initial O
Au B
- I
Ag I
nanocages O
. O

Prenatal O
bisphenol B
a I
exposure O
alters O
sex O
- O
specific O
estrogen B
receptor O
expression O
in O
the O
neonatal O
rat O
hypothalamus O
and O
amygdala O
. O

Bisphenol B
A I
( O
BPA B
) O
exposure O
is O
ubiquitous O
, O
and O
in O
laboratory O
animals O
, O
early O
- O
life O
BPA B
exposure O
has O
been O
shown O
to O
alter O
sex O
- O
specific O
neural O
organization O
, O
neuroendocrine O
physiology O
, O
and O
behavior O
. O

The O
specific O
mechanisms O
underlying O
these O
brain O
- O
related O
outcomes O
, O
however O
, O
remain O
largely O
unknown O
, O
constraining O
the O
capacity O
to O
ascertain O
the O
potential O
human O
relevance O
of O
neural O
effects O
observed O
in O
animal O
models O
. O

In O
the O
perinatal O
rat O
brain O
, O
estrogen B
is O
masculinizing O
, O
suggesting O
that O
BPA B
- O
induced O
perturbation O
of O
estrogen B
receptor O
( O
ESR O
) O
expression O
may O
underpin O
later O
in O
- O
life O
neuroendocrine O
effects O
. O

We O
hypothesized O
that O
prenatal O
BPA B
exposure O
alters O
sex O
- O
specific O
ESR1 O
( O
ER O
alpha O
) O
and O
ESR2 O
( O
ER O
beta O
) O
expression O
in O
postnatal O
limbic O
nuclei O
. O

Sprague O
Dawley O
rats O
were O
mated O
and O
gavaged O
on O
gestational O
days O
( O
GDs O
) O
6 O
- O
21 O
with O
vehicle O
, O
2 O
. O
5 O
or O
25 O
mu O
g O
/ O
kg O
bw O
/ O
day O
BPA B
, O
or O
5 O
or O
10 O
mu O
g O
/ O
kg O
bw O
/ O
day O
ethinyl B
estradiol I
. O

An O
additional O
group O
was O
restrained O
but O
not O
gavaged O
( O
na O
i O
ve O
control O
) O
. O

Offspring O
were O
sacrificed O
the O
day O
after O
birth O
to O
quantify O
ESR O
gene O
expression O
throughout O
the O
hypothalamus O
and O
amygdala O
by O
in O
situ O
hybridization O
. O

Relative O
to O
the O
vehicle O
group O
, O
significant O
effects O
of O
BPA B
were O
observed O
on O
ESR1 O
and O
ESR2 O
expression O
throughout O
the O
mediobasal O
hypothalamus O
and O
amygdala O
in O
both O
sexes O
. O

Significant O
differences O
in O
ESR O
expression O
were O
also O
observed O
in O
the O
mediobasal O
hypothalamus O
and O
amygdala O
of O
the O
na O
i O
ve O
control O
group O
compared O
with O
the O
vehicle O
group O
, O
highlighting O
the O
potential O
for O
gavage O
to O
influence O
gene O
expression O
in O
the O
developing O
brain O
. O

These O
results O
indicate O
that O
ESR O
expression O
in O
the O
neonatal O
brain O
of O
both O
sexes O
can O
be O
altered O
by O
low O
- O
dose O
prenatal O
BPA B
exposure O
. O

Ultrasensitive O
optical O
shape O
characterization O
of O
gold O
nanoantennas O
using O
second O
harmonic O
generation O
. O

Second O
harmonic O
generation O
from O
plasmonic O
nanoantennas O
is O
investigated O
numerically O
using O
a O
surface O
integral O
formulation O
for O
the O
calculation O
of O
both O
the O
fundamental O
and O
the O
second O
harmonic O
electric O
field O
. O

The O
comparison O
between O
a O
realistic O
and O
an O
idealized O
gold O
nanoantenna O
shows O
that O
second O
harmonic O
generation O
is O
extremely O
sensitive O
to O
asymmetry O
in O
the O
nanostructure O
shape O
even O
in O
cases O
where O
the O
linear O
response O
is O
barely O
modified O
. O

Interestingly O
, O
minute O
geometry O
asymmetry O
and O
surface O
roughness O
are O
clearly O
revealed O
by O
far O
- O
field O
analysis O
, O
demonstrating O
that O
second O
harmonic O
generation O
is O
a O
promising O
tool O
for O
the O
sensitive O
optical O
characterization O
of O
plasmonic O
nanostructures O
. O

Furthermore O
, O
defects O
located O
where O
the O
linear O
field O
is O
strong O
( O
e O
. O
g O
. O
, O
in O
the O
antenna O
gap O
) O
do O
not O
necessarily O
have O
the O
strongest O
impact O
on O
the O
second O
harmonic O
signal O
. O

Cellulose O
- O
ethylenediaminetetra B
Acid I
conjugates O
protect O
Mammalian O
cells O
from O
bacterial O
cells O
. O

Cellulose O
- O
ethylenediaminetetra B
acid I
( O
EDTA B
) O
conjugates O
were O
synthesized O
by O
the O
esterification O
of O
cellulose O
with O
ethylenediaminetetra B
dianhydride I
( O
EDTAD B
) O
. O

The O
new O
materials O
provided O
potent O
antimicrobial O
activities O
against O
Staphylococcus O
aureus O
( O
S O
. O
aureus O
, O
Gram O
- O
positive O
bacteria O
) O
and O
Pseudomonas O
aeruginosa O
( O
P O
. O
aeruginosa O
, O
Gram O
- O
negative O
bacteria O
) O
, O
and O
inhibited O
the O
formation O
of O
bacterial O
biofilms O
. O

The O
biocompatibility O
of O
the O
new O
cellulose O
- O
EDTA B
conjugates O
was O
evaluated O
with O
mouse O
skin O
fibroblasts O
for O
up O
to O
14 O
days O
. O

SEM O
observation O
and O
DNA O
content O
analysis O
suggested O
that O
the O
new O
materials O
sustained O
the O
viability O
of O
fibroblast O
cells O
. O

Moreover O
, O
in O
mouse O
skin O
fibroblast O
- O
bacteria O
co O
- O
culture O
systems O
, O
the O
new O
cellulose O
- O
EDTA B
conjugates O
prevented O
bacterial O
biofilm O
formation O
and O
protected O
the O
mammalian O
cells O
from O
the O
bacterial O
cells O
for O
at O
least O
one O
day O
. O

High O
quality O
CdHgTe B
nanocrystals O
with O
strong O
near O
- O
infrared O
emission O
: O
relationship O
between O
composition O
and O
cytotoxic O
effects O
. O

High O
quality O
CdHgTe O
quasi O
core O
/ O
shell O
nanocrystals O
( O
NCs O
) O
were O
prepared O
via O
the O
one O
- O
step O
method O
. O

The O
relationship O
between O
the O
composition O
, O
structure O
, O
and O
property O
was O
systematically O
investigated O
by O
the O
combination O
of O
X O
- O
ray O
photoelectron O
spectroscopy O
( O
XPS O
) O
, O
inductively O
coupled O
plasma O
atomic O
emission O
( O
ICP O
) O
, O
and O
the O
photoluminescence O
( O
PL O
) O
measurements O
. O

The O
quantum O
yield O
( O
QY O
) O
was O
~ O
50 O
% O
when O
the O
feed O
ratio O
of O
Cd B
( I
2 I
+ I
) I
to O
Hg B
( I
2 I
+ I
) I
was O
equal O
to O
1 O
. O

The O
PL O
property O
was O
further O
polished O
, O
and O
the O
QY O
was O
improved O
to O
~ O
80 O
% O
through O
the O
variance O
of O
the O
prepared O
conditions O
such O
as O
the O
ratio O
of O
ligand O
to O
metal O
ion O
and O
HTe B
( I
- I
) I
to O
metal O
ion O
, O
pH O
value O
, O
and O
temperature O
. O

In O
addition O
, O
the O
cytotoxic O
effects O
of O
CdHgTe O
NCs O
were O
systematically O
studied O
. O

The O
results O
showed O
that O
, O
for O
Cd0 B
. I
21Hg0 I
. I
79Te I
NCs O
, O
its O
quasi O
core O
/ O
shell O
structure O
was O
very O
stable O
and O
little O
cadmium B
ions O
were O
released O
. O

As O
a O
result O
, O
such O
NCs O
showed O
little O
cytotoxicity O
and O
would O
find O
applications O
in O
tissue O
imaging O
or O
detection O
. O

Isolation O
of O
thermally O
stable O
cellulose O
nanocrystals O
by O
phosphoric B
Acid I
hydrolysis O
. O

On O
account O
of O
their O
intriguing O
mechanical O
properties O
, O
low O
cost O
, O
and O
renewable O
nature O
, O
high O
- O
aspect O
- O
ratio O
cellulose O
nanocrystals O
( O
CNCs O
) O
are O
an O
attractive O
component O
for O
many O
nanomaterials O
. O

Due O
to O
hydrogen B
bonding O
between O
their O
surface O
hydroxyl B
groups O
, O
unmodified O
CNCs O
( O
H O
- O
CNCs O
) O
aggregate O
easily O
and O
are O
often O
difficult O
to O
disperse O
. O

It O
is O
shown O
here O
that O
on O
account O
of O
ionic O
repulsion O
between O
charged O
surface O
groups O
, O
slightly O
phosphorylated O
CNCs O
( O
P O
- O
CNCs O
, O
average O
dimensions O
31 O
+ O
/ O
- O
14 O
x O
316 O
+ O
/ O
- O
127 O
nm O
, O
surface O
charge O
density O
= O
10 O
. O
8 O
+ O
/ O
- O
2 O
. O
7 O
mmol O
/ O
kg O
cellulose O
) O
, O
prepared O
by O
controlled O
hydrolysis O
of O
cotton O
with O
phosphoric B
acid I
, O
are O
readily O
dispersible O
and O
form O
stable O
dispersions O
in O
polar O
solvents O
such O
as O
water O
, O
dimethyl B
sulfoxide I
, O
and O
dimethylformamide B
. O

Thermogravimetric O
analyses O
reveal O
that O
these O
P O
- O
CNCs O
exhibit O
a O
much O
higher O
thermal O
stability O
than O
partially O
sulfated O
CNCs O
( O
S O
- O
CNCs O
) O
, O
which O
are O
frequently O
employed O
, O
but O
suffer O
from O
limited O
thermal O
stability O
. O

Nanocomposites O
of O
an O
ethylene B
oxide I
- O
epichlorohydrin B
copolymer O
and O
H O
- O
CNCs O
, O
S O
- O
CNCs O
, O
and O
P O
- O
CNCs O
were O
prepared O
, O
and O
their O
mechanical O
properties O
were O
studied O
by O
dynamic O
mechanical O
thermal O
analysis O
. O

The O
results O
show O
that O
P O
- O
CNCs O
offer O
a O
reinforcing O
capability O
that O
is O
comparable O
to O
that O
of O
H O
- O
CNCs O
or O
S O
- O
CNCs O
. O

Electronic O
transitions O
of O
protonated O
and O
deprotonated O
amino B
acids I
in O
aqueous O
solution O
in O
the O
region O
145 O
- O
300 O
nm O
studied O
by O
attenuated O
total O
reflection O
far O
- O
ultraviolet O
spectroscopy O
. O

The O
electronic O
transitions O
of O
20 O
naturally O
occurring O
amino B
acids I
in O
aqueous O
solution O
were O
studied O
with O
attenuated O
total O
reflection O
far O
- O
ultraviolet O
( O
ATR O
- O
FUV O
) O
spectroscopy O
in O
the O
region O
from O
145 O
to O
300 O
nm O
. O

From O
the O
measured O
ATR O
spectra O
of O
sample O
solutions O
, O
the O
FUV O
absorption O
spectra O
attributed O
to O
the O
amino B
acids I
were O
separated O
from O
the O
intense O
solvent O
absorption O
by O
using O
a O
modified O
Kramers O
- O
Kronig O
transformation O
method O
. O

The O
FUV O
absorption O
spectra O
of O
the O
amino B
acids I
reflect O
the O
protonation O
states O
of O
the O
backbone O
and O
side O
- O
chain O
structures O
. O

The O
contributions O
of O
the O
side O
chains O
to O
the O
spectra O
were O
also O
examined O
from O
the O
difference O
spectra O
subtracting O
the O
corresponding O
Gly B
spectrum O
from O
each O
spectrum O
. O

The O
observed O
spectra O
were O
compared O
mostly O
with O
the O
electronic O
transition O
studies O
of O
the O
molecular O
fragments O
of O
the O
amino B
acids I
in O
gas O
phase O
. O

The O
FUV O
spectra O
of O
the O
amino B
acids I
exhibited O
the O
intra O
- O
and O
intermolecular O
electronic O
interactions O
of O
the O
solute O
- O
solute O
as O
well O
as O
the O
solute O
- O
solvent O
, O
and O
those O
are O
essential O
factors O
to O
elucidate O
UV O
photochemical O
processes O
of O
the O
amino B
acids I
in O
aqueous O
solution O
. O

Perspectives O
offered O
by O
single O
- O
domain O
antibodies O
in O
clinical O
diagnostic O
of O
pediatric O
tumors O
. O

The O
results O
accrued O
in O
the O
last O
few O
years O
have O
clearly O
showed O
that O
recombinant O
antibodies O
, O
and O
specifically O
single O
- O
domain O
antibodies O
, O
represent O
valid O
alternatives O
to O
conventional O
IgGs O
for O
in O
vivo O
imaging O
. O

It O
does O
not O
simply O
mean O
that O
antibody O
fragments O
can O
substitute O
full O
- O
length O
antibodies O
, O
but O
that O
they O
are O
substantially O
more O
suitable O
for O
some O
applications O
and O
can O
perform O
other O
functions O
for O
which O
no O
real O
alternative O
is O
available O
. O

Brain O
imaging O
with O
multi O
- O
functional O
probes O
is O
an O
evident O
example O
, O
but O
the O
promising O
results O
obtained O
with O
micro O
- O
PET O
and O
- O
SPECT O
in O
murine O
models O
could O
lead O
in O
short O
time O
to O
a O
revolutionary O
change O
in O
clinical O
diagnostics O
. O

Brilliant O
applications O
of O
single O
- O
domain O
antibody O
- O
dependent O
imaging O
have O
enabled O
us O
to O
understand O
how O
the O
tracer O
mass O
and O
avidity O
can O
be O
engineered O
to O
modulate O
pharmacokinetic O
features O
such O
as O
clearance O
, O
tumor O
penetration O
, O
and O
binding O
affinity O
with O
the O
aim O
of O
optimizing O
specific O
responses O
. O

The O
potential O
of O
these O
reagents O
and O
the O
increasing O
interest O
for O
them O
is O
evidenced O
by O
the O
exponential O
growth O
of O
publications O
and O
the O
multiplication O
of O
the O
proposed O
applications O
in O
which O
they O
are O
used O
. O

This O
review O
wishes O
to O
provide O
an O
update O
of O
this O
fast O
moving O
subject O
and O
to O
indicate O
what O
may O
be O
the O
next O
foreseeable O
technical O
progress O
. O

Artificial O
neural O
network O
analysis O
of O
data O
from O
multiple O
in O
vitro O
assays O
for O
prediction O
of O
skin O
sensitization O
potency O
of O
chemicals O
. O

In O
order O
to O
develop O
in O
vitro O
risk O
assessment O
systems O
for O
skin O
sensitization O
, O
it O
is O
important O
to O
predict O
a O
threshold O
from O
the O
murine O
local O
lymph O
node O
assay O
( O
LLNA O
) O
. O

We O
first O
confirmed O
that O
the O
combination O
of O
the O
human O
Cell O
Line O
Activation O
Test O
( O
h O
- O
CLAT O
) O
and O
the O
SH O
test O
improved O
the O
accuracy O
and O
sensitivity O
of O
prediction O
of O
LLNA O
data O
compared O
with O
each O
individual O
test O
. O

Next O
, O
we O
assessed O
the O
mutual O
correlations O
among O
maximum O
amount O
of O
change O
of O
cell O
- O
surface O
thiols B
( O
MAC O
value O
) O
in O
the O
SH O
test O
, O
CV75 O
value O
( O
concentration O
giving O
75 O
% O
cell O
viability O
) O
in O
a O
cytotoxicity O
assay O
, O
EC150 O
and O
EC200 O
values O
( O
thresholds O
concentrations O
of O
CD86 O
and O
CD54 O
expression O
, O
respectively O
) O
in O
h O
- O
CLAT O
and O
published O
LLNA O
thresholds O
of O
64 O
chemicals O
. O

Based O
on O
the O
results O
, O
we O
selected O
MAC O
value O
and O
the O
minimum O
of O
CV75 O
, O
EC150 O
( O
CD86 O
) O
and O
EC200 O
( O
CD54 O
) O
as O
descriptors O
for O
the O
input O
layer O
of O
an O
artificial O
neural O
network O
( O
ANN O
) O
system O
. O

The O
ANN O
- O
predicted O
values O
were O
well O
correlated O
with O
reported O
LLNA O
thresholds O
. O

We O
also O
found O
a O
correlation O
between O
the O
SH O
test O
and O
the O
peptide O
- O
binding O
assay O
used O
to O
evaluate O
hapten O
- O
protein O
complex O
formation O
. O

Thus O
, O
this O
model O
, O
which O
we O
designate O
as O
the O
" O
iSENS O
ver O
. O

1 O
" O
, O
may O
be O
useful O
for O
risk O
assessment O
of O
skin O
sensitization O
potential O
of O
chemicals O
from O
in O
vitro O
test O
data O
. O

Considering O
the O
impact O
drug O
- O
like O
properties O
have O
on O
the O
chance O
of O
success O
. O

Many O
definitions O
of O
' O
drug O
- O
like O
' O
compound O
properties O
have O
been O
published O
; O
based O
on O
the O
analysis O
of O
simple O
molecular O
properties O
of O
successful O
drugs O
. O

These O
are O
typically O
presented O
as O
rules O
that O
define O
acceptable O
boundaries O
for O
these O
properties O
. O

When O
a O
compound O
does O
not O
' O
fit O
' O
within O
these O
boundaries O
then O
its O
properties O
differ O
from O
those O
of O
the O
majority O
of O
drugs O
, O
which O
could O
indicate O
a O
higher O
risk O
of O
poor O
pharmacokinetics O
or O
safety O
outcomes O
in O
vivo O
. O

Here O
, O
we O
review O
the O
strengths O
and O
weaknesses O
of O
these O
rules O
and O
note O
, O
in O
particular O
, O
that O
the O
overly O
rigid O
application O
of O
strict O
cut O
- O
off O
points O
can O
introduce O
artificial O
distinctions O
between O
similar O
compounds O
, O
running O
the O
risk O
of O
missing O
valuable O
opportunities O
. O

Alternatively O
, O
compounds O
can O
be O
ranked O
according O
to O
their O
similarity O
to O
marketed O
drugs O
using O
a O
continuous O
measure O
of O
drug O
- O
likeness O
. O

However O
, O
being O
similar O
to O
known O
drugs O
does O
not O
necessarily O
mean O
that O
a O
compound O
is O
more O
likely O
to O
become O
a O
drug O
and O
we O
demonstrate O
how O
a O
new O
approach O
, O
employing O
Bayesian O
methods O
, O
can O
be O
used O
to O
compare O
a O
set O
of O
successful O
drugs O
with O
a O
set O
of O
non O
- O
drug O
compounds O
to O
identify O
those O
properties O
that O
give O
the O
greatest O
distinction O
between O
the O
two O
sets O
, O
and O
hence O
the O
greatest O
increase O
in O
the O
likelihood O
of O
a O
compound O
becoming O
a O
successful O
drug O
. O

This O
analysis O
further O
illustrates O
that O
guidelines O
for O
drug O
- O
likeness O
might O
not O
be O
generally O
applicable O
across O
all O
compound O
and O
target O
classes O
or O
therapeutic O
indications O
. O

Therefore O
, O
it O
might O
be O
more O
appropriate O
to O
consider O
specific O
guidelines O
for O
drug O
- O
likeness O
that O
are O
project O
specific O
. O

Synthesis O
of O
a O
paraffin B
phase O
change O
material O
microencapsulated O
in O
a O
siloxane B
polymer O
. O

The O
coemulsification O
method O
suitable O
for O
the O
formulation O
of O
microcapsules O
of O
n B
- I
eicosane I
coated O
with O
a O
polysiloxane B
is O
developed O
. O

This O
method O
allows O
to O
synthesize O
core O
- O
shell O
microcapsules O
of O
paraffin B
which O
have O
the O
shape O
of O
spheres O
or O
distorted O
spheres O
and O
are O
designed O
for O
the O
use O
as O
phase O
change O
materials O
. O

The O
microcapsules O
are O
formed O
in O
aqueous O
phase O
by O
the O
precipitation O
of O
n B
- I
eicosane I
together O
with O
modified O
polyhydromethylsilox B
from O
a O
common O
solvent O
which O
is O
miscible O
with O
aqueous O
media O
. O

The O
polysiloxane B
is O
modified O
by O
the O
attachment O
of O
silylvinyl B
and O
alkoxy B
functions O
before O
coemulsification O
with O
the O
paraffin B
. O

It O
also O
contains O
the O
Pt B
( I
0 I
) I
Karstedt O
catalyst O
. O

The O
microcapsules O
formed O
by O
coemulsification O
are O
stabilized O
by O
the O
in O
situ O
cross O
- O
linking O
of O
the O
polysiloxane B
shell O
. O

The O
shell O
is O
additionally O
modified O
by O
the O
in O
situ O
generation O
of O
silanol B
groups O
which O
provide O
colloidal O
stabilization O
of O
microspheres O
in O
aqueous O
phase O
. O

Microcapsules O
were O
studied O
by O
DSC O
, O
SEM O
, O
optical O
polarized O
microscope O
, O
and O
by O
thermooptical O
analysis O
( O
TOA O
) O
. O

Differential O
surface O
properties O
of O
commercial O
crystalline O
telmisartan B
samples O
. O

The O
aim O
of O
the O
present O
study O
was O
to O
investigate O
differences O
in O
surface O
chemistry O
of O
commercially O
available O
telmisartan B
( O
TMS B
) O
samples O
in O
Indian O
market O
and O
to O
correlate O
them O
to O
the O
surface O
molecular O
environment O
. O

Comprehensive O
characterization O
of O
material O
properties O
of O
four O
TMS B
samples O
from O
different O
sources O
showed O
that O
all O
samples O
exhibited O
same O
polymorphic O
form O
, O
but O
different O
particle O
shape O
, O
particle O
size O
distribution O
, O
surface O
energetics O
and O
surface O
chemistry O
. O

Wettability O
and O
surface O
free O
energy O
were O
determined O
using O
sessile O
drop O
contact O
angle O
technique O
. O

TMS O
samples O
exhibited O
significant O
variations O
in O
their O
wetting O
behavior O
. O

The O
role O
of O
crystal O
shape O
, O
particle O
size O
distribution O
, O
surface O
energetics O
and O
surface O
chemistry O
in O
controlling O
TMS B
powder O
wettability O
was O
collectively O
explored O
by O
contact O
angle O
experiments O
. O

Evaluation O
of O
work O
of O
adhesion O
( O
Wa O
) O
, O
immersion O
( O
Wi O
) O
and O
spreading O
( O
Ws O
) O
indicated O
that O
samples O
had O
differential O
wetting O
behavior O
. O

The O
surface O
chemistry O
was O
elucidated O
by O
X O
- O
ray O
photoelectron O
spectroscopy O
( O
XPS O
) O
. O

The O
surface O
polarity O
index O
was O
determined O
by O
XPS O
and O
expressed O
as O
( O
oxygen B
+ O
nitrogen B
) O
- O
to O
- O
( O
carbon B
) O
atomic O
concentration O
ratio O
. O

It O
was O
found O
to O
be O
different O
for O
all O
four O
TMS O
samples O
. O

Crystal O
morphology O
of O
TMS O
polymorph O
A O
was O
predicted O
using O
Bravais O
- O
Friedel O
Donnay O
- O
Harker O
( O
BFDH O
) O
method O
. O

Molecular O
lipophilic O
surface O
potential O
( O
MLSP O
) O
data O
for O
TMS B
showed O
the O
varied O
surface O
lipophilic O
environment O
throughout O
the O
molecule O
. O

Hence O
it O
can O
be O
concluded O
that O
the O
differential O
abundance O
of O
surface O
elements O
play O
an O
important O
role O
in O
controlling O
the O
biopharmaceutical O
performance O
of O
TMS O
powder O
samples O
. O

Analytical O
chemistry O
, O
toxicology O
, O
epidemiology O
and O
health O
impact O
assessment O
of O
melamine B
in O
infant O
formula O
: O
Recent O
progress O
and O
developments O
. O

This O
review O
summarizes O
the O
most O
recent O
scientific O
literature O
and O
regulations O
regarding O
analytical O
chemistry O
, O
toxicology O
, O
epidemiology O
, O
exposure O
, O
and O
risk O
assessment O
of O
melamine B
in O
infant O
formula O
. O

For O
analyses O
, O
enzyme O
- O
linked O
immunosorbent O
assay O
, O
high O
- O
performance O
liquid O
chromatography O
, O
capillary O
electrophoresis O
, O
gas O
chromatography O
coupled O
with O
mass O
spectrometry O
and O
liquid O
chromatography O
coupled O
with O
tandem O
mass O
spectrometry O
have O
commonly O
been O
used O
. O

Organization O
of O
proficiency O
test O
programs O
provided O
good O
evidence O
to O
facilitate O
granting O
laboratories O
accreditation O
and O
to O
ascertain O
the O
measurement O
reliability O
of O
melamine B
methods O
. O

Metabolic O
studies O
demonstrated O
that O
melamine B
is O
predominantly O
restricted O
to O
blood O
or O
extracellular O
fluid O
and O
is O
not O
extensively O
distributed O
to O
organs O
and O
tissues O
. O

Studies O
of O
human O
renal O
histopathology O
and O
clinical O
diagnoses O
indicated O
that O
melamine B
- O
related O
obstructive O
nephropathy O
derives O
from O
melamine B
precipitation O
in O
the O
lower O
urinary O
tract O
, O
with O
stones O
that O
are O
thought O
to O
be O
melamine B
- O
uric B
acid I
complexes O
. O

Epidemiologic O
studies O
showed O
that O
the O
occurrence O
of O
melamine B
- O
related O
urolithiasis O
is O
related O
to O
both O
the O
concentration O
of O
melamine B
in O
ingested O
milk O
products O
and O
the O
duration O
of O
ingestion O
. O

Long O
- O
term O
follow O
- O
up O
cohort O
studies O
should O
be O
continued O
to O
further O
investigate O
the O
epidemic O
and O
chronic O
hazard O
of O
melamine B
- O
induced O
nephrotoxicity O
. O

The O
World O
Health O
Organization O
set O
a O
tolerable O
daily O
intake O
of O
0 O
. O
2mg O
/ O
kgbw O
/ O
day O
to O
be O
applied O
to O
" O
the O
whole O
population O
including O
infants O
" O
. O

Other O
authorities O
and O
research O
institutes O
have O
set O
/ O
proposed O
lower O
values O
. O

Differential O
phosphoproteome O
of O
the O
striatum O
from O
pleiotrophin O
knockout O
and O
midkine O
knockout O
mice O
treated O
with O
amphetamine B
: O
Correlations O
with O
amphetamine B
- O
induced O
neurotoxicity O
. O

The O
neurotrophic O
factors O
pleiotrophin O
( O
PTN O
) O
and O
midkine O
( O
MK O
) O
have O
been O
shown O
to O
modulate O
amphetamine B
- O
induced O
neurotoxicity O
. O

Accordingly O
, O
PTN B
- O
/ O
- O
and O
MK O
- O
/ O
- O
mice O
show O
an O
increased O
vulnerability O
to O
amphetamine B
- O
induced O
neurotoxic O
effects O
. O

In O
an O
effort O
to O
uncover O
new O
pharmacological O
targets O
to O
prevent O
amphetamine B
neurotoxic O
effects O
, O
we O
have O
now O
used O
a O
proteomic O
approach O
to O
study O
protein O
phosphorylation O
, O
in O
which O
we O
combined O
phosphoprotein O
enrichment O
, O
by O
immobilized O
metal O
affinity O
chromatography O
( O
IMAC O
) O
, O
with O
two O
- O
dimensional O
gel O
electrophoresis O
and O
mass O
spectrometry O
, O
in O
order O
to O
identify O
the O
phosphoproteins O
regulated O
in O
the O
striatum O
of O
PTN O
- O
/ O
- O
, O
MK O
- O
/ O
- O
and O
wild O
type O
( O
WT O
) O

mice O
treated O
with O
amphetamine B
. O

We O
identified O
13 O
differentially O
expressed O
phosphoproteins O
that O
are O
judged O
to O
be O
relevant O
in O
the O
neuroprotective O
roles O
of O
PTN B
and O
MK O
against O
amphetamine B
- O
induced O
neurotoxicity O
. O

It O
is O
very O
interesting O
to O
note O
that O
4 O
of O
these O
phosphoproteins O
, O
annexin O
A7 O
( O
ANXA7 O
) O
, O
COP9 O
signalosome O
subunit O
5 O
( O
COPS5 O
) O
, O
aldehyde B
dehydrogenase O
family O
1 O
member O
A1 O
( O
ALDH1A1 O
) O
and O
creatine B
kinase O
U O
- O
type O
( O
CKMT1 O
) O
, O
are O
known O
to O
be O
involved O
in O
Parkinson O
' O
s O
disease O
, O
a O
result O
of O
significant O
importance O
since O
PTN O
and O
MK O
have O
been O
also O
demonstrated O
to O
limit O
Parkinson O
' O
s O
disease O
( O
PD O
) O
progress O
and O
have O
been O
suggested O
to O
be O
among O
the O
important O
genetic O
factors O
possibly O

preventing O
the O
development O
of O
PD O
in O
methamphetamine B
abusers O
. O

The O
data O
identify O
phosphoproteins O
differentially O
regulated O
by O
amphetamine B
treatment O
and O
/ O
or O
the O
presence O
of O
endogenous O
PTN O
/ O
MK O
which O
may O
be O
relevant O
mediators O
of O
PTN O
/ O
MK O
neuroprotective O
effects O
against O
amphetamine B
- O
induced O
neurotoxicity O
. O

The O
data O
support O
further O
studies O
to O
validate O
the O
phosphoproteins O
here O
identified O
as O
possible O
new O
pharmacological O
targets O
to O
prevent O
amphetamine B
neurotoxic O
effects O
. O

COMT O
Val158Met O
modulates O
subjective O
responses O
to O
intravenous O
nicotine B
and O
cognitive O
performance O
in O
abstinent O
smokers O
. O

The O
catechol B
- O
O B
- O
methyltransferase O
( O
COMT O
) O
Val158Met O
polymorphism O
may O
be O
a O
risk O
factor O
for O
nicotine B
addiction O
. O

This O
study O
examined O
the O
influence O
of O
the O
COMT O
Val158Met O
polymorphism O
on O
subjective O
, O
physiological O
and O
cognitive O
effects O
of O
intravenous O
( O
IV O
) O
nicotine B
use O
in O
African O
Americans O
( O
AAs O
; O
n O
= O
56 O
) O
and O
European O
Americans O
( O
EAs O
; O
n O
= O
68 O
) O
smokers O
. O

Overnight O
abstinent O
smokers O
received O
saline O
followed O
by O
0 O
. O
5 O
and O
1 O
. O
0 O
mg O
per O
70 O
kg O
doses O
of O
nicotine B
, O
administered O
30 O
min O
apart O
. O

Smokers O
with O
valine B
( O
Val B
) O
/ O
Val B
genotype O
, O
compared O
with O
methionine B
( O
Met B
) O
carriers O
, O
had O
greater O
negative O
subjective O
effects O
from O
IV O
nicotine B
and O
had O
more O
severe O
withdrawal O
severity O
following O
overnight O
abstinence O
from O
smoking O
. O

Women O
with O
Val B
/ O
Val B
genotype O
reported O
greater O
difficulty O
concentrating O
and O
irritability O
than O
men O
with O
Val B
/ O
Val B
or O
Met B
carrier O
genotypes O
. O

The O
Val B
/ O
Val O
genotype O
was O
associated O
with O
better O
performance O
on O
the O
math O
task O
and O
in O
AA O
smokers O
it O
was O
associated O
with O
greater O
systolic O
blood O
pressure O
. O

These O
results O
support O
the O
rationale O
of O
pharmacologically O
inhibiting O
COMT O
to O
aid O
with O
smoking O
cessation O
among O
Val O
/ O
Val O
genotype O
smokers O
. O
The O
Pharmacogenomics O
Journal O
advance O
online O
publication O
, O
5 O
March O
2013 O
; O
doi O
: O
10 O
. O
1038 O
/ O
tpj O
. O
2013 O
. O
1 O
. O

Exclusive O
skeletal O
muscle O
correction O
does O
not O
modulate O
dystrophic O
heart O
disease O
in O
the O
aged O
mdx O
model O
of O
Duchenne O
cardiomyopathy O
. O

Duchenne O
muscular O
dystrophy O
( O
DMD O
) O
is O
characterized O
by O
severe O
degeneration O
and O
necrosis O
of O
both O
skeletal O
and O
cardiac O
muscle O
. O

While O
many O
experimental O
therapies O
have O
shown O
great O
promise O
in O
treating O
skeletal O
muscle O
disease O
, O
an O
effective O
therapy O
for O
Duchenne O
cardiomyopathy O
remains O
a O
challenge O
in O
large O
animal O
models O
and O
human O
patients O
. O

The O
current O
views O
on O
cardiac O
consequences O
of O
skeletal O
muscle O
- O
centered O
therapy O
are O
controversial O
. O

Studies O
performed O
in O
young O
adult O
mdx O
mice O
( O
a O
mild O
DMD O
mouse O
model O
) O
have O
yielded O
opposing O
results O
. O

Since O
mdx O
mice O
do O
not O
develop O
dystrophic O
cardiomyopathy O
until O
> O
= O
21 O
months O
of O
age O
, O
we O
reasoned O
that O
old O
mdx O
mice O
may O
represent O
a O
better O
model O
to O
assess O
the O
impact O
of O
skeletal O
muscle O
rescue O
on O
dystrophic O
heart O
disease O
. O

Here O
, O
we O
aged O
skeletal O
muscle O
- O
specific O
micro O
- O
dystrophin O
transgenic O
mdx O
mice O
to O
23 O
months O
and O
examined O
the O
cardiac O
phenotype O
. O

As O
expected O
, O
transgenic O
mdx O
mice O
had O
minimal O
skeletal O
muscle O
disease O
and O
they O
also O
outperformed O
original O
mdx O
mice O
on O
treadmill O
running O
. O

On O
cardiac O
examination O
, O
the O
dystrophin O
- O
null O
heart O
of O
transgenic O
mdx O
mice O
displayed O
severe O
cardiomyopathy O
matching O
that O
of O
non O
- O
transgenic O
mdx O
mice O
. O

Specifically O
, O
both O
the O
strains O
showed O
similar O
heart O
fibrosis O
and O
cardiac O
function O
deterioration O
in O
systole O
and O
diastole O
. O

Cardiac O
output O
and O
ejection O
fraction O
were O
also O
equally O
compromised O
. O

Our O
results O
suggest O
that O
skeletal O
muscle O
rescue O
neither O
aggravates O
nor O
alleviates O
cardiomyopathy O
in O
aged O
mdx O
mice O
. O

These O
findings O
underscore O
the O
importance O
of O
treating O
both O
skeletal O
and O
cardiac O
muscles O
in O
DMD O
therapy O
. O

Transfection O
of O
Mammalian O
Cells O
Using O
Block O
Copolypeptide O
Vesicles O
. O

An O
arginine B
- O
leucine B
block O
copolypeptide O
( O
R60 O
L20 O
) O
is O
synthesized O
, O
which O
is O
capable O
of O
forming O
vesicles O
with O
controllable O
sizes O
, O
able O
to O
transport O
hydrophilic O
cargo O
across O
the O
cell O
membrane O
, O
and O
exhibit O
relatively O
low O
cytotoxicity O
. O

The O
R60 O
L20 O
vesicles O
also O
possess O
the O
ability O
to O
deliver O
DNA O
into O
mammalian O
cells O
for O
transfection O
. O

Although O
the O
transfection O
efficiency O
is O
lower O
than O
that O
of O
the O
commercially O
available O
transfection O
agent O
Lipofectamine O
2000 O
, O
the O
R60 O
L20 O
vesicles O
are O
able O
to O
achieve O
transfection O
with O
significantly O
lower O
cytotoxicity O
and O
immunogenicity O
. O

This O
behavior O
is O
potentially O
due O
to O
its O
stronger O
interaction O
with O
DNA O
which O
subsequently O
provides O
better O
protection O
against O
anionic O
heparin O
. O

Buffer O
- O
Stable O
Chitosan O
- O
Polyglutamic B
Acid I
Hybrid O
Nanoparticles O
for O
Biomedical O
Applications O
. O

In O
spite O
of O
their O
attractive O
features O
, O
widespread O
biomedical O
applications O
of O
CS O
nanoparticles O
are O
yet O
to O
be O
realized O
due O
to O
their O
poor O
stability O
in O
physiological O
conditions O
, O
such O
as O
in O
buffer O
system O
at O
pH O
7 O
. O
4 O
. O

Buffer O
- O
stable O
chitosan O
- O
based O
hybrid O
NPs O
( O
HNPs O
) O
are O
reported O
and O
characterized O
. O

Buffer O
stability O
is O
achieved O
by O
introducing O
polyglutamic B
acid I
to O
chitosan O
. O

The O
effect O
of O
PGA B
to O
CS O
molar O
ratio O
and O
crosslinking O
on O
HNP O
integrity O
, O
buffer O
stability O
, O
and O
biodegradability O
are O
studied O
. O

Preliminary O
in O
vitro O
studies O
are O
carried O
out O
to O
evaluate O
targeted O
uptake O
efficiency O
of O
folate B
conjugated O
HNPs O
. O

Successful O
demonstration O
of O
buffer O
stability O
and O
cancer O
cell O
targeting O
by O
HNPs O
achieves O
important O
milestones O
for O
chitosan O
- O
based O
nanoparticle O
technology O
. O

Ni B
( I
II I
) I
- I
NTA I
Modified O
Poly B
( I
ethylene I
imine I
) I
Glycopolymers O
: O
Physicochemical O
Properties O
and O
First O
In O
Vitro O
Study O
of O
Polyplexes O
Formed O
with O
HIV O
- O
Derived O
Peptides O
. O

Alternative O
delivery O
entities O
are O
desirable O
in O
immunotherapies O
in O
which O
polyplexes B
are O
widely O
formed O
by O
electrostatic O
interactions O
to O
induce O
cellular O
uptake O
processes O
for O
bioactive O
molecules O
. O

In O
our O
study O
, O
biocompatible O
Ni B
( I
II I
) I
- O
nitrilo B
( I
triacetic I
acid I
) I
- O
modified O
poly B
( I
ethylene I
imine I
) I
- O
maltose B
( O
Ni B
- I
NTA I
- I
DG I
) O
is O
realized O
and O
evaluated O
as O
complexation O
agent O
against O
His O
- O
tagged O
peptides O
using O
fluorescence O
polarization O
and O
dynamic O
light O
scattering O
. O

The O
polyplexes B
are O
stable O
until O
a O
pH O
of O
6 O
. O
5 O
- O
6 O
. O
0 O
, O
and O
also O
up O
to O
50 O
mM O
of O
imidazole B
. O

A O
first O
uptake O
approach O
shows O
that O
polyplexes B
lead O
to O
an O
increase O
in O
peptide O
uptake O
in O
monocyte O
- O
derived O
immature O
dendritic O
cells O
. O

In O
summary O
, O
Ni B
- I
NTA I
- I
DG I
represents O
a O
promising O
( O
delivery O
) O
platform O
for O
forthcoming O
in O
vitro O
applications O
. O

Supramolecular O
cl O
. O
. O
. O
h B
and O
o B
. O
. O
. O
h B
interactions O
in O
self O
- O
assembled O
1 B
, I
5 I
- I
dichloroanthraquinon I
layers O
on O
au B
( I
111 I
) I
. O

The O
role O
of O
halogen B
bonds O
in O
self O
- O
assembled O
networks O
for O
systems O
with O
Br B
and O
I B
ligands O
has O
recently O
been O
studied O
with O
scanning O
tunneling O
microscopy O
( O
STM O
) O
, O
which O
provides O
physical O
insight O
at O
the O
atomic O
scale O
. O

Here O
, O
we O
study O
the O
supramolecular O
interactions O
of O
1 B
, I
5 I
- I
dichloroanthraquinon I
molecules O
on O
Au B
( I
111 I
) I
, O
including O
Cl B
ligands O
, O
by O
using O
STM O
. O

Two O
different O
molecular O
structures O
of O
chevron O
and O
square O
networks O
are O
observed O
, O
and O
their O
molecular O
models O
are O
proposed O
. O

Both O
molecular O
structures O
are O
stabilized O
by O
intermolecular O
Cl B
. O
. O
. O
H B
and O
O B
. O
. O
. O
H B
hydrogen B
bonds O
with O
marginal O
contributions O
from O
Cl B
- O
related O
halogen B
bonds O
, O
as O
revealed O
by O
density O
functional O
theory O
calculations O
. O

Our O
study O
shows O
that O
, O
in O
contrast O
to O
Br B
- O
and O
I B
- O
related O
halogen B
bonds O
, O
Cl B
- O
related O
halogen B
bonds O
weakly O
contribute O
to O
the O
molecular O
structure O
due O
to O
a O
modest O
positive O
potential O
( O
sigma O
hole O
) O
of O
the O
Cl B
ligands O
. O

Dissecting O
the O
relative O
contribution O
of O
OATP1B1 O
- O
mediated O
uptake O
of O
xenobiotics O
into O
human O
hepatocytes O
using O
siRNA O
. O

Abstract O
1 O
. O

Organic O
anion O
transporting O
polypeptide O
1B1 O
plays O
a O
pivotal O
role O
in O
the O
disposition O
of O
many O
anionic O
drugs O
. O

Significant O
overlap O
in O
substrate O
specificity O
between O
individual O
OATP O
isoforms O
has O
hampered O
the O
identification O
of O
the O
relative O
importance O
of O
individual O
isoforms O
for O
hepatic O
uptake O
of O
xenobiotics O
. O

2 O
. O

The O
present O
study O
focused O
on O
the O
use O
of O
siRNA O
technology O
to O
decrease O
OATP1B1 O
selectively O
in O
human O
hepatocytes O
. O

Following O
delivery O
of O
siRNA O
by O
the O
novel O
lipid O
, O
AtuFECT01 O
, O
mRNA O
expression O
of O
OATP1B1 O
was O
reduced O
by O
94 O
% O
- O
98 O
% O
with O
no O
significant O
toxicity O
. O

Off O
- O
target O
effects O
were O
also O
shown O
to O
be O
minimal O
as O
evidenced O
by O
the O
expression O
of O
common O
drug O
metabolizing O
enzymes O
, O
transporters O
, O
nuclear O
receptors O
and O
associated O
co O
- O
regulators O
. O

Uptake O
of O
estrone B
- I
3 I
- I
sulfate I
( O
5 O
nM O
) O
by O
OATP1B1 O
was O
reduced O
by O
82 O
% O
- O
95 O
% O
. O

This O
methodology O
was O
subsequently O
used O
to O
assess O
the O
relative O
contribution O
of O
OATP1B1 O
uptake O
in O
human O
hepatocytes O
for O
olmesartan B
( O
42 O
% O
- O
62 O
% O
) O
, O
valsartan B
( O
28 O
% O
- O
81 O
% O
) O
, O
rosuvastatin B
( O
64 O
% O
- O
72 O
% O
) O
, O
pitavastatin B
( O
84 O
% O
- O
98 O
% O
) O
and O
lopinavir B
( O
64 O
% O
- O
89 O
% O
) O
. O

These O
data O
are O
consistent O
with O
previous O
values O
obtained O
using O
a O
relative O
activity O
factor O
approach O
. O

3 O
. O

The O
siRNA O
approach O
provides O
a O
robust O
and O
reproducible O
method O
for O
assessing O
the O
relative O
contribution O
of O
OATP1B1 O
to O
hepatic O
uptake O
of O
new O
chemical O
entities O
. O

The O
technique O
also O
has O
potential O
utility O
in O
facilitating O
detailed O
characterization O
of O
drug O
- O
drug O
interactions O
involving O
hepatic O
drug O
transporters O
. O

Synthesis O
of O
mixed O
ceramic O
Mg B
( I
x I
) I
Zn I
( I
1 I
- I
x I
) I
O I
nanofibers O
via O
Mg2 B
+ I
doping O
using O
sol O
- O
gel O
electrospinning O
. O

We O
report O
on O
the O
synthesis O
of O
tuned O
energy O
band O
gap O
Mg B
( I
x I
) I
Zn I
( I
1 I
- I
x I
) I
O I
nanofibers O
( O
NFs O
) O
with O
different O
Mg B
( I
2 I
+ I
) I
content O
via O
the O
sol O
- O
gel O
electrospinning O
( O
ES O
) O
technique O
wherein O
the O
addition O
of O
the O
doping O
material O
affects O
not O
only O
the O
morphologies O
of O
as O
- O
spun O
ZnAc B
/ O
PVA B
and O
MgAc B
/ O
ZnAc B
/ O
PVA B
nanofibers O
but O
also O
the O
crystal O
microstructure O
and O
optical O
properties O
of O
calcined O
ZnO B
and O
Mg B
( I
x I
) I
Zn I
( O

1 O
- O
x O
) O
O O
nanofibers O
. O

Following O
an O
appropriate O
aqueous O
solution O
preparation O
of O
magnesium B
acetate I
( O
MgAc B
) O
and O
zinc B
acetate I
( O
ZnAc B
) O
with O
poly B
( I
vinyl I
alcohol I
) I
( O
PVA B
) O
, O
electrospinning O
is O
performed O
and O
then O
as O
- O
spun O
nanofibers O
are O
calcined O
in O
an O
air O
atmosphere O
at O
600 O
degrees O
C O
for O
3 O
h O
. O

As O
- O
spun O
and O
calcined O
nanofiber O
diameters O
and O
morphologies O
are O
evaluated O
with O
scanning O
( O
SEM O
) O
and O
transmission O
( O
TEM O
) O
electron O
microscopies O
, O
whereas O
crystalline O
microstructural O
interpretations O
of O
ZnO B
and O
Mg B
( I
x I
) I
Zn I
( I
1 I
- I
x I
) I
O I
are O
conducted O
with O
wide O
- O
angle O
X O
- O
ray O
diffraction O
spectra O
( O
XRD O
) O
. O

Surface O
chemical O
composition O
and O
elemental O
evaluation O
of O
calcined O
nanofibers O
are O
examined O
with O
X O
- O
ray O
photoelectron O
spectroscopy O
( O
XPS O
) O
, O
and O
optical O
properties O
and O
crystal O
defect O
analyses O
of O
the O
calcined O
nanofibers O
are O
conducted O
with O
photoluminescence O
spectra O
( O
PL O
) O
. O

We O
observe O
a O
sharp O
reduction O
in O
fiber O
diameter O
upon O
calcination O
as O
a O
result O
of O
the O
removal O
of O
organic O
species O
from O
the O
fibers O
and O
conversion O
of O
ceramic O
precursors O
into O
ceramic O
nanofibers O
, O
and O
the O
appearance O
of O
a O
range O
of O
fiber O
morphologies O
from O
" O
bead O
in O
a O
string O
" O
to O
" O
sesame O
seed O
" O
coverage O
depending O
on O
fiber O
composition O
. O

Because O
Zn B
( I
2 I
+ I
) I
and O
Mg B
( I
2 I
+ I
) I
have O
similar O
ionicity O
and O
atomic O
radii O
, O
some O
Zn B
( I
2 I
+ I
) I
atoms O
are O
replaced O
by O
Mg B
( I
2 I
+ I
) I
atoms O
in O
the O
crystals O
, O
leading O
to O
a O
change O
in O
the O
properties O
of O
crystal O
lattices O
. O

The O
band O
gap O
energy O
of O
the O
calcined O
fibers O
increases O
significantly O
with O
addition O
of O
Mg B
( I
2 I
+ I
) I
along O
with O
an O
increase O
in O
the O
ultraviolet O
( O
UV O
) O
photoluminescence O
emission O
of O
the O
fibers O
. O

Fengycin B
C I
Produced O
by O
Bacillus O
subtilis O
EA O
- O
CB0015 O
. O

Bacillus O
subtilis O
EA O
- O
CB0015 O
was O
isolated O
from O
the O
phyllosphere O
of O
a O
banana O
plant O
and O
tested O
for O
its O
potential O
to O
produce O
bioactive O
compounds O
against O
Mycosphaerella O
fijiensis O
. O

Using O
a O
dual O
plate O
culture O
technique O
the O
cell O
- O
free O
supernatant O
of O
B O
. O
subtilis O
EA O
- O
CB0015 O
produced O
inhibition O
values O
of O
89 O
+ O
/ O
- O
1 O
% O
. O

The O
active O
compounds O
were O
purified O
by O
solid O
- O
phase O
extraction O
and O
HPLC O
, O
and O
their O
primary O
structures O
determined O
using O
mass O
spectrometry O
and O
amino B
acid I
analysis O
. O

A O
new O
fengycin B
isoform O
, O
fengycin B
C I
, O
with O
the O
amino B
acid I
sequence O
Glu B
- I
Orn I
- I
Tyr I
- I
Thr I
- I
Glu I
- I
Val I
- I
Pro I
- I
Gln I
- I
Thr I
- I
Ile I
was O
isolated O
. O

The O
peptidic O
moiety O
differs O
from O
fengycin B
B I
at O
position O
9 O
and O
from O
fengycin B
A I
at O
positions O
6 O
and O
9 O
. O

The O
beta B
- I
hydroxy I
fatty I
acyl I
chain O
is O
connected O
to O
the O
N B
- O
terminal O
of O
the O
decapeptide B
and O
can O
be O
saturated O
or O
unsaturated O
, O
ranging O
from O
14 O
to O
18 O
carbons B
. O

The O
C B
- O
terminal O
residue O
of O
the O
peptidic O
moiety O
is O
linked O
to O
the O
tyrosine B
residue O
at O
position O
3 O
, O
forming O
the O
branching O
point O
of O
the O
acyl B
peptide O
and O
the O
eight O
- O
membered O
cyclic O
lactone B
. O

Controlling O
spontaneous O
emission O
with O
plasmonic O
optical O
patch O
antennas O
. O

We O
experimentally O
demonstrate O
the O
control O
of O
the O
spontaneous O
emission O
rate O
and O
the O
radiation O
pattern O
of O
colloidal O
quantum O
dots O
deterministically O
positioned O
in O
a O
plasmonic O
patch O
antenna O
. O

The O
antenna O
consists O
of O
a O
thin O
gold O
microdisk O
separated O
from O
a O
planar O
gold O
layer O
by O
a O
few O
tens O
of O
nanometers O
thick O
dielectric O
layer O
. O

The O
emitters O
are O
shown O
to O
radiate O
through O
the O
entire O
patch O
antenna O
in O
a O
highly O
directional O
and O
vertical O
radiation O
pattern O
. O

Strong O
acceleration O
of O
spontaneous O
emission O
is O
observed O
, O
depending O
on O
the O
antenna O
geometry O
. O

Considering O
the O
double O
dipole O
structure O
of O
the O
emitters O
, O
this O
corresponds O
to O
a O
Purcell O
factor O
up O
to O
80 O
for O
dipoles O
perpendicular O
to O
the O
disk O
. O

Redox O
regulation O
of O
protein O
kinases O
. O

Reactive O
oxygen B
species O
( O
ROS O
) O
have O
been O
long O
regarded O
as O
by O
- O
products O
of O
a O
cascade O
of O
reactions O
stemming O
from O
cellular O
oxygen B
metabolism O
, O
which O
, O
if O
they O
accumulate O
to O
toxic O
levels O
, O
can O
have O
detrimental O
effects O
on O
cellular O
biomolecules O
. O

However O
, O
more O
recently O
, O
the O
recognition O
of O
ROS O
as O
mediators O
of O
cellular O
communications O
has O
led O
to O
their O
classification O
as O
signalling O
mediators O
in O
their O
own O
right O
. O

The O
prototypic O
redox O
- O
regulated O
targets O
downstream O
of O
ROS O
are O
the O
protein O
tyrosine B
phosphatases O
, O
and O
the O
wealth O
of O
research O
that O
has O
focused O
on O
this O
area O
has O
come O
to O
shape O
our O
understanding O
of O
how O
redox O
- O
signalling O
contributes O
to O
and O
facilitates O
protein O
tyrosine B
phosphorylation O
signalling O
cascades O
. O

However O
, O
it O
is O
becoming O
increasingly O
apparent O
that O
there O
is O
more O
to O
this O
system O
than O
simply O
the O
negative O
regulation O
of O
protein O
tyrosine B
phosphatases O
. O

Identification O
of O
redox O
- O
sensitive O
kinases O
such O
as O
Src O
led O
to O
the O
slow O
emergence O
of O
a O
role O
for O
redox O
regulation O
of O
tyrosine B
kinases O
. O

A O
flow O
of O
evidence O
, O
which O
has O
increased O
exponentially O
in O
recent O
times O
as O
a O
result O
of O
the O
development O
of O
new O
methods O
for O
the O
detection O
of O
oxidative O
modifications O
, O
demonstrates O
that O
, O
by O
concurrent O
oxidative O
activation O
of O
tyrosine B
kinases O
, O
ROS O
fine O
tune O
the O
duration O
and O
amplification O
of O
the O
phosphorylation O
signal O
. O

A O
more O
thorough O
understanding O
of O
the O
complex O
regulatory O
mechanism O
of O
redox O
- O
modification O
will O
allow O
targeting O
of O
both O
the O
production O
of O
ROS O
and O
their O
downstream O
effectors O
for O
therapeutic O
purposes O
. O

The O
present O
review O
assesses O
the O
most O
relevant O
recent O
literature O
that O
demonstrates O
a O
role O
for O
kinase O
regulation O
by O
oxidation O
, O
highlights O
the O
most O
significant O
findings O
and O
proposes O
future O
directions O
for O
this O
crucial O
area O
of O
redox O
biology O
. O

Antitubercular O
diterpenoids B
from O
Vitex O
trifolia O
. O

A O
new O
halimane B
diterpenoid I
, O
13 B
- I
hydroxy I
- I
5 I
( I
10 I
) I
, I
14 I
- I
halimadien I
- I
6 I
- I
one I
( O
1 O
) O
and O
two O
new O
labdane B
diterpenoids I
, O
6 B
alpha I
, I
7 I
alpha I
- I
diacetoxy I
- I
13 I
- I
hydroxy I
- I
8 I
( I
9 I
) I
, I
14 I
- I
labdadien I
( O
2 O
) O
and O
9 B
- I
hydroxy I
- I
13 I
( I
14 I
) I
- I
labden I
- I
15 I
, I
16 I
- I
olide I
( O
3 O
) O
, O
were O
isolated O
for O
the O
first O
time O
, O
along O
with O
fifteen O
known O
compounds O
, O
from O
the O
hexane B
soluble O
fraction O
of O
methanolic O
extract O
of O

Vitex O
trifolia O
leaves O
. O

The O
structures O
of O
these O
new O
diterpenoids B
were O
elucidated O
by O
spectral O
analysis O
. O

Their O
relative O
configurations O
were O
established O
using O
analysis O
of O
NOESY O
correlations O
and O
coupling O
constants O
observed O
in O
( B
1 I
) I
H I
NMR O
. O

Compounds O
2 O
, O
3 O
and O
another O
known O
diterpenoid B
, O
isoambreinolide B
( O
4 O
) O
were O
evaluated O
for O
antitubercular O
activity O
. O

3 O
and O
4 O
exhibited O
antitubercular O
activity O
( O
MIC O
= O
100 O
and O
25 O
mu O
g O
/ O
ml O
) O
against O
Mycobacterium O
tuberculosis O
H37Rv O
in O
BACTEC O
- O
460 O
assay O
. O

Aldehyde B
oxidase O
importance O
in O
vivo O
in O
xenobiotic O
metabolism O
: O
imidacloprid B
nitroreduction O
in O
mice O
. O

Aldehyde B
oxidase O
( O
AOX O
) O
metabolizes O
many O
xenobiotics O
in O
vitro O
, O
but O
its O
importance O
in O
vivo O
is O
usually O
unknown O
relative O
to O
cytochrome O
P450s O
( O
CYPs O
) O
and O
other O
detoxification O
systems O
. O

Currently O
, O
the O
most O
important O
insecticides O
are O
neonicotinoids O
, O
which O
are O
metabolized O
in O
vitro O
by O
AOX O
on O
reduction O
of O
the O
nitroimino B
group O
and O
by O
CYPs O
via O
oxidation O
reactions O
. O

The O
goal O
of O
this O
study O
was O
to O
establish O
the O
relative O
importance O
of O
AOX O
and O
CYPs O
in O
vivo O
using O
the O
mouse O
model O
. O

The O
procedure O
was O
to O
reduce O
liver O
AOX O
activity O
by O
providing O
tungsten B
or O
hydralazine B
in O
the O
drinking O
water O
or O
to O
use O
the O
AOX O
- O
deficient O
DBA O
/ O
2 O
mouse O
strain O
. O

None O
of O
these O
approaches O
reduced O
CYP O
activity O
measured O
in O
vitro O
with O
an O
isozyme O
nonspecific O
substrate O
. O

Liver O
AOX O
activity O
was O
reduced O
by O
45 O
% O
with O
tungsten B
and O
61 O
% O
with O
hydralazine B
and O
81 O
% O
in O
AOX O
- O
deficient O
mice O
relative O
to O
controls O
. O

When O
mice O
were O
treated O
ip O
with O
the O
major O
neonicotinoid O
imidacloprid B
( O
IMI B
) O
, O
metabolism O
by O
CYP O
oxidation O
reactions O
was O
not O
appreciably O
affected O
, O
whereas O
the O
AOX O
- O
generated O
nitrosoguanidine B
metabolite O
was O
decreased O
by O
30 O
% O
with O
tungsten B
and O
56 O
% O
with O
hydralazine B
and O
86 O
% O
in O
the O
AOX O
- O
deficient O
mice O
. O

The O
other O
IMI B
nitroreduction O
metabolite O
, O
desnitro B
- I
IMI I
, O
was O
decreased O
by O
55 O
% O
, O
65 O
% O
, O
and O
81 O
% O
with O
tungsten B
, O
hydralazine B
, O
and O
in O
the O
AOX O
- O
deficient O
mice O
, O
respectively O
. O

Thus O
, O
decreasing O
liver O
AOX O
activity O
by O
three O
quite O
different O
procedures O
gave O
a O
corresponding O
decrease O
for O
in O
vivo O
reductive O
metabolites O
in O
the O
liver O
of O
IMI B
- O
treated O
mice O
. O

Possible O
AOX O
involvement O
in O
IMI O
metabolism O
in O
insects O
was O
evaluated O
using O
AOX O
- O
expressing O
and O
AOX O
- O
deficient O
Drosophila O
, O
but O
no O
differences O
were O
found O
in O
IMI O
nitroreduction O
or O
sensitivity O
between O
the O
two O
strains O
. O

This O
is O
the O
first O
study O
to O
establish O
the O
in O
vivo O
relevance O
of O
AOX B
in O
neonicotinoid O
metabolism O
in O
mammals O
and O
one O
of O
the O
first O
for O
xenobiotics O
in O
general O
. O

Modulation O
of O
membrane O
phospholipids O
, O
the O
cytosolic O
calcium B
influx O
and O
cell O
proliferation O
following O
treatment O
of O
B16 O
- O
F10 O
cells O
with O
recombinant O
phospholipase O
- O
D O
from O
Loxosceles O
intermedia O
( O
brown O
spider O
) O
venom O
. O

The O
mechanism O
through O
which O
brown O
spiders O
( O
Loxosceles O
genus O
) O
cause O
dermonecrosis O
, O
dysregulated O
inflammatory O
responses O
, O
hemolysis O
and O
platelet O
aggregation O
, O
which O
are O
effects O
reported O
following O
spider O
bites O
, O
is O
currently O
attributed O
to O
the O
presence O
of O
phospholipase O
- O
D O
in O
the O
venom O
. O

In O
the O
present O
investigation O
, O
through O
two O
- O
dimensional O
immunoblotting O
, O
we O
observed O
immunological O
cross O
- O
reactivity O
for O
at O
least O
25 O
spots O
in O
crude O
Loxosceles O
intermedia O
venom O
, O
indicating O
high O
expression O
levels O
for O
different O
isoforms O
of O
phospholipase O
- O
D O
. O

Using O
a O
recombinant O
phospholipase O
- O
D O
from O
the O
venom O
gland O
of O
L O
. O
intermedia O
( O
LiRecDT1 O
) O
in O
phospholipid O
- O
degrading O
kinetic O
experiments O
, O
we O
determined O
that O
this O
phospholipase O
- O
D O
mainly O
hydrolyzes O
synthetic O
sphingomyelin B
in O
a O
time O
- O
dependent O
manner O
, O
generating O
ceramide B
1 I
- I
phosphate I
plus O
choline B
, O
as O
well O
as O
lysophosphatidylchol B
, O
generating O
lysophosphatidic B
acid I
plus O
choline B
, O
but O
exhibits O
little O
activity O
against O

phosphatidylcholine B
. O

Through O
immunofluorescence O
assays O
with O
antibodies O
against O
LiRecDT1 O
and O
using O
a O
recombinant O
GFP O
- O
LiRecDT1 O
fusion O
protein O
, O
we O
observed O
direct O
binding O
of O
LiRecDT1 O
to O
the O
membrane O
of O
B16 O
- O
F10 O
cells O
. O

We O
determined O
that O
LiRecDT1 O
hydrolyzes O
phospholipids O
in O
detergent O
extracts O
and O
from O
ghosts O
of O
B16 O
- O
F10 O
cells O
, O
generating O
choline B
, O
indicating O
that O
the O
enzyme O
can O
access O
and O
modulate O
and O
has O
activity O
against O
membrane O
phospholipids O
. O

Additionally O
, O
using O
Fluo B
- I
4 I
, O
a O
calcium B
- O
sensitive O
fluorophore O
, O
it O
was O
shown O
that O
treatment O
of O
cells O
with O
phospholipase O
- O
D O
induced O
an O
increase O
in O
the O
calcium B
concentration O
in O
the O
cytoplasm O
, O
but O
without O
altering O
viability O
or O
causing O
damage O
to O
cells O
. O

Finally O
, O
based O
on O
the O
known O
endogenous O
activity O
of O
phospholipase O
- O
D O
as O
an O
inducer O
of O
cell O
proliferation O
and O
the O
fact O
that O
LiRecDT1 O
binds O
to O
the O
cell O
surface O
, O
hydrolyzing O
phospholipids O
to O
generate O
bioactive O
lipids O
, O
we O
employed O
LiRecDT1 O
as O
an O
exogenous O
source O
of O
phospholipase O
- O
D O
in O
B16 O
- O
F10 O
cells O
. O

Treatment O
of O
the O
cells O
was O
effective O
in O
increasing O
their O
proliferation O
in O
a O
time O
- O
and O
concentration O
- O
dependent O
manner O
, O
especially O
in O
the O
presence O
of O
synthetic O
sphingomyelin B
in O
the O
medium O
. O

The O
results O
described O
herein O
indicate O
the O
ability O
of O
brown O
spider O
phospholipase O
- O
D O
to O
induce O
the O
generation O
of O
bioactive O
phospholipids O
, O
calcium B
influx O
into O
the O
cytoplasm O
and O
cell O
proliferation O
, O
suggesting O
that O
this O
molecule O
can O
be O
used O
as O
a O
bioactive O
tool O
for O
experimental O
protocols O
in O
cell O
biology O
. O

Identification O
of O
functionally O
relevant O
lysine B
residues O
that O
modulate O
human O
farnesoid O
x O
receptor O
activation O
. O

Base O
amino B
acid I
lysine B
residues O
play O
an O
important O
role O
in O
regulation O
of O
nuclear O
receptors O
[ O
e O
. O
g O
. O
, O
farnesyl O
X O
receptor O
( O
FXR O
) O
] O
, O
leading O
to O
enhanced O
or O
suppressed O
biologic O
activity O
. O

To O
understand O
the O
molecular O
mechanisms O
and O
the O
subsequent O
effects O
in O
modulating O
FXR O
functions O
in O
diverse O
biologic O
processes O
, O
we O
individually O
replaced O
eight O
highly O
conserved O
lysine B
residues O
of O
human O
FXR O
( O
hFXR O
) O
with O
arginine B
. O

The O
effects O
of O
each O
mutated O
FXR O
on O
target O
gene O
activation O
, O
subcellular O
localization O
, O
protein O
- O
protein O
association O
, O
and O
protein O
- O
DNA O
interaction O
were O
investigated O
. O

Results O
demonstrated O
that O
K122R O
, O
K210R O
, O
K339R O
, O
and O
K460R O
mutants O
of O
hFXR O
significantly O
impaired O
target O
gene O
[ O
organic O
solute O
transporter O
alpha O
/ O
beta O
and O
bile B
salt I
export O
pump O
( O
BSEP O
) O
] O
promoter O
reporter O
activity O
in O
a O
ligand O
- O
dependent O
fashion O
. O

None O
of O
the O
four O
mutants O
affected O
the O
nuclear O
localization O
of O
FXR O
. O

Protein O
interaction O
studies O
show O
that O
K210R O
slightly O
but O
significantly O
decreased O
FXR O
/ O
retinoid B
X O
receptor O
( O
RXR O
) O
binding O
affinity O
but O
enhanced O
the O
interaction O
of O
FXR O
with O
lysine B
methyltransferase O
Set7 O
/ O
9 O
by O
~ O
21 O
% O
. O

K460R O
decreased O
the O
FXR O
interaction O
with O
Set7 O
/ O
9 O
by O
~ O
45 O
% O
but O
had O
no O
significant O
effects O
on O
interaction O
with O
RXR O
. O

Electrophoretic O
mobility O
shift O
assays O
demonstrated O
that O
hFXR O
- O
K210R O
and O
- O
K339R O
reduced O
the O
protein O
- O
DNA O
( O
IR1 O
element O
at O
hBSEP O
promoter O
) O
binding O
affinity O
by O
~ O
80 O
and O
~ O
90 O
% O
, O
respectively O
. O

Computational O
- O
based O
protein O
modeling O
studies O
were O
consistent O
with O
these O
results O
and O
provided O
further O
insights O
into O
the O
potential O
underlying O
mechanisms O
responsible O
for O
these O
results O
. O

In O
conclusion O
, O
four O
highly O
conserved O
lysine B
residues O
of O
hFXR O
, O
K122 O
, O
K210 O
, O
K339 O
, O
and O
K460 O
, O
have O
been O
identified O
that O
play O
a O
critical O
role O
in O
FXR O
target O
gene O
regulation O
and O
molecular O
interaction O
( O
protein O
- O
protein O
and O
protein O
- O
DNA O
) O
. O

NMR O
- O
based O
metabonomic O
in O
hippocampus O
, O
nucleus O
accumbens O
and O
prefrontal O
cortex O
of O
methamphetamine B
- O
sensitized O
rats O
. O

( B
1 I
) I
H I
NMR O
spectroscopy O
was O
applied O
to O
investigate O
the O
changes O
of O
cerebral O
metabolites O
in O
brain O
hippocampus O
, O
nucleus O
accumbens O
( O
NAC O
) O
and O
prefrontal O
cortex O
( O
PFC O
) O
of O
the O
rats O
subjected O
to O
subcutaneous O
twice O
- O
daily O
injections O
of O
2 O
. O
5mg O
/ O
kg O
methamphetamine B
( O
MAP B
) O
for O
7 O
days O
. O

The O
results O
indicated O
that O
MAP B
exposure O
induced O
significant O
behavioral O
sensitization O
and O
altered O
cerebral O
metabolites O
in O
rats O
. O

The O
neurotransmitters O
glutamate B
, O
glutamine B
and O
GABA B
significantly O
decreased O
in O
hippocampus O
, O
NAC O
and O
PFC O
. O

Specifically O
, O
increased O
succinic B
acid I
semialdehyde I
, O
a O
metabolism O
product O
of O
GABA B
, O
was O
observed O
in O
hippocampus O
. O

Additionally O
, O
decreased O
serotonin B
was O
observed O
in O
both O
NAC O
and O
PFC O
, O
whereas O
decreased O
dopamine B
was O
only O
observed O
in O
NAC O
after O
repeated O
MAP B
treatment O
. O

Glutathione B
obviously O
decreased O
in O
above O
brain O
regions O
, O
whereas O
acetylcysteine B
declined O
in O
hippocampus O
and O
NAC O
, O
and O
taurine B
declined O
in O
NAC O
and O
PFC O
. O

Homocysteic B
acid I
was O
elevated O
in O
hippocampus O
and O
NAC O
by O
repeated O
MAP B
administration O
. O

Membrane O
ingredients O
like O
phosphocholine B
elevated O
in O
response O
to O
MAP B
administration O
in O
NAC O
and O
PFC O
. O

N B
- I
Acetyl I
- I
aspartate I
, O
a O
marker O
of O
neuronal O
viability O
, O
decreased O
in O
the O
three O
regions O
; O
however O
, O
myo B
- I
inositol I
, O
a O
glial O
cell O
marker O
, O
increased O
in O
hippocampus O
and O
PFC O
. O

Tricarboxylic B
acid I
cycle O
intermediate O
products O
, O
such O
as O
alpha B
- I
ketoglutarate I
, O
succinate B
, O
citrate B
and O
the O
methionine B
significantly O
decreased O
in O
above O
three O
brain O
regions O
after O
MAP O
administration O
; O
however O
, O
ADP B
decreased O
in O
hippocampus O
. O

These O
results O
indicate O
that O
repeated O
MAP B
treatment O
causes O
neurotransmitters O
disturbance O
, O
imbalance O
between O
oxidative O
stress O
and O
antioxidants O
, O
and O
gliosis O
in O
hippocampus O
, O
NAC O
and O
PFC O
. O

Profound O
metabolic O
changes O
detected O
across O
brain O
regions O
provide O
the O
first O
evidence O
of O
metabonomic O
changes O
in O
MAP O
- O
induced O
sensitized O
rats O
. O

Alcohol B
cirrhosis O
alters O
nuclear O
receptor O
and O
drug O
transporter O
expression O
in O
human O
liver O
. O

Unsafe O
use O
of O
alcohol B
results O
in O
approximately O
2 O
. O
5 O
million O
deaths O
worldwide O
, O
with O
cirrhosis O
contributing O
to O
16 O
. O
6 O
% O
of O
reported O
deaths O
. O

Serum O
insulin O
levels O
are O
often O
elevated O
in O
alcoholism O
and O
may O
result O
in O
diabetes O
, O
which O
is O
why O
alcoholic O
liver O
disease O
and O
diabetes O
often O
are O
present O
together O
. O

Because O
there O
is O
a O
sizable O
population O
with O
these O
diseases O
alone O
or O
in O
combination O
, O
the O
purpose O
of O
this O
study O
was O
to O
determine O
whether O
transporter O
expression O
in O
human O
liver O
is O
affected O
by O
alcoholic O
cirrhosis O
, O
diabetes O
, O
and O
alcoholic O
cirrhosis O
coexisting O
with O
diabetes O
. O

Transporters O
aid O
in O
hepatobiliary O
excretion O
of O
many O
drugs O
and O
toxic O
chemicals O
and O
can O
be O
determinants O
of O
drug O
- O
induced O
liver O
injury O
. O

Drug O
transporter O
expression O
and O
transcription O
factor O
- O
relative O
mRNA O
and O
protein O
expression O
in O
normal O
, O
diabetic O
, O
cirrhotic O
, O
and O
cirrhosis O
with O
diabetes O
human O
livers O
were O
quantified O
. O

Cirrhosis O
significantly O
increased O
ABCC4 O
, O
5 O
, O
ABCG2 O
, O
and O
solute O
carrier O
organic O
anion O
( O
SLCO O
) O
2B1 O
mRNA O
expression O
and O
decreased O
SLCO1B3 O
mRNA O
expression O
in O
the O
liver O
. O

ABCC1 O
, O
3 O
- O
5 O
, O
and O
ABCG2 O
protein O
expression O
was O
also O
upregulated O
by O
alcoholic O
cirrhosis O
. O

ABCC3 O
- O
5 O
and O
ABCG2 O
protein O
expression O
was O
also O
upregulated O
in O
diabetic O
cirrhosis O
. O

Cirrhosis O
increased O
nuclear O
factor O
E2 O
- O
related O
factor O
2 O
mRNA O
expression O
, O
whereas O
it O
decreased O
pregnane B
- O
X O
- O
receptor O
and O
farnesoid O
- O
X O
- O
receptor O
mRNA O
expression O
in O
comparison O
with O
normal O
livers O
. O

Hierarchical O
cluster O
analysis O
indicated O
that O
expressions O
of O
ABCC2 O
, O
3 O
, O
and O
6 O
; O
SLCO1B1 O
and O
1B3 O
; O
and O
ABCC4 O
and O
5 O
were O
more O
closely O
related O
in O
the O
livers O
from O
this O
cohort O
. O

Overall O
, O
alcoholic O
cirrhosis O
altered O
transporter O
expression O
in O
human O
liver O
. O

Octahedral O
Co3O4 B
particles O
threaded O
by O
carbon B
nanotube O
arrays O
as O
integrated O
structure O
anodes O
for O
lithium B
ion O
batteries O
. O

Octahedral O
Co3O4 B
particles O
threaded O
by O
ultra O
- O
long O
multi O
- O
walled O
carbon B
nanotube O
( O
MWCNT O
) O
arrays O
were O
prepared O
by O
a O
hydrothermal O
process O
and O
subsequent O
calcination O
. O

The O
Co3O4 B
octahedron O
with O
the O
( O
111 O
) O
facets O
attaches O
to O
MWCNTs O
uniformly O
and O
closely O
. O

The O
composite O
can O
be O
used O
as O
an O
integrated O
anode O
for O
lithium B
ion O
batteries O
( O
LIBs O
) O
without O
any O
other O
additives O
( O
such O
as O
conductive O
additives O
and O
polymer O
binder O
) O
, O
which O
exhibits O
a O
high O
reversible O
capacity O
of O
725 O
mA O
h O
g O
( O
- O
1 O
) O
at O
a O
current O
density O
of O
100 O
mA O
g O
( O
- O
1 O
) O
, O
and O
excellent O
cyclic O
stability O
without O
capacity O
degradation O
over O
100 O
cycles O
at O
a O
current O
density O
of O
500 O
mA O
g O
( O
- O
1 O
) O
. O

The O
high O
performance O
can O
be O
attributed O
to O
the O
unique O
structure O
: O
( O
i O
) O
the O
ultra O
- O
long O
MWCNT O
array O
facilitates O
fast O
electron O
transfer O
; O
( O
ii O
) O
the O
tight O
adhesion O
between O
Co3O4 B
and O
MWCNTs O
prevents O
particle O
drifting O
and O
agglomeration O
; O
( O
iii O
) O
the O
free O
space O
between O
MWCNTs O
promotes O
fast O
ion O
transport O
and O
alleviates O
the O
large O
volume O
variation O
during O
discharge O
- O
charge O
process O
. O

This O
work O
demonstrates O
the O
great O
potential O
of O
MWCNT O
arrays O
as O
substrate O
and O
provides O
insights O
for O
the O
design O
and O
direct O
use O
of O
MWCNT O
array O
- O
based O
materials O
in O
LIBs O
, O
which O
will O
be O
helpful O
for O
future O
development O
of O
high O
- O
performance O
electrode O
materials O
. O

Clinical O
proof O
- O
of O
- O
concept O
study O
with O
MSDC B
- I
0160 I
, O
a O
prototype O
mTOT O
- O
modulating O
insulin O
sensitizer O
. O

It O
may O
be O
possible O
to O
achieve O
insulin O
sensitivity O
through O
the O
recently O
identified O
mitochondrial O
target O
of O
thiazolidinediones B
( O
mTOT O
) O
, O
thereby O
avoiding O
peroxisome O
proliferator O
- O
activated O
receptor O
- O
gamma O
( O
PPAR O
- O
gamma O
) O
- O
dependent O
side O
effects O
. O

In O
this O
phase O
IIb O
clinical O
trial O
, O
258 O
patients O
with O
type O
2 O
diabetes O
completed O
a O
12 O
- O
week O
protocol O
with O
50 O
, O
100 O
, O
or O
150 O
mg O
of O
MSDC B
- I
0160 I
( O
an O
mTOT O
modulator O
) O
, O
45 O
mg O
pioglitazone B
HCl I
( O
a O
PPAR O
- O
gamma O
agonist O
) O
, O
or O
a O
placebo O
. O

The O
two O
active O
treatments O
lowered O
fasting O
glucose B
levels O
to O
the O
same O
extent O
. O

The O
decreases O
in O
glycated O
hemoglobin O
( O
HbA1c O
) O
observed O
with O
the O
two O
higher O
doses O
of O
MSDC O
- I
0160 I
were O
not O
different O
from O
those O
associated O
with O
pioglitazone B
. O

By O
contrast O
, O
fluid O
retention O
as O
evidenced O
by O
reduction O
in O
hematocrit O
, O
red O
blood O
cells O
, O
and O
total O
hemoglobin O
was O
50 O
% O
less O
in O
the O
MSDC O
- O
0160 O
- O
treated O
groups O
. O

There O
was O
also O
a O
smaller O
increase O
in O
high O
- O
molecular O
- O
weight O
( O
HMW O
) O
adiponectin O
with O
MSDC O
- O
0160 O
than O
with O
pioglitazone B
( O
P O
< O
0 O
. O
0001 O
) O
, O
suggesting O
that O
MSDC O
- O
0160 O
produces O
less O
expansion O
of O
white O
adipose O
tissue O
. O

Thus O
, O
mTOT O
modulators O
may O
have O
glucose B
- O
lowering O
effects O
similar O
to O
those O
of O
pioglitazone B
but O
without O
the O
adverse O
effects O
associated O
with O
PPAR O
- O
gamma O
agonists O
. O

Novel O
insights O
into O
the O
biology O
of O
interleukin O
- O
32 O
. O

Interleukin O
( O
IL O
) O
- O
32 O
is O
known O
as O
a O
proinflammatory O
cytokine O
that O
is O
likely O
involved O
in O
several O
diseases O
, O
including O
infections O
, O
chronic O
inflammation O
, O
and O
cancer O
. O

Since O
the O
first O
report O
in O
2005 O
, O
IL O
- O
32 O
has O
been O
the O
subject O
of O
numerous O
studies O
to O
unravel O
the O
biological O
function O
of O
this O
molecule O
. O

For O
example O
, O
silencing O
of O
endogenous O
IL O
- O
32 O
in O
primary O
or O
cell O
lines O
of O
human O
origin O
consistently O
suppressed O
responses O
to O
Toll O
- O
like O
receptors O
. O

The O
protein O
folding O
structure O
of O
the O
six O
isoforms O
of O
IL O
- O
32 O
does O
not O
resemble O
that O
of O
any O
classical O
cytokine O
and O
as O
of O
this O
writing O
, O
a O
specific O
IL O
- O
32 O
receptor O
has O
not O
been O
identified O
. O

Instead O
, O
we O
propose O
a O
mechanism O
by O
which O
exposure O
to O
extracellular O
IL O
- O
32 O
or O
overexpression O
of O
the O
molecule O
results O
in O
binding O
to O
intracellular O
partners O
that O
influences O
functions O
such O
as O
gene O
expression O
, O
cell O
death O
, O
or O
survival O
. O

As O
such O
, O
this O
review O
offers O
insights O
into O
the O
role O
of O
IL O
- O
32 O
in O
several O
diseases O
, O
host O
defense O
, O
inflammation O
, O
immune O
function O
, O
and O
cancer O
. O

Finally O
, O
possibilities O
to O
target O
IL O
- O
32 O
in O
several O
diseases O
are O
proposed O
. O

A O
method O
for O
non O
- O
invasive O
full O
- O
field O
imaging O
and O
quantification O
of O
chemical O
species O
. O

We O
present O
a O
novel O
method O
for O
full O
- O
field O
scalar O
visualization O
and O
quantification O
of O
species O
concentration O
fields O
. O

We O
term O
this O
method O
species O
- O
altered O
fluorescence O
imaging O
( O
SAFI O
) O
. O

The O
method O
employs O
electrically O
neutral O
fluorescent O
dyes O
whose O
quantum O
yields O
are O
selectively O
quenched O
or O
enhanced O
by O
species O
of O
interest O
. O

SAFI O
enables O
simultaneous O
imaging O
of O
material O
interfaces O
and O
provides O
non O
- O
invasive O
, O
scalar O
- O
field O
quantitation O
of O
two O
- O
dimensional O
species O
concentration O
fields O
. O

We O
describe O
criteria O
for O
choosing O
SAFI O
dyes O
and O
tabulate O
35 O
promising O
SAFI O
dyes O
and O
their O
relevant O
properties O
. O

Next O
, O
we O
describe O
species O
concentration O
quantification O
with O
SAFI O
via O
Stern O
- O
Volmer O
quenching O
and O
discuss O
the O
sensitivity O
and O
resolution O
of O
our O
method O
. O

We O
demonstrate O
this O
method O
with O
two O
dyes O
, O
6 B
- I
methoxy I
- I
N I
- I
( I
3 I
- I
sulfopropyl I
) I
quinolinium I
( O
SPQ B
) O
and O
10 B
- I
( I
3 I
- I
sulfopropyl I
) I
acridinium I
betaine I
( O
SAB B
) O
. O

We O
demonstrate O
our O
method O
in O
full O
- O
field O
visualization O
of O
several O
challenging O
electrokinetic O
flows O
: O
isotachophoresis O
( O
ITP O
) O
in O
both O
cationic O
and O
anionic O
modes O
, O
and O
in O
a O
convective O
electrokinetic O
instability O
( O
EKI O
) O
flow O
. O

Through O
these O
experiments O
we O
collectively O
quantify O
ion O
concentration O
shock O
velocities O
, O
simultaneously O
measure O
concentrations O
of O
five O
species O
, O
and O
quantify O
the O
development O
of O
an O
unsteady O
, O
chaotic O
, O
2D O
flow O
. O

Gram O
- O
scale O
synthesis O
of O
graphene B
sheets O
by O
a O
catalytic O
arc O
- O
discharge O
method O
. O

Flake O
graphite B
is O
used O
as O
carbon B
source O
and O
ZnO B
or O
ZnS B
as O
catalyst O
in O
the O
synthesis O
of O
high O
- O
quality O
graphene B
sheets O
. O

A O
catalytic O
growth O
mechanism O
for O
cathode O
- O
part O
graphene B
synthesis O
in O
the O
arc O
- O
discharge O
apparatus O
and O
an O
exfoliation O
mechanism O
for O
wall O
- O
part O
graphene B
synthesis O
are O
introduced O
. O

N O
- O
doped O
cathode O
- O
part O
graphene B
and O
undoped O
wall O
- O
part O
graphene B
are O
formed O
simultaneously O
. O

Peptides O
as O
the O
next O
generation O
of O
anti O
- O
infectives O
. O

Synthesis O
and O
large O
- O
scale O
manufacturing O
technologies O
are O
now O
available O
for O
the O
commercial O
production O
of O
even O
the O
most O
complex O
peptide O
anti O
- O
infectives O
. O

Married O
with O
the O
potential O
of O
this O
class O
of O
molecule O
as O
the O
next O
generation O
of O
effective O
, O
resistance O
- O
free O
and O
safe O
antimicrobials O
, O
and O
a O
much O
better O
understanding O
of O
their O
biology O
, O
pharmacology O
and O
pharmacodynamics O
, O
the O
first O
regulatory O
approvals O
and O
introduction O
into O
clinical O
practice O
of O
these O
promising O
drug O
candidates O
will O
likely O
be O
soon O
. O

This O
is O
a O
key O
juncture O
in O
the O
history O
/ O
life O
cycle O
of O
peptide O
anti O
- O
infectives O
and O
, O
perhaps O
, O
their O
commercial O
and O
therapeutic O
potential O
is O
about O
to O
be O
realized O
. O

This O
review O
highlights O
the O
promise O
of O
these O
agents O
as O
the O
next O
generation O
of O
therapeutics O
and O
summarizes O
the O
challenges O
faced O
in O
, O
and O
lessons O
learned O
from O
, O
the O
past O
. O

Simultaneously O
strong O
and O
tough O
ultrafine O
continuous O
nanofibers O
. O

Strength O
of O
structural O
materials O
and O
fibers O
is O
usually O
increased O
at O
the O
expense O
of O
strain O
at O
failure O
and O
toughness O
. O

Recent O
experimental O
studies O
have O
demonstrated O
improvements O
in O
modulus O
and O
strength O
of O
electrospun O
polymer O
nanofibers O
with O
reduction O
of O
their O
diameter O
. O

Nanofiber O
toughness O
has O
not O
been O
analyzed O
; O
however O
, O
from O
the O
classical O
materials O
property O
trade O
- O
off O
, O
one O
can O
expect O
it O
to O
decrease O
. O

Here O
, O
on O
the O
basis O
of O
a O
comprehensive O
analysis O
of O
long O
( O
5 O
- O
10 O
mm O
) O
individual O
polyacrylonitrile B
nanofibers O
, O
we O
show O
that O
nanofiber O
toughness O
also O
dramatically O
improves O
. O

Reduction O
of O
fiber O
diameter O
from O
2 O
. O
8 O
mu O
m O
to O
~ O
100 O
nm O
resulted O
in O
simultaneous O
increases O
in O
elastic O
modulus O
from O
0 O
. O
36 O
to O
48 O
GPa O
, O
true O
strength O
from O
15 O
to O
1750 O
MPa O
, O
and O
toughness O
from O
0 O
. O
25 O
to O
605 O
MPa O
with O
the O
largest O
increases O
recorded O
for O
the O
ultrafine O
nanofibers O
smaller O
than O
250 O
nm O
. O

The O
observed O
size O
effects O
showed O
no O
sign O
of O
saturation O
. O

Structural O
investigations O
and O
comparisons O
with O
mechanical O
behavior O
of O
annealed O
nanofibers O
allowed O
us O
to O
attribute O
ultrahigh O
ductility O
( O
average O
failure O
strain O
stayed O
over O
50 O
% O
) O
and O
toughness O
to O
low O
nanofiber O
crystallinity O
resulting O
from O
rapid O
solidification O
of O
ultrafine O
electrospun O
jets O
. O

Demonstrated O
superior O
mechanical O
performance O
coupled O
with O
the O
unique O
macro O
- O
nano O
nature O
of O
continuous O
nanofibers O
makes O
them O
readily O
available O
for O
macroscopic O
materials O
and O
composites O
that O
can O
be O
used O
in O
safety O
- O
critical O
applications O
. O

The O
proposed O
mechanism O
of O
simultaneously O
high O
strength O
, O
modulus O
, O
and O
toughness O
challenges O
the O
prevailing O
50 O
year O
old O
paradigm O
of O
high O
- O
performance O
polymer O
fiber O
development O
calling O
for O
high O
polymer O
crystallinity O
and O
may O
have O
broad O
implications O
in O
fiber O
science O
and O
technology O
. O

Diameter O
- O
Dependent O
Photocurrent O
in O
InAsSb O
Nanowire O
Infrared O
Photodetectors O
. O

Photoconductors O
using O
vertical O
arrays O
of O
InAs B
/ O
InAs1 B
- I
xSbx I
nanowires O
with O
varying O
Sb B
composition O
x O
have O
been O
fabricated O
and O
characterized O
. O

The O
spectrally O
resolved O
photocurrents O
are O
strongly O
diameter O
dependent O
with O
peaks O
, O
which O
are O
red O
- O
shifted O
with O
diameter O
, O
appearing O
for O
thicker O
wires O
. O

Results O
from O
numerical O
simulations O
are O
in O
good O
agreement O
with O
the O
experimental O
data O
and O
reveal O
that O
the O
peaks O
are O
due O
to O
resonant O
modes O
that O
enhance O
the O
coupling O
of O
light O
into O
the O
wires O
. O

Through O
proper O
selection O
of O
wire O
diameter O
, O
the O
absorptance O
can O
be O
increased O
by O
more O
than O
1 O
order O
of O
magnitude O
at O
a O
specific O
wavelength O
compared O
to O
a O
thin O
planar O
film O
with O
the O
same O
amount O
of O
material O
. O

A O
maximum O
20 O
% O
cutoff O
wavelength O
of O
5 O
. O
7 O
mu O
m O
is O
obtained O
at O
5 O
K O
for O
a O
wire O
diameter O
of O
717 O
nm O
at O
a O
Sb B
content O
of O
x O
= O
0 O
. O
62 O
, O
but O
simulations O
predict O
that O
detection O
at O
longer O
wavelengths O
can O
be O
achieved O
by O
increasing O
the O
diameter O
. O

Furthermore O
, O
photodetection O
in O
InAsSb O
nanowire O
arrays O
integrated O
on O
Si B
substrates O
is O
also O
demonstrated O
. O

Slip O
length O
measurement O
of O
confined O
air O
flow O
on O
three O
smooth O
surfaces O
. O

An O
experimental O
measurement O
of O
the O
slip O
length O
of O
air O
flow O
close O
to O
three O
different O
solid O
surfaces O
is O
presented O
. O

The O
substrate O
was O
driven O
by O
a O
nanopositioner O
moving O
toward O
an O
oscillating O
glass O
sphere O
glued O
to O
an O
atomic O
force O
microscopy O
( O
AFM O
) O
cantilever O
. O

A O
large O
separation O
distance O
was O
used O
to O
get O
more O
effective O
data O
. O

The O
slip O
length O
value O
was O
obtained O
by O
analyzing O
the O
amplitude O
and O
phase O
data O
of O
the O
cantilever O
. O

The O
measurements O
show O
that O
the O
slip O
length O
does O
not O
depend O
on O
the O
oscillation O
amplitude O
of O
the O
cantilever O
. O

Because O
of O
the O
small O
difference O
among O
the O
slip O
lengths O
of O
the O
three O
surfaces O
, O
a O
simplified O
analysis O
method O
was O
used O
. O

The O
results O
show O
that O
on O
glass O
, O
graphite B
, O
and O
mica B
surfaces O
the O
slip O
lengths O
are O
98 O
, O
234 O
, O
and O
110 O
nm O
, O
respectively O
. O

Templating O
Sub O
- O
10 O
nm O
Atomic O
Layer O
Deposited O
Oxide B
Nanostructures O
on O
Graphene B
via O
One O
- O
Dimensional O
Organic O
Self O
- O
Assembled O
Monolayers O
. O

Molecular O
- O
scale O
control O
over O
the O
integration O
of O
disparate O
materials O
on O
graphene B
is O
a O
critical O
step O
in O
the O
development O
of O
graphene B
- O
based O
electronics O
and O
sensors O
. O

Here O
, O
we O
report O
that O
self O
- O
assembled O
monolayers O
of O
10 B
, I
12 I
- I
pentacosadiynoic I
acid I
( O
PCDA B
) O
on O
epitaxial O
graphene B
can O
be O
used O
to O
template O
the O
reaction O
and O
directed O
growth O
of O
atomic O
layer O
deposited O
( O
ALD O
) O
oxide B
nanostructures O
with O
sub O
- O
10 O
nm O
lateral O
resolution O
. O

PCDA B
spontaneously O
assembles O
into O
well O
- O
ordered O
domains O
consisting O
of O
one O
- O
dimensional O
molecular O
chains O
that O
coat O
the O
entire O
graphene B
surface O
in O
a O
manner O
consistent O
with O
the O
symmetry O
of O
the O
underlying O
graphene B
lattice O
. O

Subsequently O
, O
zinc B
oxide I
and O
alumina B
ALD O
precursors O
are O
shown O
to O
preferentially O
react O
with O
the O
functional O
moieties O
of O
PCDA B
, O
resulting O
in O
templated O
oxide B
nanostructures O
. O

The O
retention O
of O
the O
original O
one O
- O
dimensional O
molecular O
ordering O
following O
ALD O
is O
dependent O
on O
the O
chemical O
reaction O
pathway O
and O
the O
stability O
of O
the O
monolayer O
, O
which O
can O
be O
enhanced O
via O
ultraviolet O
- O
induced O
molecular O
cross O
- O
linking O
. O

Oversampling O
to O
Overcome O
Overfitting O
: O
Exploring O
the O
Relationship O
between O
Data O
Set O
Composition O
, O
Molecular O
Descriptors O
, O
and O
Predictive O
Modeling O
Methods O
. O

The O
traditional O
biological O
assay O
is O
very O
time O
- O
consuming O
, O
and O
thus O
the O
ability O
to O
quickly O
screen O
large O
numbers O
of O
compounds O
against O
a O
specific O
biological O
target O
is O
appealing O
. O

To O
speed O
up O
the O
biological O
evaluation O
of O
compounds O
, O
high O
- O
throughput O
screening O
is O
widely O
used O
in O
the O
fields O
of O
biomedical O
, O
biological O
information O
, O
and O
drug O
discovery O
. O

The O
research O
presented O
in O
this O
study O
focuses O
on O
the O
use O
of O
support O
vector O
machines O
, O
a O
machine O
learning O
method O
, O
various O
classes O
of O
molecular O
descriptors O
, O
and O
different O
sampling O
techniques O
to O
overcome O
overfitting O
to O
classify O
compounds O
for O
cytotoxicity O
with O
respect O
to O
the O
Jurkat O
cell O
line O
. O

The O
cell O
cytotoxicity O
data O
set O
is O
imbalanced O
( O
a O
few O
active O
compounds O
and O
very O
many O
inactive O
compounds O
) O
, O
and O
the O
ability O
of O
the O
predictive O
modeling O
methods O
is O
adversely O
affected O
in O
these O
situations O
. O

Commonly O
imbalanced O
data O
sets O
are O
overfit O
with O
respect O
to O
the O
dominant O
classified O
end O
point O
; O
in O
this O
study O
the O
models O
routinely O
overfit O
toward O
inactive O
( O
noncytotoxic O
) O
compounds O
when O
the O
imbalance O
was O
substantial O
. O

Support O
vector O
machine O
( O
SVM O
) O
models O
were O
used O
to O
probe O
the O
proficiency O
of O
different O
classes O
of O
molecular O
descriptors O
and O
oversampling O
ratios O
. O

The O
SVM O
models O
were O
constructed O
from O
4D O
- O
FPs O
, O
MOE O
( O
1D O
, O
2D O
, O
and O
21 O
/ O
2D O
) O
, O
noNP O
+ O
MOE O
, O
and O
CATS2D O
trial O
descriptors O
pools O
and O
compared O
to O
the O
predictive O
abilities O
of O
CATS2D O
- O
based O
random O
forest O
models O
. O

Compared O
to O
previous O
results O
in O
the O
literature O
, O
the O
SVM O
models O
built O
from O
oversampled O
data O
sets O
exhibited O
better O
predictive O
abilities O
for O
the O
training O
and O
external O
test O
sets O
. O

Isolation O
of O
Ciliatamide B
D I
from O
a O
Marine O
Sponge O
Stelletta O
sp O
. O
and O
a O
Reinvestigation O
of O
the O
Configuration O
of O
Ciliatamide B
A I
. O

A O
new O
lipopeptide B
, O
ciliatamide B
D I
( O
1 O
) O
, O
was O
isolated O
from O
a O
marine O
sponge O
Stelletta O
sp O
. O
, O
collected O
at O
Oshimashinsone O
, O
together O
with O
the O
known O
compound O
ciliatamide B
A I
( O
2 O
) O
. O

Ciliatamide B
D I
( O
1 O
) O
is O
a O
congener O
of O
2 O
, O
in O
which O
N B
- I
Me I
- I
Phe I
is O
replaced O
by O
N B
- I
Me I
- I
Met I
( O
O O
) O
. O

Marfey O
' O
s O
analysis O
of O
the O
acid O
hydrolysate O
of O
1 O
demonstrated O
that O
the O
two O
constituent O
amino B
acids I
were O
both O
in O
the O
l O
- O
form O
. O

This O
result O
prompted O
us O
to O
carefully O
investigate O
the O
configuration O
of O
2 O
, O
resulting O
in O
the O
assignment O
of O
the O
l O
- O
form O
for O
both O
residues O
. O

Chemical O
ligation O
of O
oligodeoxynucleotide O
by O
X O
- O
irradiation O
and O
its O
application O
to O
regulation O
of O
G O
- O
quadruplex O
formation O
. O

We O
demonstrated O
radiolytic O
ligation O
of O
oligodeoxynucleotide O
( O
ODNs O
) O
possessing O
disulfide B
bond O
and O
its O
application O
to O
regulation O
of O
DNA O
quadruplex O
formation O
. O

G O
- O
rich O
hexamer O
ODNs O
had O
poor O
ability O
to O
form O
quadruplex O
, O
while O
X O
- O
irradiation O
of O
the O
ODNs O
induced O
interstrand O
exchange O
reaction O
at O
disulfide B
bond O
to O
form O
ligated O
12 O
mer O
ODNs O
, O
leading O
to O
the O
ready O
formation O
of O
quadruplex O
due O
to O
the O
entropic O
effect O
. O

Since O
complexation O
of O
the O
ligated O
ODNs O
with O
hemin O
in O
the O
presence O
of O
K B
( I
+ I
) I
showed O
strong O
soret O
band O
absorption O
and O
also O
catalyzed O
the O
H B
( I
2 I
) I
O I
( I
2 I
) I
- O
mediated O
oxidation O
of O
luminol B
, O
it O
appears O
that O
the O
quadruplex O
formed O
from O
ligated O
ODNs O
showed O
a O
function O
similar O
to O
native O
DNA O
quadruplex O
. O

Anti O
- O
adipogenic O
diarylheptanoids B
from O
Alnus O
hirsuta O
f O
. O
sibirica O
on O
3T3 O
- O
L1 O
cells O
. O

A O
new O
diarylheptanoid B
, O
( B
5S I
) I
- I
hydroxy I
- I
1 I
- I
( I
3 I
, I
4 I
- I
dihydroxyphenyl I
) I
- I
7 I
- I
( I
4 I
- I
hydroxyphenyl I
) I
- I
hepta I
- I
1E I
- I
en I
- I
3 I
- I
one I
( O
1 O
) O
, O
was O
isolated O
along O
with O
seventeen O
known O
diarylheptanoids B
( O
2 O
- O
18 O
) O
from O
the O
methanol B
extract O
of O
Alnus O
hirsuta O
f O
. O
sibirica O
leaves O
using O
bioactivity O
- O
guided O
fractionation O
. O

Among O
the O
isolated O
compounds O
, O
compounds O
1 O
and O
2 O
and O
4 O
- O
12 O
reduced O
lipid O
accumulation O
dose O
- O
dependently O
in O
3T3 O
- O
L1 O
preadipocytes O
. O

Of O
the O
compounds O
active O
in O
the O
present O
assay O
system O
, O
the O
most O
potent O
compound O
7 O
, O
platyphyllonol B
- I
5 I
- I
O I
- I
beta I
- I
d I
- I
xylopyranoside I
, O
significantly O
suppressed O
the O
induction O
of O
peroxisome O
proliferator O
activated O
receptor O
gamma O
( O
PPAR O
gamma O
and O
CCAAT O
/ O
enhancer O
binding O
protein O
alpha O
( O
C O
/ O
EBP O
alpha O
) O
protein O
expression O
, O
and O
inhibited O
adipocyte O
differentiation O
induced O
by O
troglitazone B
, O
a O
PPAR O
gamma O
agonist O
. O

It O
was O
demonstrated O
that O
compound O
7 O
has O
anti O
- O
adipogenic O
activity O
mediated O
by O
the O
regulation O
of O
PPAR O
gamma O
dependent O
pathways O
. O

Experience O
- O
dependent O
homeostatic O
synaptic O
plasticity O
in O
neocortex O
. O

The O
organism O
' O
s O
ability O
to O
adapt O
to O
the O
changing O
sensory O
environment O
is O
due O
in O
part O
to O
the O
ability O
of O
the O
nervous O
system O
to O
change O
with O
experience O
. O

Input O
and O
synapse O
specific O
Hebbian O
plasticity O
, O
such O
as O
long O
- O
term O
potentiation O
( O
LTP O
) O
and O
long O
- O
term O
depression O
( O
LTD O
) O
, O
are O
critical O
for O
sculpting O
the O
nervous O
system O
to O
wire O
its O
circuit O
in O
tune O
with O
the O
environment O
and O
for O
storing O
memories O
. O

However O
, O
these O
synaptic O
plasticity O
mechanisms O
are O
innately O
unstable O
and O
require O
another O
mode O
of O
plasticity O
that O
maintains O
homeostasis O
to O
allow O
neurons O
to O
function O
within O
a O
desired O
dynamic O
range O
. O

Several O
modes O
of O
homeostatic O
adaptation O
are O
known O
, O
some O
of O
which O
work O
at O
the O
synaptic O
level O
. O

This O
review O
will O
focus O
on O
the O
known O
mechanisms O
of O
experience O
- O
induced O
homeostatic O
synaptic O
plasticity O
in O
the O
neocortex O
and O
their O
potential O
function O
in O
sensory O
cortex O
plasticity O
. O

This O
article O
is O
part O
of O
a O
Special O
Issue O
entitled O
' O
Homeostatic O
Plasticity O
' O
. O

Gimatecan B
and O
other O
camptothecin B
derivatives O
poison O
Leishmania O
DNA O
- O
topoisomerase O
IB O
leading O
to O
a O
strong O
leishmanicidal O
effect O
. O

The O
aim O
of O
this O
work O
is O
the O
in O
vitro O
and O
ex O
vivo O
assessment O
of O
the O
leishmanicidal O
activity O
of O
camptothecin B
and O
three O
analogues O
used O
in O
cancer O
therapy O
: O
topotecan B
( O
Hycantim B
( O
( O
R O
) O
) O
) O
, O
gimatecan B
( O
ST1481 B
) O
and O
the O
pro O
- O
drug O
irinotecan B
( O
Camptosar B
( O
( O
R O
) O
) O
) O
as O
well O
as O
its O
active O
metabolite O
SN B
- I
38 I
against O
Leishmania O
infantum O
. O

The O
activity O
of O
camptothecin B
and O
its O
derivatives O
was O
studied O
on O
extracellular O
L O
. O
infantum O
infrared O
- O
emitting O
promastigotes O
and O
on O
an O
ex O
vivo O
murine O
model O
of O
infected O
splenocytes O
with O
L O
. O
infantum O
fluorescent O
amastigotes O
. O

In O
situ O
formation O
of O
SDS B
/ O
KCl B
precipitable O
DNA O
- O
protein O
complexes O
in O
Leishmania O
promastigotes O
indicated O
that O
these O
drugs O
are O
DNA O
topoisomerase O
IB O
poisons O
. O

The O
inhibitory O
potency O
of O
camptothecin B
derivatives O
on O
recombinant O
L O
. O
infantum O
topoisomerase O
IB O
was O
assessed O
in O
vitro O
showing O
that O
gimatecan B
is O
the O
most O
active O
compound O
preventing O
the O
relaxation O
of O
supercoiled O
DNA O
at O
submicromolar O
concentrations O
. O

Cleavage O
equilibrium O
assays O
in O
Leishmania O
topoisomerase O
IB O
show O
that O
gimatecan B
changes O
the O
equilibrium O
towards O
cleavage O
at O
much O
lower O
concentrations O
than O
the O
other O
camptothecin B
derivatives O
and O
that O
this O
effect O
persists O
over O
time O
. O

Gimatecan B
and O
camptothecin B
were O
the O
most O
powerful O
compounds O
preventing O
cell O
growth O
of O
free O
- O
living O
L O
. O
infantum O
promastigotes O
within O
the O
same O
concentration O
range O
. O

All O
these O
compounds O
killed O
L O
. O
infantum O
splenocyte O
- O
infecting O
amastigotes O
within O
the O
nanomolar O
range O
. O

The O
amastigote O
form O
showed O
higher O
sensitivity O
to O
topoisomerase O
IB O
poisons O
( O
with O
high O
therapeutic O
selectivity O
indexes O
) O
than O
free O
- O
living O
promastigotes O
. O

All O
the O
compounds O
assayed O
poisoned O
L O
. O
infantum O
DNA O
topoisomerase O
IB O
leading O
to O
a O
strong O
leishmanicidal O
effect O
. O

Camptothecin B
derivatives O
are O
suitable O
for O
reducing O
the O
parasitic O
burden O
of O
ex O
vivo O
infected O
splenocytes O
. O

The O
selectivity O
index O
of O
gimatecan B
makes O
it O
a O
promising O
drug O
against O
this O
neglected O
disease O
. O

Molecular O
markers O
from O
three O
organellar O
genomes O
unravel O
complex O
taxonomic O
relationships O
within O
the O
coralline O
algal O
genus O
Chiharaea O
( O
Corallinales O
, O
Rhodophyta O
) O
. O

The O
use O
of O
molecular O
markers O
in O
taxonomic O
studies O
has O
become O
a O
standard O
practice O
in O
biology O
. O

However O
, O
consensus O
on O
which O
markers O
to O
use O
at O
the O
species O
level O
is O
lacking O
because O
evolutionary O
lineages O
show O
differences O
in O
divergence O
rates O
between O
organellar O
genomes O
. O

Ideally O
, O
researchers O
use O
multiple O
lines O
of O
evidence O
when O
first O
describing O
a O
species O
, O
such O
as O
the O
incorporation O
of O
several O
molecular O
markers O
from O
varied O
genomes O
( O
mitochondrion O
, O
plastid O
and O
nucleus O
) O
. O

This O
study O
examined O
species O
boundaries O
in O
the O
red O
algal O
genus O
Chiharaea O
. O

We O
used O
five O
molecular O
markers O
, O
with O
at O
least O
one O
marker O
from O
each O
genome O
, O
coupled O
with O
thorough O
morphological O
analyses O
. O

We O
recognized O
three O
species O
in O
Chiharaea O
( O
C O
. O
americana O
, O
C O
. O
rhododactyla O
sp O
. O
nov O
. O
, O
C O
. O
silvae O
) O
and O
two O
forms O
( O
C O
. O
americana O
f O
. O
americana O
and O
C O
. O
americana O
f O
. O
bodegensis O
( O
H O
. O
W O
. O
Johansen O
) O
stat O
. O
nov O
. O
) O
. O

For O
C O
. O
americana O
f O
. O
americana O
and O
C O
. O
americana O
f O
. O
bodegensis O
differentiation O
based O
on O
morphological O
data O
was O
reflected O
in O
the O
plastid O
- O
encoded O
large O
subunit O
of O
RuBisCO O
( O
rbcL O
) O
, O
but O
was O
not O
concordant O
with O
either O
the O
mitochondrial O
cytochrome O
c O
oxidase O
subunit O
1 O
( O
COI O
- O
5P O
) O
or O
nuclear O
internal O
transcribed O
spacer O
( O
ITS O
) O
sequence O
data O
. O

We O
suggest O
that O
this O
discordance O
is O
indicative O
of O
ongoing O
hybridization O
and O
introgression O
between O
populations O
of O
C O
. O
americana O
f O
. O
americana O
and O
C O
. O
americana O
f O
. O
bodegensis O
. O

In O
addition O
, O
we O
used O
a O
PCR O
assay O
with O
ITS O
specific O
primers O
to O
amplify O
multiple O
ITS O
variants O
for O
collections O
assignable O
to O
C O
. O
americana O
indicating O
that O
there O
is O
genetic O
variability O
within O
ITS O
copies O
most O
likely O
due O
to O
introgression O
, O
crossing O
over O
and O
/ O
or O
the O
retention O
of O
ancestral O
variants O
. O

Theoretical O
realization O
of O
robust O
broadband O
transparency O
in O
ultrathin O
seamless O
nanostructures O
by O
dual O
blackbodies O
for O
near O
infrared O
light O
. O

We O
propose O
a O
counter O
- O
intuitive O
mechanism O
of O
constructing O
an O
ultrathin O
broadband O
transparent O
device O
with O
two O
perfect O
blackbodies O
. O

By O
introducing O
hybridization O
of O
plasmon O
modes O
, O
resonant O
modes O
with O
different O
symmetries O
coexist O
in O
this O
system O
. O

A O
broadband O
transmission O
spectrum O
in O
the O
near O
infrared O
regime O
is O
achieved O
through O
controlling O
their O
coupling O
strengths O
, O
which O
is O
governed O
by O
the O
thickness O
of O
high O
refractive O
index O
layer O
. O

Meanwhile O
, O
the O
transparency O
bandwidth O
is O
found O
to O
be O
tunable O
in O
a O
large O
range O
by O
varying O
the O
geometric O
dimension O
. O

More O
significantly O
, O
from O
the O
point O
view O
of O
applications O
, O
the O
proposed O
method O
of O
achieving O
broadband O
transparency O
can O
perfectly O
tolerate O
the O
misalignment O
and O
asymmetry O
of O
periodic O
nanoparticles O
on O
the O
top O
and O
bottom O
, O
which O
is O
empowered O
by O
the O
unique O
dual O
of O
coupling O
- O
in O
and O
coupling O
- O
out O
processes O
within O
the O
pair O
of O
blackbodies O
. O

Moreover O
, O
roughness O
has O
little O
influence O
on O
its O
transmission O
performance O
. O

According O
to O
the O
coupled O
mode O
theory O
, O
the O
distinguished O
transmittance O
performance O
is O
physically O
interpreted O
by O
the O
radiative O
decay O
rate O
of O
the O
entire O
system O
. O

In O
addition O
to O
the O
feature O
of O
uniquely O
robust O
broadband O
transparency O
, O
such O
a O
ultrathin O
seamless O
nanostructure O
( O
in O
the O
presence O
of O
a O
uniform O
silver B
layer O
) O
also O
provides O
polarization O
- O
independent O
and O
angle O
- O
independent O
operations O
. O

Therefore O
, O
it O
may O
power O
up O
a O
wide O
spectrum O
of O
exciting O
applications O
in O
thin O
film O
protection O
, O
touch O
screen O
techniques O
, O
absorber O
- O
emitter O
transformation O
, O
etc O
. O

Benzenesulfonamides B
: O
a O
unique O
class O
of O
chemokine O
receptor O
type O
4 O
inhibitors O
. O

The O
interaction O
of O
CXCR4 O
with O
CXCL12 O
( O
SDF O
- O
1 O
) O
plays O
a O
critical O
role O
in O
cancer O
metastasis O
by O
facilitating O
the O
homing O
of O
tumor O
cells O
to O
metastatic O
sites O
. O

Based O
on O
our O
previously O
published O
work O
on O
CXCR4 O
antagonists O
, O
we O
have O
synthesized O
a O
series O
of O
aryl B
sulfonamides I
that O
inhibit O
the O
CXCR4 O
/ O
CXCL12 O
interaction O
. O

Analogue O
bioactivities O
were O
assessed O
with O
binding O
affinity O
and O
Matrigel O
invasion O
assays O
. O

Computer O
modeling O
was O
employed O
to O
evaluate O
a O
selection O
of O
the O
new O
analogues O
docked O
into O
the O
CXCR4 O
X O
- O
ray O
structure O
and O
to O
rationalize O
discrepancies O
between O
the O
affinity O
and O
Matrigel O
in O
vitro O
assays O
. O

A O
lead O
compound O
displays O
nanomolar O
potency O
in O
the O
binding O
affinity O
assay O
( O
IC O
( O
50 O
) O
= O
8 O
. O
0 O
nM O
) O
and O
the O
Matrigel O
invasion O
assay O
( O
100 O
% O
blockade O
of O
invasion O
at O
10 O
nM O
) O
. O

These O
data O
demonstrate O
that O
benzenesulfonamides B
are O
a O
unique O
class O
of O
CXCR4 O
inhibitors O
with O
high O
potency O
. O

Hydrogen B
- O
bond O
reinforced O
vanadia B
nanofiber O
paper O
of O
high O
stiffness O
. O

Low O
- O
temperature O
, O
solution O
- O
based O
self O
- O
assembly O
of O
vanadia B
nanofibers O
yields O
a O
free O
- O
standing O
, O
ceramic O
paper O
with O
an O
outstanding O
combination O
of O
high O
strength O
, O
stiffness O
, O
and O
macroscopic O
flexibility O
. O

Its O
excellent O
mechanical O
performance O
results O
from O
a O
brick O
- O
and O
- O
mortar O
like O
architecture O
, O
which O
combines O
strong O
covalent O
bonding O
within O
the O
single O
- O
crystalline O
nanofibers O
with O
an O
intricate O
hydrogen B
bonding O
network O
between O
them O
. O

Hedgehog O
signaling O
acts O
with O
the O
temporal O
cascade O
to O
promote O
neuroblast O
cell O
cycle O
exit O
. O

In O
Drosophila O
postembryonic O
neuroblasts O
, O
transition O
in O
gene O
expression O
programs O
of O
a O
cascade O
of O
transcription O
factors O
( O
also O
known O
as O
the O
temporal O
series O
) O
acts O
together O
with O
the O
asymmetric O
division O
machinery O
to O
generate O
diverse O
neurons O
with O
distinct O
identities O
and O
regulate O
the O
end O
of O
neuroblast O
proliferation O
. O

However O
, O
the O
underlying O
mechanism O
of O
how O
this O
" O
temporal O
series O
" O
acts O
during O
development O
remains O
unclear O
. O

Here O
, O
we O
show O
that O
Hh O
signaling O
in O
the O
postembryonic O
brain O
is O
temporally O
regulated O
; O
excess O
( O
earlier O
onset O
of O
) O
Hh O
signaling O
causes O
premature O
neuroblast O
cell O
cycle O
exit O
and O
under O
- O
proliferation O
, O
whereas O
loss O
of O
Hh O
signaling O
causes O
delayed O
cell O
cycle O
exit O
and O
excess O
proliferation O
. O

Moreover O
, O
the O
Hh O
pathway O
functions O
downstream O
of O
Castor O
but O
upstream O
of O
Grainyhead O
, O
two O
components O
of O
the O
temporal O
series O
, O
to O
schedule O
neuroblast O
cell O
cycle O
exit O
. O

Interestingly O
, O
hh O
is O
likely O
a O
target O
of O
Castor O
. O

Hence O
, O
Hh O
signaling O
provides O
a O
link O
between O
the O
temporal O
series O
and O
the O
asymmetric O
division O
machinery O
in O
scheduling O
the O
end O
of O
neurogenesis O
. O

Influence O
of O
aqueous O
media O
properties O
on O
aggregation O
and O
solubility O
of O
four O
structurally O
related O
meso B
- I
porphyrin I
photosensitizers O
evaluated O
by O
spectrophotometric O
measurements O
. O

Porphyrin B
photosensitizers O
tend O
to O
aggregate O
in O
aqueous O
solutions O
even O
in O
the O
micromolar O
concentration O
range O
. O

This O
is O
a O
challenge O
during O
formulation O
of O
e O
. O
g O
. O
, O
parenteral O
preparations O
for O
photodynamic O
cancer O
therapy O
, O
or O
preparations O
for O
local O
or O
topical O
administration O
in O
antimicrobial O
photodynamic O
therapy O
. O

Monomerization O
is O
essential O
to O
achieve O
biocompatible O
drug O
formulations O
of O
high O
bioavailability O
and O
physiological O
response O
( O
i O
. O
e O
. O
, O
photoreactivity O
) O
and O
low O
toxicity O
. O

The O
aggregation O
and O
solubilization O
of O
four O
structurally O
related O
meso B
- I
tetraphenyl I
porphyrin I
photosensitizers O
with O
nonionic O
( O
4 B
- I
hydroxy I
) O
, O
anionic O
( O
4 B
- I
sulphonate I
; O
4 B
- I
carboxy I
) O
and O
cationic O
( O
4 B
- I
trimethylanilinium I
) O
substituents O
were O
evaluated O
in O
various O
vehicles O
by O
use O
of O
UV O
- O
Vis O
spectroscopy O
. O

Substituents O
, O
overall O
charge O
and O
charge O
distribution O
influenced O
the O
pKa O
- O
values O
and O
interaction O
of O
the O
porphyrins B
with O
different O
solvents O
, O
excipients O
and O
impurities O
. O

Modification O
of O
medium O
polarity O
and O
solubilization O
by O
the O
nonionic O
surfactant O
Tween B
80 I
adjusted O
the O
acid O
- O
base O
equilibria O
and O
increased O
the O
solubility O
by O
reduction O
of O
porphyrin B
aggregation O
. O

The O
selected O
porphyrins B
were O
sensitive O
towards O
ionic O
strength O
, O
temperature O
and O
inorganic O
impurities O
to O
various O
extents O
. O

The O
results O
will O
be O
further O
used O
during O
development O
of O
parenteral O
and O
topical O
formulations O
of O
porphyrin B
photosensitizers O
for O
use O
in O
photodynamic O
therapy O
of O
cancer O
and O
bacterial O
infections O
. O

Folate B
Conjugation O
to O
Polymeric O
Micelles O
via O
Boronic B
Acid I
Ester I
to O
Deliver O
Platinum B
Drugs O
to O
Ovarian O
Cancer O
Cell O
Lines O
. O

In O
this O
study O
, O
a O
novel O
technique O
was O
used O
for O
the O
reversible O
attachment O
of O
folic B
acid I
on O
the O
surface O
of O
polymeric O
micelles O
for O
a O
tumor O
- O
specific O
drug O
delivery O
system O
. O

The O
reversible O
conjugation O
is O
based O
on O
the O
interaction O
between O
phenylboronic B
acid I
( O
PBA B
) O
and O
dopamine B
to O
form O
a O
borate B
ester I
. O

The O
conjugation O
is O
fast O
and O
efficient O
and O
in O
vitro O
experiments O
via O
confocal O
fluorescent O
microscopy O
show O
that O
the O
linker O
is O
stable O
in O
for O
several O
hours O
. O

Reversible O
addition O
- O
fragmentation O
chain O
transfer O
( O
RAFT O
) O
polymerization O
was O
used O
to O
synthesize O
two O
various O
sized O
water O
- O
soluble O
block O
copolymer O
of O
oligoethylene B
glycol I
methylether I
methacylate I
and O
methyl B
acrylic I
acid I
( O
POEGMEMA35 B
- I
b I
- I
PMAA200 I
and O
POEGMEMA26 B
- I
b I
- I
PMAA90 I
) O
. O

The O
platinum B
drug O
, O
oxoplatin B
, O
was O
then O
subsequently O
attached O
to O
the O
polymer O
via O
ester B
formation O
leading O
to O
platinum B
loading O
of O
12 O
wt O
% O
as O
determined O
by O
TGA O
. O

The O
platinum B
- O
induced O
amphiphilic O
block O
copolymers O
that O
consequently O
led O
to O
the O
formation O
of O
micelles O
of O
sizes O
150 O
and O
20 O
nm O
in O
an O
aqueous O
environment O
with O
the O
longer O
PMAA B
block O
forming O
larger O
micelles O
. O

The O
small O
micelles O
were O
in O
addition O
cross O
- O
linked O
using O
1 B
, I
8 I
- I
diaminooctane I
to O
further O
stabilize O
their O
structure O
. O

The O
targeting O
ability O
of O
folate B
conjugated O
polymeric O
micelles O
was O
investigated O
against O
two O
types O
of O
tumor O
cell O
lines O
: O
A549 O
( O
- O
FR O
) O
and O
OVCAR O
- O
3 O
( O
+ O
FR O
) O
. O

The O
cell O
line O
growth O
inhibitory O
efficacy O
of O
material O
synthesized O
was O
evaluated O
by O
using O
SRB O
method O
. O

The O
results O
revealed O
that O
folate B
conjugated O
micelles O
showed O
higher O
activity O
in O
FR O
+ O
OVCAR O
- O
3 O
cells O
but O
not O
in O
FR O
- O
A549 O
cells O
. O

Similar O
results O
were O
obtained O
for O
both O
small O
and O
large O
micelles O
without O
the O
conjugation O
of O
folate B
. O

Comparing O
large O
and O
small O
micelles O
it O
can O
be O
observed O
that O
larger O
micelles O
are O
more O
efficient O
, O
which O
has O
been O
attributed O
to O
the O
lower O
stability O
of O
the O
smaller O
micelles O
. O

Micelle O
stabilization O
via O
cross O
- O
linking O
could O
indeed O
increase O
the O
toxicity O
of O
the O
drug O
carrier O
. O

Synthesis O
and O
relaxometric O
characterization O
of O
a O
MRI O
Gd B
- O
based O
probe O
responsive O
to O
glutamic B
acid I
decarboxylase O
enzymatic O
activity O
. O

Novel O
contrast O
agent O
based O
systems O
, O
which O
selectively O
visualize O
specific O
cells O
, O
e O
. O
g O
. O
, O
neurons O
in O
the O
brain O
, O
would O
be O
of O
substantial O
importance O
for O
the O
fast O
developing O
field O
of O
molecular O
magnetic O
resonance O
imaging O
( O
MRI O
) O
. O

We O
report O
here O
the O
synthesis O
and O
in O
vitro O
validation O
of O
a O
Gd B
( I
III I
) I
- O
based O
contrast O
agent O
designed O
to O
act O
as O
an O
MRI O
responsive O
probe O
for O
imaging O
the O
activity O
of O
the O
enzyme O
glutamic B
acid I
decarboxylase O
( O
GAD O
) O
present O
in O
neurons O
. O

Upon O
the O
action O
of O
the O
enzyme O
, O
the O
Gd B
( I
III I
) I
complex O
increases O
its O
hydration O
sphere O
and O
takes O
on O
a O
residual O
positive O
charge O
that O
promotes O
its O
binding O
to O
endogenous O
macromolecules O
. O

Both O
effects O
contribute O
in O
a O
synergic O
way O
to O
generate O
a O
marked O
relaxation O
enhancement O
, O
which O
directly O
reports O
enzyme O
activity O
and O
will O
allow O
activity O
detection O
of O
GAD O
positive O
cells O
in O
vitro O
and O
in O
vivo O
selectively O
. O

The O
finely O
regulating O
well O
- O
defined O
functional O
polymeric O
nanocarriers O
for O
anti O
- O
tumor O
immunotherapy O
. O

Cancer O
is O
the O
second O
leading O
cause O
of O
death O
around O
the O
world O
. O

Cancer O
may O
be O
induced O
by O
viral O
infection O
( O
EBV O
, O
HBV O
and O
HPV O
) O
, O
bacterial O
infection O
( O
Helicobacter O
pylori O
) O
, O
carcinogen O
, O
ultraviolet O
( O
UV O
) O
radiation O
exposure O
, O
and O
genetic O
mutation O
. O

Tumor O
can O
be O
suppressed O
by O
traditional O
surgery O
, O
radiotherapy O
, O
and O
/ O
or O
chemotherapy O
with O
devastating O
side O
effects O
and O
very O
poor O
quality O
of O
postoperative O
life O
. O

The O
therapeutic O
index O
has O
been O
further O
promoted O
by O
the O
newly O
developed O
nanomedicine O
. O

However O
, O
the O
disseminated O
tumor O
cells O
can O
result O
in O
micrometastases O
. O

So O
the O
cancer O
can O
just O
be O
supresssed O
but O
not O
cured O
by O
these O
ways O
. O

Fortunately O
, O
the O
developments O
of O
immunology O
have O
successfully O
improved O
many O
disciplines O
with O
special O
effort O
on O
oncology O
. O

Various O
immune O
cells O
including O
B O
cells O
, O
T O
- O
lymphocytes O
( O
TL O
) O
, O
natural O
killer O
( O
NK O
) O
cells O
, O
dendritic O
cells O
( O
DCs O
) O
, O
macrophages O
, O
and O
polymorphonuclear O
leukocytes O
are O
recruited O
to O
the O
tumor O
. O

These O
immune O
cells O
can O
recognize O
, O
eliminate O
, O
and O
protect O
the O
body O
from O
viral O
, O
bacterial O
infections O
, O
and O
the O
transformed O
cells O
( O
pre O
- O
cancer O
cell O
) O
extension O
. O

The O
modification O
of O
host O
immune O
system O
, O
and O
/ O
or O
the O
utilization O
of O
components O
of O
the O
immune O
system O
for O
cancer O
treatment O
are O
called O
immunotherapy O
. O

The O
immunotherapy O
is O
not O
only O
to O
target O
and O
kill O
tumor O
cells O
in O
aspecific O
manner O
, O
but O
also O
to O
alert O
the O
immune O
system O
to O
eradicate O
the O
disseminated O
tumor O
cells O
present O
in O
the O
blood O
circulation O
and O
micro O
- O
metastases O
in O
remote O
organs O
. O

Herein O
, O
the O
development O
of O
immunology O
, O
cancer O
immunotherapy O
, O
tumor O
immuno O
escape O
was O
introduced O
firstly O
. O

Then O
the O
correlations O
between O
host O
, O
the O
tumor O
and O
the O
nano O
particulates O
were O
proposed O
. O

And O
how O
to O
improve O
the O
cancer O
immunotherapy O
by O
finely O
nanocarrier O
' O
s O
engineering O
( O
nanoimmunotherapy O
) O
was O
systematically O
illustrated O
with O
special O
focus O
on O
the O
unique O
pathology O
of O
tumor O
microenviroments O
and O
properties O
of O
immuno O
cells O
. O

A O
new O
sesquiterpene B
lactone I
from O
Salvia O
plebeia O
. O

A O
new O
eudesmanolide B
, O
1 B
alpha I
- I
acetoxy I
- I
8 I
alpha I
, I
9 I
beta I
- I
dihydroxy I
- I
2 I
- I
oxo I
- I
eudesman I
- I
3 I
, I
7 I
( I
11 I
) I
- I
dien I
- I
8 I
, I
12 I
- I
olide I
( O
2 O
) O
, O
together O
with O
a O
known O
eudesmanolide B
, O
1 B
alpha I
- I
acetoxy I
- I
8 I
alpha I
- I
hydroxy I
- I
2 I
- I
oxo I
- I
eudesman I
- I
3 I
, I
7 I
( I
11 I
) I
- I
dien I
- I
8 I
, I
12 I
- I
olide I
( O
1 O
) O
, O
and O
a O
known O
flavone B
, O
4 B
' I
, I
5 I
, I
7 I
- I

trihydroxy I
- I
6 I
- I
methoxyflavone I
( O
3 O
) O
, O
was O
isolated O
from O
the O
plant O
of O
Salvia O
plebeia O
. O

Three O
compounds O
were O
structurally O
elucidated O
by O
spectroscopic O
and O
chemical O
methods O
. O

The O
role O
of O
endothelin O
system O
in O
cardiovascular O
disease O
and O
the O
potential O
therapeutic O
perspectives O
of O
its O
inhibition O
. O

Since O
its O
identification O
in O
1988 O
and O
the O
recognition O
of O
its O
primary O
role O
as O
a O
potent O
vasoconstrictor O
, O
endothelin O
has O
been O
extensively O
studied O
and O
is O
now O
considered O
as O
a O
ubiquitous O
protein O
, O
involved O
in O
important O
aspects O
of O
human O
homeostasis O
as O
well O
as O
in O
several O
pathophysiological O
pathways O
, O
mostly O
associated O
with O
cardiovascular O
disease O
. O

From O
an O
evolutionary O
point O
of O
view O
, O
endothelin O
consists O
a O
primitive O
molecule O
with O
the O
rare O
characteristic O
of O
being O
exactly O
the O
same O
in O
all O
mammals O
, O
thus O
permitting O
scientists O
to O
perform O
experiments O
in O
animals O
and O
doing O
predictions O
for O
humans O
. O

The O
understanding O
of O
its O
contribution O
to O
the O
genesis O
, O
evolution O
and O
maintenance O
of O
disease O
through O
activation O
of O
special O
receptor O
subtypes O
has O
led O
to O
the O
development O
of O
both O
selective O
and O
unselective O
receptor O
antagonists O
. O

Despite O
the O
disappointing O
results O
of O
these O
antagonists O
in O
the O
field O
of O
heart O
failure O
, O
almost O
from O
the O
initial O
animal O
trials O
of O
bosentan B
, O
a O
dual O
endothelin O
receptor O
antagonist O
, O
in O
pulmonary O
arterial O
hypertension O
, O
it O
has O
been O
demonstrated O
that O
the O
drug O
leads O
at O
least O
to O
hemodynamic O
and O
clinical O
improvement O
of O
the O
patients O
, O
thus O
receiving O
official O
approval O
for O
the O
management O
of O
this O
rare O
but O
eventually O
lethal O
disease O
. O

Resistant O
hypertension O
is O
another O
area O
where O
endothelin O
receptor O
blockers O
might O
potentially O
play O
a O
role O
, O
while O
the O
pathophysiological O
role O
of O
endothelin O
in O
atherosclerotic O
coronary O
artery O
disease O
is O
well O
- O
established O
and O
the O
relative O
research O
goes O
on O
. O

The O
main O
goal O
of O
this O
review O
is O
to O
describe O
the O
endothelin O
system O
and O
mostly O
to O
enlighten O
its O
role O
in O
pathophysiologic O
pathways O
, O
as O
well O
to O
state O
the O
relative O
research O
in O
the O
various O
fields O
of O
cardiovascular O
disease O
and O
also O
highlight O
its O
prognostic O
significance O
wherever O
there O
exists O
one O
. O

Asymmetric O
Dimethylarginine B
( O
ADMA O
) O
: O
A O
Promising O
Biomarker O
for O
Cardiovascular O
Disease O
? O

Asymmetric O
Dimethylarginine B
( O
ADMA O
) O
is O
an O
endogenous O
inhibitor O
of O
nitric B
oxide I
( O
NO B
) O
production O
. O

ADMA O
is O
generated O
from O
methylation O
of O
arginine B
residues O
by O
protein O
arginine B
methyltransferases O
( O
PRMTs O
) O
and O
subsequent O
proteolysis O
, O
while O
its O
elimination O
is O
achieved O
mainly O
by O
degradation O
with O
dimethylarginine B
dimethylaminohydrola I
( O
DDAH B
) O
. O

Oxidative O
stress O
, O
endothelial O
nitric B
oxide I
synthase O
( O
eNOS O
) O
inhibition O
, O
eNOS O
uncoupling O
, O
inflammation O
and O
shear O
stress O
play O
a O
pivotal O
role O
in O
ADMA O
pathophysiology O
by O
managing O
PRMT O
/ O
DDAH O
expression O
and O
NO B
synthesis O
and O
leading O
to O
a O
common O
result O
- O
endothelial O
dysfunction O
. O

Endothelial O
dysfunction O
seems O
to O
be O
the O
common O
finding O
in O
studies O
investigating O
the O
role O
of O
ADMA O
in O
cardiovascular O
disease O
( O
CVD O
) O
. O

High O
- O
performance O
liquid O
chromatography O
( O
HPLC O
) O
, O
mass O
spectrometry O
( O
MS O
) O
and O
enzyme O
- O
linked O
immunosorbent O
assay O
( O
ELISA O
) O
are O
the O
existing O
methods O
for O
ADMA O
quantification O
. O

However O
, O
none O
of O
them O
fulfils O
all O
the O
criteria O
to O
be O
characterized O
as O
" O
gold O
standard O
" O
. O

ADMA O
is O
significantly O
associated O
with O
risk O
factors O
for O
CVD O
and O
almost O
with O
every O
disease O
of O
the O
cardiovascular O
system O
; O
showing O
an O
independent O
, O
strong O
prognostic O
value O
for O
mortality O
and O
future O
cardiovascular O
events O
. O

This O
article O
aims O
to O
review O
the O
current O
knowledge O
about O
ADMA O
biology O
and O
metabolism O
, O
pathophysiological O
mechanisms O
implicating O
ADMA O
in O
CVD O
, O
methods O
for O
the O
determination O
of O
ADMA O
and O
its O
association O
with O
CVD O
risk O
factors O
and O
established O
CVDs O
. O

Chitosan O
- O
thioglycolic B
Acid I
as O
a O
versatile O
antimicrobial O
agent O
. O

As O
functionalized O
chitosans O
hold O
great O
potential O
for O
the O
development O
of O
effective O
and O
broad O
- O
spectrum O
antibiotics O
, O
representative O
chitosan O
derivatives O
were O
tested O
for O
antimicrobial O
activity O
in O
neutral O
media O
: O
trimethyl B
chitosan O
( O
TMC O
) O
, O
carboxy B
- I
methyl I
chitosan O
( O
CMC O
) O
, O
and O
chitosan O
- O
thioglycolic B
acid I
( O
TGA B
; O
medium O
molecular O
weight O
: O
MMW O
- O
TGA B
; O
low O
molecular O
weight O
: O
LMW O
- O
TGA B
) O
. O

Colony O
forming O
assays O
indicated O
that O
LMW O
- O
TGA B
displayed O
superior O
antimicrobial O
activity O
over O
the O
other O
derivatives O
tested O
: O
a O
30 O
min O
incubation O
killed O
100 O
% O
Streptococcus O
sobrinus O
( O
Gram O
- O
positive O
bacteria O
) O
and O
reduced O
colony O
counts O
by O
99 O
. O
99 O
% O
in O
Neisseria O
subflava O
( O
Gram O
- O
negative O
bacteria O
) O
and O
99 O
. O
97 O
% O
in O
Candida O
albicans O
( O
fungi O
) O
. O

To O
elucidate O
LMW O
- O
TGA B
effects O
at O
the O
cellular O
level O
, O
microscopic O
studies O
were O
performed O
. O

Use O
of O
fluorescein B
isothiocyanate I
( O
FITC B
) O
- O
labeled O
chitosan O
derivates O
in O
confocal O
microscopy O
showed O
that O
LMW O
- O
TGA O
attaches O
to O
microbial O
cell O
walls O
, O
while O
transmission O
electron O
microscopy O
indicated O
that O
this O
derivative O
severely O
affects O
cell O
wall O
integrity O
and O
intracellular O
ultrastructure O
in O
all O
species O
tested O
. O

We O
therefore O
propose O
LMW O
- O
TGA B
as O
a O
promising O
and O
effective O
broad O
- O
band O
antimicrobial O
compound O
. O

New O
surface O
- O
enhanced O
Raman O
scattering O
platforms O
: O
composite O
calcium B
carbonate I
microspheres O
coated O
with O
astralen O
and O
silver B
nanoparticles O
. O

Surface O
- O
enhanced O
Raman O
scattering O
( O
SERS O
) O
microspectroscopy O
is O
a O
very O
promising O
label O
- O
free O
, O
noncontact O
, O
and O
nondestructive O
method O
for O
real O
- O
time O
monitoring O
of O
extracellular O
matrix O
( O
ECM O
) O
development O
and O
cell O
integration O
in O
scaffolds O
for O
tissue O
engineering O
. O

Here O
, O
we O
prepare O
a O
new O
type O
of O
micrometer O
- O
sized O
SERS O
substrate O
, O
core O
- O
shell O
microparticles O
composed O
of O
solid O
carbonate B
core O
coated O
with O
silver B
nanoparticles O
and O
polyhedral O
multishell O
fullerene B
- O
like O
structure O
, O
astralen O
. O

Astralen O
has O
been O
assembled O
with O
polyallylamine B
hydrochloride I
( O
PAH B
) O
by O
the O
layer O
- O
by O
- O
layer O
manner O
followed O
by O
Ag B
nanoparticle O
formation O
by O
means O
of O
a O
silver B
mirror O
reaction O
, O
giving O
the O
final O
structure O
of O
composite O
particles O
CaCO3 B
( I
PAH B
/ O
astralen B
) I
x O
/ O
Ag B
, O
where O
x O
= O
1 O
- O
3 O
. O

The O
components O
of O
the O
microparticle O
carry O
multiple O
functionalities O
: O
( O
i O
) O
an O
easy O
identification O
by O
Raman O
imaging O
( O
photostable O
astralen O
) O
and O
( O
ii O
) O
SERS O
due O
to O
a O
rough O
surface O
of O
Ag B
nanoparticles O
. O

A O
combination O
of O
Ag B
and O
astralen O
nanoparticles O
provides O
an O
enhancement O
of O
astralen O
Raman O
signal O
by O
more O
than O
1 O
order O
of O
magnitude O
. O

Raman O
signals O
of O
commonly O
used O
scaffold O
components O
such O
as O
polylactide B
and O
polyvinyl B
alcohol I
as O
well O
as O
ECM O
component O
( O
hyaluronic O
acid O
) O
are O
significantly O
enhanced O
. O

Thus O
, O
we O
demonstrate O
that O
new O
mechanically O
robust O
and O
easily O
detectable O
( O
by O
astralen O
signal O
or O
optically O
) O
core O
- O
shell O
microspheres O
based O
on O
biocompatible O
CaCO3 B
can O
be O
used O
as O
SERS O
platform O
. O

Particle O
design O
opens O
many O
future O
perspectives O
for O
fabrication O
of O
SERS O
platforms O
with O
multiple O
functions O
for O
biomedical O
applications O
, O
for O
example O
, O
for O
theranostic O
. O

Safety O
assessment O
of O
Apoaequorin O
, O
a O
protein O
preparation O
: O
Subchronic O
toxicity O
study O
in O
rats O
. O

Apoaequorin O
, O
a O
calcium B
- O
binding O
protein O
originally O
isolated O
from O
jellyfish O
is O
available O
commercially O
as O
a O
dietary O
supplement O
. O

The O
objective O
of O
the O
present O
study O
was O
to O
investigate O
potential O
adverse O
effects O
, O
if O
any O
, O
of O
Apoaequorin O
, O
a O
recombinant O
protein O
preparation O
, O
in O
rats O
following O
subchronic O
administration O
. O

For O
this O
study O
, O
Sprague O
- O
Dawley O
( O
Hsd O
: O
SD O
( O
R O
) O
) O
rats O
( O
10 O
/ O
sex O
/ O
group O
) O
were O
administered O
via O
oral O
gavage O
0 O
( O
control O
) O
, O
92 O
. O
6 O
, O
462 O
. O
9 O
, O
and O
926 O
. O
0mg O
/ O
kg O
body O
weight O
( O
bw O
) O
/ O
day O
of O
Apoaequorin O
preparation O
, O
for O
90days O
. O

The O
corresponding O
amount O
of O
Apoaequorin O
protein O
was O
0 O
, O
66 O
. O
7 O
, O
333 O
. O
3 O
and O
666 O
. O
7mg O
/ O
kg O
bw O
/ O
day O
, O
respectively O
. O

Administration O
of O
the O
Apoaequorin O
preparation O
did O
not O
result O
in O
any O
mortality O
. O

There O
were O
no O
clinical O
or O
ophthalmological O
signs O
, O
body O
weight O
, O
body O
weight O
gain O
, O
food O
consumption O
, O
food O
efficiency O
, O
clinical O
pathology O
or O
histopathological O
changes O
attributable O
to O
administration O
of O
Apoaequorin O
. O

Any O
changes O
noted O
were O
incidental O
and O
in O
agreement O
with O
those O
historically O
observed O
in O
the O
age O
and O
strain O
of O
rats O
used O
in O
this O
study O
. O

Based O
on O
the O
results O
of O
this O
study O
, O
the O
No O
Observed O
- O
Adverse O
- O
Effect O
Level O
( O
NOAEL O
) O
for O
Apoaequorin O
was O
determined O
as O
666 O
. O
7mg O
/ O
kg O
bw O
/ O
day O
, O
the O
highest O
dose O
tested O
. O

Environmental O
stress O
, O
oxytocin B
receptor O
gene O
( O
OXTR O
) O
polymorphism O
, O
and O
mental O
health O
following O
collective O
stress O
. O

We O
examined O
whether O
the O
oxytocin B
receptor O
gene O
( O
OXTR O
) O
single O
nucleotide O
polymorphism O
( O
SNP O
) O
rs53576 O
genotype O
buffers O
the O
combined O
impact O
of O
negative O
social O
environments O
( O
e O
. O
g O
. O
, O
interpersonal O
conflict O
/ O
constraint O
) O
and O
economic O
stress O
on O
post O
- O
traumatic O
stress O
( O
PTS O
) O
symptoms O
and O
impaired O
daily O
functioning O
following O
collective O
stress O
( O
September O
11th O
terrorist O
attacks O
) O
. O

Saliva O
was O
collected O
by O
mail O
and O
used O
to O
genotype O
704 O
respondents O
. O

Participants O
completed O
Web O
- O
based O
assessments O
of O
pre O
- O
9 O
/ O
11 O
mental O
health O
, O
acute O
stress O
9 O
- O
23days O
after O
9 O
/ O
11 O
, O
the O
quality O
of O
social O
environments O
1year O
post O
- O
9 O
/ O
11 O
, O
economic O
stress O
18months O
post O
- O
9 O
/ O
11 O
, O
and O
PTS O
symptoms O
and O
impaired O
functioning O
2 O
and O
3years O
post O
- O
9 O
/ O
11 O
. O

Interactions O
between O
negative O
social O
environments O
and O
economic O
stress O
were O
examined O
separately O
based O
on O
OXTR O
rs53576 O
genotype O
( O
GG O
vs O
. O
any O
A O
allele O
) O
. O

For O
individuals O
with O
an O
A O
allele O
, O
a O
negative O
social O
environment O
significantly O
increased O
PTS O
symptoms O
without O
regard O
to O
the O
level O
of O
economic O
stress O
experienced O
. O

However O
, O
for O
respondents O
with O
a O
GG O
genotype O
, O
negative O
social O
environments O
predicted O
elevated O
PTS O
symptoms O
only O
for O
those O
also O
experiencing O
high O
economic O
stress O
. O

Gender O
moderated O
associations O
between O
negative O
social O
environments O
, O
economic O
stress O
, O
and O
impaired O
functioning O
. O

The O
functioning O
of O
females O
was O
most O
affected O
by O
negative O
social O
environments O
regardless O
of O
genotype O
and O
economic O
stress O
, O
whereas O
the O
functioning O
of O
males O
was O
differentially O
susceptible O
to O
economic O
stress O
depending O
on O
OXTR O
genotype O
and O
negative O
social O
environments O
. O

These O
findings O
suggest O
that O
it O
is O
important O
to O
consider O
the O
combined O
impact O
of O
gender O
and O
ongoing O
stress O
in O
different O
domains O
as O
moderators O
of O
genetic O
vulnerability O
following O
collective O
stress O
. O

Oroxylin B
A I
reverses O
P O
- O
glycoprotein O
- O
mediated O
multidrug O
resistance O
of O
MCF7 O
/ O
ADR O
cells O
by O
G2 O
/ O
M O
arrest O
. O

Oroxylin B
A I
is O
a O
naturally O
occurring O
monoflavonoid B
isolated O
from O
the O
root O
of O
Scutellaria O
baicalensis O
Georgi O
, O
which O
has O
been O
used O
in O
traditional O
Chinese O
medicine O
for O
its O
anti O
- O
tumor O
, O
anti O
- O
inflammatory O
and O
anti O
- O
bacterial O
properties O
. O

The O
purpose O
of O
this O
study O
is O
to O
investigate O
the O
reversal O
effect O
and O
the O
fundamental O
mechanisms O
of O
oroxylin B
A I
in O
MCF7 O
/ O
ADR O
cells O
. O

Data O
indicated O
that O
oroxylin B
A I
showed O
strong O
reversal O
potency O
in O
MCF7 O
/ O
ADR O
cells O
and O
the O
reversal O
fold O
( O
RF O
) O
reached O
4 O
. O
68 O
. O

After O
treatment O
with O
oroxylin B
A I
, O
MCF7 O
/ O
ADR O
cells O
displayed O
reduced O
functional O
activity O
and O
expression O
of O
MDR1 O
at O
both O
the O
protein O
and O
mRNA O
levels O
. O

Meanwhile O
, O
oroxylin B
A I
induced O
cells O
G2 O
/ O
M O
arrest O
in O
a O
concentration O
- O
dependent O
manner O
by O
increasing O
the O
expression O
of O
p O
- O
Chk2 O
( O
Thr68 B
) O
. O

Moreover O
, O
western O
blot O
and O
EMSA O
assays O
were O
used O
to O
reveal O
the O
inhibition O
of O
NF O
- O
kappa O
B O
in O
nucleus O
and O
the O
suppression O
of O
NF O
- O
kappa O
B O
binding O
activity O
by O
oroxylin B
A I
. O

NSC B
109555 I
ditosylate I
- O
Chk2 O
inhibitor O
partly O
dismissed O
G2 O
/ O
M O
arrest O
induced O
by O
oroxylin B
A I
, O
reversed O
the O
increased O
trend O
of O
p O
- O
Chk2 O
and O
p O
- O
P53 O
( O
Ser20 B
) O
, O
inhibited O
the O
decreasing O
effect O
of O
oroxylin B
A I
on O
the O
expression O
of O
P O
- O
gp O
and O
decreased O
the O
reversal O
fold O
of O
90 O
mu O
M O
oroxylin B
A I
from O
4 O
. O
68 O
fold O
to O
1 O
. O
73 O
fold O
. O

In O
conclusion O
, O
we O
suggested O
that O
oroxylin B
A I
reversed O
MDR O
by O
G2 O
/ O
M O
arrest O
and O
the O
underlying O
mechanism O
attributed O
to O
the O
suppression O
of O
P O
- O
gp O
expression O
via O
Chk2 O
/ O
P53 O
/ O
NF O
- O
kappa O
B O
signaling O
pathway O
. O

Neurotrophin O
3 O
genotype O
and O
emotional O
adverse O
effects O
of O
osmotic O
- O
release O
oral O
system O
methylphenidate B
( O
OROS O
- O
MPH B
) O
in O
children O
with O
attention O
- O
deficit O
/ O
hyperactivity O
disorder O
. O

Neurotrophin O
3 O
( O
NTF3 O
) O
has O
been O
studied O
in O
relation O
to O
the O
pathophysiology O
of O
attention O
- O
deficit O
/ O
hyperactivity O
disorder O
( O
ADHD O
) O
and O
mood O
disorders O
as O
well O
as O
psychostimulant O
action O
. O

We O
hypothesized O
that O
the O
risk O
of O
an O
emotional O
side O
effect O
to O
methylphenidate B
( O
MPH B
) O
treatment O
may O
be O
associated O
with O
NTF3 O
genotypes O
. O

Ninety O
- O
six O
medication O
- O
na O
i O
ve O
children O
with O
ADHD O
( O
mean O
age O
8 O
. O
70 O
, O
standard O
deviation O
1 O
. O
41 O
years O
, O
79 O
males O
) O
were O
genotyped O
and O
treated O
with O
MPH B
. O

At O
baseline O
, O
which O
was O
prior O
to O
MPH B
treatment O
, O
and O
after O
two O
weeks O
of O
medication O
, O
investigators O
asked O
children O
and O
their O
parents O
or O
caregivers O
about O
adverse O
events O
using O
a O
symptom O
rating O
scale O
. O

ADHD O
subjects O
with O
the O
A O
/ O
A O
genotype O
at O
the O
NTF3 O
rs6332 O
polymorphism O
showed O
the O
highest O
' O
Emotionality O
' O
and O
' O
Over O
- O
focus O
/ O
euphoria O
' O
factor O
scores O
, O
followed O
by O
those O
with O
the O
G O
/ O
A O
genotype O
and O
those O
with O
the O
G O
/ O
G O
genotype O
( O
p O
= O
0 O
. O
042 O
and O
p O
= O
0 O
. O
045 O
, O
respectively O
) O
. O

ADHD O
subjects O
with O
the O
A O
/ O
A O
genotype O
at O
the O
NTF3 O
rs6332 O
polymorphism O
showed O
the O
highest O
' O
Proneness O
to O
crying O
' O
and O
' O
Nail O
biting O
' O
item O
scores O
, O
followed O
by O
those O
with O
the O
G O
/ O
A O
genotype O
and O
those O
with O
the O
G O
/ O
G O
genotype O
( O
p O
= O
0 O
. O
047 O
and O
p O
= O
0 O
. O
017 O
, O
respectively O
) O
. O

These O
data O
provide O
preliminary O
evidence O
that O
genetic O
variation O
in O
the O
NTF3 O
gene O
is O
related O
to O
susceptibility O
to O
emotional O
side O
effects O
in O
response O
to O
MPH B
treatment O
in O
Korean O
children O
with O
ADHD O
. O

Resveratrol B
protects O
against O
arsenic B
trioxide I
- O
induced O
nephrotoxicity O
by O
facilitating O
arsenic B
metabolism O
and O
decreasing O
oxidative O
stress O
. O

Arsenic B
trioxide I
( O
As2O3 B
) O
is O
an O
environmental O
toxicant O
and O
a O
potent O
antineoplastic O
agent O
. O

Exposure O
to O
arsenic B
causes O
renal O
cancer O
. O

Resveratrol B
is O
a O
well O
- O
known O
polyphenolic B
compound O
that O
is O
reported O
to O
reduce O
As2O3 B
- O
induced O
cardiotoxicity O
. O

The O
present O
study O
aimed O
to O
investigate O
the O
effect O
of O
resveratrol B
on O
As2O3 B
- O
induced O
nephrotoxicity O
and O
arsenic B
metabolism O
. O

Chinese O
Dragon O
- O
Li O
cats O
were O
injected O
with O
1 O
mg O
/ O
kg O
As2O3 B
on O
alternate O
days O
; O
resveratrol B
( O
3 O
mg O
/ O
kg O
) O
was O
administered O
via O
the O
forearm O
vein O
1 O
h O
before O
the O
As2O3 B
treatment O
. O

On O
the O
sixth O
day O
, O
the O
cats O
were O
killed O
to O
determine O
the O
histological O
renal O
damage O
, O
renal O
function O
, O
the O
accumulation O
of O
arsenic B
, O
and O
antioxidant O
activities O
in O
the O
kidney O
. O

Urine O
samples O
were O
taken O
for O
arsenic B
speciation O
. O

In O
the O
resveratrol B
+ O
As2O3 B
- O
treated O
group O
, O
activities O
of O
glutathione B
peroxidase O
, O
catalase O
, O
and O
superoxide B
dismutase O
, O
the O
ratio O
of O
reduced B
glutathione I
to O
oxidized B
glutathione I
, O
the O
total O
arsenic B
concentrations O
, O
and O
the O
percentage O
of O
methylated B
arsenic I
in O
urine O
were O
significantly O
increased O
. O

The O
concentrations O
of O
renal O
malondialdehyde B
, O
reactive O
oxygen B
species O
, O
8 B
- I
hydroxydeoxyguanosin I
, O
serum O
creatinine B
, O
blood O
urea B
nitrogen B
, O
and O
renal O
arsenic B
accumulation O
were O
significantly O
decreased O
and O
reduced O
renal O
morphologic O
injury O
was O
observed O
compared O
with O
the O
As2O3 B
- O
treated O
group O
. O

These O
results O
demonstrate O
that O
resveratrol B
could O
significantly O
scavenge O
reactive O
oxygen B
species O
, O
inhibit O
As2O3 B
- O
induced O
oxidative O
damage O
, O
and O
significantly O
attenuate O
the O
accumulation O
of O
arsenic B
in O
renal O
tissues O
by O
facilitating O
As2O3 B
metabolism O
. O

These O
data O
suggest O
that O
use O
of O
resveratrol B
as O
postremission O
therapy O
for O
acute O
promyelocytic O
leukemia O
as O
well O
as O
adjunctive O
therapy O
in O
patients O
with O
exposure O
to O
arsenic B
may O
decrease O
arsenic B
nephrotoxicity O
. O

Global O
analysis O
of O
Drosophila O
Cys2 O
- O
His2 O
zinc O
finger O
proteins O
reveals O
a O
multitude O
of O
novel O
recognition O
motifs O
and O
binding O
determinants O
. O

Cys2 B
- O
His2 O
zinc B
finger O
proteins O
( O
ZFPs O
) O
are O
the O
largest O
group O
of O
transcription O
factors O
in O
higher O
metazoans O
. O

A O
complete O
characterization O
of O
these O
ZFPs O
and O
their O
associated O
target O
sequences O
is O
pivotal O
to O
fully O
annotate O
transcriptional O
regulatory O
networks O
in O
metazoan O
genomes O
. O

As O
a O
first O
step O
in O
this O
process O
, O
we O
have O
characterized O
the O
DNA O
- O
binding O
specificities O
of O
129 O
zinc B
finger O
sets O
from O
Drosophila O
using O
a O
bacterial O
one O
- O
hybrid O
system O
. O

This O
data O
set O
contains O
the O
DNA O
- O
binding O
specificities O
for O
at O
least O
one O
encoded O
ZFP O
from O
70 O
unique O
genes O
and O
23 O
alternate O
splice O
isoforms O
representing O
the O
largest O
set O
of O
characterized O
ZFPs O
from O
any O
organism O
described O
to O
date O
. O

These O
recognition O
motifs O
can O
be O
used O
to O
predict O
genomic O
binding O
sites O
for O
these O
factors O
within O
the O
fruit O
fly O
genome O
. O

Subsets O
of O
fingers O
from O
these O
ZFPs O
were O
characterized O
to O
define O
their O
orientation O
and O
register O
on O
their O
recognition O
sequences O
, O
thereby O
allowing O
us O
to O
define O
the O
recognition O
diversity O
within O
this O
finger O
set O
. O

We O
find O
that O
the O
characterized O
fingers O
can O
specify O
47 O
of O
the O
64 O
possible O
DNA O
triplets O
. O

To O
confirm O
the O
utility O
of O
our O
finger O
recognition O
models O
, O
we O
employed O
subsets O
of O
Drosophila O
fingers O
in O
combination O
with O
an O
existing O
archive O
of O
artificial O
zinc B
finger O
modules O
to O
create O
ZFPs O
with O
novel O
DNA O
- O
binding O
specificity O
. O

These O
hybrids O
of O
natural O
and O
artificial O
fingers O
can O
be O
used O
to O
create O
functional O
zinc B
finger O
nucleases O
for O
editing O
vertebrate O
genomes O
. O

Cobicistat B
: O
A O
New O
Boost O
for O
the O
Treatment O
of O
Human O
Immunodeficiency O
Virus O
Infection O
. O

Ritonavir B
is O
commonly O
used O
as O
a O
pharmacokinetic O
booster O
for O
antiretroviral O
regimens O
in O
the O
management O
of O
human O
immunodeficiency O
virus O
infections O
. O

Limitations O
to O
ritonavir B
boosting O
include O
increased O
pill O
burden O
, O
adverse O
effects O
, O
and O
a O
wide O
range O
of O
clinically O
significant O
drug O
- O
drug O
interactions O
. O

Cobicistat B
is O
a O
new O
pharmacokinetic O
booster O
that O
is O
a O
selective O
inhibitor O
of O
cytochrome O
P450 O
3A O
, O
the O
main O
metabolizing O
pathway O
of O
several O
antiretrovirals O
. O

Cobicistat B
has O
been O
studied O
as O
a O
booster O
for O
elvitegravir B
, O
a O
second O
- O
generation O
integrase O
inhibitor O
, O
and O
protease O
inhibitors O
. O

Based O
on O
successful O
clinical O
trials O
, O
a O
new O
single O
- O
tablet O
regimen O
of O
elvitegravir B
, O
cobicistat B
, O
emtricitabine B
, O
and O
tenofovir B
has O
been O
approved O
for O
the O
management O
of O
treatment O
- O
na O
i O
ve O
patients O
. O

Additional O
studies O
are O
underway O
investigating O
the O
safety O
and O
efficacy O
of O
cobicistat B
- O
boosted O
protease O
inhibitor O
regimens O
for O
both O
treatment O
- O
na O
i O
ve O
and O
treatment O
- O
experienced O
patients O
. O

Cobicistat B
is O
well O
tolerated O
and O
may O
become O
a O
preferred O
booster O
for O
antiretroviral O
regimens O
, O
as O
it O
can O
be O
coformulated O
with O
several O
agents O
to O
create O
simpler O
regimens O
. O

Tumor O
- O
suppressive O
Maspin O
Functions O
as O
a O
Reactive O
Oxygen B
Species O
Scavenger O
: O
IMPORTANCE O
OF O
CYSTEINE B
RESIDUES O
. O

Maspin O
is O
a O
member O
of O
the O
serine B
protease O
inhibitor O
( O
serpin O
) O
superfamily O
and O
displays O
tumor O
- O
suppressing O
activity O
by O
controlling O
cell O
migration O
, O
proliferation O
, O
apoptosis O
, O
and O
adhesion O
. O

Here O
, O
we O
provide O
evidence O
that O
maspin O
acts O
as O
a O
reactive O
oxygen B
species O
( O
ROS O
) O
scavenger O
through O
oxidation O
of O
three O
structurally O
exposed O
cysteine B
thiols I
to O
sulfenic B
acid I
. O

Ablation O
of O
these O
cysteine B
residues O
in O
maspin O
resulted O
in O
a O
significant O
increase O
in O
total O
ROS O
production O
in O
mouse O
mammary O
TM40D O
cells O
. O

Also O
, O
cells O
containing O
a O
triple O
- O
cysteine B
mutant O
of O
maspin O
showed O
elevated O
ERK1 O
/ O
2 O
activity O
, O
a O
downstream O
target O
of O
ROS O
, O
and O
enhanced O
proliferation O
and O
colony O
formation O
. O

These O
findings O
establish O
a O
novel O
mechanism O
by O
which O
maspin O
utilizes O
its O
cysteine B
thiols I
to O
inhibit O
oxidative O
stress O
and O
cell O
growth O
. O

Biosafety O
data O
as O
confidential O
business O
information O
. O

Removal O
of O
confidentiality O
claims O
on O
biosafety O
data O
is O
necessary O
to O
adhere O
to O
standard O
scientific O
procedures O
of O
quality O
assurance O
, O
to O
increase O
transparency O
, O
to O
minimize O
impacts O
of O
conflicts O
of O
interests O
, O
and O
ultimately O
to O
improve O
public O
confidence O
in O
GMOs O
. O

Global O
iodine B
nutrition O
: O
where O
do O
we O
stand O
in O
2013 O
? O

Background O
: O
Dietary O
iodine B
intake O
is O
required O
for O
the O
production O
of O
thyroid O
hormone O
. O

Consequences O
of O
iodine B
deficiency O
include O
goiter O
, O
intellectual O
impairments O
, O
growth O
retardation O
, O
neonatal O
hypothyroidism O
, O
and O
increased O
pregnancy O
loss O
and O
infant O
mortality O
. O

Summary O
: O
In O
1990 O
, O
the O
United O
Nations O
World O
Summit O
for O
Children O
established O
the O
goal O
of O
eliminating O
iodine B
deficiency O
worldwide O
. O

Considerable O
progress O
has O
since O
been O
achieved O
, O
largely O
through O
programs O
of O
universal O
salt O
iodization O
. O

Approximately O
70 O
% O
of O
all O
households O
worldwide O
currently O
have O
access O
to O
adequately O
iodized O
salt O
. O

In O
2013 O
, O
as O
defined O
by O
a O
national O
or O
subnational O
median O
urinary O
iodine B
concentration O
of O
100 O
- O
299 O
mu O
g O
/ O
L O
in O
school O
- O
aged O
children O
, O
111 O
countries O
have O
sufficient O
iodine B
intake O
. O

Thirty O
countries O
remain O
iodine B
- O
deficient O
; O
9 O
are O
moderately O
deficient O
, O
21 O
are O
mildly O
deficient O
, O
and O
none O
are O
currently O
considered O
severely O
iodine B
- O
deficient O
. O

Ten O
countries O
have O
excessive O
iodine B
intake O
. O

In O
North O
America O
, O
both O
the O
United O
States O
and O
Canada O
are O
generally O
iodine B
- O
sufficient O
, O
although O
recent O
data O
suggest O
pregnant O
U O
. O
S O
. O
women O
are O
mildly O
iodine B
- O
deficient O
. O

Emerging O
issues O
include O
discrepancies O
between O
urinary O
iodine B
status O
in O
pregnant O
women O
compared O
to O
school O
- O
aged O
children O
in O
some O
populations O
, O
the O
problem O
of O
re O
- O
emerging O
iodine B
deficiency O
in O
parts O
of O
the O
developed O
world O
, O
the O
importance O
of O
food O
industry O
use O
of O
iodized O
salt O
, O
regions O
of O
iodine B
excess O
, O
and O
the O
potential O
effects O
of O
initiatives O
to O
lower O
population O
sodium B
consumption O
on O
iodine B
intake O
. O

Conclusions O
: O
Although O
substantial O
progress O
has O
been O
made O
over O
the O
last O
several O
decades O
, O
iodine B
deficiency O
remains O
a O
significant O
health O
problem O
worldwide O
and O
affects O
both O
industrialized O
and O
developing O
nations O
. O

The O
ongoing O
monitoring O
of O
population O
iodine B
status O
remains O
crucially O
important O
, O
and O
particular O
attention O
may O
need O
to O
be O
paid O
to O
monitoring O
the O
status O
of O
vulnerable O
populations O
, O
such O
as O
pregnant O
women O
and O
infants O
. O

There O
is O
also O
need O
for O
ongoing O
monitoring O
of O
iodized O
salt O
and O
other O
dietary O
iodine B
sources O
in O
order O
to O
prevent O
excess O
as O
well O
as O
insufficient O
iodine B
nutrition O
. O

Finally O
, O
it O
will O
be O
essential O
to O
coordinate O
interventions O
designed O
to O
reduce O
population O
sodium B
intake O
with O
salt O
iodization O
programs O
in O
order O
to O
maintain O
adequate O
levels O
of O
iodine B
nutrition O
as O
salt O
intake O
declines O
. O

In O
vivo O
HIF O
- O
mediated O
reductive O
carboxylation O
is O
regulated O
by O
citrate B
levels O
and O
sensitizes O
VHL O
- O
deficient O
cells O
to O
glutamine B
deprivation O
. O

Hypoxic O
and O
VHL O
- O
deficient O
cells O
use O
glutamine B
to O
generate O
citrate B
and O
lipids O
through O
reductive O
carboxylation O
( O
RC O
) O
of O
alpha B
- I
ketoglutarate I
. O

To O
gain O
insights O
into O
the O
role O
of O
HIF O
and O
the O
molecular O
mechanisms O
underlying O
RC O
, O
we O
took O
advantage O
of O
a O
panel O
of O
disease O
- O
associated O
VHL O
mutants O
and O
showed O
that O
HIF O
expression O
is O
necessary O
and O
sufficient O
for O
the O
induction O
of O
RC O
in O
human O
renal O
cell O
carcinoma O
( O
RCC O
) O
cells O
. O

HIF O
expression O
drastically O
reduced O
intracellular O
citrate B
levels O
. O

Feeding O
VHL O
- O
deficient O
RCC O
cells O
with O
acetate B
or O
citrate B
or O
knocking O
down O
PDK O
- O
1 O
and O
ACLY B
restored O
citrate B
levels O
and O
suppressed O
RC O
. O

These O
data O
suggest O
that O
HIF O
- O
induced O
low O
intracellular O
citrate B
levels O
promote O
the O
reductive O
flux O
by O
mass O
action O
to O
maintain O
lipogenesis O
. O

Using O
[ B
( I
1 I
- I
13 I
) I
C I
] I
glutamine I
, O
we O
demonstrated O
in O
vivo O
RC O
activity O
in O
VHL O
- O
deficient O
tumors O
growing O
as O
xenografts O
in O
mice O
. O

Lastly O
, O
HIF O
rendered O
VHL O
- O
deficient O
cells O
sensitive O
to O
glutamine B
deprivation O
in O
vitro O
, O
and O
systemic O
administration O
of O
glutaminase O
inhibitors O
suppressed O
the O
growth O
of O
RCC O
cells O
as O
mice O
xenografts O
. O

The O
mitochondrial O
RNA O
- O
binding O
protein O
GRSF1 O
localizes O
to O
RNA O
granules O
and O
is O
required O
for O
posttranscriptional O
mitochondrial O
gene O
expression O
. O

RNA O
- O
binding O
proteins O
are O
at O
the O
heart O
of O
posttranscriptional O
gene O
regulation O
, O
coordinating O
the O
processing O
, O
storage O
, O
and O
handling O
of O
cellular O
RNAs O
. O

We O
show O
here O
that O
GRSF1 O
, O
previously O
implicated O
in O
the O
binding O
and O
selective O
translation O
of O
influenza O
mRNAs O
, O
is O
targeted O
to O
mitochondria O
where O
it O
forms O
granules O
that O
colocalize O
with O
foci O
of O
newly O
synthesized O
mtRNA O
next O
to O
mitochondrial O
nucleoids O
. O

GRSF1 O
preferentially O
binds O
RNAs O
transcribed O
from O
three O
contiguous O
genes O
on O
the O
light O
strand O
of O
mtDNA O
, O
the O
ND6 O
mRNA O
, O
and O
the O
long O
noncoding O
RNAs O
for O
cytb O
and O
ND5 O
, O
each O
of O
which O
contains O
multiple O
consensus O
binding O
sequences O
. O

RNAi O
- O
mediated O
knockdown O
of O
GRSF1 O
leads O
to O
alterations O
in O
mitochondrial O
RNA O
stability O
, O
abnormal O
loading O
of O
mRNAs O
and O
lncRNAs O
on O
the O
mitochondrial O
ribosome O
, O
and O
impaired O
ribosome O
assembly O
. O

This O
results O
in O
a O
specific O
protein O
synthesis O
defect O
and O
a O
failure O
to O
assemble O
normal O
amounts O
of O
the O
oxidative O
phosphorylation O
complexes O
. O

These O
data O
implicate O
GRSF1 O
as O
a O
key O
regulator O
of O
posttranscriptional O
mitochondrial O
gene O
expression O
. O

Adipose O
subtype O
- O
selective O
recruitment O
of O
TLE3 O
or O
Prdm16 O
by O
PPAR O
gamma O
specifies O
lipid O
storage O
versus O
thermogenic O
gene O
programs O
. O

Transcriptional O
effectors O
of O
white O
adipocyte O
- O
selective O
gene O
expression O
have O
not O
been O
described O
. O

Here O
we O
show O
that O
TLE3 O
is O
a O
white O
- O
selective O
cofactor O
that O
acts O
reciprocally O
with O
the O
brown O
- O
selective O
cofactor O
Prdm16 O
to O
specify O
lipid O
storage O
and O
thermogenic O
gene O
programs O
. O

Occupancy O
of O
TLE3 O
and O
Prdm16 O
on O
certain O
promoters O
is O
mutually O
exclusive O
, O
due O
to O
the O
ability O
of O
TLE3 O
to O
disrupt O
the O
physical O
interaction O
between O
Prdm16 O
and O
PPAR O
gamma O
. O

When O
expressed O
at O
elevated O
levels O
in O
brown O
fat O
, O
TLE3 O
counters O
Prdm16 O
, O
suppressing O
brown O
- O
selective O
genes O
and O
inducing O
white O
- O
selective O
genes O
, O
resulting O
in O
impaired O
fatty B
acid I
oxidation O
and O
thermogenesis O
. O

Conversely O
, O
mice O
lacking O
TLE3 O
in O
adipose O
tissue O
show O
enhanced O
thermogenesis O
in O
inguinal O
white O
adipose O
depots O
and O
are O
protected O
from O
age O
- O
dependent O
deterioration O
of O
brown O
adipose O
tissue O
function O
. O

Our O
results O
suggest O
that O
the O
establishment O
of O
distinct O
adipocyte O
phenotypes O
with O
different O
capacities O
for O
thermogenesis O
and O
lipid O
storage O
is O
accomplished O
in O
part O
through O
the O
cell O
- O
type O
- O
selective O
recruitment O
of O
TLE3 O
or O
Prdm16 O
to O
key O
adipocyte O
target O
genes O
. O

Mechanistic O
investigation O
of O
seeded O
growth O
in O
triblock O
copolymer O
stabilized O
gold O
nanoparticles O
. O

We O
report O
the O
seeded O
synthesis O
of O
gold O
nanoparticles O
( O
GNPs O
) O
via O
the O
reduction O
of O
HAuCl4 B
by O
( O
L31 O
and O
F68 O
) O
triblock O
copolymer O
( O
TBP B
) O
mixtures O
. O

In O
the O
present O
study O
, O
we O
focused O
on O
[ O
TBP B
] O
/ O
[ O
Au B
( I
III I
) I
] O
ratios O
of O
1 O
- O
5 O
( O
= O
~ O
1 O
mM O
HAuCl4 B
) O
and O
seed O
sizes O
~ O
20 O
nm O
. O

Under O
these O
conditions O
, O
the O
GNP O
growth O
rate O
is O
dominated O
by O
both O
the O
TBP O
and O
seed O
concentrations O
. O

With O
seeding O
, O
the O
final O
GNP O
size O
distributions O
are O
bimodal O
. O

Increasing O
the O
seed O
concentration O
( O
up O
to O
~ O
0 O
. O
1 O
nM O
) O
decreases O
the O
mean O
particle O
sizes O
10 O
- O
fold O
, O
from O
~ O
1000 O
to O
100 O
nm O
. O

The O
particles O
in O
the O
bimodal O
distribution O
are O
formed O
by O
the O
competitive O
direct O
growth O
in O
solution O
and O
the O
aggregative O
growth O
on O
the O
seeds O
. O

By O
monitoring O
kinetics O
of O
GNP O
growth O
, O
we O
propose O
that O
( O
1 O
) O
the O
surface O
of O
the O
GNP O
seeds O
embedded O
in O
the O
TBP O
cavities O
form O
catalytic O
centers O
for O
GNP O
growth O
and O
( O
2 O
) O
large O
GNPs O
are O
formed O
by O
the O
aggregation O
of O
GNP O
seeds O
in O
an O
autocatalytic O
growth O
process O
. O

Systematic O
study O
of O
the O
basis O
set O
superposition O
error O
in O
core O
- O
electron O
correlation O
effects O
. O

In O
a O
recent O
paper O
, O
Xu O
et O
al O
. O

[ O
J O
. O
Phys O
. O
Chem O
. O
A2012 O
, O
116 O
, O
11668 O
] O
emphasized O
the O
importance O
of O
core O
- O
electron O
correlation O
effects O
to O
describe O
the O
Si2H6BH3 B
complex O
and O
related O
systems O
properly O
. O

Unexpected O
large O
energy O
differences O
between O
a O
frozen O
core O
and O
all O
electron O
treatment O
were O
observed O
. O

In O
the O
present O
study O
, O
it O
will O
be O
shown O
that O
these O
energy O
differences O
are O
an O
artifact O
of O
an O
insufficient O
choice O
of O
basis O
set O
and O
can O
be O
attributed O
to O
an O
intramolecular O
basis O
set O
superposition O
error O
( O
BSSE O
) O
. O

Although O
the O
general O
problem O
is O
known O
, O
systematic O
studies O
on O
the O
effect O
are O
scarce O
. O

Therefore O
, O
the O
BSSE O
in O
related O
systems O
is O
investigated O
. O

This O
study O
shows O
that O
the O
problem O
of O
BSSE O
for O
core O
- O
electron O
correlation O
is O
quite O
common O
if O
inadequate O
basis O
sets O
are O
applied O
and O
that O
it O
amounts O
to O
2 O
kcal O
mol O
( O
- O
1 O
) O
on O
average O
in O
binding O
energies O
for O
the O
given O
test O
set O
( O
with O
a O
maximum O
of O
5 O
. O
8 O
kcal O
mol O
( O
- O
1 O
) O
) O
. O

Molecular O
interactions O
in O
1 B
- I
butanol I
+ O
IL O
solutions O
by O
measuring O
and O
modeling O
activity O
coefficients O
. O

Molecular O
interactions O
in O
1 B
- I
butanol I
+ O
ionic O
liquid O
( O
IL O
) O
solutions O
have O
been O
investigated O
by O
measuring O
and O
modeling O
activity O
- O
coefficient O
data O
. O

The O
activity O
coefficients O
in O
binary O
solutions O
containing O
1 B
- I
butanol I
and O
an O
IL O
were O
determined O
experimentally O
: O
the O
ILs O
studied O
were O
1 B
- I
decyl I
- I
3 I
- I
methyl I
- I
imidazolium I
tetracyanoborate I
( O
[ B
Im10 I
. I
1 I
] I
( I
+ I
) I
[ I
tcb I
] I
( I
- I
) I
) O
, O
4 B
- I
decyl I
- I
4 I
- I
methyl I
- I
morpholinium I
tetracyanoborate I
( O
[ B
Mo10 I
. I
1 I
] I
( I
+ I
) I
[ I
tcb I
] I
( I
- I
) I
) O
, O
1 B
- I
decyl I
- I
3 I
- I
methyl I
- I
imidazolium I
bis I

( I
trifluoromethylsulfo I
) I
imide I
( O
[ B
Im10 I
. I
1 I
] I
( I
+ I
) I
[ I
ntf2 I
] I
( I
- I
) I
) O
, O
and O
4 B
- I
decyl I
- I
4 I
- I
methyl I
- I
morpholinium I
bis I
( I
trifluoromethylsulfo I
) I
imide I
( O
[ B
Mo10 I
. I
1 I
] I
( I
+ I
) I
[ I
ntf2 I
] I
( I
- I
) I
) O
. O

The O
methods O
used O
to O
determine O
the O
activity O
coefficients O
included O
vapor O
- O
pressure O
osmometry O
, O
headspace O
- O
gas O
chromatography O
, O
and O
gas O
- O
liquid O
chromatography O
. O

The O
results O
from O
all O
of O
these O
techniques O
were O
combined O
to O
obtain O
activity O
- O
coefficient O
data O
over O
the O
entire O
IL O
concentration O
range O
, O
and O
the O
ion O
- O
specific O
interactions O
of O
the O
ILs O
investigated O
were O
identified O
with O
1 B
- I
butanol I
. O

The O
highest O
( O
1 I
- I
butanol I
) O
- O
IL O
interactions O
of O
the O
ILs O
considered O
in O
this O
work O
were O
found O
for O
[ B
Im10 I
. I
1 I
] I
( I
+ I
) I
[ I
tcb I
] I
( I
- I
) I
; O
thus O
, O
[ B
Im10 I
. I
1 I
] I
( I
+ I
) I
[ I
tcb I
] I
( I
- I
) I
showed O
the O
highest O
affinity O
for O
1 B
- I
butanol I
in O
a O
binary O
mixture O
. O

The O
experimental O
data O
were O
modeled O
with O
the O
Perturbed O
- O
Chain O
Statistical O
Associating O
Fluid O
Theory O
( O
PC O
- O
SAFT O
) O
. O

PC O
- O
SAFT O
was O
able O
to O
accurately O
describe O
the O
pure O
IL O
and O
( B
1 I
- I
butanol I
) O
- O
IL O
data O
. O

Moreover O
, O
the O
model O
was O
shown O
to O
be O
predictive O
and O
extrapolative O
with O
respect O
to O
concentration O
and O
temperature O
. O

Chemical O
informatics O
uncovers O
a O
new O
role O
for O
moexipril B
as O
a O
novel O
inhibitor O
of O
cAMP B
phosphodiesterase O
- O
4 O
( O
PDE4 O
) O
. O

PDE4 O
is O
one O
of O
eleven O
known O
cyclic O
nucleotide B
phosphodiesterase O
families O
and O
plays O
a O
pivotal O
role O
in O
mediating O
hydrolytic O
degradation O
of O
the O
important O
cyclic O
nucleotide B
second O
messenger O
, O
cyclic B
3 I
' I
5 I
' I
adenosine I
monophosphate I
( O
cAMP B
) O
. O

PDE4 O
inhibitors O
are O
known O
to O
have O
anti O
- O
inflammatory O
properties O
, O
but O
their O
use O
in O
the O
clinic O
has O
been O
hampered O
by O
mechanism O
- O
associated O
side O
effects O
that O
limit O
maximally O
tolerated O
doses O
. O

In O
an O
attempt O
to O
initiate O
the O
development O
of O
better O
- O
tolerated O
PDE4 O
inhibitors O
we O
have O
surveyed O
existing O
approved O
drugs O
for O
PDE4 O
- O
inhibitory O
activity O
. O

With O
this O
objective O
, O
we O
utilised O
a O
high O
- O
throughput O
computational O
approach O
that O
identified O
moexipril B
, O
a O
well O
tolerated O
and O
safe O
angiotensin O
- O
converting O
enzyme O
( O
ACE O
) O
inhibitor O
, O
as O
a O
PDE4 O
inhibitor O
. O

Experimentally O
we O
showed O
that O
moexipril B
and O
two O
structurally O
related O
analogues O
acted O
in O
the O
micro O
molar O
range O
to O
inhibit O
PDE4 O
activity O
. O

Employing O
a O
FRET O
- O
based O
biosensor O
constructed O
from O
the O
nucleotide B
binding O
domain O
of O
the O
type O
1 O
exchange O
protein O
activated O
by O
cAMP B
, O
EPAC1 O
, O
we O
demonstrated O
that O
moexipril B
markedly O
potentiated O
the O
ability O
of O
forskolin B
to O
increase O
intracellular O
cAMP B
levels O
. O

Finally O
, O
we O
demonstrated O
that O
the O
PDE4 O
inhibitory O
effect O
of O
moexipril B
is O
functionally O
able O
to O
induce O
phosphorylation O
of O
the O
small O
heat O
shock O
protein O
, O
Hsp20 O
, O
by O
cAMP B
dependent O
protein O
kinase O
A O
. O

Our O
data O
suggest O
that O
moexipril B
is O
a O
bona O
fide O
PDE4 O
inhibitor O
that O
may O
provide O
the O
starting O
point O
for O
development O
of O
novel O
PDE4 O
inhibitors O
with O
an O
improved O
therapeutic O
window O
. O

Lipid O
raft O
modulation O
by O
Rp1 O
reverses O
multidrug O
resistance O
via O
inactivating O
MDR O
- O
1 O
and O
Src O
inhibition O
. O

Multidrug O
resistance O
( O
MDR O
) O
is O
a O
major O
obstacle O
to O
effective O
cancer O
therapy O
. O

The O
membrane O
transporter O
MDR O
- O
1 O
( O
P O
- O
gp O
, O
ABCB1 O
) O
, O
a O
member O
of O
the O
ATP B
- O
binding O
cassette O
( O
ABC O
) O
transporter O
family O
, O
effluxes O
anti O
- O
cancer O
drugs O
from O
cancer O
cells O
. O

Increased O
activity O
of O
MDR O
- O
1 O
is O
known O
to O
be O
the O
main O
mechanism O
for O
multidrug O
resistance O
. O

MDR O
- O
1 O
is O
known O
to O
be O
localized O
in O
the O
cholesterol B
- O
and O
sphingolipid B
- O
enriched O
plasma O
membrane O
microdomains O
, O
known O
as O
lipid O
rafts O
. O

Disruption O
of O
lipid O
rafts O
by O
cholesterol B
depletion O
alters O
lipid O
raft O
functions O
, O
indicating O
that O
cholesterol B
is O
critical O
for O
raft O
function O
. O

Because O
ginsenosides B
are O
structurally O
similar O
to O
cholesterol B
, O
in O
this O
study O
, O
we O
investigated O
the O
effect O
of O
Rp1 B
, O
a O
novel O
ginsenoside B
derivative O
, O
on O
drug O
resistance O
using O
drug O
- O
sensitive O
OVCAR O
- O
8 O
and O
drug O
- O
resistant O
NCI O
/ O
ADR O
- O
RES O
and O
DXR O
cells O
. O

Rp1 O
treatment O
resulted O
in O
an O
accumulation O
of O
doxorubicin B
or O
rhodamine B
123 I
by O
decreasing O
MDR O
- O
1 O
activity O
in O
doxorubicin B
- O
resistant O
cells O
. O

Rp1 O
synergistically O
induced O
cell O
death O
with O
actinomycin B
D I
in O
DXR O
cells O
. O

Rp1 O
appeared O
to O
redistribute O
lipid O
rafts O
and O
MDR O
- O
1 O
protein O
. O

Moreover O
, O
Rp1 O
reversed O
resistance O
to O
actinomycin B
D I
by O
decreasing O
MDR O
- O
1 O
protein O
levels O
and O
Src O
phosphorylation O
with O
modulation O
of O
lipid O
rafts O
. O

Addition O
of O
cholesterol B
attenuated O
Rp1 O
- O
induced O
raft O
aggregation O
and O
MDR O
- O
1 O
redistribution O
. O

Rp1 O
and O
actinomycin B
D I
reduced O
Src O
activity O
, O
and O
overexpression O
of O
active O
Src O
decreased O
the O
synergistic O
effect O
of O
Rp1 O
with O
actinomycin B
D I
. O

Rp1 O
- O
induced O
drug O
sensitization O
was O
also O
observed O
with O
several O
anti O
- O
cancer O
drugs O
, O
including O
doxorubicin B
. O

These O
data O
suggest O
that O
lipid O
raft O
- O
modulating O
agents O
can O
be O
used O
to O
inhibit O
MDR O
- O
1 O
activity O
and O
thus O
overcome O
drug O
resistance O
. O

Robust O
PEGylated O
hyaluronic O
acid O
nanoparticles O
as O
the O
carrier O
of O
doxorubicin B
: O
Mineralization O
and O
its O
effect O
on O
tumor O
targetability O
in O
vivo O
. O

The O
in O
vivo O
stability O
and O
tumor O
targetability O
of O
self O
- O
assembled O
polymeric O
nanoparticles O
are O
crucial O
for O
effective O
drug O
delivery O
. O

In O
this O
study O
, O
to O
develop O
biostable O
nanoparticles O
with O
high O
tumor O
targetability O
, O
poly B
( I
ethylene I
glycol I
) I
- O
conjugated O
hyaluronic O
acid O
nanoparticles O
( O
PEG B
- O
HANPs O
) O
were O
mineralized O
through O
controlled O
deposition O
of O
inorganic O
calcium B
and O
phosphate B
ions O
on O
the O
nanoparticular O
shell O
via O
a O
sequential O
addition O
method O
. O

The O
resulting O
nanoparticles O
( O
M O
- O
PEG B
- O
HANPs O
) O
had O
a O
smaller O
size O
( O
153 O
. O
7 O
+ O
/ O
- O
4 O
. O
5nm O
) O
than O
bare O
PEG B
- O
HANPs O
( O
265 O
. O
1 O
+ O
/ O
- O
9 O
. O
5nm O
) O
, O
implying O
that O
mineralization O
allows O
the O
formation O
of O
compact O
nanoparticles O
. O

Interestingly O
, O
when O
the O
mineralized O
nanoparticles O
were O
exposed O
to O
acidic O
buffer O
conditions O
( O
< O
pH6 O
. O
5 O
) O
, O
their O
sizes O
increased O
rapidly O
due O
to O
dissolution O
of O
the O
inorganic O
minerals O
. O

Doxorubicin B
( O
DOX B
) O
, O
chosen O
as O
the O
model O
anticancer O
drug O
, O
was O
effectively O
encapsulated O
into O
the O
bare O
and O
mineralized O
nanoparticles O
. O

For O
bare O
PEG B
- O
HANPs O
, O
DOX B
was O
released O
in O
a O
sustained O
manner O
and O
its O
release O
rate O
was O
not O
dependent O
on O
the O
pH O
of O
the O
solution O
. O

On O
the O
other O
hand O
, O
DOX B
release O
from O
M O
- O
PEG B
- O
HANPs O
was O
pH O
- O
dependent O
: O
i O
. O
e O
. O
DOX B
was O
slowly O
released O
from O
nanoparticles O
under O
physiological O
condition O
( O
pH7 O
. O
4 O
) O
, O
whereas O
its O
release O
rates O
were O
much O
higher O
at O
mildly O
acidic O
environments O
( O
< O
pH6 O
. O
5 O
) O
. O

From O
in O
vivo O
biodistribution O
study O
, O
it O
was O
found O
that O
M O
- O
PEG B
- O
HANPs O
could O
reach O
the O
tumor O
site O
more O
effectively O
than O
bare O
PEG B
- O
HANPs O
. O

The O
antitumor O
efficacy O
of O
DOX B
- O
loaded O
nanoparticles O
was O
evaluated O
after O
systemic O
administration O
into O
the O
tumor O
- O
bearing O
mice O
. O

Of O
the O
samples O
tested O
, O
the O
most O
effective O
antitumor O
efficacy O
was O
observed O
for O
DOX B
- O
loaded O
M O
- O
PEG B
- O
HANPs O
. O

Overall O
, O
these O
results O
suggest O
that O
M O
- O
PEG B
- O
HANPs O
could O
be O
a O
promising O
carrier O
for O
an O
anticancer O
drug O
. O

The O
role O
of O
DNA O
methylation O
and O
histone O
acetylation O
in O
the O
regulation O
of O
progesterone B
receptor O
isoforms O
expression O
in O
human O
astrocytoma O
cell O
lines O
. O

Many O
progesterone B
( O
P4 O
) O
effects O
are O
mediated O
by O
its O
intracellular O
receptor O
( O
PR O
) O
, O
which O
has O
two O
isoforms O
, O
PR O
- O
A O
and O
PR O
- O
B O
, O
each O
of O
them O
with O
different O
function O
and O
regulation O
. O

Differential O
PR O
expression O
in O
cancer O
cells O
has O
been O
associated O
to O
a O
PR O
isoform O
- O
specific O
promoter O
methylation O
. O

In O
astrocytomas O
, O
the O
most O
frequent O
and O
aggressive O
brain O
tumors O
, O
PR O
isoforms O
expression O
is O
directly O
correlated O
to O
the O
tumor O
' O
s O
evolution O
grade O
. O

However O
, O
there O
is O
no O
evidence O
of O
the O
role O
of O
epigenetic O
regulation O
of O
PR O
expression O
in O
astrocytomas O
. O

We O
evaluated O
the O
effect O
of O
the O
demethylating O
agent O
5 B
- I
aza I
- I
2 I
' I
- I
deoxycytidine I
( O
5AzadC B
) O
and O
the O
histone O
deacetylase O
inhibitor O
trichostatin B
A I
( O
TSA B
) O
on O
PR O
expression O
in O
human O
astrocytoma O
cell O
lines O
U373 O
( O
grade O
III O
) O
and O
D54 O
( O
grade O
IV O
) O
by O
RT O
- O
PCR O
and O
Western O
blot O
. O

Total O
PR O
expression O
increased O
with O
5 O
mu O
M O
5AzadC B
treatment O
, O
whereas O
PR O
- O
B O
expression O
increased O
with O
5 O
and O
10 O
mu O
M O
5AzadC B
treatment O
in O
U373 O
cells O
, O
but O
not O
in O
D54 O
cells O
. O

In O
U373 O
cells O
, O
PR O
- O
A O
protein O
content O
augmented O
with O
10 O
mu O
M O
5AzadC B
treatment O
, O
while O
PR O
- O
B O
content O
increased O
with O
5 O
and O
10 O
mu O
M O
5AzadC B
. O

PR O
- O
B O
expression O
was O
not O
modified O
by O
the O
TSA B
concentrations O
that O
were O
used O
, O
and O
the O
combination O
with O
5AzadC O
did O
not O
change O
the O
effects O
of O
the O
latter O
. O

The O
study O
of O
5AzadC B
effects O
on O
the O
number O
of O
astrocytoma O
cells O
showed O
that O
P4 O
treatment O
increased O
the O
number O
of O
U373 O
cells O
, O
whereas O
5AzadC B
and O
the O
combined O
treatment O
with O
P4 O
reduced O
it O
. O

Our O
results O
suggest O
that O
PR O
- O
B O
expression O
is O
regulated O
by O
methylation O
and O
not O
by O
histone O
acetylation O
in O
U373 O
cells O
, O
and O
that O
DNA O
demethylation O
reduced O
the O
number O
of O
U373 O
cells O
. O

Neutralization O
of O
Apis O
mellifera O
bee O
venom O
activities O
by O
suramin B
. O

In O
this O
work O
we O
evaluated O
the O
ability O
of O
suramin B
, O
a O
polysulfonated B
naphthylurea I
derivative O
, O
to O
antagonize O
the O
cytotoxic O
and O
enzymatic O
effects O
of O
the O
crude O
venom O
of O
Apis O
mellifera O
. O

Suramin B
was O
efficient O
to O
decrease O
the O
lethality O
in O
a O
dose O
- O
dependent O
way O
. O

The O
hemoconcentration O
caused O
by O
lethal O
dose O
injection O
of O
bee O
venom O
was O
abolished O
by O
suramin B
( O
30 O
mu O
g O
/ O
g O
) O
. O

The O
edematogenic O
activity O
of O
the O
venom O
( O
0 O
. O
3 O
mu O
g O
/ O
g O
) O
was O
antagonized O
by O
suramin B
( O
10 O
mu O
g O
/ O
g O
) O
in O
all O
treatment O
protocols O
. O

The O
changes O
in O
the O
vascular O
permeability O
caused O
by O
A O
. O
mellifera O
( O
1 O
mu O
g O
/ O
g O
) O
venom O
were O
inhibited O
by O
suramin B
( O
30 O
mu O
g O
/ O
g O
) O
in O
the O
pre O
- O
and O
posttreatment O
as O
well O
as O
when O
the O
venom O
was O
preincubated O
with O
suramin B
. O

In O
addition O
, O
suramin B
also O
inhibited O
cultured O
endothelial O
cell O
lesion O
, O
as O
well O
as O
in O
vitro O
myotoxicity O
, O
evaluated O
in O
mouse O
extensor O
digitorumlongus O
muscle O
, O
which O
was O
inhibited O
by O
suramin B
( O
10 O
and O
25 O
mu O
M O
) O
, O
decreasing O
the O
rate O
of O
CK O
release O
, O
showing O
that O
suramin B
protected O
the O
sarcolemma O
against O
damage O
induced O
by O
components O
of O
bee O
venom O
( O
2 O
. O
5 O
mu O
g O
/ O
mL O
) O
. O

Moreover O
, O
suramin B
inhibited O
the O
in O
vivo O
myotoxicity O
induced O
by O
i O
. O
m O
. O
injection O
of O
A O
. O
mellifera O
venom O
in O
mice O
( O
0 O
. O
5 O
mu O
g O
/ O
g O
) O
. O

The O
analysis O
of O
the O
area O
under O
the O
plasma O
CK O
vs O
. O
time O
curve O
showed O
that O
preincubation O
, O
pre O
- O
and O
posttreatment O
with O
suramin B
( O
30 O
mu O
g O
/ O
g O
) O
inhibited O
bee O
venom O
myotoxic O
activity O
in O
mice O
by O
about O
89 O
% O
, O
45 O
% O
and O
40 O
% O
, O
respectively O
. O

Suramin B
markedly O
inhibited O
the O
PLA2 O
activity O
in O
a O
concentration O
- O
dependent O
way O
( O
1 O
- O
30 O
mu O
M O
) O
. O

Being O
suramin B
a O
polyanion O
molecule O
, O
the O
effects O
observed O
may O
be O
due O
to O
the O
interaction O
of O
its O
charges O
with O
the O
polycation O
components O
present O
in O
A O
. O
mellifera O
bee O
venom O
. O

Effects O
of O
perinatal O
exposure O
to O
waterborne O
fluoxetine B
on O
memory O
processing O
in O
the O
cuttlefish O
Sepia O
officinalis O
. O

Recent O
ecotoxicological O
studies O
highlight O
the O
increasing O
presence O
of O
pharmaceuticals O
discharged O
in O
the O
aquatic O
environment O
. O

Amongst O
them O
is O
the O
antidepressant O
fluoxetine B
( O
FLX B
) O
, O
a O
selective O
serotonin B
reuptake O
inhibitor O
, O
primarily O
indicated O
for O
treatment O
of O
depression O
. O

The O
effect O
of O
chronic O
exposure O
to O
FLX B
on O
memory O
processing O
in O
1 O
- O
month O
- O
old O
cuttlefish O
Sepia O
officinalis O
was O
evaluated O
. O

Three O
groups O
of O
new O
- O
borns O
were O
reared O
in O
different O
conditions O
: O
one O
control O
group O
( O
no O
FLX B
) O
and O
two O
groups O
exposed O
to O
environmental O
concentrations O
of O
FLX B
( O
1 O
and O
100ng O
/ O
L O
) O
from O
15 O
days O
pre O
- O
hatching O
to O
1 O
month O
post O
- O
hatching O
. O

Acquisition O
and O
retention O
performances O
were O
assessed O
using O
the O
' O
prawn O
- O
in O
- O
the O
- O
tube O
' O
procedure O
. O

Perinatal O
exposure O
to O
fluoxetine B
led O
to O
significant O
changes O
in O
memory O
processing O
of O
the O
animals O
. O

The O
lowest O
observed O
effect O
concentration O
of O
this O
antidepressant O
on O
learning O
and O
retention O
was O
1ng O
/ O
L O
which O
is O
under O
the O
range O
of O
environmental O
contamination O
. O

Cuttlefish O
exposed O
at O
low O
FLX B
concentration O
had O
impaired O
acquisition O
capabilities O
and O
animals O
exposed O
at O
high O
FLX B
concentration O
displayed O
a O
deficit O
of O
memory O
retention O
compared O
to O
the O
control O
group O
that O
had O
nonimpaired O
initial O
acquisition O
and O
retention O
performances O
. O

The O
results O
subsequently O
suggested O
that O
FLX B
- O
induced O
changes O
in O
cognitive O
capacities O
could O
potentially O
lead O
to O
inappropriate O
predatory O
behaviors O
in O
the O
natural O
environment O
. O

The O
study O
provides O
the O
basis O
for O
future O
studies O
on O
how O
pharmaceutical O
contaminants O
disrupt O
cognition O
in O
ecologically O
and O
economically O
relevant O
marine O
invertebrates O
. O

Synergistic O
effects O
between O
pesticide O
stress O
and O
predator O
cues O
: O
Conflicting O
results O
from O
life O
history O
and O
physiology O
in O
the O
damselfly O
Enallagma O
cyathigerum O
. O

There O
is O
increasing O
awareness O
that O
the O
negative O
effects O
of O
anthropogenic O
stressors O
may O
be O
magnified O
in O
the O
presence O
of O
natural O
stressors O
. O

Very O
few O
of O
these O
studies O
have O
included O
physiology O
, O
yet O
including O
physiological O
studies O
may O
help O
learning O
about O
the O
mechanistic O
base O
of O
such O
synergisms O
at O
the O
life O
history O
level O
and O
identify O
synergistic O
interactions O
not O
translated O
in O
life O
history O
traits O
. O

We O
studied O
in O
Enallagma O
cyathigerum O
damselfly O
larvae O
potential O
synergistic O
effects O
between O
exposure O
to O
the O
pesticide O
glyphosate B
and O
predator O
cues O
on O
a O
key O
life O
history O
trait O
, O
growth O
rate O
, O
its O
associated O
behavioural O
trait O
, O
food O
intake O
, O
and O
three O
types O
of O
physiological O
traits O
known O
to O
be O
affected O
by O
both O
stressors O
in O
isolation O
: O
the O
stress O
protein O
Hsp70 O
, O
energy O
storage O
and O
variables O
related O
to O
oxidative O
stress O
and O
damage O
. O

The O
pesticide O
and O
predator O
cues O
reduced O
growth O
rate O
in O
an O
additive O
way O
. O

Food O
intake O
increased O
under O
pesticide O
exposure O
and O
was O
not O
affected O
by O
the O
predator O
cues O
, O
indicating O
physiological O
mediation O
of O
the O
growth O
reduction O
. O

One O
potential O
physiological O
mechanism O
was O
that O
both O
stressors O
additively O
increased O
Hsp70 O
levels O
, O
this O
may O
also O
have O
contributed O
to O
the O
reduced O
levels O
of O
total O
carbohydrates B
when O
exposed O
to O
predator O
cues O
. O

Chronic O
exposure O
to O
predator O
cues O
reduced O
oxygen B
consumption O
, O
possibly O
to O
avoid O
too O
high O
costs O
of O
an O
increased O
metabolic O
rate O
. O

This O
reduction O
did O
not O
occur O
in O
the O
presence O
of O
the O
pesticide O
, O
reflecting O
the O
need O
for O
energetically O
expensive O
defence O
mechanisms O
( O
such O
as O
Hsp70 O
upregulation O
) O
. O

When O
both O
stressors O
were O
combined O
, O
there O
was O
a O
reduction O
of O
the O
antioxidant O
enzyme O
superoxide B
dismutase O
activity O
( O
SOD O
) O
and O
an O
associated O
increase O
of O
oxidative O
damage O
in O
lipids O
. O

While O
synergistic O
interactions O
were O
not O
present O
for O
growth O
rate O
and O
food O
intake O
, O
they O
were O
identified O
for O
antioxidant O
defence O
and O
oxidative O
damage O
. O

This O
novel O
type O
of O
" O
hidden O
" O
synergistic O
interaction O
may O
have O
profound O
fitness O
implications O
, O
and O
when O
ignored O
will O
lead O
to O
underestimations O
of O
the O
impact O
of O
pollutants O
in O
natural O
populations O
where O
predators O
are O
omnipresent O
. O

Can O
acetylcholinesterase O
activity O
be O
considered O
as O
a O
reliable O
biomarker O
for O
the O
assessment O
of O
cadmium B
- O
induced O
neurotoxicity O
? O

Gon O
c O
alves O
et O
al O
. O

( O
2012 O
) O
recently O
reported O
the O
findings O
of O
a O
long O
- O
awaited O
study O
on O
the O
effects O
of O
long O
- O
term O
dietary O
- O
induced O
exposure O
to O
cadmium B
( O
Cd B
) O
on O
the O
acetylcholinesterase O
( O
AChE O
) O
activity O
of O
adult O
rodents O
' O
brain O
regions O
. O

Their O
study O
can O
be O
regarded O
as O
a O
significant O
contribution O
to O
the O
field O
, O
as O
there O
is O
paucity O
of O
information O
on O
the O
AChE O
activity O
in O
brain O
regions O
following O
exposure O
to O
Cd B
. O

However O
, O
the O
Cd B
- O
induced O
modulation O
of O
AChE O
activity O
is O
an O
issue O
surrounded O
by O
controversy O
. O

We O
, O
herein O
, O
discuss O
and O
summarize O
the O
relative O
in O
vivo O
and O
in O
vitro O
experimental O
data O
, O
and O
set O
out O
to O
answer O
the O
straightforward O
question O
: O
can O
AChE O
activity O
be O
considered O
as O
a O
reliable O
biomarker O
for O
the O
assessment O
of O
Cd B
- O
induced O
neurotoxicity O
? O

At O
this O
time O
, O
we O
can O
not O
answer O
in O
the O
affirmative O
because O
of O
the O
variation O
in O
techniques O
used O
and O
conclusions O
reached O
. O

We O
make O
a O
plea O
that O
authors O
aiming O
to O
explore O
this O
potential O
use O
of O
brain O
AChE O
activity O
in O
the O
future O
: O
( O
a O
) O
are O
aware O
of O
the O
biases O
that O
their O
experimental O
approach O
might O
exert O
upon O
this O
neurochemical O
parameter O
, O
( O
b O
) O
avoid O
the O
use O
of O
anaesthesia O
as O
a O
mode O
of O
sacrifice O
and O
clarify O
its O
timing O
, O
( O
c O
) O
decide O
upon O
the O
use O
of O
previously O
- O
studied O
in O
vivo O
experimental O
schemes O
( O
so O
that O
they O
can O
provide O
comparable O
results O
) O
, O
and O
finally O
, O
( O
d O
) O
identify O
pharmacological O
, O
biochemical O
and O
molecular O
approaches O
that O
are O
appropriate O
to O
clarify O
the O
implicated O
mechanism O
( O
s O
) O
through O
which O

Cd B
modifies O
AChE O
activity O
. O

Frank O
A O
. O
Beach O
Award O
: O
Programming O
of O
neuroendocrine O
function O
by O
early O
- O
life O
experience O
: O
A O
critical O
role O
for O
the O
immune O
system O
. O

Many O
neuropsychiatric O
disorders O
are O
associated O
with O
a O
strong O
dysregulation O
of O
the O
immune O
system O
, O
and O
several O
have O
a O
striking O
etiology O
in O
development O
as O
well O
. O

Our O
recent O
evidence O
using O
a O
rodent O
model O
of O
neonatal O
Escherichiacoli O
infection O
has O
revealed O
novel O
insight O
into O
the O
mechanisms O
underlying O
cognitive O
deficits O
in O
adulthood O
, O
and O
suggests O
that O
the O
early O
- O
life O
immune O
history O
of O
an O
individual O
may O
be O
critical O
to O
understanding O
the O
relative O
risk O
of O
developing O
later O
- O
life O
mental O
health O
disorders O
in O
humans O
. O

A O
single O
neonatal O
infection O
programs O
the O
function O
of O
immune O
cells O
within O
the O
brain O
, O
called O
microglia O
, O
for O
the O
life O
of O
the O
rodent O
such O
that O
an O
adult O
immune O
challenge O
results O
in O
exaggerated O
cytokine O
production O
within O
the O
brain O
and O
associated O
cognitive O
deficits O
. O

I O
describe O
the O
important O
role O
of O
the O
immune O
system O
, O
notably O
microglia O
, O
during O
brain O
development O
, O
and O
discuss O
some O
of O
the O
many O
ways O
in O
which O
immune O
activation O
during O
early O
brain O
development O
can O
affect O
the O
later O
- O
life O
outcomes O
of O
neural O
function O
, O
immune O
function O
, O
and O
cognition O
. O

Changes O
in O
Insulin O
Resistance O
and O
HbA1c O
Are O
Related O
to O
Exercise O
- O
Mediated O
Changes O
in O
Body O
Composition O
in O
Older O
Adults O
With O
Type O
2 O
Diabetes O
: O
Interim O
outcomes O
from O
the O
GREAT2DO O
Trial O
. O

OBJECTIVETo O
investigate O
changes O
in O
body O
composition O
after O
12 O
months O
of O
high O
- O
intensity O
progressive O
resistance O
training O
( O
PRT O
) O
in O
relation O
to O
changes O
in O
insulin O
resistance O
( O
IR O
) O
or O
glucose B
homeostasis O
in O
older O
adults O
with O
type O
2 O
diabetes O
. O
RESEARCH O
DESIGN O
AND O
METHODSOne O
- O
hundred O
three O
participants O
were O
randomized O
to O
receive O
either O
PRT O
or O
sham O
exercise O
3 O
days O
per O
week O
for O
12 O
months O
. O

Homeostatic O
model O
of O
assessment O
2 O
( O
HOMA2 O
- O
IR O
) O
and O
glycosylated O
hemoglobin O
( O
HbA1c O
) O
were O
used O
as O
indices O
of O
IR O
and O
glucose B
homeostasis O
. O

Skeletal O
muscle O
mass O
( O
SkMM O
) O
and O
total O
fat O
mass O
were O
assessed O
using O
bioelectrical O
impedance O
. O

Visceral O
adipose O
tissue O
, O
mid O
- O
thigh O
cross O
- O
sectional O
area O
, O
and O
mid O
- O
thigh O
muscle O
attenuation O
were O
quantified O
using O
computed O
tomography O
. O
RESULTSWithin O
the O
PRT O
group O
, O
changes O
in O
HOMA2 O
- O
IR O
were O
associated O
with O
changes O
in O
SkMM O
( O
r O
= O
- O
0 O
. O
38 O
; O
P O
= O
0 O
. O
04 O
) O
and O
fat O
mass O
( O
r O
= O
0 O
. O
42 O
; O
P O
= O
0 O
. O
02 O
) O
. O

Changes O
in O
visceral O
adipose O
tissue O
tended O
to O
be O
related O
to O
changes O
in O
HOMA2 O
- O
IR O
( O
r O
= O
0 O
. O
35 O
; O
P O
= O
0 O
. O
07 O
) O
. O

Changes O
in O
HbA1c O
were O
related O
to O
changes O
in O
mid O
- O
thigh O
muscle O
attenuation O
( O
r O
= O
0 O
. O
52 O
; O
P O
= O
0 O
. O
001 O
) O
. O

None O
of O
these O
relationships O
were O
present O
in O
the O
sham O
group O
( O
P O
> O
0 O
. O
05 O
) O
. O

Using O
ANCOVA O
models O
, O
participants O
in O
the O
PRT O
group O
who O
had O
increased O
SkMM O
had O
decreased O
HOMA2 O
- O
IR O
( O
P O
= O
0 O
. O
05 O
) O
and O
HbA1c O
( O
P O
= O
0 O
. O
09 O
) O
compared O
with O
those O
in O
the O
PRT O
group O
who O
lost O
SkMM O
. O

Increases O
in O
SkMM O
in O
the O
PRT O
group O
decreased O
HOMA2 O
- O
IR O
( O
P O
= O
0 O
. O
07 O
) O
and O
HbA1c O
( O
P O
< O
0 O
. O
05 O
) O
compared O
with O
those O
who O
had O
increased O
SkMM O
in O
the O
sham O
group O
. O
CONCLUSIONSImproveme O
in O
metabolic O
health O
in O
older O
adults O
with O
type O
2 O
diabetes O
were O
mediated O
through O
improvements O
in O
body O
composition O
only O
if O
they O
were O
achieved O
through O
high O
- O
intensity O
PRT O
. O

Mn B
@ O
Si14 B
+ I
: O
a O
singlet O
fullerene B
- O
like O
endohedrally O
doped O
silicon B
cluster O
. O

The O
electronic O
structure O
of O
Mn B
@ O
Si14 B
( I
+ I
) I
is O
determined O
using O
DFT O
and O
CASPT2 O
/ O
CASSCF O
( O
14 O
, O
15 O
) O
computations O
with O
large O
basis O
sets O
. O

The O
endohedrally O
Mn B
- O
doped O
Si B
cationic O
cluster O
has O
a O
D3h O
fullerene B
- O
like O
structure O
featuring O
a O
closed O
- O
shell O
singlet O
ground O
state O
with O
a O
singlet O
- O
triplet O
gap O
of O
~ O
1 O
eV O
. O

A O
strong O
stabilizing O
interaction O
occurs O
between O
the O
3d O
( O
Mn B
) O
and O
the O
2D O
- O
shell O
( O
Si14 B
) O
orbitals O
, O
and O
a O
large O
amount O
of O
charge O
is O
transferred O
from O
the O
Si14 B
cage O
to O
the O
Mn B
dopant O
. O

The O
3d O
( O
Mn B
) O
orbitals O
are O
filled O
by O
encapsulation O
, O
and O
the O
magnetic O
moment O
of O
Mn B
is O
completely O
quenched O
. O

Full O
occupation O
of O
[ O
2S O
, O
2P O
, O
2D O
] O
shell O
orbitals O
by O
18 O
delocalized O
electrons O
confers O
the O
doped O
Mn B
@ O
Si14 B
( I
+ I
) I
cluster O
a O
spherically O
aromatic O
character O
. O

Influence O
of O
the O
novel O
histamine B
H3 O
receptor O
antagonist O
ST1283 B
on O
voluntary O
alcohol B
consumption O
and O
ethanol B
- O
induced O
place O
preference O
in O
mice O
. O

RATIONALE O
: O
Growing O
evidence O
supports O
a O
role O
for O
the O
central O
histaminergic O
system O
to O
have O
a O
modulatory O
influence O
on O
drug O
addiction O
in O
general O
and O
alcohol B
- O
use O
disorders O
in O
particular O
through O
histamine B
H3 O
receptors O
( O
H3R O
) O
. O

OBJECTIVE O
: O
In O
the O
present O
study O
, O
the O
effects O
of O
systemic O
injection O
of O
the O
newly O
synthesized O
H3R O
antagonist O
ST1283 B
on O
ethanol B
( O
EtOH B
) O
voluntary O
intake O
and O
EtOH B
- O
conditioned O
reward O
in O
mice O
have O
been O
investigated O
. O

METHODS O
: O
Oral O
EtOH B
, O
saccharin B
, O
and O
quinine B
intake O
was O
assessed O
in O
a O
two O
- O
bottle O
choice O
paradigm O
using O
escalating O
concentrations O
of O
alcohol B
or O
tastant O
solutions O
. O

EtOH B
- O
induced O
place O
preference O
( O
CPP O
) O
, O
EtOH B
- O
induced O
locomotor O
activity O
, O
and O
blood O
ethanol B
concentration O
( O
BEC O
) O
were O
also O
measured O
. O

RESULTS O
: O
Following O
administration O
of O
the O
H3R O
antagonist O
( O
2 O
. O
5 O
, O
5 O
, O
and O
10 O
mg O
/ O
kg O
, O
i O
. O
p O
. O
) O
, O
there O
was O
a O
significant O
dose O
- O
dependent O
decrease O
in O
alcohol B
consumption O
and O
preference O
. O

Importantly O
, O
vehicle O
- O
and O
ST1283 B
( O
5 O
mg O
/ O
kg O
) O
- O
treated O
mice O
showed O
similar O
consumption O
and O
preference O
to O
increasing O
concentration O
of O
both O
sweet O
and O
bitter O
tastes O
. O

More O
interestingly O
, O
systemic O
administration O
of O
ST1283 B
inhibited O
EtOH B
- O
CPP O
and O
EtOH B
- O
enhanced O
locomotion O
. O

This O
inhibition O
was O
blocked O
when O
mice O
were O
pretreated O
with O
the O
selective O
H3R O
agonist O
R B
- I
( I
alpha I
) I
- I
methyl I
- I
histamine I
( O
10 O
mg O
/ O
kg O
) O
. O

Finally O
, O
vehicle O
- O
and O
ST1283 B
- O
treated O
mice O
had O
similar O
BECs O
. O

CONCLUSION O
: O
Our O
results O
show O
that O
ST1283 B
may O
decrease O
voluntary O
EtOH B
consumption O
and O
EtOH B
- O
CPP O
by O
altering O
its O
reinforcing O
effects O
, O
suggesting O
a O
novel O
role O
for O
histamine B
signaling O
in O
regulation O
of O
alcoholism O
. O

Lastly O
, O
the O
results O
add O
to O
the O
growing O
literature O
on O
H3R O
modulation O
in O
the O
pharmacotherapy O
of O
EtOH B
addiction O
. O

Delineating O
multiple O
functions O
of O
VEGF O
- O
A O
in O
the O
adult O
brain O
. O

Vascular O
endothelial O
growth O
factor O
- O
A O
( O
abbreviated O
throughout O
this O
review O
as O
VEGF O
) O
is O
mostly O
known O
for O
its O
angiogenic O
activity O
, O
for O
its O
activity O
as O
a O
vascular O
permeability O
factor O
, O
and O
for O
its O
vascular O
survival O
activity O
[ O
1 O
] O
. O

There O
is O
a O
growing O
body O
of O
evidence O
, O
however O
, O
that O
VEGF O
fulfills O
additional O
less O
' O
traditional O
' O
functions O
in O
multiple O
organs O
, O
both O
during O
development O
, O
as O
well O
as O
homeostatic O
functions O
in O
fully O
developed O
organs O
. O

This O
review O
focuses O
on O
the O
multiple O
roles O
of O
VEGF O
in O
the O
adult O
brain O
and O
is O
less O
concerned O
with O
the O
roles O
played O
by O
VEGF O
during O
brain O
development O
, O
functions O
described O
elsewhere O
in O
this O
review O
series O
. O

Most O
functions O
of O
VEGF O
that O
are O
essential O
for O
proper O
brain O
development O
are O
, O
in O
fact O
, O
dispensable O
in O
the O
adult O
brain O
as O
was O
clearly O
demonstrated O
using O
a O
conditional O
brain O
- O
specific O
VEGF O
loss O
- O
of O
- O
function O
( O
LOF O
) O
approach O
. O

Thus O
, O
in O
contrast O
to O
VEGF O
LOF O
in O
the O
developing O
brain O
, O
a O
process O
which O
is O
detrimental O
for O
the O
growth O
and O
survival O
of O
blood O
vessels O
and O
leads O
to O
massive O
neuronal O
apoptosis O
[ O
2 O
- O
4 O
] O
, O
continued O
signaling O
by O
VEGF O
in O
the O
mature O
brain O
is O
no O
longer O
required O
for O
maintaining O
already O
established O
cerebral O
vasculature O
and O
its O
inhibition O
does O
not O
cause O
appreciable O
vessel O
regression O
, O
hypoxia O
or O
apoptosis O
[ O
4 O
- O
7 O
] O
. O

Yet O
, O
VEGF O
continues O
to O
be O
expressed O
in O
the O
adult O
brain O
in O
a O
constitutive O
manner O
. O

Moreover O
, O
VEGF O
is O
expressed O
in O
the O
adult O
brain O
in O
a O
region O
- O
specific O
manner O
and O
in O
distinctive O
spatial O
patterns O
incompatible O
with O
an O
angiogenic O
role O
( O
see O
below O
) O
, O
strongly O
suggesting O
angiogenesis O
- O
independent O
and O
possibly O
also O
perfusion O
- O
independent O
functions O
. O

Here O
we O
review O
current O
knowledge O
on O
some O
of O
these O
' O
non O
- O
traditional O
' O
, O
often O
unexpected O
homeostatic O
VEGF O
functions O
, O
including O
those O
unrelated O
to O
its O
effects O
on O
the O
brain O
vasculature O
. O

These O
effects O
could O
be O
mediated O
directly O
( O
on O
non O
- O
vascular O
cells O
expressing O
cognate O
VEGF O
receptors O
) O
or O
indirectly O
( O
via O
the O
endothelium O
) O
. O

Experimental O
approaches O
aimed O
at O
distinguishing O
between O
these O
possibilities O
for O
each O
particular O
VEGF O
function O
will O
be O
described O
. O

This O
review O
is O
only O
concerned O
with O
homeostatic O
functions O
of O
VEGF O
in O
the O
normal O
, O
non O
- O
injured O
brain O
. O

The O
reader O
is O
referred O
elsewhere O
in O
this O
series O
for O
a O
review O
on O
VEGF O
actions O
in O
response O
to O
various O
forms O
of O
brain O
injury O
and O
/ O
or O
brain O
pathology O
. O

Selenium B
Attenuates O
Adriamycin B
- O
Induced O
Cardiac O
Dysfunction O
via O
Restoring O
Expression O
of O
ATP B
- O
Sensitive O
Potassium B
Channels O
in O
Rats O
. O

The O
possible O
mechanism O
of O
adriamycin B
( O
ADR B
) O
and O
/ O
or O
selenium B
( O
Se B
) O
deficiency O
- O
induced O
cardiac O
dysfunction O
, O
and O
cardioprotective O
effects O
of O
Se B
against O
ADR B
- O
induced O
cardiac O
toxicity O
were O
investigated O
in O
this O
study O
. O

Cardiac O
function O
was O
evaluated O
by O
plasma O
brain O
natriuretic O
peptide O
level O
and O
echocardiographic O
and O
hemodynamic O
parameters O
. O

Cardiac O
glutathione B
peroxidase O
( O
GPx O
) O
activity O
was O
assessed O
spectrophotometrical O
. O

Expression O
of O
ATP B
- O
sensitive O
potassium B
channels O
( O
KATP O
) O
subunits O
- O
SUR2A O
and O
Kir6 O
. O
2 O
- O
were O
examined O
by O
real O
- O
time O
PCR O
and O
Western O
blotting O
. O

The O
results O
showed O
that O
cardiac O
function O
and O
cardiac O
GPx O
activity O
decreased O
remarkably O
after O
administration O
of O
ADR O
or O
Se B
deficiency O
; O
more O
dramatic O
impairment O
of O
cardiac O
function O
and O
cardiac O
GPx O
activity O
were O
observed O
after O
co O
- O
administration O
of O
ADR B
and O
Se B
deficiency O
. O

Mechanically O
, O
it O
is O
novel O
for O
us O
to O
find O
down O
- O
regulation O
of O
KATP O
subunits O
gene O
expression O
in O
cardiac O
tissue O
after O
administration O
of O
ADR B
or O
Se B
deficiency O
, O
and O
more O
significant O
inhibition O
of O
cardiac O
KATP O
gene O
expression O
was O
identified O
after O
co O
- O
administration O
of O
ADR B
and O
Se B
deficiency O
. O

Furthermore O
, O
cardiac O
toxicity O
of O
ADR O
was O
found O
alleviated O
by O
Se B
supplementation O
, O
accompanied O
by O
restoring O
of O
cardiac O
GPx O
activity O
and O
cardiac O
KATP O
gene O
expression O
. O

These O
results O
indicate O
that O
decreased O
expression O
of O
cardiac O
KATP O
is O
involved O
in O
adriamycin B
and O
/ O
or O
Se B
deficiency O
- O
induced O
cardiac O
dysfunction O
; O
Se B
deficiency O
exacerbates O
adriamycin B
- O
induced O
cardiac O
dysfunction O
by O
future O
inhibition O
of O
KATP O
expression O
; O
Se B
supplementation O
seems O
to O
protect O
against O
adriamycin B
- O
induced O
cardiac O
dysfunction O
via O
restoring O
KATP O
expression O
, O
showing O
potential O
clinical O
application O
in O
cancer O
chemotherapy O
. O

Characteristics O
and O
determinants O
of O
adult O
patients O
with O
acute O
poisoning O
attending O
the O
accident O
and O
emergency O
department O
of O
a O
teaching O
hospital O
in O
Qatar O
. O

Data O
about O
etiologic O
and O
demographic O
characteristics O
of O
acute O
poisoning O
in O
adults O
in O
Qatar O
are O
lacking O
. O

This O
prospective O
observational O
study O
was O
undertaken O
to O
analyze O
characteristics O
and O
possible O
determinants O
of O
acute O
poisoning O
in O
adults O
in O
Qatar O
. O

During O
2010 O
, O
18 O
, O
073 O
patients O
attended O
the O
emergency O
department O
of O
Hamad O
General O
Hospital O
, O
a O
teaching O
hospital O
in O
Qatar O
. O

Out O
of O
them O
, O
599 O
( O
3 O
. O
3 O
% O
) O
patients O
were O
diagnosed O
as O
" O
poisoning O
case O
" O
with O
either O
chemical O
or O
pharmaceutical O
substances O
. O

The O
prevalence O
rate O
of O
poisoning O
incidence O
was O
35 O
. O
3 O
/ O
100 O
, O
000 O
population O
. O

Seven O
patients O
died O
, O
corresponding O
with O
a O
case O
- O
fatality O
rate O
of O
0 O
. O
39 O
/ O
1000 O
. O

The O
majority O
were O
male O
( O
65 O
% O
) O
and O
the O
mean O
age O
was O
34 O
years O
. O

The O
poisons O
involved O
were O
mainly O
chemicals O
( O
61 O
. O
6 O
% O
) O
and O
pharmaceuticals O
( O
38 O
. O
4 O
% O
) O
. O

Female O
, O
mainly O
single O
, O
suffered O
more O
intentional O
poisoning O
compared O
to O
male O
. O

Of O
the O
patients O
aged O
60 O
years O
and O
above O
( O
7 O
. O
2 O
% O
) O
, O
the O
majority O
( O
95 O
. O
3 O
% O
) O
suffered O
unintentional O
poisoning O
with O
pharmaceuticals O
; O
56 O
% O
with O
warfarin B
, O
12 O
% O
with O
digoxin B
and O
7 O
% O
with O
insulin O
. O

Multivariate O
analysis O
shows O
that O
female O
gender O
, O
single O
status O
, O
younger O
than O
35 O
years O
of O
age O
, O
being O
poisoned O
by O
pharmaceutical O
products O
, O
and O
the O
need O
for O
hospitalization O
are O
significant O
determinants O
for O
acute O
intentional O
poisoning O
after O
adjusting O
all O
other O
possible O
covariates O
. O

The O
findings O
of O
this O
study O
can O
be O
used O
to O
establish O
awareness O
and O
prophylactic O
campaigns O
in O
Qatar O
. O

Stacking O
of O
Short O
DNA O
Induces O
the O
Gyroid O
Cubic O
- O
to O
- O
Inverted O
Hexagonal O
Phase O
Transition O
in O
Lipid O
- O
DNA O
Complexes O
. O

Lyotropic O
phases O
of O
amphiphiles O
are O
a O
prototypical O
example O
of O
self O
- O
assemblies O
. O

Their O
structure O
is O
generally O
determined O
by O
amphiphile O
shape O
and O
their O
phase O
transitions O
are O
primarily O
governed O
by O
composition O
. O

In O
this O
paper O
, O
we O
demonstrate O
a O
new O
paradigm O
for O
membrane O
shape O
control O
where O
the O
electrostatic O
coupling O
of O
charged O
membranes O
to O
short O
DNA O
( O
sDNA O
) O
, O
with O
tunable O
temperature O
- O
dependent O
end O
- O
to O
- O
end O
stacking O
interactions O
, O
enables O
switching O
between O
the O
inverted O
gyroid O
cubic O
structure O
( O
QII O
( O
G O
) O
) O
and O
the O
inverted O
hexagonal O
phase O
( O
HII O
( O
C O
) O
) O
. O

We O
investigated O
the O
structural O
shape O
transitions O
induced O
in O
the O
QII O
( O
G O
) O
phase O
upon O
complexation O
with O
a O
series O
of O
sDNAs O
( O
5 O
, O
11 O
, O
24 O
, O
and O
48 O
bp O
) O
with O
three O
types O
of O
end O
structure O
( O
" O
sticky O
" O
adenine B
( O
A O
) O
- O
thymine B
( O
T O
) O
( O
dAdT B
) O
overhangs O
, O
no O
overhang O
( O
blunt O
) O
, O
and O
" O
nonsticky O
" O
dTdT B
overhangs O
) O
using O
synchrotron O
small O
- O
angle O
X O
- O
ray O
scattering O
. O

Very O
short O
5 O
bp O
sDNA O
with O
dAdT O
overhangs O
and O
blunt O
ends O
induce O
coexistence O
of O
the O
QII O
( O
G O
) O
and O
the O
HII O
( O
C O
) O
phase O
, O
with O
the O
fraction O
of O
QII O
( O
G O
) O
increasing O
with O
temperature O
. O

Phase O
coexistence O
for O
blunt O
5 O
bp O
sDNA O
is O
observed O
from O
27 O
degrees O
C O
to O
about O
65 O
degrees O
C O
, O
where O
the O
HII O
( O
C O
) O
phase O
disappears O
and O
the O
temperature O
dependence O
of O
the O
lattice O
spacing O
of O
the O
QII O
( O
G O
) O
phase O
indicates O
that O
the O
sDNA O
duplexes O
melt O
into O
single O
strands O
. O

The O
only O
other O
sDNA O
for O
which O
melting O
is O
observed O
is O
5 O
bp O
sDNA O
with O
dTdT B
overhangs O
, O
which O
forms O
the O
QII O
( O
G O
) O
phase O
throughout O
the O
studied O
range O
of O
temperature O
( O
27 O
degrees O
C O
to O
85 O
. O
2 O
degrees O
C O
) O
. O

The O
longer O
11 O
bp O
sDNA O
forms O
coexisting O
QII O
( O
G O
) O
and O
HII O
( O
C O
) O
phases O
( O
with O
the O
fraction O
of O
QII O
( O
G O
) O
again O
increasing O
with O
temperature O
) O
only O
for O
" O
nonsticky O
" O
dTdT B
overhangs O
, O
while O
dAdT O
overhangs O
and O
blunt O
ends O
exclusively O
template O
the O
HII O
( O
C O
) O
phase O
. O

For O
24 O
and O
48 O
bp O
sDNAs O
the O
HII O
( O
C O
) O
phase O
replaces O
the O
QII O
( O
G O
) O
phase O
at O
all O
investigated O
temperatures O
, O
independent O
of O
sDNA O
end O
structure O
. O

Our O
work O
demonstrates O
how O
the O
combined O
effects O
of O
sDNA O
length O
and O
end O
structure O
( O
which O
determine O
the O
temperature O
- O
dependent O
stacking O
length O
) O
tune O
the O
phase O
behavior O
of O
the O
complexes O
. O

These O
findings O
are O
consistent O
with O
the O
hypothesis O
that O
sDNAs O
and O
sDNA O
stacks O
with O
lengths O
comparable O
to O
or O
larger O
than O
the O
cubic O
unit O
cell O
length O
disfavor O
the O
highly O
curved O
channels O
present O
in O
the O
QII O
( O
G O
) O
phase O
, O
thus O
driving O
the O
QII O
( O
G O
) O
- O
to O
- O
HII O
( O
C O
) O
phase O
transition O
. O

As O
the O
temperature O
is O
increased O
, O
the O
breaking O
of O
stacks O
due O
to O
thermal O
fluctuations O
restores O
increasing O
percentages O
of O
the O
QII O
( O
G O
) O
phase O
. O

Sensing O
of O
biologically O
important O
cations O
such O
as O
na B
( I
+ I
) I
, O
k B
( I
+ I
) I
, O
ca B
( I
2 I
+ I
) I
, O
cu B
( I
2 I
+ I
) I
, O
and O
fe B
( I
3 I
+ I
) I
using O
magnetic O
nanoemulsions O
. O

We O
report O
a O
simple O
approach O
to O
the O
ultrasensitive O
detection O
of O
biologically O
important O
metal O
ions O
using O
a O
magnetic O
nanoemulsion O
. O

The O
nanoemulsion O
used O
in O
our O
study O
was O
an O
oil O
- O
in O
- O
water O
emulsion O
droplet O
of O
average O
size O
~ O
190 O
nm O
containing O
ferrimagnetic O
iron B
oxide I
nanoparticles O
of O
average O
size O
~ O
10 O
nm O
. O

In O
a O
static O
magnetic O
field O
, O
the O
emulsion O
droplets O
self O
- O
assemble O
into O
a O
nanoarray O
with O
distinct O
interdroplet O
spacing O
. O

In O
the O
presence O
of O
cations O
in O
the O
solution O
, O
the O
nanofluid O
array O
shows O
a O
large O
blue O
shift O
in O
the O
diffracted O
Bragg O
peak O
and O
a O
visually O
perceivable O
color O
change O
due O
to O
changes O
in O
the O
electrical O
double O
layer O
upon O
the O
diffusion O
of O
cations O
. O

The O
colloidal O
force O
- O
distance O
measurements O
in O
the O
presence O
of O
cations O
show O
large O
variations O
at O
the O
onset O
of O
repulsion O
in O
the O
presence O
of O
cations O
. O

The O
sensor O
shows O
good O
selectivity O
to O
Na B
( I
+ I
) I
, O
K B
( I
+ I
) I
, O
Ca B
( I
2 I
+ I
) I
, O
Cu B
( I
2 I
+ I
) I
, O
and O
Fe B
( I
3 I
+ I
) I
ions O
and O
offers O
a O
rapid O
response O
compared O
to O
conventional O
techniques O
. O

This O
approach O
can O
be O
useful O
for O
the O
recognition O
of O
biologically O
important O
cations O
. O

Steroids O
Glycosylated O
with O
Both O
d B
- I
and I
l I
- I
Arabinoses I
from O
the O
South O
China O
Sea O
Gorgonian O
Dichotella O
gemmacea O
. O

Three O
new O
19 B
- I
hydroxy I
steroidal I
glycosides I
, O
namely O
, O
junceellosides B
E I
- I
G I
( O
2 O
- O
4 O
) O
, O
were O
isolated O
together O
with O
the O
known O
analogue O
junceelloside B
C I
( O
1 O
) O
from O
the O
South O
China O
Sea O
gorgonian O
Dichotella O
gemmacea O
. O

The O
structures O
of O
these O
compounds O
were O
elucidated O
by O
a O
combination O
of O
detailed O
spectroscopic O
analyses O
, O
chemical O
methods O
, O
and O
comparison O
with O
reported O
data O
. O

These O
glycosides O
are O
found O
to O
have O
sugar B
moieties O
of O
both O
beta B
- I
l I
- I
and I
beta I
- I
d I
- I
arabinopyranoses I
by O
HPLC O
analysis O
of O
their O
thiocarbamoyl B
- I
thiazolidine I
derivatives O
and O
those O
of O
authentic O
d B
- I
and I
l I
- I
arabinoses I
, O
leading O
to O
the O
structure O
revision O
of O
junceelloside B
C I
( O
1 O
) O
. O

This O
is O
the O
first O
report O
of O
steroidal B
glycosides I
from O
the O
gorgonian O
D O
. O
gemmacea O
and O
the O
first O
report O
of O
glycosides O
with O
beta B
- I
l I
- I
arabinopyranose I
from O
marine O
sources O
. O

In O
situ O
forming O
reduction O
- O
sensitive O
degradable O
nanogels O
for O
facile O
loading O
and O
triggered O
intracellular O
release O
of O
proteins O
. O

In O
situ O
forming O
reduction O
- O
sensitive O
degradable O
nanogels O
were O
designed O
and O
developed O
based O
on O
poly B
( I
ethylene I
glycol I
) I
- I
b I
- I
poly I
( I
2 I
- I
( I
hydroxyethyl I
) I
methacrylate I
- I
co I
- I
acryloyl I
carbonate I
) I
( O
PEG B
- I
P I
( I
HEMA I
- I
co I
- I
AC I
) I
) O
block O
copolymers O
for O
efficient O
loading O
as O
well O
as O
triggered O
intracellular O
release O
of O
proteins O
. O

PEG B
- I
P I
( I
HEMA I
- I
co I
- I
AC I
) I
copolymers O
were O
prepared O
with O
controlled O
Mn O
of O
9 O
. O
1 O
, O
9 O
. O
5 O
, O
and O
9 O
. O
9 O
kg O
/ O
mol O
and O
varying O
numbers O
of O
AC O
units O
per O
molecule O
of O
7 O
, O
9 O
and O
11 O
, O
respectively O
( O
denoted O
as O
copolymer O
1 O
, O
2 O
, O
and O
3 O
) O
by O
reversible O
addition O
- O
fragmentation O
chain O
transfer O
copolymerization O
. O

These O
copolymers O
were O
freely O
soluble O
in O
phosphate B
buffer O
but O
formed O
disulfide B
- O
cross O
- O
linked O
nanogels O
with O
defined O
sizes O
ranging O
from O
72 O
. O
5 O
to O
124 O
. O
1 O
nm O
in O
the O
presence O
of O
cystamine B
via O
ring O
- O
opening O
reaction O
with O
cyclic B
carbonate I
groups O
. O

The O
sizes O
of O
nanogels O
decreased O
with O
increasing O
AC O
units O
as O
a O
result O
of O
increased O
cross O
- O
linking O
density O
. O

Dynamic O
light O
scattering O
studies O
showed O
that O
these O
nanogels O
though O
stable O
at O
physiological O
conditions O
were O
rapidly O
dissociated O
in O
response O
to O
10 O
mM O
dithiothreitol B
( O
DTT B
) O
. O

Interestingly O
, O
FITC B
- O
labeled O
cytochrome O
C O
( O
FITC B
- O
CC O
) O
could O
be O
readily O
loaded O
into O
nanogels O
with O
remarkable O
loading O
efficiencies O
( O
up O
to O
98 O
. O
2 O
% O
) O
and O
loading O
contents O
( O
up O
to O
48 O
. O
2 O
wt O
. O
% O
) O
. O

The O
in O
vitro O
release O
studies O
showed O
that O
release O
of O
FITC B
- I
CC I
was O
minimal O
under O
physiological O
conditions O
but O
significantly O
enhanced O
under O
reductive O
conditions O
in O
the O
presence O
of O
10 O
mM O
DTT B
with O
about O
96 O
. O
8 O
% O
of O
FITC B
- I
CC I
released O
in O
22 O
h O
from O
nanogel O
1 O
. O

In O
contrast O
, O
protein O
release O
from O
1 B
, I
4 I
- I
butanediamine I
cross O
- O
linked O
nanogels O
( O
reduction O
- O
insensitive O
control O
) O
remained O
low O
under O
otherwise O
the O
same O
conditions O
. O

MTT B
assays O
showed O
that O
these O
nanogels O
were O
nontoxic O
to O
HeLa O
cells O
up O
to O
a O
tested O
concentration O
of O
2 O
mg O
/ O
mL O
. O

Confocal O
microscopy O
results O
showed O
that O
nanogel O
1 O
delivered O
and O
released O
FITC B
- I
CC I
into O
the O
perinuclei O
region O
of O
HeLa O
cells O
following O
8 O
h O
incubation O
. O

CC O
- O
loaded O
reductively O
degradable O
nanogels O
demonstrated O
apparently O
better O
apoptotic O
activity O
than O
free O
CC O
as O
well O
as O
reduction O
- O
insensitive O
controls O
. O

These O
in O
situ O
forming O
, O
surfactant O
and O
oil O
- O
free O
, O
and O
reduction O
- O
sensitive O
degradable O
nanogels O
are O
highly O
promising O
for O
targeted O
protein O
therapy O
. O

Age O
- O
Related O
Macular O
Degeneration O
- O
Associated O
Silent O
Polymorphisms O
in O
HtrA1 O
Impair O
Its O
Ability O
To O
Antagonize O
Insulin O
- O
Like O
Growth O
Factor O
1 O
. O

Synonymous O
single O
nucleotide B
polymorphisms O
( O
SNPs O
) O
within O
a O
transcript O
' O
s O
coding O
region O
produce O
no O
change O
in O
the O
amino B
acid I
sequence O
of O
the O
protein O
product O
and O
are O
therefore O
intuitively O
assumed O
to O
have O
a O
neutral O
effect O
on O
protein O
function O
. O

We O
report O
that O
two O
common O
variants O
of O
high O
- O
temperature O
requirement O
A1 O
( O
HTRA1 O
) O
that O
increase O
the O
inherited O
risk O
of O
neovascular O
age O
- O
related O
macular O
degeneration O
( O
NvAMD O
) O
harbor O
synonymous O
SNPs O
within O
exon O
1 O
of O
HTRA1 O
that O
convert O
common O
codons O
for O
Ala34 B
and O
Gly36 B
to O
less O
frequently O
used O
codons O
. O

The O
frequent O
- O
to O
- O
rare O
codon O
conversion O
reduced O
the O
mRNA O
translation O
rate O
and O
appeared O
to O
compromise O
HtrA1 O
' O
s O
conformation O
and O
function O
. O

The O
protein O
product O
generated O
from O
the O
SNP O
- O
containing O
cDNA O
displayed O
enhanced O
susceptibility O
to O
proteolysis O
and O
a O
reduced O
affinity O
for O
an O
anti O
- O
HtrA1 O
antibody O
. O

The O
NvAMD O
- O
associated O
synonymous O
polymorphisms O
lie O
within O
HtrA1 O
' O
s O
putative O
insulin O
- O
like O
growth O
factor O
1 O
( O
IGF O
- O
1 O
) O
binding O
domain O
. O

They O
reduced O
HtrA1 O
' O
s O
abilities O
to O
associate O
with O
IGF O
- O
1 O
and O
to O
ameliorate O
IGF O
- O
1 O
- O
stimulated O
signaling O
events O
and O
cellular O
responses O
. O

These O
observations O
highlight O
the O
relevance O
of O
synonymous O
codon O
usage O
to O
protein O
function O
and O
implicate O
homeostatic O
protein O
quality O
control O
mechanisms O
that O
may O
go O
awry O
in O
NvAMD O
. O

Global O
Gene O
Expression O
Profiling O
Reveals O
Functional O
Importance O
of O
Sirt2 O
in O
Endothelial O
Cells O
under O
Oxidative O
Stress O
. O

The O
NAD B
+ I
- O
dependent O
deacetylases O
Sirt1 O
and O
Sirt2 O
mediate O
cellular O
stress O
responses O
and O
are O
highly O
expressed O
in O
vascular O
endothelial O
cells O
. O

In O
contrast O
to O
the O
well O
- O
documented O
protective O
actions O
of O
Sirt1 O
, O
the O
role O
of O
endothelial O
Sirt2 O
remains O
unknown O
. O

Using O
cDNA O
microarray O
and O
PCR O
validation O
, O
we O
examined O
global O
gene O
expression O
changes O
in O
response O
to O
Sirt2 O
knock O
down O
in O
primary O
human O
umbilical O
vein O
endothelial O
cells O
under O
oxidative O
stress O
. O

We O
found O
that O
Sirt2 O
knock O
down O
changed O
expression O
of O
340 O
genes O
, O
which O
are O
mainly O
involved O
in O
cellular O
processes O
including O
actin O
binding O
, O
cellular O
amino B
acid I
metabolic O
process O
, O
transmembrane O
receptor O
protein O
serine B
/ O
threonine B
kinase O
signaling O
, O
ferrous B
iron I
transport O
, O
protein O
transport O
and O
localization O
, O
cell O
morphogenesis O
, O
and O
functions O
associated O
with O
endosome O
membrane O
and O
the O
trans O
- O
Golgi O
network O
. O

These O
genes O
and O
associated O
functions O
were O
largely O
non O
- O
overlapping O
with O
those O
altered O
by O
Sirt1 O
knock O
down O
. O

Moreover O
, O
we O
showed O
that O
pharmacological O
inhibition O
of O
Sirt2 O
attenuated O
oxidant O
- O
induced O
cell O
toxicity O
in O
endothelial O
cells O
. O

These O
suggest O
that O
Sirt2 O
is O
functionally O
important O
in O
endothelial O
cells O
under O
oxidative O
stress O
, O
and O
may O
have O
a O
primarily O
distinct O
role O
as O
compared O
to O
Sirt1 O
. O

Our O
results O
may O
provide O
a O
basis O
for O
future O
studies O
aiming O
to O
dissect O
the O
specific O
signaling O
pathway O
( O
s O
) O
that O
mediates O
specific O
Sirt2 O
functions O
in O
endothelial O
cells O
. O

Genotoxic O
effects O
of O
the O
water O
- O
soluble O
fraction O
of O
heavy O
oil O
in O
the O
brackish O
/ O
freshwater O
amphipod O
Quadrivisio O
aff O
. O
lutzi O
( O
Gammaridea O
) O
as O
assessed O
using O
the O
comet O
assay O
. O

Amphipod O
crustaceans O
have O
been O
widely O
used O
as O
invertebrate O
models O
in O
ecotoxicology O
due O
to O
their O
importance O
in O
the O
food O
chain O
. O

However O
, O
few O
studies O
have O
evaluated O
the O
genotoxic O
effects O
of O
pollutants O
in O
this O
model O
using O
the O
comet O
assay O
. O

The O
main O
obstacle O
to O
using O
amphipods O
in O
the O
comet O
assay O
is O
the O
difficulty O
in O
obtaining O
enough O
blood O
cells O
from O
a O
single O
individual O
. O

In O
this O
study O
, O
we O
evaluated O
the O
genotoxic O
effects O
of O
the O
water O
- O
soluble O
fraction O
( O
WSF O
) O
of O
heavy O
oil O
on O
the O
brackish O
/ O
freshwater O
amphipod O
Quadrivisio O
aff O
. O
lutzi O
, O
which O
is O
common O
in O
the O
coastal O
lagoons O
of O
southeastern O
Brazil O
, O
using O
hemocytes O
obtained O
from O
single O
amphipods O
( O
without O
pooling O
) O
after O
optimizing O
hemolymph O
extraction O
. O

The O
comet O
assay O
revealed O
significantly O
higher O
DNA O
damage O
levels O
( O
2 O
- O
to O
6 O
- O
fold O
higher O
) O
in O
treated O
amphipods O
compared O
to O
untreated O
ones O
with O
a O
sublethal O
concentration O
of O
17 O
. O
6 O
% O
of O
the O
WSF O
within O
72 O
h O
of O
treatment O
. O

Two O
independent O
experiments O
confirmed O
an O
" O
up O
and O
down O
" O
pattern O
of O
DNA O
damage O
, O
measured O
as O
the O
% O
of O
DNA O
contained O
in O
the O
tail O
of O
the O
comets O
. O

Elevations O
in O
DNA O
damage O
levels O
were O
observed O
at O
the O
6 O
and O
48 O
h O
time O
points O
, O
while O
very O
low O
levels O
of O
DNA O
damage O
were O
observed O
at O
the O
24 O
and O
72 O
h O
time O
points O
. O

Furthermore O
, O
the O
comet O
assay O
revealed O
gender O
variability O
in O
the O
levels O
of O
DNA O
damage O
after O
short O
- O
term O
exposure O
. O

Selective O
poisoning O
of O
Ctnnb1 O
- O
mutated O
hepatoma O
cells O
in O
mouse O
liver O
tumors O
by O
a O
single O
application O
of O
acetaminophen B
. O

Mouse O
liver O
tumors O
that O
harbor O
activating O
mutations O
in O
Ctnnb1 O
, O
encoding O
beta O
- O
catenin O
, O
express O
high O
levels O
of O
various O
cytochromes O
P450 O
( O
CYP O
) O
, O
including O
CYP2E1 O
and O
CYP1A2 O
. O

Acetaminophen B
( O
AAP B
) O
is O
metabolized O
in O
hepatocytes O
by O
these O
CYPs O
to O
the O
reactive O
intermediate O
N B
- I
acetyl I
- I
p I
- I
benzoquinone I
- I
imine I
, O
which O
is O
toxic O
to O
hepatocytes O
at O
high O
doses O
where O
depletion O
of O
glutathione B
occurs O
. O

We O
have O
induced O
liver O
tumors O
in O
mice O
by O
treatment O
with O
the O
liver O
carcinogen O
N B
- I
nitrosodiethylamine I
followed O
by O
chronic O
treatment O
with O
the O
tumor O
promoter O
phenobarbital B
. O

Under O
this O
protocol O
, O
~ O
80 O
% O
of O
tumors O
display O
Ctnnb1 O
mutations O
and O
express O
high O
levels O
of O
various O
CYP O
isoforms O
. O

Tumor O
- O
bearing O
animals O
were O
given O
a O
single O
intraperitoneal O
injection O
of O
300 O
mg O
/ O
kg O
body O
weight O
AAP B
, O
which O
was O
well O
tolerated O
by O
the O
animals O
. O

This O
dose O
, O
however O
, O
eradicated O
essentially O
all O
larger O
Ctnnb1 O
- O
mutated O
, O
CYP O
- O
positive O
liver O
tumors O
, O
killing O
> O
90 O
% O
of O
hepatoma O
cells O
: O
at O
2 O
days O
after O
AAP B
, O
large O
necrotic O
areas O
filled O
with O
cell O
debris O
were O
observed O
in O
tumors O
. O

These O
were O
infiltrated O
in O
the O
following O
days O
by O
immune O
cells O
starting O
from O
the O
outer O
parts O
of O
the O
damaged O
areas O
slowly O
closing O
the O
" O
wounds O
" O
left O
from O
the O
poisoned O
tumor O
cells O
. O

During O
this O
period O
, O
there O
was O
increased O
proliferation O
of O
normal O
hepatocytes O
, O
but O
some O
residual O
tumor O
cells O
were O
also O
proliferating O
. O

Our O
results O
show O
that O
a O
selective O
poisoning O
of O
Ctnnb1 O
- O
mutated O
liver O
tumors O
by O
administration O
of O
AAP B
is O
possible O
in O
this O
experimental O
system O
. O

Application O
of O
an O
adapted O
protocol O
could O
be O
envisaged O
for O
neo O
- O
adjuvant O
treatment O
of O
human O
hepatoblastoma O
which O
are O
frequently O
mutated O
in O
CTNNB1 O
and O
often O
show O
high O
expression O
of O
CYP2E1 O
. O

Theoretical O
study O
of O
the O
thermodynamic O
and O
burning O
properties O
of O
oxygen B
- O
rich O
hydrazine B
derivatives O
- O
green O
and O
powerful O
oxidants O
for O
energetic O
materials O
. O

A O
series O
of O
no B
- O
chlorine B
and O
oxygen B
- O
rich O
hydrazine B
derivatives O
( O
hydrazine B
modified O
with O
- O
NO2 B
and O
NO3 B
( I
- I
) I
groups O
) O
was O
designed O
and O
optimized O
to O
obtain O
molecular O
geometries O
and O
electronic O
structures O
at O
density O
functional O
theory O
- O
B3PW91 O
/ O
6 O
- O
311 O
+ O
+ O
G O
( O
3df O
, O
3pd O
) O
level O
. O

Some O
important O
properties O
such O
as O
bond O
dissociation O
enthalpy O
, O
density O
, O
natural O
bond O
orbitals O
, O
thermodynamic O
parameters O
, O
molecular O
orbital O
energy O
and O
burning O
rate O
were O
then O
calculated O
. O

The O
simulation O
results O
revealed O
that O
these O
compounds O
exhibit O
excellent O
performance O
, O
with O
significant O
superiority O
over O
traditional O
oxidants O
found O
in O
propellants O
. O

Flavonoids B
and O
3 B
- I
Arylcoumarin I
from O
Pterocarpus O
soyauxii O
. O

Phytochemical O
study O
on O
the O
constituents O
of O
the O
heartwood O
of O
Pterocarpus O
soyauxii O
led O
to O
the O
isolation O
of O
five O
new O
isoflavonoids B
and O
one O
new O
3 B
- I
arylcoumarin I
, O
pterosonins B
A I
- I
F I
( O
1 O
- O
6 O
) O
, O
together O
with O
17 O
known O
analogues O
, O
among O
which O
8 O
, O
9 O
, O
and O
18 O
were O
reported O
as O
natural O
products O
for O
the O
first O
time O
. O

Structure O
elucidation O
was O
achieved O
by O
way O
of O
spectroscopic O
measurements O
as O
well O
as O
by O
comparison O
with O
literature O
data O
. O

Only O
Compound O
6 O
showed O
potent O
cytotoxicity O
against O
human O
non O
- O
small O
cell O
lung O
cancer O
( O
A549 O
) O
, O
pancreatic O
cancer O
( O
Panc O
- O
28 O
) O
, O
and O
colon O
carcinoma O
( O
HCT O
- O
116 O
) O
cells O
with O
GI50 O
values O
at O
7 O
. O
39 O
, O
25 O
, O
and O
19 O
. O
17 O
micro O
M O
, O
respectively O
; O
the O
other O
isolates O
showed O
no O
cytotoxicity O
against O
the O
above O
tested O
cell O
lines O
with O
GI50 O
values O
> O
50 O
micro O
M O
. O

Dyslipidemia O
in O
type O
2 O
diabetes O
: O
prevalence O
, O
pathophysiology O
, O
and O
management O
. O

Dyslipidemia O
is O
one O
of O
the O
key O
risk O
factors O
for O
cardiovascular O
disease O
( O
CVD O
) O
in O
diabetes O
mellitus O
. O

Despite O
the O
mounting O
clinical O
trial O
data O
, O
the O
management O
of O
dyslipidemia O
other O
than O
lowering O
the O
low O
density O
lipoprotein O
cholesterol B
( O
LDL O
- O
c O
) O
continues O
to O
be O
controversial O
. O

The O
characteristic O
features O
of O
diabetic O
dyslipidemia O
are O
high O
plasma O
triglyceride B
concentration O
, O
reduced O
high O
density O
lipoprotein O
cholesterol B
( O
HDL O
- O
c O
) O
concentration O
, O
and O
increased O
concentration O
of O
small O
dense O
LDL O
particles O
. O

These O
changes O
are O
caused O
by O
increased O
free O
fatty B
acid I
flux O
secondary O
to O
insulin O
resistance O
and O
aggravated O
by O
increased O
inflammatory O
adipokines O
. O

The O
availability O
of O
several O
lipid O
- O
lowering O
drugs O
and O
nutritional O
supplements O
offers O
novel O
and O
effective O
options O
for O
achieving O
target O
lipid O
levels O
in O
people O
with O
diabetes O
. O

While O
initiation O
of O
drug O
therapy O
based O
on O
differences O
in O
the O
lipid O
profile O
is O
an O
option O
, O
most O
practice O
guidelines O
recommend O
statins B
as O
first O
- O
line O
therapy O
. O

Although O
the O
evidence O
for O
clinical O
utility O
of O
combination O
of O
statins O
with O
fibrates O
or O
nicotinic B
acid I
in O
reducing O
cardiovascular O
events O
remains O
inconclusive O
, O
the O
preponderance O
of O
evidence O
suggests O
that O
a O
subgroup O
who O
have O
high O
triglycerides B
and O
low O
HDL O
- O
c O
levels O
may O
benefit O
from O
combination O
therapy O
of O
statins O
and O
fibrates O
. O

The O
goal O
of O
therapy O
is O
to O
achieve O
at O
least O
30 O
- O
40 O
% O
reduction O
in O
LDL O
- O
c O
levels O
. O

Preferably O
the O
LDL O
- O
c O
should O
be O
less O
than O
100 O
mg O
/ O
dL O
in O
low O
- O
risk O
people O
and O
less O
than O
70 O
mg O
/ O
dL O
in O
those O
at O
high O
risk O
, O
including O
people O
with O
established O
CVD O
. O

Crystal O
Structures O
of O
a O
Glycoside O
Hydrolase O
Family O
20 O
Lacto O
- O
N B
- O
biosidase O
from O
Bifidobacterium O
bifidum O
. O

Human O
milk O
oligosaccharides O
contain O
a O
large O
variety O
of O
oligosaccharides O
, O
of O
which O
lacto B
- I
N I
- I
biose I
I I
( O
Gal B
- I
beta I
1 I
, I
3 I
- I
GlcNAc I
; O
LNB O
) O
predominates O
as O
a O
major O
core O
structure O
. O

A O
unique O
metabolic O
pathway O
specific O
for O
LNB O
has O
recently O
been O
identified O
in O
the O
human O
commensal O
bifidobacteria O
. O

Several O
strains O
of O
infant O
gut O
- O
associated O
bifidobacteria O
possess O
lacto O
- O
N O
- O
biosidase O
, O
a O
membrane O
- O
anchored O
extracellular O
enzyme O
, O
that O
liberates O
LNB O
from O
the O
nonreducing O
end O
of O
human O
milk O
oligosaccharides O
and O
plays O
a O
key O
role O
in O
the O
metabolic O
pathway O
of O
these O
compounds O
. O

Lacto O
- O
N B
- O
biosidase O
belongs O
to O
the O
glycoside O
hydrolase O
family O
20 O
, O
and O
its O
reaction O
proceeds O
via O
a O
substrate O
- O
assisted O
catalytic O
mechanism O
. O

Several O
crystal O
structures O
of O
GH20 O
beta O
- O
N O
- O
acetylhexosaminidase O
, O
which O
release O
monosaccharide B
GlcNAc B
from O
its O
substrate O
, O
have O
been O
determined O
, O
but O
to O
date O
, O
a O
structure O
of O
lacto O
- O
N B
- O
biosidase O
is O
unknown O
. O

Here O
, O
we O
have O
determined O
the O
first O
three O
- O
dimensional O
structures O
of O
lacto O
- O
N B
- O
biosidase O
from O
Bifidobacterium O
bifidum O
JCM1254 O
in O
complex O
with O
LNB O
and O
LNB O
- O
thiazoline B
( O
Gal B
- I
beta I
1 I
, I
3 I
- I
GlcNAc I
- I
thiazoline I
) O
at O
1 O
. O
8 O
- O
A O
resolution O
. O

Lacto O
- O
N B
- O
biosidase O
consists O
of O
three O
domains O
, O
and O
the O
C B
- O
terminal O
domain O
has O
a O
unique O
beta O
- O
trefoil O
- O
like O
fold O
. O

Compared O
with O
other O
beta O
- O
N B
- O
acetylhexosaminidase O
, O
lacto O
- O
N B
- O
biosidase O
has O
a O
wide O
substrate O
- O
binding O
pocket O
with O
a O
- O
2 O
subsite O
specific O
for O
beta O
- O
1 O
, O
3 O
- O
linked O
Gal B
, O
and O
the O
residues O
responsible O
for O
Gal B
recognition O
were O
identified O
. O

The O
bound O
ligands O
are O
recognized O
by O
extensive O
hydrogen B
bonds O
at O
all O
of O
their O
hydroxyls B
consistent O
with O
the O
enzyme O
' O
s O
strict O
substrate O
specificity O
for O
the O
LNB O
moiety O
. O

The O
GlcNAc B
sugar B
ring O
of O
LNB O
is O
in O
a O
distorted O
conformation O
near O
( O
4 O
) O
E O
, O
whereas O
that O
of O
LNB O
- O
thiazoline B
is O
in O
a O
( O
4 O
) O
C1 O
conformation O
. O

A O
possible O
conformational O
pathway O
for O
the O
lacto O
- O
N B
- O
biosidase O
reaction O
is O
discussed O
. O

Degradation O
and O
Rearrangement O
of O
a O
Lung O
Surfactant O
Lipid O
at O
the O
Air O
- O
Water O
Interface O
during O
Exposure O
to O
the O
Pollutant O
Gas O
Ozone B
. O

The O
presence O
of O
unsaturated O
lipids O
in O
lung O
surfactant O
is O
important O
for O
proper O
respiratory O
function O
. O

In O
this O
work O
, O
we O
have O
used O
neutron O
reflection O
and O
surface O
pressure O
measurements O
to O
study O
the O
reaction O
of O
the O
ubiquitous O
pollutant O
gas O
- O
phase O
ozone B
, O
O3 B
, O
with O
pure O
and O
mixed O
phospholipid O
monolayers O
at O
the O
air O
- O
water O
interface O
. O

The O
results O
reveal O
that O
the O
reaction O
of O
the O
unsaturated O
lipid O
1 B
- I
palmitoyl I
- I
2 I
- I
oleoyl I
- I
sn I
- I
glycero I
- I
3 I
- I
phosphocholine I
, O
POPC B
, O
with O
ozone B
leads O
to O
the O
rapid O
loss O
of O
the O
terminal O
C9 O
portion O
of O
the O
oleoyl B
strand O
of O
POPC B
from O
the O
air O
- O
water O
interface O
. O

The O
loss O
of O
the O
C9 B
portion O
from O
the O
interface O
is O
accompanied O
by O
an O
increase O
in O
the O
surface O
pressure O
( O
decrease O
in O
surface O
tension O
) O
of O
the O
film O
at O
the O
air O
- O
water O
interface O
. O

The O
results O
suggest O
that O
the O
portion O
of O
the O
oxidized O
oleoyl B
strand O
that O
is O
still O
attached O
to O
the O
lipid O
headgroup O
rapidly O
reverses O
its O
orientation O
and O
penetrates O
the O
air O
- O
water O
interface O
alongside O
the O
original O
headgroup O
, O
thus O
increasing O
the O
surface O
pressure O
. O

The O
reaction O
of O
POPC B
with O
ozone B
also O
leads O
to O
a O
loss O
of O
material O
from O
the O
palmitoyl B
strand O
, O
but O
the O
loss O
of O
palmitoyl B
material O
occurs O
after O
the O
loss O
of O
the O
terminal O
C9 O
portion O
from O
the O
oleoyl B
strand O
of O
the O
molecule O
, O
suggesting O
that O
the O
palmitoyl B
material O
is O
lost O
in O
a O
secondary O
reaction O
step O
. O

Further O
experiments O
studying O
the O
reaction O
of O
mixed O
monolayers O
composed O
of O
unsaturated O
lipid O
POPC B
and O
saturated O
lipid O
dipalmitoyl B
- I
sn I
- I
glycero I
- I
3 I
- I
phosphocholine I
, O
DPPC B
, O
revealed O
that O
no O
loss O
of O
DPPC B
from O
the O
air O
- O
water O
interface O
occurs O
, O
eliminating O
the O
possibility O
that O
a O
reactive O
species O
such O
as O
an O
OH B
radical O
is O
formed O
and O
is O
able O
to O
attack O
nearby O
lipid O
chains O
. O

The O
reaction O
of O
ozone B
with O
the O
mixed O
films O
does O
cause O
a O
significant O
change O
in O
the O
surface O
pressure O
of O
the O
air O
- O
water O
interface O
. O

Thus O
, O
the O
reaction O
of O
unsaturated O
lipids O
in O
lung O
surfactant O
changes O
and O
impairs O
the O
physical O
properties O
of O
the O
film O
at O
the O
air O
- O
water O
interface O
. O

MD O
simulations O
of O
the O
formation O
of O
stable O
clusters O
in O
mixtures O
of O
alkaline O
salts O
and O
imidazolium B
- O
based O
ionic O
liquids O
. O

Structural O
and O
dynamical O
properties O
of O
room O
- O
temperature O
ionic O
liquids O
containing O
the O
cation O
1 B
- I
butyl I
- I
3 I
- I
methylimidazolium I
( O
[ B
BMIM I
] I
( I
+ I
) I
) O
and O
three O
different O
anions O
( O
hexafluorophosphate B
, O
[ B
PF6 I
] I
( I
- I
) I
, O
tetrafluoroborate B
, O
[ B
BF4 I
] I
( I
- I
) I
, O
and O
bis B
( I
trifluoromethylsulfo I
) I
imide I
, O
[ B
NTf2 I
] I
( I
- I
) I
) O
doped O
with O
several O
molar O
fractions O
of O
lithium B
salts O
with O
a O
common O
anion O

at O
298 O
. O
15 O
K O
and O
1 O
atm O
were O
investigated O
by O
means O
of O
molecular O
dynamics O
simulations O
. O

The O
effect O
of O
the O
size O
of O
the O
salt O
cation O
was O
also O
analyzed O
by O
comparing O
these O
results O
with O
those O
for O
mixtures O
of O
[ B
BMIM I
] I
[ I
PF6 I
] I
with O
NaPF6 B
. O

Lithium B
/ O
sodium B
solvation O
and O
ionic O
mobilities O
were O
analyzed O
via O
the O
study O
of O
radial O
distribution O
functions O
, O
coordination O
numbers O
, O
cage O
autocorrelation O
functions O
, O
mean O
- O
square O
displacements O
( O
including O
the O
analysis O
of O
both O
ballistic O
and O
diffusive O
regimes O
) O
, O
self O
- O
diffusion O
coefficients O
of O
all O
the O
ionic O
species O
, O
velocity O
and O
current O
autocorrelation O
functions O
, O
and O
ionic O
conductivity O
in O
all O
the O
ionic O
liquid O
/ O
salt O
systems O
. O

We O
found O
that O
lithium B
and O
sodium B
cations O
are O
strongly O
coordinated O
in O
two O
different O
positions O
with O
the O
anion O
present O
in O
the O
mixture O
. O

Moreover O
, O
[ B
Li I
] I
( I
+ I
) I
and O
[ B
Na I
] I
( I
+ I
) I
cations O
were O
found O
to O
form O
bonded O
- O
like O
, O
long O
- O
lived O
aggregates O
with O
the O
anions O
in O
their O
first O
solvation O
shell O
, O
which O
act O
as O
very O
stable O
kinetic O
entities O
within O
which O
a O
marked O
rattling O
motion O
of O
salt O
ions O
takes O
place O
. O

With O
very O
long O
MD O
simulation O
runs O
, O
this O
phenomenon O
is O
proved O
to O
be O
on O
the O
basis O
of O
the O
decrease O
of O
self O
- O
diffusion O
coefficients O
and O
ionic O
conductivities O
previously O
reported O
in O
experimental O
and O
computational O
results O
. O

The O
Emerging O
Use O
of O
Ketamine B
for O
Anesthesia O
and O
Sedation O
in O
Traumatic O
Brain O
Injuries O
. O

BACKGROUND O
: O
Traditionally O
, O
the O
use O
of O
ketamine B
for O
patients O
with O
traumatic O
brain O
injuries O
is O
contraindicated O
due O
to O
the O
concern O
of O
increasing O
intracranial O
pressure O
( O
ICP O
) O
. O

These O
concerns O
, O
however O
, O
originated O
from O
early O
studies O
and O
case O
reports O
that O
were O
inadequately O
controlled O
and O
designed O
. O

Recently O
, O
the O
concern O
of O
using O
ketamine B
in O
these O
patients O
has O
been O
challenged O
by O
a O
number O
of O
published O
studies O
demonstrating O
that O
the O
use O
of O
ketamine B
was O
safe O
in O
these O
patients O
. O

AIMS O
: O
The O
purpose O
of O
this O
article O
was O
to O
review O
the O
current O
literature O
in O
regards O
to O
using O
ketamine B
in O
patients O
with O
traumatic O
brain O
injuries O
in O
different O
clinical O
settings O
associated O
with O
anesthesia O
, O
as O
well O
as O
review O
the O
potential O
mechanisms O
underlying O
the O
neuroprotective O
effects O
of O
ketamine B
. O

RESULTS O
: O
Studies O
examining O
the O
use O
of O
ketamine B
for O
induction O
, O
maintenance O
, O
and O
sedation O
in O
patients O
with O
TBI O
have O
had O
promising O
results O
. O

The O
use O
of O
ketamine B
in O
a O
controlled O
ventilation O
setting O
and O
in O
combination O
with O
other O
sedative O
agents O
has O
demonstrated O
no O
increase O
in O
ICP O
. O

CONCLUSIONS O
: O
The O
role O
of O
ketamine B
as O
a O
neuroprotective O
agent O
in O
humans O
remains O
inconclusive O
and O
adequately O
powered O
; O
randomized O
controlled O
trials O
performed O
in O
patients O
undergoing O
surgery O
for O
traumatic O
brain O
injury O
are O
necessary O
. O

Killed O
Bacillus O
subtilis O
spores O
expressing O
streptavidin O
: O
a O
novel O
carrier O
of O
drugs O
to O
target O
cancer O
cells O
. O

Abstract O
Carriers O
of O
drugs O
in O
cancer O
therapy O
are O
required O
to O
reduce O
side O
- O
effects O
of O
the O
drugs O
to O
normal O
cells O
. O

Here O
we O
constructed O
killed O
recombinant O
Bacillus O
subtilis O
spores O
( O
SA1 O
) O
that O
expressed O
streptavidin O
as O
a O
chimeric O
fusion O
to O
the O
spore O
coat O
protein O
CotB O
and O
used O
the O
spores O
as O
bioparticle O
carrier O
. O

When O
bound O
with O
biotinylated O
cetuximab O
these O
spores O
could O
specifically O
target O
to O
the O
epidermal O
growth O
factor O
receptor O
on O
HT O
29 O
colon O
cancer O
cells O
, O
thereby O
delivered O
paclitaxel B
to O
the O
cells O
with O
4 O
- O
fold O
higher O
efficiency O
, O
as O
indicated O
by O
fluorescent O
intensity O
of O
paclitaxel B
Oregon B
Green I
488 I
bound O
to O
HT29 O
cells O
. O

Based O
on O
real O
- O
time O
monitoring O
of O
cell O
index O
, O
the O
IC50 O
of O
growth O
of O
HT29 O
cells O
by O
paclitaxel B
- O
SA1 O
- O
cetuximab O
was O
estimated O
to O
be O
2 O
. O
9 O
nM O
approximately O
5 O
- O
fold O
lower O
than O
water O
- O
soluble O
paclitaxel B
( O
14 O
. O
5 O
nM O
) O
. O

Instability O
of O
DNA O
content O
was O
observed O
when O
cells O
were O
treated O
with O
16 O
nM O
paclitaxel B
- O
SA1 O
- O
cetuximab O
, O
resulting O
in O
a O
2 O
- O
fold O
enhancement O
in O
polyploidy O
cells O
. O

Thus O
, O
by O
targeting O
the O
release O
of O
paclitaxel B
to O
HT29 O
cells O
, O
spore O
- O
associated O
cetuximab O
augmented O
the O
inhibitory O
effect O
of O
paclitaxel B
on O
cell O
division O
and O
proliferation O
. O

The O
SA1 O
could O
be O
used O
as O
a O
" O
universal O
" O
drug O
carrier O
to O
target O
specific O
biomarkers O
on O
cancer O
cells O
by O
conjugating O
with O
suitable O
biotinylated O
antibodies O
. O

9G O
DNAChip O
Technology O
: O
Self O
- O
Assembled O
Monolayer O
( O
SAM O
) O
of O
ssDNA O
for O
Ultra O
- O
Sensitive O
Detection O
of O
Biomarkers O
. O

A O
9G O
DNAChip O
obtained O
by O
allowing O
the O
formation O
of O
a O
self O
- O
assembled O
monolayer O
( O
SAM O
) O
of O
oligonucleotides O
appended O
with O
nine O
consecutive O
guanines B
on O
the O
chip O
surface O
has O
been O
applied O
in O
the O
detection O
of O
biomarkers O
. O

Using O
a O
9G O
DNAChip O
, O
biomarker O
in O
the O
concentration O
range O
of O
4 O
pg O
/ O
mL O
to O
40 O
fg O
/ O
mL O
can O
be O
easily O
differentiated O
in O
the O
buffer O
matrix O
. O

Moreover O
, O
it O
is O
the O
first O
time O
that O
a O
biomarker O
with O
a O
concentration O
of O
40 O
fg O
/ O
mL O
has O
been O
detected O
in O
a O
mixture O
of O
proteins O
without O
use O
of O
any O
signal O
amplification O
technique O
. O

Preclinical O
Activity O
of O
Simvastatin B
Induces O
Cell O
Cycle O
Arrest O
in O
G1 O
via O
Blockade O
of O
Cyclin O
D O
- O
Cdk4 O
Expression O
in O
Non O
- O
Small O
Cell O
Lung O
Cancer O
( O
NSCLC O
) O
. O

Lung O
cancer O
is O
the O
most O
common O
cause O
of O
cancer O
- O
related O
death O
. O

Nonetheless O
, O
a O
decrease O
in O
overall O
incidence O
and O
mortality O
has O
been O
observed O
in O
the O
last O
30 O
years O
due O
to O
prevention O
strategies O
and O
improvements O
in O
the O
use O
of O
chemotherapeutic O
agents O
. O

In O
recent O
studies O
, O
Simvastatin B
( O
SIM O
) O
has O
demonstrated O
anti O
- O
tumor O
activity O
, O
as O
well O
as O
potent O
chemopreventive O
action O
. O

As O
an O
inhibitor O
of O
3 B
- I
hydroxy I
- I
3 I
- I
methylglutaryl I
- I
coenzyme I
A I
reductase O
( O
HMG B
- I
CoA I
) O
, O
SIM O
has O
been O
shown O
to O
stimulate O
apoptotic O
cell O
death O
. O

In O
this O
study O
, O
an O
MTT B
assay O
revealed O
the O
cytotoxic O
activity O
of O
SIM O
against O
human O
large O
cell O
lung O
cancer O
( O
Non O
- O
small O
cell O
lung O
cancer O
; O
NSCLC O
) O
cells O
( O
NCI O
- O
H460 O
) O
; O
however O
, O
induced O
apoptosis O
was O
not O
observed O
in O
NCI O
- O
H460 O
cells O
. O

Protein O
expression O
levels O
of O
cell O
cycle O
regulating O
proteins O
Cdk4 O
, O
Cyclin O
D1 O
, O
p16 O
and O
p27 O
were O
markedly O
altered O
by O
SIM B
. O

Collectively O
, O
our O
results O
indicate O
that O
SIM O
inhibits O
cell O
proliferation O
and O
arrests O
NCI O
- O
H460 O
cell O
cycle O
progression O
via O
inhibition O
of O
cyclin O
- O
dependent O
kinases O
and O
cyclins O
and O
the O
enhancement O
of O
CDK O
inhibitors O
p16 O
and O
p27 O
. O

Our O
findings O
suggest O
that O
, O
in O
addition O
to O
the O
known O
effects O
on O
hypercholesterolemia O
therapy O
, O
SIM O
may O
also O
provide O
antitumor O
activity O
in O
established O
NSCLC O
. O

Substituted O
1 B
, I
6 I
- I
diphenylnaphthalenes I
as O
FtsZ O
- O
targeting O
antibacterial O
agents O
. O

Bacterial O
cell O
division O
occurs O
in O
conjunction O
with O
the O
formation O
of O
a O
cytokinetic O
Z O
- O
ring O
structure O
comprised O
of O
FtsZ O
subunits O
. O

Agents O
that O
disrupt O
Z O
- O
ring O
formation O
have O
the O
potential O
, O
through O
this O
unique O
mechanism O
, O
to O
be O
effective O
against O
several O
of O
the O
newly O
emerging O
multidrug O
- O
resistant O
strains O
of O
infectious O
bacteria O
. O

Several O
1 B
- I
phenylbenzo I
[ I
c I
] I
phenanthridines I
exhibit O
notable O
antibacterial O
activity O
. O

Based O
upon O
their O
structural O
similarity O
to O
these O
compounds O
, O
a O
distinct O
series O
of O
substituted O
1 B
, I
6 I
- I
diphenylnaphthalenes I
were O
synthesized O
and O
evaluated O
for O
antibacterial O
activity O
against O
Staphylococcus O
aureus O
and O
Enterococcus O
faecalis O
. O

In O
addition O
, O
the O
effect O
of O
select O
1 B
, I
6 I
- I
diphenylnaphthalenes I
on O
the O
polymerization O
dynamics O
of O
S O
. O
aureus O
FtsZ O
and O
mammalian O
beta O
- O
tubulin O
was O
also O
assessed O
. O

The O
presence O
of O
a O
basic O
functional O
group O
or O
a O
quaternary B
ammonium I
substituent O
on O
the O
6 B
- I
phenylnaphthalene I
was O
required O
for O
significant O
antibacterial O
activity O
. O

Diphenylnaphthalene B
derivatives O
that O
were O
active O
as O
antibiotics O
, O
did O
exert O
a O
pronounced O
effect O
on O
bacterial O
FtsZ O
polymerization O
and O
do O
not O
appear O
to O
cross O
- O
react O
with O
mammalian O
tubulin O
to O
any O
significant O
degree O
. O

Characterization O
of O
the O
5 B
- I
hydroxymethylcytosin I
- O
specific O
DNA O
restriction O
endonucleases O
. O

In O
T4 O
bacteriophage O
, O
5 B
- I
hydroxymethylcytosin I
( O
5hmC B
) O
is O
incorporated O
into O
DNA O
during O
replication O
. O

In O
response O
, O
bacteria O
may O
have O
developed O
modification O
- O
dependent O
type O
IV O
restriction O
enzymes O
to O
defend O
the O
cell O
from O
T4 O
- O
like O
infection O
. O

PvuRts1I O
was O
the O
first O
identified O
restriction O
enzyme O
to O
exhibit O
specificity O
toward O
hmC B
over O
5 B
- I
methylcytosine I
( O
5mC B
) O
and O
cytosine B
. O

By O
using O
PvuRts1I O
as O
the O
original O
member O
, O
we O
identified O
and O
characterized O
a O
number O
of O
homologous O
proteins O
. O

Most O
enzymes O
exhibited O
similar O
cutting O
properties O
to O
PvuRts1I O
, O
creating O
a O
double O
- O
stranded O
cleavage O
on O
the O
3 O
' O
side O
of O
the O
modified O
cytosine B
. O

In O
addition O
, O
for O
efficient O
cutting O
, O
the O
enzymes O
require O
two O
cytosines B
21 O
- O
22 O
- O
nt O
apart O
and O
on O
opposite O
strands O
where O
one O
cytosine B
must O
be O
modified O
. O

Interestingly O
, O
the O
specificity O
determination O
unveiled O
a O
new O
layer O
of O
complexity O
where O
the O
enzymes O
not O
only O
have O
specificity O
for O
5 B
- I
beta I
- I
glucosylated I
hmC I
( O
5 B
beta I
ghmC I
) O
but O
also O
5 B
- I
alpha I
- I
glucosylated I
hmC I
( O
5 B
alpha I
ghmC I
) O
. O

In O
some O
cases O
, O
the O
enzymes O
are O
inhibited O
by O
5 O
beta I
ghmC I
, O
whereas O
in O
others O
they O
are O
inhibited O
by O
5 B
alpha I
ghmC I
. O

These O
observations O
indicate O
that O
the O
position O
of O
the O
sugar B
ring O
relative O
to O
the O
base O
is O
a O
determining O
factor O
in O
the O
substrate O
specificity O
of O
the O
PvuRts1I O
homologues O
. O

Lastly O
, O
we O
envision O
that O
the O
unique O
properties O
of O
select O
PvuRts1I O
homologues O
will O
permit O
their O
use O
as O
an O
additive O
or O
alternative O
tool O
to O
map O
the O
hydroxymethylome O
. O

Chirality O
sensing O
using O
stereodynamic O
probes O
with O
distinct O
electronic O
circular O
dichroism O
output O
. O

Circular O
dichroism O
( O
CD O
) O
spectroscopy O
is O
one O
of O
the O
most O
useful O
techniques O
for O
the O
stereochemical O
analysis O
of O
chiral O
biopolymers O
and O
fine O
chemicals O
. O

It O
has O
become O
invaluable O
for O
the O
assignment O
of O
the O
absolute O
configuration O
, O
the O
study O
of O
conformational O
isomers O
, O
and O
the O
determination O
of O
racemization O
kinetics O
of O
CD O
active O
chiral O
compounds O
. O

Molecular O
interactions O
between O
a O
nonracemic O
chiral O
substrate O
and O
a O
chromophoric O
, O
CD O
- O
silent O
probe O
that O
is O
achiral O
or O
exists O
as O
a O
racemic O
mixture O
of O
rapidly O
interconverting O
enantiomeric O
conformations O
or O
configurations O
can O
induce O
a O
strong O
, O
characteristic O
chiroptical O
readout O
. O

A O
covalent O
or O
noncovalent O
binding O
event O
that O
coincides O
with O
a O
well O
- O
defined O
asymmetric O
induction O
process O
can O
effectively O
imprint O
the O
chiral O
information O
of O
the O
substrate O
on O
the O
stereodynamic O
sensor O
and O
thus O
generate O
intense O
Cotton O
effects O
in O
the O
UV O
region O
of O
the O
latter O
. O

The O
probe O
can O
thus O
function O
as O
a O
stereochemical O
reporter O
unit O
and O
analysis O
of O
the O
CD O
spectrum O
often O
provides O
accurate O
information O
about O
the O
absolute O
configuration O
and O
enantiomeric O
composition O
of O
the O
substrate O
used O
. O

In O
this O
review O
, O
recent O
developments O
in O
circular O
dichroism O
analysis O
of O
chiral O
compounds O
with O
stereodynamic O
probes O
are O
described O
and O
particular O
emphasis O
is O
given O
to O
sensor O
design O
, O
chiral O
induction O
processes O
and O
applications O
scope O
. O

The O
induction O
of O
mitochondria O
- O
mediated O
apoptosis O
in O
cancer O
cells O
by O
ruthenium B
( I
ii I
) I
asymmetric O
complexes O
. O

Four O
ruthenium B
( I
ii I
) I
asymmetric O
complexes O
, O
[ B
Ru I
( I
bpy I
) I
2 I
( I
PAIDH I
) I
] I
( I
2 I
+ I
) I
( O
bpy B
= O
2 B
, I
2 I
' I
- I
bipyridine I
, O
PAIDH B
= O
2 B
- I
pyridyl I
- I
1H I
- I
anthra I
[ I
1 I
, I
2 I
- I
d I
] I
imidazole I
- I
6 I
, I
11 I
- I
dione I
, O
) O
, O
[ B
Ru I
( I
phen I
) I
2 I
( I
PAIDH I
) I
] I
( I
2 I
+ I
) I
( O
phen B
= O
1 B
, I
10 I
- I
phenanthroline I
, O
) O
, O
[ B
Ru I
( I
dmp I
) I
2 I
( O

PAIDH I
) I
] I
( I
2 I
+ I
) I
( O
dmp B
= O
4 B
, I
7 I
- I
dimethyl I
- I
1 I
, I
10 I
- I
phenanthroline I
, O
) O
and O
[ B
Ru I
( I
dip I
) I
2 I
( I
PAIDH I
) I
] I
( I
2 I
+ I
) I
( O
dip B
= O
4 B
, I
7 I
- I
diphenyl I
- I
1 I
, I
10 I
- I
phenanthroline I
, O
) O
, O
have O
been O
synthesized O
and O
characterized O
. O

These O
complexes O
displayed O
potent O
anti O
- O
proliferation O
activity O
against O
various O
cancer O
cell O
lines O
and O
had O
high O
selectivity O
between O
tumor O
cells O
and O
normal O
cells O
. O

HeLa O
cells O
exhibited O
the O
highest O
sensitivity O
to O
complex O
, O
accounting O
for O
the O
greatest O
cellular O
uptake O
. O

Complex O
was O
shown O
to O
accumulate O
preferentially O
in O
the O
mitochondria O
of O
HeLa O
cells O
and O
induced O
apoptosis O
via O
the O
mitochondrial O
pathway O
, O
which O
involved O
ROS O
generation O
, O
mitochondrial O
membrane O
potential O
depolarisation O
, O
and O
Bcl O
- O
2 O
and O
caspase O
family O
members O
activation O
. O

These O
results O
demonstrated O
that O
complex O
induced O
cancer O
cell O
apoptosis O
by O
acting O
on O
mitochondrial O
pathways O
. O

Mechanisms O
of O
RAS O
/ O
beta O
- O
catenin O
interactions O
. O

Signaling O
through O
the O
WNT O
/ O
beta O
- O
catenin O
and O
the O
RAS O
( O
rat O
sarcoma O
) O
/ O
MAPK O
( O
mitogen O
- O
activated O
protein O
kinase O
) O
pathways O
plays O
a O
key O
role O
in O
the O
regulation O
of O
various O
physiological O
cellular O
processes O
including O
proliferation O
, O
differentiation O
, O
and O
cell O
death O
. O

Aberrant O
mutational O
activation O
of O
these O
signaling O
pathways O
is O
closely O
linked O
to O
the O
development O
of O
cancer O
in O
many O
organs O
, O
in O
humans O
as O
well O
as O
in O
laboratory O
animals O
. O

Over O
the O
past O
years O
, O
more O
and O
more O
evidence O
for O
a O
close O
linkage O
of O
the O
two O
oncogenic O
signaling O
cascades O
has O
accumulated O
. O

Using O
different O
experimental O
approaches O
, O
model O
systems O
, O
and O
experimental O
conditions O
, O
a O
variety O
of O
molecular O
mechanisms O
have O
been O
identified O
by O
which O
signal O
transduction O
through O
WNT O
/ O
beta O
- O
catenin O
and O
RAS O
interact O
, O
either O
in O
a O
synergistic O
or O
an O
antagonistic O
manner O
. O

Mechanisms O
of O
interaction O
comprise O
an O
upstream O
crosstalk O
at O
the O
level O
of O
pathway O
- O
activating O
ligands O
and O
their O
receptors O
, O
interrelations O
of O
cytosolic O
kinases O
involved O
in O
either O
pathways O
, O
as O
well O
as O
interaction O
in O
the O
nucleus O
related O
to O
the O
joint O
regulation O
of O
target O
gene O
transcription O
. O

Here O
, O
we O
present O
a O
comprehensive O
review O
of O
the O
current O
knowledge O
on O
the O
interaction O
of O
RAS O
/ O
MAPK O
- O
and O
WNT O
/ O
beta O
- O
catenin O
- O
driven O
signal O
transduction O
in O
mammalian O
cells O
. O

Progress O
and O
Developments O
in O
Tau O
Aggregation O
Inhibitors O
for O
Alzheimer O
Disease O
. O

Pharmacological O
approaches O
directed O
toward O
Alzheimer O
disease O
are O
diversifying O
in O
parallel O
with O
a O
growing O
number O
of O
promising O
targets O
. O

Investigations O
on O
the O
microtubule O
- O
associated O
protein O
tau O
yielded O
innovative O
targets O
backed O
by O
recent O
findings O
about O
the O
central O
role O
of O
tau O
in O
numerous O
neurodegenerative O
diseases O
. O

In O
this O
review O
, O
we O
summarize O
the O
recent O
evolution O
in O
the O
development O
of O
nonpeptidic O
small O
molecules O
tau O
aggregation O
inhibitors O
( O
TAGIs O
) O
and O
their O
advancement O
toward O
clinical O
trials O
. O

The O
compounds O
are O
classified O
according O
to O
their O
chemical O
structures O
, O
providing O
correlative O
insights O
into O
their O
pharmacology O
. O

Overall O
, O
shared O
structure O
- O
activity O
traits O
are O
emerging O
, O
as O
well O
as O
specific O
binding O
modes O
related O
to O
their O
ability O
to O
engage O
in O
hydrogen B
bonding O
. O

Medicinal O
chemistry O
efforts O
on O
TAGIs O
together O
with O
encouraging O
in O
vivo O
data O
argue O
for O
successful O
translation O
to O
the O
clinic O
. O

Optimization O
of O
Chloronitrobenzamide B
( O
CNBs B
) O
as O
Therapeutic O
Leads O
for O
Human O
African O
Trypanosomiasis O
( O
HAT O
) O
. O

We O
previously O
reported O
the O
discovery O
of O
the O
activity O
of O
chloronitrobenzamide B
( O
CNBs B
) O
against O
bloodstream O
forms O
of O
Trypanosoma O
brucei O
. O

Herein O
we O
disclose O
extensive O
structure O
- O
activity O
relationship O
and O
structure O
- O
property O
relationship O
studies O
aimed O
at O
identification O
of O
tractable O
early O
leads O
for O
clinical O
development O
. O

These O
studies O
revealed O
a O
promising O
lead O
compound O
, O
17b O
, O
that O
exhibited O
nanomolar O
potency O
against O
T O
. O
brucei O
( O
EC50 O
= O
27 O
nM O
for O
T O
. O
b O
. O
brucei O
, O
7 O
nM O
for O
T O
. O
b O
. O
rhodesiense O
, O
and O
2 O
nM O
for O
T O
. O
b O
. O
gambiense O
) O
with O
excellent O
selectivity O
for O
parasite O
cells O
relative O
to O
mammalian O
cell O
lines O
( O
EC50 O
> O
25 O
mu O
M O
) O
. O

In O
addition O
compound O
17b O
displayed O
suitable O
physiochemical O
characteristics O
and O
microsomal O
stability O
( O
t1 O
/ O
2 O
> O
4 O
h O
for O
human O
and O
mouse O
) O
to O
justify O
pursuing O
in O
vivo O
studies O
. O

Adsorption O
of O
Primary O
Substituted O
Hydrocarbons B
onto O
Solid O
Gallium B
Substrates O
. O

Adsorption O
of O
a O
series O
of O
primary B
substituted I
hydrocarbons I
( O
RX O
; O
C18H37PO B
( I
OH I
) I
2 I
( O
ODPA B
) O
, O
C17H35COOH B
, O
C18H37OH B
, O
C18H37NH2 B
, O
and O
C18H37SH B
) O
onto O
solid O
gallium B
substrates O
with O
and O
without O
UV O
/ O
ozone B
treatment O
was O
studied O
using O
contact O
angle O
goniometry O
, O
spectroscopic O
ellipsometry O
, O
and O
cyclic O
voltammetry O
( O
CV O
) O
. O

UV O
/ O
ozone B
treatment O
offered O
a O
hydrophilic O
surface O
( O
water O
contact O
angle O
( O
theta O
( O
water O
) O
) O
less O
than O
10 O
degrees O
) O
, O
reflecting O
the O
formation O
of O
a O
surface O
oxide B
layer O
with O
the O
maximum O
thickness O
of O
ca O
. O

1 O
nm O
and O
possibly O
the O
removal O
of O
surface O
contaminants O
. O

Upon O
immersion O
in O
a O
toluene B
solution O
of O
a O
RX O
, O
theta O
( O
water O
) O
increased O
due O
to O
adsorption O
of O
the O
RX O
onto O
gallium B
substrates O
. O

In O
particular O
, O
UV O
/ O
ozone B
- O
treated O
gallium B
substrates O
( O
UV O
- O
Ga O
) O
immersed O
in O
an O
ODPA O
solution O
exhibited O
theta O
( O
water O
) O
close O
to O
105 O
degrees O
. O

The O
ellipsometric O
thickness O
of O
the O
adsorbed O
ODPA B
layer O
was O
ca O
. O

2 O
. O
4 O
nm O
, O
and O
CV O
data O
measured O
in O
an O
acetonitrile B
solution O
showed O
significant O
inhibition O
of O
redox O
reaction O
on O
the O
substrate O
surface O
. O

These O
results O
indicate O
the O
formation O
of O
a O
densely O
packed O
ODPA B
monolayer O
on O
UV O
- O
Ga O
. O

The O
coverage O
of O
a O
C17H35COOH B
layer O
adsorbed O
onto O
UV O
- O
Ga O
was O
lower O
, O
as O
shown O
by O
smaller O
theta O
( O
water O
) O
( O
ca O
. O
99 O
degrees O
) O
, O
smaller O
ellipsometric O
thickness O
( O
ca O
. O
1 O
. O
3 O
nm O
) O
, O
and O
smaller O
electrode O
reaction O
inhibition O
. O

Adsorption O
of O
the O
other O
RX O
onto O
UV O
- O
Ga O
was O
weaker O
, O
as O
indicated O
by O
smaller O
theta O
( O
water O
) O
( O
82 O
degrees O
- O
92 O
degrees O
) O
. O

ODPA B
did O
not O
strongly O
adsorb O
onto O
UV O
- O
untreated O
gallium B
substrates O
, O
suggesting O
that O
the O
ODPA B
adsorption O
mainly O
originates O
from O
hydrogen B
bond O
interaction O
of O
a O
phosphonate B
group O
with O
surface O
oxide B
. O

These O
results O
will O
provide O
a O
means O
for O
controlling O
the O
surface O
properties O
of O
oxide B
- O
coated O
gallium B
that O
play O
an O
essential O
role O
in O
monolayer O
conductivity O
measurements O
and O
electroanalytical O
applications O
. O

Diarylheptanoids B
and O
Flavonoids B
from O
Viscum O
album O
Inhibit O
LPS O
- O
Stimulated O
Production O
of O
Pro O
- O
inflammatory O
Cytokines O
in O
Bone O
Marrow O
- O
Derived O
Dendritic O
Cells O
. O

Three O
new O
diarylheptanoids B
, O
( B
3S I
, I
5R I
) I
- I
3 I
- I
hydroxy I
- I
5 I
- I
methoxy I
- I
1 I
, I
7 I
- I
bis I
( I
4 I
- I
hydroxyphenyl I
) I
- I
6E I
- I
heptene I
( O
1 O
) O
, O
( B
3S I
, I
5S I
) I
- I
3 I
- I
hydroxy I
- I
5 I
- I
methoxy I
- I
1 I
, I
7 I
- I
bis I
( I
4 I
- I
hydroxyphenyl I
) I
- I
6E I
- I
heptene I
( O
2 O
) O
, O
and O
( B
3S I
) I
- I
3 I
- I
hydroxy I
- I
1 I
, I
7 I
- I
bis I
( I
4 I
- I

hydroxyphenyl I
) I
- I
6E I
- I
hepten I
- I
5 I
- I
one I
( O
3 O
) O
, O
four O
new O
flavonoid B
glycosides I
, O
3 B
, I
7 I
, I
3 I
' I
- I
tri I
- I
O I
- I
methylquercetin I
- I
4 I
' I
- I
O I
- I
beta I
- I
d I
- I
apiofuranosyl I
- I
( I
1 I
- I
- I
> I
2 I
) I
- I
O I
- I
beta I
- I
d I
- I
glucopyranoside I
( O
4 O
) O
, O
7 B
, I
3 I
' I
- I
di I
- I
O I
- I
methylquercetin I
- I
4 I
' I
- I
O I
- I
beta I
- I
d I
- I
glucopyranosyl I
- I
3 I
- I
O I
- I
[ I

6 I
' I
' I
' I
- I
( I
3 I
- I
hydroxy I
- I
3 I
- I
methylglutaroyl I
) I
] I
- I
alpha I
- I
d I
- I
glucopyranoside I
( O
5 O
) O
, O
7 B
, I
3 I
' I
- I
di I
- I
O I
- I
methylquercetin I
- I
4 I
' I
- I
O I
- I
beta I
- I
d I
- I
glucopyranosyl I
- I
3 I
- I
O I
- I
[ I
( I
6 I
' I
' I
' I
' I
' I
- I
- I
> I
5 I
' I
' I
' I
' I
) I
- I
O I
- I
1 I
' I
' I
' I
' I
' I
- I
( I
sinap I
- I
4 I
- I
yl I
) I
- I
beta I
- I
d I
- I
glucopyranosyl I
- I
6 I
' I
' I
' I
- I
( I
3 I

- I
hydroxy I
- I
3 I
- I
methylglutaroyl I
) I
] I
- I
alpha I
- I
d I
- I
glucopyranoside I
( O
6 O
) O
, O
and O
( B
2S I
) I
- I
5 I
- I
hydroxy I
- I
7 I
, I
3 I
' I
- I
dimethoxyflavanone I
- I
4 I
' I
- I
O I
- I
beta I
- I
d I
- I
apiofuranosyl I
- I
( I
1 I
- I
- I
> I
5 I
) I
- I
O I
- I
beta I
- I
d I
- I
apiofuranosyl I
- I
( I
1 I
- I
- I
> I
2 I
) I
- I
O I
- I
beta I
- I
d I
- I
glucopyranoside I
( O
9 O
) O
, O
and O
17 O
known O
compounds O
were O
isolated O
from O
the O
leaves O
and O

twigs O
of O
Viscum O
album O
. O

Compounds O
1 O
, O
4 O
, O
and O
19 O
significantly O
inhibited O
LPS O
- O
stimulated O
production O
of O
TNF O
- O
alpha O
, O
IL O
- O
6 O
, O
and O
IL O
- O
12p40 O
with O
IC50 O
values O
ranging O
from O
0 O
. O
09 O
+ O
/ O
- O
0 O
. O
01 O
to O
8 O
. O
96 O
+ O
/ O
- O
0 O
. O
45 O
mu O
M O
. O

( B
+ I
) I
- I
Medioresinol I
( O
13 O
) O
showed O
inhibitory O
effects O
on O
LPS O
- O
stimulated O
production O
of O
IL O
- O
12p40 O
with O
an O
IC50 O
value O
of O
2 O
. O
00 O
+ O
/ O
- O
0 O
. O
15 O
mu O
M O
. O

Ultrathin O
2D O
Coordination O
Polymer O
Nanosheets O
by O
Surfactant O
- O
Mediated O
Synthesis O
. O

Low O
- O
dimensional O
nanostructures O
offer O
a O
host O
of O
intriguing O
properties O
which O
are O
distinct O
from O
those O
of O
the O
bulk O
material O
, O
owing O
to O
size O
- O
confinement O
effects O
and O
amplified O
surface O
areas O
. O

Here O
, O
we O
report O
on O
the O
scalable O
, O
bottom O
- O
up O
synthesis O
of O
ultrathin O
coordination O
polymer O
nanosheets O
via O
surfactant O
- O
mediated O
synthesis O
and O
subsequent O
exfoliation O
. O

Layers O
of O
a O
two O
- O
dimensional O
( O
2D O
) O
zinc B
coordination O
polymer O
are O
self O
- O
assembled O
in O
the O
interlamellar O
space O
of O
a O
reverse O
microemulsion O
mesophase O
into O
stacks O
of O
nanosheets O
interleaved O
with O
cethyltrimethylammon B
bromide I
( O
CTAB B
) O
at O
regular O
intervals O
, O
thus O
giving O
rise O
to O
a O
lamellar O
hybrid O
mesostructure O
with O
a O
lattice O
period O
of O
~ O
8 O
nm O
and O
an O
underlying O
highly O
crystalline O
substructure O
. O

The O
basic O
structural O
motif O
is O
composed O
of O
2D O
acetato B
- I
benzimidazolato I
- I
zinc I
layers O
of O
tetrahedrally O
coordinated O
zinc B
joined O
together O
by O
anionic O
acetate B
and O
benzimidazolate B
ligands O
. O

The O
hierarchical O
structure O
was O
studied O
by O
PXRD O
, O
TEM O
, O
EDX O
, O
EELS O
, O
AFM O
, O
and O
solid O
- O
state O
NMR O
spectroscopy O
, O
revealing O
a O
high O
level O
of O
order O
on O
both O
the O
atomic O
and O
mesoscale O
, O
suggesting O
fairly O
strong O
interactions O
along O
the O
organic O
- O
inorganic O
hybrid O
interface O
. O

Exfoliation O
of O
the O
hybrid O
material O
in O
organic O
solvents O
such O
as O
THF B
and O
chloroform B
yields O
sheet O
- O
and O
belt O
- O
like O
nanostructures O
with O
lateral O
sizes O
between O
10 O
' O
s O
and O
100 O
' O
s O
of O
nanometers O
and O
a O
height O
of O
about O
10 O
nm O
measured O
by O
AFM O
, O
which O
precisely O
maps O
the O
basal O
spacing O
of O
the O
lamellar O
mesostructure O
; O
further O
exfoliation O
results O
in O
nanobelts O
with O
minimum O
sizes O
around O
4 O
nm O
. O

Finally O
, O
the O
sheetlike O
nanostructures O
behave O
as O
morphological O
chameleons O
, O
transforming O
into O
highly O
regular O
multiwalled O
coordination O
polymer O
nanotubes O
upon O
treatment O
with O
organic O
solvents O
. O

Computational O
study O
of O
the O
coordination O
of O
methane B
to O
first O
row O
transition B
metal I
dication O
complexes O
. O

The O
coordination O
of O
methane B
, O
the O
first O
step O
in O
methane B
activation O
, O
to O
coordinately O
unsaturated O
first O
row O
transition B
metal I
dication O
complexes O
has O
been O
studied O
computationally O
to O
determine O
the O
most O
stable O
metal O
- O
methane B
interaction O
. O

The O
geometries O
and O
the O
vibrational O
frequencies O
of O
the O
encounter O
complexes O
[ B
M I
( I
pyridine I
) I
2 I
( I
CH4 I
) I
] I
( I
2 I
+ I
) I
have O
been O
determined O
using O
density O
functional O
theory O
with O
the O
omega O
B97XD O
hybrid O
functional O
and O
triple O
- O
zeta O
basis O
sets O
. O

The O
structure O
is O
dependent O
on O
the O
metal O
center O
; O
for O
the O
early O
transition B
metals I
eta O
( O
3 O
) O
coordination O
is O
favored O
, O
whereas O
eta O
( O
2 O
) O
is O
more O
favorable O
for O
the O
later O
transition B
metals I
. O

The O
periodic O
trend O
in O
methane B
binding O
energies O
in O
the O
[ B
M I
( I
pyridine I
) I
2 I
( I
CH4 I
) I
] I
( I
2 I
+ I
) I
complexes O
follows O
the O
trend O
in O
electron O
affinity O
until O
the O
Mn B
complex O
but O
then O
exhibits O
decreasing O
energies O
from O
Fe B
to O
Zn B
. O

This O
is O
attributed O
to O
increasing O
Pauli O
repulsion O
and O
ligand O
- O
ligand O
repulsion O
. O

For O
the O
most O
stable O
complex O
, O
[ B
Cr I
( I
pyridine I
) I
2 I
( I
CH4 I
) I
] I
( I
2 I
+ I
) I
, O
the O
structures O
, O
energies O
, O
and O
spin O
states O
of O
the O
key O
intermediates O
and O
products O
in O
the O
oxidative O
addition O
/ O
reductive O
elimination O
pathway O
have O
been O
investigated O
. O

It O
is O
found O
that O
the O
reaction O
is O
thermodynamically O
favorable O
and O
indicates O
that O
two O
- O
state O
reactivity O
may O
play O
an O
important O
role O
in O
lowering O
the O
energy O
of O
the O
hydridomethyl B
intermediate O
. O

Synergistic O
interactions O
of O
epigallocatechin B
gallate I
and O
oxytetracycline B
against O
various O
drug O
resistant O
Staphylococcus O
aureus O
strains O
in O
vitro O
. O

Epigallocatechin B
gallate I
( O
EGCG B
) O
, O
the O
major O
catechin B
contained O
in O
tea O
leaves O
, O
is O
known O
to O
possess O
the O
synergistic O
anti O
- O
staphylococcal O
activity O
in O
combination O
with O
various O
beta B
- I
lactam I
antibiotics O
and O
tetracycline B
. O

In O
the O
present O
study O
, O
we O
explored O
the O
in O
vitro O
combinatory O
effect O
of O
EGCG B
in O
combination O
with O
oxytetracycline B
against O
eight O
standard O
strains O
and O
clinical O
isolates O
of O
Staphylococcus O
aureus O
, O
including O
erythromycin B
, O
methicillin B
and O
tetracycline B
resistant O
strains O
. O

The O
minimum O
inhibitory O
concentrations O
were O
determined O
by O
the O
broth O
microdilution O
assay O
and O
the O
data O
were O
evaluated O
according O
to O
the O
sum O
of O
fractional O
inhibitory O
concentrations O
( O
sum O
FIC O
) O
. O

Our O
results O
showed O
synergistic O
and O
additive O
interactions O
against O
all O
S O
. O
aureus O
strains O
tested O
( O
sum O
FIC O
0 O
. O
288 O
- O
0 O
. O
631 O
) O
, O
two O
of O
which O
were O
multidrug O
resistant O
. O

According O
to O
our O
best O
knowledge O
, O
it O
is O
the O
first O
report O
on O
the O
EGCG B
synergy O
with O
oxytetracycline B
. O

Considering O
its O
significant O
synergistic O
antimicrobial O
effect O
and O
low O
toxicity O
, O
we O
suggest O
EGCG B
as O
a O
promising O
compound O
for O
the O
development O
of O
new O
anti O
- O
staphylococcal O
formulations O
. O

Orally O
bioavailable O
and O
brain O
- O
penetrant O
pyridazine B
and O
pyridine B
- O
derived O
gamma O
- O
secretase O
modulators O
reduced O
amyloidogenic O
A O
beta O
peptides O
in O
vivo O
. O

Accumulation O
of O
amyloid O
beta O
( O
A O
beta O
) O
in O
brain O
is O
a O
pathological O
hallmark O
of O
Alzheimer O
' O
s O
disease O
( O
AD O
) O
. O

A O
beta O
is O
generated O
after O
sequential O
cleavage O
of O
its O
parental O
molecule O
, O
amyloid O
precursor O
protein O
( O
APP O
) O
, O
by O
beta O
- O
and O
gamma O
- O
secretases O
. O

Inhibition O
of O
gamma O
- O
secretase O
activity O
is O
an O
effective O
approach O
for O
the O
reduction O
of O
A O
beta O
levels O
. O

Since O
gamma O
- O
secretase O
targets O
many O
different O
substrates O
, O
selective O
inhibition O
of O
its O
cleavage O
of O
APP O
is O
believed O
to O
be O
critical O
in O
order O
to O
avoid O
undesirable O
side O
effects O
. O

gamma O
- O
Secretase O
modulator O
( O
GSM O
) O
shifts O
the O
cleavage O
site O
on O
APP O
and O
production O
of O
amyloidogenic O
to O
non O
- O
amyloidogenic O
A O
beta O
fragments O
. O

Since O
GSMs B
only O
modulate O
and O
do O
not O
block O
cleavage O
of O
gamma O
- O
secretase O
substrates O
, O
they O
are O
believed O
less O
likely O
to O
produce O
untoward O
adverse O
reactions O
. O

Here O
, O
we O
report O
in O
vivo O
A O
beta O
- O
lowering O
profiles O
of O
a O
pyridazine B
and O
a O
pyridine B
- O
derived O
GSM O
: O
GSM O
- O
C O
( O
Wan O
et O
al O
. O
, O
2011a O
) O
and O
GSM O
- O
D O
( O
Wan O
et O
al O
. O
, O
2011b O
) O
. O

Both O
compounds O
reduced O
A O
beta O
40 O
and O
A O
beta O
42 O
productions O
, O
increased O
shorter O
A O
beta O
fragments O
, O
and O
had O
little O
effect O
on O
Notch O
signaling O
( O
~ O
100 O
- O
fold O
selective O
) O
. O

They O
had O
excellent O
oral O
bioavailability O
( O
97 O
. O
8 O
% O
for O
GSM O
- O
C O
, O
~ O
100 O
% O
for O
GSM O
- O
D O
) O
and O
good O
brain O
permeability O
( O
free O
brain O
to O
free O
blood O
AUC O
ratio O
of O
0 O
. O
41 O
and O
1 O
. O
10 O
for O
GSM O
- O
C O
and O
GSM O
- O
D O
, O
respectively O
) O
. O

Oral O
administration O
of O
these O
compounds O
in O
both O
acute O
and O
sub O
- O
chronic O
conditions O
reduced O
A O
beta O
levels O
in O
plasma O
and O
brain O
in O
rats O
in O
a O
dose O
- O
and O
time O
- O
dependent O
manner O
. O

Therefore O
, O
GSM B
- I
C I
and O
GSM B
- I
D I
represent O
two O
GSMs O
that O
are O
orally O
bioavailable O
and O
brain O
- O
permeable O
. O

They O
could O
serve O
as O
excellent O
tools O
in O
the O
investigation O
of O
the O
role O
of O
A O
beta O
peptides O
in O
AD O
pathogenesis O
. O

Research O
on O
cholinesterases O
in O
the O
Soviet O
Union O
and O
Russia O
: O
A O
historical O
perspective O
. O

Research O
on O
cholinesterases O
and O
effects O
of O
their O
inhibition O
in O
the O
USSR O
and O
Russia O
since O
1930 O
- O
1940s O
till O
present O
is O
exposed O
in O
historical O
aspects O
. O

The O
first O
physiological O
and O
toxicological O
effects O
of O
cholinesterase O
inhibition O
were O
reported O
by O
Alexander O
Ginetsinsky O
during O
World O
War O
II O
, O
when O
academic O
institutions O
were O
evacuated O
from O
Leningrad O
to O
Kazan O
. O

The O
main O
scientific O
schools O
that O
initiated O
research O
on O
chemistry O
, O
enzymology O
and O
physiology O
of O
cholinesterases O
and O
their O
inhibitors O
were O
leaded O
by O
Alexandr O
and O
Boris O
Arbuzovs O
, O
Victor O
Rozengart O
, O
Viktor O
Yakovlev O
, O
Michael O
Michelson O
, O
Martin O
Kabachnik O
, O
Mikhail O
Voronkov O
, O
Ivan O
Knunyants O
, O
Alexandr O
Bretskin O
and O
others O
. O

They O
investigated O
the O
main O
physiological O
effects O
of O
cholinesterase O
inhibitors O
, O
and O
analyzed O
the O
catalytic O
mechanisms O
of O
cholinesterases O
and O
related O
enzymes O
. O

Their O
contributions O
are O
landmarks O
in O
the O
history O
of O
cholinesterase O
research O
. O

At O
the O
present O
time O
revival O
of O
research O
on O
cholinesterases O
in O
different O
universities O
and O
institutes O
is O
vivid O
, O
in O
particular O
at O
the O
Moscow O
State O
University O
, O
research O
institutes O
of O
Russian O
Academy O
of O
Sciences O
and O
Kazan O
Scientific O
Center O
. O

Protective O
effect O
of O
bark O
and O
empty O
pod O
extracts O
from O
Acacia O
auriculiformis O
against O
paracetamol B
intoxicated O
liver O
injury O
and O
alloxan B
induced O
type O
II O
diabetes O
. O

The O
present O
study O
is O
designed O
to O
decipher O
a O
clinical O
evidence O
and O
biochemical O
support O
for O
hepatoprotective O
and O
antidiabetic O
efficacy O
of O
Acacia O
auriculiformis O
by O
its O
bark O
and O
empty O
pods O
. O

Animal O
models O
with O
paracetamol B
intoxicated O
liver O
injury O
and O
alloxan B
induced O
diabetes O
were O
used O
in O
a O
7 O
and O
14days O
trial O
respectively O
. O

The O
interventions O
were O
tested O
at O
200 O
and O
400mg O
/ O
kg O
b O
. O
w O
. O
for O
bark O
extract O
; O
100 O
and O
200mg O
/ O
kg O
b O
. O
w O
. O
for O
empty O
pod O
extract O
. O

Both O
interventions O
restored O
the O
liver O
function O
markers O
( O
alanine B
transaminase O
: O
ALT O
, O
aspartate B
transaminase O
: O
AST O
, O
alkaline O
phosphatase O
: O
ALP O
, O
total O
bilirubin B
and O
total O
protein O
) O
and O
hepatic O
antioxidants O
( O
superoxide B
dismutase O
: O
SOD O
, O
catalase O
: O
CAT O
, O
reduced B
glutathione I
: O
GSH B
and O
glutathione B
peroxidase O
: O
GPx O
) O
to O
the O
normal O
levels O
than O
elevated O
levels O
noticed O
on O
paracetamol B
control O
at O
P O
< O
0 O
. O
001 O
. O

Reversal O
of O
hepatoarchitecture O
has O
also O
been O
registered O
and O
the O
hepatoprotection O
is O
comparable O
to O
the O
reference O
drug O
silymarin B
. O

Similarly O
, O
substantial O
elevations O
of O
blood O
glucose B
, O
distorted O
lipid O
profile O
( O
total O
cholesterol B
: O
TC O
, O
triglycerides B
: O
TGs B
, O
high O
density O
lipoprotein O
cholesterol B
: O
HDL O
- O
C O
and O
low O
density O
lipoprotein O
cholesterol B
: O
LDL O
- O
C O
) O
and O
kidney O
function O
signs O
( O
creatinine B
and O
urea B
) O
have O
been O
refurbished O
to O
the O
desirable O
levels O
on O
par O
with O
the O
standard O
antidiabetic O
glibenclamide B
. O

The O
results O
signify O
the O
importance O
of O
bark O
and O
empty O
pod O
extracts O
of O
A O
. O
auriculiformis O
as O
good O
therapeutic O
candidates O
for O
liver O
injury O
and O
diabetes O
. O

The O
influence O
of O
study O
design O
and O
sex O
- O
differences O
on O
results O
from O
developmental O
neurotoxicity O
studies O
of O
bisphenol B
A I
, O
implications O
for O
toxicity O
testing O
. O

Developmental O
neurotoxicity O
( O
DNT O
) O
of O
bisphenol B
A I
( O
BPA B
) O
has O
been O
investigated O
in O
a O
large O
number O
of O
studies O
. O

However O
, O
there O
are O
discrepancies O
in O
the O
results O
reported O
between O
the O
studies O
. O

The O
aim O
of O
this O
study O
was O
to O
identify O
and O
analyze O
factors O
that O
may O
contribute O
to O
these O
differences O
and O
to O
assess O
whether O
there O
are O
sex O
- O
differences O
in O
the O
sensitivity O
of O
certain O
endpoints O
or O
tests O
used O
in O
DNT O
- O
studies O
. O

Forty O
- O
four O
DNT O
studies O
of O
BPA B
were O
identified O
from O
the O
open O
literature O
. O

Details O
about O
study O
design O
and O
results O
from O
each O
study O
, O
as O
well O
as O
the O
criteria O
for O
DNT O
testing O
according O
to O
the O
standardized O
OECD O
test O
guideline O
( O
TG O
) O
426 O
, O
were O
collected O
in O
a O
database O
. O

This O
enabled O
systematic O
and O
detailed O
comparisons O
between O
studies O
as O
well O
as O
to O
the O
criteria O
and O
recommendations O
stated O
in O
TG O
426 O
. O

Multivariate O
analyses O
were O
also O
used O
to O
investigate O
how O
different O
factors O
of O
the O
study O
design O
contributed O
to O
differences O
in O
study O
results O
. O

The O
analyses O
showed O
behavioral O
effects O
were O
often O
observed O
for O
endpoints O
that O
are O
not O
required O
according O
to O
OECD O
TG O
426 O
, O
such O
as O
anxiety O
- O
related O
, O
social O
and O
sexual O
behaviors O
, O
especially O
at O
very O
low O
doses O
and O
in O
female O
offspring O
. O

On O
the O
other O
hand O
relatively O
few O
studies O
observed O
any O
effects O
on O
motor O
activity O
, O
which O
is O
commonly O
used O
in O
screening O
for O
neurotoxic O
effects O
in O
regulatory O
testing O
. O

However O
, O
varied O
and O
to O
some O
extent O
seemingly O
contradictory O
results O
have O
been O
reported O
in O
these O
studies O
, O
especially O
for O
endpoints O
related O
to O
motor O
activity O
and O
anxiety O
and O
exploration O
. O

Many O
studies O
were O
also O
poorly O
reported O
, O
limiting O
these O
analyses O
. O

No O
strong O
conclusions O
could O
be O
drawn O
from O
the O
multivariate O
analyses O
. O

A O
few O
factors O
of O
study O
design O
, O
such O
as O
the O
size O
of O
the O
dose O
and O
number O
of O
dose O
levels O
used O
and O
the O
use O
of O
litter O
or O
individual O
pup O
as O
statistical O
unit O
seemed O
to O
have O
some O
influence O
on O
study O
results O
. O

In O
conclusion O
, O
this O
analysis O
suggests O
that O
DNT O
- O
studies O
conducted O
according O
to O
the O
standardized O
OECD O
TG O
426 O
may O
overlook O
sensitive O
effects O
of O
BPA B
, O
and O
possibly O
other O
potential O
endocrine O
disruptors O
, O
especially O
in O
female O
offspring O
. O

High O
- O
throughput O
quantification O
of O
the O
mechanical O
competence O
of O
murine O
femora O
- O
A O
highly O
automated O
approach O
for O
large O
- O
scale O
genetic O
studies O
. O

Animal O
models O
are O
widely O
used O
to O
gain O
insight O
into O
the O
role O
of O
genetics O
on O
bone O
structure O
and O
function O
. O

One O
of O
the O
main O
strategies O
to O
map O
the O
genes O
regulating O
specific O
traits O
is O
called O
quantitative O
trait O
loci O
( O
QTL O
) O
analysis O
, O
which O
generally O
requires O
a O
very O
large O
number O
of O
animals O
( O
often O
more O
than O
1000 O
) O
to O
reach O
statistical O
significance O
. O

QTL O
analysis O
for O
mechanical O
traits O
has O
been O
mainly O
based O
on O
experimental O
mechanical O
testing O
, O
which O
, O
in O
view O
of O
the O
large O
number O
of O
animals O
, O
is O
time O
consuming O
. O

Hence O
, O
the O
goal O
of O
the O
present O
work O
was O
to O
introduce O
an O
automated O
method O
for O
large O
- O
scale O
high O
- O
throughput O
quantification O
of O
the O
mechanical O
properties O
of O
murine O
femora O
. O

Specifically O
, O
our O
aims O
were O
, O
first O
, O
to O
develop O
and O
validate O
an O
automated O
method O
to O
quantify O
murine O
femoral O
bone O
stiffness O
. O

Second O
, O
to O
test O
its O
high O
- O
throughput O
capabilities O
on O
murine O
femora O
from O
a O
large O
genetic O
study O
, O
more O
specifically O
, O
femora O
from O
two O
growth O
hormone O
( O
GH O
) O
deficient O
inbred O
strains O
of O
mice O
( O
B6 O
- O
lit O
/ O
lit O
and O
C3 O
. O
B6 O
- O
lit O
/ O
lit O
) O
and O
their O
first O
( O
F1 O
) O
and O
second O
( O
F2 O
) O
filial O
offsprings O
. O

Automated O
routines O
were O
developed O
to O
convert O
micro O
- O
computed O
tomography O
( O
micro O
- O
CT O
) O
images O
of O
femora O
into O
micro O
- O
finite O
element O
( O
micro O
- O
FE O
) O
models O
. O

The O
method O
was O
experimentally O
validated O
on O
femora O
from O
C57BL O
/ O
6J O
and O
C3H O
/ O
HeJ O
mice O
: O
for O
both O
inbred O
strains O
the O
micro O
- O
FE O
models O
closely O
matched O
the O
experimentally O
measured O
bone O
stiffness O
when O
using O
a O
single O
tissue O
modulus O
of O
13 O
. O
06GPa O
. O

The O
mechanical O
analysis O
of O
the O
entire O
dataset O
( O
n O
= O
1990 O
) O
took O
approximately O
44 O
CPU O
hours O
on O
a O
supercomputer O
. O

In O
conclusion O
, O
our O
approach O
, O
in O
combination O
with O
QTL O
analysis O
could O
help O
to O
locate O
genes O
directly O
involved O
in O
controlling O
bone O
mechanical O
competence O
. O

Pediatric O
insecticide O
chalk O
exposures O
reported O
to O
Texas O
poison O
centers O
. O

The O
pesticide O
Miraculous O
Insecticide O
Chalk O
( O
TM O
) O
is O
illegal O
in O
the O
United O
States O
but O
can O
be O
obtained O
through O
a O
variety O
of O
sources O
. O

Because O
it O
is O
a O
stick O
similar O
in O
appearance O
to O
common O
blackboard O
chalk O
, O
children O
might O
play O
with O
it O
and O
put O
it O
in O
their O
mouths O
. O

All O
Miraculous O
Insecticide O
Chalk O
exposures O
involving O
children O
5 O
years O
or O
younger O
reported O
to O
Texas O
poison O
centers O
during O
2000 O
- O
2010 O
were O
identified O
. O

The O
distribution O
by O
selected O
demographic O
and O
clinical O
factors O
was O
calculated O
. O

Of O
the O
total O
188 O
exposures O
, O
the O
mean O
age O
was O
1 O
. O
5 O
years O
( O
range O
6 O
months O
- O
5 O
years O
) O
and O
60 O
. O
6 O
% O
were O
male O
. O

Ingestions O
were O
reported O
in O
97 O
. O
3 O
% O
of O
the O
exposures O
, O
and O
these O
were O
reported O
to O
involve O
at O
most O
one O
stick O
of O
the O
chalk O
. O

The O
lowest O
exposure O
rates O
per O
100 O
, O
000 O
population O
of O
5 O
years O
or O
younger O
were O
reported O
in O
the O
Public O
Health O
Regions O
in O
northern O
and O
eastern O
Texas O
( O
0 O
. O
00 O
- O
2 O
. O
30 O
) O
and O
the O
highest O
rates O
in O
the O
Public O
Health O
Regions O
in O
southern O
and O
western O
Texas O
( O
19 O
. O
08 O
- O
39 O
. O
50 O
) O
. O

Of O
the O
187 O
exposures O
not O
involving O
other O
substances O
, O
96 O
. O
8 O
% O
were O
known O
or O
expected O
to O
result O
in O
at O
most O
minor O
effects O
, O
and O
71 O
. O
1 O
% O
were O
managed O
on O
site O
( O
at O
residence O
) O
. O

Synthesis O
and O
application O
of O
FePt B
/ O
CNTs O
nanocomposite O
as O
a O
sensor O
and O
novel O
amide B
ligand O
as O
a O
mediator O
for O
simultaneous O
determination O
of O
glutathione B
, O
nicotinamide B
adenine I
dinucleotide I
and O
tryptophan B
. O

In O
this O
study O
, O
we O
report O
the O
synthesis O
and O
application O
of O
a O
FePt B
/ O
CNTs O
nanocomposite O
as O
a O
highly O
sensitive O
sensor O
and O
novel O
amide B
ligand O
( B
9 I
, I
10 I
- I
dihydro I
- I
9 I
, I
10 I
- I
ethanoanthracene I
- I
11 I
, I
12 I
- I
dicarboximido I
) I
- I
4 I
- I
ethylbenzene I
- I
1 I
, I
2 I
- I
diol I
as O
a O
mediator O
for O
the O
determination O
of O
glutathione B
( O
GSH B
) O
, O
nicotinamide B
adenine I
dinucleotide I
( O
NADH B
) O
and O
tryptophan B
( O
Trp B
) O

. O

The O
synthesized O
materials O
were O
characterized O
with O
different O
methods O
such O
as O
NMR O
, O
IR O
spectroscopy O
, O
TEM O
, O
XRD O
, O
FESEM O
, O
cyclic O
voltammetry O
, O
electrochemical O
impedance O
spectroscopy O
and O
square O
wave O
voltammetry O
( O
SWV O
) O
. O

The O
modified O
electrode O
exhibited O
a O
potent O
and O
persistent O
electron O
mediating O
behavior O
followed O
by O
well O
- O
separated O
oxidation O
peaks O
of O
GSH B
, O
NADH B
and O
Trp B
. O

The O
peak O
currents O
were O
linearly O
dependent O
on O
GSH B
, O
NADH B
and O
Trp B
concentrations O
in O
the O
range O
of O
0 O
. O
08 O
- O
220 O
, O
1 O
. O
0 O
- O
400 O
and O
5 O
. O
0 O
- O
500 O
mu O
mol O
L O
( O
- O
1 O
) O
, O
with O
detection O
limits O
of O
0 O
. O
05 O
, O
0 O
. O
8 O
and O
1 O
. O
0 O
mu O
mol O
L O
( O
- O
1 O
) O
, O
respectively O
. O

The O
modified O
electrode O
was O
used O
for O
the O
determination O
of O
these O
compounds O
in O
real O
samples O
. O

Channel O
Size O
Conversion O
of O
Phi29 O
DNA O
- O
Packaging O
Nanomotor O
for O
Discrimination O
of O
Single O
- O
and O
Double O
- O
Stranded O
Nucleic O
Acids O
. O

Nanopores O
have O
been O
utilized O
to O
detect O
the O
conformation O
and O
dynamics O
of O
polymers O
, O
including O
DNA O
and O
RNA O
. O

Biological O
pores O
are O
extremely O
reproducible O
at O
the O
atomic O
level O
with O
uniform O
channel O
sizes O
. O

The O
channel O
of O
the O
bacterial O
virus O
phi29 O
DNA O
- O
packaging O
motor O
is O
a O
natural O
conduit O
for O
the O
transportation O
of O
double O
- O
stranded O
DNA O
( O
dsDNA O
) O
and O
has O
the O
largest O
diameter O
among O
the O
well O
- O
studied O
biological O
channels O
. O

The O
larger O
channel O
facilitates O
translocation O
of O
dsDNA O
and O
offers O
more O
space O
for O
further O
channel O
modification O
and O
conjugation O
. O

Interestingly O
, O
the O
relatively O
large O
wild O
- O
type O
channel O
, O
which O
translocates O
dsDNA O
, O
cannot O
detect O
single O
- O
stranded O
nucleic O
acids O
( O
ssDNA O
or O
ssRNA O
) O
under O
the O
current O
experimental O
conditions O
. O

Herein O
, O
we O
reengineered O
this O
motor O
channel O
by O
removing O
the O
internal O
loop O
segment O
of O
the O
channel O
. O

The O
modification O
resulted O
in O
two O
classes O
of O
channels O
. O

One O
class O
was O
the O
same O
size O
as O
the O
wild O
- O
type O
channel O
, O
while O
the O
other O
class O
had O
a O
cross O
- O
sectional O
area O
about O
60 O
% O
of O
the O
wild O
- O
type O
. O

This O
smaller O
channel O
was O
able O
to O
detect O
the O
real O
- O
time O
translocation O
of O
single O
- O
stranded O
nucleic O
acids O
at O
single O
- O
molecule O
level O
. O

While O
the O
wild O
- O
type O
connector O
exhibited O
a O
one O
- O
way O
traffic O
property O
with O
respect O
to O
dsDNA O
translocation O
, O
the O
loop O
- O
deleted O
connector O
was O
able O
to O
translocate O
ssDNA O
and O
ssRNA O
with O
equal O
competencies O
from O
both O
termini O
. O

This O
finding O
of O
size O
alterations O
in O
reengineered O
motor O
channels O
expands O
the O
potential O
application O
of O
the O
phi29 O
DNA O
- O
packaging O
motor O
in O
nanomedicine O
, O
nanobiotechnology O
, O
and O
high O
- O
throughput O
single O
- O
pore O
DNA O
sequencing O
. O

Columnar O
Cell O
Variant O
of O
Papillary O
Thyroid O
Carcinoma O
: O
A O
Study O
of O
Ten O
Cases O
with O
Emphasis O
On O
CDX O
- O
2 O
Expression O
. O

Background O
: O
Columnar O
cell O
variant O
is O
a O
recognized O
rare O
variant O
of O
papillary O
thyroid O
carcinoma O
associated O
with O
an O
uncertain O
clinical O
course O
. O

This O
variant O
has O
two O
sub O
variants O
, O
and O
one O
is O
regarded O
as O
a O
more O
aggressive O
form O
in O
comparison O
to O
the O
more O
common O
classical O
and O
follicular O
variants O
. O

These O
tumors O
have O
morphological O
resemblance O
with O
endometrial O
or O
colonic O
adenocarcinoma O
. O

CDX2 O
, O
a O
transcription O
factor O
of O
the O
caudal O
homeobox O
family O
, O
plays O
a O
key O
role O
in O
intestinal O
development O
and O
differentiation O
and O
it O
is O
widely O
used O
as O
a O
marker O
to O
detect O
adenocarcinoma O
of O
intestinal O
and O
colonic O
origin O
. O

CDX2 O
has O
been O
rarely O
reported O
in O
papillary O
thyroid O
carcinoma O
. O

Methods O
: O
We O
studied O
ten O
cases O
of O
columnar O
cell O
variant O
of O
papillary O
thyroid O
carcinoma O
. O

The O
histological O
, O
architectural O
, O
and O
cytological O
features O
fulfilled O
the O
diagnostic O
criteria O
of O
the O
columnar O
cell O
variant O
of O
papillary O
thyroid O
carcinoma O
as O
defined O
by O
the O
current O
WHO O
classification O
. O

Ten O
patients O
( O
6M O
: O
4F O
) O
ranging O
from O
32 O
to O
90 O
years O
of O
age O
( O
mean O
58 O
. O
3 O
years O
) O
presented O
with O
tumors O
classified O
as O
indolent O
( O
4 O
cases O
) O
or O
aggressive O
( O
6 O
cases O
) O
; O
3 O
with O
BRAFV600E O
mutation O
. O

All O
cases O
were O
- O
Catenin O
negative O
. O

The O
Ki O
- O
67 O
proliferative O
index O
was O
up O
to O
50 O
% O
. O

All O
cases O
were O
TTF O
- O
1 O
positive O
. O

Using O
paraffin O
embedded O
blocks O
, O
immunohistochemistry O
for O
CDX2 O
was O
performed O
to O
evaluate O
the O
reactivity O
of O
this O
antibody O
to O
this O
variant O
of O
papillary O
thyroid O
carcinoma O
. O

Results O
: O
Nuclear O
positivity O
for O
CDX2 O
was O
detected O
in O
one O
out O
of O
the O
ten O
cases O
studied O
( O
10 O
% O
) O
; O
the O
other O
nine O
cases O
did O
not O
express O
CDX2 O
. O

Conclusion O
: O
Only O
one O
of O
our O
cases O
showed O
nuclear O
positivity O
for O
CDX2 O
, O
therefore O
our O
study O
failed O
to O
confirm O
this O
as O
a O
marker O
for O
columnar O
cell O
variant O
of O
papillary O
thyroid O
carcinoma O
. O

The O
absence O
of O
CDX2 O
in O
the O
majority O
of O
the O
cases O
does O
not O
support O
the O
theory O
of O
CDX2 O
playing O
a O
role O
in O
the O
intestinal O
phenotype O
of O
these O
tumors O
. O

KEYWORDS O
: O
Papillary O
Thyroid O
Carcinoma O
, O
CDX O
- O
2 O
, O
Columnar O
Cell O
, O
Immunohistochemistry O
. O

Iodine B
Status O
in O
Pregnant O
Women O
in O
the O
United O
States O
: O
National O
Children O
' O
s O
Study O
and O
National O
Health O
and O
Nutrition O
Examination O
Survey O
. O

Background O
: O
This O
report O
presents O
iodine B
data O
from O
NHANES O
and O
from O
a O
sample O
of O
pregnant O
women O
in O
the O
National O
Children O
' O
s O
Study O
( O
NCS O
) O
Vanguard O
Study O
. O

Methods O
: O
UI O
was O
measured O
in O
a O
one O
third O
subsample O
of O
NHANES O
2005 O
- O
2006 O
, O
and O
2009 O
- O
2010 O
participants O
and O
in O
all O
2007 O
- O
2008 O
participants O
age O
six O
years O
and O
older O
. O

These O
measurements O
are O
representative O
of O
the O
general O
U O
. O
S O
. O
population O
. O

UI O
was O
also O
measured O
in O
a O
convenience O
sample O
of O
501 O
pregnant O
women O
enrolled O
in O
the O
NCS O
initial O
Vanguard O
Study O
from O
seven O
study O
sites O
across O
the O
U O
. O
S O
. O

Results O
: O
NHANES O
median O
UI O
concentration O
in O
2009 O
- O
2010 O
( O
144 O
micro O
g O
/ O
L O
) O
was O
significantly O
lower O
than O
in O
2007 O
- O
2008 O
( O
164 O
micro O
g O
/ O
L O
) O
. O

Non O
- O
Hispanic O
blacks O
had O
the O
lowest O
UI O
concentrations O
( O
131 O
micro O
g O
/ O
L O
) O
compared O
to O
non O
- O
Hispanic O
whites O
or O
Hispanics O
( O
147 O
and O
148 O
micro O
g O
/ O
L O
, O
respectively O
) O
. O

The O
median O
for O
all O
pregnant O
women O
in O
NHANES O
2005 O
- O
2010 O
was O
less O
than O
adequate O
( O
129 O
micro O
g O
/ O
L O
) O
, O
the O
third O
trimester O
women O
had O
UI O
concentrations O
that O
were O
adequate O
( O
median O
UI O
172 O
micro O
g O
/ O
L O
) O
. O

Third O
trimester O
women O
participating O
in O
the O
NCS O
study O
similarly O
had O
an O
adequate O
level O
of O
iodine B
intake O
, O
with O
a O
median O
UI O
concentration O
of O
167 O
micro O
g O
/ O
L O
. O

Furthermore O
, O
NCS O
median O
UI O
concentrations O
varied O
by O
geographic O
location O
. O

Conclusions O
: O
Dairy O
, O
but O
not O
salt O
, O
seafood O
or O
grain O
consumption O
, O
was O
significantly O
positively O
associated O
with O
median O
UI O
concentration O
in O
women O
of O
childbearing O
age O
. O

Pregnant O
women O
in O
their O
third O
trimester O
in O
the O
NHANES O
2005 O
- O
2010 O
had O
adequate O
median O
UI O
concentrations O
, O
but O
pregnant O
women O
in O
NHANES O
who O
were O
in O
their O
first O
or O
second O
trimesters O
had O
median O
UI O
concentrations O
that O
were O
less O
than O
adequate O
. O

Non O
- O
Hispanic O
black O
pregnant O
women O
from O
both O
the O
NHANES O
2005 O
- O
20010 O
and O
the O
NCS O
consistently O
had O
lower O
UI O
median O
concentrations O
than O
non O
- O
Hispanic O
whites O
or O
Hispanics O
. O

The O
use O
of O
U O
- O
500 O
regular O
insulin O
in O
the O
management O
of O
patients O
with O
obesity O
and O
insulin O
resistance O
. O

The O
rise O
in O
prevalence O
of O
obesity O
and O
diabetes O
has O
created O
a O
challenge O
in O
managing O
increasing O
numbers O
of O
patients O
who O
require O
high O
doses O
of O
insulin O
. O

This O
article O
reviews O
the O
published O
literature O
on O
the O
properties O
of O
U O
- O
500 O
insulin O
and O
its O
use O
in O
clinical O
practice O
. O

U O
- O
500 O
insulin O
is O
likely O
to O
have O
a O
longer O
time O
to O
peak O
effect O
and O
a O
longer O
duration O
of O
action O
than O
similar O
doses O
of O
U O
- O
100 O
insulin O
. O

Evidence O
for O
its O
use O
in O
clinical O
practice O
rests O
on O
retrospective O
case O
series O
, O
which O
suggests O
that O
the O
use O
of O
U O
- O
500 O
insulin O
either O
by O
multiple O
daily O
injections O
or O
a O
continuous O
subcutaneous O
insulin O
infusion O
is O
effective O
in O
improving O
glycaemic O
control O
. O

To O
prevent O
insulin O
dosing O
and O
administration O
errors O
, O
great O
care O
must O
be O
taken O
in O
providing O
staff O
and O
patient O
education O
, O
and O
in O
developing O
policies O
for O
the O
management O
of O
patients O
on O
U O
- O
500 O
insulin O
who O
are O
admitted O
to O
hospital O
. O

The O
use O
of O
insulin O
analogues O
in O
pregnancy O
. O

Excellent O
glycaemic O
control O
is O
essential O
in O
pregnancy O
to O
optimise O
maternal O
and O
foetal O
outcomes O
. O

The O
aim O
of O
this O
review O
is O
to O
assess O
the O
efficacy O
and O
safety O
of O
insulin O
analogues O
in O
pregnancy O
. O

Insulin O
lispro O
and O
insulin O
aspart O
are O
safe O
in O
pregnancy O
and O
may O
improve O
post O
- O
prandial O
glycaemic O
control O
in O
women O
with O
type O
1 O
diabetes O
. O

However O
, O
a O
lack O
of O
data O
indicating O
improved O
foetal O
outcomes O
would O
suggest O
that O
there O
is O
no O
imperative O
to O
switch O
to O
a O
short O
- O
acting O
analogue O
where O
the O
woman O
' O
s O
diabetes O
is O
well O
controlled O
with O
human O
insulin O
. O

There O
are O
no O
reports O
of O
the O
use O
of O
insulin O
glulisine B
in O
pregnancy O
and O
so O
its O
use O
cannot O
be O
recommended O
. O

Most O
studies O
of O
insulin O
glargine O
in O
pregnancy O
are O
small O
, O
retrospective O
and O
include O
women O
with O
pre O
- O
existing O
diabetes O
and O
gestational O
diabetes O
. O

There O
appear O
to O
be O
no O
major O
safety O
concerns O
and O
so O
it O
seems O
reasonable O
to O
continue O
insulin O
glargine O
if O
required O
to O
achieve O
excellent O
glycaemic O
control O
. O

A O
head O
- O
to O
- O
head O
comparison O
between O
insulin O
detemir O
and O
NPH O
insulin O
in O
women O
with O
type O
1 O
diabetes O
showed O
that O
while O
foetal O
outcomes O
did O
not O
differ O
, O
fasting O
plasma O
glucose B
improved O
with O
insulin O
detemir O
without O
an O
increased O
incidence O
of O
hypoglycaemia O
. O

The O
greater O
evidence O
base O
supports O
the O
use O
of O
insulin O
detemir O
as O
the O
first O
line O
long O
- O
acting O
analogue O
in O
pregnancy O
but O
the O
lack O
of O
definitive O
foetal O
benefits O
means O
that O
there O
is O
no O
strong O
need O
to O
switch O
a O
woman O
who O
is O
well O
controlled O
on O
NPH O
insulin O
. O

There O
seems O
little O
justification O
in O
using O
long O
acting O
insulin O
analogues O
in O
women O
with O
gestational O
diabetes O
or O
type O
2 O
diabetes O
where O
the O
risk O
of O
hypoglycaemia O
is O
low O
. O

Synthesis O
and O
evaluation O
of O
cholecystokinin O
trimers O
: O
a O
multivalent O
approach O
to O
pancreatic O
cancer O
detection O
and O
treatment O
. O

In O
the O
quest O
for O
novel O
tools O
for O
early O
detection O
and O
treatment O
of O
cancer O
, O
we O
propose O
the O
use O
of O
multimers O
targeting O
overexpressed O
receptors O
at O
the O
cancer O
cell O
surface O
. O

Indeed O
, O
multimers O
are O
prone O
to O
create O
multivalent O
interactions O
, O
more O
potent O
and O
specific O
than O
their O
corresponding O
monovalent O
versions O
, O
thus O
enabling O
the O
potential O
for O
early O
detection O
. O

There O
is O
a O
lack O
of O
tools O
for O
early O
detection O
of O
pancreatic O
cancer O
, O
one O
of O
the O
deadliest O
forms O
of O
cancer O
, O
but O
CCK2 O
- O
R O
overexpression O
on O
pancreatic O
cancer O
cells O
makes O
CCK O
based O
multimers O
potential O
markers O
for O
these O
cells O
. O

In O
this O
Letter O
, O
we O
describe O
the O
synthesis O
and O
evaluation O
of O
CCK O
trimers O
targeting O
overexpressed O
CCK2 O
- O
R O
. O

Anti O
- O
influenza O
active O
and O
low O
toxic O
N B
- I
phenyl I
- I
substituted I
beta I
- I
amidoamidines I
structurally O
related O
to O
natural O
antibiotic O
amidinomycin B
. O

A O
set O
of O
racemic O
N B
- I
phenyl I
- I
substituted I
beta I
- I
amidoamidines I
hydrochlorides I
4 O
, O
which O
are O
structurally O
related O
to O
natural O
antiviral O
agent O
amidinomycin B
( O
1 O
) O
, O
was O
synthesized O
in O
four O
steps O
starting O
from O
methacryloyl B
anilide I
( O
5 O
) O
. O

In O
the O
final O
step O
of O
the O
synthetic O
route O
, O
an O
uncommon O
monoacylation O
of O
beta B
- I
aminoamidine I
8 O
at O
the O
less O
reactive O
beta B
- I
phenylamino I
- O
group O
took O
place O
. O

To O
rationalize O
this O
result O
, O
a O
mechanism O
which O
involves O
initial O
acylation O
at O
the O
more O
active O
amidine B
- O
function O
followed O
by O
intramolecular O
acyl B
- O
group O
transfer O
to O
beta B
- I
phenylamino I
- O
group O
was O
suggested O
. O

All O
three O
beta B
- I
amidoamidines I
4d O
- O
f O
bearing O
long O
linear O
aliphatic O
chain O
( O
from O
n B
- I
C8H17 I
to O
n B
- I
C12H25 I
) O
revealed O
significant O
in O
vitro O
activity O
against O
influenza O
A O
virus O
( O
H3N2 O
) O
and O
modest O
cytotoxicity O
. O

The O
in O
vitro O
antiviral O
potency O
of O
4d O
, O
e O
is O
6 O
- O
20 O
times O
greater O
than O
that O
of O
commercial O
rimantadine B
with O
lower O
EC50 O
values O
and O
higher O
therapeutic O
index O
. O

The O
non O
- O
toxic O
in O
vivo O
compounds O
4d O
- O
f O
showed O
a O
beneficial O
protective O
effect O
in O
influenza O
A O
( O
H3N2 O
) O
infected O
mice O
. O

Peripubertal O
female O
athletes O
in O
high O
- O
impact O
sports O
show O
improved O
bone O
mass O
acquisition O
and O
bone O
geometry O
. O

OBJECTIVE O
: O
Intensive O
physical O
training O
may O
have O
a O
sport O
- O
dependent O
effect O
on O
bone O
mass O
acquisition O
. O

This O
cross O
- O
sectional O
study O
evaluated O
bone O
mass O
acquisition O
in O
girls O
practicing O
sports O
that O
put O
different O
mechanical O
loads O
on O
bone O
. O

MATERIALS O
/ O
METHODS O
: O
Eighty O
girls O
from O
10 O
. O
7 O
to O
18 O
. O
0years O
old O
( O
mean O
13 O
. O
83 O
+ O
/ O
- O
1 O
. O
97 O
) O
were O
recruited O
: O
20 O
artistic O
gymnasts O
( O
AG O
; O
high O
- O
impact O
activity O
) O
, O
20 O
rhythmic O
gymnasts O
( O
RG O
; O
medium O
- O
impact O
activity O
) O
, O
20 O
swimmers O
( O
SW O
, O
no O
- O
impact O
activity O
) O
, O
and O
20 O
age O
- O
matched O
controls O
( O
CON O
; O
leisure O
physical O
activity O
< O
3h O
/ O
wk O
) O
. O

Areal O
bone O
mineral O
density O
( O
aBMD O
) O
was O
determined O
using O
DEXA O
. O

Hip O
structural O
analysis O
applied O
at O
the O
femur O
evaluated O
cross O
- O
sectional O
area O
( O
CSA O
, O
cm O
( O
2 O
) O
) O
, O
section O
modulus O
( O
Z O
, O
cm O
( O
3 O
) O
) O
, O
and O
buckling O
ratio O
. O

Bone O
turnover O
markers O
and O
OPG O
/ O
RANKL O
levels O
were O
analyzed O
. O

RESULTS O
: O
AG O
had O
higher O
aBMD O
than O
SW O
and O
CON O
at O
all O
bone O
sites O
and O
higher O
values O
than O
RG O
in O
the O
lumbar O
spine O
and O
radius O
. O

RG O
had O
higher O
aBMD O
than O
SW O
and O
CON O
only O
in O
the O
femoral O
region O
. O

CSA O
and O
mean O
cortical O
thickness O
were O
significantly O
higher O
and O
the O
buckling O
ratio O
was O
significantly O
lower O
in O
both O
gymnast O
groups O
compared O
with O
SW O
and O
CON O
. O

In O
RG O
only O
, O
endocortical O
diameter O
and O
width O
were O
reduced O
, O
while O
Z O
was O
only O
increased O
in O
AG O
compared O
with O
SW O
and O
CON O
. O

Reduced O
bone O
remodeling O
was O
observed O
in O
RG O
compared O
with O
AG O
only O
when O
groups O
were O
subdivided O
according O
to O
menarcheal O
status O
. O

All O
groups O
showed O
similar O
OPG O
concentrations O
, O
while O
RANKL O
concentrations O
increased O
with O
age O
and O
were O
decreased O
in O
SW O
. O

CONCLUSION O
: O
High O
- O
impact O
activity O
clearly O
had O
a O
favorable O
effect O
on O
aBMD O
and O
bone O
geometry O
during O
the O
growth O
period O
, O
although O
the O
bone O
health O
benefits O
seem O
to O
be O
more O
marked O
after O
menarche O
. O

Differential O
Expression O
of O
Human O
Cytochrome O
P450 O
Enzymes O
from O
the O
CYP3A O
Subfamily O
in O
the O
Brains O
of O
Alcoholics O
and O
Drug O
Free O
Controls O
. O

Cytochrome O
P450 O
( O
P450 O
, O
CYP O
) O
enzymes O
are O
responsible O
for O
the O
metabolism O
of O
most O
commonly O
used O
drugs O
. O

Amongst O
these O
enzymes O
, O
CYP3A O
forms O
mediate O
the O
clearance O
of O
around O
40 O
- O
50 O
% O
of O
drugs O
and O
may O
also O
play O
roles O
in O
the O
biotransformation O
of O
endogenous O
compounds O
. O

CYP3A O
forms O
are O
expressed O
both O
in O
the O
liver O
and O
extrahepatically O
. O

However O
little O
is O
known O
about O
the O
expression O
of O
CYP3A O
proteins O
in O
specific O
regions O
of O
the O
human O
brain O
. O

In O
this O
study O
, O
form O
- O
selective O
antibodies O
raised O
to O
CYP3A4 O
and O
CYP3A5 O
were O
utilized O
to O
characterize O
the O
expression O
of O
these O
forms O
in O
the O
human O
brain O
. O

Both O
CYP3A4 O
and O
CYP3A5 O
immunoreactivity O
was O
found O
to O
varying O
extents O
in O
the O
microsomal O
fractions O
of O
cortex O
, O
hippocampus O
, O
basal O
ganglia O
, O
amygdala O
and O
cerebellum O
. O

However O
, O
only O
CYP3A4 O
expression O
was O
observed O
in O
the O
mitochondrial O
fractions O
of O
these O
brain O
regions O
. O

N B
- O
terminal O
sequencing O
confirmed O
the O
principal O
antigen O
detected O
by O
the O
anti O
- O
CYP3A4 O
antibody O
in O
cortical O
microsomes O
to O
be O
CYP3A4 O
. O

Immunohistochemical O
analysis O
revealed O
that O
CYP3A4 O
and O
CYP3A5 O
expression O
was O
primarily O
localized O
in O
the O
soma O
and O
axonal O
hillock O
of O
neurons O
and O
varied O
according O
to O
cell O
type O
and O
cell O
layer O
within O
brain O
regions O
. O

Finally O
, O
analysis O
of O
the O
frontal O
cortex O
of O
chronic O
alcohol B
abusers O
revealed O
elevated O
expression O
of O
CYP3A4 O
in O
microsomal O
but O
not O
mitochondrial O
fractions O
; O
CYP3A5 O
expression O
was O
unchanged O
. O

The O
site O
- O
specific O
expression O
of O
CYP3A4 O
and O
CYP3A5 O
in O
the O
human O
brain O
may O
have O
implications O
for O
the O
role O
of O
these O
enzymes O
in O
both O
normal O
brain O
physiology O
and O
the O
response O
to O
drugs O
. O

Polybrominated B
Dibenzo I
- I
p I
- I
dioxins I
( O
PBDDs B
) O
, O
Dibenzofurans B
( O
PBDFs B
) O
and O
Biphenyls B
( O
PBBs B
) O
- O
Inclusion O
in O
the O
Toxicity O
Equivalency O
Factor O
Concept O
for O
Dioxin B
- O
like O
Compounds O
- O

In O
2011 O
a O
joint O
World O
Health O
Organization O
( O
WHO O
) O
and O
United O
Nations O
Environment O
Programme O
( O
UNEP O
) O
expert O
consultation O
took O
place O
, O
during O
which O
the O
possible O
inclusion O
of O
brominated O
analogues O
of O
the O
dioxin B
- O
like O
compounds O
in O
the O
WHO O
Toxicity O
Equivalency O
Factor O
( O
TEF O
) O
scheme O
were O
evaluated O
. O

The O
expert O
panel O
concluded O
that O
polybrominated B
dibenzo I
- I
p I
- I
dioxins I
( O
PBDDs B
) O
, O
dibenzofurans B
( O
PBDFs B
) O
, O
and O
some O
dioxin B
- O
like O
biphenyls B
( O
dl B
- I
PBBs I
) O
may O
contribute O
significantly O
in O
daily O
human O
background O
exposure O
to O
the O
total O
dioxin B
toxic O
equivalencies O
( O
TEQs O
) O
. O

These O
compounds O
are O
also O
commonly O
found O
in O
the O
aquatic O
environment O
. O

Available O
data O
for O
fish O
toxicity O
were O
evaluated O
for O
possible O
inclusion O
in O
the O
WHO O
- O
UNEP O
TEF O
scheme O
( O
Van O
den O
Berg O
et O
al O
. O
, O
1998 O
) O
. O

Because O
of O
the O
limited O
database O
it O
was O
decided O
not O
to O
derive O
specific O
WHO O
- O
UNEP O
TEFs O
for O
fish O
, O
but O
for O
ecotoxicological O
risk O
assessment O
the O
use O
of O
specific O
relative O
effect O
potencies O
( O
REPs O
) O
from O
fish O
embryo O
assays O
is O
recommended O
. O

Based O
on O
the O
limited O
mammalian O
REP O
database O
for O
these O
brominated O
compounds O
, O
it O
was O
concluded O
that O
sufficient O
differentiation O
from O
the O
present O
TEF O
values O
of O
the O
chlorinated O
analogues O
( O
Van O
den O
Berg O
et O
al O
. O
, O
2005 O
) O
was O
not O
possible O
. O

However O
, O
the O
REPs O
for O
PBDDs B
, O
PBDFs B
, O
and O
non B
- I
ortho I
dl I
- I
PBBs I
in O
mammals O
closely O
follow O
those O
of O
the O
chlorinated O
analogues O
, O
at O
least O
within O
one O
order O
of O
magnitude O
. O

Therefore O
, O
the O
use O
of O
similar O
interim O
TEF O
values O
for O
brominated O
and O
chlorinated O
congeners O
for O
human O
risk O
assessment O
is O
recommended O
, O
pending O
more O
detailed O
information O
in O
the O
future O
. O

Yeast O
Proteome O
Variations O
Reveal O
Different O
Adaptive O
Responses O
to O
Grape O
Must O
Fermentation O
. O

Saccharomyces O
cerevisiae O
and O
S O
. O
uvarum O
are O
two O
domesticated O
species O
of O
the O
Saccharomyces O
sensu O
stricto O
clade O
that O
diverged O
around O
100 O
Ma O
after O
whole O
- O
genome O
duplication O
. O

Both O
have O
retained O
many O
duplicated O
genes O
associated O
with O
glucose B
fermentation O
and O
are O
characterized O
by O
the O
ability O
to O
achieve O
grape O
must O
fermentation O
. O

Nevertheless O
, O
these O
two O
species O
differ O
for O
many O
other O
traits O
, O
indicating O
that O
they O
underwent O
different O
evolutionary O
histories O
. O

To O
determine O
how O
the O
evolutionary O
histories O
of O
S O
. O
cerevisiae O
and O
S O
. O
uvarum O
are O
mirrored O
on O
the O
proteome O
, O
we O
analyzed O
the O
genetic O
variability O
of O
the O
proteomes O
of O
domesticated O
strains O
of O
these O
two O
species O
by O
quantitative O
mass O
spectrometry O
. O

Overall O
, O
445 O
proteins O
were O
quantified O
. O

Massive O
variations O
of O
protein O
abundances O
were O
found O
, O
that O
clearly O
differentiated O
the O
two O
species O
. O

Abundance O
variations O
in O
specific O
metabolic O
pathways O
could O
be O
related O
to O
phenotypic O
traits O
known O
to O
discriminate O
the O
two O
species O
. O

In O
addition O
, O
proteins O
encoded O
by O
duplicated O
genes O
were O
shown O
to O
be O
differently O
recruited O
in O
each O
species O
. O

Comparing O
the O
strain O
differentiation O
based O
on O
the O
proteome O
variability O
to O
those O
based O
on O
the O
phenotypic O
and O
genetic O
variations O
further O
revealed O
that O
the O
strains O
of O
S O
. O
uvarum O
and O
some O
strains O
of O
S O
. O
cerevisiae O
displayed O
similar O
fermentative O
performances O
despite O
strong O
proteomic O
and O
genomic O
differences O
. O

Altogether O
, O
these O
results O
indicate O
that O
the O
ability O
of O
S O
. O
cerevisae O
and O
S O
. O
uvarum O
to O
complete O
grape O
must O
fermentation O
arose O
through O
different O
evolutionary O
roads O
, O
involving O
different O
metabolic O
pathways O
and O
duplicated O
genes O
. O

Dexamethasone B
- O
mediated O
changes O
in O
adipose O
triacylglycerol B
metabolism O
are O
exaggerated O
, O
not O
diminished O
, O
in O
the O
absence O
of O
a O
functional O
GR O
dimerization O
domain O
. O

The O
glucocorticoid O
( O
GC O
) O
receptor O
( O
GR O
) O
has O
multiple O
effector O
mechanisms O
, O
including O
dimerization O
- O
mediated O
transactivation O
of O
target O
genes O
via O
DNA O
binding O
and O
transcriptional O
repression O
mediated O
by O
protein O
- O
protein O
interactions O
. O

Much O
attention O
has O
been O
focused O
on O
developing O
selective O
GR O
modulators O
that O
would O
dissociate O
adverse O
effects O
from O
therapeutic O
anti O
- O
inflammatory O
effects O
. O

The O
GR O
( O
dim O
/ O
dim O
) O
mouse O
has O
a O
mutation O
in O
the O
dimerization O
domain O
of O
GR O
and O
has O
been O
shown O
to O
have O
attenuated O
transactivation O
with O
intact O
repression O
. O

To O
understand O
the O
role O
of O
GR O
dimerization O
- O
dependent O
targets O
in O
multiple O
tissues O
, O
we O
measured O
metabolic O
fluxes O
through O
several O
disease O
- O
relevant O
GC O
target O
pathways O
using O
heavy O
water O
labeling O
and O
mass O
spectrometry O
in O
wild O
- O
type O
and O
GR O
( O
dim O
/ O
dim O
) O
mice O
administered O
the O
potent O
GC O
dexamethasone B
( O
DEX B
) O
. O

Absolute O
triglyceride B
synthesis O
was O
increased O
in O
both O
wild O
- O
type O
and O
GR O
( O
dim O
/ O
dim O
) O
mice O
by O
DEX B
in O
the O
inguinal O
and O
epididymal O
fat O
depots O
. O

GR O
( O
dim O
/ O
dim O
) O
mice O
showed O
an O
exaggerated O
response O
to O
DEX B
in O
both O
depots O
. O

De O
novo O
lipogenesis O
was O
also O
greatly O
increased O
in O
both O
depots O
in O
response O
to O
DEX B
in O
GR O
( O
dim O
/ O
dim O
) O
, O
but O
not O
wild O
- O
type O
mice O
. O

In O
contrast O
, O
the O
inhibitory O
effect O
of O
DEX B
on O
bone O
and O
skin O
collagen O
synthesis O
rates O
was O
greater O
in O
wild O
- O
type O
compared O
with O
GR O
( O
dim O
/ O
dim O
) O
mice O
. O

Wild O
- O
type O
mice O
were O
more O
sensitive O
to O
DEX B
- O
dependent O
decreases O
in O
insulin O
sensitivity O
than O
GR O
( O
dim O
/ O
dim O
) O
mice O
. O

Wild O
- O
type O
and O
GR O
( O
dim O
/ O
dim O
) O
mice O
were O
equally O
sensitive O
to O
DEX B
- O
dependent O
decreases O
in O
muscle O
protein O
synthesis O
. O

Chronic O
elevation O
of O
GCs O
in O
GR O
( O
dim O
/ O
dim O
) O
mice O
results O
in O
severe O
runting O
and O
lethality O
. O

In O
conclusion O
, O
some O
metabolic O
effects O
of O
GC O
treatment O
are O
exaggerated O
in O
adipose O
tissue O
of O
GR O
( O
dim O
/ O
dim O
) O
mice O
, O
suggesting O
that O
selective O
GR O
modulators O
based O
on O
dissociating O
GR O
transactivation O
from O
repression O
should O
be O
evaluated O
carefully O
. O

X O
- O
box O
binding O
protein O
1 O
is O
essential O
for O
insulin O
regulation O
of O
pancreatic O
alpha O
cell O
function O
. O

Type O
2 O
diabetes O
mellitus O
( O
T2D O
) O
patients O
often O
exhibit O
hyperglucagonemia O
despite O
hyperglycemia O
suggesting O
defective O
alpha O
- O
cell O
function O
. O

While O
endoplasmic O
reticulum O
( O
ER O
) O
stress O
has O
been O
suggested O
to O
underlie O
beta O
- O
cell O
dysfunction O
in O
T2D O
, O
its O
role O
in O
alpha O
- O
cell O
biology O
remains O
unclear O
. O

X O
- O
box O
binding O
protein O
1 O
( O
XBP1 O
) O
is O
a O
transcription O
factor O
that O
plays O
a O
crucial O
role O
in O
the O
unfolded O
protein O
response O
( O
UPR O
) O
and O
its O
deficiency O
in O
beta O
- O
cells O
has O
been O
reported O
to O
impair O
insulin O
secretion O
leading O
to O
glucose B
intolerance O
. O

To O
evaluate O
the O
role O
of O
XBP1 O
in O
alpha O
- O
cells O
, O
we O
created O
complementary O
in O
vivo O
( O
alpha O
- O
cell O
specific O
XBP1 O
knockout O
( O
alpha O
XBPKO O
) O
mice O
) O
and O
in O
vitro O
( O
stable O
XBP1 O
knock O
down O
alpha O
- O
cell O
line O
, O
alpha O
XBPKD O
) O
models O
. O

alpha O
XBPKO O
mice O
exhibited O
glucose B
intolerance O
, O
mild O
insulin O
resistance O
and O
an O
inability O
to O
suppress O
glucagon O
secretion O
following O
glucose B
stimulation O
. O

alpha O
XBPKD O
cells O
exhibited O
activation O
of O
IRE1 O
, O
an O
upstream O
activator O
of O
XBP1 O
, O
leading O
to O
phosphorylation O
of O
JNK O
. O

Interestingly O
, O
insulin O
treatment O
of O
alpha O
XBPKD O
cells O
reduced O
tyrosine B
phosphorylation O
of O
IRS O
- O
1 O
( O
pY O
( O
896 O
) O
) O
, O
and O
phosphorylation O
of O
Akt O
, O
while O
enhancing O
serine B
phosphorylation O
( O
pS O
( O
307 O
) O
) O
of O
IRS O
- O
1 O
. O

Consequently O
the O
alpha O
XBPKD O
cells O
exhibited O
blunted O
suppression O
of O
glucagon O
secretion O
following O
insulin O
treatment O
in O
the O
presence O
of O
high O
glucose B
. O

Together O
, O
these O
data O
indicate O
that O
XBP1 O
deficiency O
in O
pancreatic O
alpha O
- O
cells O
induces O
altered O
insulin O
signaling O
and O
dysfunctional O
glucagon O
secretion O
. O

Fabrication O
and O
multifunction O
integration O
of O
microfluidic O
chips O
by O
femtosecond O
laser O
direct O
writing O
. O

In O
the O
pursuit O
of O
modern O
microfluidic O
chips O
with O
multifunction O
integration O
, O
micronanofabrication O
techniques O
play O
an O
increasingly O
important O
role O
. O

Despite O
the O
fact O
that O
conventional O
fabrication O
approaches O
such O
as O
lithography O
, O
imprinting O
and O
soft O
lithography O
have O
been O
widely O
used O
for O
the O
preparation O
of O
microfluidic O
chips O
, O
it O
is O
still O
challenging O
to O
achieve O
complex O
microfluidic O
chips O
with O
multifunction O
integration O
. O

Therefore O
, O
novel O
micronanofabrication O
approaches O
that O
could O
be O
used O
to O
achieve O
this O
end O
are O
highly O
desired O
. O

As O
a O
powerful O
3D O
processing O
tool O
, O
femtosecond O
laser O
fabrication O
shows O
great O
potential O
to O
endow O
general O
microfluidic O
chips O
with O
multifunctional O
units O
. O

In O
this O
review O
, O
we O
briefly O
introduce O
the O
fundamental O
principles O
of O
femtosecond O
laser O
micronanofabrication O
. O

With O
the O
help O
of O
laser O
techniques O
, O
both O
the O
preparation O
and O
functionalization O
of O
advanced O
microfluidic O
chips O
are O
summarized O
. O

Finally O
, O
the O
current O
challenges O
and O
future O
perspective O
of O
this O
dynamic O
field O
are O
discussed O
based O
on O
our O
own O
opinion O
. O

LDL O
Cholesterol B
Goals O
in O
High O
- O
Risk O
Patients O
: O
How O
Low O
Do O
We O
Go O
and O
How O
Do O
We O
Get O
There O
? O

It O
is O
widely O
recognised O
that O
low O
- O
density O
lipoprotein O
cholesterol B
( O
LDL O
- O
C O
) O
is O
one O
of O
the O
most O
important O
and O
modifiable O
risk O
factors O
for O
cardiovascular O
disease O
( O
CVD O
) O
. O

Statins O
( O
HMG O
- O
CoA B
reductase O
inhibitors O
) O
have O
consistently O
been O
shown O
to O
decrease O
both O
LDL O
- O
C O
and O
CVD O
risk O
in O
almost O
all O
patient O
categories O
, O
with O
the O
exception O
of O
heart O
and O
kidney O
failure O
as O
well O
as O
advanced O
aortic O
stenosis O
. O

As O
a O
consequence O
, O
statins B
have O
become O
the O
cornerstone O
in O
current O
prevention O
guidelines O
. O

In O
patients O
who O
do O
not O
reach O
the O
LDL O
- O
C O
target O
, O
combination O
therapy O
with O
additional O
LDL O
- O
C O
lowering O
drugs O
( O
e O
. O
g O
. O
ezetimibe B
, O
bile B
acid I
sequestrants O
or O
fibrates O
) O
should O
be O
considered O
. O

Guidelines O
provide O
different O
LDL O
- O
C O
levels O
to O
strive O
for O
, O
depending O
on O
the O
CVD O
risk O
. O

In O
this O
review O
, O
we O
describe O
the O
rationale O
for O
these O
LDL O
- O
C O
targets O
and O
how O
these O
goals O
might O
be O
reached O
by O
current O
and O
future O
therapies O
. O

The O
clinical O
characteristics O
at O
diagnosis O
of O
type O
2 O
diabetes O
in O
a O
multi O
- O
ethnic O
population O
: O
the O
South O
London O
Diabetes O
cohort O
( O
SOUL O
- O
D O
) O
. O

AIMS O
/ O
HYPOTHESIS O
: O
This O
study O
aimed O
to O
investigate O
the O
clinical O
features O
of O
newly O
diagnosed O
type O
2 O
diabetes O
in O
an O
urban O
multi O
- O
ethnic O
cohort O
. O

METHODS O
: O
A O
population O
- O
based O
cross O
- O
sectional O
design O
was O
used O
. O

People O
diagnosed O
with O
type O
2 O
diabetes O
in O
the O
preceding O
6 O
months O
were O
recruited O
from O
primary O
care O
practices O
in O
three O
adjacent O
inner O
- O
city O
boroughs O
of O
South O
London O
, O
serving O
a O
population O
in O
which O
20 O
% O
of O
residents O
are O
of O
black O
African O
or O
Caribbean O
ethnicity O
. O

Sociodemographic O
and O
biomedical O
data O
were O
collected O
by O
standardised O
clinical O
assessment O
and O
from O
medical O
records O
. O

Multiple O
logistic O
regression O
methods O
were O
used O
to O
report O
associations O
between O
ethnicity O
and O
diabetes O
- O
complication O
status O
. O

RESULTS O
: O
From O
96 O
general O
practices O
, O
1 O
, O
506 O
patients O
were O
recruited O
. O

Their O
mean O
age O
was O
55 O
. O
6 O
( O
+ O
/ O
- O
11 O
. O
07 O
) O
years O
, O
55 O
% O
were O
men O
, O
60 O
% O
were O
asymptomatic O
at O
diagnosis O
and O
51 O
% O
, O
38 O
% O
and O
11 O
% O
were O
of O
white O
, O
black O
and O
South O
Asian O
/ O
other O
ethnicity O
, O
respectively O
. O

Compared O
with O
white O
participants O
, O
black O
and O
South O
Asian O
/ O
other O
participants O
were O
: O
younger O
( O
mean O
age O
58 O
. O
9 O
[ O
+ O
/ O
- O
10 O
. O
09 O
] O
, O
52 O
. O
4 O
[ O
+ O
/ O
- O
11 O
. O
19 O
] O
and O
51 O
. O
5 O
[ O
+ O
/ O
- O
10 O
. O
42 O
] O
years O
, O
respectively O
; O
p O
< O
0 O
. O
0001 O
) O
; O
less O
likely O
to O
have O
neuropathy O
( O
10 O
. O
1 O
% O
, O
3 O
. O
6 O
% O
and O
4 O
. O
4 O
% O
; O
p O
< O
0 O
. O
0001 O
) O
or O
report O
coronary O
artery O
disease O
( O
12 O
. O
7 O
% O
, O
4 O
. O
8 O
% O
and O
7 O
. O
3 O
% O
; O
p O
< O
0 O
. O
0001 O
) O
. O

In O
logistic O
regression O
, O
compared O
with O
white O
participants O
, O
black O
participants O
had O
lower O
levels O
of O
macrovascular O
complications O
( O
OR O
0 O
. O
52 O
, O
95 O
% O
CI O
0 O
. O
32 O
, O
0 O
. O
84 O
; O
p O
= O
0 O
. O
01 O
) O
. O

Male O
sex O
was O
independently O
associated O
with O
microvascular O
disease O
( O
OR O
1 O
. O
69 O
, O
95 O
% O
CI O
1 O
. O
26 O
, O
2 O
. O
28 O
; O
p O
< O
0 O
. O
0001 O
) O
. O

CONCLUSIONS O
/ O
INTERPRETATION O
: O
The O
prevalence O
of O
complications O
at O
time O
of O
diagnosis O
was O
lower O
than O
expected O
, O
especially O
in O
black O
and O
South O
Asian O
/ O
other O
ethnic O
groups O
. O

However O
, O
in O
multi O
- O
ethnic O
inner O
- O
city O
populations O
, O
onset O
of O
type O
2 O
diabetes O
occurred O
almost O
10 O
years O
earlier O
in O
non O
- O
white O
populations O
than O
in O
white O
participants O
, O
predicating O
a O
prolonged O
morbidity O
. O

Neuroprotection O
against O
neuroblastoma O
cell O
death O
induced O
by O
depletion O
of O
mitochondrial O
glutathione B
. O

Mitochondrial O
glutathione B
pool O
is O
vital O
in O
protecting O
cells O
against O
oxidative O
stress O
as O
the O
majority O
of O
the O
cellular O
reactive O
oxygen B
species O
are O
generated O
in O
mitochondria O
. O

Oxidative O
stress O
is O
implicated O
as O
a O
causative O
factor O
in O
neuronal O
death O
in O
neurodegenerative O
disorders O
. O

We O
hypothesized O
that O
depletion O
of O
mitochondrial O
glutathione B
leads O
to O
mitochondrial O
dysfunction O
and O
apoptotic O
death O
of O
SK O
- O
N O
- O
SH O
( O
human O
neuroblastoma O
) O
cells O
and O
investigated O
the O
neuroprotective O
strategies O
against O
GSH B
depletion O
. O

SK O
- O
N O
- O
SH O
cells O
were O
treated O
with O
two O
distinct O
inhibitors O
of O
glutathione B
metabolism O
: O
L B
- I
buthionine I
- I
( I
S I
, I
R I
) I
- I
sulfoximine I
( O
BSO B
) O
and O
ethacrynic B
acid I
( O
EA O
) O
. O

EA O
treatment O
caused O
depletion O
of O
both O
the O
total O
and O
mitochondrial O
glutathione B
( O
while O
BSO B
had O
no O
effect O
on O
mitochondrial O
glutathione B
) O
, O
enhanced O
rotenone B
- O
induced O
ROS O
production O
, O
and O
reduced O
the O
viability O
of O
SK O
- O
N O
- O
SH O
cells O
. O

Glutathione B
depletion O
by O
BSO B
or O
EA O
demonstrated O
positive O
features O
of O
mitochondria O
- O
mediated O
apoptosis O
in O
neuroblastoma O
cell O
death O
. O

Prevention O
of O
apoptosis O
by O
Bcl2 O
overexpression O
or O
use O
of O
antioxidant O
ebselen B
did O
not O
confer O
neuroprotection O
. O

Co O
- O
culture O
with O
U O
- O
87 O
( O
human O
glioblastoma O
) O
cells O
protected O
SK O
- O
N O
- O
SH O
cells O
from O
the O
cell O
death O
. O

Our O
data O
suggest O
that O
depletion O
of O
mitochondrial O
glutathione B
leads O
to O
mitochondrial O
dysfunction O
and O
apoptosis O
. O

The O
study O
indicates O
that O
preventing O
mitochondrial O
glutathione B
depletion O
could O
become O
a O
novel O
strategy O
for O
the O
development O
of O
neuroprotective O
therapeutics O
in O
neurodegenerative O
disorders O
. O

Structure O
of O
dipeptides B
having O
N B
- O
terminal O
selenocysteine B
residues O
: O
a O
DFT O
study O
in O
gas O
and O
aqueous O
phase O
. O

Over O
the O
last O
few O
decades O
, O
dipeptides B
as O
well O
as O
their O
analogues O
have O
served O
as O
important O
model O
systems O
for O
the O
computational O
studies O
concerning O
the O
structure O
of O
protein O
and O
energetics O
of O
protein O
folding O
. O

Here O
, O
we O
present O
a O
density O
functional O
structural O
study O
on O
a O
set O
of O
seven O
dipeptides B
having O
N B
- O
terminal O
selenocysteine B
residues O
( O
the O
component O
in O
the O
C B
- O
terminus O
is O
varied O
with O
seven O
different O
combinations O
viz O
. O
Ala B
, O
Phe B
, O
Glu B
, O
Thr B
, O
Asn B
, O
Arg B
and O
Sec B
) O
in O
gas O
and O
simulated O
aqueous O
phase O
using O
a O
polarizable O
continuum O
model O
( O
PCM O
) O
. O

The O
molecular O
geometries O
of O
the O
dipeptides B
are O
fully O
optimized O
at O
B3LYP O
/ O
6 O
- O
311 O
+ O
+ O
G O
( O
d O
, O
p O
) O
level O
and O
subsequent O
frequency O
calculations O
confirm O
them O
as O
true O
minima O
. O

The O
effects O
of O
solvation O
and O
identity O
of O
the O
varying O
C B
- O
terminal O
residue O
on O
the O
energetics O
, O
structural O
features O
of O
the O
peptide O
planes O
, O
values O
of O
the O
psi O
and O
phi O
dihedrals O
, O
geometry O
around O
the O
alpha B
- I
carbon I
atoms O
and O
theoretically O
predicted O
vibrational O
spectra O
of O
the O
dipeptides B
are O
investigated O
. O

Two O
types O
of O
intramolecular O
H B
- O
bonds O
, O
namely O
N B
. O
. O
. O
H B
- I
N I
and O
O B
. O
. O
. O
H B
- I
C I
, O
are O
found O
to O
play O
important O
roles O
in O
influencing O
the O
planarity O
of O
the O
peptide O
planes O
and O
geometry O
around O
the O
alpha B
- I
carbon I
atoms O
of O
the O
dipeptides B
. O

The O
identity O
of O
the O
varying O
C B
- O
terminal O
residue O
influences O
the O
values O
of O
phi O
, O
planarity O
of O
the O
peptide O
planes O
and O
geometry O
around O
the O
C7 B
alpha I
- I
carbon I
atoms O
while O
the O
solvation O
effects O
are O
evident O
on O
the O
values O
of O
bond O
lengths O
and O
bond O
angles O
of O
the O
amide B
planes O
. O

The O
Role O
of O
Traditional O
Chinese O
Medicines O
in O
Osteogenesis O
and O
Angiogenesis O
. O

The O
article O
aims O
to O
review O
various O
Traditional O
Chinese O
Medicines O
( O
TCMs O
) O
with O
both O
osteogenic O
and O
angiogenic O
effects O
, O
alone O
and O
in O
combination O
, O
and O
to O
consider O
whether O
these O
TCMs O
promote O
osteogenesis O
via O
angiogenesis O
and O
vascular O
endothelial O
growth O
factor O
( O
VEGF O
) O
. O

Each O
of O
the O
TCMs O
involving O
in O
osteogenesis O
was O
searched O
through O
PubMed O
and O
CBMdisc O
using O
its O
Latin O
name O
and O
English O
name O
, O
and O
keywords O
such O
as O
' O
osteogenesis O
' O
, O
' O
bone O
' O
, O
' O
osteoblast O
' O
, O
' O
angiogenesis O
' O
, O
' O
VEGF O
' O
were O
used O
. O

A O
total O
of O
241 O
articles O
were O
screened O
from O
PubMed O
and O
CBMdisc O
. O

The O
articles O
were O
only O
chosen O
if O
they O
discussed O
the O
relationship O
of O
the O
TCMs O
with O
bone O
formation O
and O
/ O
or O
angiogenesis O
. O

Twenty O
- O
seven O
articles O
were O
chosen O
, O
of O
which O
16 O
were O
in O
English O
and O
11 O
were O
in O
Chinese O
with O
English O
abstract O
. O

As O
a O
result O
, O
the O
TCMs O
( O
Danshen O
or O
Salvia O
miltiorrhiza O
Bunge O
, O
Danggui O
or O
Angelica O
sinensis O
, O
Astragalus O
membranaceus O
Bunge O
or O
Huangqi O
, O
and O
Ge O
Gan O
or O
Puerarin B
radix O
) O
that O
have O
a O
relationship O
with O
both O
osteogenesis O
and O
angiogenesis O
were O
screened O
out O
. O

It O
is O
found O
that O
the O
aforementioned O
TCMs O
enhance O
angiogenesis O
and O
osteogenesis O
. O

They O
show O
a O
positive O
effect O
on O
bone O
formation O
, O
and O
the O
possible O
mechanisms O
may O
be O
related O
to O
their O
ability O
to O
promote O
angiogenesis O
via O
an O
effect O
on O
substances O
such O
as O
VEGF O
. O

Copyright O
( O
c O
) O
2013 O
John O
Wiley O
& O
Sons O
, O
Ltd O
. O

Nickel B
sulfide I
/ O
nitrogen B
- O
doped O
graphene B
composites O
: O
phase O
- O
controlled O
synthesis O
and O
high O
performance O
anode O
materials O
for O
lithium B
ion O
batteries O
. O

Phase O
- O
controlled O
nickel B
sulfide I
( O
Ni3 B
S4 I
and O
NiS1 B
. I
03 I
) O
nanoparticle O
( O
NP O
) O
/ O
nitrogen B
- O
doped O
graphene B
( O
NG O
) O
composites O
are O
prepared O
through O
a O
facile O
one O
- O
pot O
hydrothermal O
process O
. O

The O
composites O
show O
ultrahigh O
capacity O
retentions O
of O
98 O
. O
87 O
% O
and O
95 O
. O
94 O
% O
for O
Ni3 B
S4 I
/ O
NG O
and O
NiS1 B
. I
03 I
/ O
NG O
electrodes O
, O
respectively O
, O
as O
anode O
materials O
for O
lithium B
ion O
batteries O
. O

( B
1 I
) I
H I
and O
( B
13 I
) I
C I
NMR O
analysis O
of O
2 B
- I
acetamido I
- I
3 I
- I
mercapto I
- I
3 I
- I
methyl I
- I
N I
- I
aryl I
- I
butanamides I
and O
2 B
- I
acetamido I
- I
3 I
- I
methyl I
- I
3 I
- I
nitrososulfanyl I
- I
N I
- I
aryl I
- I
butanamide I
derivatives O
. O

The O
complete O
assignment O
of O
the O
( B
1 I
) I
H I
and O
( B
13 I
) I
C I
NMR O
spectra O
of O
various O
2 B
- I
acetamido I
- I
3 I
- I
mercapto I
- I
3 I
- I
methyl I
- I
N I
- I
aryl I
- I
butanamides I
and O
2 B
- I
acetamide I
- I
3 I
- I
methyl I
- I
3 I
- I
nitrososulfanyl I
- I
N I
- I
aryl I
- I
butanamides I
with O
p B
- I
methoxy I
, O
o B
- I
chloro I
and O
m B
- I
chloro I
substituents O
is O
reported O
. O

Copyright O
( O
c O
) O
2013 O
John O
Wiley O
& O
Sons O
, O
Ltd O
. O

Targeting O
protein O
- O
protein O
interactions O
within O
the O
cyclic B
AMP I
signaling O
system O
as O
a O
therapeutic O
strategy O
for O
cardiovascular O
disease O
. O

The O
cAMP B
signaling O
system O
can O
trigger O
precise O
physiological O
cellular O
responses O
that O
depend O
on O
the O
fidelity O
of O
many O
protein O
- O
protein O
interactions O
, O
which O
act O
to O
bring O
together O
signaling O
intermediates O
at O
defined O
locations O
within O
cells O
. O

In O
the O
heart O
, O
cAMP B
participates O
in O
the O
fine O
control O
of O
excitation O
- O
contraction O
coupling O
, O
hence O
, O
any O
disregulation O
of O
this O
signaling O
cascade O
can O
lead O
to O
cardiac O
disease O
. O

Due O
to O
the O
ubiquitous O
nature O
of O
the O
cAMP B
pathway O
, O
general O
inhibitors O
of O
cAMP B
signaling O
proteins O
such O
as O
PKA O
, O
EPAC O
and O
PDEs O
would O
act O
non O
- O
specifically O
and O
universally O
, O
increasing O
the O
likelihood O
of O
serious O
' O
off O
target O
' O
effects O
. O

Recent O
advances O
in O
the O
discovery O
of O
peptides O
and O
small O
molecules O
that O
disrupt O
the O
protein O
- O
protein O
interactions O
that O
underpin O
cellular O
targeting O
of O
cAMP B
signaling O
proteins O
are O
described O
and O
discussed O
. O

Identification O
of O
Transglutaminase O
Substrates O
from O
Porcine O
Nucleus O
Pulposus O
as O
Potential O
Amplifiers O
in O
Cross O
- O
Linking O
Cell O
Scaffolds O
. O

Nucleus O
pulposus O
from O
the O
porcine O
intervertebral O
disc O
was O
separated O
chromatographically O
to O
discover O
substrates O
of O
microbial O
transglutaminase O
. O

Highly O
purified O
proteins O
were O
prepared O
, O
among O
them O
type O
II O
collagen O
, O
the O
major O
protein O
of O
the O
nucleus O
pulposus O
. O

Determination O
of O
substrates O
was O
performed O
by O
transglutaminase O
- O
mediated O
incorporation O
of O
biotinylated O
probes O
displaying O
several O
glutamine B
and O
lysine B
donor O
proteins O
. O

Type O
II O
collagen O
was O
only O
labeled O
if O
smaller O
nucleus O
pulposus O
proteins O
were O
present O
. O

One O
of O
the O
modulating O
proteins O
was O
serotransferrin O
, O
a O
lysine B
donor O
substrate O
of O
bacterial O
transglutaminase O
. O

An O
additional O
substrate O
was O
the O
carboxy B
- O
terminal O
propeptide O
of O
type O
II O
collagen O
, O
chondrocalcin O
. O

Chondrocalcin O
, O
a O
regulator O
of O
type O
II O
collagen O
fibrillogenesis O
, O
occurs O
abundantly O
in O
juvenile O
cartilage O
and O
nucleus O
pulposus O
. O

Accordingly O
, O
the O
protein O
may O
be O
regarded O
as O
an O
excellent O
additive O
for O
the O
preparation O
of O
injectable O
stem O
cells O
in O
nucleus O
pulposus O
- O
like O
matrices O
cross O
- O
linked O
by O
microbial O
transglutaminase O
. O

From O
synaptic O
spines O
to O
nuclear O
signaling O
: O
nuclear O
and O
synaptic O
actions O
of O
the O
amyloid O
precursor O
protein O
. O

Despite O
intensive O
studies O
of O
the O
secretase O
- O
mediated O
processing O
of O
the O
amyloid O
precursor O
protein O
( O
APP O
) O
to O
form O
the O
amyloid O
beta O
- O
peptide O
( O
A O
beta O
) O
, O
in O
relation O
to O
Alzheimer O
' O
s O
disease O
( O
AD O
) O
, O
no O
new O
therapeutic O
agents O
have O
reached O
the O
clinics O
based O
on O
reducing O
A O
beta O
levels O
through O
the O
use O
of O
secretase O
inhibitors O
or O
immunotherapy O
. O

Furthermore O
, O
the O
normal O
neuronal O
functions O
of O
APP O
and O
its O
various O
metabolites O
still O
remain O
under O
- O
investigated O
and O
unclear O
. O

Here O
, O
we O
highlight O
emerging O
areas O
of O
APP O
function O
that O
may O
provide O
new O
insights O
into O
synaptic O
development O
, O
cognition O
, O
and O
gene O
regulation O
. O

By O
modulating O
expression O
levels O
of O
endogenous O
APP O
in O
primary O
cortical O
neurons O
, O
the O
frequency O
and O
amplitude O
of O
calcium B
oscillations O
is O
modified O
, O
implying O
a O
key O
role O
for O
APP O
in O
maintaining O
neuronal O
calcium B
homeostasis O
essential O
for O
synaptic O
transmission O
. O

Disruption O
of O
this O
homeostatic O
mechanism O
predisposes O
to O
aging O
and O
AD O
. O

Synaptic O
spine O
loss O
is O
a O
feature O
of O
neurogeneration O
resulting O
in O
learning O
and O
memory O
deficits O
, O
and O
emerging O
evidence O
indicates O
a O
role O
for O
APP O
, O
probably O
mediated O
via O
one O
or O
more O
of O
its O
metabolites O
, O
in O
spine O
structure O
and O
functions O
. O

The O
intracellular O
domain O
of O
APP O
( O
AICD O
) O
has O
also O
emerged O
as O
a O
key O
epigenetic O
regulator O
of O
gene O
expression O
controlling O
a O
diverse O
range O
of O
genes O
, O
including O
APP O
itself O
, O
the O
amyloid O
- O
degrading O
enzyme O
neprilysin O
, O
and O
aquaporin O
- O
1 O
. O

A O
fuller O
understanding O
of O
the O
physiological O
and O
pathological O
actions O
of O
APP O
and O
its O
metabolic O
network O
could O
provide O
new O
opportunities O
for O
therapeutic O
intervention O
in O
AD O
. O

The O
effect O
of O
rituximab O
on O
thyroid O
function O
and O
autoimmunity O
. O

no O
abstract O
required O
. O

Pyridone B
Alkaloids I
from O
a O
Marine O
- O
Derived O
Fungus O
, O
Stagonosporopsis O
cucurbitacearum O
, O
and O
Their O
Activities O
against O
Azole B
- O
Resistant O
Candida O
albicans O
. O

Four O
new O
4 B
- I
hydroxy I
- I
2 I
- I
pyridone I
alkaloids I
, O
didymellamides B
A I
- I
D I
( O
1 O
- O
4 O
) O
, O
were O
isolated O
from O
the O
marine O
- O
derived O
fungus O
Stagonosporopsis O
cucurbitacearum O
. O

The O
structures O
of O
1 O
- O
4 O
were O
elucidated O
from O
spectroscopic O
data O
( O
NMR O
, O
MS O
, O
and O
IR O
) O
, O
and O
the O
absolute O
configuration O
of O
1 O
was O
determined O
by O
X O
- O
ray O
diffraction O
analysis O
. O

Didymellamide B
A I
( O
1 O
) O
exhibited O
antifungal O
activity O
against O
azole B
- O
resistant O
Candida O
albicans O
. O

Chemical O
composition O
and O
antioxidant O
activity O
of O
dried O
powder O
formulations O
of O
Agaricus O
blazei O
and O
Lentinus O
edodes O
. O

Several O
mushroom O
species O
have O
been O
pointed O
out O
as O
sources O
of O
antioxidant O
compounds O
, O
in O
addition O
to O
their O
important O
nutritional O
value O
. O

Agaricus O
blazei O
and O
Lentinus O
edodes O
are O
among O
the O
most O
studied O
species O
all O
over O
the O
world O
, O
but O
those O
studies O
focused O
on O
their O
fruiting O
bodies O
instead O
of O
other O
presentations O
, O
such O
as O
powdered O
preparations O
, O
used O
as O
supplements O
. O

In O
the O
present O
work O
the O
chemical O
composition O
( O
nutrients O
and O
bioactive O
compounds O
) O
and O
antioxidant O
activity O
( O
free O
radical O
scavenging O
activity O
, O
reducing O
power O
and O
lipid O
peroxidation O
inhibition O
) O
of O
dried O
powder O
formulations O
of O
the O
mentioned O
mushroom O
species O
( O
APF O
and O
LPF O
, O
respectively O
) O
were O
evaluated O
. O

Powder O
formulations O
of O
both O
species O
revealed O
the O
presence O
of O
essential O
nutrients O
, O
such O
as O
proteins O
, O
carbohydrates B
and O
unsaturated B
fatty I
acids I
. O

Furthermore O
, O
they O
present O
a O
low O
fat O
content O
( O
< O
2g O
/ O
100g O
) O
and O
can O
be O
used O
in O
low O
- O
calorie O
diets O
, O
just O
like O
the O
mushrooms O
fruiting O
bodies O
. O

APF O
showed O
higher O
antioxidant O
activity O
and O
higher O
content O
of O
tocopherols B
and O
phenolic B
compounds O
( O
124 O
and O
770 O
mu O
g O
/ O
100g O
, O
respectively O
) O
than O
LPF O
( O
32 O
and O
690 O
mu O
g O
/ O
100g O
) O
. O

Both O
formulations O
could O
be O
used O
as O
antioxidant O
sources O
to O
prevent O
diseases O
related O
to O
oxidative O
stress O
. O

The O
antioxidants O
in O
oils O
heated O
at O
frying O
temperature O
, O
whether O
natural O
or O
added O
, O
could O
protect O
against O
postprandial O
oxidative O
stress O
in O
obese O
people O
. O

We O
have O
investigated O
the O
effects O
of O
the O
intake O
of O
oils O
heated O
at O
frying O
temperature O
in O
order O
to O
find O
an O
oil O
model O
for O
deep O
- O
frying O
that O
prevents O
postprandial O
oxidative O
stress O
. O

Twenty O
obese O
people O
received O
four O
breakfasts O
following O
a O
randomised O
crossover O
design O
consisting O
of O
different O
oils O
( O
virgin O
olive O
oil O
( O
VOO O
) O
, O
sunflower O
oil O
( O
SFO O
) O
, O
and O
a O
mixed O
seed O
oil O
( O
SFO O
/ O
canola O
oil O
) O
with O
added O
dimethylpolysiloxane B
( O
SOX O
) O
or O
natural O
antioxidants O
from O
olives O
( O
SOP O
) O
) O
, O
which O
were O
subjected O
to O
20 O
heating O
cycles O
. O

The O
intake O
of O
SFO B
- O
breakfast O
reduced O
plasma O
GSH B
levels O
and O
the O
GSH B
/ O
GSSG B
ratio O
, O
increased O
protein O
carbonyl B
levels O
, O
and O
induced O
a O
higher O
gene O
expression O
of O
the O
different O
NADPH B
- O
oxidase O
subunits O
, O
Nrf2 O
- O
Keap1 O
activation O
, O
gene O
expression O
of O
the O
antioxidant O
enzymes O
in O
peripheral O
blood O
mononuclear O
cells O
and O
antioxidant O
plasma O
activities O
than O
the O
intake O
of O
the O
breakfasts O
prepared O
with O
VOO O
, O
SOP O
and O
SOX O
. O

Oils O
with O
phenolic B
compounds O
, O
whether O
natural O
( O
VOO O
) O
or O
artificially O
added O
( O
SOP O
) O
, O
or O
with O
artificial O
antioxidant O
( O
SOX O
) O
, O
could O
reduce O
postprandial O
oxidative O
stress O
compared O
with O
sunflower O
oil O
. O

Rapid O
monitoring O
of O
heat O
- O
accelerated O
reactions O
in O
vegetable O
oils O
using O
direct O
analysis O
in O
real O
time O
ionization O
coupled O
with O
high O
resolution O
mass O
spectrometry O
. O

Transmission O
- O
mode O
direct O
analysis O
in O
real O
time O
ionization O
coupled O
with O
high O
resolution O
mass O
spectrometry O
( O
TM O
- O
DART O
- O
HRMS O
) O
was O
used O
to O
monitor O
chemical O
changes O
in O
various O
vegetable O
oils O
( O
olive O
, O
rapeseed O
, O
soybean O
and O
sunflower O
oil O
) O
during O
their O
thermally O
- O
induced O
oxidation O
. O

This O
novel O
instrumental O
approach O
enabled O
rapid O
fingerprinting O
of O
examined O
samples O
and O
detection O
of O
numerous O
sample O
components O
, O
such O
as O
triacylglycerols B
( O
TAGs B
) O
, O
phytosterols B
, O
free O
fatty B
acids I
( O
FFA O
) O
, O
and O
their O
respective O
oxidation O
products O
. O

Mass O
spectra O
obtained O
from O
DART O
were O
processed O
with O
the O
use O
of O
principal O
component O
analysis O
( O
PCA O
) O
in O
order O
to O
assess O
the O
compositional O
differences O
between O
heated O
and O
non O
- O
heated O
samples O
. O

Good O
correlation O
was O
observed O
between O
the O
normalized O
intensities O
of O
the O
pre O
- O
selected O
ion O
corresponding O
to O
mono O
- O
oxidized O
TAG B
and O
' O
classic O
' O
criterion O
represented O
by O
the O
levels O
of O
TAG B
polymers O
determined O
by O
high O
performance O
- O
size O
exclusion O
chromatography O
with O
refractometric O
detection O
( O
HP O
- O
SEC O
- O
RID O
) O
. O

Calcium B
hydroxy I
palmitate I
: O
possible O
precursor O
phase O
in O
calcium B
precipitation O
by O
palmitate B
. O

Calcium B
( I
II I
) I
precipitates O
with O
palmitate B
( O
Pal B
( I
- I
) I
) O
, O
a O
process O
affecting O
calcium B
absorption O
in O
the O
gut O
, O
in O
a O
first O
- O
order O
reaction O
, O
as O
followed O
by O
a O
calcium B
electrode O
in O
neutral O
aqueous O
solution O
for O
excess O
of O
calcium B
( I
II I
) I
, O
with O
a O
rate O
constant O
showing O
a O
minimum O
at O
physiological O
ionic O
strength O
of O
0 O
. O
32 O
+ O
/ O
- O
0 O
. O
09 O
d O
( O
- O
1 O
) O
at O
25 O
degrees O
C O
with O
a O
stoichiometry O
of O
1 O
. O
79 O
+ O
/ O
- O
0 O
. O
03 O
, O
lower O
than O
the O
expected O
1 O
: O
2 O
. O

During O
ageing O
of O
precipitate O
, O
pH O
increases O
in O
the O
supernatant O
, O
while O
pH O
decreases O
for O
precipitation O
with O
excess O
of O
palmitate B
. O

Increasing O
pH O
, O
as O
in O
some O
aged O
food O
products O
, O
decreases O
the O
solubility O
, O
and O
Ksp O
( O
' O
) O
= O
[ B
Ca I
( I
2 I
+ I
) I
] I
[ I
Pal I
( I
- I
) I
] I
[ I
OH I
( I
- I
) I
] I
is O
found O
constant O
rather O
than O
Ksp O
= O
[ B
Ca I
( I
2 I
+ I
) I
] I
[ I
Pal I
( I
- I
) I
] I
( I
2 I
) I
in O
agreement O
with O
an O
initial O
precipitation O
of O
Ca B
( I
OH I
) I
( O
Pal B
) O
, O
which O
slowly O
may O
convert O
into O
Ca B
( I
Pal I
) I
2 I
. O
Ca B
( I
OH I
) I
( O
Pal B
) O
has O
a O
solubility O
minimum O
at O
physiological O
ionic O
strength O
with O
Ksp O
( O

' O
) O
= O
( O
1 O
. O
4 O
+ O
/ O
- O
0 O
. O
4 O
) O
10 O
( O
- O
16 O
) O
M O
( O
3 O
) O
. O

X O
- O
ray O
diffraction O
showed O
a O
d O
- O
spacing O
of O
44 O
. O
15 O
A O
( O
different O
from O
45 O
. O
2 O
A O
reported O
for O
Ca B
( I
Pal I
) I
2 I
) O
, O
and O
infrared O
spectroscopy O
confirmed O
the O
presence O
of O
a O
hydroxy B
group O
. O

Sensory O
quality O
and O
compositional O
characteristics O
of O
blackcurrant O
juices O
produced O
by O
different O
processes O
. O

Effects O
of O
enzymatic O
and O
non O
- O
enzymatic O
juice O
pressing O
on O
key O
orosensory O
and O
chemical O
quality O
factors O
of O
blackcurrant O
juices O
were O
studied O
in O
laboratory O
scale O
using O
berries O
of O
five O
different O
cultivars O
( O
Mortti O
, O
Mikael O
, O
Marski O
, O
Ola O
and O
Breed15 O
) O
. O

Enzymatic O
processing O
increased O
the O
juice O
yield O
by O
10 O
- O
22 O
% O
and O
the O
content O
of O
various O
phenolic B
compounds O
in O
juice O
by O
4 O
- O
10 O
- O
fold O
as O
compared O
to O
the O
non O
- O
enzymatic O
process O
. O

Higher O
intensity O
of O
the O
mouth O
- O
drying O
astringency O
of O
the O
enzyme O
- O
aided O
juice O
was O
the O
most O
significant O
orosensory O
difference O
between O
the O
processes O
. O

Juices O
of O
different O
blackcurrant O
cultivars O
varied O
in O
sweetness O
, O
sourness O
and O
bitterness O
. O

The O
most O
intensive O
sensory O
attributes O
of O
the O
juices O
were O
sourness O
and O
puckering O
astringency O
regardless O
of O
processing O
method O
. O

They O
correlated O
positively O
with O
each O
other O
and O
were O
contributed O
by O
acid O
content O
and O
pH O
. O

In O
enzyme O
- O
aided O
juices O
, O
the O
contents O
of O
flavonol B
glycosides I
and O
hydroxycinnamic B
acids I
were O
associated O
with O
mouth O
- O
drying O
astringency O
, O
and O
sugar B
/ O
acid O
ratio O
correlated O
with O
sweetness O
. O

These O
correlations O
were O
less O
clear O
in O
non O
- O
enzyme O
juices O
possibly O
due O
to O
lower O
content O
of O
phenolic B
compounds O
and O
the O
high O
content O
of O
pectin O
. O

Nuclear O
positioning O
. O

The O
nucleus O
is O
the O
largest O
organelle O
and O
is O
commonly O
depicted O
in O
the O
center O
of O
the O
cell O
. O

Yet O
during O
cell O
division O
, O
migration O
, O
and O
differentiation O
, O
it O
frequently O
moves O
to O
an O
asymmetric O
position O
aligned O
with O
cell O
function O
. O

We O
consider O
the O
toolbox O
of O
proteins O
that O
move O
and O
anchor O
the O
nucleus O
within O
the O
cell O
and O
how O
forces O
generated O
by O
the O
cytoskeleton O
are O
coupled O
to O
the O
nucleus O
to O
move O
it O
. O

The O
significance O
of O
proper O
nuclear O
positioning O
is O
underscored O
by O
numerous O
diseases O
resulting O
from O
genetic O
alterations O
in O
the O
toolbox O
proteins O
. O

Finally O
, O
we O
discuss O
how O
nuclear O
position O
may O
influence O
cellular O
organization O
and O
signaling O
pathways O
. O

Antibodies O
targeting O
extracellular O
domain O
of O
connexins O
for O
studies O
of O
hemichannels O
. O

Hemichannels O
are O
transmembrane O
channels O
composed O
of O
either O
a O
connexin O
or O
pannexin O
hexamer O
. O

The O
docking O
of O
the O
extracellular O
domains O
of O
connexin O
hemichannels O
contributed O
by O
neighboring O
cells O
forms O
a O
gap O
junction O
channel O
that O
joins O
the O
cytoplasm O
of O
adjacent O
cells O
. O

Connexins O
are O
expressed O
ubiquitously O
in O
different O
organs O
, O
but O
some O
subtypes O
are O
expressed O
exclusively O
in O
certain O
tissues O
and O
tumors O
. O

Both O
gap O
junction O
channels O
and O
hemichannels O
participate O
in O
diverse O
physiological O
and O
pathological O
responses O
. O

However O
, O
the O
lack O
of O
specific O
reagents O
that O
inhibit O
only O
gap O
junction O
channels O
or O
hemichannels O
is O
a O
challenge O
that O
makes O
it O
different O
to O
discern O
the O
specific O
roles O
of O
either O
channel O
. O

Fortunately O
, O
the O
available O
information O
regarding O
the O
connexin O
sequence O
, O
secondary O
and O
tertiary O
structure O
, O
and O
their O
biochemical O
and O
physiological O
properties O
permits O
the O
development O
of O
strategies O
to O
block O
exclusively O
the O
hemichannel O
activity O
exclusively O
, O
with O
no O
effect O
on O
gap O
junction O
activity O
. O

This O
task O
is O
accomplished O
through O
the O
use O
of O
specifics O
antibodies O
that O
target O
the O
extracellular O
sites O
of O
desired O
connexin O
subtype O
. O

However O
, O
the O
underlying O
mechanism O
of O
how O
antibodies O
targeting O
extracellular O
connexin O
epitopes O
actually O
inhibit O
hemichannels O
remains O
unknown O
. O

Although O
these O
antibodies O
are O
being O
used O
for O
detecting O
and O
blocking O
of O
hemichannels O
in O
normal O
and O
tumor O
cells O
, O
they O
can O
also O
be O
potentially O
used O
for O
tissue O
- O
specific O
treatment O
and O
drug O
delivery O
in O
clinical O
applications O
. O

In O
this O
article O
, O
we O
will O
first O
review O
the O
literature O
concerning O
the O
structure O
of O
connexins O
and O
the O
unique O
properties O
of O
extracellular O
loop O
domains O
of O
the O
connexins O
. O

Furthermore O
, O
we O
will O
discuss O
briefly O
the O
development O
of O
connexin O
( O
Cx O
) O
43 O
( O
E2 O
) O
antibody O
, O
a O
specific O
antibody O
which O
detects O
the O
second O
extracellular O
loop O
of O
Cx43 O
and O
specifically O
prevents O
the O
opening O
of O
Cx43 O
hemichannels O
. O

We O
will O
then O
summarize O
the O
reported O
studies O
of O
specific O
reagents O
used O
for O
the O
inhibition O
of O
connexin O
hemichannels O
including O
antibodies O
developed O
against O
extracellular O
loop O
domains O
. O

This O
article O
is O
part O
of O
a O
Special O
Issue O
entitled O
' O
Connexin O
based O
channels O
' O
. O

Identification O
of O
pyrrolo B
[ I
2 I
, I
3 I
- I
g I
] I
indazoles I
as O
new O
Pim O
kinase O
inhibitors O
. O

The O
synthesis O
and O
Pim O
kinase O
inhibition O
potency O
of O
a O
new O
series O
of O
pyrrolo B
[ I
2 I
, I
3 I
- I
g I
] I
indazole I
derivatives O
is O
described O
. O

The O
results O
obtained O
in O
this O
preliminary O
structure O
- O
activity O
relationship O
study O
pointed O
out O
that O
sub O
- O
micromolar O
Pim O
- O
1 O
and O
Pim O
- O
3 O
inhibitory O
potencies O
could O
be O
obtained O
in O
this O
series O
, O
more O
particularly O
for O
compounds O
10 O
and O
20 O
, O
showing O
that O
pyrrolo B
[ I
2 I
, I
3 I
- I
g I
] I
indazole I
scaffold O
could O
be O
used O
for O
the O
development O
of O
new O
potent O
Pim O
kinase O
inhibitors O
. O

Molecular O
modeling O
experiments O
were O
also O
performed O
to O
study O
the O
binding O
mode O
of O
these O
compounds O
in O
Pim O
- O
3 O
ATP B
- O
binding O
pocket O
. O

The O
bizarre O
pharmacology O
of O
the O
ATP B
release O
channel O
pannexin1 O
. O

Pannexins O
were O
originally O
thought O
to O
represent O
a O
second O
and O
redundant O
family O
of O
gap O
junction O
proteins O
in O
addition O
to O
the O
well O
characterized O
connexins O
. O

However O
, O
it O
is O
now O
evident O
that O
pannexins O
function O
as O
unapposed O
membrane O
channels O
and O
the O
major O
role O
of O
Panx1 O
is O
that O
of O
an O
ATP B
release O
channel O
. O

Despite O
the O
contrasting O
functional O
roles O
, O
connexins O
, O
innexins O
and O
pannexins O
share O
pharmacological O
properties O
. O

Most O
gap O
junction O
blockers O
also O
attenuate O
the O
function O
of O
Panx1 O
, O
including O
carbenoxolone B
, O
mefloquine B
and O
flufenamic B
acid I
. O

However O
, O
in O
contrast O
to O
connexin O
based O
gap O
junction O
channels O
, O
Panx1 O
channel O
activity O
can O
be O
attenuated O
by O
several O
groups O
of O
drugs O
hitherto O
considered O
very O
specific O
for O
other O
proteins O
. O

The O
drugs O
affecting O
Panx1 O
channels O
include O
several O
transport O
inhibitors O
, O
chloride B
channel O
blockers O
, O
mitochondrial O
inhibitors O
, O
P2X7 O
receptor O
ligands O
, O
inflammasome O
inhibitors O
and O
malaria O
drugs O
. O

These O
observations O
indicate O
that O
Panx1 O
may O
play O
an O
extended O
role O
in O
a O
wider O
spectrum O
of O
physiological O
functions O
. O

Alternatively O
, O
Panx1 O
may O
share O
structural O
domains O
with O
other O
proteins O
, O
not O
readily O
revealed O
by O
sequence O
alignments O
. O

This O
article O
is O
part O
of O
a O
Special O
Issue O
entitled O
' O
Connexin O
based O
channels O
' O

Angiotensin O
- O
( O
1 O
- O
7 O
) O
inhibits O
autophagy O
in O
the O
brain O
of O
spontaneously O
hypertensive O
rats O
. O

Autophagy O
is O
an O
important O
cellular O
process O
that O
mediates O
lysosomal O
degradation O
of O
damaged O
organelles O
, O
which O
is O
activated O
in O
response O
to O
a O
variety O
of O
stress O
- O
related O
diseases O
, O
including O
hypertension O
. O

The O
basal O
level O
of O
autophagy O
plays O
an O
important O
role O
in O
the O
maintenance O
of O
cellular O
homeostasis O
, O
whereas O
excessive O
autophagic O
activity O
leads O
to O
cell O
death O
and O
is O
considered O
as O
a O
contributing O
factor O
to O
several O
disorders O
. O

Recent O
works O
have O
demonstrated O
that O
Angiotensin O
- O
( O
1 O
- O
7 O
) O
[ O
Ang O
- O
( O
1 O
- O
7 O
) O
] O
exerted O
its O
neuroprotective O
effects O
by O
modulating O
classic O
components O
of O
renin O
- O
angiotensin O
system O
associated O
with O
reducing O
oxidative O
stress O
and O
apoptosis O
in O
brains O
of O
spontaneously O
hypertensive O
rats O
( O
SHRs O
) O
. O

However O
, O
the O
effect O
of O
Ang O
- O
( O
1 O
- O
7 O
) O
on O
autophagic O
activity O
in O
brain O
of O
hypertensive O
individual O
remains O
unclear O
. O

In O
this O
study O
, O
Wistar O
- O
Kyoto O
rats O
received O
intracerebroventricu O
( O
I O
. O
C O
. O
V O
. O
) O
infusion O
of O
artificial O
cerebrospinal O
fluid O
( O
aCSF O
) O
while O
SHRs O
received O
I O
. O
C O
. O
V O
. O
infusion O
of O
aCSF B
, O
Ang O
- O
( O
1 O
- O
7 O
) O
, O
Mas O
receptor O
antagonist O
A B
- I
779 I
, O
or O
angiotensin O
II O
type O
2 O
receptor O
antagonist O
PD123319 B
for O
4 O
weeks O
. O

Brain O
tissues O
were O
collected O
and O
analyzed O
by O
western O
blotting O
analysis O
, O
immunofluorescence O
assay O
, O
and O
transmission O
electron O
microscopic O
examination O
. O

Our O
study O
showed O
that O
infusion O
of O
Ang O
- O
( O
1 O
- O
7 O
) O
for O
4 O
weeks O
inhibited O
the O
increase O
of O
microtubule O
- O
associated O
protein O
1 O
light O
chain O
3 O
( O
LC3 O
) O
- O
II O
and O
Beclin O
- O
1 O
levels O
, O
as O
well O
as O
the O
autophagosome O
formation O
in O
SHR O
brain O
. O

Meanwhile O
, O
the O
reduction O
of O
p62 O
expression O
in O
SHR O
brain O
was O
also O
reversed O
by O
Ang O
- O
( O
1 O
- O
7 O
) O
. O

Of O
note O
, O
the O
anti O
- O
autophagic O
effects O
of O
Ang O
- O
( O
1 O
- O
7 O
) O
were O
independent O
of O
blood O
pressure O
reduction O
and O
can O
be O
inhibited O
by O
A B
- I
779 I
and O
PD123319 B
. O

These O
findings O
suggest O
that O
treatment O
with O
Ang O
- O
( O
1 O
- O
7 O
) O
may O
be O
useful O
to O
prevent O
hypertension O
- O
induced O
excessive O
autophagic O
activation O
in O
brain O
. O

Steroidal B
glycosides I
from O
the O
bulbs O
of O
Fritillaria O
meleagris O
and O
their O
cytotoxic O
activities O
. O

Steroidal B
glycosides I
( O
1 O
- O
18 O
) O
, O
including O
10 O
new O
compounds O
( O
1 O
- O
10 O
) O
, O
were O
isolated O
from O
the O
bulbs O
of O
Fritillaria O
meleagris O
( O
Liliaceae O
) O
. O

The O
structures O
of O
the O
new O
compounds O
were O
determined O
by O
two O
- O
dimensional O
( O
2D O
) O
NMR O
analysis O
, O
and O
by O
hydrolytic O
cleavage O
followed O
by O
spectroscopic O
and O
chromatographic O
analysis O
. O

The O
isolated O
compounds O
and O
their O
aglycones O
were O
evaluated O
for O
cytotoxic O
activity O
against O
HL O
- O
60 O
human O
promyelocytic O
leukemia O
cells O
and O
A549 O
human O
lung O
adenocarcinoma O
cells O
. O

Morphological O
observation O
and O
flow O
cytometry O
analysis O
showed O
that O
5 B
beta I
- I
spirostanol I
glycoside I
( O
2 O
) O
and O
a O
cholestane B
derivative O
( O
17a O
) O
induced O
apoptotic O
cell O
death O
in O
HL O
- O
60 O
cells O
through O
different O
mechanisms O
of O
action O
. O

Furthermore O
, O
the O
( B
22R I
) I
- I
spirosolanol I
glycoside I
( O
11 O
) O
selectively O
induced O
apoptosis O
in O
A549 O
cells O
without O
affecting O
the O
caspase O
- O
3 O
activity O
level O
. O

Arrhythmogenic O
effect O
of O
a O
crude O
extract O
from O
sea O
anemone O
Condylactis O
gigantea O
: O
Possible O
involvement O
of O
rErg1 O
channels O
. O

Sea O
anemones O
possess O
a O
number O
of O
peptide O
toxins O
that O
target O
ion O
channels O
which O
provide O
powerful O
tools O
to O
study O
the O
molecular O
basis O
of O
diverse O
signaling O
pathways O
. O

It O
is O
also O
acknowledged O
that O
currents O
through O
Erg1 O
K B
( I
+ I
) I
channels O
in O
cardiac O
myocytes O
are O
important O
for O
electrical O
stability O
of O
the O
heart O
and O
alterations O
in O
its O
activity O
has O
been O
linked O
to O
the O
onset O
of O
a O
potentially O
life O
- O
threatening O
heart O
condition O
named O
long O
QT O
syndrome O
type O
2 O
. O

Here O
, O
we O
report O
that O
a O
crude O
extract O
from O
sea O
anemone O
Condylactis O
gigantea O
significantly O
increases O
the O
QT O
interval O
and O
has O
arrhythmogenic O
effects O
in O
the O
rat O
heart O
. O

Furthermore O
, O
a O
bioassay O
- O
guided O
purification O
procedure O
allowed O
the O
isolation O
of O
a O
chromatographic O
fraction O
containing O
a O
major O
component O
with O
a O
molecular O
mass O
of O
4478 O
Da O
from O
the O
crude O
extract O
, O
which O
causes O
a O
significant O
inhibition O
of O
whole O
- O
cell O
patch O
- O
clamp O
currents O
through O
recombinant O
Erg1 O
channels O
, O
responsible O
of O
the O
rapid O
delayed O
rectifying O
current O
crucial O
for O
electrical O
activity O
in O
the O
heart O
. O

Further O
studies O
could O
provide O
relevant O
information O
on O
the O
molecular O
mechanism O
of O
C O
. O
gigantea O
peptide O
toxins O
which O
represent O
promising O
tools O
in O
studying O
the O
physiology O
of O
diverse O
ion O
channels O
. O

Delivery O
of O
definable O
number O
of O
drug O
or O
growth O
factor O
loaded O
poly B
( I
dl I
- I
lactic I
acid I
- I
co I
- I
glycolic I
acid I
) I
microparticles O
within O
human O
embryonic O
stem O
cell O
derived O
aggregates O
. O

Embryoid O
bodies O
( O
EBs O
) O
generated O
from O
embryonic O
stem O
cells O
are O
used O
to O
study O
processes O
of O
differentiation O
within O
a O
three O
dimensional O
( O
3D O
) O
cell O
environment O
. O

In O
many O
instances O
however O
, O
EBs O
are O
dispersed O
to O
single O
cell O
suspensions O
with O
a O
subsequent O
monolayer O
culture O
. O

Moreover O
, O
where O
the O
3D O
integrity O
of O
an O
EB O
is O
maintained O
, O
cytokines O
or O
drugs O
of O
interest O
to O
stimulate O
differentiation O
are O
often O
added O
directly O
to O
the O
culture O
medium O
at O
fixed O
concentrations O
and O
effects O
are O
usually O
limited O
to O
the O
outer O
layers O
of O
the O
EB O
. O

The O
aim O
of O
this O
study O
was O
to O
create O
an O
EB O
model O
with O
localised O
drug O
and O
or O
growth O
factor O
delivery O
directly O
within O
the O
EB O
. O

Using O
poly B
( I
DL I
- I
lactic I
acid I
- I
co I
- I
glycolic I
acid I
) I
microparticles O
( O
MPs O
) O
with O
an O
average O
diameter O
of O
13 O
mu O
m O
, O
we O
have O
demonstrated O
controllable O
incorporation O
of O
defined O
numbers O
of O
MPs O
within O
human O
ES O
cell O
derived O
EBs O
, O
down O
to O
1 O
MP O
per O
EB O
. O

This O
was O
achieved O
by O
coating O
MPs O
with O
human O
ES O
cell O
lysate O
and O
centrifugation O
of O
specific O
ratios O
of O
ES O
cells O
and O
MPs O
to O
form O
3D O
aggregates O
. O

Using O
MPs O
loaded O
with O
simvastatin B
( O
pro O
or O
active O
drug O
) O
or O
BMP O
- O
2 O
, O
we O
have O
demonstrated O
osteogenic O
differentiation O
within O
the O
3D O
aggregates O
, O
maintained O
in O
culture O
for O
up O
to O
21days O
, O
and O
quantified O
by O
real O
time O
QPCR O
for O
osteocalcin O
. O

Immunostaining O
for O
RUNX2 O
and O
osteocalcin O
, O
and O
also O
histochemical O
staining O
with O
picrosirius B
red I
to O
demonstrate O
collage O
type O
1 O
and O
Alizarin B
red I
to O
demonstrate O
calcium B
/ O
mineralisation O
further O
demonstrated O
osteogenic O
differentiation O
and O
revealed O
regional O
staining O
associated O
with O
the O
locations O
of O
MPs O
within O
the O
aggregates O
. O

We O
also O
demonstrated O
endothelial O
differentiation O
within O
human O
ES O
cell O
- O
derived O
aggregates O
using O
VEGF O
loaded O
MPs O
. O

In O
conclusion O
, O
we O
demonstrate O
an O
effective O
and O
reliable O
approach O
for O
engineering O
stem O
aggregates O
with O
definable O
number O
of O
MPs O
within O
the O
3D O
cellular O
structure O
. O

We O
also O
achieved O
localised O
osteogenic O
and O
endothelial O
differentiation O
associated O
with O
MPs O
releasing O
encapsulated O
drug O
molecules O
or O
cytokines O
directly O
within O
the O
cell O
aggregate O
. O

This O
provides O
a O
powerful O
tool O
for O
controlling O
and O
investigating O
differentiation O
within O
3D O
cell O
cultures O
and O
has O
applications O
to O
drug O
delivery O
, O
drug O
discovery O
, O
stem O
cell O
biology O
, O
tissue O
engineering O
and O
regenerative O
medicine O
. O

Raft O
forming O
system O
- O
An O
upcoming O
approach O
of O
gastroretentive O
drug O
delivery O
system O
. O

In O
recent O
era O
various O
technologies O
have O
been O
made O
in O
research O
and O
development O
of O
controlled O
release O
oral O
drug O
delivery O
system O
to O
overcome O
various O
physiological O
difficulties O
such O
as O
variation O
in O
gastric O
retention O
and O
emptying O
time O
. O

To O
overcome O
this O
drawback O
and O
to O
maximize O
the O
oral O
absorption O
of O
various O
drugs O
, O
novel O
drug O
delivery O
systems O
have O
been O
developed O
. O

Gastroretentive O
drug O
delivery O
system O
is O
facing O
many O
challenges O
which O
can O
be O
overcome O
by O
upcoming O
newly O
emerging O
approach O
i O
. O
e O
. O
raft O
forming O
system O
. O

The O
purpose O
of O
writing O
this O
review O
is O
to O
focus O
on O
recent O
development O
of O
stomach O
specific O
floating O
drug O
delivery O
system O
to O
circumvent O
the O
difficulties O
associated O
with O
formulation O
design O
. O

Various O
gastroretentive O
approaches O
that O
have O
been O
developed O
till O
now O
are O
also O
discussed O
. O

The O
present O
study O
provides O
valuable O
information O
& O
highlights O
advances O
in O
this O
raft O
forming O
system O
. O

This O
review O
attempts O
to O
discuss O
various O
factors O
like O
physiological O
factors O
, O
physicochemical O
factors O
and O
formulation O
factors O
to O
be O
considered O
in O
the O
development O
of O
the O
raft O
forming O
system O
. O

Different O
types O
of O
smart O
polymers O
used O
for O
their O
formulation O
have O
also O
been O
summarized O
. O

The O
review O
focuses O
on O
the O
mechanism O
, O
formulation O
and O
development O
of O
the O
raft O
forming O
system O
. O

This O
review O
also O
summarizes O
the O
studies O
to O
evaluate O
the O
performance O
and O
application O
of O
these O
systems O
. O

The O
study O
finally O
highlights O
advantages O
, O
disadvantages O
, O
and O
marketed O
preparation O
of O
the O
raft O
forming O
system O
. O

Analysis O
of O
the O
enhanced O
oral O
bioavailability O
of O
fenofibrate B
lipid O
formulations O
in O
fasted O
humans O
using O
an O
in O
vitro O
- O
in O
silico O
- O
in O
vivo O
approach O
. O

Lipid O
- O
based O
formulations O
have O
established O
a O
significant O
role O
in O
the O
formulation O
of O
poorly O
soluble O
drugs O
for O
oral O
administration O
. O

In O
order O
to O
better O
understand O
their O
potential O
advantages O
over O
solid O
oral O
dosage O
forms O
, O
we O
studied O
the O
solubility O
and O
dissolution O
/ O
precipitation O
characteristics O
of O
three O
self O
- O
microemulsifying O
drug O
delivery O
system O
( O
SMEDDS O
) O
formulations O
and O
one O
suspension O
of O
micronized O
fenofibrate B
in O
lipid O
excipients O
, O
for O
which O
pharmacokinetic O
studies O
had O
already O
been O
reported O
in O
the O
open O
literature O
. O

The O
in O
vitro O
dispersion O
/ O
dissolution O
studies O
were O
carried O
out O
in O
biorelevant O
media O
using O
USP O
II O
apparatus O
. O

These O
were O
followed O
up O
by O
in O
silico O
simulations O
using O
STELLA O
( O
R O
) O
software O
, O
in O
which O
not O
only O
dispersion O
/ O
dissolution O
, O
but O
also O
the O
precipitation O
and O
re O
- O
dissolution O
of O
fenofibrate B
was O
taken O
into O
account O
. O

While O
unformulated O
drug O
exhibited O
poor O
solubility O
( O
0 O
. O
22 O
mu O
g O
/ O
mL O
in O
FaSSGF O
and O
4 O
. O
31 O
mu O
g O
/ O
mL O
in O
FaSSIF O
- O
V2 O
( O
PO4 B
) O
) O
and O
dissolved O
less O
than O
2 O
% O
in O
dissolution O
tests O
, O
the O
solubility O
of O
fenofibrate B
in O
the O
presence O
of O
the O
lipid O
excipients O
increased O
dramatically O
( O
e O
. O
g O
. O
, O
to O
65 O
. O
44 O
mu O
g O
/ O
mL O
in O
the O
presence O
of O
the O
Myritol B
318 I
/ O
TPGS B
/ O
Tween B
80 I
SMEDDS O
) O
and O
there O
was O
an O

attendant O
increase O
in O
the O
dissolution O
( O
over O
80 O
% O
from O
capsules O
containing O
the O
Myritol B
318 I
/ O
TPGS B
/ O
Tween B
80 I
SMEDDS O
and O
about O
20 O
% O
from O
the O
dispersion O
of O
fenofibrate B
in O
lipid O
excipients O
) O
. O

For O
the O
four O
lipid O
- O
based O
fenofibrate B
formulations O
studied O
, O
combining O
in O
vitro O
data O
in O
biorelevant O
media O
with O
in O
silico O
simulation O
resulted O
in O
accurate O
prediction O
of O
the O
in O
vivo O
human O
plasma O
profiles O
. O

The O
point O
estimates O
of O
Cmax O
and O
AUC O
ratio O
calculated O
from O
the O
in O
silico O
and O
in O
vivo O
plasma O
profiles O
fell O
within O
the O
0 O
. O
8 O
- O
1 O
. O
25 O
range O
for O
the O
SMEDDS O
solution O
and O
capsule O
formulations O
, O
suggesting O
an O
accurate O
simulation O
of O
the O
in O
vivo O
profiles O
. O

This O
similarity O
was O
confirmed O
by O
calculation O
of O
the O
respective O
f2 O
factors O
. O

Sensitivity O
analysis O
of O
the O
simulation O
profiles O
revealed O
that O
the O
SMEDDS O
formulations O
had O
virtually O
removed O
any O
dependency O
of O
absorption O
on O
the O
dissolution O
rate O
in O
the O
small O
intestine O
, O
whereas O
for O
the O
dispersion O
in O
lipid O
excipients O
, O
this O
barrier O
remained O
. O

Such O
results O
pave O
the O
way O
to O
optimizing O
the O
performance O
of O
oral O
lipid O
- O
based O
formulations O
via O
an O
in O
vitro O
- O
in O
silico O
- O
in O
vivo O
approach O
. O

Evaluation O
of O
the O
pharmacodynamics O
and O
pharmacokinetics O
of O
brucine B
following O
transdermal O
administration O
. O

Before O
the O
design O
of O
brucine B
- O
containing O
transdermal O
formulations O
, O
the O
pharmacodynamics O
and O
pharmacokinetics O
of O
brucine B
following O
transdermal O
administration O
should O
be O
evaluated O
. O

In O
this O
study O
, O
the O
effect O
of O
addition O
of O
ethanol B
on O
solubility O
of O
bruicne O
was O
investigated O
and O
20 O
% O
ethanol B
was O
added O
into O
PBS O
to O
obtain O
10mg O
/ O
mL O
brucine B
solution O
. O

Then O
three O
transdermal O
doses O
( O
10 O
, O
20 O
and O
40mg O
/ O
kg O
) O
were O
administered O
to O
mice O
to O
evaluate O
pharmacological O
activity O
. O

It O
had O
been O
demonstrated O
that O
brucine B
possessed O
analgesic O
and O
anti O
- O
inflammatory O
activity O
in O
a O
dose O
- O
dependent O
manner O
. O

Cytotoxicities O
of O
brucine B
against O
various O
tumor O
cells O
including O
skin O
tumor O
cell O
were O
also O
compared O
in O
vitro O
. O

Brucine B
was O
found O
to O
possess O
antitumor O
activity O
in O
a O
concentration O
and O
time O
- O
dependent O
manner O
and O
gastrointestinal O
tumor O
cells O
seemed O
to O
be O
more O
sensitive O
to O
brucine B
. O

Then O
in O
vitro O
skin O
permeation O
behavior O
and O
in O
vivo O
pharmacokinetics O
following O
transdermal O
administration O
were O
further O
investigated O
. O

The O
cumulative O
amounts O
of O
brucine B
across O
mouse O
skin O
in O
vitro O
were O
found O
to O
be O
higher O
than O
90 O
% O
. O

The O
absolute O
bioavailability O
of O
brucine B
was O
determined O
to O
be O
40 O
. O
83 O
% O
. O

And O
compared O
with O
intravenous O
administration O
, O
MRT O
and O
T1 O
/ O
2 O
values O
were O
increased O
about O
8 O
~ O
12 O
- O
fold O
by O
transdermal O
route O
. O

Moreover O
, O
fluctuations O
of O
drug O
levels O
were O
found O
to O
be O
significantly O
decreased O
in O
tissues O
, O
especially O
in O
brain O
. O

Finally O
, O
no O
dermal O
toxicity O
of O
brucine B
was O
observed O
. O

The O
results O
of O
this O
study O
indicated O
that O
transdermal O
administration O
might O
be O
beneficial O
for O
the O
sustained O
efficacy O
and O
reduced O
toxicity O
of O
brucine B
. O

The O
vascular O
protective O
properties O
of O
kinsenoside B
isolated O
from O
Anoectochilus O
roxburghii O
under O
high O
glucose B
condition O
. O

Anoectochilus O
roxburghii O
is O
a O
traditional O
Chinese O
herb O
used O
for O
the O
treatment O
of O
diabetes O
and O
some O
other O
diseases O
. O

The O
vascular O
protective O
effect O
of O
its O
major O
active O
ingredient O
, O
kinsenoside B
, O
in O
high O
glucose B
conditions O
was O
investigated O
in O
in O
vivo O
and O
in O
vitro O
experiments O
. O

In O
in O
vivo O
tests O
, O
kinsenoside B
( O
50 O
and O
100mg O
/ O
kg O
) O
efficiently O
lowered O
blood O
glucose B
and O
cholesterol B
levels O
and O
it O
enhanced O
the O
oxidation O
resistance O
of O
diabetic O
mice O
induced O
by O
streptozotocin B
. O

In O
the O
in O
vitro O
assay O
, O
kinsenoside B
( O
20 O
and O
50 O
mu O
g O
/ O
mL O
) O
markedly O
inhibited O
changes O
in O
various O
biochemical O
substances O
( O
nitric B
oxide I
( O
NO B
) O
, O
lactic O
dehydrogenase O
( O
LDH O
) O
, O
superoxide B
dismutase O
( O
SOD O
) O
, O
and O
catalase O
( O
CAT O
) O
) O
in O
human O
umbilical O
vein O
endothelial O
cells O
( O
HUVECs O
) O
damaged O
by O
high O
glucose B
( O
35mM O
) O
and O
restored O
vascular O
endothelial O
structure O
by O
balancing O
the O
matrix O
metalloproteinases O
- O
the O
tissue O
inhibitors O
of O
matrix O

metalloproteinases O
( O
MMP O
- O
TIMP O
) O
system O
. O

The O
vascular O
protective O
effects O
of O
kinsenoside B
were O
speculated O
to O
be O
attributed O
to O
oxidative O
stress O
inhibition O
and O
the O
reduction O
of O
nuclear O
factor O
kappa O
B O
( O
NF O
- O
kappa O
B O
) O
mRNA O
expression O
levels O
in O
high O
glucose B
conditions O
. O

Moreover O
, O
histological O
examination O
, O
including O
hematoxylin B
- O
eosin B
( O
H O
& O
E O
) O
staining O
, O
masson O
trichrome O
( O
Masson O
) O
staining O
, O
and O
periodic O
Schiff O
- O
methenamine B
( O
PASM O
) O
staining O
, O
greatly O
supported O
the O
morphological O
and O
functional O
amelioration O
of O
diabetes O
- O
related O
changes O
in O
mice O
aortas O
after O
kinsenoside B
( O
20 O
and O
50 O
mu O
g O
/ O
mL O
) O
treatment O
. O

These O
results O
indicated O
that O
kinsenoside B
might O
be O
a O
promising O
agent O
for O
the O
treatment O
of O
diabetic O
vascular O
disease O
. O

The O
application O
of O
a O
DNA O
- O
based O
identification O
technique O
to O
over O
- O
the O
- O
counter O
herbal O
medicines O
. O

Reliable O
methods O
to O
identify O
medicinal O
plant O
material O
are O
becoming O
more O
important O
in O
an O
increasingly O
regulated O
market O
place O
. O

DNA O
- O
based O
methods O
have O
been O
recognised O
as O
a O
valuable O
tool O
in O
this O
area O
with O
benefits O
such O
as O
being O
unaffected O
by O
the O
age O
of O
the O
plant O
material O
, O
growth O
conditions O
and O
harvesting O
techniques O
. O

It O
is O
possible O
that O
the O
methods O
of O
production O
used O
for O
medicinal O
plant O
products O
will O
degrade O
or O
remove O
DNA O
. O

So O
how O
applicable O
are O
these O
techniques O
to O
processed O
medicinal O
plant O
products O
? O

A O
simple O
PCR O
- O
based O
identification O
technique O
has O
been O
developed O
for O
St O
. O

John O
' O
s O
Wort O
, O
Hypericum O
perforatum O
L O
. O

Thirteen O
St O
. O

John O
' O
s O
Wort O
products O
were O
purchased O
including O
capsules O
, O
tablets O
and O
tinctures O
. O

DNA O
was O
extracted O
from O
each O
product O
, O
and O
the O
species O
specific O
PCR O
test O
conducted O
. O

DNA O
was O
successfully O
extracted O
from O
all O
thirteen O
products O
, O
using O
a O
fast O
and O
efficient O
modified O
method O
for O
extracting O
DNA O
from O
tinctures O
. O

Only O
four O
products O
yielded O
the O
full O
length O
ITS O
region O
( O
850bp O
) O
due O
to O
the O
quality O
of O
the O
DNA O
. O

All O
of O
the O
products O
tested O
positive O
for O
H O
. O
perforatum O
DNA O
. O

DNA O
- O
based O
identification O
methods O
can O
complement O
existing O
methods O
of O
authentication O
. O

This O
paper O
shows O
that O
these O
methods O
are O
applicable O
to O
a O
wide O
range O
of O
processed O
products O
, O
provided O
that O
they O
are O
designed O
to O
account O
for O
the O
possibility O
of O
DNA O
degradation O
. O

Bioactive O
carbazole B
alkaloids I
from O
Murraya O
koenigii O
( O
L O
. O
) O
Spreng O
. O

Four O
new O
carbazole B
alkaloids I
( O
1 O
- O
4 O
) O
and O
fourteen O
known O
carbazole B
alkaloids I
( O
5 O
- O
18 O
) O
were O
isolated O
from O
Murraya O
koenigii O
. O

Their O
structures O
were O
elucidated O
on O
the O
basis O
of O
extensive O
spectroscopic O
analysis O
. O

Compounds O
4 O
, O
6 O
, O
16 O
, O
and O
17 O
( O
10 O
mu O
M O
) O
had O
moderate O
hepatoprotective O
activities O
against O
d B
- I
galactosamine I
- O
induced O
HL O
- O
7702 O
cell O
damage O
. O

Compounds O
11 O
, O
12 O
and O
18 O
showed O
significant O
PTP1B O
inhibitory O
activity O
with O
IC50 O
values O
of O
1 O
. O
773 O
, O
1 O
. O
875 O
and O
2 O
. O
286 O
mu O
M O
, O
respectively O
. O

Curcumin B
attenuates O
allergic O
airway O
inflammation O
by O
regulation O
of O
CD4 O
( O
+ O
) O
CD25 O
( O
+ O
) O
regulatory O
T O
cells O
( O
Tregs O
) O
/ O
Th17 O
balance O
in O
ovalbumin O
- O
sensitized O
mice O
. O

The O
present O
study O
aimed O
to O
determine O
the O
protective O
effects O
and O
the O
underlying O
mechanisms O
of O
curcumin B
on O
ovalbumin O
( O
OVA O
) O
- O
induced O
allergic O
inflammation O
in O
a O
mouse O
model O
of O
allergic O
asthma O
. O

Asthma O
mice O
model O
was O
established O
by O
ovalbumin O
. O

A O
total O
of O
60 O
mice O
were O
randomly O
assigned O
to O
six O
experimental O
groups O
: O
control O
, O
model O
, O
dexamethasone B
( O
2mg O
/ O
kg O
) O
, O
and O
curcumin B
( O
50mg O
/ O
kg O
, O
100mg O
/ O
kg O
, O
200mg O
/ O
kg O
) O
. O

Airway O
resistance O
( O
Raw O
) O
was O
measured O
by O
the O
forced O
oscillation O
technique O
, O
differential O
cell O
count O
in O
BAL O
fluid O
( O
BALF O
) O
was O
measured O
by O
Wright O
- O
Giemsa O
staining O
, O
histological O
assessment O
was O
measured O
by O
hematoxylin B
and O
eosin B
( O
HE O
) O
staining O
, O
BALF O
levels O
of O
Treg O
/ O
Th17 O
cytokines O
were O
measured O
by O
enzyme O
- O
linked O
immunosorbent O
assay O
, O
Treg O
cells O
and O
Th17 O
cells O
were O
evaluated O
by O
flow O
cytometry O
( O
FCM O
) O
. O

Our O
study O
demonstrated O
that O
curcumin B
inhibited O
OVA O
- O
induced O
increases O
in O
eosinophil O
count O
; O
interleukin O
( O
IL O
) O
- O
17A O
level O
were O
recovered O
in O
bronchoalveolar O
lavage O
fluid O
increased O
IL O
- O
10 O
level O
in O
bronchoalveolar O
lavage O
fluid O
. O

Histological O
studies O
demonstrated O
that O
curcumin B
substantially O
inhibited O
OVA O
- O
induced O
eosinophilia O
in O
lung O
tissue O
. O

Flow O
cytometry O
( O
FCM O
) O
studies O
demonstrated O
that O
curcumin B
remarkably O
inhibited O
Th17 O
cells O
and O
significantly O
increased O
Treg O
cells O
. O

The O
results O
in O
vivo O
show O
ovalbumin O
- O
induced O
significantly O
broke O
Treg O
/ O
Th17 O
balance O
; O
curcumin B
treatments O
markedly O
attenuated O
the O
inflammatory O
in O
asthma O
model O
by O
regulating O
Treg O
/ O
Th17 O
balance O
. O

Our O
findings O
support O
the O
possible O
use O
of O
curcumin B
as O
a O
therapeutic O
drug O
for O
patients O
with O
allergic O
asthma O
. O

Identification O
, O
assessment O
and O
management O
of O
" O
endocrine O
disruptors O
" O
in O
wildlife O
in O
the O
EU O
substance O
legislation O
- O
Discussion O
paper O
from O
the O
German O
Federal O
Environment O
Agency O
( O
UBA O
) O
. O

A O
discussion O
paper O
was O
developed O
by O
a O
panel O
of O
experts O
of O
the O
German O
Federal O
Environment O
Agency O
( O
UBA O
) O
contributing O
to O
the O
on O
- O
going O
debate O
on O
the O
identification O
, O
assessment O
and O
management O
of O
endocrine O
disruptors O
with O
a O
view O
to O
protect O
wildlife O
according O
to O
the O
EU O
substance O
legislation O
( O
plant O
protection O
products O
, O
biocides O
, O
industrial O
chemicals O
) O
. O

Based O
on O
a O
critical O
synthesis O
of O
the O
state O
- O
of O
- O
the O
- O
art O
regarding O
regulatory O
requirements O
, O
testing O
methods O
, O
assessment O
schemes O
, O
decision O
- O
making O
criteria O
and O
risk O
management O
options O
, O
we O
advise O
an O
appropriate O
and O
consistent O
implementation O
of O
this O
important O
subject O
into O
existing O
chemicals O
legislation O
in O
Europe O
. O

Our O
proposal O
for O
a O
balanced O
risk O
management O
of O
endocrine O
disruptors O
essentially O
advocates O
transparent O
regulatory O
decision O
making O
based O
on O
a O
scientifically O
robust O
weight O
of O
evidence O
approach O
and O
an O
adequate O
risk O
management O
consistent O
across O
different O
legislations O
. O

With O
respect O
to O
the O
latter O
, O
a O
more O
explicit O
consideration O
of O
the O
principle O
of O
proportionality O
of O
regulatory O
decision O
making O
and O
socio O
- O
economic O
benefits O
in O
the O
on O
- O
going O
debate O
is O
further O
encouraged O
. O

The O
C B
- O
Terminal O
Region O
of O
Cytoplasmic O
Polyadenylation O
Element O
Binding O
Protein O
Is O
a O
ZZ O
Domain O
with O
Potential O
for O
Protein O
- O
Protein O
Interactions O
. O

Cytoplasmic O
polyadenylation O
element O
binding O
protein O
( O
CPEB O
) O
provides O
temporal O
and O
spatial O
control O
of O
protein O
synthesis O
required O
for O
early O
development O
and O
neuronal O
synaptic O
plasticity O
. O

CPEB O
regulates O
protein O
expression O
by O
inhibiting O
polyadenylation O
of O
selected O
mRNA O
transcripts O
, O
which O
prevents O
binding O
of O
the O
ribosome O
for O
protein O
synthesis O
. O

Two O
RNA O
recognition O
motif O
domains O
and O
a O
C B
- O
terminal O
binuclear O
zinc B
- O
binding O
domain O
are O
required O
for O
mRNA O
binding O
, O
but O
the O
zinc B
- O
binding O
domain O
is O
not O
required O
for O
sequence O
- O
specific O
recognition O
of O
the O
targeted O
mRNA O
transcript O
. O

The O
structure O
and O
function O
of O
the O
zinc B
- O
binding O
domain O
of O
CPEB O
are O
unknown O
. O

The O
C B
- O
terminal O
region O
of O
CPEB O
may O
participate O
in O
assembly O
of O
the O
ribonucleoprotein O
complex O
that O
includes O
the O
scaffold O
protein O
, O
Symplekin O
, O
and O
the O
cleavage O
and O
polyadenylation O
specificity O
factor O
. O

Sumoylation O
of O
Symplekin O
is O
required O
for O
polyadenylation O
, O
and O
both O
cleavage O
and O
polyadenylation O
specificity O
factor O
and O
poly O
( O
A O
) O
polymerase O
are O
sumoylated O
. O

The O
foreshortened O
poly O
( O
A O
) O
tail O
is O
maintained O
by O
poly O
( O
A O
) O
ribonuclease O
, O
which O
associates O
with O
CPEB O
. O

While O
zinc B
- O
binding O
domains O
are O
renowned O
for O
nucleic O
acid O
recognition O
, O
binuclear O
zinc B
- O
binding O
structural O
motifs O
, O
such O
as O
LIM O
( O
Lin O
- O
11 O
, O
Isl O
- O
1 O
, O
Mec O
- O
3 O
) O
, O
RING O
( O
really O
interesting O
new O
gene O
) O
, O
PHD O
( O
plant O
homeodomain O
) O
and O
ZZ O
( O
ZZ O
- O
type O
zinc B
finger O
) O
domains O
, O
participate O
in O
protein O
- O
protein O
interactions O
. O

Here O
, O
we O
report O
the O
solution O
structure O
of O
the O
C B
- O
terminal O
zinc B
- O
binding O
domain O
of O
CPEB1 O
( O
CPEB1 O
- O
ZZ O
) O
, O
which O
has O
a O
cross O
- O
braced O
zinc B
binding O
topology O
. O

The O
structural O
similarity O
to O
other O
ZZ O
domains O
suggests O
that O
the O
CPEB1 O
- O
ZZ O
domain O
recruits O
sumoylated O
proteins O
during O
assembly O
of O
the O
ribonucleoprotein O
complex O
prior O
to O
mRNA O
export O
from O
the O
nucleus O
. O

Characterization O
of O
monomeric O
and O
multimeric O
snake O
neurotoxins O
and O
other O
bioactive O
proteins O
from O
the O
venom O
of O
the O
lethal O
Australian O
common O
copperhead O
( O
Austrelaps O
superbus O
) O
. O

Envenomation O
by O
Australian O
copperheads O
results O
mainly O
in O
muscle O
paralysis O
largely O
attributed O
to O
the O
presence O
of O
postsynaptic O
alpha O
- O
neurotoxins O
. O

However O
, O
poorly O
reversible O
neurotoxic O
effects O
suggest O
that O
these O
venoms O
may O
contain O
snake O
presynaptic O
phospholipase O
A2 O
neurotoxins O
( O
SPANs O
) O
that O
irreversibly O
inhibit O
neurotransmitter O
release O
. O

Using O
size O
- O
exclusion O
liquid O
chromatography O
, O
the O
present O
study O
isolated O
the O
first O
multimeric O
SPAN O
complex O
from O
the O
venom O
of O
the O
Australian O
common O
copperhead O
, O
Austrelaps O
superbus O
. O

The O
multimeric O
SPAN O
P O
- O
elapitoxin O
- O
As1a O
( O
P O
- O
EPTX O
- O
As1a O
) O
along O
with O
two O
novel O
monomeric O
SPANs O
and O
a O
new O
postsynaptic O
alpha O
- O
neurotoxin O
were O
then O
pharmacologically O
characterized O
using O
the O
chick O
biventer O
cervicis O
nerve O
- O
muscle O
preparation O
. O

All O
SPANs O
inhibited O
nerve O
- O
evoked O
twitch O
contractions O
at O
the O
neuromuscular O
junction O
without O
inhibiting O
contractile O
responses O
to O
cholinergic O
agonists O
or O
KCl B
. O

These O
actions O
are O
consistent O
with O
a O
prejunctional O
action O
to O
inhibit O
neurotransmitter O
release O
, O
without O
direct O
myotoxicity O
. O

Furthermore O
, O
the O
multimeric O
P O
- O
EPTX O
- O
As1a O
caused O
tetanic O
' O
fade O
' O
in O
muscle O
tension O
under O
high O
frequency O
nerve O
stimulation O
, O
and O
produced O
a O
triphasic O
alteration O
to O
neurotransmitter O
release O
. O

These O
actions O
have O
been O
previously O
noted O
with O
other O
multimeric O
SPAN O
complexes O
such O
as O
taipoxin O
. O

Moreover O
, O
the O
neurotoxic O
alpha O
- O
subunit O
of O
P O
- O
EPTX O
- O
As1a O
shows O
high O
homology O
to O
taipoxin O
alpha O
- O
chain O
. O

Several O
other O
coagulopathic O
and O
myotoxic O
high O
mass O
proteins O
including O
a O
class O
PIII O
snake O
venom O
metalloproteinase O
, O
C O
- O
type O
lectin O
, O
l B
- I
amino I
acid I
oxidase O
, O
acetylcholinesterase O
and O
phospholipase O
B O
were O
also O
identified O
that O
may O
contribute O
to O
the O
overall O
toxicity O
of O
A O
. O
superbus O
venom O
. O

In O
conclusion O
, O
clinicians O
should O
be O
aware O
that O
early O
antivenom O
intervention O
might O
be O
necessary O
to O
prevent O
the O
onset O
of O
irreversible O
presynaptic O
neurotoxicity O
caused O
by O
multimeric O
and O
monomeric O
SPANs O
and O
that O
A O
. O
superbus O
venom O
is O
potentially O
capable O
of O
producing O
coagulopathic O
and O
myotoxic O
effects O
. O

Analysis O
by O
liquid O
chromatography O
- O
mass O
spectrometry O
of O
sterols B
and O
oxysterols B
in O
brain O
of O
the O
newborn O
Dhcr7 O
( O
Delta O
3 O
- O
5 O
/ O
T93M O
) O
mouse O
: O
A O
model O
of O
Smith O
- O
Lemli O
- O
Opitz O
syndrome O
. O

In O
this O
study O
the O
sterol B
and O
oxysterol B
profile O
of O
newborn O
brain O
from O
the O
Dhcr7 O
( O
Delta O
3 O
- O
5 O
/ O
T93M O
) O
mouse O
model O
of O
Smith O
- O
Lemli O
- O
Opitz O
syndrome O
( O
SLOS O
) O
has O
been O
investigated O
. O

This O
is O
a O
viable O
mouse O
model O
which O
is O
compound O
heterozygous O
containing O
one O
null O
allele O
and O
one O
T93M O
mutation O
on O
Dhcr7 O
. O

We O
find O
the O
SLOS O
mouse O
has O
reduced O
levels O
of O
cholesterol B
and O
desmosterol B
and O
increased O
levels O
of O
7 B
- I
and I
8 I
- I
dehydrocholesterol I
and O
of O
7 B
- I
and I
8 I
- I
dehydrodesmosterol I
in O
brain O
compared O
to O
the O
wild O
type O
. O

The O
profile O
of O
enzymatically O
formed O
oxysterols B
in O
the O
SLOS O
mouse O
resembles O
that O
in O
the O
wild O
type O
but O
the O
level O
of O
24S B
- I
hydroxycholesterol I
, O
the O
dominating O
cholesterol B
metabolite O
, O
is O
reduced O
in O
a O
similar O
proportion O
to O
that O
of O
cholesterol B
. O

A O
number O
of O
oxysterols B
abundant O
in O
the O
SLOS O
mouse O
are O
probably O
derived O
from O
7 B
- I
dehydrocholesterol I
, O
however O
, O
the O
mechanism O
of O
their O
formation O
is O
unclear O
. O

Interrelationship O
between O
ATP B
- O
binding O
cassette O
transporters O
and O
oxysterols B
. O

ATP B
- O
binding O
cassette O
( O
ABC O
) O
transporters O
constitute O
a O
ubiquitous O
superfamily O
of O
membrane O
proteins O
responsible O
for O
the O
translocation O
of O
several O
substances O
across O
membranes O
using O
the O
chemical O
energy O
provided O
by O
ATP B
hydrolysis O
. O

ABC O
transporters O
participate O
in O
many O
physiological O
and O
pathophysiological O
processes O
, O
including O
cholesterol B
and O
lipid O
transportation O
and O
multidrug O
resistance O
. O

Oxysterols B
are O
the O
products O
of O
cholesterol B
oxidation O
, O
formed O
by O
both O
enzymatic O
and O
non O
- O
enzymatic O
mechanisms O
. O

The O
role O
of O
oxysterols B
in O
cholesterol B
metabolism O
and O
several O
diseases O
has O
been O
widely O
investigated O
, O
but O
many O
questions O
remain O
to O
be O
answered O
. O

Several O
lines O
of O
evidence O
link O
ABC O
transporter O
functions O
with O
cholesterol B
and O
oxysterol B
metabolism O
. O

This O
review O
discusses O
ABC O
transporters O
, O
oxysterols B
, O
and O
how O
they O
interact O
with O
each O
other O
. O

Donor O
substrate O
specificity O
of O
bovine O
kidney O
gamma O
- O
glutamyltransferase O
. O

The O
enzyme O
gamma O
- O
glutamyltransferase O
( O
GGT O
) O
catalyzes O
the O
hydrolysis O
of O
the O
gamma B
- I
glutamyl I
isopeptide B
bond O
of O
glutathione B
conjugates O
( O
donor O
substrates O
) O
, O
releasing O
glutamic B
acid I
, O
or O
the O
transfer O
of O
the O
donor O
' O
s O
gamma B
- I
glutamyl I
group O
to O
an O
acceptor O
substrate O
, O
such O
as O
a O
dipeptide B
. O

The O
specificity O
of O
GGT O
for O
xenobiotic O
donor O
substrates O
has O
not O
been O
fully O
characterized O
. O

The O
transpeptidation O
activity O
of O
bovine O
kidney O
GGT O
was O
measured O
with O
glycylglycine B
as O
the O
acceptor O
substrate O
and O
several O
glutathione B
conjugate O
donor O
substrates O
, O
representative O
of O
detoxication O
products O
of O
polycyclic B
aromatic I
xenobiotics O
. O

HPLC O
separation O
with O
UV O
detection O
was O
used O
for O
quantitation O
. O

The O
commonly O
- O
used O
chromogenic O
substrate O
gamma B
- I
glutamyl I
- I
p I
- I
nitroanilide I
was O
also O
tested O
. O

Michaelis O
constants O
( O
Km O
) O
were O
obtained O
for O
4 B
- I
nitrobenzylglutathio I
( O
0 O
. O
075mM O
) O
, O
2 B
, I
4 I
- I
dinitrophenylglutath I
( O
0 O
. O
30mM O
) O
, O
4 B
- I
methylbiphenylylglut I
( O
0 O
. O
12mM O
) O
, O
1 B
- I
menaphthylglutathion I
( O
0 O
. O
23mM O
) O
, O
and O
9 B
- I
methylanthracenylglu I
( O
0 O
. O
22mM O
) O
, O
indicating O
a O
trend O
towards O
higher O
values O
for O
bulkier O
substrates O
. O

These O
results O
provide O
insight O
into O
the O
capacity O
of O
GGT O
to O
act O
in O
the O
biotransformation O
of O
aromatic O
compounds O
, O
many O
of O
which O
are O
of O
toxicological O
importance O
. O

Anti O
- O
fibrotic O
effects O
of O
puerarin B
on O
CCl4 B
- O
induced O
hepatic O
fibrosis O
in O
rats O
possibly O
through O
the O
regulation O
of O
PPAR O
- O
gamma O
expression O
and O
inhibition O
of O
PI3K O
/ O
Akt O
pathway O
. O

Hepatic O
fibrosis O
( O
HF O
) O
is O
a O
chronic O
disease O
, O
which O
primarily O
leads O
to O
liver O
unregulated O
metabolism O
. O

In O
this O
study O
, O
we O
aimed O
to O
investigate O
the O
therapeutic O
effects O
of O
puerarin B
( O
PR O
) O
, O
an O
active O
ingredient O
from O
kudzu O
root O
, O
on O
CCl4 B
- O
induced O
HF O
rats O
. O

PR O
effectively O
ameliorated O
the O
liver O
metabolic O
function O
, O
resulting O
in O
reduced O
serum O
enzymatic O
activities O
of O
alanine B
aminotransferase O
( O
ALT O
) O
, O
aspartate B
aminotransferase O
( O
AST O
) O
, O
total O
- O
bilirubin B
( O
T O
- O
bilirubin B
) O
, O
extracellular O
matrix O
( O
ECM O
) O
contents O
and O
increased O
levels O
of O
albumin O
, O
total O
- O
protein O
( O
T O
- O
protein O
) O
in O
HF O
rats O
. O

Similarly O
, O
pathological O
examination O
showed O
that O
the O
CCl4 B
- O
lesioned O
liver O
was O
mitigated O
by O
PR O
treatments O
. O

Meanwhile O
, O
we O
also O
detected O
significantly O
reduced O
levels O
of O
hydroxyproline B
( O
Hyp B
) O
, O
type O
III O
precollagen O
( O
PCIII O
) O
and O
collagen O
I O
( O
Col O
I O
) O
in O
the O
liver O
tissue O
of O
HF O
rats O
, O
whereas O
the O
peroxisome O
proliferator O
- O
activated O
receptor O
- O
gamma O
( O
PPAR O
- O
gamma O
) O
expression O
was O
effectively O
increased O
. O

Moreover O
, O
the O
expression O
of O
tissue O
inhibitor O
of O
metal O
protease O
- O
1 O
( O
TIMP O
- O
1 O
) O
was O
decreased O
, O
while O
the O
expression O
of O
matrix O
metalloproteinase O
- O
2 O
( O
MMP O
- O
2 O
) O
was O
increased O
. O

In O
addition O
, O
the O
expression O
of O
p O
- O
PI3K O
and O
p O
- O
Akt O
was O
significantly O
down O
- O
regulated O
by O
PR O
treatments O
. O

Taken O
together O
, O
PR O
could O
attenuate O
the O
CCl4 B
- O
induced O
toxicity O
in O
the O
hepatocytes O
of O
HF O
rats O
. O

It O
played O
a O
protective O
role O
in O
the O
liver O
tissue O
probably O
through O
regulating O
the O
PPAR O
- O
gamma O
expression O
and O
blocking O
the O
PI3K O
/ O
Akt O
pathway O
to O
inhibit O
the O
excessive O
deposition O
of O
collagen O
. O

Dietary O
exposure O
of O
juvenile O
female O
mice O
to O
polyhalogenated O
seafood O
contaminants O
( O
HBCD B
, O
BDE B
- I
47 I
, O
PCB B
- I
153 I
, O
TCDD B
) O
: O
Comparative O
assessment O
of O
effects O
in O
potential O
target O
tissues O
. O

Fish O
represents O
source O
of O
nutrients O
and O
major O
dietary O
vehicle O
of O
lipophilic O
persistent O
contaminants O
. O

The O
study O
compared O
the O
effects O
of O
two O
legacy O
and O
two O
emerging O
fish O
pollutants O
( O
Hexabromocyclododeca B
HBCD B
; O
2 B
, I
2 I
' I
, I
4 I
, I
4 I
' I
- I
Tetrabromodiphenyl I
ether I
BDE B
- I
47 I
; O
2 B
, I
2 I
' I
, I
4 I
, I
4 I
' I
, I
5 I
, I
5 I
' I
- I
Hexachlorobiphenyl I
PCB I
- I
153 I
; O
2 B
, I
3 I
, I
7 I
, I
8 I
- I
Tetrachlorodibenzo I
- I
p I
- I
doxin I
TCDD I
) O
in O
juvenile O
female O
mice O
exposed O
through O
a O
salmon O
based O
rodent O
diet O
for O
28days O
( O

dietary O
doses O
: O
HBCD B
199mg O
/ O
kg O
bw O
/ O
day O
; O
BDE B
- I
47 I
450 O
mu O
g O
/ O
kg O
bw O
/ O
day O
; O
PCB B
- I
153 I
195 O
mu O
g O
/ O
kg O
bw O
/ O
day O
; O
TCDD B
90ng O
/ O
kg O
bw O
/ O
day O
) O
. O

Dose O
levels O
were O
comparable O
to O
previously O
reported O
developmental O
Lowest O
Observed O
Adverse O
Effect O
Levels O
. O

None O
of O
the O
treatments O
elicited O
signs O
of O
overt O
toxicity O
, O
but O
HBCD B
increased O
relative O
liver O
weight O
. O

All O
compounds O
caused O
changes O
in O
liver O
, O
thymus O
and O
thyroid O
; O
spleen O
was O
affected O
by O
BDE B
- I
47 I
and O
PCB B
- I
153 I
; O
no O
effects O
were O
seen O
in O
uterus O
and O
adrenals O
. O

Strongest O
effects O
in O
thyroid O
follicles O
were O
elicited O
by O
PCB B
- I
153 I
, O
in O
thymus O
and O
liver O
by O
BDE B
- I
47 I
. O

HBCD B
and O
BDE B
- I
47 I
induced O
liver O
fatty O
changes O
, O
but O
appeared O
to O
be O
less O
potent O
in O
the O
other O
tissues O
. O

HBCD B
, O
BDE B
- I
47 I
and O
TCDD B
increased O
serum O
testosterone B
levels O
and O
the O
testosterone B
/ O
estradiol B
ratio O
, O
suggesting O
a O
potential O
involvement O
of O
pathways O
related O
to O
sex O
steroid B
biosynthesis O
and O
/ O
or O
metabolism O
. O

The O
results O
support O
the O
role O
of O
toxicological O
studies O
on O
juvenile O
rodents O
in O
the O
hazard O
characterization O
of O
chemicals O
, O
due O
to O
endocrine O
and O
/ O
or O
immune O
effects O
. O

Gambogic B
acid I
inhibits O
angiogenesis O
through O
inhibiting O
PHD2 O
- O
VHL O
- O
HIF O
- O
1 O
alpha O
pathway O
. O

Our O
previous O
studies O
revealed O
that O
gambogic B
acid I
( O
GA O
) O
, O
the O
major O
active O
ingredient O
of O
gamboge O
, O
possessed O
antiangiogenic O
activities O
. O

In O
this O
study O
, O
we O
further O
explored O
the O
mechanism O
of O
inhibition O
effects O
of O
GA O
in O
tumor O
angiogenesis O
. O

The O
results O
of O
luciferase O
, O
RT O
- O
PCR O
, O
and O
ELISA O
assays O
indicated O
that O
GA O
significantly O
decreased O
transcription O
activation O
, O
mRNA O
expression O
, O
and O
secretion O
of O
VEGF O
in O
hypoxia O
. O

We O
detected O
that O
GA O
had O
no O
effect O
on O
mRNA O
level O
of O
HIF O
- O
1 O
alpha O
which O
targets O
VEGF O
gene O
, O
but O
the O
increase O
of O
HIF O
- O
1 O
alpha O
protein O
expression O
in O
hypoxia O
was O
repressed O
by O
GA O
, O
which O
can O
be O
reversed O
by O
proteasomal O
inhibitor O
MG132 B
and O
siRNA O
of O
VHL O
. O

But O
GA O
exhibited O
no O
effect O
on O
expression O
of O
VHL O
both O
in O
normoxia O
and O
hypoxia O
. O

HIF O
prolyl B
hydroxylases O
( O
PHD O
enzymes O
) O
act O
as O
oxygen B
sensors O
regulating O
HIF O
, O
and O
hence O
angiogenesis O
. O

Our O
results O
showed O
that O
GA O
potentially O
enhanced O
level O
of O
PHD2 O
, O
the O
most O
important O
HIF O
hydroxylase O
, O
and O
showed O
no O
effect O
on O
PHD1 O
and O
PHD3 O
. O

Transient O
transfection O
of O
siRNA O
of O
PHD2 O
could O
eliminate O
GA O
- O
induced O
VEGF O
secretion O
increase O
. O

Growth O
of O
HepG2 O
xenografts O
in O
BALB O
/ O
cA O
nude O
mice O
was O
inhibited O
by O
GA O
and O
angiogenesis O
was O
repressed O
significantly O
in O
tumor O
xenografts O
by O
immunohistochemical O
staining O
of O
CD O
- O
31 O
, O
a O
vascular O
endothelial O
marker O
, O
accompanied O
with O
decrease O
of O
HIF O
- O
1 O
alpha O
and O
increase O
of O
PHD2 O
expression O
in O
tissue O
extracts O
. O

This O
work O
provides O
the O
demonstration O
that O
GA O
shows O
anti O
- O
angiogenic O
effects O
via O
inhibiting O
PHD2 O
- O
VHL O
- O
HIF O
- O
1 O
alpha O
pathway O
. O

Coumarins B
hinged O
directly O
on O
benzimidazoles B
and O
their O
ribofuranosides B
to O
inhibit O
hepatitis O
C O
virus O
. O

A O
new O
compound O
library O
that O
contained O
20 O
hinged O
benzimidazole B
- O
coumarin B
hybrids O
and O
their O
beta B
- I
d I
- I
ribofuranosides I
was O
established O
. O

The O
anti O
- O
hepatitis O
C O
virus O
( O
HCV O
) O
activity O
of O
all O
novel O
coumarin B
derivatives O
, O
which O
were O
obtained O
by O
use O
of O
organic O
synthetic O
methods O
, O
was O
tested O
. O

Two O
of O
these O
hybrids O
exhibited O
appealing O
EC50 O
values O
of O
as O
low O
as O
3 O
. O
0 O
and O
5 O
. O
5 O
mu O
M O
. O

The O
best O
selectivity O
index O
was O
14 O
. O

The O
incorporation O
of O
a O
d B
- I
ribofuranose I
into O
the O
hinged O
hybrids O
provided O
the O
corresponding O
nucleosides B
with O
the O
beta O
configuration O
, O
one O
of O
which O
inhibited O
HCV O
replication O
with O
an O
EC50 O
value O
of O
20 O
mu O
M O
. O

Additionally O
, O
the O
structure O
- O
activity O
relationship O
is O
elucidated O
on O
the O
basis O
of O
the O
functional O
groups O
that O
were O
attached O
to O
the O
nuclei O
of O
benzimidazole B
, O
coumarin B
, O
and O
ribofuranose B
of O
the O
hybrids O
. O

The O
protective O
role O
of O
l B
- I
carnitine I
against O
cylindrospermopsin B
- O
induced O
oxidative O
stress O
in O
tilapia O
( O
Oreochromis O
niloticus O
) O
. O

Cylindrospermopsin B
( O
CYN B
) O
is O
one O
of O
the O
most O
important O
cyanotoxins O
in O
terms O
of O
both O
human O
health O
and O
environmental O
quality O
and O
is O
produced O
by O
several O
different O
species O
of O
cyanobacteria O
, O
including O
Aphanizomenon O
ovalisporum O
. O

The O
principal O
mechanisms O
of O
action O
of O
CYN B
involve O
inhibition O
of O
protein O
and O
glutathione B
synthesis O
. O

In O
addition O
, O
CYN B
- O
mediated O
genotoxicity O
results O
from O
DNA O
fragmentation O
. O

The O
results O
of O
both O
in O
vivo O
and O
in O
vitro O
studies O
suggest O
that O
oxidative O
stress O
also O
plays O
a O
significant O
role O
in O
CYN B
pathogenesis O
in O
fish O
. O

We O
investigated O
the O
protective O
effects O
of O
l B
- I
carnitine I
( O
LC O
) O
pre O
- O
treatment O
on O
A O
. O
ovalisporum O
- O
induced O
oxidative O
stress O
in O
cells O
containing O
CYN B
and O
deoxy B
- I
CYN I
, O
or O
pure O
standard O
CYN B
, O
in O
tilapia O
( O
Oreochromis O
niloticus O
) O
that O
had O
been O
acutely O
exposed O
via O
oral O
administration O
. O

Various O
oxidative O
stress O
markers O
, O
including O
lipid O
peroxidation O
( O
LPO O
) O
, O
protein O
oxidation O
, O
DNA O
oxidation O
, O
and O
the O
ratio O
of O
reduced B
glutathione I
to O
oxidised O
glutathione I
( O
GSH B
/ O
GSSG B
) O
, O
and O
the O
activities O
of O
NADPH B
oxidase O
, O
superoxide B
dismutase O
( O
SOD O
) O
, O
catalase O
( O
CAT O
) O
, O
and O
gamma B
- I
glutamyl I
- I
cysteine I
synthetase O
( O
gamma O
- O
GCS O
) O
, O
were O
evaluated O
in O
the O
livers O
and O
kidneys O
of O
fish O
in O
the O
absence O
and O
presence O
of O

400 O
or O
880mgLC O
/ O
kgfish O
/ O
day O
during O
a O
21 O
day O
period O
prior O
to O
CYN B
- O
intoxication O
. O

The O
results O
of O
our O
study O
demonstrated O
for O
the O
first O
time O
the O
beneficial O
antioxidant O
effects O
of O
LC O
dietary O
supplementation O
on O
oxidative O
stress O
status O
in O
fish O
. O

No O
pro O
- O
oxidant O
effects O
were O
detected O
at O
any O
of O
the O
LC O
doses O
assayed O
, O
suggesting O
that O
LC O
is O
a O
chemoprotectant O
that O
reduces O
hepatic O
and O
renal O
oxidative O
stress O
and O
may O
be O
effective O
when O
used O
for O
the O
prophylaxis O
and O
treatment O
of O
CYN B
- O
related O
intoxication O
in O
fish O
. O

A O
child O
exposed O
to O
primidone B
not O
prescribed O
for O
her O
. O

A O
7 O
. O
5 O
- O
year O
- O
old O
girl O
who O
was O
treated O
with O
phenobarbital B
( O
PHB B
) O
for O
epilepsy O
was O
admitted O
with O
decreased O
levels O
of O
consciousness O
. O

She O
had O
been O
known O
to O
have O
high O
PHB B
levels O
of O
unknown O
cause O
, O
without O
symptoms O
. O

Her O
PHB B
levels O
were O
very O
high O
, O
as O
expected O
, O
but O
primidone B
levels O
were O
also O
detected O
although O
she O
and O
her O
parents O
denied O
history O
of O
primidone B
administration O
. O

We O
wished O
to O
rule O
out O
intentional O
unprescribed O
use O
of O
primidone B
. O

Our O
retrospective O
review O
showed O
3 O
other O
children O
with O
high O
PHB B
concentrations O
where O
primidone B
was O
also O
detected O
when O
PHB B
levels O
were O
over O
130 O
mu O
mol O
/ O
L O
. O

Complementary O
studies O
confirmed O
that O
high O
- O
dose O
PHB B
can O
convert O
to O
its O
prodrug O
primidone B
, O
which O
has O
not O
been O
reported O
previously O
. O

Systematic O
review O
of O
population O
pharmacokinetic O
analyses O
of O
imatinib B
and O
relationships O
with O
treatment O
outcomes O
. O

Several O
population O
pharmacokinetic O
( O
PPK O
) O
analyses O
of O
the O
anticancer O
drug O
imatinib B
have O
been O
performed O
to O
investigate O
different O
patient O
populations O
and O
covariate O
effects O
. O

The O
present O
analysis O
offers O
a O
systematic O
qualitative O
and O
quantitative O
summary O
and O
comparison O
of O
those O
. O

Its O
primary O
objective O
was O
to O
provide O
useful O
information O
for O
evaluating O
the O
expectedness O
of O
imatinib B
plasma O
concentration O
measurements O
in O
the O
frame O
of O
therapeutic O
drug O
monitoring O
. O

The O
secondary O
objective O
was O
to O
review O
clinically O
important O
concentration O
- O
effect O
relationships O
to O
provide O
help O
in O
evaluating O
the O
potential O
suitability O
of O
plasma O
concentration O
values O
. O

Nine O
PPK O
models O
describing O
total O
imatinib B
plasma O
concentration O
were O
identified O
. O

Parameter O
estimates O
were O
standardized O
to O
common O
covariate O
values O
whenever O
possible O
. O

Predicted O
median O
exposure O
( O
C O
min O
) O
was O
derived O
by O
simulations O
and O
ranged O
between O
models O
from O
555 O
to O
1388 O
ng O
/ O
mL O
( O
grand O
median O
: O
870 O
ng O
/ O
mL O
and O
interquartile O
" O
reference O
" O
range O
: O
520 O
- O
1390 O
ng O
/ O
mL O
) O
. O

Covariates O
of O
potential O
clinical O
importance O
( O
up O
to O
30 O
% O
change O
in O
pharmacokinetic O
predicted O
by O
at O
least O
1 O
model O
) O
included O
body O
weight O
, O
albumin O
, O
alpha O
1 O
acid O
glycoprotein O
, O
and O
white O
blood O
cell O
count O
. O

Various O
other O
covariates O
were O
included O
but O
were O
statistically O
not O
significant O
or O
seemed O
clinically O
less O
important O
or O
physiologically O
controversial O
. O

Concentration O
- O
response O
relationships O
had O
more O
importance O
below O
the O
average O
reference O
range O
and O
concentration O
- O
toxicity O
relationships O
above O
. O

Therapeutic O
drug O
monitoring O
- O
guided O
dosage O
adjustment O
seems O
justified O
for O
imatinib B
, O
but O
a O
formal O
predictive O
therapeutic O
range O
remains O
difficult O
to O
propose O
in O
the O
absence O
of O
prospective O
target O
concentration O
intervention O
trials O
. O

To O
evaluate O
the O
expectedness O
of O
a O
drug O
concentration O
measurement O
in O
practice O
, O
this O
review O
allows O
comparison O
of O
the O
measurement O
either O
to O
the O
average O
reference O
range O
or O
to O
a O
specific O
range O
accounting O
for O
individual O
patient O
characteristics O
. O

For O
future O
research O
, O
external O
PPK O
model O
validation O
or O
meta O
- O
model O
development O
should O
be O
considered O
. O

Enteropathogenic O
Escherichia O
coli O
- O
induced O
macrophage O
inhibitory O
cytokine O
1 O
mediates O
cancer O
cell O
survival O
: O
an O
in O
vitro O
implication O
of O
infection O
- O
linked O
tumor O
dissemination O
. O

Mucosally O
adherent O
Escherichia O
coli O
is O
frequently O
observed O
in O
intestinal O
surface O
of O
patients O
with O
colorectal O
cancer O
, O
but O
rarely O
in O
healthy O
control O
. O

Particularly O
, O
enteropathogenic O
Escherichia O
coli O
( O
EPEC O
) O
is O
known O
to O
be O
closely O
associated O
with O
colorectal O
carcinogenesis O
in O
human O
. O

In O
this O
study O
, O
one O
consequence O
of O
EPEC O
infection O
in O
human O
intestinal O
cancer O
cells O
was O
induction O
of O
macrophage O
inhibitory O
cytokine O
1 O
( O
MIC O
- O
1 O
) O
, O
which O
is O
a O
multifunctional O
cytokine O
with O
biological O
activities O
involved O
in O
cancer O
cell O
growth O
, O
differentiation O
and O
migration O
. O

The O
present O
investigation O
assessed O
the O
involvement O
of O
MIC O
- O
1 O
protein O
in O
EPEC O
infection O
- O
mediated O
cancer O
cell O
survival O
. O

The O
challenge O
with O
EPEC O
induced O
cancer O
cell O
detachment O
via O
cytoskeleton O
rearrangement O
, O
which O
was O
positively O
associated O
with O
induced O
MIC O
- O
1 O
expression O
. O

Moreover O
, O
MIC O
- O
1 O
also O
mediated O
RhoA O
GTPase O
- O
linked O
survival O
of O
the O
detached O
cancer O
cells O
. O

Blocking O
of O
MIC O
- O
1 O
or O
RhoA O
activity O
increased O
cellular O
apoptosis O
of O
the O
detached O
cancer O
cells O
. O

In O
terms O
of O
signaling O
pathway O
, O
MIC O
- O
1 O
triggered O
transforming O
growth O
factor O
beta O
- O
activated O
kinase O
1 O
( O
TAK1 O
) O
, O
which O
enhanced O
expression O
of O
RhoA O
GTPase O
. O

We O
conclude O
that O
EPEC O
enhances O
MIC O
- O
1 O
gene O
expression O
in O
the O
human O
intestinal O
cancer O
cells O
, O
which O
can O
be O
associated O
with O
enhanced O
tumor O
cell O
resistance O
to O
anchorage O
- O
dependent O
tumor O
cell O
death O
via O
enhanced O
TAK1 O
and O
RhoA O
GTPase O
. O
Oncogene O
advance O
online O
publication O
, O
18 O
March O
2013 O
; O
doi O
: O
10 O
. O
1038 O
/ O
onc O
. O
2012 O
. O
508 O
. O

The O
regulatory O
roles O
of O
phosphatases O
in O
cancer O
. O

The O
relevance O
of O
potentially O
reversible O
post O
- O
translational O
modifications O
required O
for O
controlling O
cellular O
processes O
in O
cancer O
is O
one O
of O
the O
most O
thriving O
arenas O
of O
cellular O
and O
molecular O
biology O
. O

Any O
alteration O
in O
the O
balanced O
equilibrium O
between O
kinases O
and O
phosphatases O
may O
result O
in O
development O
and O
progression O
of O
various O
diseases O
, O
including O
different O
types O
of O
cancer O
, O
though O
phosphatases O
are O
relatively O
under O
- O
studied O
. O

Loss O
of O
phosphatases O
such O
as O
PTEN O
( O
phosphatase O
and O
tensin O
homologue O
deleted O
on O
chromosome O
10 O
) O
, O
a O
known O
tumour O
suppressor O
, O
across O
tumour O
types O
lends O
credence O
to O
the O
development O
of O
phosphatidylinositol B
3 O
- O
- O
kinase O
inhibitors O
alongside O
the O
use O
of O
phosphatase O
expression O
as O
a O
biomarker O
, O
though O
phase O
3 O
trial O
data O
are O
lacking O
. O

In O
this O
review O
, O
we O
give O
an O
updated O
report O
on O
phosphatase O
dysregulation O
linked O
to O
organ O
- O
specific O
malignancies O
. O
Oncogene O
advance O
online O
publication O
, O
18 O
March O
2013 O
; O
doi O
: O
10 O
. O
1038 O
/ O
onc O
. O
2013 O
. O
80 O
. O

Sol O
- O
gel O
nanoglues O
for O
an O
organic O
binder O
- O
free O
TiO2 B
nanofiber O
anode O
for O
lithium B
ion O
batteries O
. O

A O
TiO2 B
nanofiber O
anode O
is O
glued O
using O
a O
sol O
- O
gel O
reaction O
to O
improve O
cycle O
performance O
and O
Coulombic O
efficiencies O
. O

The O
hydrolysis O
- O
condensation O
process O
produces O
TiO2 B
nanoglues O
consisting O
of O
TiO2 B
nanoparticles O
, O
providing O
strong O
adhesion O
between O
nanofibers O
and O
the O
current O
collector O
as O
well O
as O
between O
nanofibers O
, O
rendering O
favourable O
transporting O
properties O
of O
electrons O
and O
Li B
ions O
in O
the O
TiO2 B
nanofiber O
electrode O
, O
and O
eventually O
leading O
to O
the O
excellent O
performance O
of O
Li B
ion O
batteries O
exhibiting O
an O
excellent O
initial O
Coulombic O
efficiency O
( O
~ O
85 O
% O
) O
, O
cycle O
performance O
up O
to O
100 O
cycles O
, O
and O
high O
rate O
capability O
( O
60 O
% O
at O
5 O
C O
) O
. O

Cellular O
effects O
of O
manufactured O
nanoparticles O
: O
effect O
of O
adsorption O
ability O
of O
nanoparticles O
. O

Nanoparticles O
are O
important O
industrial O
materials O
. O

However O
, O
many O
nanoparticles O
show O
biological O
effects O
, O
including O
toxic O
activity O
. O

Metal O
ion O
release O
is O
the O
most O
important O
factor O
affecting O
the O
biological O
effects O
of O
nanoparticles O
. O

In O
addition O
, O
nanoparticles O
have O
large O
adsorption O
ability O
. O

The O
adsorption O
ability O
, O
in O
particular O
protein O
adsorption O
to O
nanoparticles O
, O
has O
an O
effect O
on O
cellular O
uptake O
and O
cellular O
metabolisms O
. O

Moreover O
, O
the O
adsorption O
ability O
of O
nanoparticles O
causes O
artificial O
effects O
in O
in O
vitro O
systems O
. O

Consequently O
, O
accurate O
determination O
of O
released O
or O
secreted O
proteins O
such O
as O
lactate B
dehydrogenase O
and O
cytokines O
adsorbed O
to O
nanoparticles O
is O
affected O
. O

In O
addition O
, O
artificial O
effects O
cause O
overestimation O
or O
underestimation O
of O
the O
cytotoxicity O
of O
nanoparticles O
. O

Therefore O
, O
measurement O
of O
the O
protein O
adsorption O
of O
nanoparticles O
is O
important O
. O

Some O
methods O
for O
the O
determination O
of O
the O
adsorption O
to O
nanoparticles O
have O
been O
suggested O
. O

The O
flow O
field O
- O
flow O
fractionation O
method O
is O
one O
of O
the O
efficient O
techniques O
for O
determining O
proteins O
on O
the O
surface O
of O
nanoparticles O
. O

The O
cellular O
effects O
caused O
by O
nanoparticles O
should O
be O
carefully O
considered O
. O

Xanthohumol B
attenuates O
tumour O
cell O
- O
mediated O
breaching O
of O
the O
lymphendothelial O
barrier O
and O
prevents O
intravasation O
and O
metastasis O
. O

Health O
beneficial O
effects O
of O
xanthohumol B
have O
been O
reported O
, O
and O
basic O
research O
provided O
evidence O
for O
anti O
- O
cancer O
effects O
. O

Furthermore O
, O
xanthohumol B
was O
shown O
to O
inhibit O
the O
migration O
of O
endothelial O
cells O
. O

Therefore O
, O
this O
study O
investigated O
the O
anti O
- O
metastatic O
potential O
of O
xanthohumol B
. O

MCF O
- O
7 O
breast O
cancer O
spheroids O
which O
are O
placed O
on O
lymphendothelial O
cells O
( O
LECs O
) O
induce O
" O
circular O
chemorepellent O
- O
induced O
defects O
" O
( O
CCIDs O
) O
in O
the O
LEC O
monolayer O
resembling O
gates O
for O
intravasating O
tumour O
bulks O
at O
an O
early O
step O
of O
lymph O
node O
colonisation O
. O

NF O
- O
kappa O
B O
reporter O
- O
, O
EROD O
- O
, O
SELE O
- O
, O
12 B
( I
S I
) I
- I
HETE I
- O
and O
adhesion O
assays O
were O
performed O
to O
investigate O
the O
anti O
- O
metastatic O
properties O
of O
xanthohumol B
. O

Western O
blot O
analyses O
were O
used O
to O
elucidate O
the O
mechanisms O
inhibiting O
CCID O
formation O
. O

Xanthohumol B
inhibited O
the O
activity O
of O
CYP O
, O
SELE O
and O
NF O
- O
kB O
and O
consequently O
, O
the O
formation O
of O
CCIDs O
at O
low O
micromolar O
concentrations O
. O

More O
specifically O
, O
xanthohumol B
affected O
ICAM O
- O
1 O
expression O
and O
adherence O
of O
MCF O
- O
7 O
cells O
to O
LECs O
, O
which O
is O
a O
prerequisite O
for O
CCID O
formation O
. O

Furthermore O
, O
markers O
of O
epithelial O
- O
to O
- O
mesenchymal O
transition O
( O
EMT O
) O
and O
of O
cell O
mobility O
such O
as O
paxillin O
, O
MCL2 O
and O
S100A4 O
were O
suppressed O
by O
xanthohumol B
. O

Xanthohumol B
attenuated O
tumour O
cell O
- O
mediated O
defects O
at O
the O
lymphendothelial O
barrier O
and O
inhibited O
EMT O
- O
like O
effects O
thereby O
providing O
a O
mechanistic O
explanation O
for O
the O
anti O
- O
intravasative O
/ O
anti O
- O
metastatic O
properties O
of O
xanthohumol B
. O

Gas O
- O
phase O
structures O
and O
thermochemistry O
of O
neutral O
histidine B
and O
its O
conjugated O
acid O
and O
base O
. O

Extensive O
exploration O
of O
the O
conformational O
space O
of O
neutral O
, O
protonated O
and O
deprotonated O
histidine B
has O
been O
conducted O
at O
the O
G4MP2 O
level O
. O

Theoretical O
protonation O
and O
deprotonation O
thermochemistry O
as O
well O
as O
heats O
of O
formation O
of O
gaseous O
histidine B
and O
its O
ionized O
forms O
have O
been O
calculated O
at O
the O
G4 O
level O
considering O
either O
the O
most O
stable O
conformers O
or O
an O
equilibrium O
population O
of O
conformers O
at O
298 O
K O
. O

These O
theoretical O
results O
were O
compared O
to O
evaluated O
experimental O
determinations O
. O

Recommended O
proton O
affinity O
and O
protonation O
entropy O
deduced O
from O
these O
comparisons O
are O
PA O
( O
His B
) O
= O
980 O
kJ O
mol O
( O
- O
1 O
) O
and O
Delta O
pS O
( O
His B
) O
~ O
0 O
J O
mol O
( O
- O
1 O
) O
K O
( O
- O
1 O
) O
, O
thus O
leading O
to O
a O
gas O
- O
phase O
basicity O
value O
of O
GB O
( O
His B
) O
= O
947 O
. O
5 O
kJ O
mol O
( O
- O
1 O
) O
. O

Similarly O
, O
gas O
phase O
acidity O
parameters O
are O
Delta O
acidH O
( O
o I
) I
( I
His I
) O
= O
1373 O
kJ O
mol O
( O
- O
1 O
) O
, O
Delta O
acidS O
( O
His B
) O
~ O
10 O
J O
mol O
( O
- O
1 O
) O
K O
( O
- O
1 O
) O
and O
Delta O
acidG O
( O
o B
) I
( O
His B
) O
= O
1343 O
kJ O
mol O
( O
- O
1 O
) O
. O

Computed O
G4 O
heats O
of O
formation O
values O
are O
equal O
to O
- O
290 O
, O
265 O
and O
- O
451 O
kJ O
mol O
( O
- O
1 O
) O
for O
gaseous O
neutral O
histidine B
and O
its O
protonated O
and O
deprotonated O
forms O
, O
respectively O
. O

The O
present O
computational O
data O
correct O
, O
and O
complete O
, O
previous O
thermochemical O
parameter O
estimates O
proposed O
for O
gas O
- O
phase O
histidine B
and O
its O
acido O
- O
basic O
properties O
. O

Maternal O
perinatal O
diet O
induces O
developmental O
programming O
of O
bone O
architecture O
. O

Maternal O
high O
- O
fat O
( O
HF O
) O
diet O
can O
alter O
offspring O
metabolism O
via O
perinatal O
developmental O
programming O
. O

This O
study O
tests O
the O
hypothesis O
that O
maternal O
HF O
diet O
also O
induces O
perinatal O
programming O
of O
offspring O
bone O
mass O
and O
strength O
. O

We O
compared O
skeletal O
acquisition O
in O
pups O
from O
C57Bl O
/ O
6J O
mice O
fed O
HF O
or O
normal O
diet O
from O
preconception O
through O
lactation O
. O

Three O
- O
week O
- O
old O
male O
and O
female O
pups O
from O
HF O
( O
HF O
- O
N O
) O
and O
normal O
mothers O
( O
N O
- O
N O
) O
were O
weaned O
onto O
normal O
diet O
. O

Outcomes O
at O
14 O
and O
26 O
weeks O
of O
age O
included O
body O
mass O
, O
body O
composition O
, O
whole O
- O
body O
bone O
mineral O
content O
( O
WBBMC O
) O
via O
peripheral O
dual O
- O
energy O
X O
- O
ray O
absorptiometry O
, O
femoral O
cortical O
and O
trabecular O
architecture O
via O
microcomputed O
tomography O
, O
and O
glucose B
tolerance O
. O

Female O
HF O
- O
N O
had O
normal O
body O
mass O
and O
glucose B
tolerance O
, O
with O
lower O
body O
fat O
( O
% O
) O
but O
higher O
serum O
leptin O
at O
14 O
weeks O
vs O
. O
N O
- O
N O
( O
P O
< O
0 O
. O
05 O
for O
both O
) O
. O

WBBMC O
was O
12 O
% O
lower O
at O
14 O
weeks O
and O
5 O
% O
lower O
at O
26 O
weeks O
, O
but O
trabecular O
bone O
volume O
fraction O
was O
20 O
% O
higher O
at O
14 O
weeks O
in O
female O
HF O
- O
N O
vs O
. O
N O
- O
N O
( O
P O
< O
0 O
. O
05 O
for O
all O
) O
. O

Male O
HF O
- O
N O
had O
normal O
body O
mass O
and O
mildly O
impaired O
glucose B
tolerance O
, O
with O
lower O
body O
fat O
( O
% O
) O
at O
14 O
weeks O
and O
lower O
serum O
leptin O
at O
26 O
weeks O
vs O
. O
N O
- O
N O
( O
P O
< O
0 O
. O
05 O
for O
both O
) O
. O

Serum O
insulin O
was O
higher O
at O
14 O
weeks O
and O
lower O
at O
26 O
weeks O
in O
HF O
- O
N O
vs O
. O
N O
- O
N O
( O
P O
< O
0 O
. O
05 O
) O
. O

Trabecular O
BV O
/ O
TV O
was O
34 O
% O
higher O
and O
cortical O
bone O
area O
was O
6 O
% O
higher O
at O
14 O
weeks O
vs O
. O
N O
- O
N O
( O
P O
< O
0 O
. O
05 O
for O
both O
) O
. O

These O
data O
suggest O
that O
maternal O
HF O
diet O
has O
complex O
effects O
on O
offspring O
bone O
, O
supporting O
the O
hypothesis O
that O
maternal O
diet O
alters O
postnatal O
skeletal O
homeostasis O
. O

LIM O
- O
homeodomain O
Transcription O
Factor O
Isl O
- O
1 O
Mediates O
the O
Effect O
of O
Leptin O
on O
Insulin O
Secretion O
in O
Mice O
. O

In O
addition O
to O
the O
well O
known O
regulating O
effects O
of O
leptin O
on O
energy O
balance O
and O
glucose B
homeostasis O
through O
the O
central O
nervous O
system O
, O
circulating O
leptin O
has O
a O
direct O
effect O
on O
pancreatic O
islet O
and O
insulin O
secretion O
through O
its O
receptor O
( O
OBRb O
) O
. O

The O
LIM O
- O
homeodomain O
transcription O
factor O
Isl O
- O
1 O
is O
expressed O
in O
all O
classes O
of O
pancreatic O
endocrine O
cells O
and O
is O
involved O
in O
regulating O
both O
islet O
development O
and O
insulin O
secretion O
. O

Both O
OBRb O
and O
Isl O
- O
1 O
mutations O
result O
in O
obesity O
- O
related O
diabetes O
. O

However O
, O
the O
interactions O
and O
physiological O
significance O
of O
leptin O
and O
Isl O
- O
1 O
in O
pancreatic O
islets O
remain O
to O
be O
established O
. O

Here O
, O
we O
show O
that O
most O
of O
leptin O
target O
cells O
in O
pancreatic O
islets O
and O
NIT O
beta O
cells O
express O
Isl O
- O
1 O
. O

Both O
in O
vivo O
and O
in O
vitro O
results O
demonstrate O
that O
leptin O
suppresses O
Isl O
- O
1 O
expression O
and O
insulin O
secretion O
in O
islet O
in O
physiological O
and O
pathophysiological O
conditions O
, O
e O
. O
g O
. O
high O
fat O
diet O
. O

This O
effect O
of O
leptin O
on O
insulin O
secretion O
is O
lost O
in O
leptin O
receptor O
- O
defective O
db O
/ O
db O
and O
Isl O
- O
1 O
- O
inducible O
knock O
- O
out O
mice O
. O

We O
conclude O
that O
the O
action O
of O
leptin O
on O
insulin O
secretion O
is O
at O
least O
partly O
mediated O
by O
Isl O
- O
1 O
. O

Another O
new O
finding O
of O
this O
study O
is O
that O
Isl O
- O
1 O
acts O
as O
a O
direct O
downstream O
target O
of O
leptin O
signaling O
molecule O
STAT3 O
to O
influence O
the O
effect O
of O
leptin O
on O
insulin O
secretion O
, O
whereas O
inversely O
, O
insulin O
has O
feedback O
regulating O
effects O
on O
Isl O
- O
1 O
expression O
through O
JAK O
- O
STAT3 O
pathway O
. O

These O
findings O
are O
crucial O
for O
understanding O
the O
mechanisms O
regulating O
insulin O
secretion O
and O
metabolism O
in O
related O
diseases O
, O
such O
as O
obesity O
and O
type O
2 O
diabetes O
. O

Testicular O
function O
and O
fertility O
in O
men O
with O
Klinefelter O
syndrome O
: O
a O
review O
. O

Klinefelter O
syndrome O
, O
47 O
, O
XXY O
( O
KS O
) O
, O
is O
the O
most O
frequent O
sex O
chromosome O
aberration O
in O
males O
, O
affecting O
1 O
in O
660 O
newborn O
boys O
. O

The O
syndrome O
is O
characterized O
by O
testicular O
destruction O
with O
extensive O
fibrosis O
and O
hyalinization O
of O
the O
seminiferous O
tubules O
resulting O
in O
small O
testes O
, O
hypergonadotropic O
hypogonadism O
, O
and O
azoospermia O
in O
the O
majority O
of O
cases O
. O

Until O
recently O
, O
infertility O
was O
considered O
an O
untreatable O
condition O
in O
KS O
. O

However O
, O
with O
the O
development O
of O
new O
advanced O
assisted O
reproductive O
techniques O
such O
as O
testicular O
sperm O
extraction O
( O
TESE O
) O
combined O
with O
ICSI O
it O
seems O
that O
KS O
patients O
should O
no O
longer O
be O
labelled O
as O
infertile O
. O

Especially O
, O
microdissection O
( O
micro O
) O
- O
TESE O
has O
proved O
to O
be O
an O
advantageous O
procedure O
for O
the O
identification O
of O
testicular O
spermatozoa O
in O
KS O
. O

The O
aim O
of O
this O
review O
was O
to O
describe O
current O
knowledge O
on O
the O
testicular O
changes O
occurring O
in O
KS O
, O
the O
associated O
changes O
in O
reproductive O
hormones O
and O
spermatogenesis O
, O
and O
the O
existing O
possibilities O
of O
biological O
fatherhood O
in O
47 O
, O
XXY O
patients O
. O

Inhibition O
of O
Protein O
Misfolding O
/ O
Aggregation O
Using O
Polyglutamine B
Binding O
Peptide O
QBP1 O
as O
a O
Therapy O
for O
the O
Polyglutamine B
Diseases O
. O

Protein O
misfolding O
and O
aggregation O
in O
the O
brain O
have O
been O
recognized O
to O
be O
crucial O
in O
the O
pathogenesis O
of O
various O
neurodegenerative O
diseases O
, O
including O
Alzheimer O
' O
s O
, O
Parkinson O
' O
s O
, O
and O
the O
polyglutamine B
( O
polyQ B
) O
diseases O
, O
which O
are O
collectively O
called O
the O
" O
protein O
misfolding O
diseases O
" O
. O

In O
the O
polyQ O
diseases O
, O
an O
abnormally O
expanded O
polyQ O
stretch O
in O
the O
responsible O
proteins O
causes O
the O
proteins O
to O
misfold O
and O
aggregate O
, O
eventually O
resulting O
in O
neurodegeneration O
. O

Hypothesizing O
that O
polyQ O
protein O
misfolding O
and O
aggregation O
could O
be O
inhibited O
by O
molecules O
specifically O
binding O
to O
the O
expanded O
polyQ O
stretch O
, O
we O
identified O
polyQ B
binding O
peptide O
1 O
( O
QBP1 O
) O
. O

We O
show O
that O
QBP1 O
does O
, O
indeed O
, O
inhibit O
misfolding O
and O
aggregation O
of O
the O
expanded O
polyQ O
protein O
in O
vitro O
. O

Furthermore O
overexpression O
of O
QBP1 O
by O
the O
crossing O
of O
transgenic O
animals O
inhibits O
neurodegeneration O
in O
Drosophila O
models O
of O
the O
polyQ O
diseases O
. O

We O
also O
introduce O
our O
attempts O
to O
deliver O
QBP1 O
into O
the O
brain O
by O
administration O
using O
viral O
vectors O
and O
protein O
transduction O
domains O
. O

Interestingly O
, O
recent O
data O
suggest O
that O
QBP1 O
can O
also O
inhibit O
the O
misfolding O
/ O
aggregation O
of O
proteins O
responsible O
for O
other O
protein O
misfolding O
diseases O
, O
highlighting O
the O
potential O
of O
QBP1 O
as O
a O
general O
therapeutic O
molecule O
for O
a O
wide O
range O
of O
neurodegenerative O
diseases O
. O

We O
hope O
that O
in O
the O
near O
future O
, O
aggregation O
inhibitor O
- O
based O
drugs O
will O
be O
developed O
and O
bring O
relief O
to O
patients O
suffering O
from O
these O
currently O
intractable O
protein O
misfolding O
diseases O
. O

The O
Pharmacokinetics O
and O
Pharmacodynamics O
of O
Zaleplon B
Delivered O
as O
a O
Thermally O
Generated O
Aerosol O
in O
a O
Single O
Breath O
to O
Volunteers O
. O

Pharmacokinetics O
, O
pharmacodynamics O
, O
safety O
, O
and O
tolerability O
of O
inhaled O
zaleplon B
were O
assessed O
in O
healthy O
volunteers O
. O

Forty O
participants O
received O
0 O
. O
5 O
, O
1 O
, O
2 O
, O
or O
4 O
mg O
zaleplon B
or O
placebo O
as O
a O
thermally O
generated O
aerosol O
in O
a O
randomized O
, O
double O
- O
blind O
, O
parallel O
- O
group O
, O
dose O
escalation O
study O
. O

Blood O
was O
collected O
up O
to O
24 O
hours O
after O
dosing O
, O
and O
sedation O
was O
assessed O
up O
to O
8 O
hours O
. O

Following O
inhalation O
, O
the O
observed O
median O
time O
to O
maximum O
plasma O
concentrations O
( O
25 O
% O
, O
75 O
% O
) O
was O
1 O
. O
89 O
( O
1 O
. O
45 O
, O
3 O
. O
08 O
) O
minutes O
and O
the O
mean O
( O
SD O
) O
elimination O
half O
- O
life O
was O
1 O
. O
24 O
( O
0 O
. O
24 O
) O
hours O
. O

The O
equilibration O
half O
- O
life O
for O
sedation O
( O
t1 O
/ O
2 O
ke0 O
) O
was O
1 O
. O
16 O
( O
0 O
. O
62 O
, O
2 O
. O
17 O
) O
minutes O
. O

The O
zaleplon B
AUC O
was O
dose O
proportional O
across O
doses O
, O
with O
a O
slope O
( O
90 O
% O
confidence O
interval O
) O
of O
log O
- O
AUC O
versus O
log O
- O
dose O
of O
0 O
. O
92 O
( O
0 O
. O
82 O
, O
1 O
. O
02 O
) O
. O

No O
clinically O
significant O
changes O
were O
noted O
in O
laboratory O
values O
, O
vital O
signs O
, O
or O
spirometry O
. O

The O
most O
common O
adverse O
events O
were O
dizziness O
, O
somnolence O
, O
euphoria O
, O
headache O
, O
and O
visual O
disturbance O
. O

Zaleplon B
inhalation O
represents O
a O
safe O
, O
well O
- O
tolerated O
means O
of O
rapidly O
achieving O
effective O
plasma O
concentrations O
. O

Exposure O
- O
Exposure O
Relationship O
of O
Tocilizumab O
, O
an O
Anti O
- O
IL O
- O
6 O
Receptor O
Monoclonal O
Antibody O
, O
in O
a O
Large O
Population O
of O
Patients O
With O
Rheumatoid O
Arthritis O
. O

Relationships O
between O
tocilizumab B
exposure O
and O
response O
were O
evaluated O
using O
data O
from O
4 O
phase O
III O
studies O
. O

Increased O
tocilizumab O
exposure O
was O
associated O
with O
improvements O
in O
Disease O
Activity O
Score O
using O
28 O
joints O
( O
DAS28 O
) O
and O
American O
College O
of O
Rheumatology O
( O
ACR O
) O
criteria O
and O
with O
a O
decrease O
in O
inflammation O
markers O
. O

A O
population O
pharmacokinetic O
/ O
pharmacodynamic O
( O
PKPD O
) O
model O
was O
developed O
to O
describe O
data O
from O
2 O
studies O
. O

An O
indirect O
- O
response O
model O
with O
a O
sigmoid O
Emax O
( O
maximal O
drug O
effect O
) O
inhibitory O
drug O
effect O
on O
DAS28 O
" O
production O
" O
rate O
adequately O
described O
the O
relationship O
between O
tocilizumab B
concentration O
and O
DAS28 O
. O

Mean O
minimum O
serum O
tocilizumab O
concentration O
at O
steady O
state O
was O
greater O
than O
the O
EC50 O
( O
concentration O
at O
which O
50 O
% O
of O
Emax O
on O
DAS28 O
is O
reached O
) O
with O
the O
8 O
- O
mg O
/ O
kg O
dose O
but O
not O
with O
the O
4 O
- O
mg O
/ O
kgdose O
. O

Simulations O
within O
a O
large O
rheumatoid O
arthritis O
( O
RA O
) O
population O
showed O
that O
DAS O
remission O
rates O
were O
38 O
% O
for O
8 O
mg O
/ O
kg O
and O
24 O
% O
for O
4 O
mg O
/ O
kg O
. O

Tocilizumab O
was O
more O
potent O
in O
RA O
patients O
with O
higher O
baseline O
interleukin O
- O
6 O
levels O
, O
but O
this O
effect O
was O
not O
clinically O
significant O
. O

Other O
covariates O
( O
eg O
, O
presence O
of O
neutralizing O
antitocilizumab O
antibodies O
) O
did O
not O
demonstrate O
a O
clinically O
meaningful O
effect O
on O
tocilizumab O
DAS28 O
dose O
- O
response O
relationships O
. O

These O
data O
support O
clinical O
observations O
that O
tocilizumab O
8 O
mg O
/ O
kg O
is O
more O
effective O
than O
4 O
mg O
/ O
kg O
in O
reducing O
disease O
activity O
. O

Sclerostin O
and O
bone O
strength O
in O
women O
in O
their O
10 O
( O
th O
) O
decade O
of O
life O
. O

Sclerostin O
is O
a O
potent O
inhibitor O
of O
bone O
formation O
but O
has O
been O
shown O
to O
correlate O
positively O
with O
areal O
bone O
mineral O
density O
( O
aBMD O
) O
. O

Little O
is O
known O
about O
its O
relationship O
to O
parameters O
of O
bone O
strength O
and O
volumentric O
BMD O
( O
vBMD O
) O
as O
measured O
by O
peripheral O
quantitative O
computed O
tomography O
( O
pQCT O
) O
. O

We O
measured O
both O
serum O
sclerostin O
and O
parameters O
of O
tibial O
bone O
size O
and O
strength O
by O
pQCT O
to O
characterize O
this O
relationship O
. O

Our O
study O
population O
consisted O
of O
223 O
Caucasian O
and O
35 O
African O
American O
women O
( O
mean O
age O
87 O
) O
from O
the O
Study O
of O
Osteoporotic O
Fractures O
( O
SOF O
) O
cohort O
, O
who O
had O
usable O
pQCT O
scans O
of O
the O
tibia O
at O
sites O
4 O
% O
( O
T4 O
% O
) O
, O
33 O
% O
( O
T33 O
% O
) O
, O
and O
66 O
% O
( O
T66 O
% O
) O
from O
the O
ankle O
. O

Analysis O
of O
covariance O
was O
used O
to O
test O
for O
differences O
in O
age O
- O
adjusted O
means O
of O
aBMD O
, O
pQCT O
variables O
, O
and O
serum O
biomarkers O
across O
sclerostin O
quartiles O
. O

Black O
women O
had O
significantly O
lower O
median O
sclerostin O
( O
34 O
. O
3 O
pmol O
/ O
L O
) O
than O
white O
women O
( O
48 O
. O
5 O
pmol O
/ O
L O
) O
( O
p O
= O
0 O
. O
05 O
) O
. O

Women O
in O
the O
highest O
sclerostin O
quartile O
had O
7 O
- O
14 O
. O
5 O
% O
higher O
hip O
aBMD O
and O
pQCT O
parameters O
of O
vBMD O
and O
bone O
size O
than O
those O
in O
the O
lowest O
quartile O
in O
multivariate O
models O
adjusting O
for O
age O
, O
race O
, O
weight O
, O
height O
and O
diabetes O
. O

The O
association O
of O
sclerostin O
with O
parameters O
of O
bone O
strength O
differed O
dramatically O
between O
T33 O
% O
and O
T66 O
% O
sites O
. O

At O
T66 O
% O
, O
women O
in O
the O
highest O
sclerostin O
quartile O
had O
pQCT O
strength O
parameters O
9 O
. O
4 O
- O
15 O
. O
3 O
% O
greater O
than O
the O
lowest O
quartile O
, O
whereas O
no O
trend O
was O
found O
for O
the O
T33 O
% O
site O
. O

Our O
results O
suggest O
paradoxical O
associations O
between O
circulating O
sclerostin O
and O
bone O
size O
, O
density O
and O
strength O
. O

( O
c O
) O
2013 O
American O
Society O
for O
Bone O
and O
Mineral O
Research O
. O

Interplay O
of O
Octahedral O
Tilts O
and O
Polar O
Order O
in O
BiFeO3 B
Films O
. O

Heterointerface O
stabilization O
of O
a O
distinct O
nonpolar O
BiFeO3 B
phase O
occurs O
simultaneously O
with O
changes O
in O
octahedral O
tilts O
. O

The O
resulting O
phase O
arises O
via O
suppression O
of O
polarization O
by O
a O
structural O
order O
parameter O
and O
can O
thus O
be O
identified O
as O
anti O
- O
ferroelectric O
( O
Fe B
displacements O
- O
bottom O
panel O
) O
. O

The O
phase O
is O
metastable O
and O
can O
be O
switched O
into O
a O
polar O
ferroelectric O
state O
( O
top O
panel O
) O
under O
an O
applied O
electric O
bias O
. O

Cobalt B
chloride I
speciation O
, O
mechanisms O
of O
cytotoxicity O
on O
human O
pulmonary O
cells O
, O
and O
synergistic O
toxicity O
with O
zinc B
. O

Cobalt B
is O
used O
in O
numerous O
industrial O
sectors O
, O
leading O
to O
occupational O
diseases O
, O
particularly O
by O
inhalation O
. O

Cobalt B
- O
associated O
mechanisms O
of O
toxicity O
are O
far O
from O
being O
understood O
and O
information O
that O
could O
improve O
knowledge O
in O
this O
area O
is O
required O
. O

We O
investigated O
the O
impact O
of O
a O
soluble O
cobalt B
compound O
, O
CoCl B
( I
2 I
) I
. I
6H I
( I
2 I
) I
O I
, O
on O
the O
BEAS O
- O
2B O
lung O
epithelial O
cell O
line O
, O
as O
well O
as O
its O
impact O
on O
metal O
homeostasis O
. O

Cobalt B
speciation O
in O
different O
culture O
media O
, O
in O
particular O
soluble O
and O
precipitated O
cobalt B
species O
, O
was O
investigated O
via O
theoretical O
and O
analytical O
approaches O
. O

The O
cytotoxic O
effects O
of O
cobalt B
on O
the O
cells O
were O
assessed O
. O

Upon O
exposure O
of O
BEAS O
- O
2B O
cells O
to O
cobalt B
, O
intracellular O
accumulation O
of O
cobalt B
and O
zinc B
was O
demonstrated O
using O
direct O
in O
situ O
microchemical O
analysis O
based O
on O
ion O
micro O
- O
beam O
techniques O
and O
analysis O
after O
cell O
lysis O
by O
inductively O
coupled O
plasma O
mass O
spectrometry O
( O
ICP O
- O
MS O
) O
. O

Microchemical O
imaging O
revealed O
that O
cobalt B
was O
rather O
homogeneously O
distributed O
in O
the O
nucleus O
and O
in O
the O
cytoplasm O
whereas O
zinc B
was O
more O
abundant O
in O
the O
nucleus O
. O

The O
modulation O
of O
zinc B
homeostasis O
led O
to O
the O
evaluation O
of O
the O
effect O
of O
combined O
cobalt B
and O
zinc B
exposure O
. O

In O
this O
case O
, O
a O
clear O
synergistic O
increase O
in O
toxicity O
was O
observed O
as O
well O
as O
a O
substantial O
increase O
in O
zinc B
content O
within O
cells O
. O

Western O
blots O
performed O
under O
the O
same O
coexposure O
conditions O
revealed O
a O
decrease O
in O
ZnT1 O
expression O
, O
suggesting O
that O
cobalt B
could O
inhibit O
zinc B
release O
through O
the O
modulation O
of O
ZnT1 O
. O

Overall O
, O
this O
study O
highlights O
the O
potential O
hazard O
to O
lung O
function O
, O
of O
combined O
exposure O
to O
cobalt B
and O
zinc B
. O

Boosting O
Immunity O
to O
Small O
Tumor O
- O
Associated O
Carbohydrates B
with O
Bacteriophage O
Q O
beta O
Capsids O
. O

The O
development O
of O
an O
effective O
immunotherapy O
is O
an O
attractive O
strategy O
toward O
cancer O
treatment O
. O

Tumor O
associated O
carbohydrate B
antigens O
( O
TACAs O
) O
are O
overexpressed O
on O
a O
variety O
of O
cancer O
cell O
surfaces O
, O
which O
present O
tempting O
targets O
for O
anticancer O
vaccine O
development O
. O

However O
, O
such O
carbohydrates B
are O
often O
poorly O
immunogenic O
. O

To O
overcome O
this O
challenge O
, O
we O
show O
here O
that O
the O
display O
of O
a O
very O
weak O
TACA O
, O
the O
monomeric O
Tn O
antigen O
, O
on O
bacteriophage O
Q O
beta O
virus O
- O
like O
particles O
elicits O
powerful O
humoral O
responses O
to O
the O
carbohydrate B
. O

The O
effects O
of O
adjuvants O
, O
antigen O
display O
pattern O
, O
and O
vaccine O
dose O
on O
the O
strength O
and O
subclasses O
of O
antibody O
responses O
were O
established O
. O

The O
local O
density O
of O
antigen O
rather O
than O
the O
total O
amount O
of O
antigen O
administered O
was O
found O
to O
be O
crucial O
for O
induction O
of O
high O
Tn O
- O
specific O
IgG O
titers O
. O

The O
ability O
to O
display O
antigens O
in O
an O
organized O
and O
high O
density O
manner O
is O
a O
key O
advantage O
of O
virus O
- O
like O
particles O
such O
as O
Q O
beta O
as O
vaccine O
carriers O
. O

Glycan O
microarray O
analysis O
showed O
that O
the O
antibodies O
generated O
were O
highly O
selective O
toward O
Tn O
antigens O
. O

Furthermore O
, O
Q B
beta I
elicited O
much O
higher O
levels O
of O
IgG O
antibodies O
than O
other O
types O
of O
virus O
- O
like O
particles O
, O
and O
the O
IgG O
antibodies O
produced O
reacted O
strongly O
with O
the O
native O
Tn O
antigens O
on O
human O
leukemia O
cells O
. O

Thus O
, O
Q O
beta O
presents O
a O
highly O
attractive O
platform O
for O
the O
development O
of O
carbohydrate B
- O
based O
anticancer O
vaccines O
. O

Cell O
Durotaxis O
on O
Polyelectrolyte O
Multilayers O
with O
Photogenerated O
Gradients O
of O
Modulus O
. O

Behaviors O
of O
rat O
aortic O
smooth O
muscle O
( O
A7r5 O
) O
and O
human O
osteosarcoma O
( O
U2OS O
) O
cells O
on O
photo O
- O
cross O
- O
linked O
polyelectrolyte O
multilayers O
( O
PEMUs O
) O
with O
uniform O
, O
or O
gradients O
of O
, O
moduli O
were O
investigated O
. O

The O
PEMUs O
were O
built O
layer O
- O
by O
- O
layer O
with O
the O
polycation O
poly B
( I
allylamine I
hydrochloride I
) I
( O
PAH B
) O
and O
a O
polyanion O
poly B
( I
acrylic I
acid I
) I
( O
PAA B
) O
that O
was O
modified O
with O
photoreactive O
4 B
- I
( I
2 I
- I
hydroxyethoxy I
) I
benzophenone I
( O
PAABp B
) O
. O

PEMUs O
with O
different O
uniform O
and O
gradients O
of O
modulus O
were O
generated O
by O
varying O
the O
time O
of O
uniform O
ultraviolet O
light O
exposure O
and O
by O
exposure O
through O
optical O
density O
gradient O
filters O
. O

Analysis O
of O
adhesion O
, O
morphology O
, O
cytoskeletal O
organization O
, O
and O
motility O
of O
the O
cells O
on O
the O
PEMUs O
revealed O
that O
A7r5 O
cells O
established O
a O
polarized O
orientation O
toward O
increasing O
modulus O
on O
shallow O
modulus O
gradients O
( O
approximately O
4 O
. O
7 O
MPa O
mm O
( O
- O
1 O
) O
) O
and O
durotaxed O
toward O
stiffer O
regions O
on O
steeper O
gradients O
( O
approximately O
55 O
MPa O
mm O
( O
- O
1 O
) O
) O
. O

In O
contrast O
, O
U2OS O
cells O
exhibited O
little O
orientation O
or O
durotaxis O
on O
modulus O
gradients O
. O

These O
results O
demonstrate O
the O
utility O
of O
photo O
- O
cross O
- O
linked O
PEMUs O
to O
direct O
vascular O
and O
osteoblast O
cell O
behavior O
, O
a O
potential O
application O
for O
PEMU O
coatings O
on O
biomedical O
implants O
. O

New O
selective O
inhibitors O
of O
MMP O
- O
13 O
for O
inflammatory O
diseases O
: O
a O
patent O
evaluation O
( O
W02012151158 O
) O
. O

A O
series O
of O
compounds O
incorporating O
an O
aromatic O
scaffold O
based O
on O
isoxazolines B
were O
prepared O
in O
the O
patent O
application O
( O
WO2012151158 O
) O
. O

The O
new O
compounds O
from O
the O
patent O
are O
defined O
to O
be O
biologically O
active O
metabolites O
, O
prodrugs O
, O
isomers O
, O
stereoisomers O
, O
solvates O
, O
hydrates O
and O
pharmaceutically O
acceptable O
salts O
, O
they O
are O
claimed O
to O
be O
useful O
for O
treating O
immunological O
conditions O
because O
of O
their O
inhibitory O
activities O
on O
matrix O
metalloproteinase O
( O
MMP O
- O
13 O
) O
, O
although O
no O
specific O
MMP O
- O
13 O
inhibition O
data O
or O
other O
rationale O
to O
explain O
their O
biological O
effects O
is O
provided O
. O

The O
compounds O
have O
a O
broad O
potential O
utility O
with O
osteoarthritis O
, O
rheumatoid O
arthritis O
, O
juvenile O
arthritis O
, O
psoriatic O
arthritis O
, O
degenerative O
joint O
disease O
or O
systemic O
lupus O
erythematosus O
among O
the O
likely O
preferred O
indications O
. O

Increased O
Levels O
of O
Inosine B
in O
a O
Mouse O
Model O
of O
Inflammation O
. O

One O
possible O
mechanism O
linking O
inflammation O
with O
cancer O
involves O
the O
generation O
of O
reactive O
oxygen B
, O
nitrogen B
, O
and O
halogen B
species O
by O
activated O
macrophages O
and O
neutrophils O
infiltrating O
sites O
of O
infection O
or O
tissue O
damage O
, O
with O
these O
chemical O
mediators O
causing O
damage O
that O
ultimately O
leads O
to O
cell O
death O
and O
mutation O
. O

To O
determine O
the O
most O
biologically O
deleterious O
chemistries O
of O
inflammation O
, O
we O
previously O
assessed O
products O
across O
the O
spectrum O
of O
DNA O
damage O
arising O
in O
inflamed O
tissues O
in O
the O
SJL O
mouse O
model O
nitric B
oxide I
overproduction O
( O
Pang O
et O
al O
. O
( O
2007 O
) O
Carcinogenesis O
28 O
, O
1807 O
- O
1813 O
) O
. O

Among O
the O
anticipated O
DNA O
damage O
chemistries O
, O
we O
observed O
significant O
changes O
only O
in O
lipid O
peroxidation O
- O
derived O
etheno B
adducts O
. O

We O
have O
now O
developed O
an O
isotope O
- O
dilution O
, O
liquid O
chromatography O
- O
coupled O
, O
tandem O
quadrupole O
mass O
spectrometric O
method O
to O
quantify O
representative O
species O
across O
the O
spectrum O
of O
RNA O
damage O
products O
predicted O
to O
arise O
at O
sites O
of O
inflammation O
, O
including O
nucleobase B
deamination O
( O
xanthosine B
and O
inosine B
) O
, O
oxidation O
( O
8 B
- I
oxoguanosine I
) O
, O
and O
alkylation O
( O
1 B
, I
N I
( I
6 I
) I
- I
ethenoadenosine I
) O
. O

Application O
of O
the O
method O
to O
the O
liver O
, O
spleen O
, O
and O
kidney O
from O
the O
SJL O
mouse O
model O
revealed O
generally O
higher O
levels O
of O
oxidative O
background O
RNA O
damage O
than O
was O
observed O
in O
DNA O
in O
control O
mice O
. O

However O
, O
compared O
to O
control O
mice O
, O
RcsX O
treatment O
to O
induce O
nitric B
oxide I
overproduction O
resulted O
in O
significant O
increases O
only O
in O
inosine B
and O
only O
in O
the O
spleen O
. O

Further O
, O
the O
nitric B
oxide I
synthase O
inhibitor O
, O
N B
- I
methylarginine I
, O
did O
not O
significantly O
affect O
the O
levels O
of O
inosine B
in O
control O
and O
RcsX O
- O
treated O
mice O
. O

The O
differences O
between O
DNA O
and O
RNA O
damage O
in O
the O
same O
animal O
model O
of O
inflammation O
point O
to O
possible O
influences O
from O
DNA O
repair O
, O
RcsX O
- O
induced O
alterations O
in O
adenosine B
deaminase O
activity O
, O
and O
differential O
accessibility O
of O
DNA O
and O
RNA O
to O
reactive O
oxygen B
and O
nitrogen B
species O
as O
determinants O
of O
nucleic O
acid O
damage O
during O
inflammation O
. O

Comprehensive O
Experimental O
and O
Computational O
Analysis O
of O
Binding O
Energy O
Hot O
Spots O
at O
the O
NF O
- O
kappa O
B O
Essential O
Modulator O
/ O
IKK O
beta O
Protein O
- O
Protein O
Interface O
. O

We O
report O
a O
comprehensive O
analysis O
of O
binding O
energy O
hot O
spots O
at O
the O
protein O
- O
protein O
interaction O
( O
PPI O
) O
interface O
between O
nuclear O
factor O
kappa O
B O
( O
NF O
- O
kappa O
B O
) O
essential O
modulator O
( O
NEMO O
) O
and O
I O
kappa O
B O
kinase O
subunit O
beta O
( O
IKK O
beta O
) O
, O
an O
interaction O
that O
is O
critical O
for O
NF O
- O
kappa O
B O
pathway O
signaling O
, O
using O
experimental O
alanine B
scanning O
mutagenesis O
and O
also O
the O
FTMap O
method O
for O
computational O
fragment O
screening O
. O

The O
experimental O
results O
confirm O
that O
the O
previously O
identified O
NEMO O
binding O
domain O
( O
NBD O
) O
region O
of O
IKK O
beta O
contains O
the O
highest O
concentration O
of O
hot O
- O
spot O
residues O
, O
the O
strongest O
of O
which O
are O
W739 O
, O
W741 O
, O
and O
L742 O
( O
Delta O
Delta O
G O
= O
4 O
. O
3 O
, O
3 O
. O
5 O
, O
and O
3 O
. O
2 O
kcal O
/ O
mol O
, O
respectively O
) O
. O

The O
region O
occupied O
by O
these O
residues O
defines O
a O
potentially O
druggable O
binding O
site O
on O
NEMO O
that O
extends O
for O
~ O
16 O
A O
to O
additionally O
include O
the O
regions O
that O
bind O
IKK O
beta O
L737 O
and O
F734 O
. O

NBD O
residues O
D738 O
and O
S740 O
are O
also O
important O
for O
binding O
but O
do O
not O
make O
direct O
contact O
with O
NEMO O
, O
instead O
likely O
acting O
to O
stabilize O
the O
active O
conformation O
of O
surrounding O
residues O
. O

We O
additionally O
found O
two O
previously O
unknown O
hot O
- O
spot O
regions O
centered O
on O
IKK O
beta O
residues O
L708 O
/ O
V709 O
and O
L719 O
/ O
I723 O
. O

The O
computational O
approach O
successfully O
identified O
all O
three O
hot O
- O
spot O
regions O
on O
IKK O
beta O
. O

Moreover O
, O
the O
method O
was O
able O
to O
accurately O
quantify O
the O
energetic O
importance O
of O
all O
hot O
- O
spot O
residues O
involving O
direct O
contact O
with O
NEMO O
. O

Our O
results O
provide O
new O
information O
to O
guide O
the O
discovery O
of O
small O
- O
molecule O
inhibitors O
that O
target O
the O
NEMO O
/ O
IKK O
beta O
interaction O
. O

They O
additionally O
clarify O
the O
structural O
and O
energetic O
complementarity O
between O
" O
pocket O
- O
forming O
" O
and O
" O
pocket O
- O
occupying O
" O
hot O
- O
spot O
residues O
, O
and O
further O
validate O
computational O
fragment O
mapping O
as O
a O
method O
for O
identifying O
hot O
spots O
at O
PPI O
interfaces O
. O

Targeting O
TRP O
Channels O
in O
Airway O
Disorders O
. O

Novel O
effective O
therapeutic O
agents O
are O
actively O
sought O
for O
the O
treatment O
of O
a O
broad O
spectrum O
of O
respiratory O
diseases O
which O
collectively O
significantly O
impact O
on O
mortality O
, O
morbidity O
and O
quality O
of O
life O
of O
hundreds O
of O
millions O
of O
people O
world O
- O
wide O
. O

These O
include O
asthma O
, O
allergic O
rhinitis O
, O
chronic O
obstructive O
pulmonary O
disease O
, O
cough O
, O
idiopathic O
pulmonary O
fibrosis O
, O
pulmonary O
arterial O
hypertension O
, O
cystic O
fibrosis O
and O
acute O
lung O
injury O
. O

TRP O
channels O
are O
broadly O
distributed O
throughout O
the O
respiratory O
tract O
and O
play O
an O
important O
physiological O
role O
in O
sensing O
and O
subsequently O
responding O
to O
a O
wide O
variety O
of O
stimuli O
, O
for O
example O
temperature O
, O
osmolarity O
and O
oxidant O
stress O
. O

In O
the O
context O
of O
respiratory O
disease O
however O
TRP O
channel O
function O
may O
be O
altered O
, O
eg O
: O
under O
conditions O
of O
oxidative O
stress O
, O
inflammation O
, O
hypoxia O
and O
mechanical O
stress O
. O

In O
addition O
there O
is O
evidence O
that O
the O
expression O
/ O
activity O
of O
TRP O
channels O
can O
be O
affected O
in O
the O
disease O
setting O
. O

Modulators O
of O
TRP O
channel O
function O
are O
therefore O
under O
investigation O
for O
a O
range O
of O
diseases O
including O
disorders O
of O
the O
respiratory O
system O
. O

Several O
excellent O
review O
articles O
have O
discussed O
in O
detail O
evidence O
that O
modulation O
of O
specific O
TRP O
channels O
may O
be O
of O
benefit O
in O
specific O
respiratory O
diseases O
. O

In O
this O
article O
we O
have O
taken O
the O
approach O
of O
reviewing O
evidence O
that O
modulation O
of O
TRP O
channel O
function O
may O
be O
able O
to O
affect O
common O
and O
over O
- O
lapping O
characteristic O
features O
of O
respiratory O
diseases O
, O
for O
example O
bronchoconstriction O
, O
airways O
hyper O
- O
responsiveness O
, O
cough O
, O
airways O
inflammation O
, O
mucus O
hyper O
- O
secretion O
, O
exacerbations O
, O
lung O
injury O
, O
hypoxia O
and O
airways O
re O
- O
modelling O
. O

The O
therapeutic O
potential O
of O
TRP O
channel O
modulators O
, O
the O
status O
of O
these O
agents O
in O
the O
clinic O
along O
with O
the O
challenges O
posed O
in O
this O
rapidly O
advancing O
field O
are O
also O
discussed O
in O
this O
review O
. O

The O
hemodynamics O
of O
septic O
shock O
: O
a O
historical O
perspective O
. O

In O
the O
late O
19th O
century O
, O
it O
was O
already O
known O
that O
severe O
infections O
could O
be O
associated O
with O
cardiovascular O
collapse O
, O
a O
fact O
essentially O
attributed O
to O
cardiac O
failure O
. O

A O
major O
experimental O
work O
in O
the O
rabbit O
, O
published O
by O
Romberg O
and O
P O
a O
ssler O
in O
1899 O
, O
shifted O
attention O
to O
disturbed O
peripheral O
vascular O
tone O
as O
the O
mechanism O
of O
hypotension O
in O
these O
conditions O
. O

In O
the O
first O
half O
of O
the O
20th O
century O
, O
great O
progresses O
were O
made O
in O
the O
pathophysiologic O
understanding O
of O
hemorrhagic O
and O
traumatic O
shocks O
, O
while O
researchers O
devoted O
relatively O
little O
attention O
to O
septic O
shock O
. O

Progress O
in O
the O
hemodynamic O
understanding O
of O
septic O
shock O
resumed O
with O
the O
advent O
of O
critical O
care O
units O
. O

The O
hyperdynamic O
state O
was O
recognized O
in O
the O
late O
fifties O
and O
early O
sixties O
. O

The O
present O
short O
review O
ends O
with O
landmark O
studies O
by O
Max O
Harry O
Weil O
, O
demonstrating O
the O
importance O
of O
venous O
pooling O
, O
and O
John O
H O
. O
Siegel O
, O
which O
introduced O
the O
concept O
of O
deficient O
peripheral O
utilization O
of O
oxygen B
, O
inspiring O
later O
work O
on O
the O
microvascular O
disturbances O
of O
septic O
shock O
. O

Effect O
of O
Enzyme O
Concentration O
of O
the O
Morphology O
and O
Properties O
of O
Enzymatically O
Triggered O
Peptide O
Hydrogels O
. O

We O
have O
recently O
shown O
that O
thermolysine O
, O
a O
protease O
enzyme O
obtained O
from O
Bacillus O
thermoproteolyticus O
rokko O
, O
can O
be O
used O
to O
trigger O
the O
gelation O
of O
FEFK O
( O
F O
, O
phenylalanine B
; O
E O
, O
glutamic B
acid I
; O
K O
, O
lysine B
) O
tetrapeptides B
through O
reverse O
hydrolysis O
and O
formation O
of O
longer O
peptide O
sequences O
, O
mainly O
octapeptides B
, O
that O
self O
- O
assemble O
readily O
. O

In O
this O
article O
we O
investigate O
the O
effect O
of O
enzyme O
concentration O
on O
the O
morphology O
and O
properties O
of O
enzymatically O
triggered O
peptide O
hydrogels O
using O
HPLC O
, O
FTIR O
, O
real O
- O
time O
SAXS O
, O
TEM O
, O
and O
shear O
rheology O
. O

We O
have O
shown O
that O
the O
enzyme O
concentration O
, O
Cenz O
, O
does O
not O
affect O
the O
final O
composition O
of O
the O
samples O
. O

Instead O
, O
this O
is O
dictated O
by O
the O
initial O
tetrapeptide B
concentration O
, O
C0 O
, O
suggesting O
the O
existence O
of O
a O
chemical O
equilibrium O
. O

We O
went O
on O
to O
show O
that O
Cenz O
does O
not O
affect O
the O
self O
- O
assembly O
of O
these O
peptides O
at O
a O
molecular O
level O
either O
nor O
the O
structure O
of O
the O
fibrillar O
network O
formed O
at O
the O
nanometer O
scale O
. O

Interestingly O
, O
the O
mechanical O
properties O
were O
found O
to O
be O
affected O
by O
Cenz O
, O
where O
the O
shear O
moduli O
of O
the O
hydrogels O
were O
found O
to O
increase O
with O
increasing O
Cenz O
. O

These O
results O
suggest O
that O
morphological O
differences O
between O
the O
hydrogels O
at O
the O
microscale O
are O
at O
the O
origin O
of O
their O
difference O
in O
mechanical O
properties O
. O

In O
this O
paper O
, O
we O
propose O
a O
morphological O
model O
in O
which O
denser O
network O
regions O
are O
found O
around O
the O
enzymes O
, O
resulting O
in O
the O
creation O
of O
heterogeneous O
networks O
. O

These O
were O
confirmed O
by O
TEM O
measurements O
. O

The O
existence O
of O
these O
denser O
network O
regions O
will O
result O
in O
the O
reinforcement O
of O
the O
hydrogels O
, O
thus O
, O
explaining O
the O
high O
shear O
moduli O
obtained O
increasing O
Cenz O
. O

Evaluation O
of O
Constituents O
of O
Piper O
retrofractum O
Fruits O
on O
Neurotrophic O
Activity O
. O

Three O
new O
compounds O
, O
1 O
- O
3 O
, O
together O
with O
22 O
known O
compounds O
, O
were O
isolated O
from O
the O
fruits O
of O
Piper O
retrofractum O
. O

The O
structures O
of O
the O
new O
compounds O
were O
elucidated O
on O
the O
basis O
of O
spectroscopic O
data O
analysis O
and O
comparison O
with O
literature O
values O
. O

Compound O
1 O
was O
found O
to O
enhance O
the O
neurite O
outgrowth O
of O
NGF O
- O
mediated O
PC12 O
cells O
at O
concentrations O
ranging O
from O
0 O
. O
1 O
to O
10 O
mu O
M O
. O

' O
Bacoside B
B I
' O
- O
the O
need O
remains O
for O
establishing O
identity O
. O

Bacopa O
monnieri O
is O
fast O
gaining O
popularity O
for O
its O
beneficial O
effects O
on O
cognition O
and O
memory O
. O

The O
active O
constituents O
of O
the O
plant O
were O
putatively O
identified O
as O
' O
bacosides B
A I
and I
B I
' O
in O
older O
publications O
. O

Subsequently O
' O
bacoside B
A I
' O
was O
identified O
as O
a O
mixture O
of O
four O
saponins B
[ O
bacoside B
A3 I
( O
1 O
) O
, O
bacopaside B
II I
( O
2 O
) O
, O
bacopasaponin B
C I
( O
3 O
) O
and O
the O
jujobogenin B
isomer O
of O
the O
latter O
( O
4 O
) O
] O
and O
was O
considered O
as O
part O
of O
major O
constituents O
of O
the O
herb O
along O
with O
bacopaside B
I I
( O
5 O
) O
. O

These O
major O
saponins B
now O
form O
part O
of O
analytical O
monographs O
in O
many O
Pharmacopoeia O
. O

However O
identity O
of O
' O
bacoside B
B I
' O
still O
appears O
controversial O
with O
seemingly O
contradictory O
information O
available O
in O
the O
scientific O
literature O
. O

At O
the O
same O
time O
quality O
of O
many O
extracts O
and O
herbal O
products O
derived O
from O
the O
plant O
is O
still O
being O
determined O
based O
on O
the O
content O
of O
' O
bacosides B
A I
and I
B I
' O
. O

We O
have O
elaborated O
these O
issues O
in O
this O
article O
along O
with O
our O
recommendations O
to O
move O
forward O
towards O
achieving O
scientific O
clarity O
on O
the O
subject O
. O

Interpretation O
of O
the O
margin O
of O
exposure O
for O
genotoxic O
carcinogens O
- O
Elicitation O
of O
expert O
knowledge O
about O
the O
form O
of O
the O
dose O
response O
curve O
at O
human O
relevant O
exposures O
. O

The O
general O
approach O
to O
risk O
assessment O
of O
genotoxic O
carcinogens O
has O
been O
to O
advise O
reduction O
of O
exposure O
to O
" O
as O
low O
as O
reasonably O
achievable O
/ O
practicable O
" O
( O
ALARA O
/ O
P O
) O
. O

However O
, O
whilst O
this O
remains O
the O
preferred O
risk O
management O
option O
, O
it O
does O
not O
provide O
guidance O
on O
the O
urgency O
or O
extent O
of O
risk O
management O
actions O
necessary O
. O

To O
address O
this O
, O
the O
" O
Margin O
of O
Exposure O
" O
( O
MOE O
) O
approach O
has O
been O
proposed O
. O

The O
MOE O
is O
the O
ratio O
between O
the O
point O
of O
departure O
for O
carcinogenesis O
and O
estimated O
human O
exposure O
. O

However O
, O
interpretation O
of O
the O
MOE O
requires O
implicit O
or O
explicit O
consideration O
of O
the O
shape O
of O
the O
dose O
- O
response O
curve O
at O
human O
relevant O
exposures O
. O

In O
a O
structured O
elicitation O
exercise O
, O
we O
captured O
expert O
opinion O
on O
available O
scientific O
evidence O
for O
low O
dose O
- O
response O
relationships O
for O
genotoxic O
carcinogens O
. O

This O
allowed O
assessment O
of O
: O
available O
evidence O
for O
the O
nature O
of O
dose O
- O
response O
relationships O
at O
human O
relevant O
exposures O
; O
the O
generality O
of O
judgments O
about O
such O
dose O
- O
response O
relationships O
; O
uncertainties O
affecting O
judgments O
on O
the O
nature O
of O
such O
dose O
- O
response O
relationships O
; O
and O
whether O
this O
last O
should O
differ O
for O
different O
classes O
of O
genotoxic O
carcinogens O
. O

Elicitation O
results O
reflected O
the O
variability O
in O
experts O
' O
views O
on O
the O
form O
of O
the O
dose O
- O
response O
curve O
for O
low O
dose O
exposure O
and O
major O
sources O
of O
uncertainty O
affecting O
the O
assumption O
of O
a O
linear O
relationship O
. O

Inhibitory O
effects O
of O
in O
vivo O
oxidized O
high O
- O
density O
lipoproteins O
on O
platelet O
aggregation O
: O
evidence O
from O
patients O
with O
abetalipoproteinemia O
. O

There O
is O
evidence O
that O
high O
- O
density O
lipoproteins O
( O
HDLs O
) O
may O
regulate O
platelet O
function O
, O
but O
disparate O
results O
exist O
regarding O
the O
effects O
of O
oxidized O
HDLs O
on O
platelets O
. O

The O
objective O
of O
our O
study O
was O
to O
determine O
the O
role O
of O
in O
vivo O
oxidized O
HDLs O
on O
platelet O
aggregation O
. O

Platelet O
aggregation O
and O
redox O
status O
were O
investigated O
in O
5 O
patients O
with O
abetalipoproteinemia O
( O
ABLP O
) O
or O
homozygous O
hypobetalipoproteine O
, O
two O
rare O
metabolic O
diseases O
characterized O
by O
the O
absence O
of O
apolipoprotein O
B O
- O
containing O
lipoproteins O
, O
compared O
to O
5 O
control O
subjects O
. O

Platelets O
isolated O
from O
plasma O
of O
patients O
with O
ABLP O
aggregated O
4 O
to O
10 O
times O
more O
than O
control O
platelets O
, O
depending O
on O
the O
agonist O
. O

By O
contrast O
, O
no O
differences O
in O
the O
extent O
of O
platelet O
aggregation O
were O
observed O
between O
ABLP O
platelet O
- O
rich O
plasma O
( O
PRP O
) O
and O
control O
PRP O
, O
suggesting O
the O
presence O
of O
a O
protective O
factor O
in O
ABLP O
plasma O
. O

ABLP O
HDLs O
inhibited O
agonist O
- O
induced O
platelet O
aggregation O
by O
binding O
to O
SR O
- O
BI O
, O
while O
control O
HDLs O
had O
no O
effect O
. O

On O
the O
other O
hand O
, O
lipoprotein O
- O
deficient O
plasma O
from O
patients O
with O
ABLP O
did O
not O
inhibit O
platelet O
aggregation O
. O

Severe O
oxidative O
stress O
was O
evidenced O
in O
patients O
with O
ABLP O
. O

Compared O
to O
control O
HDLs O
, O
ABLP O
HDLs O
showed O
a O
40 O
% O
decrease O
of O
alpha B
- I
tocopherol I
and O
an O
11 O
- O
fold O
increased O
malondialdehyde B
concentration O
. O

These O
results O
demonstrate O
that O
in O
vivo O
oxidized O
HDLs O
do O
not O
lose O
their O
antiaggregatory O
properties O
despite O
oxidation O
. O
- O
Calzada O
, O
C O
. O
, O
V O
e O
ricel O
, O
E O
. O
, O
Colas O
, O
R O
. O
, O
Guillot O
, O
N O
. O
, O
El O
Khoury O
, O
G O
. O
, O
Drai O
, O
J O
. O
, O
Sassolas O
, O
A O
. O
, O
Peretti O
, O
N O
. O
, O
Ponsin O
, O
G O
. O
, O
Lagarde O
, O
M O
. O
, O
Moulin O
, O
P O
. O

Inhibitory O
effects O
of O
in O
vivo O
oxidized O
high O
- O
density O
lipoproteins O
on O
platelet O
aggregation O
: O
evidence O
from O
patients O
with O
abetalipoproteinemia O
. O

A O
genome O
- O
wide O
association O
study O
of O
bronchodilator O
response O
in O
asthmatics O
. O

Reversibility O
of O
airway O
obstruction O
in O
response O
to O
beta O
2 O
- O
agonists O
is O
highly O
variable O
among O
asthmatics O
, O
which O
is O
partially O
attributed O
to O
genetic O
factors O
. O

In O
a O
genome O
- O
wide O
association O
study O
of O
acute O
bronchodilator O
response O
( O
BDR O
) O
to O
inhaled O
albuterol B
, O
534 O
290 O
single O
- O
nucleotide O
polymorphisms O
( O
SNPs O
) O
were O
tested O
in O
403 O
white O
trios O
from O
the O
Childhood O
Asthma O
Management O
Program O
using O
five O
statistical O
models O
to O
determine O
the O
most O
robust O
genetic O
associations O
. O

The O
primary O
replication O
phase O
included O
1397 O
polymorphisms O
in O
three O
asthma O
trials O
( O
pooled O
n O
= O
764 O
) O
. O

The O
second O
replication O
phase O
tested O
13 O
SNPs O
in O
three O
additional O
asthma O
populations O
( O
n O
= O
241 O
, O
n O
= O
215 O
and O
n O
= O
592 O
) O
. O

An O
intergenic O
SNP O
on O
chromosome O
10 O
, O
rs11252394 O
, O
proximal O
to O
several O
excellent O
biological O
candidates O
, O
significantly O
replicated O
( O
P O
= O
1 O
. O
98 O
x O
10 O
( O
- O
7 O
) O
) O
in O
the O
primary O
replication O
trials O
. O

An O
intronic O
SNP O
( O
rs6988229 O
) O
in O
the O
collagen O
( O
COL22A1 O
) O
locus O
also O
provided O
strong O
replication O
signals O
( O
P O
= O
8 O
. O
51 O
x O
10 O
( O
- O
6 O
) O
) O
. O

This O
study O
applied O
a O
robust O
approach O
for O
testing O
the O
genetic O
basis O
of O
BDR O
and O
identified O
novel O
loci O
associated O
with O
this O
drug O
response O
in O
asthmatics O
. O
The O
Pharmacogenomics O
Journal O
advance O
online O
publication O
, O
19 O
March O
2013 O
; O
doi O
: O
10 O
. O
1038 O
/ O
tpj O
. O
2013 O
. O
5 O
. O

Differential O
tolerance O
to O
copper B
, O
but O
no O
evidence O
of O
population O
- O
level O
genetic O
differences O
in O
a O
widely O
- O
dispersing O
native O
barnacle O
. O

Despite O
many O
estuaries O
having O
high O
levels O
of O
metal O
pollution O
, O
species O
are O
found O
to O
persist O
in O
these O
stressful O
environments O
. O

Populations O
of O
estuarine O
invertebrates O
exposed O
to O
toxic O
concentrations O
of O
such O
metals O
may O
be O
under O
selection O
. O

However O
, O
in O
species O
with O
a O
wide O
- O
dispersal O
potential O
, O
any O
short O
- O
term O
results O
of O
localized O
selection O
may O
be O
counteracted O
by O
external O
recruitment O
from O
populations O
not O
under O
selection O
. O

The O
barnacle O
Amphibalanus O
variegatus O
is O
found O
in O
nearshore O
coastal O
environments O
as O
well O
as O
sheltered O
embayments O
and O
estuaries O
, O
including O
metal O
- O
impacted O
estuaries O
, O
from O
New O
South O
Wales O
, O
Australia O
to O
Western O
Australia O
. O

The O
fertilised O
eggs O
of O
A O
. O
variegatus O
are O
brooded O
internally O
and O
released O
as O
larvae O
( O
nauplii O
) O
, O
which O
remain O
in O
the O
water O
- O
column O
for O
~ O
14 O
days O
before O
settling O
. O

Hence O
the O
species O
has O
a O
considerable O
dispersal O
capacity O
. O

The O
purpose O
of O
this O
study O
was O
to O
examine O
whether O
populations O
of O
A O
. O
variegatus O
from O
metal O
- O
impacted O
sites O
, O
displayed O
a O
greater O
tolerance O
to O
a O
toxicant O
( O
copper B
) O
than O
reference O
populations O
. O

Adult O
barnacles O
where O
collected O
from O
twenty O
sites O
within O
two O
metal O
- O
impacted O
and O
fourteen O
sites O
within O
two O
reference O
estuaries O
. O

Within O
24 O
h O
, O
adults O
were O
induced O
to O
spawn O
and O
the O
offspring O
were O
exposed O
to O
copper B
in O
a O
laboratory O
assay O
. O

Larvae O
collected O
from O
the O
metal O
- O
impacted O
estuaries O
demonstrated O
a O
greater O
tolerance O
to O
copper B
compared O
to O
those O
from O
reference O
sites O
. O

To O
determine O
if O
selection O
/ O
localised O
in O
the O
metal O
impacted O
sites O
was O
occurring O
, O
the O
genetic O
structure O
of O
populations O
at O
three O
sites O
was O
examined O
using O
an O
AFLP O
methodology O
. O

No O
evidence O
of O
unique O
population O
identity O
and O
or O
selection O
( O
outlier O
loci O
) O
was O
detected O
suggesting O
that O
: O
( O
1 O
) O
the O
tolerance O
displayed O
in O
the O
assay O
was O
derived O
from O
acclimation O
during O
development O
; O
and O
/ O
or O
( O
2 O
) O
that O
the O
populations O
are O
open O
preventing O
the O
fixation O
of O
any O
unique O
alleles O
. O

Diurnal O
pituitary O
- O
adrenal O
activity O
during O
schedule O
- O
induced O
polydipsia O
of O
water O
and O
ethanol B
in O
cynomolgus O
monkeys O
( O
Macaca O
fascicularis O
) O
. O

RATIONALE O
: O
Intermittent O
delivery O
of O
an O
important O
commodity O
( O
e O
. O
g O
. O
, O
food O
pellets O
) O
generates O
excessive O
behaviors O
as O
an O
adjunct O
to O
the O
schedule O
of O
reinforcement O
( O
adjunctive O
behaviors O
) O
that O
are O
hypothesized O
to O
be O
due O
to O
conflict O
between O
engaging O
and O
escaping O
a O
situation O
where O
reinforcement O
is O
delivered O
, O
but O
at O
suboptimal O
rates O
. O

OBJECTIVES O
: O
This O
study O
characterized O
the O
endocrine O
correlates O
during O
schedule O
- O
induced O
polydipsia O
of O
water O
and O
ethanol B
using O
a O
longitudinal O
approach O
in O
non O
- O
human O
primates O
. O

METHODS O
: O
Plasma O
adrenocorticotropic O
hormone O
( O
ACTH O
) O
and O
cortisol B
were O
measured O
in O
samples O
from O
awake O
cynomolgus O
monkeys O
( O
Macaca O
fascicularis O
, O
11 O
adult O
males O
) O
obtained O
at O
the O
onset O
, O
mid O
- O
day O
, O
and O
offset O
of O
their O
12 O
- O
h O
light O
cycle O
. O

The O
monkeys O
were O
induced O
to O
drink O
water O
and O
ethanol B
( O
4 O
% O
w O
/ O
v O
, O
in O
water O
) O
using O
a O
fixed O
time O
( O
FT O
) O
300 O
- O
s O
interval O
schedule O
of O
pellet O
delivery O
. O

The O
induction O
fluid O
changed O
every O
30 O
sessions O
in O
the O
following O
order O
: O
water O
, O
0 O
. O
5 O
g O
/ O
kg O
ethanol B
, O
1 O
. O
0 O
g O
/ O
kg O
ethanol B
, O
and O
1 O
. O
5 O
g O
/ O
kg O
ethanol B
. O

Following O
induction O
, O
ethanol B
and O
water O
were O
concurrently O
available O
for O
22 O
h O
/ O
day O
. O

RESULTS O
: O
The O
FT O
300 O
- O
s O
schedule O
gradually O
increased O
ACTH O
, O
but O
not O
cortisol B
, O
during O
water O
induction O
to O
a O
plateau O
sustained O
throughout O
ethanol B
induction O
in O
every O
monkey O
. O

Upon O
termination O
of O
the O
schedule O
, O
ACTH O
decreased O
to O
baseline O
and O
cortisol B
below O
baseline O
. O

Diurnal O
ACTH O
and O
cortisol B
were O
unrelated O
to O
the O
dose O
of O
ethanol B
, O
but O
ACTH O
rhythm O
flattened O
at O
0 O
. O
5 O
g O
/ O
kg O
/ O
day O
and O
remained O
flattened O
. O

CONCLUSIONS O
: O
The O
coincidence O
of O
elevated O
ACTH O
with O
the O
initial O
experience O
of O
drinking O
to O
intoxication O
may O
have O
altered O
the O
mechanisms O
involved O
in O
the O
transition O
to O
heavy O
drinking O
. O

Repressive O
Epigenetic O
Changes O
at O
the O
Mglu2 O
Promoter O
in O
Frontal O
Cortex O
of O
5 O
- O
HT2A O
Knockout O
Mice O
. O

Serotonin B
5 O
- O
HT2A O
and O
metabotropic O
glutamate B
2 O
( O
mGlu2 O
) O
are O
G O
protein O
- O
coupled O
receptors O
suspected O
in O
the O
pathophysiology O
of O
psychiatric O
disorders O
such O
as O
schizophrenia O
, O
depression O
and O
suicide O
. O

Previous O
findings O
demonstrate O
that O
mGlu2 O
mRNA O
expression O
is O
down O
- O
regulated O
in O
brain O
cortical O
regions O
of O
5 O
- O
HT2A O
knockout O
( O
KO O
) O
mice O
. O

However O
, O
the O
molecular O
mechanism O
responsible O
for O
this O
alteration O
remains O
unknown O
. O

We O
show O
here O
repressive O
epigenetic O
changes O
at O
the O
promoter O
region O
of O
the O
mGlu2 O
gene O
in O
frontal O
cortex O
of O
5 O
- O
HT2A O
- O
KO O
mice O
. O

Disruption O
of O
5 O
- O
HT2A O
receptor O
- O
dependent O
signaling O
in O
mice O
was O
associated O
with O
decreased O
acetylation O
of O
histone O
H3 O
( O
H3ac O
) O
and O
H4 O
( O
H4ac O
) O
, O
and O
increased O
tri O
- O
methylation O
of O
histone O
H3 O
at O
lysine B
27 O
( O
H3K27me3 O
) O
at O
the O
mGlu2 O
promoter O
- O
epigenetic O
changes O
that O
correlate O
with O
transcriptional O
repression O
. O

Neither O
methylation O
of O
histone O
H3 O
at O
lysine B
4 O
( O
H3K4me1 O
/ O
2 O
/ O
3 O
) O
nor O
tri O
- O
methylation O
of O
histone O
H3 O
at O
lysine B
9 O
( O
H3K9me3 O
) O
was O
affected O
. O

We O
found O
that O
Egr1 O
, O
a O
transcription O
factor O
whose O
promoter O
activity O
was O
positively O
regulated O
by O
the O
5 O
- O
HT2A O
receptor O
agonist O
TCB B
- I
2 I
, O
binds O
less O
to O
the O
mGlu2 O
promoter O
in O
frontal O
cortex O
of O
5 O
- O
HT2A O
- O
KO O
as O
compared O
to O
wild O
- O
type O
mice O
. O

Furthermore O
, O
expression O
of O
mGlu2 O
was O
increased O
by O
viral O
- O
mediated O
gene O
transfer O
of O
Flag O
- O
tagged O
Egr1 O
in O
mouse O
frontal O
cortex O
. O

Together O
, O
these O
observations O
suggest O
that O
5 O
- O
HT2A O
receptor O
- O
dependent O
signaling O
epigenetically O
affects O
mGlu2 O
transcription O
in O
mouse O
frontal O
cortex O
. O

Relationship O
of O
Dehydroepiandrostero B
Sulfate I
with O
Overweight O
and O
Insulin O
Sensitivity O
in O
12 O
- O
16 O
- O
Year O
- O
old O
Spanish O
Children O
. O

DHEA B
- O
S O
is O
the O
most O
abundant O
steroid B
hormone O
in O
human O
circulation O
. O

Although O
a O
relationship O
of O
DHEA B
- O
S O
with O
obesity O
- O
related O
diseases O
has O
been O
reported O
, O
the O
metabolic O
role O
of O
this O
hormone O
remains O
unclear O
, O
particularly O
in O
children O
. O

In O
our O
study O
, O
we O
have O
investigated O
the O
relationship O
of O
DHEA B
- O
S O
levels O
with O
anthropometric O
variables O
, O
insulin O
, O
HOMA O
, O
and O
free O
fatty B
acids I
in O
adolescents O
. O

The O
study O
sample O
included O
812 O
healthy O
12 O
- O
16 O
- O
year O
- O
old O
children O
( O
383 O
boys O
and O
429 O
girls O
) O
. O

Plasma O
DHEA B
- O
S O
was O
determined O
by O
RIA O
, O
insulin O
concentrations O
by O
IRMA O
, O
and O
free O
fatty B
acids I
by O
using O
a O
commercial O
kit O
. O

Insulin O
resistance O
was O
estimated O
using O
the O
HOMA O
index O
. O

No O
significant O
differences O
in O
plasma O
DHEA B
- O
S O
levels O
were O
found O
between O
sexes O
. O

DHEA B
- O
S O
levels O
in O
overweight O
children O
were O
significantly O
higher O
than O
in O
normal O
- O
weight O
children O
. O

DHEA B
- O
S O
levels O
were O
significantly O
correlated O
with O
weight O
and O
BMI O
after O
adjusting O
for O
age O
. O

Significant O
positive O
correlations O
between O
DHEA B
- O
S O
and O
free O
fatty B
acids I
levels O
were O
found O
after O
adjusting O
for O
age O
and O
BMI O
, O
particularly O
in O
boys O
, O
but O
not O
between O
DHEA B
- O
S O
levels O
and O
insulin O
or O
HOMA O
in O
either O
gender O
. O

DHEA B
- O
S O
levels O
in O
12 O
- O
16 O
- O
year O
- O
old O
children O
are O
correlated O
with O
weight O
and O
BMI O
independently O
of O
age O
. O

We O
failed O
to O
find O
any O
association O
between O
DHEA B
- O
S O
and O
insulin O
levels O
, O
but O
we O
did O
find O
a O
- O
significant O
correlation O
between O
DHEA B
- O
S O
and O
free O
fatty B
acids I
levels O
, O
suggesting O
that O
its O
association O
with O
free O
fatty B
acids I
may O
be O
related O
to O
the O
onset O
of O
the O
association O
of O
DHEA B
- O
S O
with O
insulin O
resi O
- O
stance O
. O

Dammarane B
- O
type O
saponins B
from O
heat O
- O
processed O
Gynostemma O
pentaphyllum O
show O
fortified O
activity O
against O
A549 O
cells O
. O

An O
ethanol B
extract O
from O
heat O
- O
processed O
Gynostemma O
pentaphyllum O
showed O
more O
potent O
cytotoxic O
activity O
against O
human O
lung O
adenocarcinoma O
A549 O
cells O
than O
that O
of O
raw O
G O
. O
pentaphyllum O
. O

Four O
constituents O
were O
isolated O
from O
heat O
- O
processed O
G O
. O
pentaphyllum O
using O
resin O
HP O
- O
20 O
, O
silica B
gel I
and O
reversed O
ODS O
column O
chromatography O
. O

They O
were O
identified O
by O
mass O
and O
NMR O
spectra O
as O
damulin B
A I
and O
damulin B
B I
, O
gypenoside B
L I
and O
gypenoside B
LI I
, O
respectively O
. O

To O
evaluate O
the O
efficacy O
of O
these O
four O
constituents O
, O
the O
MTT B
cytotoxicity O
assay O
was O
performed O
using O
A549 O
cells O
. O

Based O
on O
the O
structure O
of O
these O
four O
constituents O
, O
the O
results O
indicate O
that O
the O
hydroxyl B
group O
in O
C O
- O
2 O
and O
double O
bond O
in O
C20 O
( O
21 O
) O
and O
C20 O
( O
22 O
) O
positions O
are O
of O
importance O
in O
inhibition O
of O
A549 O
cell O
proliferation O
. O

Two O
new O
tirucallane B
triterpenoids B
from O
the O
leaves O
of O
Aquilaria O
sinensis O
. O

Two O
new O
tirucallane B
triterpenoids B
, O
aquilacallanes B
A I
- I
B I
( O
1 O
- O
2 O
) O
, O
together O
with O
15 O
known O
compounds O
( O
3 O
- O
17 O
) O
were O
isolated O
from O
the O
leaves O
of O
Aquilaria O
sinensis O
. O

The O
structures O
of O
these O
new O
compounds O
were O
elucidated O
on O
the O
basis O
of O
extensive O
spectroscopic O
analyses O
. O

All O
compounds O
were O
evaluated O
for O
their O
cytotoxic O
activity O
against O
five O
human O
cancer O
cell O
lines O
. O

The O
known O
compounds O
, O
ursolic B
acid I
( O
7 O
) O
and O
5 B
, I
7 I
, I
4 I
' I
- I
trimethoxyflavone I
( O
14 O
) O
, O
exhibited O
weak O
cytotoxic O
activity O
against O
some O
cells O
. O

Free O
radical O
reactions O
in O
two O
dimensions O
: O
a O
case O
study O
on O
photochlorination O
of O
graphene B
. O

Graphene B
, O
a O
two O
- O
dimensional O
giant O
- O
molecule O
of O
sp O
( O
2 O
) O
- O
bonded O
carbon B
atoms O
, O
provides O
a O
perfect O
platform O
for O
studying O
free O
radical O
reaction O
chemistry O
in O
two O
- O
dimensions O
, O
which O
holds O
promise O
to O
control O
the O
chemical O
functionality O
of O
graphene B
. O

Free O
- O
radical O
photochlorination O
of O
graphene B
is O
used O
as O
an O
example O
to O
investigate O
the O
thickness O
, O
stacking O
order O
, O
and O
single O
- O
and O
double O
- O
side O
dependent O
reactivity O
in O
graphene B
. O

Anomalously O
low O
reactivity O
is O
observed O
in O
the O
photochlorination O
of O
AB O
- O
stacked O
bilayer O
graphene B
in O
comparison O
with O
that O
of O
few O
- O
layer O
graphene B
. O

Double O
- O
sided O
chlorination O
of O
graphene B
shows O
higher O
reactivity O
and O
chlorine B
coverage O
than O
single O
- O
sided O
reaction O
. O

It O
is O
also O
experimentally O
and O
theoretically O
demonstrated O
that O
chlorine B
free O
radicals O
at O
low O
coverage O
prefer O
to O
form O
a O
stable O
charge O
- O
transfer O
complex O
with O
graphene B
, O
which O
highly O
enhances O
graphene B
' O
s O
conductivity O
and O
simultaneously O
generates O
a O
pseudo O
- O
bandgap O
through O
noninvasive O
doping O
. O

Moreover O
, O
the O
initial O
accumulation O
of O
chlorine B
radicals O
is O
considered O
as O
the O
rate O
- O
determining O
step O
of O
photochlorination O
of O
graphene B
. O

Enhanced O
Replication O
of O
R5 O
HIV O
- O
1 O
Isolates O
in O
vitro O
by O
a O
Small O
- O
Molecule O
Reagent O
Targeting O
HIV O
- O
1 O
Protease O
. O

Chemical O
enhancement O
: O
Designed O
to O
target O
HIV O
- O
1 O
protease O
, O
a O
novel O
gamma B
- I
hydroxyphosphonate I
has O
been O
found O
to O
significantly O
enhance O
viral O
replication O
in O
a O
panel O
of O
clinically O
relevant O
R5 O
HIV O
- O
1 O
isolates O
. O

This O
unexpected O
result O
constitutes O
the O
first O
instance O
of O
a O
small O
molecule O
capable O
of O
doing O
this O
, O
and O
it O
has O
implications O
for O
the O
preparation O
and O
use O
of O
R5 O
isolates O
in O
vaccine O
and O
drug O
development O
. O

Synthesis O
and O
evaluation O
of O
stable O
substrate O
analogs O
as O
potential O
modulators O
of O
cyclodiphosphate B
synthase O
IspF O
. O

Stable O
IspF O
substrate O
analogs O
were O
synthesized O
. O

In O
the O
presence O
of O
substrate O
analogs O
, O
the O
E O
. O
coli O
IspF O
- O
MEP O
complex O
shows O
activities O
distinct O
from O
IspF O
, O
and O
bisphosphonates B
( O
BP O
) O
behave O
differently O
than O
their O
diphosphate B
( O
DP O
) O
counterparts O
. O

Bisphosphonate B
analogs O
activate O
and O
/ O
or O
stabilize O
IspF O
, O
and O
only O
the O
closest O
structural O
substrate O
analog O
weakly O
inhibits O
the O
IspF O
- O
MEP O
complex O
. O

Scopoletin B
and O
Scopolin B
Isolated O
from O
Artemisia O
iwayomogi O
Suppress O
Differentiation O
of O
Osteoclastic O
Macrophage O
RAW O
264 O
. O
7 O
Cells O
by O
Scavenging O
Reactive O
Oxygen B
Species O
. O

Artemisia O
iwayomogi O
has O
been O
used O
as O
a O
folk O
medicine O
for O
treating O
various O
diseases O
including O
inflammatory O
and O
immune O
- O
related O
diseases O
. O

Scopoletin B
( O
1 O
) O
and O
scopolin B
( O
2 O
) O
were O
isolated O
from O
this O
species O
. O

Scopoletin B
( O
1 O
) O
showed O
more O
potent O
peroxyl B
radical O
- O
scavenging O
capacity O
, O
reducing O
capacity O
, O
and O
cellular O
antioxidant O
capacity O
compared O
to O
scopolin B
( O
2 O
) O
. O

The O
inhibitory O
effect O
of O
1 O
on O
the O
receptor O
activator O
of O
nuclear O
factor O
kappa O
B O
ligand O
- O
induced O
osteoclastic O
differentiation O
of O
RAW O
264 O
. O
7 O
macrophage O
cells O
was O
also O
more O
potent O
than O
that O
of O
2 O
. O

The O
production O
of O
general O
reactive O
oxygen B
species O
( O
ROS O
) O
and O
superoxide B
anions O
during O
differentiation O
of O
preosteoclastic O
RAW O
264 O
. O
7 O
cells O
into O
osteoclasts O
was O
attenuated O
by O
compounds O
1 O
and O
2 O
. O

These O
findings O
indicate O
that O
the O
suppressive O
effects O
of O
1 O
and O
2 O
on O
the O
differentiation O
of O
preosteoclastic O
RAW O
264 O
. O
7 O
cells O
is O
partially O
due O
to O
their O
intracellular O
antioxidant O
capacity O
, O
as O
they O
can O
scavenge O
ROS O
and O
play O
an O
important O
signaling O
role O
in O
the O
differentiation O
process O
. O

Acoustics O
as O
a O
Tool O
for O
Better O
Characterization O
of O
Ionic O
Liquids O
: O
A O
Comparative O
Study O
of O
1 B
- I
Alkyl I
- I
3 I
- I
methylimidazolium I
Bis I
[ I
( I
trifluoromethyl I
) I
sulfonyl I
] I
imide I
Room O
- O
Temperature O
Ionic O
Liquids O
. O

Acoustic O
properties O
of O
three O
( B
1 I
- I
ethyl I
- I
, I
1 I
- I
butyl I
- I
, I
and I
1 I
- I
octyl I
- I
) I
1 I
- I
alkyl I
- I
3 I
- I
methylimidazolium I
bis I
[ I
( I
trifluoromethyl I
) I
sulfonyl I
] I
imide I
room O
- O
temperature O
ionic O
liquids O
are O
reported O
and O
discussed O
. O

The O
speeds O
of O
sound O
in O
RTILs O
were O
measured O
as O
a O
function O
of O
temperature O
in O
the O
range O
288 O
- O
323 O
K O
by O
means O
of O
a O
sing O
around O
method O
. O

The O
densities O
and O
isobaric O
heat O
capacities O
were O
determined O
from O
288 O
. O
15 O
to O
363 O
. O
15 O
K O
and O
from O
293 O
. O
15 O
to O
323 O
. O
15 O
K O
, O
respectively O
. O

The O
related O
properties O
, O
like O
isentropic O
and O
isothermal O
compressibilities O
, O
isobaric O
coefficients O
of O
thermal O
expansion O
, O
molar O
isochoric O
heat O
capacities O
, O
and O
internal O
pressures O
, O
were O
calculated O
. O

It O
was O
found O
that O
for O
some O
ionic O
liquids O
, O
temperature O
dependence O
of O
isobaric O
coefficients O
of O
thermal O
expansion O
is O
small O
and O
negative O
. O

All O
investigations O
were O
completed O
by O
the O
ultrasound O
absorption O
coefficient O
measurements O
in O
1 B
- I
ethyl I
- I
and I
1 I
- I
octyl I
- I
3 I
- I
methylimidazolium I
bis I
[ I
( I
trifluoromethyl I
) I
sulfonyl I
] I
imide I
as O
a O
function O
of O
frequency O
from O
10 O
to O
300 O
MHz O
at O
temperatures O
293 O
. O
15 O
- O
298 O
. O
15 O
K O
. O

The O
ultrasound O
absorption O
spectra O
indicate O
relaxation O
frequencies O
in O
the O
megahertz O
range O
. O

Ectopic O
Thyroid O
Tissue O
in O
the O
Adrenal O
Gland O
: O
Report O
of O
2 O
Cases O
with O
Pathogenetic O
Implications O
. O

Background O
: O
Ectopic O
thyroid O
tissue O
is O
usually O
found O
anywhere O
along O
the O
embryonic O
descent O
pathway O
of O
the O
medial O
thyroid O
anlage O
from O
the O
tongue O
to O
the O
trachea O
( O
W O
o O
lfler O
area O
) O
. O

However O
, O
ectopic O
thyroid O
tissue O
in O
the O
adrenal O
gland O
( O
ETTAG O
) O
is O
not O
easy O
to O
understand O
on O
the O
basis O
of O
thyroid O
embryology O
; O
because O
it O
is O
so O
rare O
, O
the O
possibility O
of O
metastasis O
should O
first O
be O
considered O
. O

Here O
, O
we O
describe O
2 O
cases O
of O
ETTAG O
with O
pathogenetic O
implications O
and O
review O
the O
literature O
. O

Patient O
findings O
: O
Two O
cases O
of O
ETTAG O
presented O
as O
incidental O
cystic O
adrenal O
masses O
in O
adult O
females O
, O
one O
having O
a O
congenital O
hernia O
of O
Morgagni O
. O

The O
ETTAG O
was O
histologically O
indistinguishable O
from O
normal O
orthotopic O
thyroid O
tissue O
, O
and O
its O
follicular O
nature O
was O
confirmed O
by O
immunohistochemical O
positivity O
for O
thyroglobulin O
, O
thyroperoxidase O
, O
thyroid O
transcription O
factor O
- O
1 O
( O
TTF O
- O
1 O
/ O
Titf O
- O
1 O
/ O
Nkx2 O
. O
1 O
) O
, O
cytokeratin O
( O
CK O
) O
AE1 O
/ O
AE3 O
, O
CK O
7 O
, O
pendrin O
, O
human O
sodium B
iodide I
symporter O
( O
hNIS O
) O
, O
paired O
box O
gene O

8 O
( O
PAX8 O
) O
and O
FOXE1 O
( O
TTF O
- O
2 O
) O
, O
as O
well O
as O
positivity O
for O
the O
messenger O
RNA O
of O
the O
thyroglobulin O
gene O
by O
in O
situ O
hybridization O
analysis O
. O

No O
C O
cells O
( O
negativity O
for O
calcitonin O
, O
cromogranin O
and O
synaptophysin O
) O
were O
present O
. O

Neither O
BRAF O
nor O
KRAS O
mutations O
were O
detected O
with O
real O
- O
time O
polymerase O
chain O
reaction O
analysis O
. O

Further O
work O
- O
up O
did O
not O
show O
evidence O
of O
thyroid O
malignancy O
. O

Summary O
: O
ETTAG O
is O
a O
rare O
finding O
, O
with O
only O
7 O
cases O
reported O
; O
women O
are O
much O
more O
frequently O
affected O
than O
men O
( O
8 O
: O
1 O
) O
and O
it O
usually O
clinically O
presents O
in O
the O
fifth O
decade O
( O
mean O
age O
: O
54 O
, O
range O
: O
38 O
- O
67 O
) O
as O
a O
cystic O
adrenal O
mass O
incidentally O
discovered O
on O
abdominal O
ultrasonography O
and O
/ O
or O
in O
computed O
tomography O
images O
. O

ETTAG O
is O
composed O
of O
normal O
follicular O
cells O
without O
C O
cells O
. O

The O
expression O
of O
some O
transcription O
factors O
( O
TTF O
- O
1 O
, O
PAX8 O
and O
FOXE1 O
) O
involved O
in O
development O
and O
/ O
or O
migration O
of O
the O
medial O
thyroid O
anlage O
is O
preserved O
. O

Coexistence O
of O
a O
congenital O
hernia O
of O
Morgagni O
in O
one O
patient O
suggests O
an O
over O
- O
descent O
of O
medial O
thyroid O
anlage O
derived O
cells O
in O
its O
pathogenesis O
. O

Conclusion O
: O
Although O
ETTAG O
pathogenesis O
remains O
unknown O
, O
the O
lack O
of O
C O
cells O
together O
with O
the O
coexistence O
of O
a O
congenital O
defect O
of O
the O
anterior O
diaphragm O
( O
hernia O
of O
Morgagni O
) O
in O
one O
of O
our O
patients O
could O
suggest O
an O
over O
- O
descent O
of O
medial O
thyroid O
anlagen O
derived O
cells O
in O
the O
origin O
of O
this O
heterotopia O
. O

Dendrimer O
Driven O
Self O
- O
Assembly O
of O
SPR O
Active O
Silver B
- O
Gold O
Nanohybrids O
. O

A O
fourth O
generation O
PAMAM B
dendrimer O
has O
been O
successfully O
employed O
for O
the O
development O
of O
a O
single O
step O
synthesis O
strategy O
for O
self O
- O
assembled O
Ag B
- I
Au I
nanohybrid O
structures O
. O

The O
surface O
plasmon O
resonance O
properties O
and O
the O
degree O
of O
self O
- O
assembly O
of O
the O
nanohybrid O
are O
strongly O
correlated O
with O
the O
stoichiometry O
of O
the O
metals O
which O
gives O
rise O
to O
enhanced O
plasmonic O
properties O
. O

The O
enhanced O
plasmonic O
response O
of O
the O
nanohybrids O
is O
modeled O
and O
is O
validated O
experimentally O
in O
a O
model O
HRP O
( O
horseradish O
peroxidise O
) O
bioassay O
carried O
out O
on O
an O
SPR O
- O
based O
biochip O
platform O
. O

H3O2 B
Bridging O
Ligand O
in O
a O
Metal O
- O
Organic O
Framework O
. O

Insight O
into O
the O
Aqua O
- O
Hydroxo B
< I
- I
- I
> I
Hydroxyl I
Equilibrium O
: O
A O
Combined O
Experimental O
and O
Theoretical O
Study O
. O

A O
metal O
- O
organic O
framework O
( O
MOF O
) O
bearing O
the O
aqua O
- I
hydroxo I
species O
( B
O2H3 B
) I
( I
- I
) I
in O
the O
framework O
, O
as O
well O
as O
the O
processes O
that O
govern O
the O
equilibrium O
aqua B
- I
hydroxo I
( O
O2H3 B
) I
( I
- I
) I
< I
- I
- I
> I
hydroxyl B
( O
OH B
) O
in O
Sc O
- O
MOFs O
, O
are O
studied O
experimentally O
and O
theoretically O
. O

Computational O
studies O
were O
employed O
to O
determine O
the O
relative O
energies O
for O
the O
two O
compounds O
that O
coexist O
under O
certain O
hydrothermal O
conditions O
at O
pH O
< O
2 O
. O
8 O
. O

The O
thermodynamically O
more O
stable O
[ B
Sc3 I
( I
3 I
, I
5 I
- I
DSB I
) I
2 I
( I
mu I
- I
O2H3 I
) I
( I
mu I
- I
OH I
) I
2 I
( I
H2O I
) I
2 I
] O
( O
from O
now O
on O
, O
( O
O2H3 B
) O
Sc O
- O
MOF O
; O
3 B
, I
5 I
- I
DSB I
= O
3 B
, I
5 I
- I
disulfobenzoic I
acid I
) O
was O
obtained O
as O
a O
pure O
and O
stable O
phase O
. O

It O
was O
impossible O
to O
isolate O
[ O
Sc3 I
( I
3 I
, I
5 I
- I
DSB I
) I
2 I
( I
mu I
- I
OH I
) I
3 I
( I
H2O I
) I
4 I
] O
as O
a O
pure O
phase O
, O
as O
it O
turned O
out O
to O
be O
the O
precursor O
of O
( O
O2H3 B
) O
Sc O
- O
MOF O
. O

Additionally O
, O
a O
third O
compound O
that O
appears O
at O
pH O
between O
3 O
. O
5 O
and O
4 O
, O
[ O
Sc3 B
( I
3 I
, I
5 I
- I
DSB I
) I
( I
mu I
- I
OH I
) I
6 I
( I
H2O I
) I
] O
and O
a O
fourth O
, O
[ B
Sc I
( I
3 I
, I
5 I
- I
DSB I
) I
( I
Phen I
) I
( I
H2O I
) I
] I
( I
H2O I
) I
, O
in O
whose O
formula O
neither O
OH B
groups O
nor O
H3O2 B
( I
- I
) I
anions O
appear O
, O
are O
reported O
for O
comparative O
purposes O
. O

A O
study O
of O
the O
( O
O2H3 I
) O
Sc O
- O
MOF O
electronic O
structure O
, O
and O
some O
heterogeneous O
catalytic O
tests O
in O
cyanosilylation O
of O
aldehydes B
reactions O
, O
are O
also O
reported O
. O

Identification O
of O
benzofurano B
[ I
3 I
, I
2 I
- I
d I
] I
pyrimidin I
- I
2 I
- I
ones I
, O
a O
new O
series O
of O
HIV O
- O
1 O
nucleotide B
- O
competing O
reverse O
transcriptase O
inhibitors O
. O

Screening O
of O
our O
sample O
collection O
led O
to O
the O
identification O
of O
a O
set O
of O
benzofurano B
[ I
3 I
, I
2 I
- I
d I
] I
pyrimidine I
- I
2 I
- I
one I
hits O
acting O
as O
nucleotide B
- O
competing O
HIV O
- O
1 O
reverse O
transcriptase O
inhibitiors O
( O
NcRTI O
) O
. O

Significant O
improvement O
in O
antiviral O
potency O
was O
achieved O
when O
substituents O
were O
introduced O
at O
positions O
N1 O
, O
C4 O
, O
C7 O
and O
C8 O
on O
the O
benzofuranopyrimidon B
scaffold O
. O

The O
series O
was O
optimized O
from O
low O
micromolar O
enzymatic O
activity O
against O
HIV O
- O
1 O
RT O
and O
no O
antiviral O
activity O
to O
low O
nanomolar O
antiviral O
potency O
. O

Further O
profiling O
of O
inhibitor O
30 O
showed O
promising O
overall O
in O
vitro O
properties O
and O
also O
demonstrated O
that O
its O
potency O
was O
maintained O
against O
viruses O
resistant O
to O
the O
other O
major O
classes O
of O
HIV O
- O
1 O
RT O
inhibitors O
. O

Is O
there O
a O
link O
between O
neutrophil O
- O
lymphocyte O
ratio O
and O
microvascular O
complications O
in O
geriatric O
diabetic O
patients O
? O

Background O
: O
Chronic O
inflammation O
plays O
an O
important O
role O
on O
development O
and O
progression O
of O
type O
2 O
diabetes O
through O
immunologic O
inflammatory O
mechanisms O
. O

Neutrophil O
to O
lymphocyte O
ratio O
( O
NLR O
) O
is O
a O
new O
, O
simple O
and O
cheap O
marker O
of O
subclinical O
inflammation O
. O

NLR O
has O
recently O
been O
used O
as O
a O
systemic O
inflammation O
marker O
in O
chronic O
diseases O
as O
well O
as O
a O
predictor O
of O
prognosis O
in O
cardiovascular O
diseases O
and O
malignancies O
. O

Aim O
: O
The O
objective O
of O
the O
present O
study O
was O
to O
investigate O
the O
relationship O
between O
NLR O
and O
microvascular O
complications O
of O
diabetes O
mellitus O
in O
elderly O
population O
. O

Subjects O
and O
methods O
: O
Two O
hundred O
and O
forty O
- O
two O
patients O
with O
DM O
( O
145 O
diabetic O
patients O
with O
complications O
, O
97 O
diabetic O
patients O
without O
complications O
) O
and O
218 O
control O
subjects O
were O
enrolled O
in O
this O
study O
. O

NLR O
and O
microvascular O
complications O
because O
of O
diabetes O
mellitus O
were O
evaluated O
and O
compared O
with O
other O
inflammatory O
markers O
. O

Results O
: O
NLR O
was O
higher O
in O
the O
diabetic O
group O
( O
2 O
. O
21 O
+ O
/ O
- O
1 O
. O
14 O
) O
than O
in O
the O
controls O
( O
2 O
. O
18 O
+ O
/ O
- O
0 O
. O
76 O
) O
. O

Furthermore O
, O
there O
was O
a O
statistically O
significant O
difference O
between O
NLR O
levels O
in O
diabetic O
patients O
with O
and O
without O
complications O
( O
2 O
. O
46 O
+ O
/ O
- O
1 O
. O
26 O
vs O
. O
2 O
. O
04 O
+ O
/ O
- O
0 O
. O
51 O
, O
respectively O
; O
P O
< O
0 O
. O
001 O
) O
. O

The O
results O
of O
the O
multiple O
logistic O
regression O
analysis O
depicted O
that O
NLR O
is O
also O
an O
independent O
predictor O
for O
microvascular O
complications O
( O
OR O
= O
2 O
. O
217 O
; O
95 O
% O
= O
1 O
. O
086 O
- O
4 O
. O
526 O
, O
P O
= O
0 O
. O
029 O
) O
. O

ROC O
curve O
analysis O
suggested O
that O
the O
optimum O
NLR O
cut O
- O
off O
point O
for O
microvascular O
complication O
was O
2 O
. O
89 O
with O
96 O
. O
72 O
% O
specificity O
, O
94 O
. O
4 O
% O
positive O
predictive O
value O
. O

Conclusion O
: O
Increased O
NLR O
levels O
may O
be O
associated O
with O
microvascular O
complications O
of O
diabetes O
mellitus O
in O
the O
elderly O
population O
. O

High O
density O
lipoprotein O
as O
a O
source O
of O
cholesterol B
for O
adrenal O
steroidogenesis O
: O
a O
study O
in O
individuals O
with O
low O
plasma O
HDL O
- O
C O
. O

Few O
studies O
have O
addressed O
the O
delivery O
of O
lipoprotein O
- O
derived O
cholesterol B
to O
the O
adrenals O
for O
steroid B
production O
in O
humans O
. O

While O
there O
is O
evidence O
against O
a O
role O
for O
low O
- O
density O
lipoprotein O
( O
LDL O
) O
, O
it O
is O
unresolved O
whether O
high O
density O
lipoprotein O
( O
HDL O
) O
contributes O
to O
adrenal O
steroidogenesis O
. O

To O
study O
this O
, O
steroid B
hormone O
profiles O
in O
urine O
were O
assessed O
in O
male O
subjects O
suffering O
from O
functional O
mutations O
in O
ATP B
binding O
cassette O
transporter O
A1 O
( O
ABCA1 O
) O
( O
n O
= O
24 O
) O
, O
lecithin O
: O
cholesterol B
acyltransferase O
( O
LCAT O
) O
( O
n O
= O
40 O
) O
, O
as O
well O
as O
in O
11 O
subjects O
with O
low O
HDL O
cholesterol B
( O
HDL O
- O
C O
) O
without O
ABCA1 O
/ O
LCAT O
mutations O
. O

HDL O
- O
C O
levels O
were O
39 O
% O
lower O
in O
the O
ABCA1 O
, O
LCAT O
, O
and O
low O
HDL O
- O
C O
groups O
compared O
with O
controls O
( O
all O
P O
< O
0 O
. O
001 O
) O
. O

In O
all O
groups O
with O
low O
HDL O
- O
C O
levels O
, O
urinary O
excretion O
of O
17 B
- I
ketogenic I
steroids I
was O
reduced O
by O
33 O
% O
, O
27 O
% O
, O
and O
32 O
% O
compared O
with O
controls O
( O
all O
P O
< O
0 O
. O
04 O
) O
. O

In O
seven O
carriers O
of O
either O
type O
of O
mutation O
, O
adrenocorticotropic O
hormone O
( O
ACTH O
) O
stimulation O
did O
not O
reveal O
differences O
from O
normolipidemic O
controls O
. O

In O
conclusion O
, O
this O
study O
shows O
that O
basal O
but O
not O
stimulated O
corticosteroid O
metabolism O
is O
attenuated O
in O
subjects O
with O
low O
HDL O
- O
C O
, O
irrespective O
of O
its O
molecular O
origin O
. O

These O
findings O
lend O
support O
to O
a O
role O
for O
HDL O
as O
a O
cholesterol B
donor O
for O
basal O
adrenal O
steroidogenesis O
in O
humans O
. O

Redox O
- O
and O
pH O
- O
Responsive O
Cysteamine B
- O
Modified O
Poly B
( I
aspartic I
acid I
) I
Showing O
a O
Reversible O
Sol O
- O
Gel O
Transition O
. O

Synthesis O
and O
characterization O
of O
a O
pH O
- O
and O
redox O
- O
sensitive O
hydrogel O
of O
poly B
( I
aspartic I
acid I
) I
are O
reported O
. O

Reversible O
gelation O
and O
dissolution O
are O
achieved O
both O
in O
dimethylformamide B
and O
in O
aqueous O
medium O
via O
a O
thiol B
- O
disulphide B
interconversion O
in O
the O
side O
chain O
of O
the O
polymers O
. O

Structural O
changes O
are O
confirmed O
by O
Raman O
microscopy O
and O
rheological O
measurements O
. O

Injectable O
aqueous O
solutions O
of O
thiolated B
poly I
( I
aspartic I
acid I
) I
can O
be O
converted O
into O
mechanically O
stable O
gels O
by O
oxidation O
, O
which O
can O
be O
useful O
for O
drug O
encapsulation O
and O
targeted O
delivery O
. O

Reduction O
- O
facilitated O
release O
of O
an O
entrapped O
drug O
from O
disulphide B
cross O
- O
linked O
hydrogels O
is O
studied O
. O

Diarylheptanoids B
from O
Alnus O
glutinosa O
Bark O
and O
Their O
Chemoprotective O
Effect O
on O
Human O
Lymphocytes O
DNA O
. O

A O
study O
of O
secondary O
metabolites O
from O
the O
bark O
of O
Alnus O
glutinosa O
led O
to O
the O
isolation O
of O
fourteen O
diarylheptanoids B
: O
oregonin B
( O
1 O
) O
, O
platyphylloside B
( O
2 O
) O
, O
rubranoside B
A I
( O
3 O
) O
, O
rubranoside B
B I
( O
4 O
) O
, O
hirsutanonol B
( O
5 O
) O
, O
hirsutenone B
( O
6 O
) O
, O
hirsutanonol B
- I
5 I
- I
O I
- I
beta I
- I
D I
- I
glucopyranoside I
( O
7 O
) O
, O
platyphyllonol B
- I
5 I
- I
O I
- I
beta I
- I
D I
- I
xylopyranoside I
( O
8 O

) O
, O
aceroside B
VII I
( O
9 O
) O
, O
alnuside B
A I
( O
10 O
) O
, O
alnuside B
B I
( O
11 O
) O
, O
1 B
, I
7 I
- I
bis I
- I
( I
3 I
, I
4 I
- I
dihydoxyphenyl I
) I
- I
5 I
- I
hydroxy I
- I
heptane I
- I
3 I
- I
O I
- I
beta I
- I
D I
- I
xylopyranoside I
( O
12 O
) O
, O
( B
5S I
) I
- I
1 I
- I
( I
4 I
- I
hydroxyphenyl I
) I
- I
7 I
- I
( I
3 I
, I
4 I
- I
dihydroxyphenyl I
) I
- I
5 I
- I
O I
- I
beta I
- I
D I
- I
glucopyranosyl I
- I

heptan I
- I
3 I
- I
one I
( O
13 O
) O
, O
and O
( B
5S I
) I
- I
1 I
, I
7 I
- I
bis I
- I
( I
3 I
, I
4 I
- I
dihydroxyphenyl I
) I
- I
5 I
- I
O I
- I
beta I
- I
D I
- I
[ I
6 I
- I
( I
3 I
, I
4 I
- I
dimethoxycinnamoylgl I
) I
] I
- I
heptan I
- I
3 I
- I
one I
( O
14 O
) O
. O

All O
of O
the O
diarylheptanoids B
, O
except O
1 O
and O
5 O
, O
were O
found O
in O
A O
. O
glutinosa O
for O
the O
first O
time O
, O
while O
13 O
and O
14 O
were O
new O
compounds O
. O

The O
structures O
were O
determined O
by O
spectroscopic O
techniques O
: O
1D O
and O
2D O
NMR O
, O
HR O
- O
ESI O
- O
MS O
, O
FTIR O
, O
UV O
, O
and O
CD O
. O

All O
isolated O
compounds O
were O
analyzed O
for O
an O
in O
vitro O
protective O
effect O
on O
chromosome O
aberrations O
in O
peripheral O
human O
lymphocytes O
using O
the O
cytokinesis O
- O
block O
micronucleus O
assay O
. O

The O
majority O
of O
them O
, O
including O
the O
new O
compounds O
13 O
and O
14 O
, O
exerted O
a O
pronounced O
effect O
in O
decreasing O
DNA O
damage O
in O
human O
lymphocytes O
. O

Diarylheptanoids B
1 O
, O
2 O
, O
5 O
, O
13 O
, O
and O
14 O
at O
a O
concentration O
of O
1 O
micro O
g O
/ O
mL O
decreased O
the O
frequency O
of O
micronuclei O
by O
52 O
. O
8 O
% O
, O
43 O
. O
8 O
% O
, O
63 O
. O
6 O
% O
, O
44 O
. O
4 O
% O
, O
and O
56 O
. O
0 O
% O
, O
respectively O
, O
exerting O
a O
much O
stronger O
effect O
than O
the O
synthetic O
protector O
amifostine B
( O
17 O
. O
2 O
% O
, O
c O
= O
1 O
micro O
g O
/ O
mL O
) O
. O

Edge O
- O
to O
- O
Edge O
Assembled O
Graphene B
Oxide I
Aerogels O
with O
Outstanding O
Mechanical O
Performance O
and O
Superhigh O
Chemical O
Activity O
. O

Aerogels O
, O
an O
extremely O
important O
aggregation O
state O
of O
various O
self O
- O
assembled O
nanoscale O
building O
blocks O
, O
have O
great O
potential O
in O
fields O
ranging O
from O
energy O
storage O
to O
thermal O
insulation O
. O

However O
, O
the O
porosity O
of O
aerogels O
makes O
them O
mechanically O
weak O
in O
most O
cases O
, O
and O
the O
chemical O
activity O
of O
the O
resulting O
aerogel O
needs O
consideration O
. O

Herein O
, O
chemically O
crosslinked O
graphene B
oxide I
( O
GO O
) O
3D O
aerogels O
with O
large O
specific O
surface O
areas O
( O
up O
to O
850 O
m O
( O
2 O
) O
g O
( O
- O
1 O
) O
) O
, O
outstanding O
mechanical O
performance O
( O
up O
to O
20 O
MPa O
Young O
' O
s O
modulus O
, O
1 O
MPa O
yield O
strength O
and O
45 O
J O
g O
( O
- O
1 O
) O
specific O
energy O
adsorption O
) O
, O
and O
superhigh O
chemical O
activity O
( O
toward O
some O
reducing O
gases O
such O
as O
H2 B
S I
, O
HI O
, O
and O
SO2 B
) O
, O
are O
fabricated O
by O
assembling O
2D O
GO O
sheets O
edge O
- O
to O
- O
edge O
into O
uniform O
, O
3D O
hydrogel O
networks O
with O
subsequent O

supercritical O
fluid O
drying O
. O

These O
aerogels O
are O
superior O
to O
other O
3D O
frameworks O
( O
e O
. O
g O
. O
graphene B
aerogels O
) O
assembled O
via O
partial O
overlapping O
of O
the O
basal O
planes O
of O
the O
2D O
building O
blocks O
. O

Mastoid O
Obliteration O
Using O
Three O
- O
Dimensional O
Composite O
Scaffolds O
Consisting O
of O
Polycaprolactone B
/ O
beta B
- I
Tricalcium I
Phosphate I
/ O
Collagen O
Nanofibers O
: O
An O
In O
Vitro O
and O
In O
Vivo O
Study O
. O

Two O
different O
composite O
scaffolds O
, O
solid O
- O
freeform O
- O
fabricated O
PCL B
/ O
beta B
- I
TCP I
supplemented O
with O
and O
without O
collagen O
nanofibers O
are O
fabricated O
. O

These O
scaffolds O
are O
evaluated O
whether O
a O
combination O
of O
collagen O
nanofibers O
with O
PCL B
/ O
beta B
- I
TCP I
can O
promote O
osteogenesis O
in O
a O
mastoid O
obliteration O
. O

To O
assess O
the O
effects O
of O
the O
cellular O
activities O
of O
osteoblast O
- O
like O
- O
cells O
( O
MG63 O
) O
, O
SEM O
images O
and O
MTT B
assays O
are O
conducted O
. O

Experimental O
mastoid O
obliteration O
is O
performed O
using O
guinea O
pigs O
that O
are O
divided O
group O
A O
( O
PCL B
/ O
beta B
- I
TCP I
/ O
collagen O
- O
nanofiber O
scaffold O
) O
and O
group O
B O
( O
PCL B
/ O
beta B
- I
TCP I
scaffold O
) O
. O

The O
results O
reveal O
that O
PCL B
/ O
beta B
- I
TCP I
/ O
collagen O
scaffold O
provide O
much O
broader O
cell O
attachment O
sites O
than O
PCL B
/ O
beta B
- I
TCP I
scaffold O
. O

The O
micro O
- O
CT O
and O
fluorescent O
microscopy O
results O
reveal O
that O
the O
acceleration O
of O
early O
new O
bone O
formation O
within O
the O
pores O
and O
scaffold O
itself O
at O
week O
4 O
post O
- O
operation O
is O
more O
effective O
in O
group O
A O
. O

In O
addition O
, O
based O
on O
the O
results O
of O
the O
histological O
and O
micro O
- O
CT O
at O
12 O
weeks O
post O
- O
surgery O
, O
the O
effective O
regeneration O
of O
bone O
in O
the O
PCL B
/ O
beta B
- I
TCP I
/ O
collagen O
scaffold O
is O
appeared O
. O

Anticonvulsant O
/ O
antiepileptic O
carbonic O
anhydrase O
inhibitors O
: O
a O
patent O
review O
. O

Introduction O
: O
An O
epileptic O
seizure O
is O
a O
transient O
occurrence O
of O
signs O
and O
/ O
or O
symptoms O
due O
to O
abnormal O
excessive O
or O
synchronous O
neuronal O
activity O
in O
the O
brain O
. O

The O
International O
League O
Against O
Epilepsy O
classifies O
seizures O
in O
two O
broad O
categories O
: O
partial O
( O
localized O
to O
one O
cerebral O
hemisphere O
) O
and O
generalized O
( O
localized O
to O
both O
cerebral O
hemispheres O
) O
. O

One O
indirect O
pathway O
for O
the O
treatment O
of O
epilepsy O
includes O
the O
inhibition O
of O
carbonic O
anhydrase O
( O
CA O
) O
, O
thereby O
increasing O
CO2 B
levels O
in O
the O
brain O
. O

Areas O
covered O
: O
Carbonic O
anhydrases O
( O
EC O
4 O
. O
2 O
. O
1 O
. O
1 O
) O
are O
ubiquitous O
metalloenzymes O
that O
catalyze O
the O
reversible O
hydration O
/ O
dehydration O
of O
CO2 B
/ O
HCO3 B
( I
- I
) I
, O
respectively O
. O

CA O
inhibitors O
( O
CAIs O
) O
such O
as O
acetazolamide B
, O
methazolamide B
, O
topiramate B
, O
zonisamide B
, O
and O
sulthiame B
can O
reduce O
seizures O
through O
perturbation O
of O
the O
CO2 B
equilibrium O
and O
/ O
or O
the O
inhibition O
of O
ion O
channels O
. O

This O
review O
focuses O
on O
the O
mechanism O
of O
epilepsy O
, O
CA O
catalysis O
, O
and O
recent O
developments O
in O
the O
treatment O
of O
epilepsy O
using O
CAIs O
. O

Expert O
opinion O
: O
Based O
on O
the O
observed O
active O
- O
site O
binding O
interactions O
of O
CAIs O
in O
crystal O
structures O
and O
their O
respective O
inhibition O
constants O
, O
structure O
- O
activity O
relationships O
can O
be O
mapped O
. O

Various O
CAIs O
along O
with O
novel O
techniques O
to O
administer O
them O
have O
been O
patented O
in O
the O
last O
four O
years O
. O

However O
, O
epilepsy O
continues O
to O
be O
a O
path O
less O
traveled O
when O
it O
comes O
to O
CAIs O
. O

A O
major O
area O
of O
research O
must O
focus O
toward O
the O
design O
of O
isoform O
- O
specific O
inhibitors O
using O
analogs O
of O
existing O
CAIs O
. O

Serotonin B
- O
kynurenine B
hypothesis O
of O
depression O
: O
historical O
overview O
and O
recent O
developments O
. O

This O
mini O
- O
review O
focuses O
on O
the O
studies O
of O
late O
Prof O
. O

IP O
Lapin O
( O
1903 O
- O
2012 O
) O
and O
his O
research O
team O
on O
the O
role O
of O
methoxyindole B
and O
kynurenine B
( O
KYN B
) O
pathways O
of O
tryptophan B
( O
TRP B
) O
metabolism O
in O
the O
pathogenesis O
of O
depression O
and O
action O
mechanisms O
of O
antidepressant O
effect O
. O

In O
the O
late O
60s O
of O
the O
last O
century O
Prof O
. O

IP O
Lapin O
suggested O
that O
" O
intensification O
of O
central O
serotoninergic O
processes O
is O
a O
determinant O
of O
the O
thymoleptic O
( O
mood O
elevating O
) O
component O
" O
while O
" O
activation O
of O
noradrenergic O
processes O
is O
responsible O
for O
psychoenergetic O
and O
motor O
- O
stimulating O
component O
of O
the O
clinical O
antidepressant O
effect O
" O
. O

The O
cause O
of O
serotonin B
deficiency O
in O
depression O
was O
attributed O
to O
the O
shunt O
of O
TRP B
" O
metabolism O
away O
from O
serotonin B
production O
towards O
KYN B
production O
" O
due O
to O
cortisol B
- O
induced O
activation O
of O
liver O
enzyme O
, O
tryptophan B
2 O
, O
3 O
- O
dioxygenase O
, O
the O
rate O
- O
limiting O
enzyme O
of O
TRP B
- O
KYN B
pathway O
. O

Prof O
. O

Lapin O
suggested O
and O
discovered O
that O
KYN B
and O
its O
metabolites O
affect O
brain O
functions O
, O
and O
proposed O
the O
role O
of O
neurokynurenines O
in O
pathogenesis O
of O
depression O
and O
action O
mechanisms O
of O
antidepressant O
effect O
( O
kynurenine B
hypothesis O
) O
. O

Further O
research O
suggested O
the O
antidepressant O
and O
cognition O
- O
enhancing O
effects O
of O
post O
- O
serotonin B
metabolite O
, O
N B
- I
acetylserotonin I
( O
NAS B
) O
, O
an O
agonist O
to O
tyrosine B
kinase O
B O
( O
TrkB O
) O
receptor O
; O
and O
link O
between O
depression O
and O
chronic O
inflammation O
- O
associated O
disorders O
( O
e O
. O
g O
. O
, O
insulin O
resistance O
, O
hepatitis O
C O
virus O
) O
via O
inflammation O
- O
induced O
activation O
of O
indoleamine B
2 O
, O
3 O
- O
dioxygenase O
, O
brain O
located O
rate O
- O
limiting O
enzyme O
of O
TRY B
- O
KYN B
metabolism O
. O

NAS O
and O
kynurenines B
might O
be O
the O
targets O
for O
prevention O
and O
treatment O
of O
depression O
and O
associated O
conditions O
. O

Insulin O
- O
Like O
Growth O
Factor O
Binding O
Protein O
2 O
( O
IGFBP O
- O
2 O
) O
Promotes O
Growth O
and O
Survival O
of O
Breast O
Epithelial O
Cells O
: O
Novel O
Regulation O
of O
the O
Estrogen B
Receptor O
. O

In O
breast O
tumors O
IGF O
binding O
protein O
- O
2 O
( O
IGFBP O
- O
2 O
) O
is O
elevated O
, O
and O
the O
presence O
of O
IGFBP O
- O
2 O
has O
been O
shown O
to O
correlate O
with O
malignancy O
. O

However O
, O
how O
IGFBP O
- O
2 O
contributes O
to O
the O
malignant O
state O
is O
still O
unclear O
. O

Silencing O
IGFBP O
- O
2 O
blocked O
cell O
proliferation O
and O
in O
MCF O
- O
7 O
cells O
increased O
cell O
death O
, O
indicating O
that O
IGFBP O
- O
2 O
was O
acting O
in O
both O
a O
mitogenic O
and O
a O
survival O
capacity O
. O

Exogenous O
IGFBP O
- O
2 O
acting O
via O
integrin O
receptors O
to O
reduce O
phosphatase O
and O
tensin O
homolog O
deleted O
from O
chromosome O
10 O
( O
PTEN O
) O
levels O
protected O
these O
cells O
against O
death O
induced O
by O
various O
chemotherapeutic O
agents O
. O

This O
was O
dependent O
on O
a O
functional O
estrogen B
receptor O
( O
ER O
) O
- O
alpha O
because O
silencing O
ER O
- O
alpha O
blocked O
the O
ability O
of O
IGFBP O
- O
2 O
to O
confer O
cell O
survival O
. O

Loss O
of O
IGFBP O
- O
2 O
increased O
levels O
of O
PTEN O
and O
improved O
chemosensitivity O
of O
the O
cells O
, O
confirming O
its O
role O
as O
a O
survival O
factor O
. O

Silencing O
IGFBP O
- O
2 O
had O
no O
effect O
on O
the O
response O
to O
IGF O
- O
II O
, O
but O
responses O
to O
estrogen B
and O
tamoxifen B
were O
no O
longer O
observed O
due O
to O
loss O
of O
ER O
- O
alpha O
, O
which O
could O
be O
prevented O
by O
the O
inhibition O
of O
PTEN O
. O

Conversely O
, O
exogenous O
IGFBP O
- O
2 O
increased O
ER O
- O
alpha O
mRNA O
and O
protein O
in O
both O
normal O
and O
cancer O
cells O
via O
its O
interaction O
with O
integrin O
receptors O
. O

These O
actions O
of O
IGFBP O
- O
2 O
on O
ER O
- O
alpha O
involved O
the O
IGF O
- O
I O
receptor O
and O
activation O
of O
phosphatidylinositol B
3 O
- O
kinase O
in O
the O
cancer O
cells O
but O
were O
independent O
of O
this O
in O
normal O
breast O
cells O
. O

The O
production O
of O
IGFBP O
- O
2 O
by O
breast O
cancer O
cells O
enhances O
their O
proliferative O
potential O
, O
increases O
their O
survival O
, O
and O
protects O
them O
against O
chemotherapy O
- O
induced O
death O
. O

IGFBP O
- O
2 O
not O
only O
modulates O
IGFs O
and O
directly O
regulates O
PTEN O
but O
also O
has O
a O
role O
in O
maintaining O
ER O
- O
alpha O
expression O
. O

Involvement O
of O
serotonin B
mechanism O
in O
methamphetamine B
- O
induced O
chronic O
pulmonary O
toxicity O
in O
rats O
. O

The O
widest O
distribution O
and O
the O
highest O
uptake O
of O
methamphetamine B
( O
MA O
) O
in O
the O
human O
body O
occurred O
in O
the O
lungs O
, O
so O
that O
more O
and O
more O
attention O
should O
be O
paid O
to O
MA O
- O
induced O
pulmonary O
toxicity O
. O

MA O
induces O
the O
release O
of O
serotonin B
, O
which O
is O
an O
important O
mediator O
in O
pulmonary O
disease O
. O

The O
purpose O
of O
this O
study O
is O
to O
investigate O
the O
chronic O
response O
of O
the O
lung O
to O
MA O
and O
its O
potential O
mechanism O
in O
rats O
. O

Models O
of O
the O
chronic O
toxicity O
of O
MA O
were O
established O
with O
MA O
of O
5 O
mg O
/ O
kg O
and O
10 O
mg O
/ O
kg O
( O
intraperitoneally O
, O
twice O
per O
day O
) O
for O
5 O
weeks O
. O

It O
was O
found O
that O
the O
high O
dose O
of O
MA O
induced O
rat O
pulmonary O
toxicity O
: O
crowded O
lung O
parenchyma O
, O
thickened O
septum O
, O
reduced O
number O
of O
alveolar O
sacs O
, O
inflammatory O
cell O
infiltration O
, O
and O
pulmonary O
arteriolar O
remodeling O
. O

In O
addition O
, O
MA O
resulted O
in O
a O
significant O
increase O
in O
the O
lung O
serotonin B
concentration O
and O
the O
marked O
upregulation O
of O
tryptophan B
hydroxylase O
1 O
, O
vesicular O
monoamine B
transporter O
2 O
, O
serotonin B
transporter O
, O
and O
downregulation O
of O
monoamine B
oxidase O
- O
A O
. O

These O
findings O
suggest O
that O
MA O
induced O
chronic O
pulmonary O
toxicity O
, O
which O
is O
concerned O
with O
the O
elevated O
serotonin B
concentration O
in O
rat O
lungs O
by O
increased O
synthesis O
, O
reduced O
metabolism O
, O
augmented O
accumulation O
, O
and O
promoted O
release O
of O
serotonin B
. O

Transforming O
growth O
factor O
beta O
1 O
and O
monocyte O
chemoattractant O
protein O
- O
1 O
as O
prognostic O
markers O
of O
diabetic O
nephropathy O
. O

We O
aimed O
to O
find O
the O
relationship O
between O
serum O
transforming O
growth O
factor O
beta O
1 O
( O
TGF O
- O
beta O
1 O
) O
and O
urinary O
monocyte O
chemoattractant O
protein O
- O
1 O
( O
MCP O
- O
1 O
) O
throughout O
the O
course O
of O
diabetic O
nephropathy O
( O
DN O
) O
and O
to O
assess O
the O
relationship O
between O
both O
levels O
and O
other O
parameters O
of O
renal O
injury O
such O
as O
albumin O
/ O
creatinine B
ratio O
and O
estimated O
glomerular O
filtration O
rate O
( O
eGFR O
) O
. O

Serum O
TGF O
- O
beta O
1 O
, O
urinary O
MCP O
- O
1 O
, O
eGFR O
, O
and O
glycosylated O
hemoglobin O
( O
HbA1c O
) O
were O
measured O
in O
60 O
patients O
with O
type O
II O
diabetes O
mellitus O
with O
different O
degrees O
of O
nephropathy O
( O
20 O
patients O
with O
normoalbuminuria O
, O
20 O
patients O
with O
microalbuminuria O
, O
and O
20 O
patients O
with O
macroalbuminuria O
) O
and O
compared O
with O
20 O
matched O
healthy O
control O
subjects O
. O

Both O
the O
levels O
of O
serum O
TGF O
- O
beta O
1 O
and O
urinary O
MCP O
- O
1 O
were O
significantly O
higher O
in O
patients O
with O
micro O
- O
and O
macroalbuminuria O
( O
137 O
. O
8 O
+ O
/ O
- O
69 O
. O
5 O
and O
329 O
. O
25 O
+ O
/ O
- O
41 O
. O
46 O
ng O
/ O
dl O
, O
respectively O
, O
for O
TGF O
- O
beta O
1 O
and O
167 O
. O
41 O
+ O
/ O
- O
50 O
. O
23 O
and O
630 O
. O
87 O
+ O
/ O
- O
318 O
. O
10 O
ng O
/ O
g O
creatinine B
, O
respectively O
, O
for O
MCP O
- O
1 O
) O
compared O
with O
normoalbuminuric O
patients O
and O
healthy O
controls O
( O
33 O
. O
25 O
+ O
/ O
- O

17 O
. O
5 O
and O
29 O
. O
64 O
+ O
/ O
- O
10 O
. O
57 O
ng O
/ O
dl O
, O
respectively O
, O
for O
TGF O
- O
beta O
1 O
and O
63 O
. O
85 O
+ O
/ O
- O
21 O
. O
15 O
and O
61 O
. O
50 O
+ O
/ O
- O
24 O
. O
81 O
ng O
/ O
g O
creatinine B
, O
respectively O
, O
for O
MCP O
- O
1 O
; O
p O
< O
0 O
. O
001 O
) O
. O

There O
was O
a O
positive O
significant O
correlation O
between O
the O
levels O
of O
serum O
TGF O
- O
beta O
1 O
and O
those O
of O
urinary O
MCP O
- O
1 O
( O
r O
= O
0 O
. O
73 O
, O
p O
< O
0 O
. O
001 O
) O
. O

Also O
, O
serum O
TGF O
- O
beta O
1 O
and O
urinary O
MCP O
- O
1 O
correlated O
positively O
with O
HbA1c O
( O
r O
= O
0 O
. O
49 O
and O
0 O
. O
55 O
, O
respectively O
, O
p O
< O
0 O
. O
05 O
for O
both O
) O
and O
inversely O
with O
eGFR O
( O
r O
= O
- O
0 O
. O
69 O
and O
- O
0 O
. O
60 O
, O
respectively O
, O
p O
< O
0 O
. O
001 O
for O
both O
) O
. O

We O
can O
conclude O
that O
serum O
TGF O
- O
beta O
1 O
and O
urinary O
MCP O
- O
1 O
can O
be O
used O
as O
the O
markers O
for O
detection O
of O
progression O
of O
DN O
. O

Antagonizing O
TGF O
- O
beta O
1 O
and O
MCP O
- O
1 O
might O
be O
helpful O
in O
attenuating O
the O
progression O
of O
nephropathy O
in O
diabetic O
patients O
. O

Efficacy O
of O
D B
- I
penicillamine I
, O
a O
sequestering O
acetaldehyde B
agent O
, O
in O
the O
prevention O
of O
alcohol B
relapse O
- O
like O
drinking O
in O
rats O
. O

RATIONALE O
: O
Nowadays O
, O
very O
few O
approved O
anti O
- O
relapse O
treatments O
for O
alcoholism O
exist O
, O
and O
their O
overall O
efficacy O
can O
be O
considered O
moderate O
. O

An O
exciting O
rationale O
drug O
development O
opportunity O
for O
the O
treatment O
of O
chronic O
alcoholism O
is O
the O
use O
of O
acetaldehyde B
sequestering O
agents O
. O

Although O
these O
compounds O
are O
able O
to O
attenuate O
or O
prevent O
most O
of O
the O
behavioral O
and O
neurochemical O
effects O
of O
ethanol B
, O
the O
efficacy O
of O
acetaldehyde B
sequestration O
, O
by O
using O
agents O
such O
as O
D B
- I
penicillamine I
( O
DP O
) O
, O
in O
relapse O
prevention O
has O
not O
been O
studied O
yet O
. O

OBJECTIVES O
: O
The O
aim O
of O
this O
study O
was O
to O
analyze O
the O
effects O
of O
DP O
treatment O
on O
the O
alcohol B
deprivation O
effect O
( O
ADE O
) O
in O
long O
- O
term O
ethanol B
- O
experienced O
rats O
as O
a O
model O
of O
relapse O
behavior O
and O
measure O
drug O
plasma O
and O
brain O
levels O
during O
treatment O
. O

METHODS O
: O
Rats O
were O
subcutaneously O
implanted O
with O
mini O
- O
osmotic O
pumps O
delivering O
0 O
, O
0 O
. O
25 O
, O
or O
1 O
mg O
/ O
h O
of O
DP O
during O
1 O
week O
. O

The O
efficacy O
to O
prevent O
ADE O
was O
determined O
. O

DP O
plasma O
and O
brain O
levels O
achieved O
during O
its O
subcutaneous O
administration O
were O
measured O
. O

In O
a O
second O
experiment O
, O
animals O
received O
bilateral O
infusions O
of O
0 O
or O
1 O
. O
5 O
mu O
g O
/ O
h O
of O
DP O
directly O
into O
pVTA O
, O
and O
the O
appearance O
of O
ADE O
was O
evaluated O
. O

RESULTS O
: O
One O
milligram O
per O
hour O
, O
but O
not O
0 O
. O
25 O
mg O
/ O
h O
, O
DP O
infusion O
prevented O
ADE O
and O
reduced O
the O
total O
ethanol B
preference O
in O
animals O
. O

DP O
plasma O
concentrations O
associated O
with O
ADE O
suppression O
were O
around O
3 O
- O
4 O
mu O
g O
/ O
ml O
, O
and O
brain O
DP O
levels O
in O
these O
conditions O
were O
about O
2 O
- O
3 O
% O
of O
those O
found O
in O
plasma O
. O

Intra O
- O
pVTA O
DP O
administration O
also O
suppressed O
ADE O
. O

CONCLUSION O
: O
DP O
is O
able O
to O
prevent O
alcohol B
- O
relapse O
- O
like O
drinking O
in O
rats O
suggesting O
that O
this O
drug O
may O
be O
a O
useful O
new O
tool O
in O
the O
management O
of O
relapse O
in O
alcohol B
- O
dependent O
patients O
. O

Sublethal O
silver B
and O
NaCl B
toxicity O
in O
Daphnia O
magna O
: O
a O
comparative O
study O
of O
standardized O
chronic O
endpoints O
and O
progeny O
phototaxis O
. O

Behavioral O
bioassays O
with O
the O
model O
freshwater O
cladoceran O
Daphnia O
magna O
have O
the O
potential O
to O
serve O
as O
nontraditional O
but O
sensitive O
endpoints O
of O
sublethal O
stress O
. O

However O
, O
few O
studies O
have O
examined O
the O
comparative O
sensitivity O
of O
neonate O
phototaxis O
perturbations O
to O
standardized O
endpoints O
commonly O
employed O
in O
chronic O
toxicity O
testing O
protocols O
. O

Even O
less O
understood O
are O
the O
consequences O
of O
prenatal O
exposure O
on O
neonate O
phototactic O
behavior O
. O

Here O
, O
we O
tested O
the O
hypothesis O
that O
D O
. O
magna O
neonate O
phototaxis O
is O
a O
more O
sensitive O
endpoint O
over O
a O
chronic O
study O
period O
than O
mortality O
and O
reproduction O
. O

D O
. O
magna O
21 O
day O
studies O
were O
conducted O
with O
model O
stressors O
of O
sodium B
chloride I
and O
dissolved O
silver B
. O

Phototaxis O
assays O
of O
progeny O
response O
to O
relative O
light O
changes O
in O
small O
water O
columns O
were O
conducted O
for O
each O
brood O
. O

Significant O
differences O
in O
neonate O
phototactic O
behavior O
were O
observed O
among O
treatment O
level O
broods O
, O
suggesting O
that O
maternal O
exposure O
to O
sublethal O
levels O
of O
NaCl B
and O
Ag B
+ I
impacted O
offspring O
. O

In O
fact O
, O
progeny O
phototactic O
response O
was O
significantly O
affected O
at O
or O
below O
21 O
- O
day O
LOEC O
thresholds O
for O
fecundity O
in O
broods O
2 O
, O
3 O
, O
5 O
and O
6 O
of O
the O
NaCl B
experiment O
and O
in O
broods O
2 O
, O
4 O
, O
5 O
and O
6 O
of O
the O
dissolved O
Ag B
+ I
study O
. O

Because O
neonate O
phototaxis O
was O
generally O
more O
sensitive O
than O
standardized O
fecundity O
thresholds O
, O
we O
suggest O
employing O
neonate O
phototaxis O
as O
an O
ecologically O
important O
endpoint O
in O
future O
ecological O
risk O
assessments O
. O

Parathyroid O
Hormone O
( O
PTH O
) O
and O
PTH O
- O
Related O
Peptide O
Domains O
Contributing O
to O
Activation O
of O
Different O
PTH O
Receptor O
- O
Mediated O
Signaling O
Pathways O
. O

Parathyroid O
hormone O
( O
PTH O
) O
and O
parathyroid O
hormone O
related O
peptide O
( O
PTHrP O
) O
, O
acting O
through O
the O
osteoblast O
PTH1R O
, O
play O
important O
roles O
in O
bone O
remodeling O
. O

Intermittent O
administration O
of O
PTH O
( O
1 O
- O
34 O
) O
( O
teriparatide O
) O
leads O
to O
bone O
formation O
while O
continuous O
administration O
paradoxically O
leads O
to O
bone O
resorption O
. O

Activation O
of O
PTH1R O
promotes O
regulation O
of O
multiple O
signaling O
pathways O
, O
including O
Gs O
/ O
cAMP B
/ O
PKA O
, O
Gq O
/ O
calcium B
/ O
PKC O
, O
beta O
- O
arrestin O
recruitment O
and O
ERK1 O
/ O
2 O
phosphorylation O
as O
well O
as O
receptor O
internalization O
but O
their O
role O
in O
promoting O
anabolic O
and O
catabolic O
actions O
of O
PTH O
( O
1 O
- O
34 O
) O
are O
unclear O
. O

In O
the O
present O
investigation O
, O
a O
collection O
of O
PTH O
( O
1 O
- O
34 O
) O
and O
PTHrP O
( O
1 O
- O
34 O
) O
peptide O
analogs O
were O
evaluated O
in O
orthogonal O
hPTH1R O
functional O
assays O
capturing O
Gs O
- O
and O
Gq O
- O
signaling O
, O
beta O
- O
arrestin O
recruitment O
, O
ERK1 O
/ O
2 O
phosphorylation O
and O
receptor O
internalization O
to O
further O
define O
patterns O
of O
of O
PTH1R O
signaling O
they O
stimulate O
and O
to O
further O
establish O
peptide O
domains O
contributing O
to O
agonist O
activity O
. O

Results O
indicate O
that O
both O
N B
- O
and O
C B
- O
terminal O
domains O
are O
critical O
for O
activation O
of O
signaling O
pathways O
. O

However O
, O
modifications O
of O
both O
regions O
leads O
to O
more O
substantial O
decreases O
in O
agonist O
potency O
and O
efficacy O
to O
stimulate O
Gq O
- O
signaling O
, O
beta O
- O
arrestin O
recruitment O
, O
ERK1 O
/ O
2 O
phosphorylation O
and O
receptor O
internalization O
than O
to O
stimulate O
Gs O
. O

The O
substantial O
contribution O
of O
the O
peptide O
C B
- O
terminal O
domain O
in O
activation O
of O
hPTH1R O
- O
signaling O
suggests O
a O
role O
in O
positioning O
of O
the O
peptide O
N B
- O
terminal O
region O
into O
the O
receptor O
J O
- O
domain O
. O

Several O
PTH O
and O
PTHrP O
peptide O
analogs O
evaluated O
in O
this O
study O
promote O
different O
patterns O
of O
biased O
agonist O
signaling O
and O
may O
serve O
as O
useful O
tools O
to O
further O
elucidate O
therapeutically O
relevant O
PTH1R O
signaling O
in O
osteoblasts O
. O

With O
a O
better O
understanding O
of O
therapeutically O
relevant O
signaling O
, O
novel O
biased O
peptides O
with O
desired O
signaling O
could O
be O
designed O
for O
safer O
and O
more O
effective O
treatment O
of O
osteoporosis O
. O

Substituted O
7 B
- I
Amino I
- I
5 I
- I
thio I
- I
thiazolo I
[ I
4 I
, I
5 I
- I
d I
] I
pyrimidines I
as O
Potent O
and O
Selective O
Antagonists O
of O
the O
Fractalkine O
Receptor O
( O
CX3CR1 O
) O
. O

We O
have O
developed O
two O
parallel O
series O
, O
A O
and O
B O
, O
of O
CX3CR1 O
antagonists O
for O
the O
treatment O
of O
multiple O
sclerosis O
. O

By O
modifying O
the O
substituents O
on O
the O
7 B
- I
amino I
- I
5 I
- I
thio I
- I
thiazolo I
[ I
4 I
, I
5 I
- I
d I
] I
pyrimidine I
core O
structure O
, O
we O
were O
able O
to O
achieve O
compounds O
with O
high O
selectivity O
for O
CX3CR1 O
over O
the O
closely O
related O
CXCR2 O
receptor O
. O

The O
structure O
- O
activity O
relationships O
showed O
that O
a O
leucinol B
moiety O
attached O
to O
the O
core O
- O
structure O
in O
the O
7 O
- O
position O
together O
with O
alpha B
- I
methyl I
branched I
benzyl I
derivatives O
in O
the O
5 O
- O
position O
displayed O
promising O
affinity O
, O
and O
selectivity O
as O
well O
as O
physicochemical O
properties O
, O
as O
exemplified O
by O
compounds O
18a O
and O
24h O
. O

We O
show O
the O
preparation O
of O
the O
first O
potent O
and O
selective O
orally O
available O
CX3CR1 O
antagonists O
. O

Therapeutic O
Agents O
Triggering O
Nonapoptotic O
Cancer O
Cell O
Death O
. O

It O
is O
widely O
recognized O
that O
the O
evasion O
of O
apoptotic O
cell O
death O
is O
one O
of O
the O
hallmarks O
of O
cancer O
. O

For O
many O
years O
cytotoxic O
agents O
have O
been O
developed O
to O
target O
apoptotic O
cell O
death O
as O
a O
main O
method O
of O
treating O
cancer O
. O

However O
, O
the O
occurrence O
of O
cellular O
defects O
involving O
the O
apoptotic O
machinery O
in O
many O
cancers O
has O
resulted O
in O
an O
acquired O
resistance O
to O
apoptotic O
cell O
death O
, O
undermining O
the O
effectiveness O
of O
chemotherapeutic O
agents O
. O

Over O
the O
past O
decade O
, O
research O
has O
revealed O
a O
growing O
number O
of O
cell O
death O
pathways O
that O
are O
not O
dependent O
on O
apoptosis O
. O

In O
addition O
, O
compounds O
specifically O
triggering O
these O
alternative O
cell O
death O
pathways O
have O
been O
identified O
and O
explored O
as O
novel O
cancer O
treatment O
options O
. O

These O
novel O
anticancer O
agents O
are O
critically O
discussed O
by O
the O
authors O
, O
and O
therefore O
, O
the O
current O
Perspective O
represents O
a O
resource O
for O
a O
practicing O
medicinal O
chemist O
looking O
for O
new O
opportunities O
to O
combat O
cancers O
resistant O
to O
the O
established O
proapoptotic O
therapeutic O
agents O
. O

Constraint O
Network O
Analysis O
( O
CNA O
) O
: O
A O
Python O
Software O
Package O
for O
Efficiently O
Linking O
Biomacromolecular O
Structure O
, O
Flexibility O
, O
( O
Thermo O
- O
) O
Stability O
, O
and O
Function O
. O

For O
deriving O
maximal O
advantage O
from O
information O
on O
biomacromolecular O
flexibility O
and O
rigidity O
, O
results O
from O
rigidity O
analyses O
must O
be O
linked O
to O
biologically O
relevant O
characteristics O
of O
a O
structure O
. O

Here O
, O
we O
describe O
the O
Python O
- O
based O
software O
package O
Constraint O
Network O
Analysis O
( O
CNA O
) O
developed O
for O
this O
task O
. O

CNA O
functions O
as O
a O
front O
- O
and O
backend O
to O
the O
graph O
- O
based O
rigidity O
analysis O
software O
FIRST O
. O

CNA O
goes O
beyond O
the O
mere O
identification O
of O
flexible O
and O
rigid O
regions O
in O
a O
biomacromolecule O
in O
that O
it O
( O
I O
) O
provides O
a O
refined O
modeling O
of O
thermal O
unfolding O
simulations O
that O
also O
considers O
the O
temperature O
- O
dependence O
of O
hydrophobic O
tethers O
, O
( O
II O
) O
allows O
performing O
rigidity O
analyses O
on O
ensembles O
of O
network O
topologies O
, O
either O
generated O
from O
structural O
ensembles O
or O
by O
using O
the O
concept O
of O
fuzzy O
noncovalent O
constraints O
, O
and O
( O
III O
) O
computes O
a O
set O
of O
global O
and O
local O
indices O
for O
quantifying O
biomacromolecular O
stability O
. O

This O
leads O
to O
more O
robust O
results O
from O
rigidity O
analyses O
and O
extends O
the O
application O
domain O
of O
rigidity O
analyses O
in O
that O
phase O
transition O
points O
( O
" O
melting O
points O
" O
) O
and O
unfolding O
nuclei O
( O
" O
structural O
weak O
spots O
" O
) O
are O
determined O
automatically O
. O

Furthermore O
, O
CNA O
robustly O
handles O
small O
- O
molecule O
ligands O
in O
general O
. O

Such O
advancements O
are O
important O
for O
applying O
rigidity O
analysis O
to O
data O
- O
driven O
protein O
engineering O
and O
for O
estimating O
the O
influence O
of O
ligand O
molecules O
on O
biomacromolecular O
stability O
. O

CNA O
maintains O
the O
efficiency O
of O
FIRST O
such O
that O
the O
analysis O
of O
a O
single O
protein O
structure O
takes O
a O
few O
seconds O
for O
systems O
of O
several O
hundred O
residues O
on O
a O
single O
core O
. O

These O
features O
make O
CNA O
an O
interesting O
tool O
for O
linking O
biomacromolecular O
structure O
, O
flexibility O
, O
( O
thermo O
- O
) O
stability O
, O
and O
function O
. O

CNA O
is O
available O
from O
http O
: O
/ O
/ O
cpclab O
. O
uni O
- O
duesseldorf O
. O
de O
/ O
software O
for O
nonprofit O
organizations O
. O

Novel O
Plasmodium O
falciparum O
Maurer O
' O
s O
clefts O
protein O
families O
implicated O
in O
the O
release O
of O
infectious O
merozoites O
. O

The O
pathogenicity O
of O
the O
most O
deadly O
human O
malaria O
parasite O
, O
Plasmodium O
falciparum O
, O
relies O
on O
the O
export O
of O
virulence O
factors O
to O
the O
surface O
of O
infected O
erythrocytes O
. O

A O
novel O
membrane O
compartment O
, O
referred O
to O
as O
Maurer O
' O
s O
clefts O
, O
is O
transposed O
to O
the O
host O
erythrocyte O
, O
acting O
as O
a O
marshal O
platform O
in O
the O
red O
blood O
cell O
cytoplasm O
, O
for O
exported O
parasite O
proteins O
addressed O
to O
the O
host O
cell O
plasma O
membrane O
. O

We O
report O
here O
the O
characterization O
of O
three O
new O
P O
. O
falciparum O
multigene O
families O
organized O
in O
9 O
highly O
conserved O
clusters O
with O
the O
Pfmc O
- O
2tm O
genes O
in O
the O
subtelomeric O
regions O
of O
parasite O
' O
s O
chromosomes O
and O
expressed O
at O
early O
trophozoite O
stages O
. O

Like O
the O
PfMC O
- O
2TM O
proteins O
, O
the O
PfEPF1 O
, O
3 O
and O
4 O
proteins O
encoded O
by O
these O
families O
are O
exported O
to O
the O
Maurer O
' O
s O
clefts O
, O
as O
peripheral O
or O
integral O
proteins O
of O
the O
Maurer O
' O
s O
cleft O
membrane O
and O
largely O
exposed O
to O
the O
red O
cell O
cytosolic O
face O
of O
this O
membrane O
. O

A O
promoter O
titration O
approach O
was O
used O
to O
question O
the O
biological O
roles O
of O
these O
P O
. O
falciparum O
- O
specific O
exported O
proteins O
. O

Using O
the O
Pfepf1 O
family O
promoter O
, O
we O
observed O
the O
specific O
downregulation O
of O
all O
four O
families O
, O
correlating O
with O
the O
inefficient O
release O
of O
merozoites O
while O
the O
parasite O
intra O
- O
erythrocytic O
maturation O
and O
Maurer O
' O
s O
clefts O
morphology O
were O
not O
impacted O
. O

Ultrafast O
Spectroscopy O
of O
Quantum O
Confined O
States O
in O
a O
Single O
CdSe B
Nanowire O
. O

We O
measure O
for O
the O
first O
time O
transient O
absorption O
spectra O
of O
individual O
CdSe B
nanowires O
with O
about O
10 O
nm O
diameter O
. O

Confinement O
of O
the O
carrier O
wave O
functions O
leads O
to O
discrete O
states O
which O
can O
be O
described O
by O
a O
six O
- O
band O
effective O
mass O
model O
. O

Combining O
transient O
absorption O
and O
luminescence O
spectroscopy O
allows O
us O
to O
track O
the O
excitation O
dynamics O
in O
the O
visible O
and O
near O
- O
infrared O
spectral O
range O
. O

About O
10 O
% O
of O
all O
absorbed O
photons O
lead O
to O
an O
excitation O
of O
the O
lowest O
energy O
state O
. O

Of O
these O
excitations O
, O
less O
than O
1 O
% O
lead O
to O
a O
photon O
in O
the O
optical O
far O
- O
field O
. O

Almost O
all O
emission O
is O
reabsorbed O
by O
other O
parts O
of O
the O
nanowire O
. O

These O
findings O
might O
explain O
the O
low O
overall O
quantum O
efficiency O
of O
CdSe B
nanowires O
. O

1 B
, I
4 I
, I
2 I
- I
Benzo I
/ I
pyridodithiazine I
1 I
, I
1 I
- I
Dioxides I
Structurally O
Related O
to O
the O
ATP B
- O
Sensitive O
Potassium B
Channel O
Openers O
1 B
, I
2 I
, I
4 I
- I
Benzo I
/ I
pyridothiadiazine I
1 I
, I
1 I
- I
Dioxides I
Exert O
a O
Myorelaxant O
Activity O
Linked O
to O
a O
Distinct O
Mechanism O
of O
Action O
. O

The O
synthesis O
of O
diversely O
substituted O
3 B
- I
alkyl I
/ I
aralkyl I
/ I
arylamino I
- I
1 I
, I
4 I
, I
2 I
- I
benzodithiazine I
1 I
, I
1 I
- I
dioxides I
and O
3 B
- I
alkylaminopyrido I
[ I
4 I
, I
3 I
- I
e I
] I
- I
1 I
, I
4 I
, I
2 I
- I
dithiazine I
1 I
, I
1 I
- I
dioxides I
is O
described O
. O

Their O
biological O
activities O
on O
pancreatic O
beta O
- O
cells O
and O
on O
smooth O
muscle O
cells O
were O
compared O
to O
those O
of O
the O
reference O
ATP B
- O
sensitive O
potassium B
channel O
( O
KATP O
channel O
) O
openers O
diazoxide B
and O
7 B
- I
chloro I
- I
3 I
- I
isopropylamino I
- I
4H I
- I
1 I
, I
2 I
, I
4 I
- I
benzothiadiazine I
1 I
, I
1 I
- I
dioxide I
. O

The O
aim O
was O
to O
assess O
the O
impact O
on O
biological O
activities O
of O
the O
replacement O
of O
the O
1 B
, I
2 I
, I
4 I
- I
thiadiazine I
ring O
by O
an O
isosteric O
1 B
, I
4 I
, I
2 I
- I
dithiazine I
ring O
. O

Most O
of O
the O
dithiazine B
analogues O
were O
found O
to O
be O
inactive O
on O
the O
pancreatic O
tissue O
, O
although O
some O
compounds O
bearing O
a O
1 B
- I
phenylethylamino I
side O
chain O
at O
the O
3 O
- O
position O
exerted O
a O
marked O
myorelaxant O
activity O
. O

Such O
an O
effect O
did O
not O
appear O
to O
be O
related O
to O
the O
opening O
of O
KATP O
channels O
but O
rather O
reflected O
a O
mechanism O
of O
action O
similar O
to O
that O
of O
calcium B
channel O
blockers O
. O

Tightly O
related O
3 B
- I
( I
1 I
- I
phenylethyl I
) I
sulfanyl I
- I
4H I
- I
1 I
, I
2 I
, I
4 I
- I
benzothiadiazine I
1 I
, I
1 I
- I
dioxides I
were O
also O
found O
to O
exert O
a O
pronounced O
myorelaxant O
activity O
, O
resulting O
from O
both O
a O
KATP O
channel O
activation O
and O
a O
calcium B
channel O
blocker O
mechanism O
. O

The O
present O
work O
highlights O
the O
critical O
importance O
of O
an O
intracyclic O
NH B
group O
at O
the O
4 O
- O
position O
, O
as O
well O
as O
an O
exocyclic O
NH B
group O
linked O
to O
the O
3 O
- O
position O
of O
the O
benzo B
- I
and I
pyridothiadiazine I
dioxides I
, O
for O
activity O
on O
KATP O
channels O
. O

Discovery O
of O
3 B
, I
3 I
' I
- I
diindolylmethanes I
as O
potent O
antileishmanial O
agents O
. O

An O
efficient O
protocol O
for O
synthesis O
of O
3 B
, I
3 I
' I
- I
diindolylmethanes I
using O
recyclable O
Fe B
- O
pillared O
interlayered O
clay O
( O
Fe B
- O
PILC O
) O
catalyst O
under O
aqueous O
medium O
has O
been O
developed O
. O

All O
synthesized O
3 B
, I
3 I
' I
- I
diindolylmethanes I
showed O
promising O
antileishmanial O
activity O
against O
Leishmania O
donovani O
promastigotes O
as O
well O
as O
axenic O
amastigotes O
. O

Structure O
- O
activity O
relationship O
analysis O
revealed O
that O
nitroaryl B
substituted O
diindolylmethanes B
showed O
potent O
antileishmanial O
activity O
. O

The O
4 B
- I
nitrophenyl I
linked O
3 B
, I
3 I
' I
- I
diindolylmethane I
8g O
was O
found O
to O
be O
the O
most O
potent O
antileishmanial O
analog O
showing O
IC50 O
values O
of O
7 O
. O
88 O
and O
8 O
. O
37 O
mu O
M O
against O
both O
L O
. O
donovani O
promastigotes O
and O
amastigotes O
, O
respectively O
. O

Further O
, O
a O
pharmacophore O
based O
QSAR O
model O
was O
established O
to O
understand O
the O
crucial O
molecular O
features O
of O
3 B
, I
3 I
' I
- I
diindolylmethanes I
essential O
for O
potent O
antileishmanial O
activity O
. O

These O
compounds O
also O
exhibited O
promising O
antifungal O
activity O
against O
Cryptococcus O
neoformans O
, O
wherein O
fluorophenyl B
substituted O
3 B
, I
3 I
' I
- I
diindolylmethanes I
were O
found O
to O
be O
most O
potent O
antifungal O
agents O
. O

Developed O
synthetic O
protocol O
will O
be O
useful O
for O
economical O
and O
eco O
- O
friendly O
synthesis O
of O
potent O
antileishmanial O
and O
antifungal O
3 B
, I
3 I
' I
- I
diindolylmethane I
class O
of O
compounds O
. O

Synthesis O
and O
selected O
immunological O
properties O
of O
substituted O
quino B
[ I
3 I
, I
2 I
- I
b I
] I
benzo I
[ I
1 I
, I
4 I
] I
thiazines I
. O

A O
new O
type O
of O
azaphenothiazines B
- O
tetracyclic B
quino I
[ I
3 I
, I
2 I
- I
b I
] I
benzo I
[ I
1 I
, I
4 I
] I
thiazines I
, O
possessing O
common O
substituents O
( O
H B
, O
CH3 B
, O
Cl B
, O
Br B
, O
F B
, O
CF3 B
, O
SCH3 B
) O
in O
positions O
8 O
- O
10 O
and O
pharmacophoric O
aminoalkyl B
substituents O
in O
position O
6 O
, O
were O
obtained O
from O
diquinodithiin B
and O
2 B
, I
2 I
' I
- I
dichloro I
- I
3 I
, I
3 I
' I
- I
diquinolinyl I
disulfide I
in O

several O
- O
step O
syntheses O
. O

Sixty O
one O
compounds O
, O
grouped O
as O
the O
6H B
, I
6 I
- I
dialkylaminoalkyl I
, O
6 B
- I
acylaminoalkyl I
and O
sulfonylaminoalkyl B
derivatives O
, O
were O
tested O
for O
cytotoxicity O
, O
their O
effects O
on O
phytohemagglutin O
A O
( O
PHA O
) O
- O
induced O
proliferative O
response O
of O
human O
peripheral O
blood O
mononuclear O
cells O
( O
PBMC O
) O
and O
lipopolysaccharide O
( O
LPS O
) O
- O
induced O
tumor O
necrosis O
factor O
alpha O
( O
TNF O
- O
alpha O
) O
production O
by O
these O
cells O
. O

The O
compounds O
exhibited O
differential O
inhibitory O
activities O
in O
these O
tests O
and O
significantly O
varied O
in O
terms O
of O
cytotoxicity O
. O

The O
most O
promising O
compounds O
were O
tested O
for O
growth O
inhibition O
of O
leukemia O
L O
- O
1210 O
cells O
, O
colon O
cancer O
SV O
- O
948 O
cells O
and O
epidermal O
carcinoma O
A O
- O
341 O
cells O
. O

The O
most O
active O
compounds O
exhibited O
anticancer O
activity O
against O
these O
cell O
lines O
comparable O
to O
that O
of O
cisplatin B
. O

The O
structure O
- O
activity O
relationship O
of O
the O
compounds O
were O
discussed O
. O

Fisetin B
regulates O
obesity O
by O
targeting O
mTORC1 O
signaling O
. O

Fisetin B
, O
a O
flavonol B
present O
in O
vegetables O
and O
fruits O
, O
possesses O
antioxidative O
and O
anti O
- O
inflammatory O
properties O
. O

In O
this O
study O
, O
we O
have O
demonstrated O
that O
fisetin B
prevents O
diet O
- O
induced O
obesity O
through O
regulation O
of O
the O
signaling O
of O
mammalian O
target O
of O
rapamycin B
complex O
1 O
( O
mTORC1 O
) O
, O
a O
central O
mediator O
of O
cellular O
growth O
, O
cellular O
proliferation O
and O
lipid O
biosynthesis O
. O

To O
evaluate O
whether O
fisetin B
regulates O
mTORC1 O
signaling O
, O
we O
investigated O
the O
phosphorylation O
and O
kinase O
activity O
of O
the O
70 O
- O
kDa O
ribosomal O
protein O
S6 O
kinase O
1 O
( O
S6K1 O
) O
and O
mTORC1 O
in O
3T3 O
- O
L1 O
preadipocytes O
. O

Fisetin B
treatment O
of O
preadipocytes O
reduced O
the O
phosphorylation O
of O
S6K1 O
and O
mTORC1 O
in O
a O
time O
- O
and O
concentration O
- O
dependent O
manner O
. O

To O
further O
our O
understanding O
of O
how O
fisetin B
negatively O
regulates O
mTORC1 O
signaling O
, O
we O
analyzed O
the O
phosphorylation O
of O
S6K1 O
, O
mTOR O
and O
Akt O
in O
fisetin B
- O
treated O
TSC2 O
- O
knockdown O
cells O
. O

The O
results O
suggested O
that O
fisetin B
treatment O
inhibits O
mTORC1 O
activity O
in O
an O
Akt O
- O
dependent O
manner O
. O

Recent O
studies O
have O
shown O
that O
adipocyte O
differentiation O
is O
dependent O
on O
mTORC1 O
activity O
. O

Fisetin B
treatment O
inhibited O
adipocyte O
differentiation O
, O
consistent O
with O
the O
negative O
effect O
of O
fisetin B
on O
mTOR O
. O

The O
inhibitory O
effect O
of O
fisetin B
on O
adipogenesis O
is O
dependent O
of O
mTOR O
activity O
, O
suggesting O
that O
fisetin B
inhibits O
adipogenesis O
and O
the O
accumulation O
of O
intracellular O
triglycerides B
during O
adipocyte O
differentiation O
by O
targeting O
mTORC1 O
signaling O
. O

Fisetin B
supplementation O
in O
mice O
fed O
a O
high O
- O
fat O
diet O
( O
HFD O
) O
significantly O
attenuated O
HFD O
- O
induced O
increases O
in O
body O
weight O
and O
white O
adipose O
tissue O
. O

We O
also O
observed O
that O
fisetin B
efficiently O
suppressed O
the O
phosphorylation O
of O
Akt O
, O
S6K1 O
and O
mTORC1 O
in O
adipose O
tissue O
. O

Collectively O
, O
these O
results O
suggest O
that O
inhibition O
of O
mTORC1 O
signaling O
by O
fisetin B
prevents O
adipocyte O
differentiation O
of O
3T3 O
- O
L1 O
preadipocytes O
and O
obesity O
in O
HFD O
- O
fed O
mice O
. O

Therefore O
, O
fisetin B
may O
be O
a O
useful O
phytochemical O
agent O
for O
attenuating O
diet O
- O
induced O
obesity O
. O

Structural O
elucidation O
of O
possible O
lutein B
oxidation O
products O
mediated O
through O
peroxyl B
radical O
inducer O
2 B
, I
2 I
' I
- I
Azobis I
( I
2 I
- I
methylpropionamidine I
) I
dihydrochloride I
: O
Antioxidant O
and O
cytotoxic O
influence O
of O
oxidized O
lutein B
in O
HeLa O
cells O
. O

Aim O
of O
this O
study O
was O
to O
elucidate O
lutein B
oxidation O
products O
mediated O
through O
peroxyl B
radical O
inducer O
2 B
, I
2 I
' I
- I
Azobis I
( I
2 I
- I
methylpropionamidine I
) I
dihydrochloride I
( O
AAPH B
) O
and O
to O
study O
antioxidant O
and O
cytotoxic O
effects O
of O
oxidized O
lutein B
using O
liposome O
and O
HeLa O
cells O
. O

Lutein B
( O
20 O
mu O
mol O
) O
with O
AAPH B
( O
5mM O
) O
in O
liposome O
' O
s O
was O
incubated O
at O
37 O
degrees O
C O
in O
dark O
for O
3h O
, O
oxidized O
lutein B
products O
were O
characterized O
by O
LC O
- O
MS O
( O
APCI B
( I
+ I
) I
) O
and O
studied O
for O
their O
free O
radical O
scavenging O
activity O
and O
cytotoxic O
effects O
in O
terms O
of O
cell O
viability O
, O
cellular O
glutathione B
, O
and O
malondialdehyde B
levels O
. O

AAPH B
mediated O
lutein O
fragmented O
ions O
were O
identified O
as O
551 O
( O
M O
( O
+ O
) O
+ O
H B
( I
+ I
) I
- O
H2O B
) O
, O
391 O
( O
M O
( O
+ O
) O
+ O
H B
( I
+ I
) I
+ O
O2 B
- I
C22H32O I
) O
and O
276 O
( O
M O
( O
+ O
) O
+ O
H B
( I
+ I
) I
+ O
O2 B
- I
C12H20O I
) O
and O
its O
isomers O
as O
13 B
- I
Z I
lutein I
, O
13 B
- I
Z I
zeaxanthin I
, O
13 B
' I
- I
Z I
zeaxanthin I
and O
all B
- I
E I
zeaxanthin I
. O

Free O
radical O
scavenging O
activity O
of O
oxidized O
lutein B
was O
higher O
by O
32 O
. O
7 O
% O
( O
IC50 O
, O
2 O
. O
64 O
mu O
g O
) O
than O
lutein B
( O
IC50 O
, O
5 O
. O
28 O
mu O
g O
) O
. O

Oxidized B
lutein I
lowered O
the O
lipid O
peroxidation O
( O
21 O
% O
) O
, O
HeLa O
cells O
viability O
( O
22 O
% O
) O
and O
glutathione B
levels O
( O
32 O
% O
) O
than O
lutein B
. O

To O
conclude O
, O
the O
oxidized O
lutein B
may O
be O
highly O
reactive O
, O
since O
oxidation O
by O
AAPH B
results O
in O
peroxyl B
radical O
ions O
, O
which O
can O
react O
with O
conjugated O
polyene O
chain O
of O
lutein B
that O
could O
lead O
to O
higher O
antioxidant O
and O
cytotoxic O
effects O
on O
HeLa O
cells O
. O

Tricyclic B
thiazoles I
are O
a O
new O
class O
of O
angiogenesis O
inhibitors O
. O

Tricyclic B
thiazoleamine I
derivatives O
that O
were O
identified O
as O
hits O
in O
a O
screen O
against O
human O
umbilical O
vein O
endothelial O
cell O
proliferation O
were O
subjected O
to O
a O
structure O
- O
activity O
relationship O
study O
. O

Two O
structurally O
superimposable O
scaffolds O
- O
4H B
- I
thiochromeno I
[ I
4 I
, I
3 I
- I
d I
] I
thiazol I
- I
2 I
- I
amine I
and O
5 B
, I
6 I
- I
dihydro I
- I
4H I
- I
benzo I
[ I
6 I
, I
7 I
] I
cyclohepta I
[ I
1 I
, I
2 I
- I
d I
] I
thiazol I
- I
2 I
- I
amine I
derivatives O
- O
yielded O
low O
- O
micromolar O
inhibitors O
, O
and O
two O
among O
them O
37 O
and O
43 O
also O
exhibited O
antiangiogenic O
activity O
in O
an O
endothelial O
tube O
formation O
assay O
. O

Thus O
, O
37 O
and O
43 O
can O
serve O
as O
leads O
to O
develop O
a O
novel O
class O
of O
antiangiogenic O
agents O
. O

Neuroprotective O
effect O
of O
sulforaphane B
in O
6 B
- I
hydroxydopamine I
- O
lesioned O
mouse O
model O
of O
Parkinson O
' O
s O
disease O
. O

Parkinson O
' O
s O
disease O
( O
PD O
) O
is O
characterized O
by O
the O
selective O
loss O
of O
dopaminergic O
nigrostriatal O
neurons O
, O
which O
leads O
to O
disabling O
motor O
disturbances O
. O

Sulforaphane B
( O
SFN B
) O
, O
found O
in O
cruciferous O
vegetables O
, O
is O
a O
potent O
indirect O
antioxidant O
and O
recent O
advances O
have O
shown O
its O
neuroprotective O
activity O
in O
various O
experimental O
models O
of O
neurodegeneration O
. O

This O
study O
was O
undertaken O
to O
examine O
the O
effects O
of O
SFN B
on O
behavioral O
changes O
and O
dopaminergic O
neurotoxicity O
in O
mice O
exposed O
to O
6 B
- I
hydroxydopamine I
( O
6 B
- I
OHDA I
) O
. O

For O
this O
purpose O
, O
mice O
were O
treated O
with O
SFN B
( O
5mg O
/ O
kg O
twice O
a O
week O
) O
for O
four O
weeks O
after O
the O
unilateral O
intrastriatal O
injection O
of O
6 B
- I
OHDA I
. O

The O
increase O
in O
6 B
- I
OHDA I
- O
induced O
rotations O
and O
deficits O
in O
motor O
coordination O
were O
ameliorated O
significantly O
by O
SFN B
treatment O
. O

In O
addition O
, O
SFN B
protected O
6 B
- I
OHDA I
- O
induced O
apoptosis O
via O
blocking O
DNA O
fragmentation O
and O
caspase O
- O
3 O
activation O
. O

These O
results O
were O
further O
supported O
by O
immunohistochemical O
findings O
in O
the O
substantia O
nigra O
that O
showed O
that O
SFN O
protected O
neurons O
from O
neurotoxic O
effects O
of O
6 B
- I
OHDA I
. O

The O
neuroprotective O
effect O
of O
SFN B
may O
be O
attributed O
to O
its O
ability O
to O
enhance O
glutathione B
levels O
and O
its O
dependent O
enzymes O
( O
glutathione B
- O
S B
- O
transferase O
and O
glutathione B
reductase O
) O
and O
to O
modulate O
neuronal O
survival O
pathways O
, O
such O
as O
ERK1 O
/ O
2 O
, O
in O
the O
brain O
of O
mice O
. O

These O
results O
suggest O
that O
SFN B
may O
potentially O
be O
effective O
in O
slowing O
down O
the O
progression O
of O
idiopathic O
PD O
by O
the O
modulation O
of O
oxidative O
stress O
and O
apoptotic O
machinery O
. O

Oxidative O
DNA O
damage O
corresponds O
to O
the O
long O
term O
survival O
of O
human O
cells O
treated O
with O
silver B
nanoparticles O
. O

We O
examined O
the O
relation O
between O
DNA O
damage O
and O
the O
clonogenic O
potential O
of O
3 O
human O
cell O
lines O
, O
HepG2 O
, O
HT29 O
and O
A549 O
, O
treated O
with O
bare O
20nm O
or O
200nm O
silver B
nanoparticles O
( O
AgNPs O
) O
. O

The O
endpoints O
examined O
were O
the O
DNA O
breakage O
estimated O
by O
the O
comet O
assay O
, O
the O
oxidative O
base O
damage O
recognized O
by O
formamido B
- I
pyrimidine I
glycosylase O
( O
FPG O
) O
and O
estimated O
with O
the O
FPG O
+ O
comet O
assay O
, O
and O
the O
frequencies O
of O
histone O
gamma O
H2AX O
foci O
and O
micronuclei O
. O

Each O
cell O
line O
studied O
had O
a O
different O
pattern O
of O
DNA O
breakage O
and O
base O
damage O
versus O
the O
NPs O
concentration O
and O
time O
of O
treatment O
. O

The O
overall O
pattern O
of O
DNA O
breakage O
and O
base O
damage O
induction O
corresponded O
to O
the O
intracellular O
generation O
of O
reactive O
oxygen B
species O
. O

There O
was O
no O
increase O
in O
the O
frequencies O
of O
histone O
gamma O
H2AX O
foci O
and O
micronuclei O
as O
compared O
to O
those O
in O
the O
untreated O
cells O
. O

The O
reported O
experiments O
suggest O
that O
only O
the O
oxidative O
DNA O
damage O
corresponds O
to O
the O
loss O
of O
the O
clonogenic O
ability O
of O
cells O
treated O
with O
AgNPs O
. O

Detecting O
genome O
- O
wide O
gene O
transcription O
profiles O
associated O
with O
high O
pollution O
burden O
in O
the O
critically O
endangered O
European O
eel O
. O

The O
European O
eel O
illustrates O
an O
example O
of O
a O
critically O
endangered O
fish O
species O
strongly O
affected O
by O
human O
stressors O
throughout O
its O
life O
cycle O
, O
in O
which O
pollution O
is O
considered O
to O
be O
one O
of O
the O
factors O
responsible O
for O
the O
decline O
of O
the O
stock O
. O

The O
objective O
of O
our O
study O
was O
to O
better O
understand O
the O
transcriptional O
response O
of O
European O
eels O
chronically O
exposed O
to O
pollutants O
in O
their O
natural O
environment O
. O

A O
total O
of O
42 O
pre O
- O
migrating O
( O
silver B
) O
female O
eels O
from O
lowly O
, O
highly O
and O
extremely O
polluted O
environments O
in O
Belgium O
and O
, O
for O
comparative O
purposes O
, O
a O
lowly O
polluted O
habitat O
in O
Italy O
were O
measured O
for O
polychlorinated B
biphenyls I
( O
PCBs B
) O
, O
organochlorine B
pesticides O
( O
OCPs O
) O
and O
brominated O
flame O
retardants O
( O
BFRs O
) O
. O

Multipollutant O
level O
of O
bioaccumulation O
was O
linked O
to O
their O
genome O
- O
wide O
gene O
transcription O
using O
an O
eel O
- O
specific O
array O
of O
14 O
, O
913 O
annotated O
cDNAs O
. O

Shared O
responses O
to O
pollutant O
exposure O
were O
observed O
when O
comparing O
the O
highly O
polluted O
site O
in O
Belgium O
with O
the O
relatively O
clean O
sites O
in O
Belgium O
and O
Italy O
. O

First O
, O
an O
altered O
pattern O
of O
transcription O
of O
genes O
was O
associated O
with O
detoxification O
, O
with O
a O
novel O
European O
eel O
CYP3A O
gene O
and O
gluthatione B
S B
- O
transferase O
transcriptionally O
up O
- O
regulated O
. O

Second O
, O
an O
altered O
pattern O
of O
transcription O
of O
genes O
associated O
with O
the O
oxidative O
phosphorylation O
pathway O
, O
with O
the O
following O
genes O
involved O
in O
the O
generation O
of O
ATP B
being O
transcriptionally O
down O
- O
regulated O
in O
individuals O
from O
the O
highly O
polluted O
site O
: O
NADH B
dehydrogenase O
, O
succinate B
dehydrogenase O
, O
ubiquinol B
- O
cytochrome O
c O
reductase O
, O
cytochrome O
c O
oxidase O
and O
ATP B
synthase O
. O

Although O
we O
did O
not O
measure O
metabolism O
directly O
, O
seeing O
that O
the O
transcription O
level O
of O
many O
genes O
encoding O
enzymes O
involved O
in O
the O
mitochondrial O
respiratory O
chain O
and O
oxidative O
phosphorylation O
were O
down O
- O
regulated O
in O
the O
highly O
polluted O
site O
suggests O
that O
pollutants O
may O
have O
a O
significant O
effect O
on O
energy O
metabolism O
in O
these O
fish O
. O

Large O
- O
scale O
synthesis O
and O
in O
situ O
functionalization O
of O
Zn3P2 B
and O
Zn4Sb3 B
nanowire O
powders O
. O

A O
simple O
method O
for O
the O
large O
- O
scale O
synthesis O
of O
gram O
quantities O
of O
compound O
semiconductor O
nanowires O
without O
the O
need O
for O
any O
external O
catalysts O
or O
templates O
is O
presented O
. O

This O
method O
is O
demonstrated O
using O
zinc B
phosphide I
( O
Zn3P2 B
) O
and O
zinc B
antimonide I
( O
beta O
- O
Zn4Sb3 B
) O
nanowires O
as O
example O
systems O
. O

Large O
- O
scale O
synthesis O
of O
Zn3P2 B
and O
Zn4Sb3 B
nanowire O
powders O
was O
accomplished O
using O
a O
hot O
- O
walled O
chemical O
vapor O
deposition O
chamber O
by O
transporting O
phosphorus B
and O
antimony B
, O
respectively O
, O
via O
the O
vapor O
phase O
onto O
heated O
zinc B
foils O
. O

The O
zinc B
foils O
were O
rolled O
concentrically O
into O
coils O
to O
maximize O
the O
substrate O
surface O
area O
, O
and O
consequently O
, O
the O
nanowire O
yield O
. O

Using O
this O
method O
, O
250 O
mg O
of O
Zn3P2 B
nanowires O
were O
obtained O
on O
480 O
cm O
( O
2 O
) O
of O
zinc B
foil O
in O
a O
span O
of O
45 O
minutes O
. O

Furthermore O
, O
a O
process O
of O
exposing O
the O
synthesized O
nanowires O
to O
a O
vapor O
of O
organic O
functional O
molecules O
immediately O
after O
their O
synthesis O
and O
before O
their O
removal O
from O
the O
vacuum O
chamber O
was O
developed O
to O
obtain O
large O
quantities O
of O
surface O
functionalized O
nanowire O
powders O
. O

This O
in O
situ O
vapor O
- O
phase O
functionalization O
procedure O
passivated O
the O
nanowire O
surfaces O
without O
adversely O
affecting O
their O
morphology O
or O
dimensions O
. O

Our O
studies O
revealed O
that O
both O
4 B
- I
aminothiophenol I
and O
3 B
- I
propanedithiol I
functionalized O
Zn3P2 B
nanowires O
were O
stable O
over O
a O
120 O
day O
duration O
without O
any O
agglomeration O
or O
degradation O
. O

This O
method O
of O
mass O
producing O
nanowires O
can O
also O
be O
extended O
to O
other O
binary O
semiconductors O
. O

Loss O
of O
Survivin O
influences O
liver O
regeneration O
and O
is O
associated O
with O
impaired O
Aurora O
B O
function O
. O

The O
chromosomal O
passenger O
complex O
( O
CPC O
) O
acts O
as O
a O
key O
regulator O
of O
mitosis O
, O
preventing O
asymmetric O
segregation O
of O
chromosomal O
material O
into O
daughter O
cells O
. O

The O
CPC O
is O
composed O
of O
three O
non O
- O
enzymatic O
components O
termed O
Survivin O
, O
the O
inner O
centromere O
protein O
( O
INCENP O
) O
and O
Borealin O
, O
and O
an O
enzymatic O
component O
, O
Aurora O
B O
kinase O
. O

Survivin O
is O
necessary O
for O
the O
appropriate O
separation O
of O
sister O
chromatids O
during O
mitosis O
and O
is O
involved O
in O
liver O
regeneration O
, O
but O
its O
role O
in O
regenerative O
processes O
is O
incompletely O
elucidated O
. O

Whether O
Survivin O
, O
which O
is O
classified O
as O
an O
inhibitor O
of O
apoptosis O
protein O
( O
IAP O
) O
based O
on O
domain O
composition O
, O
also O
has O
a O
role O
in O
apoptosis O
is O
controversial O
. O

The O
present O
study O
examined O
the O
in O
vivo O
effects O
of O
Survivin O
ablation O
in O
the O
liver O
and O
during O
liver O
regeneration O
after O
70 O
% O
hepatectomy O
in O
a O
hepatocyte O
- O
specific O
knockout O
mouse O
model O
. O

The O
absence O
of O
Survivin O
caused O
a O
reduction O
in O
the O
number O
of O
hepatocytes O
in O
the O
liver O
, O
together O
with O
an O
increase O
in O
cell O
volume O
, O
macronucleation O
and O
polyploidy O
, O
but O
no O
changes O
in O
apoptosis O
. O

During O
liver O
regeneration O
, O
mitosis O
of O
hepatocytes O
was O
associated O
with O
mislocalization O
of O
the O
members O
of O
the O
CPC O
, O
which O
were O
no O
longer O
detectable O
at O
the O
centromere O
despite O
an O
unchanged O
protein O
amount O
. O

Furthermore O
, O
the O
loss O
of O
survivin O
in O
regenerating O
hepatocytes O
was O
associated O
with O
reduced O
levels O
of O
phosphorylated O
Histone O
H3 O
at O
serine B
28 O
and O
abolished O
phosphorylation O
of O
CENP O
- O
A O
and O
Hec1 O
at O
serine B
55 O
, O
which O
is O
a O
consequence O
of O
decreased O
Aurora O
B O
kinase O
activity O
. O

These O
data O
indicate O
that O
Survivin O
expression O
determines O
hepatocyte O
number O
during O
liver O
development O
and O
liver O
regeneration O
. O

Lack O
of O
Survivin O
causes O
mislocalization O
of O
the O
CPC O
members O
in O
combination O
with O
reduced O
Aurora O
B O
activity O
, O
leading O
to O
impaired O
phosphorylation O
of O
its O
centromeric O
target O
proteins O
and O
inappropriate O
cytokinesis O
. O

Predictive O
factors O
of O
sensitivity O
to O
elisidepsin B
, O
a O
novel O
kahalalide B
f I
- O
derived O
marine O
compound O
. O

Elisidepsin B
( O
PM02734 B
, O
Irvalec B
( O
R O
) O
) O
is O
a O
synthetic O
marine O
- O
derived O
cyclic O
peptide O
of O
the O
Kahalalide B
F I
family O
currently O
in O
phase O
II O
clinical O
development O
. O

Elisidepsin B
was O
shown O
to O
induce O
rapid O
oncosis O
in O
ErbB3 O
- O
expressing O
cells O
. O

Other O
predictive O
factors O
of O
elisidepsin B
sensitivity O
remained O
unknown O
. O

A O
panel O
of O
23 O
cancer O
cell O
lines O
of O
different O
origin O
was O
assessed O
for O
elisidepsin B
cytotoxicity O
and O
correlated O
with O
mutational O
state O
, O
mRNA O
and O
protein O
expression O
of O
selected O
genes O
. O

Elisidepsin B
showed O
potent O
and O
broad O
cytotoxic O
effects O
in O
our O
cancer O
cell O
line O
panel O
, O
being O
active O
at O
concentrations O
ranging O
from O
0 O
. O
4 O
to O
2 O
mu O
M O
that O
may O
be O
relevant O
for O
clinical O
settings O
. O

We O
have O
shown O
that O
elisidepsin O
is O
more O
active O
in O
cells O
harboring O
epithelial O
phenotype O
with O
high O
E O
- O
cadherin O
and O
low O
vimentin O
expression O
. O

In O
addition O
, O
high O
ErbB3 O
and O
Muc1 O
expression O
was O
correlated O
with O
sensitivity O
to O
elisidepsin B
, O
whereas O
the O
presence O
of O
KRAS O
activating O
mutations O
was O
associated O
with O
resistance O
. O

In O
DU O
- O
PM O
cells O
with O
acquired O
resistance O
to O
elisidepsin B
, O
ErbB3 O
expression O
was O
decreased O
, O
while O
Bcl2 O
was O
increased O
. O

DU O
- O
PM O
cells O
displayed O
higher O
sensitivity O
to O
ErbB1 O
- O
inhibitors O
suggesting O
possible O
cross O
- O
talk O
of O
ErbB1 O
and O
ErbB3 O
signaling O
pathways O
. O

Combinations O
of O
elisidepsin B
with O
lapatinib B
and O
several O
chemotherapies O
including O
5 B
- I
FU I
and O
oxaliplatin B
resulted O
in O
synergistic O
effects O
that O
offer O
the O
potential O
of O
clinical O
use O
of O
elisidepsin B
in O
combination O
settings O
. O

Gold O
nanoparticle O
- O
enhanced O
luminescence O
of O
silicon B
quantum O
dots O
co O
- O
encapsulated O
in O
polymer O
nanoparticles O
. O

The O
preparation O
of O
two O
- O
component O
polymer O
composite O
nanoparticles O
encapsulating O
both O
Si B
quantum O
dots O
( O
SiQDs O
) O
and O
Au B
nanoparticles O
( O
AuNPs O
) O
by O
a O
single O
step O
miniemulsion O
polymerization O
of O
divinylbenzene B
is O
described O
. O

This O
simple O
and O
robust O
method O
affords O
well O
- O
defined O
polymer O
composite O
nanoparticles O
with O
mean O
diameters O
in O
a O
range O
of O
100 O
- O
200 O
nm O
and O
with O
narrow O
polydispersity O
indices O
as O
determined O
by O
dynamic O
light O
scattering O
and O
transmission O
electron O
microscopy O
. O

The O
successful O
encapsulation O
of O
AuNPs O
within O
poly B
( I
divinylbenzene I
) I
was O
confirmed O
by O
UV O
- O
visible O
spectroscopy O
and O
from O
TEM O
images O
. O

Plasmon O
- O
enhanced O
fluorescence O
of O
the O
luminescence O
of O
the O
SiQDs O
by O
AuNPs O
encapsulated O
within O
the O
polymer O
composite O
nanoparticles O
was O
evaluated O
by O
confocal O
microspectroscopy O
, O
and O
luminescence O
enhancements O
of O
up O
to O
15 O
times O
were O
observed O
. O

These O
observations O
indicate O
that O
the O
luminescence O
of O
the O
SiQDs O
is O
enhanced O
by O
the O
proximity O
of O
the O
AuNPs O
. O

The O
polymer O
composite O
nanoparticles O
were O
successfully O
ink O
- O
jet O
printed O
onto O
a O
glass O
substrate O
, O
which O
demonstrates O
that O
these O
composites O
are O
processable O
in O
printing O
applications O
. O

Novel O
Phosphorylation O
and O
Ubiquitination O
Sites O
Regulate O
Reactive O
Oxygen B
Species O
- O
dependent O
Degradation O
of O
Anti O
- O
apoptotic O
c O
- O
FLIP O
Protein O
. O

The O
cytosolic O
protein O
c O
- O
FLIP O
( O
cellular O
Fas O
- O
associated O
death O
domain O
- O
like O
interleukin O
1 O
beta O
- O
converting O
enzyme O
inhibitory O
protein O
) O
is O
an O
inhibitor O
of O
death O
receptor O
- O
mediated O
apoptosis O
that O
is O
up O
- O
regulated O
in O
a O
variety O
of O
cancers O
, O
contributing O
to O
apoptosis O
resistance O
. O

Several O
compounds O
found O
to O
restore O
sensitivity O
of O
cancer O
cells O
to O
TRAIL O
, O
a O
TNF O
family O
death O
ligand O
with O
promising O
therapeutic O
potential O
, O
act O
by O
targeting O
c O
- O
FLIP O
ubiquitination O
and O
degradation O
by O
the O
proteasome O
. O

The O
generation O
of O
reactive O
oxygen B
species O
( O
ROS O
) O
has O
been O
implicated O
in O
c O
- O
FLIP O
protein O
degradation O
. O

However O
, O
the O
mechanism O
by O
which O
ROS O
post O
- O
transcriptionally O
regulate O
c O
- O
FLIP O
protein O
levels O
is O
not O
well O
understood O
. O

We O
show O
here O
that O
treatment O
of O
prostate O
cancer O
PPC O
- O
1 O
cells O
with O
the O
superoxide B
generators O
menadione B
, O
paraquat B
, O
or O
buthionine B
sulfoximine I
down O
- O
regulates O
c O
- O
FLIP O
long O
( O
c O
- O
FLIPL O
) O
protein O
levels O
, O
which O
is O
prevented O
by O
the O
proteasome O
inhibitor O
MG132 O
. O

Furthermore O
, O
pretreatment O
of O
PPC O
- O
1 O
cells O
with O
a O
ROS O
scavenger O
prevented O
ubiquitination O
and O
loss O
of O
c O
- O
FLIPL O
protein O
induced O
by O
menadione B
or O
paraquat B
. O

We O
identified O
lysine B
167 O
as O
a O
novel O
ubiquitination O
site O
of O
c O
- O
FLIPL O
important O
for O
ROS O
- O
dependent O
degradation O
. O

We O
also O
identified O
threonine B
166 O
as O
a O
novel O
phosphorylation O
site O
and O
demonstrate O
that O
Thr B
- O
166 O
phosphorylation O
is O
required O
for O
ROS O
- O
induced O
Lys B
- O
167 O
ubiquitination O
. O

The O
mutation O
of O
either O
Thr B
- O
166 O
or O
Lys B
- O
167 O
was O
sufficient O
to O
stabilize O
c O
- O
FLIP O
protein O
levels O
in O
PPC O
- O
1 O
, O
HEK293T O
, O
and O
HeLa O
cancer O
cells O
treated O
with O
menadione B
or O
paraquat B
. O

Accordingly O
, O
expression O
of O
c O
- O
FLIP O
T166A O
or O
K167R O
mutants O
protected O
cells O
from O
ROS O
- O
mediated O
sensitization O
to O
TRAIL O
- O
induced O
cell O
death O
. O

Our O
findings O
reveal O
novel O
ROS O
- O
dependent O
post O
- O
translational O
modifications O
of O
the O
c O
- O
FLIP O
protein O
that O
regulate O
its O
stability O
, O
thus O
impacting O
sensitivity O
of O
cancer O
cells O
to O
TRAIL O
. O

Nicotine B
- O
, O
tobacco O
particulate O
matter O
- O
and O
methamphetamine B
- O
produced O
locomotor O
sensitisation O
in O
rats O
. O

RATIONALE O
: O
Repeated O
nicotine B
exposure O
produces O
a O
weak O
and O
transient O
sensitised O
locomotor O
response O
in O
rats O
. O

Since O
tobacco O
smoke O
contains O
thousands O
of O
non O
- O
nicotine B
chemical O
constituents O
, O
these O
could O
alter O
the O
sensitised O
response O
. O

OBJECTIVES O
: O
This O
study O
aims O
to O
compare O
the O
magnitude O
, O
persistence O
and O
spatial O
distribution O
of O
locomotor O
sensitisation O
produced O
by O
repeated O
doses O
of O
nicotine B
, O
aqueous O
tobacco O
particulate O
matter O
( O
TPM O
) O
and O
a O
positive O
methamphetamine B
control O
. O

METHODS O
: O
Male O
Sprague O
- O
Dawley O
rats O
received O
five O
nicotine B
( O
0 O
. O
0 O
, O
0 O
. O
2 O
or O
0 O
. O
4 O
mg O
/ O
kg O
) O
, O
TPM O
( O
containing O
0 O
. O
2 O
or O
0 O
. O
4 O
mg O
/ O
kg O
nicotine B
) O
or O
methamphetamine B
( O
0 O
. O
5 O
mg O
/ O
kg O
) O
injections O
every O
second O
day O
, O
followed O
by O
a O
4 O
- O
day O
withdrawal O
before O
the O
first O
challenge O
( O
Challenge O
1 O
, O
C1 O
) O
. O

The O
animals O
were O
re O
- O
challenged O
again O
at O
15 O
days O
post O
C1 O
to O
test O
for O
the O
persistence O
of O
sensitisation O
( O
Challenge O
2 O
, O
C2 O
) O
. O

RESULTS O
: O
There O
were O
no O
major O
differences O
in O
sensitisation O
profile O
between O
nicotine B
and O
TPM O
. O

At O
the O
lowest O
0 O
. O
2 O
mg O
/ O
kg O
nicotine B
/ O
TPM O
dose O
, O
however O
, O
small O
differences O
emerged O
on O
select O
test O
days O
. O

CONCLUSIONS O
: O
The O
results O
indicated O
that O
the O
non O
- O
nicotinic O
agents O
in O
TPM O
did O
not O
greatly O
impact O
the O
nicotine B
- O
produced O
locomotor O
- O
sensitised O
response O
. O

These O
findings O
might O
suggest O
that O
the O
differential O
pharmacological O
properties O
of O
TPM O
do O
not O
have O
major O
clinical O
significance O
. O

Alternatively O
, O
the O
locomotor O
model O
might O
not O
expose O
effects O
of O
non O
- O
nicotinic O
constituents O
, O
and O
furthermore O
, O
might O
not O
closely O
relate O
to O
human O
tobacco O
dependence O
. O

Different O
reward O
- O
related O
behavioural O
models O
should O
also O
be O
utilised O
to O
assess O
potential O
effects O
of O
non O
- O
nicotinic O
constituents O
before O
a O
role O
in O
dependence O
is O
discounted O
. O

Treatment O
of O
Primary O
Chronic O
Glomerulonephritis O
with O
Rehmannia O
Glutinosa O
Acteosides B
in O
Combination O
with O
the O
Angiotensin O
Receptor O
Blocker O
Irbesartan B
: O
A O
Randomized O
Controlled O
Trial O
. O

This O
study O
aims O
to O
assess O
the O
efficacy O
and O
safety O
of O
Rehmannia O
glutinosa O
acteosides B
used O
in O
combination O
with O
the O
angiotensin O
receptor O
blocker O
irbesartan B
to O
treat O
primary O
chronic O
glomerulonephritis O
. O

A O
total O
of O
479 O
patients O
diagnosed O
with O
primary O
chronic O
glomerulonephritis O
were O
recruited O
from O
outpatient O
clinics O
and O
were O
randomly O
assigned O
to O
the O
treatment O
group O
( O
Rehmannia O
glutinosa O
acteosides B
, O
two O
200 O
- O
mg O
capsules O
, O
bid O
; O
and O
irbesartan B
, O
one O
150 O
- O
mg O
tablet O
, O
qd O
) O
or O
the O
control O
group O
( O
irbesartan B
, O
one O
150 O
- O
mg O
tablet O
, O
qd O
) O
. O

The O
primary O
outcome O
was O
24 O
- O
h O
urinary O
protein O
. O

Secondary O
outcome O
measures O
included O
blood O
pressure O
, O
estimated O
glomerular O
filtration O
rate O
, O
erythrocyturia O
, O
serum O
alanine B
aminotransferase O
, O
aspartate B
transaminase O
and O
electrolytes O
. O

After O
8 O
weeks O
of O
treatment O
, O
the O
treatment O
group O
showed O
a O
mean O
reduction O
in O
24 O
- O
h O
proteinuria O
of O
36 O
. O
42 O
% O
compared O
to O
baseline O
, O
which O
was O
significantly O
higher O
than O
the O
mean O
reduction O
from O
baseline O
of O
27 O
. O
97 O
% O
in O
the O
control O
group O
( O
P O
= O
0 O
. O
0278 O
) O
. O
Adverse O
drug O
reactions O
occurred O
at O
a O
similarly O
low O
rate O
in O
the O
treatment O
group O
( O
0 O
. O
4 O
% O
) O
and O
control O
group O
( O
1 O
. O
2 O
% O
, O
P O
= O
0 O
. O
3724 O
) O
. O

In O
the O
treatment O
of O
chronic O
glomerulonephritis O
, O
the O
combination O
of O
Rehmannia O
glutinosa O
acteosides B
and O
irbesartan B
can O
reduce O
proteinuria O
more O
effectively O
than O
irbesartan B
alone O
. O

Copyright O
( O
c O
) O
2013 O
John O
Wiley O
& O
Sons O
, O
Ltd O
. O

6 B
- I
Gingerol I
Inhibits O
Rosiglitazone B
- O
Induced O
Adipogenesis O
in O
3T3 O
- O
L1 O
Adipocytes O
. O

We O
investigated O
the O
effects O
of O
6 B
- I
gingerol I
( O
( B
S I
) I
- I
5 I
- I
hydroxy I
- I
1 I
- I
( I
4 I
- I
hydroxy I
- I
3 I
- I
methoxyphenyl I
) I
- I
3 I
- I
decanone I
) O
on O
the O
inhibition O
of O
rosiglitazone B
( O
RGZ B
) O
- O
induced O
adipogenesis O
in O
3T3 O
- O
L1 O
cells O
. O

The O
morphological O
changes O
were O
photographed O
based O
on O
staining O
lipid O
accumulation O
by O
Oil B
- I
Red I
O I
in O
RGZ B
( O
1 O
micro O
mol O
/ O
l O
) O
- O
treated O
3T3 O
- O
L1 O
cells O
without O
or O
with O
various O
concentrations O
of O
6 B
- I
gingerol I
on O
differentiation O
day O
8 O
. O

Quantitation O
of O
triglycerides B
content O
was O
performed O
in O
cells O
on O
day O
8 O
after O
differentiation O
induction O
. O

Differentiated O
cells O
were O
lysed O
to O
detect O
mRNA O
and O
protein O
levels O
of O
adipocyte O
- O
specific O
transcription O
factors O
by O
real O
- O
time O
reverse O
transcription O
- O
polymerase O
chain O
reaction O
and O
Western O
blot O
analysis O
, O
respectively O
. O

6 B
- I
gingerol I
( O
50 O
micro O
mol O
/ O
l O
) O
effectively O
suppressed O
oil O
droplet O
accumulation O
and O
reduced O
the O
sizes O
of O
the O
droplets O
in O
RGZ B
- O
induced O
adipocyte O
differentiation O
in O
3T3 O
- O
L1 O
cells O
. O

The O
triglyceride B
accumulation O
induced O
by O
RGZ B
in O
differentiated O
3T3 O
- O
L1 O
cells O
was O
also O
reduced O
by O
6 B
- I
gingerol I
( O
50 O
micro O
mol O
/ O
l O
) O
. O

Treatment O
of O
differentiated O
3T3 O
- O
L1 O
cells O
with O
6 B
- I
gingerol I
( O
50 O
micro O
mol O
/ O
l O
) O
antagonized O
RGZ B
- O
induced O
gene O
expression O
of O
peroxisome O
proliferator O
- O
activated O
receptor O
( O
PPAR O
) O
gamma O
and O
CCAAT O
/ O
enhancer O
- O
binding O
protein O
alpha O
. O

Additionally O
, O
the O
increased O
levels O
of O
mRNA O
and O
protein O
in O
adipocyte O
- O
specific O
fatty B
acid I
binding O
protein O
4 O
and O
fatty B
acid I
synthase O
induced O
by O
RGZ B
in O
3T3 O
- O
L1 O
cells O
were O
decreased O
upon O
treatment O
with O
6 B
- I
gingerol I
. O

Our O
data O
suggests O
that O
6 B
- I
gingerol I
may O
be O
beneficial O
in O
obesity O
, O
by O
reducing O
adipogenesis O
partly O
through O
the O
down O
- O
regulating O
PPAR O
gamma O
activity O
. O

Copyright O
( O
c O
) O
2013 O
John O
Wiley O
& O
Sons O
, O
Ltd O
. O

Multisite O
quantitative O
ultrasound O
for O
the O
prediction O
of O
fractures O
over O
five O
years O
of O
follow O
- O
up O
: O
The O
Canadian O
Multicentre O
Osteoporosis O
Study O
. O

This O
study O
assessed O
the O
ability O
of O
multisite O
quantitative O
ultrasound O
( O
mQUS O
) O
to O
predict O
fracture O
over O
a O
five O
- O
year O
follow O
- O
up O
. O

Participants O
were O
a O
subset O
of O
the O
Canadian O
Multicentre O
Osteoporosis O
Study O
. O

mQUS O
- O
assessed O
speed O
of O
sound O
( O
SOS O
in O
m O
/ O
s O
) O
at O
three O
sites O
( O
distal O
radius O
, O
tibia O
and O
phalanx O
) O
and O
extensive O
questionnaires O
were O
completed O
, O
after O
which O
participants O
were O
followed O
for O
five O
years O
and O
incident O
fractures O
recorded O
. O

Two O
survival O
analyses O
were O
completed O
for O
each O
site O
- O
a O
univariate O
analysis O
and O
an O
adjusted O
multivariate O
analysis O
controlling O
for O
age O
, O
anti O
- O
resorptive O
use O
, O
femoral O
neck O
bone O
mineral O
density O
, O
number O
of O
diseases O
, O
previous O
fractures O
, O
BMI O
, O
parental O
history O
of O
hip O
fracture O
, O
current O
smoking O
, O
current O
alcoholic O
drinks O
> O
3 O
per O
day O
, O
current O
using O
glucocorticoids O
, O
and O
rheumatoid O
arthritis O
diagnosis O
( O
variables O
from O
the O
FRAX O
10 O
- O
year O
fracture O
risk O
assessment O
tool O
) O
. O

The O
unit O
of O
change O
for O
regression O
analyses O
was O
one O
standard O
deviation O
for O
all O
measurement O
sites O
, O
specific O
to O
site O
and O
sex O
. O

Separate O
analyses O
were O
completed O
for O
all O
clinical O
fractures O
, O
non O
- O
vertebral O
fractures O
and O
hip O
fractures O
by O
sex O
. O

There O
were O
2633 O
women O
and O
1108 O
men O
included O
and O
they O
experienced O
204 O
incident O
fractures O
over O
five O
years O
( O
5 O
. O
5 O
% O
fractured O
) O
. O

Univariate O
models O
revealed O
statistically O
significant O
( O
p O
< O
0 O
. O
05 O
) O
predictive O
ability O
of O
mQUS O
for O
all O
three O
measurement O
sites O
for O
women O
alone O
for O
all O
three O
fracture O
types O
( O
one O
standard O
deviation O
decrease O
in O
SOS O
was O
associated O
with O
a O
52 O
- O
130 O
% O
increase O
in O
the O
risk O
of O
fracture O
) O
, O
but O
not O
for O
the O
men O
' O
s O
group O
. O

The O
adjusted O
model O
found O
that O
measures O
at O
the O
distal O
radius O
and O
tibia O
in O
the O
women O
' O
s O
group O
could O
significantly O
( O
p O
< O
0 O
. O
05 O
) O
predict O
all O
clinical O
fractures O
and O
non O
- O
vertebral O
fractures O
within O
the O
next O
five O
years O
( O
one O
standard O
deviation O
decrease O
in O
SOS O
was O
associated O
with O
a O
25 O
- O
31 O
% O
increase O
in O
the O
risk O
of O
fracture O
) O
. O

mQUS O
provided O
significant O
five O
- O
year O
clinical O
fracture O
prediction O
in O
women O
, O
independent O
of O
bone O
mineral O
density O
and O
other O
significant O
risk O
factors O
for O
fracture O
, O
when O
measured O
at O
the O
distal O
radius O
and O
tibia O
sites O
. O

( O
c O
) O
2013 O
American O
Society O
for O
Bone O
and O
Mineral O
Research O
. O

Library O
construction O
and O
biological O
evaluation O
of O
enmein B
- O
type O
diterpenoid B
analogues O
as O
potential O
anticancer O
agents O
. O

A O
library O
of O
promising O
enmein B
- O
type O
14 B
- I
O I
- I
diterpenoid I
derivatives O
was O
constructed O
from O
a O
commercially O
available O
kaurene B
- O
type O
oridonin B
by O
practical O
and O
efficient O
synthetic O
methods O
. O

These O
synthetic O
derivatives O
were O
evaluated O
for O
their O
antiproliferative O
activities O
against O
a O
set O
of O
four O
human O
cancer O
cell O
lines O
. O

The O
IC50 O
values O
are O
similar O
to O
or O
improved O
over O
those O
of O
the O
parent O
molecule O
and O
paclitaxel B
, O
the O
latter O
of O
which O
was O
used O
as O
a O
positive O
control O
. O

Compound O
29 O
was O
further O
investigated O
for O
its O
apoptotic O
properties O
against O
human O
hepatocarcinoma O
Bel O
- O
7402 O
cells O
to O
better O
understand O
its O
mode O
of O
action O
. O

Moreover O
, O
compound O
29 O
was O
shown O
to O
have O
potent O
antitumor O
activity O
in O
vivo O
in O
studies O
with O
a O
murine O
model O
of O
gastric O
cancer O
( O
MGC O
- O
803 O
mice O
) O
. O

These O
results O
warrant O
further O
preclinical O
investigations O
of O
these O
diterpenoid B
- O
based O
analogues O
as O
potential O
novel O
anticancer O
chemotherapeutics O
. O

PHARMACODYNAMIC O
EFFECTS O
OF O
A O
D B
- I
AMINO I
ACID I
OXIDASE O
INHIBITOR O
INDICATE O
A O
SPINAL O
SITE O
OF O
ACTION O
IN O
RAT O
MODELS O
OF O
NEUROPATHIC O
PAIN O
. O

Inhibition O
of O
D B
- I
amino I
acid I
oxidase O
( O
DAAO O
) O
activity O
is O
a O
potential O
target O
for O
the O
treatment O
of O
chronic O
pain O
. O

Here O
we O
characterized O
the O
effects O
of O
systemic O
administration O
of O
the O
DAAO O
inhibitor O
4H B
- I
furo I
[ I
3 I
, I
2 I
- I
b I
] I
pyrrole I
- I
5 I
- I
carboxylic I
acid I
( O
SUN B
) O
in O
rat O
models O
of O
neuropathic O
and O
inflammatory O
pain O
. O

Oral O
administration O
of O
SUN B
dose O
- O
dependently O
attenuated O
tactile O
allodynia O
induced O
by O
ligation O
of O
the O
L5 O
spinal O
nerve O
( O
SNL O
) O
, O
and O
similarly O
reversed O
thermal O
hyperalgesia O
produced O
by O
chronic O
constriction O
injury O
( O
CCI O
) O
. O

In O
addition O
, O
SUN B
was O
efficacious O
against O
Complete O
Freund O
' O
s O
Adjuvant O
( O
CFA O
) O
- O
induced O
thermal O
hyperalgesia O
. O

In O
these O
models O
, O
maximal O
reversal O
of O
pain O
- O
related O
behaviors O
corresponded O
with O
maximum O
rates O
- O
of O
- O
increase O
in O
brain O
and O
plasma O
D B
- I
serine I
concentrations O
, O
indicative O
of O
full O
inhibition O
of O
DAAO O
activity O
. O

To O
investigate O
the O
possible O
site O
( O
s O
) O
of O
action O
, O
we O
recorded O
spontaneous O
nerve O
activity O
and O
mechanically O
- O
evoked O
responses O
of O
central O
spinal O
cord O
dorsal O
horn O
neurons O
and O
compared O
these O
to O
spontaneous O
activity O
of O
peripheral O
dorsal O
root O
filaments O
in O
anesthetized O
SNL O
model O
animals O
. O

Oral O
SUN B
reduced O
spontaneous O
activity O
in O
both O
central O
and O
peripheral O
recordings O
at O
doses O
and O
pretreatment O
times O
that O
corresponded O
to O
reduced O
mechanical O
allodynia O
in O
behavioral O
experiments O
. O

Following O
i O
. O
v O
. O
administration O
of O
SUN B
, O
the O
onset O
of O
action O
for O
this O
central O
effect O
was O
rapid O
( O
maximal O
effects O
within O
30 O
minutes O
) O
, O
but O
was O
abolished O
by O
severing O
afferent O
inputs O
to O
the O
dorsal O
horn O
. O

Overall O
, O
these O
results O
indicate O
that O
inhibition O
of O
DAAO O
in O
peripheral O
afferent O
- O
spinal O
circuits O
reduced O
spontaneous O
neuronal O
activity O
to O
attenuate O
pain O
- O
related O
behaviors O
in O
rat O
models O
of O
neuropathic O
and O
inflammatory O
pain O
. O

Synthesis O
and O
Structure O
- O
Activity O
Relationships O
of O
5 B
, I
6 I
, I
7 I
- I
Substituted I
Pyrazolopyrimidines I
: O
Discovery O
of O
a O
Novel O
TSPO O
PET O
Ligand O
for O
Cancer O
Imaging O
. O

Focused O
library O
synthesis O
and O
structure O
- O
activity O
relationship O
development O
of O
5 B
, I
6 I
, I
7 I
- I
substituted I
pyrazolopyrimidines I
led O
to O
the O
discovery O
of O
2 B
- I
( I
5 I
, I
7 I
- I
diethyl I
- I
2 I
- I
( I
4 I
- I
( I
2 I
- I
fluoroethoxy I
) I
phenyl I
) I
pyrazolo I
[ I
1 I
, I
5 I
- I
a I
] I
pyrimidin I
- I
3 I
- I
yl I
) I
- I
N I
, I
N I
- I
diethylacetamide I
( O
6b O
) O
, O
a O
novel O
translocator O
protein O
( O
TSPO O
) O
ligand O
exhibiting O
a O
36 O
- O
fold O
enhancement O
in O
affinity O
compared O
to O
another O

pyrazolopyrimidine B
- O
based O
TSPO O
ligand O
, O
6a O
( O
DPA B
- I
714 I
) O
. O

Radiolabeling O
with O
fluorine B
- I
18 I
( O
( B
18 I
) I
F I
) O
facilitated O
production O
of O
2 B
- I
( I
5 I
, I
7 I
- I
diethyl I
- I
2 I
- I
( I
4 I
- I
( I
2 I
- I
[ I
( I
18 I
) I
F I
] I
fluoroethoxy I
) I
phenyl I
) I
pyrazolo I
[ I
1 I
, I
5 I
- I
a I
] I
pyrimidin I
- I
3 I
- I
yl I
) I
- I
N I
, I
N I
- I
diethylacetamide I
( O
( B
18 I
) I
F I
- O
6b O
) O
in O
high O
radiochemical O
yield O
and O
specific O
activity O
. O

In O
vivo O
studies O
of O
( B
18 I
) I
F I
- O
6b O
were O
performed O
which O
illuminated O
this O
agent O
as O
an O
improved O
probe O
for O
molecular O
imaging O
of O
TSPO O
- O
expressing O
cancers O
. O

A O
new O
sesquiterpene B
from O
the O
mangrove O
endophytic O
fungus O
Aspergillus O
terreus O
( O
No O
. O
GX7 O
- O
3B O
) O
. O

A O
new O
compound O
1 O
( O
named O
botryosphaerin B
F I
) O
, O
along O
with O
other O
three O
known O
compounds O
2 O
( O
13 B
, I
14 I
, I
15 I
, I
16 I
- I
tetranorlabd I
- I
7 I
- I
ene I
- I
19 I
, I
6b I
: I
12 I
, I
17 I
- I
diolide I
) O
, O
3 O
( O
botryosphaerin B
B I
) O
and O
4 O
( O
LL B
- I
Z1271 I
beta I
) O
, O
has O
been O
isolated O
from O
the O
mangrove O
fungus O
Aspergillus O
terreus O
( O
No O
. O
GX7 O
- O
3B O
) O
. O

The O
structure O
of O
the O
new O
compound O
was O
established O
by O
analysis O
of O
spectroscopic O
data O
. O

The O
hypothetical O
biogenic O
relationship O
of O
four O
sesquiterpene B
analogues O
was O
also O
described O
in O
this O
paper O
. O

Furthermore O
, O
in O
the O
cytotoxicity O
assays O
, O
compound O
1 O
showed O
potent O
inhibiting O
activity O
towards O
MCF O
- O
7 O
and O
HL O
- O
60 O
cancer O
cell O
lines O
with O
50 O
% O
inhibition O
of O
cell O
growth O
( O
IC50 O
) O
values O
of O
4 O
. O
49 O
and O
3 O
. O
43 O
mu O
M O
, O
respectively O
, O
and O
compound O
4 O
exhibited O
promising O
activity O
against O
HL O
- O
60 O
cell O
line O
with O
an O
IC50 O
value O
of O
0 O
. O
6 O
mu O
M O
. O

Comparison O
of O
transcriptomic O
signature O
of O
post O
- O
Chernobyl O
and O
post O
- O
radiotherapy O
thyroid O
tumors O
. O

Background O
: O
We O
previously O
identified O
two O
highly O
discriminating O
and O
predictive O
radiation O
- O
induced O
transcriptomic O
signatures O
by O
comparing O
series O
of O
sporadic O
and O
post O
- O
radiotherapy O
thyroid O
tumors O
( O
322 O
- O
gene O
signature O
) O
, O
and O
by O
re O
- O
analyzing O
a O
previously O
published O
dataset O
of O
sporadic O
and O
post O
- O
Chernobyl O
thyroid O
tumors O
( O
106 O
- O
gene O
signature O
) O
. O

The O
aim O
of O
the O
present O
work O
was O
1 O
) O
to O
compare O
the O
two O
signatures O
in O
terms O
of O
gene O
expression O
deregulations O
and O
molecular O
features O
/ O
pathways O
and O
2 O
) O
to O
test O
the O
capacity O
of O
the O
post O
- O
radiotherapy O
signature O
in O
classifying O
the O
post O
- O
Chernobyl O
series O
of O
tumors O
and O
reciprocally O
of O
the O
post O
Chernobyl O
signature O
in O
classifying O
the O
post O
- O
radiotherapy O
induced O
tumors O
. O

Methods O
: O
We O
now O
explored O
if O
post O
- O
radiotherapy O
and O
post O
- O
Chernobyl O
thyroid O
papillary O
carcinomas O
( O
PTC O
) O
display O
common O
molecular O
features O
by O
comparing O
molecular O
pathways O
deregulated O
in O
the O
two O
tumor O
series O
and O
test O
the O
potential O
of O
gene O
subsets O
of O
the O
post O
- O
radiotherapy O
signature O
to O
classify O
the O
post O
- O
Chernobyl O
series O
( O
14 O
sporadic O
and O
12 O
post O
- O
Chernobyl O
PTC O
) O
, O
and O
reciprocally O
of O
gene O
subsets O
of O
the O
post O
- O
Chernobyl O
signature O
to O
classify O
the O
post O
- O
radiotherapy O
series O
( O

15 O
sporadic O
and O
12 O
post O
- O
radiotherapy O
PTC O
) O
, O
by O
using O
conventional O
Principal O
Component O
Analysis O
. O

Results O
: O
We O
found O
that O
the O
5 O
genes O
common O
to O
the O
two O
signatures O
classified O
the O
learning O
/ O
training O
tumors O
( O
used O
to O
search O
these O
signatures O
) O
of O
both O
the O
post O
- O
radiotherapy O
( O
7 O
PTC O
) O
and O
the O
post O
- O
Chernobyl O
( O
6 O
PTC O
) O
thyroid O
tumor O
series O
as O
compared O
with O
the O
sporadic O
tumors O
( O
7 O
sporadic O
PTC O
in O
each O
series O
) O
. O

Importantly O
, O
these O
5 O
genes O
were O
also O
effective O
for O
classifying O
independent O
series O
of O
post O
- O
radiotherapy O
( O
5 O
PTC O
) O
and O
post O
- O
Chernobyl O
( O
6 O
PTC O
) O
tumors O
compared O
to O
independent O
series O
of O
sporadic O
tumors O
( O
8 O
PTC O
and O
6 O
PTC O
, O
respectively O
) O
( O
testing O
tumors O
) O
Moreover O
, O
part O
of O
each O
post O
- O
radiotherapy O
( O
32 O
genes O
) O
and O
post O
- O
Chernobyl O
signature O
( O
16 O
genes O
) O
cross O
- O
classified O
the O
respective O
series O
of O
thyroid O
tumors O
. O

Finally O
, O
several O
molecular O
pathways O
deregulated O
in O
post O
- O
Chernobyl O
tumors O
matched O
those O
found O
to O
be O
deregulated O
in O
post O
- O
radiotherapy O
tumors O
. O

Conclusions O
Overall O
, O
our O
data O
suggest O
that O
thyroid O
tumors O
that O
developed O
following O
either O
external O
exposure O
or O
internal O
131I B
contamination O
shared O
common O
molecular O
features O
, O
related O
to O
DNA O
repair O
, O
oxidative O
and O
endoplasmic O
reticulum O
stresses O
, O
allowing O
their O
classification O
as O
radiation O
- O
induced O
tumors O
in O
comparison O
with O
sporadic O
counterparts O
, O
independently O
of O
doses O
and O
dose O
rates O
, O
which O
suggests O
there O
may O
be O
a O
" O
general O
" O
radiation O
- O
induced O
signature O
of O
thyroid O
tumors O
. O

Baeckein B
E I
, O
a O
new O
bioactive O
C B
- I
methylated I
biflavonoid I
from O
the O
roots O
of O
Baeckea O
frutescens O
. O

A O
phytochemical O
study O
of O
Baeckea O
frutescens O
afforded O
a O
new O
biflavonoid B
named O
as O
baeckein B
E I
( O
1 O
) O
, O
along O
with O
four O
known O
C B
- I
methylated I
flavonols I
, O
baeckeins B
A I
( I
2 I
) I
and I
B I
( O
3 O
) O
, O
6 B
- I
methylquercetin I
( O
6 O
) O
and O
6 B
- I
methylquercetin I
- I
4 I
' I
- I
O I
- I
beta I
- I
d I
- I
glucopyranoside I
( O
7 O
) O
, O
and O
two O
known O
biflavonoids B
baeckeins B
C I
( I
4 I
) I
and I
D I
( O
5 O
) O
. O

The O
structure O
of O
compound O
1 O
was O
elucidated O
on O
the O
basis O
of O
spectroscopic O
analysis O
, O
including O
HR O
- O
ESI O
- O
MS O
, O
1D O
and O
2D O
NMR O
spectra O
, O
and O
the O
absolute O
configurations O
of O
C O
- O
2 O
and O
C O
- O
3 O
for O
compound O
1 O
were O
assigned O
by O
circular O
dichroism O
spectrometry O
combined O
with O
quantum O
chemical O
calculations O
. O

The O
antioxidant O
and O
cytoprotective O
activities O
of O
compounds O
1 O
- O
7 O
were O
also O
investigated O
. O

Controlled O
Assembly O
of O
Gold O
Nanoparticles O
through O
Antibody O
Recognition O
: O
Study O
and O
Utilizing O
the O
Effect O
of O
Particle O
Size O
on O
Interparticle O
Distance O
. O

An O
assembly O
of O
gold O
nanoparticle O
through O
the O
recognition O
of O
unmodified O
antibody O
was O
developed O
. O

The O
use O
of O
peptide O
( O
Cys B
- I
Ala I
- I
Leu I
- I
Asn I
- I
Asn I
) O
as O
ligands O
to O
stabilize O
and O
functionalize O
gold O
nanoparticles O
provides O
technical O
and O
operational O
convenience O
. O

These O
peptide O
- O
capped O
particles O
in O
different O
sizes O
are O
recognized O
by O
antibody O
and O
assembly O
to O
form O
dimers O
and O
expanded O
hybrid O
material O
by O
controlling O
the O
conditions O
. O

The O
interparticle O
spacing O
of O
these O
assemblies O
was O
well O
studied O
with O
small O
- O
angle O
X O
- O
ray O
scattering O
measurements O
, O
and O
it O
was O
found O
that O
the O
interparticle O
spacing O
is O
inversely O
dependent O
on O
the O
particle O
size O
. O

This O
relationship O
of O
interparticle O
spacing O
and O
particle O
size O
is O
closely O
related O
to O
the O
structure O
of O
antibody O
linker O
. O

Therefore O
, O
analyzing O
the O
interparticle O
spacing O
of O
assemblies O
can O
reveal O
the O
equilibrium O
configuration O
of O
IgG O
. O

Based O
on O
the O
investigation O
, O
the O
Fab O
- O
Fab O
angle O
of O
IgG O
is O
obtained O
to O
be O
= O
~ O
102 O
degrees O
and O
the O
Fab O
arms O
are O
= O
~ O
7 O
. O
8 O
nm O
. O

These O
results O
provide O
new O
experimental O
data O
on O
the O
structure O
of O
flexible O
IgG O
. O

Time O
- O
split O
cross O
- O
validation O
as O
a O
method O
for O
estimating O
the O
goodness O
of O
prospective O
prediction O
. O

Cross O
- O
validation O
is O
a O
common O
method O
to O
validate O
a O
QSAR O
model O
. O

In O
cross O
- O
validation O
, O
some O
compounds O
are O
held O
out O
as O
a O
test O
set O
, O
while O
the O
remaining O
compounds O
form O
a O
training O
set O
. O

A O
model O
is O
built O
from O
the O
training O
set O
, O
and O
the O
test O
set O
compounds O
are O
predicted O
on O
that O
model O
. O

The O
agreement O
of O
the O
predicted O
and O
observed O
activity O
values O
of O
the O
test O
set O
( O
measured O
by O
, O
say O
, O
R O
( O
2 O
) O
) O
is O
an O
estimate O
of O
the O
self O
- O
consistency O
of O
the O
model O
and O
is O
sometimes O
taken O
as O
an O
indication O
of O
the O
predictivity O
of O
the O
model O
. O

This O
estimate O
of O
predictivity O
can O
be O
optimistic O
or O
pessimistic O
compared O
to O
true O
prospective O
prediction O
, O
depending O
how O
compounds O
in O
the O
test O
set O
are O
selected O
. O

Here O
, O
we O
show O
that O
time O
- O
split O
selection O
gives O
an O
R O
( O
2 O
) O
that O
is O
more O
like O
that O
of O
true O
prospective O
prediction O
than O
the O
R O
( O
2 O
) O
from O
random O
selection O
( O
too O
optimistic O
) O
or O
from O
our O
analog O
of O
leave O
- O
class O
- O
out O
selection O
( O
too O
pessimistic O
) O
. O

Time O
- O
split O
selection O
should O
be O
used O
in O
addition O
to O
random O
selection O
as O
a O
standard O
for O
cross O
- O
validation O
in O
QSAR O
model O
building O
. O

Discovery O
of O
oxysterol B
- O
derived O
pharmacological O
chaperones O
for O
NPC1 O
: O
implication O
for O
the O
existence O
of O
second O
sterol B
- O
binding O
site O
. O

Niemann O
- O
Pick O
type O
C1 O
( O
NPC1 O
) O
is O
a O
polytopic O
endosomal O
membrane O
protein O
required O
for O
efflux O
of O
LDL O
- O
derived O
cholesterol B
from O
endosomes O
, O
and O
mutations O
of O
this O
protein O
are O
associated O
with O
Niemann O
- O
Pick O
disease O
type O
C O
, O
a O
fatal O
neurodegenerative O
disease O
. O

At O
least O
one O
prevalent O
mutation O
( O
I1061T O
) O
has O
been O
shown O
to O
cause O
a O
folding O
defect O
, O
which O
results O
in O
failure O
of O
endosomal O
localization O
, O
leading O
to O
a O
loss O
- O
of O
- O
function O
phenotype O
. O

Here O
, O
we O
show O
that O
several O
oxysterols B
and O
their O
derivatives O
act O
as O
pharmacological O
chaperones O
; O
binding O
of O
these O
compounds O
to O
I1061T O
NPC1 O
corrects O
the O
localization O
/ O
maturation O
defect O
of O
the O
mutant O
protein O
. O

Further O
, O
these O
compounds O
alleviate O
intracellular O
cholesterol B
accumulation O
in O
patient O
- O
derived O
fibroblasts O
, O
suggesting O
that O
they O
may O
have O
therapeutic O
potential O
. O

These O
oxysterol B
derivatives O
bind O
to O
a O
domain O
of O
NPC1 O
that O
is O
different O
from O
the O
known O
N B
- O
terminal O
sterol B
- O
binding O
domain O
; O
i O
. O
e O
. O
, O
there O
is O
an O
additional O
sterol B
- O
binding O
site O
on O
NPC1 O
. O

Mouse O
DNA O
polymerase O
kappa O
has O
a O
functional O
role O
in O
the O
repair O
of O
DNA O
strand O
breaks O
. O

The O
Y O
- O
family O
of O
DNA O
polymerases O
support O
of O
translesion O
DNA O
synthesis O
( O
TLS O
) O
associated O
with O
stalled O
DNA O
replication O
by O
DNA O
damage O
. O

Recently O
, O
a O
number O
of O
studies O
suggest O
that O
some O
specialized O
TLS O
polymerases O
also O
support O
other O
aspects O
of O
DNA O
metabolism O
beyond O
TLS O
in O
vivo O
. O

Here O
we O
show O
that O
mouse O
polymerase O
kappa O
( O
Pol O
kappa O
) O
could O
accumulate O
at O
laser O
- O
induced O
sites O
of O
damage O
in O
vivo O
resembling O
polymerases O
eta O
and O
iota O
. O

The O
recruitment O
was O
mediated O
through O
Pol O
kappa O
C B
- O
terminus O
which O
contains O
the O
PCNA O
- O
interacting O
peptide O
, O
ubiquitin O
zinc B
finger O
motif O
2 O
and O
nuclear O
localization O
signal O
. O

Interestingly O
, O
this O
recruitment O
was O
significantly O
reduced O
in O
MSH2 O
- O
deficient O
LoVo O
cells O
and O
Rad18 O
- O
depleted O
cells O
. O

We O
further O
observed O
that O
Pol O
kappa O
- O
deficient O
mouse O
embryo O
fibroblasts O
were O
abnormally O
sensitive O
to O
H2O2 B
treatment O
and O
displayed O
defects O
in O
both O
single O
- O
strand O
break O
repair O
and O
double O
- O
strand O
break O
repair O
. O

We O
speculate O
that O
Pol O
kappa O
may O
have O
an O
important O
role O
in O
strand O
break O
repair O
following O
oxidative O
stress O
in O
vivo O
. O

In O
silico O
identification O
of O
poly B
( I
ADP I
- I
ribose I
) I
polymerase O
- O
1 O
inhibitors O
and O
their O
chemosensitizing O
effects O
against O
cisplatin B
- O
resistant O
human O
gastric O
cancer O
cells O
. O

Poly B
( I
ADP I
- I
ribose I
) I
polymerase O
- O
1 O
( O
PARP O
- O
1 O
) O
enzyme O
is O
involved O
in O
the O
repair O
of O
DNA O
damages O
made O
by O
certain O
anticancer O
agents O
. O

It O
is O
suggested O
that O
PARP O
- O
1 O
inhibitors O
potentiate O
the O
cytotoxic O
effects O
and O
circumvent O
the O
resistance O
of O
DNA O
- O
modifying O
anticancer O
agents O
such O
as O
cisplatin B
. O

In O
this O
study O
, O
we O
conducted O
virtual O
screening O
of O
Korea O
Chemical O
Bank O
database O
targeting O
PARP O
- O
1 O
and O
identified O
several O
potent O
PARP O
- O
1 O
inhibitors O
with O
submicromolar O
IC50 O
values O
( O
77 O
- O
79nM O
) O
. O

We O
then O
examined O
the O
chemosensitization O
of O
cisplatin B
by O
pre O
- O
treatment O
of O
PARP O
- O
1 O
inhibitors O
in O
cisplatin B
- O
resistant O
human O
gastric O
cancer O
cells O
. O

Our O
results O
show O
that O
PARP O
- O
1 O
inhibitors O
suppress O
the O
formation O
of O
poly B
( I
ADP I
- I
ribose I
) I
and O
enhance O
the O
cytotoxicity O
of O
cisplatin B
. O

Activation O
of O
PPAR O
gamma O
is O
required O
for O
hydroxysafflor B
yellow I
A I
of O
Carthamus O
tinctorius O
to O
attenuate O
hepatic O
fibrosis O
induced O
by O
oxidative O
stress O
. O

Oxidative O
stress O
caused O
hepatic O
fibrosis O
by O
activating O
hepatic O
stellate O
cells O
( O
HSCs O
) O
, O
which O
were O
implemented O
by O
depressing O
PPAR O
gamma O
activation O
. O

Hydroxysafflor B
yellow I
A I
( O
HSYA B
) O
as O
a O
nature O
active O
ingredient O
with O
antioxidant O
capacity O
was O
able O
to O
effectively O
attenuate O
oxidative O
stress O
mediated O
injury O
. O

So O
it O
will O
be O
very O
interesting O
to O
study O
effect O
of O
HSYA B
on O
HSCs O
activation O
and O
liver O
fibrosis O
, O
and O
reveal O
the O
role O
of O
PPAR O
gamma O
. O
CCl4 B
and O
H2O2 B
were O
used O
to O
mimic O
oxidative O
stress O
mediated O
hepatic O
injury O
in O
vitro O
and O
in O
vivo O
respectively O
. O

The O
anti O
- O
fibrosis O
effects O
of O
HSYA B
were O
evaluated O
and O
its O
mechanisms O
were O
disclosed O
by O
applying O
western O
blot O
, O
histopathological O
analysis O
, O
flow O
cytometry O
, O
RT O
- O
PCR O
and O
ELISA O
. O

Our O
results O
showed O
that O
HSCs O
activation O
and O
proliferation O
could O
be O
induced O
by O
oxidative O
stress O
, O
and O
the O
expressive O
levels O
of O
TGF O
- O
beta O
1 O
and O
TIMP O
- O
1 O
, O
the O
serum O
levels O
of O
ALT O
, O
AST O
, O
HA O
, O
LN O
, O
III O
- O
C O
and O
IV O
- O
C O
were O
also O
enhanced O
by O
oxidative O
stress O
, O
which O
is O
correlated O
with O
liver O
fibrosis O
( O
p O
< O
0 O
. O
05 O
or O
p O
< O
0 O
. O
01 O
) O
. O

HSYA O
was O
able O
to O
effectively O
inhibit O
oxidative O
stress O
mediated O
hepatic O
injury O
by O
increasing O
the O
activities O
of O
antioxidant O
enzymes O
, O
up O
regulating O
the O
expression O
of O
PPAR O
gamma O
and O
MMP O
- O
2 O
, O
and O
down O
regulating O
the O
expression O
of O
TGF O
- O
beta O
1 O
and O
TIMP O
- O
1 O
, O
and O
reducing O
alpha O
- O
SMA O
level O
. O

The O
protective O
effect O
of O
HSYA B
can O
be O
significantly O
attenuated O
by O
GW9662 B
via O
blocking O
PPAR O
gamma O
( O
p O
< O
0 O
. O
05 O
or O
p O
< O
0 O
. O
01 O
) O
. O

Taken O
together O
, O
these O
results O
demonstrate O
that O
HSYA B
is O
able O
to O
significantly O
protect O
the O
liver O
from O
oxidative O
stress O
, O
which O
requires O
for O
HSYA B
to O
stimulate O
PPAR O
gamma O
activity O
, O
reduce O
cell O
proliferation O
and O
suppress O
ECM O
synthesis O
. O

Targeting O
kinases O
: O
a O
new O
approach O
to O
treating O
inflammatory O
rheumatic O
diseases O
. O

After O
two O
decades O
of O
research O
and O
development O
activity O
focussed O
on O
orally O
active O
kinase O
inhibitors O
, O
the O
first O
such O
drug O
( O
the O
JAK O
inhibitor O
Xeljanz B
, O
tofacitinib B
) O
was O
approved O
by O
the O
FDA O
in O
November O
2012 O
for O
the O
treatment O
of O
rheumatoid O
arthritis O
( O
RA O
) O
. O

There O
is O
an O
intense O
activity O
in O
many O
companies O
both O
on O
expanding O
the O
utility O
of O
JAK O
inhibitors O
in O
other O
auto O
- O
immune O
indications O
and O
in O
discovering O
inhibitors O
of O
the O
JAK O
family O
with O
different O
and O
more O
selective O
profiles O
. O

Progress O
is O
also O
being O
made O
with O
orally O
active O
Syk O
inhibitors O
. O

One O
such O
inhibitor O
( O
fostamatinib B
) O
is O
currently O
in O
large O
- O
scale O
phase O
3 O
trials O
, O
and O
there O
are O
others O
in O
clinical O
development O
. O

The O
last O
two O
to O
three O
years O
have O
been O
transformative O
for O
kinase O
inhibitors O
in O
auto O
- O
immune O
diseases O
, O
as O
several O
inhibitors O
have O
finally O
progressed O
beyond O
phase O
2 O
trials O
after O
so O
many O
failures O
on O
other O
targets O
. O

Thus O
, O
there O
are O
new O
treatment O
options O
for O
RA O
patients O
beyond O
existing O
oral O
DMARDs O
and O
parenteral O
biologics O
. O

An O
Ancient O
Transcription O
Factor O
Initiates O
the O
Burst O
of O
piRNA O
Production O
during O
Early O
Meiosis O
in O
Mouse O
Testes O
. O

Animal O
germ O
cells O
produce O
PIWI O
- O
interacting O
RNAs O
( O
piRNAs O
) O
, O
small O
silencing O
RNAs O
that O
suppress O
transposons O
and O
enable O
gamete O
maturation O
. O

Mammalian O
transposon O
- O
silencing O
piRNAs O
accumulate O
early O
in O
spermatogenesis O
, O
whereas O
pachytene O
piRNAs O
are O
produced O
later O
during O
postnatal O
spermatogenesis O
and O
account O
for O
> O
95 O
% O
of O
all O
piRNAs O
in O
the O
adult O
mouse O
testis O
. O

Mutants O
defective O
for O
pachytene O
piRNA O
pathway O
proteins O
fail O
to O
produce O
mature O
sperm O
, O
but O
neither O
the O
piRNA O
precursor O
transcripts O
nor O
the O
trigger O
for O
pachytene O
piRNA O
production O
is O
known O
. O

Here O
, O
we O
show O
that O
the O
transcription O
factor O
A O
- O
MYB O
initiates O
pachytene O
piRNA O
production O
. O

A O
- O
MYB O
drives O
transcription O
of O
both O
pachytene O
piRNA O
precursor O
RNAs O
and O
the O
mRNAs O
for O
core O
piRNA O
biogenesis O
factors O
including O
MIWI O
, O
the O
protein O
through O
which O
pachytene O
piRNAs O
function O
. O

A O
- O
MYB O
regulation O
of O
piRNA O
pathway O
proteins O
and O
piRNA O
genes O
creates O
a O
coherent O
feedforward O
loop O
that O
ensures O
the O
robust O
accumulation O
of O
pachytene O
piRNAs O
. O

This O
regulatory O
circuit O
, O
which O
can O
be O
detected O
in O
rooster O
testes O
, O
likely O
predates O
the O
divergence O
of O
birds O
and O
mammals O
. O

Structure O
of O
the O
Polycomb O
Group O
Protein O
PCGF1 O
in O
Complex O
with O
BCOR O
Reveals O
Basis O
for O
Binding O
Selectivity O
of O
PCGF O
Homologs O
. O

Polycomb O
- O
group O
RING O
finger O
homologs O
( O
PCGF1 O
, O
PCGF2 O
, O
PCGF3 O
, O
PCGF4 O
, O
PCGF5 O
, O
and O
PCGF6 O
) O
are O
critical O
components O
in O
the O
assembly O
of O
distinct O
Polycomb O
repression O
complex O
1 O
( O
PRC1 O
) O
- O
related O
complexes O
. O

Here O
, O
we O
identify O
a O
protein O
interaction O
domain O
in O
BCL6 O
corepressor O
, O
BCOR O
, O
which O
binds O
the O
RING O
finger O
- O
and O
WD40 O
- O
associated O
ubiquitin O
- O
like O
( O
RAWUL O
) O
domain O
of O
PCGF1 O
( O
NSPC1 O
) O
and O
PCGF3 O
but O
not O
of O
PCGF2 O
( O
MEL18 O
) O
or O
PCGF4 O
( O
BMI1 O
) O
. O

Because O
of O
the O
selective O
binding O
, O
we O
have O
named O
this O
domain O
PCGF O
Ub O
- O
like O
fold O
discriminator O
( O
PUFD O
) O
. O

The O
structure O
of O
BCOR O
PUFD O
bound O
to O
PCGF1 O
reveals O
that O
( O
1 O
) O
PUFD O
binds O
to O
the O
same O
surfaces O
as O
observed O
for O
a O
different O
Polycomb O
group O
RAWUL O
domain O
and O
( O
2 O
) O
the O
ability O
of O
PUFD O
to O
discriminate O
among O
RAWULs O
stems O
from O
the O
identity O
of O
specific O
residues O
within O
these O
interaction O
surfaces O
. O

These O
data O
show O
the O
molecular O
basis O
for O
determining O
the O
binding O
preference O
for O
a O
PCGF O
homolog O
, O
which O
ultimately O
helps O
determine O
the O
identity O
of O
the O
larger O
PRC1 O
- O
like O
assembly O
. O

Characterization O
of O
the O
first O
K B
( I
+ I
) I
channel O
blockers O
from O
the O
venom O
of O
the O
Moroccan O
scorpion O
Buthus O
occitanus O
Paris O
. O

The O
availability O
of O
a O
large O
variety O
of O
specific O
blockers O
, O
which O
inhibit O
different O
K B
( I
+ I
) I
currents O
, O
would O
help O
to O
elucidate O
their O
differences O
in O
physiological O
function O
. O

Short O
peptide O
toxins O
isolated O
from O
scorpion O
venoms O
are O
able O
to O
block O
voltage O
- O
dependent O
or O
Ca B
( I
2 I
+ I
) I
- O
activated O
K B
( I
+ I
) I
channels O
. O

Here O
, O
we O
have O
studied O
the O
venom O
of O
the O
Moroccan O
scorpion O
Buthus O
occitanus O
Paris O
( O
BoP O
) O
in O
order O
to O
find O
new O
peptides O
, O
which O
could O
enlarge O
our O
structure O
- O
function O
relationship O
knowledge O
on O
the O
Kv1 O
. O
3 O
blocker O
Kaliotoxin O
( O
KTX O
) O
that O
belongs O
to O
the O
alpha O
- O
KTx3 O
. O
1 O
family O
. O

Indeed O
and O
since O
more O
a O
decade O
, O
KTX O
is O
widely O
used O
by O
international O
investigators O
because O
it O
exhibits O
a O
quite O
sharp O
specificity O
and O
a O
high O
- O
affinity O
for O
the O
Kv1 O
. O
3 O
channel O
, O
which O
is O
not O
only O
a O
neuronal O
channel O
but O
also O
a O
therapeutic O
target O
for O
diverse O
autoimmune O
diseases O
such O
as O
multiple O
sclerosis O
, O
type O
1 O
diabetes O
, O
and O
rheumatoid O
arthritis O
. O

The O
BoP O
venom O
was O
first O
investigated O
using O
HPLC O
and O
MALDI O
- O
TOF O
/ O
MS O
. O

Further O
, O
the O
HPLC O
fractions O
were O
screened O
by O
ELISA O
with O
antibodies O
raised O
against O
KTX B
. O

These O
antibodies O
recognized O
at O
least O
three O
components O
toxic O
in O
mice O
by O
intracerebroventricu O
injection O
. O

They O
were O
further O
pharmacologically O
characterized O
by O
competition O
using O
( B
125 I
) I
I I
- I
KTX I
bound O
to O
its O
specific O
binding O
sites O
on O
rat O
brain O
synaptosomes O
. O

A O
single O
component O
( O
4161 O
Da O
) O
inhibited O
totally O
the O
( B
125 I
) I
I I
- I
KTX I
binding O
and O
with O
high O
- O
affinity O
( O
IC50 O
= O
0 O
. O
1 O
nM O
) O
, O
while O
the O
two O
other O
components O
poorly O
competed O
with O
( O
IC50 O
> O
100 O
nM O
) O
. O

These O
toxins O
were O
sequenced O
in O
full O
by O
Edman O
' O
s O
degradation O
. O

The O
high O
- O
affinity O
ligand O
( O
BoPKTX O
) O
shares O
86 O
% O
sequence O
identity O
with O
KTX O
and O
was O
classified O
as O
toxin O
alpha O
- O
KTx3 O
. O
17 O
. O

The O
two O
others O
peptides O
( O
BoP1 O
and O
BoP2 O
, O
4093 O
Da O
and O
4121 O
Da O
, O
respectively O
) O
only O
differ O
by O
a O
Lys B
/ O
Arg B
mutation O
. O

Their O
amino B
acid I
sequences O
were O
related O
to O
Martentoxin B
, O
which O
has O
been O
characterized O
from O
the O
Chinese O
scorpion O
Buthus O
martenzi O
Karch O
and O
described O
as O
both O
a O
BKCa O
and O
Kv1 O
. O
3 O
blocker O
. O

Accordingly O
, O
they O
belong O
to O
the O
alpha O
- O
KTx16 O
family O
. O

Towards O
the O
bioequivalence O
of O
pressurised O
metered O
dose O
inhalers O
1 O
: O
Design O
and O
characterisation O
of O
aerodynamically O
equivalent O
beclomethasone B
dipropionate I
inhalers O
with O
and O
without O
glycerol B
as O
a O
non O
- O
volatile O
excipient O
. O

A O
series O
of O
semi O
- O
empirical O
equations O
were O
utilised O
to O
design O
two O
solution O
based O
pressurised O
metered O
dose O
inhaler O
( O
pMDI O
) O
formulations O
, O
with O
equivalent O
aerosol O
performance O
but O
different O
physicochemical O
properties O
. O

Both O
inhaler O
formulations O
contained O
the O
drug O
, O
beclomethasone B
dipropionate I
( O
BDP B
) O
, O
a O
volatile O
mixture O
of O
ethanol B
co O
- O
solvent O
and O
propellant O
( O
hydrofluoroalkane B
- O
HFA B
) O
. O

However O
, O
one O
formulation O
was O
designed O
such O
that O
the O
emitted O
aerosol O
particles O
contained O
BDP B
and O
glycerol B
, O
a O
common O
inhalation O
particle O
modifying O
excipient O
, O
in O
a O
1 O
: O
1 O
mass O
ratio O
. O

By O
modifying O
the O
formulation O
parameters O
, O
including O
actuator O
orifice O
, O
HFA O
and O
metering O
volumes O
, O
it O
was O
possible O
to O
produce O
two O
formulations O
( O
glycerol B
- O
free O
and O
glycerol B
- O
containing O
) O
which O
had O
identical O
mass O
median O
aerodynamic O
diameters O
( O
2 O
. O
4 O
mu O
m O
+ O
/ O
- O
0 O
. O
1 O
and O
2 O
. O
5 O
mu O
m O
+ O
/ O
- O
0 O
. O
2 O
) O
, O
fine O
particle O
dose O
( O
> O
= O
5 O
mu O
m O
; O
66 O
mu O
g O
+ O
/ O
- O
6 O
and O
68 O
mu O
g O
+ O
/ O
- O
2 O
) O
and O
fine O
particle O
fractions O
( O
28 O
% O
+ O
/ O
- O
2 O
% O
and O
30 O

% O
+ O
/ O
- O
1 O
% O
) O
, O
respectively O
. O

These O
observations O
demonstrate O
that O
it O
is O
possible O
to O
engineer O
formulations O
that O
generate O
aerosol O
particles O
with O
very O
different O
compositions O
to O
have O
similar O
emitted O
dose O
and O
in O
vitro O
deposition O
profiles O
, O
thus O
making O
them O
equivalent O
in O
terms O
of O
aerosol O
performance O
. O

Analysis O
of O
the O
physicochemical O
properties O
of O
each O
formulation O
identified O
significant O
differences O
in O
terms O
of O
morphology O
, O
thermal O
properties O
and O
drug O
dissolution O
of O
emitted O
particles O
. O

The O
particles O
produced O
from O
both O
formulations O
were O
amorphous O
; O
however O
, O
the O
formulation O
containing O
glycerol B
generated O
particles O
with O
a O
porous O
structure O
, O
while O
the O
glycerol B
- O
free O
formulation O
generated O
particles O
with O
a O
primarily O
spherical O
morphology O
. O

Furthermore O
, O
the O
glycerol B
- O
containing O
particles O
had O
a O
significantly O
lower O
dissolution O
rate O
( O
7 O
. O
8 O
% O
+ O
/ O
- O
2 O
. O
1 O
% O
, O
over O
180min O
) O
compared O
to O
the O
glycerol B
- O
free O
particles O
( O
58 O
. O
0 O
% O
+ O
/ O
- O
2 O
. O
9 O
% O
, O
over O
60min O
) O
when O
measured O
using O
a O
Franz O
diffusion O
cell O
. O

It O
is O
hypothesised O
that O
the O
presence O
of O
glycerol B
in O
the O
emitted O
aerosol O
particles O
altered O
solubility O
and O
drug O
transport O
, O
which O
may O
have O
implications O
for O
BDP B
pharmacokinetics O
after O
deposition O
in O
the O
respiratory O
tract O
. O

5 O
- O
HT1A O
receptors O
direct O
the O
orientation O
of O
plasticity O
in O
layer O
5 O
pyramidal O
neurons O
of O
the O
mouse O
prefrontal O
cortex O
. O

Several O
psychiatric O
disorders O
involving O
the O
prefrontal O
cortex O
( O
PFC O
) O
are O
associated O
with O
a O
dysfunction O
of O
5 O
- O
HT1A O
receptors O
( O
5 O
- O
HT1AR O
) O
. O

These O
receptors O
, O
located O
on O
interneurons O
and O
pyramidal O
neurons O
, O
may O
influence O
neuronal O
excitability O
through O
a O
regulation O
of O
the O
balance O
between O
excitation O
( O
E O
) O
and O
inhibition O
( O
I O
) O
. O

Patch O
- O
clamp O
recordings O
in O
mouse O
cortical O
slices O
were O
performed O
to O
determine O
the O
modulatory O
role O
of O
5 O
- O
HT1AR O
on O
the O
excitability O
and O
the O
synaptic O
plasticity O
of O
layer O
5 O
pyramidal O
neurons O
( O
L5PyNs O
) O
of O
the O
PFC O
. O

This O
was O
done O
by O
a O
comparison O
of O
postsynaptic O
currents O
evoked O
by O
electrical O
stimulation O
in O
layer O
2 O
/ O
3 O
of O
5 O
- O
HT1AR O
- O
KO O
and O
wild O
- O
type O
( O
WT O
) O
mice O
. O

We O
observed O
that O
the O
E O
- O
I O
balance O
was O
significantly O
changed O
from O
20 O
% O
E O
- O
80 O
% O
I O
in O
WT O
mice O
to O
23 O
% O
E O
- O
77 O
% O
I O
in O
5 O
- O
HT1AR O
- O
KO O
mice O
, O
demonstrating O
that O
5 O
- O
HT1ARs O
contribute O
to O
the O
control O
of O
the O
balance O
between O
excitation O
and O
inhibition O
. O

Furthermore O
, O
we O
show O
that O
interfering O
with O
5 O
- O
HT1AR O
reduced O
the O
magnitude O
of O
the O
long O
term O
potentiation O
of O
excitation O
( O
eLTP O
) O
( O
induced O
by O
high O
frequency O
stimulation O
) O
. O

In O
addition O
, O
we O
show O
that O
5 O
- O
HT1ARs O
determine O
the O
orientation O
of O
the O
synaptic O
plasticity O
towards O
LTP O
or O
LTD O
or O
no O
plasticity O
through O
the O
modulation O
of O
NMDAR O
- O
mediated O
currents O
. O

Our O
data O
point O
out O
to O
a O
unique O
role O
of O
5 O
- O
HT1A O
postsynaptic O
receptors O
in O
PFC O
to O
adapt O
the O
functional O
plasticity O
of O
L5PyNs O
towards O
LTP O
, O
LTD O
or O
no O
plasticity O
. O

This O
brings O
a O
new O
way O
to O
intervene O
on O
neuronal O
networks O
of O
the O
PFC O
in O
anxiety O
disorders O
and O
schizophrenia O
. O

Baicalein B
attenuates O
bleomycin B
- O
induced O
pulmonary O
fibrosis O
in O
rats O
through O
inhibition O
of O
miR O
- O
21 O
. O

Currently O
, O
there O
is O
no O
satisfactory O
treatment O
for O
pulmonary O
fibrosis O
, O
and O
effective O
agents O
urgently O
need O
to O
be O
developed O
. O

The O
aim O
of O
the O
present O
study O
was O
to O
investigate O
the O
effects O
of O
baicalein B
on O
bleomycin B
- O
induced O
pulmonary O
fibrosis O
, O
and O
the O
novel O
mechanisms O
involved O
in O
the O
anti O
- O
fibrosis O
effects O
. O

Pulmonary O
fibrosis O
was O
induced O
by O
a O
single O
intratracheal O
instillation O
of O
5 O
mg O
/ O
kg O
bleomycin B
. O

Two O
bleomycin B
- O
treated O
groups O
were O
orally O
administered O
daily O
with O
50 O
and O
100 O
mg O
/ O
kg O
of O
baicalein B
from O
day O
1 O
to O
28 O
. O

The O
results O
showed O
baicalein B
decreased O
hydroxyproline B
content O
and O
alpha O
- O
SMA O
levels O
and O
increased O
lung O
index O
. O

Histopathological O
examinations O
demonstrated O
baicalein B
could O
obviously O
lower O
the O
degree O
of O
alveolitis O
and O
lung O
fibrosis O
. O

The O
total O
antioxidant O
capacity O
in O
bleomycin B
- O
treated O
rats O
with O
baicalein B
was O
also O
remarkably O
higher O
than O
in O
those O
without O
baicalein B
. O

Baicalein B
remarkably O
decreased O
miR O
- O
21 O
levels O
and O
inhibited O
the O
increased O
expression O
of O
TGF O
- O
beta O
1 O
and O
p O
- O
Smad O
- O
2 O
/ O
3 O
in O
bleomycin B
- O
treated O
rats O
. O

Baicalein B
can O
attenuate O
bleomycin B
- O
induced O
pulmonary O
fibrosis O
. O

The O
attenuation O
is O
partly O
achieved O
by O
improving O
antioxidant O
activity O
, O
alleviating O
inflammation O
, O
repressing O
miR O
- O
21 O
, O
and O
inhibiting O
TGF O
- O
beta O
/ O
Smad O
signaling O
. O

Quercetin B
and O
epigallocatechin B
- I
3 I
- I
gallate I
effect O
on O
the O
anisotropy O
of O
model O
membranes O
with O
cholesterol B
. O

Cell O
membrane O
fluidity O
, O
which O
can O
be O
altered O
by O
oxidative O
stress O
, O
plays O
an O
important O
role O
in O
the O
cell O
physiology O
. O

Flavonoids B
are O
among O
the O
most O
studied O
food O
substances O
that O
prevent O
and O
/ O
or O
reduce O
oxidative O
stress O
, O
but O
their O
action O
mechanisms O
are O
far O
from O
being O
understood O
. O

We O
performed O
a O
study O
on O
the O
effect O
of O
quercetin B
and O
epigallocatechin B
- I
3 I
- I
gallate I
on O
2 B
- I
Dimyristoyl I
- I
sn I
- I
glycero I
- I
3 I
- I
phosphocholine I
small O
unilamellar O
vesicles O
( O
SUVs O
) O
with O
different O
amounts O
of O
cholesterol B
, O
using O
Laurdan B
as O
a O
fluorescent O
probe O
, O
to O
put O
into O
evidence O
the O
perturbations O
of O
the O
phospholipid O
membrane O
fluidity O
and O
local O
lipid O
order O
in O
an O
attempt O
to O
decipher O
the O
action O
mechanism O
of O
the O
flavonoids B
at O
the O
cell O
membrane O
level O
. O

Results O
indicate O
that O
polyphenols B
modulate O
the O
transition O
from O
the O
gel O
phase O
to O
the O
liquid O
crystalline O
phase O
of O
SUVs O
in O
all O
studied O
membranes O
. O

SUVs O
with O
cholesterol B
have O
by O
themselves O
higher O
phase O
transition O
temperature O
and O
the O
presence O
of O
polyphenols B
stabilizes O
further O
the O
membrane O
. O

Quercetin B
has O
a O
dose O
- O
dependent O
effect O
on O
the O
fluidity O
and O
local O
order O
of O
the O
lipid O
membranes O
, O
whilst O
epigallocatechin B
- I
3 I
- I
gallate I
action O
is O
not O
dose O
- O
dependent O
, O
the O
differences O
being O
attributable O
to O
the O
hydrophobic O
/ O
hydrophilic O
character O
of O
the O
substances O
. O

The O
findings O
are O
discussed O
within O
the O
frame O
of O
earlier O
reports O
on O
the O
effect O
of O
polyphenols B
on O
artificial O
membranes O
. O

Cytotoxic O
mechanism O
of O
Piper O
gaudichaudianum O
Kunth O
essential O
oil O
and O
its O
major O
compound O
nerolidol B
. O

Piper O
gaudichaudianum O
Kunth O
is O
used O
in O
popular O
medicine O
as O
anti O
- O
inflamatory O
and O
against O
liver O
disorders O
. O

One O
of O
the O
most O
studied O
components O
of O
the O
plant O
is O
the O
essential O
oil O
for O
which O
chemical O
analysis O
revealed O
( B
E I
) I
- I
nerolidol I
as O
major O
compound O
. O

Recently O
, O
we O
have O
shown O
that O
P O
. O
gaudichaudianum O
essential O
oil O
possesses O
strong O
cytotoxic O
effects O
in O
mammalian O
V79 O
cells O
. O

The O
aim O
of O
this O
study O
was O
to O
analyze O
the O
cytotoxicity O
and O
mutagenicity O
of O
P O
. O
gaudichaudianum O
essential O
oil O
and O
nerolidol B
using O
Saccharomyces O
cerevisiae O
as O
model O
study O
. O

Treatment O
of O
the O
XV185 O
- O
14c O
and O
N123 O
strains O
with O
essential O
oil O
and O
nerolidol B
led O
to O
cytotoxicity O
but O
did O
not O
induce O
mutagenicity O
. O

Our O
results O
revealed O
an O
important O
role O
of O
base O
excision O
repair O
( O
BER O
) O
as O
the O
ntg1 O
, O
ntg2 O
, O
apn1 O
and O
apn2 O
mutants O
showed O
pronounced O
sensitivity O
to O
essential O
oil O
and O
nerolidol B
. O

In O
the O
absence O
of O
superoxide B
dismutase O
( O
in O
sod1 O
Delta O
mutant O
strain O
) O
sensitivity O
to O
the O
essential O
oil O
and O
nerolidol B
increased O
indicating O
that O
this O
oil O
and O
nerolidol B
are O
generating O
reactive O
oxygen B
species O
( O
ROS O
) O
. O

The O
ROS O
production O
was O
confirmed O
by O
DCF B
- O
DA O
probing O
assay O
in O
Sod O
- O
deficient O
strains O
. O

From O
this O
, O
we O
conclude O
that O
the O
observed O
cytotoxicity O
to O
P O
. O
gaudichaudianum O
essential O
oil O
and O
nerolidol B
is O
mainly O
related O
to O
ROS O
and O
DNA O
single O
strand O
breaks O
generated O
by O
the O
presence O
of O
oxidative O
lesions O
. O

Differential O
effects O
of O
acute O
and O
chronic O
zinc B
( O
Zn B
) O
exposure O
on O
hepatic O
lipid O
deposition O
and O
metabolism O
in O
yellow O
catfish O
Pelteobagrus O
fulvidraco O
. O

The O
present O
study O
is O
conducted O
to O
determine O
the O
potential O
mechanisms O
of O
Zn B
on O
hepatic O
lipid O
deposition O
and O
metabolism O
for O
yellow O
catfish O
Pelteobagrus O
fulvidraco O
with O
8 O
- O
week O
chronic O
exposure O
to O
low O
Zn B
levels O
( O
Zn B
levels O
: O
0 O
. O
05 O
, O
0 O
. O
35 O
and O
0 O
. O
86mg O
/ O
l O
Zn B
, O
respectively O
) O
and O
96 O
- O
h O
acute O
exposure O
to O
a O
high O
Zn B
level O
( O
Zn B
level O
: O
4 O
. O
71mg O
/ O
l O
Zn B
, O
respectively O
) O
. O

For O
that O
purpose O
, O
hepatic O
lipid O
deposition O
and O
Zn B
accumulation O
, O
hepatic O
carnitine B
palmitoyltransferase O
I O
( O
CPT O
I O
) O
and O
lipoprotein O
lipase O
( O
LPL O
) O
activities O
, O
and O
the O
hepatic O
mRNA O
expression O
of O
ten O
genes O
involved O
in O
lipid O
metabolism O
are O
determined O
. O

Chronic O
( O
8 O
weeks O
) O
exposure O
to O
low O
Zn B
levels O
apparently O
increases O
hepatic O
lipid O
content O
, O
hepatosomatic O
index O
( O
HSI O
) O
( O
P O
< O
0 O
. O
05 O
) O
and O
LPL O
activity O
, O
and O
reduces O
hepatic O
CPT O
I O
activity O
. O

In O
contrast O
, O
the O
acute O
( O
96h O
) O
exposure O
to O
high O
Zn B
level O
reduces O
hepatic O
lipid O
content O
, O
HSI O
and O
LPL O
activity O
, O
and O
increases O
CPT O
I O
activity O
. O

The O
change O
of O
mRNA O
levels O
of O
genes O
related O
to O
lipid O
metabolism O
is O
Zn B
concentration O
- O
dependent O
. O

Pearson O
correlations O
among O
mRNA O
expression O
levels O
, O
lipid O
content O
, O
CPT O
I O
and O
LPL O
activities O
in O
liver O
are O
also O
observed O
in O
yellow O
catfish O
with O
the O
8 O
- O
week O
chronic O
Zn B
exposure O
. O

For O
the O
first O
time O
, O
our O
study O
demonstrates O
the O
effect O
of O
waterborne O
Zn B
exposure O
on O
lipid O
metabolism O
at O
the O
molecular O
levels O
in O
fish O
, O
which O
may O
contribute O
to O
understanding O
the O
mechanism O
of O
Zn B
- O
induced O
hepatic O
toxicity O
in O
fish O
. O

The O
force O
of O
the O
spontaneously O
contracting O
zebrafish O
heart O
, O
in O
the O
assessment O
of O
cardiovascular O
toxicity O
: O
Application O
on O
adriamycin B
. O

The O
heart O
of O
the O
zebrafish O
has O
been O
used O
extensively O
to O
assess O
the O
cardiotoxic O
effect O
of O
compounds O
, O
using O
the O
frequency O
of O
heart O
contractions O
as O
the O
main O
index O
of O
cardiac O
response O
to O
drugs O
. O

In O
this O
study O
, O
the O
force O
and O
the O
frequency O
generated O
by O
the O
spontaneously O
contracting O
zebrafish O
heart O
, O
isolated O
in O
saline O
, O
were O
found O
to O
be O
0 O
. O
87 O
+ O
/ O
- O
0 O
. O
05mN O
and O
1 O
. O
54 O
+ O
/ O
- O
0 O
. O
03Hz O
( O
n O
= O
6 O
) O
respectively O
within O
the O
first O
hour O
of O
recording O
. O

Both O
values O
of O
force O
and O
frequency O
remained O
constant O
for O
over O
8h O
. O

The O
advantage O
of O
prolonged O
vitality O
in O
the O
assessment O
of O
cardiovascular O
toxicity O
was O
shown O
using O
the O
well O
- O
known O
anticancer O
drug O
adriamycin B
, O
which O
has O
severe O
cardiotoxic O
side O
effects O
. O

At O
10 O
. O
0 O
mu O
M O
there O
was O
a O
21 O
. O
05 O
+ O
/ O
- O
4 O
. O
42 O
% O
( O
p O
= O
0 O
. O
02 O
, O
n O
= O
4 O
) O
decrease O
in O
the O
force O
of O
contraction O
, O
while O
the O
frequency O
was O
not O
affected O
after O
3h O
treatment O
( O
p O
> O
0 O
. O
05 O
) O
. O

At O
50 O
. O
0 O
and O
100 O
. O
0 O
mu O
M O
there O
was O
a O
33 O
. O
24 O
+ O
/ O
- O
3 O
. O
0 O
and O
46 O
. O
6 O
+ O
/ O
- O
4 O
. O
80 O
% O
irreversible O
decrease O
in O
force O
( O
p O
< O
0 O
. O
05 O
, O
n O
= O
4 O
) O
, O
while O
a O
18 O
. O
02 O
+ O
/ O
- O
4 O
. O
07 O
% O
and O
16 O
. O
16 O
+ O
/ O
- O
4 O
. O
07 O
% O
reversible O
increase O
was O
observed O
in O
the O
frequency O
( O
p O
= O
0 O
. O
02 O
, O
n O
= O
4 O
) O
. O

These O
contradictory O
positive O
chronotropic O
and O
negative O
inotropic O
responses O
indicate O
the O
strong O
inhibitory O
effect O
of O
adriamycin B
on O
ventricular O
cardiomyocytes O
and O
its O
excitatory O
effects O
on O
auto O
- O
rhythmical O
pacemaker O
cells O
. O

If O
heart O
frequency O
was O
the O
only O
parameter O
used O
to O
assess O
the O
cardiotoxic O
effect O
of O
adriamycin B
, O
at O
the O
above O
range O
of O
concentrations O
, O
this O
compound O
would O
have O
been O
classified O
as O
non O
- O
cardiotoxic O
. O

Potentiation O
of O
morphine B
- O
induced O
mechanical O
antinociception O
by O
sigma O
1 O
receptor O
inhibition O
: O
Role O
of O
peripheral O
sigma O
1 O
receptors O
. O

We O
studied O
the O
modulation O
of O
morphine B
- O
induced O
mechanical O
antinociception O
and O
side O
effects O
by O
sigma O
1 O
receptor O
inhibition O
. O

Both O
wild O
- O
type O
( O
WT O
) O
and O
sigma O
1 O
receptor O
knockout O
( O
sigma O
1 O
- O
KO O
) O
mice O
showed O
similar O
responses O
to O
paw O
pressure O
( O
100 O
- O
600 O
g O
) O
. O

The O
systemic O
( O
subcutaneous O
) O
or O
local O
( O
intraplantar O
) O
administration O
of O
sigma O
1 O
antagonists O
( O
BD B
- I
1063 I
, O
BD B
- I
1047 I
, O
NE B
- I
100 I
and O
S1RA B
) O
was O
devoid O
of O
antinociceptive O
effects O
in O
WT O
mice O
. O

However O
, O
sigma O
1 O
- O
KO O
mice O
exhibited O
an O
enhanced O
mechanical O
antinociception O
in O
response O
to O
systemic O
morphine B
( O
1 O
- O
16 O
mg O
/ O
kg O
) O
. O

Similarly O
, O
systemic O
treatment O
of O
WT O
mice O
with O
sigma O
1 O
antagonists O
markedly O
potentiated O
morphine B
- O
induced O
antinociception O
, O
and O
its O
effects O
were O
reversed O
by O
the O
selective O
sigma O
1 O
agonist O
PRE B
- I
084 I
. O

Although O
the O
local O
administration O
of O
morphine B
( O
50 O
- O
200 O
mu O
g O
) O
was O
devoid O
of O
antinociceptive O
effects O
in O
WT O
mice O
, O
it O
induced O
dose O
- O
dependent O
antinociception O
in O
sigma O
1 O
- O
KO O
mice O
. O

This O
effect O
was O
limited O
to O
the O
injected O
paw O
. O

Enhancement O
of O
peripheral O
morphine B
antinociception O
was O
replicated O
in O
WT O
mice O
locally O
co O
- O
administered O
with O
sigma O
1 O
antagonists O
and O
the O
opioid O
. O

None O
of O
the O
sigma O
1 O
antagonists O
tested O
enhanced O
morphine B
- O
antinociception O
in O
sigma O
1 O
- O
KO O
mice O
, O
confirming O
a O
sigma O
1 O
- O
mediated O
action O
. O

Morphine B
- O
induced O
side O
- O
effects O
( O
hyperlocomotion O
and O
inhibition O
of O
gastrointestinal O
transit O
) O
were O
unaltered O
in O
sigma O
1 O
- O
KO O
mice O
. O

These O
results O
cannot O
be O
explained O
by O
a O
direct O
interaction O
of O
sigma O
1 O
ligands O
with O
mu O
- O
opioid O
receptors O
or O
adaptive O
changes O
of O
mu O
- O
receptors O
in O
sigma O
1 O
- O
KO O
mice O
, O
given O
that O
[ B
( I
3 I
) I
H I
] I
DAMGO I
binding O
in O
forebrain O
, O
spinal O
cord O
, O
and O
hind O
- O
paw O
skin O
membranes O
was O
unaltered O
in O
mutant O
mice O
, O
and O
none O
of O
the O
sigma O
1 O
drugs O
tested O
bound O
to O
mu O
- O
opioid O
receptors O
. O

These O
results O
show O
that O
sigma O
1 O
receptor O
inhibition O
potentiates O
morphine B
- O
induced O
mechanical O
analgesia O
but O
not O
its O
acute O
side O
effects O
, O
and O
that O
this O
enhanced O
analgesia O
can O
be O
induced O
at O
peripheral O
level O
. O

Accumulation O
of O
phenolic B
compounds O
in O
in O
vitro O
cultures O
and O
wild O
plants O
of O
Lavandula O
viridis O
L O
' O
H O
e O
r O
and O
their O
antioxidant O
and O
anti O
- O
cholinesterase O
potential O
. O

In O
this O
study O
, O
we O
evaluated O
the O
phenolic O
profile O
, O
antioxidant O
and O
anti O
- O
cholinesterase O
potential O
of O
different O
extracts O
from O
wild O
plants O
and O
in O
vitro O
cultures O
of O
Lavandula O
viridis O
L O
' O
H O
e O
r O
. O

The O
HPLC O
- O
DAD O
analysis O
allowed O
the O
identification O
and O
quantification O
of O
3 B
- I
O I
- I
caffeoylquinic I
, I
4 I
- I
O I
- I
caffeoylquinic I
, I
5 I
- I
O I
- I
caffeoylquinic I
and I
rosmarinic I
acids I
, O
and O
luteolin B
and O
pinocembrin B
. O

Water O
/ O
ethanol B
extract O
from O
in O
vitro O
cultures O
contained O
the O
highest O
amount O
of O
the O
identified O
phenolic O
compounds O
( O
51652 O
. O
92mg O
/ O
kg O
) O
. O

To O
investigate O
the O
antioxidant O
activity O
we O
used O
Trolox B
equivalent O
antioxidant O
capacity O
, O
oxygen B
radical O
absorbance O
capacity O
, O
Fe B
( I
2 I
+ I
) I
chelation O
activity O
and O
the O
inhibition O
of O
Fe B
( I
2 I
+ I
) I
- O
induced O
lipid O
peroxidation O
in O
mouse O
brain O
homogenates O
( O
in O
vitro O
) O
. O

Overall O
, O
all O
the O
extracts O
from O
both O
wild O
plants O
and O
in O
vitro O
cultures O
exhibited O
ability O
to O
scavenge O
free O
radicals O
, O
to O
chelate O
Fe B
( I
2 I
+ I
) I
and O
to O
protect O
against O
lipid O
peroxidation O
. O

In O
addition O
, O
the O
extracts O
from O
L O
. O
viridis O
were O
active O
in O
inhibiting O
both O
acetylcholinesterase O
and O
butyrylcholinesteras O
( O
Ellman O
' O
s O
method O
) O
. O

Our O
findings O
suggest O
that O
L O
. O
viridis O
in O
vitro O
cultures O
represent O
a O
promising O
alternative O
for O
the O
production O
of O
active O
metabolites O
with O
antioxidant O
and O
anti O
- O
cholinesterase O
activity O
. O

Hypocholesterolemic O
effect O
of O
daily O
fisetin B
supplementation O
in O
high O
fat O
fed O
Sprague O
- O
Dawley O
rats O
. O

We O
aimed O
to O
test O
whether O
fisetin B
could O
modulate O
cholesterol B
homeostasis O
in O
rats O
with O
diet O
- O
induced O
hypercholesterolemia O
, O
and O
further O
investigated O
the O
underlying O
mechanisms O
by O
which O
fisetin B
exerts O
its O
cholesterol B
lowering O
effect O
. O

Blood O
lipid O
profile O
, O
hepatic O
cholesterol B
content O
, O
as O
well O
as O
gene O
expressions O
in O
cholesterol B
metabolism O
were O
examined O
. O

Elevated O
levels O
of O
total O
cholesterol B
and O
LDL O
- O
cholesterol B
, O
along O
with O
hepatic O
cholesterol B
content O
in O
a O
high O
fat O
group O
were O
found O
to O
be O
significantly O
reduced O
by O
fisetin B
. O

The O
high O
fat O
diet O
significantly O
decreased O
hepatic O
mRNA O
levels O
of O
LDLR O
, O
SREBP2 O
, O
HMGCR O
and O
PCSK9 O
in O
comparison O
to O
the O
control O
diet O
, O
however O
, O
fisetin B
did O
not O
further O
elicit O
any O
changes O
in O
mRNA O
levels O
of O
the O
same O
genes O
. O

The O
high O
fat O
diet O
dramatically O
increased O
the O
transcript O
levels O
of O
CYP7A1 O
, O
which O
was O
subsequently O
reversed O
by O
the O
fisetin B
. O

In O
HepG2 O
cells O
, O
fisetin B
was O
found O
to O
increase O
the O
levels O
of O
a O
nuclear O
form O
of O
SREBP2 O
and O
LDLR O
. O

In O
conclusion O
, O
fisetin B
supplementation O
displayed O
hypocholesterolemic O
effects O
by O
modulating O
the O
expression O
of O
genes O
associated O
with O
cholesterol B
and O
bile B
acid I
metabolism O
. O

Phenolic B
compounds O
from O
Jacaranda O
caroba O
( O
Vell O
. O
) O
A O
. O

DC O
. O
: O
Approaches O
to O
neurodegenerative O
disorders O
. O

Diseases O
affecting O
the O
central O
nervous O
system O
are O
spread O
throughout O
the O
world O
. O

As O
so O
, O
more O
efficient O
and O
safe O
neuroprotective O
drugs O
are O
required O
. O

The O
present O
study O
describes O
, O
for O
the O
first O
time O
, O
the O
phenolic O
composition O
and O
bioactivity O
of O
Jacaranda O
caroba O
( O
Vell O
. O
) O
A O
. O

DC O
, O
a O
species O
whose O
infusion O
is O
consumed O
as O
traditional O
medicine O
. O

The O
HPLC O
- O
DAD O
- O
ESI O
/ O
MS O
( O
n O
) O
analysis O
revealed O
the O
presence O
of O
four O
dicaffeoyl B
acid I
derivatives O
and O
nine O
flavonoids B
, O
comprising O
quercetin B
, O
kaempferol B
and O
isorhamnetin B
derivatives O
. O

Twelve O
compounds O
are O
described O
for O
the O
first O
time O
in O
Jacaranda O
genus O
. O

Although O
isorhamnetin B
- I
3 I
- I
O I
- I
rhmanoside I
- I
7 I
, I
4 I
' I
- I
di I
- I
O I
- I
glucoside I
and O
quercetin B
- I
3 I
- I
O I
- I
( I
2 I
- I
pentosyl I
) I
hexoside I
are O
the O
main O
metabolites O
in O
both O
aqueous O
and O
hydromethanolic O
extracts O
, O
qualitative O
and O
quantitative O
differences O
were O
found O
between O
them O
. O

Aqueous O
extract O
is O
richer O
in O
dicaffeoyl B
acid I
derivatives O
. O

Both O
extracts O
proved O
to O
be O
strong O
radicals O
' O
scavengers O
and O
effective O
monoamine B
- O
oxidase O
A O
inhibitors O
, O
but O
showed O
weak O
protection O
against O
cholinesterases O
' O
activity O
. O

The O
results O
highlight O
the O
value O
of O
J O
. O
caroba O
as O
a O
source O
of O
health O
- O
promoting O
antioxidants O
and O
antidepressant O
compounds O
. O

The O
mycotoxin O
T B
- I
2 I
inhibits O
hepatic O
cytochrome O
P4503A O
activity O
in O
pigs O
. O

Mycotoxins O
are O
toxic O
metabolites O
produced O
by O
fungi O
that O
readily O
colonize O
crops O
. O

After O
ingestion O
, O
these O
mycotoxins O
can O
compromise O
intestinal O
health O
, O
and O
once O
entering O
the O
blood O
stream O
, O
even O
affect O
the O
liver O
and O
its O
metabolizing O
enzymes O
. O

It O
was O
therefore O
the O
aim O
of O
the O
present O
study O
to O
investigate O
the O
effect O
of O
T B
- I
2 I
toxin I
, O
an O
emerging O
and O
potent O
Fusarium O
mycotoxin O
, O
on O
the O
enzymatic O
activity O
of O
cytochrome O
P4503A O
( O
CYP3A O
) O
metabolizing O
enzymes O
in O
the O
liver O
of O
pigs O
. O

In O
addition O
, O
a O
yeast O
- O
derived O
feed O
additive O
that O
claims O
to O
bind O
T O
- O
2 O
toxin O
was O
included O
in O
the O
study O
to O
evaluate O
its O
efficacy O
. O

Our O
results O
demonstrated O
that O
a O
14 O
- O
days O
intake O
of O
T B
- I
2 I
toxin I
contaminated O
feed O
at O
a O
dose O
of O
903 O
mu O
g O
/ O
kg O
feed O
, O
whether O
or O
not O
combined O
with O
the O
mycotoxin O
binder O
, O
results O
in O
a O
substantial O
inhibition O
of O
the O
CYP3A O
activity O
in O
the O
liver O
of O
pigs O
. O

This O
result O
may O
be O
of O
importance O
for O
animal O
health O
, O
the O
pharmacokinetics O
and O
the O
withdrawal O
time O
of O
drugs O
that O
are O
substrate O
of O
CYP3A O
enzymes O
, O
and O
consequently O
can O
be O
a O
threat O
for O
public O
health O
with O
respect O
to O
tissue O
residues O
of O
these O
drugs O
. O

Metabolism O
Studies O
of O
Unformulated O
Internally O
[ B
3H I
] I
- O
labeled O
siRNAs O
in O
Mice O
. O

Absorption O
, O
distribution O
, O
metabolism O
, O
and O
excretion O
properties O
of O
two O
unformulated O
model O
siRNAs O
were O
determined O
using O
a O
single O
internal O
[ O
( B
3 I
) I
H I
] O
- O
radiolabeling O
procedure O
, O
where O
the O
full O
- O
length O
oligonucleotides O
were O
radiolabeled O
by O
Br B
/ O
( B
3 I
) I
H I
- O
exchange O
. O

Tissue O
distribution O
, O
excretion O
, O
and O
mass O
balance O
of O
radioactivity O
were O
investigated O
in O
male O
CD O
- O
1 O
mice O
, O
following O
a O
single O
intravenous O
administration O
of O
the O
[ O
( B
3 I
) I
H I
] O
- O
siRNAs O
, O
at O
a O
target O
dose O
level O
of O
5 O
mg O
/ O
kg O
. O

Quantitative O
whole O
- O
body O
autoradiography O
( O
QWBA O
) O
and O
liquid O
scintillation O
counting O
techniques O
were O
used O
to O
determine O
tissue O
distribution O
. O

Radiochromatogram O
profiles O
were O
determined O
in O
plasma O
, O
tissue O
extracts O
and O
urine O
. O

Metabolites O
were O
separated O
by O
liquid O
chromatography O
and O
identified O
by O
radiodetection O
and O
high O
- O
resolution O
accurate O
mass O
spectrometry O
. O

In O
general O
, O
there O
was O
little O
difference O
in O
the O
distribution O
of O
total O
radiolabeled O
components O
after O
administration O
of O
the O
two O
unformulated O
[ O
( B
3 I
) I
H I
] O
- O
siRNAs O
. O

The O
radioactivity O
was O
rapidly O
and O
widely O
distributed O
throughout O
the O
body O
, O
and O
remained O
detectable O
in O
all O
tissues O
investigated O
at O
later O
time O
points O
( O
24 O
and O
48 O
hours O
for O
[ O
( B
3 I
) I
H I
] O
- O
MRP4 O
and O
[ O
( B
3 I
) I
H I
] O
- O
SSB O
siRNA O
, O
respectively O
) O
. O

After O
an O
initial O
rapid O
decline O
, O
concentrations O
of O
total O
radiolabeled O
components O
in O
dried O
blood O
declined O
at O
a O
much O
slower O
rate O
. O

A O
nearly O
complete O
mass O
balance O
was O
obtained O
for O
the O
[ O
( B
3 I
) I
H I
] O
- O
SSB O
siRNA O
and O
renal O
excretion O
was O
the O
main O
route O
of O
elimination O
( O
38 O
% O
) O
. O

The O
metabolism O
of O
the O
two O
model O
siRNAs O
was O
rapid O
and O
extensive O
. O

Five O
minutes O
after O
administration O
, O
no O
parent O
compound O
could O
be O
detected O
in O
plasma O
. O

Instead O
, O
radiolabeled O
nucleosides B
resulting O
from O
nuclease O
hydrolysis O
were O
observed O
. O

In O
the O
metabolism O
profiles O
obtained O
from O
various O
tissues O
only O
radiolabeled O
nucleosides O
were O
found O
, O
suggesting O
that O
siRNAs O
are O
rapidly O
metabolized O
and O
that O
the O
distribution O
pattern O
of O
total O
radiolabeled O
components O
can O
be O
ascribed O
to O
small O
molecular O
weight O
metabolites O
. O

Enhanced O
broadband O
and O
omnidirectional O
performance O
of O
Cu B
( I
In I
, I
Ga I
) I
Se2 I
solar O
cells O
with O
ZnO B
functional O
nanotree O
arrays O
. O

An O
effective O
approach O
is O
demonstrated O
for O
enhancing O
photoelectric O
conversion O
of O
Cu B
( I
In I
, I
Ga I
) I
Se2 I
( O
CIGS B
) O
solar O
cells O
with O
three O
- O
dimensional O
ZnO B
nanotree O
arrays O
. O

Under O
a O
simulated O
one O
- O
sun O
condition O
, O
cells O
with O
ZnO B
nanotree O
arrays O
enhance O
the O
short O
- O
circuit O
current O
density O
by O
10 O
. O
62 O
% O
. O

The O
omnidirectional O
anti O
- O
reflection O
of O
CIGS B
solar O
cells O
with O
various O
ZnO B
nanostructures O
is O
also O
investigated O
. O

The O
solar O
- O
spectrum O
weighted O
reflectance O
is O
approximately O
less O
than O
5 O
% O
for O
incident O
angles O
of O
up O
to O
60 O
degrees O
and O
for O
the O
wavelengths O
primarily O
from O
400 O
nm O
to O
1000 O
nm O
. O

This O
enhancement O
in O
light O
harvesting O
is O
attributable O
to O
the O
gradual O
refractive O
index O
profile O
between O
the O
ZnO B
nanostructures O
and O
air O
. O

Serotonergic O
hallucinogens O
differentially O
modify O
gamma O
and O
high O
frequency O
oscillations O
in O
the O
rat O
nucleus O
accumbens O
. O

RATIONALE O
: O
The O
nucleus O
accumbens O
( O
NAc O
) O
is O
a O
site O
critical O
for O
the O
actions O
of O
many O
drugs O
of O
abuse O
. O

Psychoactive O
compounds O
, O
such O
as O
N B
- I
methyl I
- I
D I
- I
aspartate I
receptor O
( O
NMDAR O
) O
antagonists O
, O
modify O
gamma O
( O
40 O
- O
90 O
) O
and O
high O
frequency O
oscillations O
( O
HFO O
, O
130 O
- O
180 O
Hz O
) O
in O
local O
field O
potentials O
( O
LFPs O
) O
recorded O
in O
the O
NAc O
. O

Lysergic B
acid I
diethylamide I
( O
LSD B
) O
and O
2 B
, I
5 I
- I
dimethoxy I
- I
4 I
- I
iodoamphetamine I
( O
DOI B
) O
are O
serotonergic O
hallucinogens O
and O
activation O
of O
5HT2A O
receptors O
likely O
underlies O
their O
hallucinogenic O
effects O
. O

Whether O
these O
compounds O
can O
also O
modulate O
LFP O
oscillations O
in O
the O
NAc O
is O
unclear O
. O

OBJECTIVE O
: O
This O
study O
aims O
to O
examine O
the O
effect O
of O
serotonergic O
hallucinogens O
on O
gamma O
and O
HFO O
recorded O
in O
the O
NAc O
and O
to O
test O
whether O
5HT2A O
receptors O
mediate O
the O
effects O
observed O
. O

METHODS O
: O
LFPs O
were O
recorded O
from O
the O
NAc O
of O
freely O
moving O
rats O
. O

Drugs O
were O
administered O
intraperitoneally O
. O

RESULTS O
: O
LSD B
( O
0 O
. O
03 O
- O
0 O
. O
3 O
mg O
/ O
kg O
) O
and O
DOI B
( O
0 O
. O
5 O
- O
2 O
. O
0 O
mg O
/ O
kg O
) O
increased O
the O
power O
and O
reduced O
the O
frequency O
of O
HFO O
. O

In O
contrast O
, O
the O
hallucinogens O
produced O
a O
robust O
reduction O
in O
the O
power O
of O
low O
( O
40 O
- O
60 O
Hz O
) O
, O
but O
not O
high O
gamma O
oscillations O
( O
70 O
- O
90 O
Hz O
) O
. O

MDL B
11939 I
( O
1 O
. O
0 O
mg O
/ O
kg O
) O
, O
a O
5HT2A O
receptor O
antagonist O
, O
fully O
reversed O
the O
changes O
induced O
by O
DOI B
on O
HFO O
but O
only O
partially O
for O
the O
low O
gamma O
band O
. O

Equivalent O
increases O
in O
HFO O
power O
were O
observed O
after O
TCB B
- I
2 I
( O
5HT2A O
receptor O
agonist O
, O
0 O
. O
1 O
- O
1 O
. O
5 O
mg O
/ O
kg O
) O
, O
but O
not O
CP B
809101 I
( O
5H2C O
receptor O
agonist O
, O
0 O
. O
1 O
- O
3 O
mg O
/ O
kg O
) O
. O

Notably O
, O
hallucinogen O
- O
induced O
increases O
in O
HFO O
power O
were O
smaller O
than O
those O
produced O
by O
ketamine B
( O
25 O
mg O
/ O
kg O
) O
. O

CONCLUSIONS O
: O
Serotonergic O
hallucinogen O
- O
induced O
changes O
in O
HFO O
and O
gamma O
are O
mediated O
, O
at O
least O
in O
part O
, O
by O
stimulation O
of O
5HT2A O
receptors O
. O

Comparison O
of O
the O
oscillatory O
changes O
produced O
by O
serotonergic O
hallucinogens O
and O
NMDAR O
antagonists O
are O
also O
discussed O
. O

Inhibition O
of O
Ebola O
Virus O
Infection O
: O
Identification O
of O
Niemann O
- O
Pick O
C1 O
as O
the O
Target O
by O
Optimization O
of O
a O
Chemical O
Probe O
. O

A O
high O
throughput O
screen O
identified O
adamantane B
dipeptide I
1 O
as O
an O
inhibitor O
of O
Ebola O
virus O
( O
EboV O
) O
infection O
. O

Hit O
- O
to O
- O
lead O
optimization O
to O
determine O
the O
structure O
- O
activity O
relationship O
( O
SAR O
) O
identified O
the O
more O
potent O
EboV O
inhibitor O
2 O
and O
a O
photoaffinity O
labeling O
agent O
3 O
. O

These O
anti O
- O
viral O
compounds O
were O
employed O
to O
identify O
the O
target O
as O
Niemann O
- O
Pick O
C1 O
( O
NPC1 O
) O
, O
a O
host O
protein O
that O
binds O
the O
EboV O
glycoprotein O
and O
is O
essential O
for O
infection O
. O

These O
studies O
establish O
NPC1 O
as O
a O
promising O
target O
for O
anti O
- O
viral O
therapy O
. O

The O
Arf O
GAP O
AGAP2 O
Interacts O
with O
beta O
Arrestin2 O
and O
Regulates O
beta O
2 O
- O
Adrenergic O
Receptor O
Recycling O
and O
Erk O
Activation O
. O

AGAP2 O
is O
a O
multidomain O
Arf O
GAP O
( O
ADP B
ribosylation O
factor O
- O
directed O
GTPase O
- O
activating O
protein O
) O
that O
was O
shown O
to O
promote O
the O
fast O
- O
recycling O
of O
transferrin O
receptors O
. O

Here O
, O
we O
tested O
the O
hypothesis O
that O
AGAP2 O
regulates O
trafficking O
of O
beta O
2 O
- O
adrenergic O
receptors O
. O

We O
found O
that O
AGAP2 O
formed O
a O
complex O
with O
beta O
Arrestin1 O
and O
beta O
Arrestin2 O
, O
proteins O
that O
are O
known O
to O
regulate O
beta O
2 O
- O
adrenergic O
receptor O
signaling O
and O
trafficking O
. O

AGAP2 O
colocalized O
with O
beta O
Arrestin2 O
on O
the O
plasma O
membrane O
, O
and O
knockdown O
of O
AGAP2 O
expression O
reduced O
plasma O
membrane O
association O
of O
beta O
Arrestin2 O
upon O
beta O
2 O
- O
adrenergic O
receptor O
activation O
. O

AGAP2 O
also O
colocalized O
with O
internalized O
beta O
2 O
- O
adrenergic O
receptors O
on O
endosomes O
, O
and O
overexpression O
of O
AGAP2 O
slowed O
accumulation O
of O
beta O
2 O
- O
adrenergic O
receptor O
in O
the O
perinuclear O
recycling O
endosomes O
. O

On O
the O
contrary O
, O
knockdown O
of O
AGAP2 O
expression O
prevented O
recycling O
of O
beta O
2 O
- O
adrenergic O
receptor O
back O
to O
the O
plasma O
membrane O
. O

In O
addition O
, O
AGAP2 O
formed O
a O
complex O
with O
endogenous O
Erk O
and O
overexpression O
of O
AGAP2 O
potentiated O
Erk O
phosphorylation O
induced O
by O
beta O
2 O
- O
adrenergic O
receptors O
. O

Taken O
together O
, O
these O
results O
support O
the O
hypothesis O
that O
AGAP2 O
plays O
a O
role O
in O
the O
signaling O
and O
recycling O
of O
beta O
2 O
- O
adrenergic O
receptors O
. O

Identification O
of O
the O
first O
synthetic O
inhibitors O
of O
the O
type O
II O
transmembrane O
serine O
protease O
TMPRSS2 O
suitable O
for O
inhibition O
of O
influenza O
virus O
activation O
. O

TMPRSS2 O
is O
a O
multidomain O
type O
II O
transmembrane O
serine O
protease O
that O
cleaves O
the O
surface O
glycoprotein O
hemagglutinin O
( O
HA O
) O
of O
influenza O
viruses O
with O
monobasic O
cleavage O
site O
, O
which O
is O
a O
prerequisite O
for O
virus O
fusion O
and O
propagation O
. O

Furthermore O
, O
it O
activates O
the O
fusion O
protein O
F O
of O
the O
human O
metapneumovirus O
and O
the O
spike O
protein O
S O
of O
the O
SARS O
coronavirus O
. O

Increased O
TMPRSS2 O
expression O
was O
also O
described O
in O
several O
tumor O
entities O
. O

Therefore O
, O
TMPRSS2 O
emerged O
as O
a O
potential O
target O
for O
drug O
design O
. O

The O
catalytic O
domain O
of O
TMPRSS2 O
was O
expressed O
in O
E O
. O
coli O
and O
used O
for O
an O
inhibitor O
screen O
with O
previously O
synthesized O
inhibitors O
of O
various O
trypsin O
- O
like O
serine B
proteases O
. O

Two O
inhibitor O
types O
were O
identified O
, O
which O
inhibit O
TMPRSS2 O
in O
the O
nanomolar O
range O
. O

The O
first O
series O
comprises O
substrate O
analogue O
inhibitors O
containing O
a O
4 B
- I
amidinobenzylamide I
moiety O
in O
P1 O
position O
, O
whereby O
some O
of O
these O
analogues O
possess O
inhibition O
constants O
around O
20 O
nM O
. O

An O
improved O
potency O
was O
found O
for O
second O
type O
derived O
from O
sulfonylated B
3 I
- I
amindinophenylalanyl I
derivates O
. O

The O
most O
potent O
derivative O
of O
this O
series O
inhibits O
TMPRSS2 O
with O
a O
Ki O
value O
of O
0 O
. O
9 O
nM O
and O
showed O
an O
efficient O
blockage O
of O
influenza O
virus O
propagation O
in O
human O
airway O
epithelial O
cells O
. O

Based O
on O
the O
inhibitor O
studies O
a O
series O
of O
new O
fluorogenic O
substrates O
containing O
a O
d B
- I
arginine I
residue O
in O
P3 O
position O
was O
synthesized O
, O
some O
of O
them O
were O
efficiently O
cleaved O
by O
TMPRSS2 O
. O

Broken O
Symmetry O
Quantum O
Hall O
States O
in O
Dual O
- O
Gated O
ABA O
Trilayer O
Graphene B
. O

ABA O
- O
stacked O
trilayer O
graphene B
is O
a O
unique O
2D O
electron O
system O
with O
mirror O
reflection O
symmetry O
and O
unconventional O
quantum O
Hall O
effect O
. O

We O
present O
low O
- O
temperature O
transport O
measurements O
on O
dual O
- O
gated O
suspended O
trilayer O
graphene B
in O
the O
quantum O
Hall O
( O
QH O
) O
regime O
. O

We O
observe O
QH O
plateaus O
at O
filling O
factors O
nu O
= O
- O
8 O
, O
- O
2 O
, O
2 O
, O
6 O
, O
and O
10 O
, O
which O
is O
in O
agreement O
with O
the O
full O
- O
parameter O
tight O
binding O
calculations O
. O

In O
high O
magnetic O
fields O
, O
odd O
- O
integer O
plateaus O
are O
also O
resolved O
, O
indicating O
almost O
complete O
lifting O
of O
the O
12 O
- O
fold O
degeneracy O
of O
the O
lowest O
Landau O
level O
( O
LL O
) O
. O

Under O
an O
out O
- O
of O
- O
plane O
electric O
field O
E O
_ O
| O
_ O
, O
we O
observe O
degeneracy O
breaking O
and O
transitions O
between O
QH O
plateaus O
. O

Interestingly O
, O
depending O
on O
its O
direction O
, O
E O
_ O
| O
_ O
selectively O
breaks O
the O
LL O
degeneracies O
in O
the O
electron O
- O
doped O
or O
hole O
- O
doped O
regimes O
. O

Our O
results O
underscore O
the O
rich O
interaction O
- O
induced O
phenomena O
in O
trilayer O
graphene B
. O

Coarse O
- O
grained O
model O
for O
predicting O
RNA O
folding O
thermodynamics O
. O

We O
present O
a O
thermodynamically O
robust O
coarse O
- O
grained O
model O
to O
simulate O
folding O
of O
RNA O
in O
monovalent O
salt O
solutions O
. O

The O
model O
includes O
stacking O
, O
hydrogen B
bond O
, O
and O
electrostatic O
interactions O
as O
fundamental O
components O
in O
describing O
the O
stability O
of O
RNA O
structures O
. O

The O
stacking O
interactions O
are O
parametrized O
using O
a O
set O
of O
nucleotide B
- O
specific O
parameters O
, O
which O
were O
calibrated O
against O
the O
thermodynamic O
measurements O
for O
single O
- O
base O
stacks O
and O
base O
- O
pair O
stacks O
. O

All O
hydrogen B
bonds O
are O
assumed O
to O
have O
the O
same O
strength O
, O
regardless O
of O
their O
context O
in O
the O
RNA O
structure O
. O

The O
ionic O
buffer O
is O
modeled O
implicitly O
, O
using O
the O
concept O
of O
counterion O
condensation O
and O
the O
Debye O
- O
H O
u O
ckel O
theory O
. O

The O
three O
adjustable O
parameters O
in O
the O
model O
were O
determined O
by O
fitting O
the O
experimental O
data O
for O
two O
RNA O
hairpins O
and O
a O
pseudoknot O
. O

A O
single O
set O
of O
parameters O
provides O
good O
agreement O
with O
thermodynamic O
data O
for O
the O
three O
RNA O
molecules O
over O
a O
wide O
range O
of O
temperatures O
and O
salt O
concentrations O
. O

In O
the O
process O
of O
calibrating O
the O
model O
, O
we O
establish O
the O
extent O
of O
counterion O
condensation O
onto O
the O
single O
- O
stranded O
RNA O
backbone O
. O

The O
reduced O
backbone O
charge O
is O
independent O
of O
the O
ionic O
strength O
and O
is O
60 O
% O
of O
the O
RNA O
bare O
charge O
at O
37 O
degrees O
C O
. O

Our O
model O
can O
be O
used O
to O
predict O
the O
folding O
thermodynamics O
for O
any O
RNA O
molecule O
in O
the O
presence O
of O
monovalent O
ions O
. O

Supramolecular O
Structure O
of O
TTBC B
J O
- O
Aggregates O
in O
Solution O
and O
on O
Surface O
. O

The O
aggregation O
behavior O
of O
cationic O
5 B
, I
5 I
' I
, I
6 I
, I
6 I
' I
- I
tetrachloro I
- I
1 I
, I
1 I
' I
, I
3 I
, I
3 I
' I
- I
tetraethylbenzimidac I
with O
chloride B
( O
TTBC B
- O
Cl B
) O
or O
iodide B
counterions O
( O
TTBC B
- O
I B
) O
in O
aqueous O
solution O
is O
investigated O
by O
absorption O
, O
linear O
dichroism O
, O
and O
fluorescence O
spectroscopies O
, O
as O
well O
as O
cryogenic O
transmission O
electron O
microscopy O
( O
cryo O
- O
TEM O
) O
and O
atomic O
force O
microscopy O
( O
AFM O
) O
. O

TTBC B
- O
Cl O
is O
found O
to O
form O
J O
- O
aggregates O
with O
a O
classical O
Davydov O
- O
split O
absorption O
band O
( O
type O
I O
spectrum O
) O
even O
under O
different O
preparation O
conditions O
. O

These O
aggregates O
remain O
stable O
for O
months O
. O

Unlike O
the O
chloride B
salt O
, O
the O
iodide B
salt O
TTBC B
- I
I I
forms O
two O
different O
types O
of O
J O
- O
aggregates O
depending O
on O
the O
pH O
of O
the O
aqueous O
solution O
. O

The O
TTBC O
- O
I O
aggregates O
prepared O
in O
pure O
water O
( O
pH O
= O
6 O
) O
are O
characterized O
by O
a O
single O
redshifted O
absorption O
band O
( O
type O
III O
spectrum O
) O
, O
whereas O
those O
prepared O
in O
alkaline O
solution O
at O
pH O
= O
13 O
show O
a O
typical O
Davydov O
- O
split O
( O
type O
I O
) O
absorption O
band O
. O

Despite O
differences O
in O
counterions O
, O
preparation O
method O
, O
stability O
, O
and O
spectroscopic O
behavior O
, O
cryo O
- O
TEM O
reveals O
an O
identical O
tubular O
architecture O
for O
all O
these O
J O
- O
aggregates O
. O

Among O
the O
new O
structure O
models O
discussed O
here O
is O
a O
cylindrical O
brickwork O
layer O
of O
dye O
molecules O
for O
single O
- O
banded O
J O
- O
aggregates O
( O
type O
III O
) O
. O

For O
Davydov O
- O
split O
aggregates O
( O
type O
I O
) O
, O
a O
molecular O
herringbone O
- O
like O
pattern O
is O
proposed O
instead O
. O

Moreover O
, O
absorption O
spectra O
have O
revealed O
an O
additional O
single O
redshifted O
absorption O
band O
( O
type O
II O
spectrum O
) O
that O
is O
assigned O
to O
a O
surface O
aggregate O
and O
is O
induced O
by O
a O
specific O
interaction O
of O
the O
dye O
cation O
with O
the O
negatively O
charged O
cuvette O
wall O
. O

AFM O
measurements O
of O
analogous O
preparations O
on O
negatively O
charged O
mica O
surfaces O
have O
supported O
this O
interpretation O
and O
revealed O
the O
formation O
of O
monolayered O
sheet O
structures O
. O

Synthesis O
of O
indolyl B
- I
3 I
- I
acetonitrile I
derivatives O
and O
their O
inhibitory O
effects O
on O
nitric B
oxide I
and O
PGE2 B
productions O
in O
LPS O
- O
induced O
RAW O
264 O
. O
7 O
cells O
. O

Arvelexin B
is O
one O
of O
major O
constituents O
of O
Brassica O
rapa O
that O
exerts O
anti O
- O
inflammatory O
activities O
. O

Several O
indolyl B
- I
3 I
- I
acetonitrile I
derivatives O
were O
synthesized O
as O
arvelexin B
analogs O
and O
evaluated O
for O
their O
abilities O
to O
inhibit O
NO B
and O
PGE2 B
productions O
in O
LPS O
- O
induced O
RAW O
264 O
. O
7 O
cells O
. O

Of O
the O
indolyl B
- I
3 I
- I
acetonitriles I
synthesized O
, O
compound O
2k O
, O
which O
possesses O
a O
hydroxyl B
group O
at O
C O
- O
7 O
position O
of O
the O
indole B
ring O
and O
an O
N B
- I
methyl I
substituent O
, O
more O
potently O
inhibited O
NO B
and O
PGE2 B
productions O
and O
was O
less O
cytotoxic O
than O
arvelexin B
on O
macrophage O
cells O
. O

Discovery O
of O
a O
synthetic O
Aminopeptidase O
N O
inhibitor O
LB B
- I
4b I
as O
a O
potential O
anticancer O
agent O
. O

APN O
inhibitors O
have O
been O
considered O
as O
potential O
anticancer O
agents O
for O
years O
. O

LB B
- I
4b I
is O
the O
first O
synthetic O
APN O
inhibitor O
to O
be O
evaluated O
for O
both O
of O
its O
anti O
- O
invasion O
and O
anti O
- O
angiogenesis O
effects O
. O

As O
a O
potent O
synthetic O
APN O
inhibitor O
( O
IC50 O
= O
850nM O
, O
versus O
bestatin B
of O
8 O
. O
1 O
mu O
M O
) O
, O
LB B
- I
4b I
was O
determined O
to O
have O
more O
significant O
block O
effects O
to O
cancer O
cell O
invasion O
and O
angiogenesis O
than O
bestatin B
. O

Besides O
, O
it O
is O
able O
to O
be O
easily O
synthesized O
with O
a O
high O
total O
yield O
, O
while O
the O
reported O
synthetic O
methods O
of O
bestatin B
are O
much O
more O
complex O
. O

Atropa O
acuminata O
Royle O
Ex O
Lindl O
. O
blunts O
production O
of O
pro O
- O
inflammatory O
mediators O
eicosanoids O
. O
, O
leukotrienes O
, O
cytokines O
in O
vitro O
and O
in O
vivo O
models O
of O
acute O
inflammatory O
responses O
. O

ETHNOPHARMACOLOGICAL O
RELEVANCE O
: O
Atropa O
acuminata O
Royle O
Ex O
Lindl O
. O
has O
been O
widely O
used O
in O
folk O
medicine O
for O
several O
inflammatory O
disorders O
such O
as O
arthritis O
, O
asthma O
, O
conjunctivitis O
, O
encephalitis O
, O
pancreatitis O
, O
peritonitis O
, O
acute O
infections O
and O
neuroinflammatory O
disorders O
. O

AIM O
OF O
THE O
STUDY O
: O
Our O
aim O
was O
to O
evaluate O
Atropa O
acuminata O
for O
its O
anti O
- O
inflammatory O
properties O
and O
to O
delineate O
its O
possible O
mechanism O
of O
action O
on O
the O
modulation O
of O
the O
inflammatory O
mediators O
. O

MATERIALS O
AND O
METHODS O
: O
We O
investigated O
the O
inhibitory O
action O
of O
ethanolic O
extract O
of O
Atropa O
acuminata O
( O
AAEE O
) O
on O
production O
of O
NO B
, O
TNF O
- O
alpha O
and O
IL O
- O
1 O
beta O
in O
lipopolysaccharide O
( O
LPS O
) O
- O
stimulated O
RAW264 O
. O
7 O
cells O
and O
also O
assayed O
it O
for O
COX O
1 O
/ O
2 O
and O
5 O
- O
LOX O
inhibitory O
activities O
. O

Next O
AAEE O
was O
tested O
in O
acute O
inflammatory O
animal O
models O
. O
, O
carragenean O
induced O
rat O
paw O
edema O
, O
carragenean O
induce O
pleurisy O
in O
rats O
and O
vascular O
permeability O
in O
mice O
and O
the O
effects O
on O
NO B
, O
PGE2 B
and O
LTB4 B
production O
in O
the O
pleural O
fluid O
and O
paw O
exudates O
were O
evaluated O
. O

In O
addition O
the O
effects O
on O
leukocyte O
migration O
and O
exudation O
and O
vascular O
permeability O
were O
also O
observed O
. O

RESULTS O
: O
Our O
findings O
summarized O
novel O
anti O
- O
inflammatory O
mechanisms O
for O
Atropa O
acuminata O
based O
on O
dual O
in O
vitro O
cyclooxygenase O
1 O
/ O
2 O
/ O
and O
5 O
- O
Lipoxygenase O
inhibitory O
activities O
and O
also O
significant O
downregulation O
of O
nitric B
oxide I
( O
NO B
) O
and O
pro O
- O
inflammatory O
cytokin O
( O
TNF O
- O
alpha O
and O
Il O
- O
1 O
beta O
) O
release O
in O
LPS O
- O
stimulated O
RAW O
246 O
. O
7 O
macrophage O
cell O
line O
. O

In O
acute O
inflammatory O
models O
in O
vivo O
( O
carragenean O
induced O
edema O
, O
carragenean O
induced O
pleurisy O
in O
rats O
and O
vascular O
permeability O
in O
mice O
) O
, O
AAEE O
exhibited O
an O
extensive O
diverse O
mechanism O
for O
anti O
- O
inflammatory O
properties O
. O

This O
was O
indicated O
on O
the O
basis O
of O
dose O
dependent O
suppression O
of O
multi O
targeted O
inflammatory O
mediators O
. O
, O
NO B
, O
TNF O
- O
alpha O
and O
IL O
- O
1 O
beta O
, O
eicosanoids O
. O
, O
PGE2 B
and O
leukotrienes B
. O
, O
LTB4 B
along O
with O
significantly O
decreased O
leucocyte O
migration O
, O
exudation O
and O
decreased O
vascular O
permeability O
. O

These O
effects O
were O
more O
potent O
and O
prolonged O
than O
traditional O
NSAIDS O
, O
thereby O
indicating O
fewer O
side O
effects O
. O

AAEE O
was O
found O
to O
be O
safe O
for O
long O
term O
administration O
, O
as O
confirmed O
by O
the O
results O
of O
acute O
toxicity O
studies O
and O
MTT B
assay O
. O

The O
complex O
mode O
of O
action O
of O
the O
herbs O
was O
attributed O
possibly O
due O
to O
the O
high O
polyphenolic B
, O
flavanol B
and O
flavonoid B
content O
present O
in O
the O
extracts O
as O
observed O
by O
means O
of O
quantitative O
screening O
for O
phytochemicals O
. O

CONCLUSION O
: O
Our O
study O
provides O
scientific O
evidence O
to O
support O
the O
traditional O
anti O
- O
inflammatory O
uses O
of O
Atropa O
acuminata O
and O
is O
probably O
due O
to O
inhibitory O
effects O
on O
multiple O
inflammatory O
mediators O
which O
indicates O
a O
promising O
potential O
for O
the O
development O
of O
a O
strong O
anti O
- O
inflammatory O
agent O
from O
this O
plant O
. O

Reversal O
of O
Morphine B
Analgesic O
Tolerance O
by O
Ethanol B
in O
the O
Mouse O
. O

The O
chronic O
use O
of O
opioids O
in O
humans O
, O
accompanied O
by O
the O
development O
of O
tolerance O
, O
is O
a O
dangerous O
phenomenon O
in O
its O
own O
right O
. O

However O
chronic O
opioid O
use O
is O
often O
made O
more O
dangerous O
by O
the O
co O
- O
consumption O
of O
other O
substances O
. O

It O
has O
been O
observed O
that O
the O
blood O
level O
of O
opioids O
in O
postmortem O
analyses O
of O
addicts O
, O
who O
consumed O
ethanol B
along O
with O
the O
opioid O
, O
was O
much O
less O
than O
that O
observed O
in O
individuals O
that O
died O
from O
opioids O
alone O
. O

This O
relationship O
between O
ethanol B
and O
opioids O
led O
us O
to O
investigate O
the O
hypothesis O
that O
ethanol B
alters O
tolerance O
to O
opioids O
. O

In O
the O
present O
study O
, O
we O
report O
that O
ethanol B
significantly O
and O
dose O
- O
dependently O
reduced O
the O
antinociceptive O
tolerance O
produced O
by O
morphine B
and O
the O
cross O
tolerance O
between O
DAMGO B
and O
morphine B
in O
the O
mouse O
tail O
- O
flick O
test O
. O

The O
reversal O
of O
morphine B
tolerance O
was O
partially O
blocked O
by O
both O
the O
GABAA O
receptor O
blocker O
bicuculline B
and O
by O
the O
GABAB O
receptor O
blocker O
phaclofen B
and O
the O
administration O
of O
both O
inhibitors O
completely O
reversed O
the O
effects O
of O
ethanol B
on O
morphine B
tolerance O
. O

Diazepam B
, O
like O
ethanol B
, O
decreased O
morphine B
tolerance O
. O

However O
, O
this O
inhibition O
was O
reversed O
by O
the O
GABAA O
antagonist O
bicuculline B
but O
not O
by O
the O
GABAB O
antagonist O
phaclofen B
. O

These O
findings O
have O
important O
implications O
for O
individuals O
who O
abuse O
opioids O
and O
ethanol B
as O
well O
as O
suggest O
a O
mechanism O
to O
reduce O
the O
amount O
of O
opioid O
needed O
in O
chronic O
pain O
treatment O
. O

Physiological O
costs O
and O
carry O
- O
over O
effects O
of O
avian O
interspecific O
brood O
parasitism O
influence O
reproductive O
tradeoffs O
. O

Although O
models O
of O
co O
- O
evolution O
between O
brood O
parasites O
and O
their O
hosts O
primarily O
focus O
upon O
the O
cost O
to O
hosts O
in O
the O
current O
reproductive O
bout O
, O
the O
impact O
of O
brood O
parasitism O
may O
carry O
over O
to O
future O
reproductive O
attempts O
by O
altering O
resource O
allocation O
. O

Glucocorticoid O
stress O
hormones O
help O
mediate O
resource O
allocation O
to O
reproduction O
, O
yet O
they O
have O
rarely O
been O
examined O
in O
brood O
parasitic O
systems O
. O

Here O
we O
determined O
if O
shifts O
in O
parental O
care O
and O
corticosterone B
had O
carry O
- O
over O
effects O
on O
future O
reproductive O
effort O
in O
the O
rufous O
- O
and O
- O
white O
wren O
( O
Thryophilus O
rufalbus O
) O
, O
a O
host O
of O
the O
Central O
American O
striped O
cuckoo O
( O
Tapera O
naevia O
) O
. O

We O
found O
that O
parasitized O
parents O
had O
significantly O
higher O
stress O
- O
induced O
, O
but O
not O
baseline O
, O
corticosterone B
than O
natural O
parents O
during O
the O
fledgling O
stage O
, O
which O
was O
associated O
with O
changes O
in O
parental O
care O
. O

The O
high O
investment O
in O
current O
reproduction O
while O
parasitized O
may O
be O
due O
to O
the O
value O
of O
fledged O
chicks O
in O
tropical O
systems O
. O

This O
maladaptive O
response O
by O
parasitized O
parents O
was O
associated O
with O
delayed O
re O
- O
nesting O
and O
a O
reduced O
likelihood O
of O
nesting O
in O
the O
subsequent O
breeding O
season O
. O

Although O
a O
reduction O
in O
future O
reproductive O
effort O
can O
result O
from O
a O
combination O
of O
factors O
, O
this O
work O
suggests O
that O
fitness O
costs O
of O
brood O
parasitism O
are O
mediated O
by O
changes O
in O
corticosterone B
and O
parental O
care O
behavior O
that O
carry O
over O
into O
subsequent O
breeding O
seasons O
. O

The O
short O
course O
in O
toxinology O
: O
Training O
the O
trainers O
. O

Clinical O
toxinology O
is O
the O
medical O
discipline O
dealing O
with O
the O
diagnosis O
, O
treatment O
and O
prevention O
of O
toxin O
diseases O
caused O
by O
exposure O
to O
venomous O
animals O
and O
poisonous O
animals O
, O
plants O
and O
mushrooms O
. O

Currently O
there O
is O
no O
national O
or O
international O
organisation O
accrediting O
or O
training O
doctors O
in O
this O
discipline O
. O

A O
few O
courses O
covering O
some O
aspects O
of O
clinical O
toxinology O
exist O
, O
either O
with O
limited O
curricula O
, O
or O
with O
only O
a O
minor O
clinical O
focus O
, O
or O
with O
a O
very O
regional O
, O
non O
- O
global O
focus O
. O

The O
only O
comprehensive O
clinical O
toxinology O
course O
is O
the O
one O
provided O
in O
Adelaide O
, O
Australia O
, O
running O
regularly O
since O
1997 O
. O

Hundreds O
of O
doctors O
from O
many O
nations O
have O
attended O
the O
course O
since O
1997 O
. O

This O
course O
covers O
venomous O
animals O
, O
poisonous O
animals O
, O
plants O
and O
mushrooms O
, O
from O
a O
full O
global O
perspective O
, O
with O
an O
international O
faculty O
and O
an O
exit O
exam O
. O

Though O
lasting O
only O
one O
week O
, O
extensive O
pre O
- O
reading O
material O
is O
mandated O
. O

The O
current O
Course O
Handbook O
is O
about O
500 O
pages O
. O

Emphasis O
is O
on O
clinically O
relevant O
information O
and O
is O
focused O
on O
the O
needs O
of O
doctors O
treating O
cases O
. O

While O
it O
is O
expected O
that O
attendees O
will O
have O
, O
or O
acquire O
, O
direct O
experience O
managing O
cases O
of O
toxin O
disease O
and O
will O
use O
the O
knowledge O
and O
skills O
gained O
in O
the O
course O
in O
direct O
patient O
care O
, O
they O
may O
also O
act O
as O
resource O
people O
in O
their O
home O
region O
/ O
nation O
to O
promote O
increased O
skills O
in O
clinical O
toxinology O
amongst O
the O
wider O
medical O
workforce O
. O

This O
course O
may O
form O
the O
nucleus O
from O
which O
IST O
can O
develop O
a O
global O
accredited O
training O
scheme O
in O
clinical O
toxinology O
. O

Such O
a O
scheme O
will O
require O
input O
from O
diverse O
global O
regions O
and O
will O
be O
far O
more O
comprehensive O
and O
over O
a O
much O
longer O
time O
than O
the O
current O
Short O
Course O
, O
though O
likely O
will O
incorporate O
the O
Short O
Course O
in O
some O
way O
, O
or O
a O
derivative O
of O
it O
. O

Two O
novel O
saponins B
of O
20 B
, I
26 I
- I
epoxy I
derivatives O
of O
pseudojujubogenin O
from O
the O
seeds O
of O
Hovenia O
trichocarpa O
. O

Two O
new O
saponins B
of O
20 B
, I
26 I
- I
epoxy I
derivatives O
of O
pseudojujubogenin B
, O
hoduloside B
XI I
( O
1 O
) O
and O
hoduloside B
XII I
( O
2 O
) O
were O
isolated O
from O
the O
seeds O
of O
Hovenia O
trichocarpa O
. O

The O
structures O
of O
the O
new O
compounds O
were O
established O
by O
extensive O
NMR O
experiments O
and O
chemical O
methods O
. O

Hoduloside B
XI I
was O
confirmed O
to O
be O
3 B
- I
O I
- I
{ I
beta I
- I
d I
- I
glucopyranosyl I
( I
1 I
- I
- I
> I
3 I
) I
- I
[ I
beta I
- I
d I
- I
xylopyranosyl I
( I
1 I
- I
- I
> I
2 I
) I
] I
- I
alpha I
- I
l I
- I
arabinopyranosyl I
} I
- I
20 I
, I
26 I
- I
epoxypseudojujubogen I
. O

Hoduloside B
XII I
was O
identified O
as O
3 B
- I
O I
- I
{ I
beta I
- I
d I
- I
xylopyranose I
( I
1 I
- I
- I
> I
2 I
) I
glucopyranosyl I
( I
1 I
- I
- I
> I
3 I
) I
[ I
rhamnopyranose I
( I
1 I
- I
- I
> I
2 I
) I
] I
beta I
- I
d I
- I
glucopyranosyl I
} I
- I
20 I
, I
26 I
- I
epoxypseudojujubogen I
. O

The O
in O
vitro O
cytotoxic O
activity O
of O
compounds O
1 O
and O
2 O
was O
assayed O
. O

They O
displayed O
inhibitive O
activities O
against O
human O
cancer O
cell O
lines O
HL60 O
and O
K562 O
. O

Antinociceptive O
effect O
and O
gastroprotective O
mechanisms O
of O
3 B
, I
5 I
- I
diprenyl I
- I
4 I
- I
hydroxyacetophenone I
from O
Ageratina O
pichinchensis O
. O

The O
present O
study O
aimed O
to O
evaluate O
the O
antinociceptive O
activity O
( O
in O
inflammatory O
and O
neuropathic O
pain O
models O
) O
and O
gastroprotective O
effect O
of O
the O
3 B
, I
5 I
- I
diprenyl I
- I
4 I
- I
hydroxyacetophenone I
( O
HYDP B
) O
, O
isolated O
from O
Ageratina O
pichinchensis O
. O

The O
gastroprotective O
activity O
of O
this O
plant O
was O
previously O
reported O
by O
our O
workgroup O
, O
finding O
encesanescin B
to O
be O
one O
active O
compound O
. O

The O
present O
results O
show O
that O
HYDP B
reduced O
nociception O
in O
a O
dose O
- O
dependent O
manner O
in O
carrageenan O
and O
L5 O
/ O
L6 O
spinal O
nerve O
ligation O
, O
with O
efficacies O
of O
72 O
. O
6 O
and O
57 O
. O
1 O
% O
, O
respectively O
, O
at O
doses O
of O
100 O
and O
562mg O
/ O
kg O
. O

HYDP O
also O
showed O
gastroprotective O
activity O
in O
the O
model O
of O
ethanol B
- O
induced O
gastric O
lesion O
, O
with O
a O
75 O
. O
59 O
% O
maximum O
inhibition O
of O
ulcers O
at O
a O
dose O
of O
100mg O
/ O
kg O
. O

This O
gastroprotective O
effect O
was O
attenuated O
by O
N B
( I
G I
) I
- I
nitro I
- I
l I
- I
arginine I
methyl I
ester I
, O
indomethacin B
and O
N B
- I
ethylmaleimide I
, O
indicating O
that O
NO B
, O
prostaglandins B
and O
sulfhydryl B
groups O
are O
involved O
in O
the O
mechanisms O
of O
action O
. O

This O
is O
the O
first O
evidence O
, O
to O
our O
knowledge O
, O
of O
the O
antinociceptive O
and O
gastroprotective O
activities O
of O
HYDP O
. O

The O
effect O
of O
sodium B
selenite I
on O
lead O
induced O
cognitive O
dysfunction O
. O

The O
effect O
of O
lead O
( O
Pb B
) O
on O
spatial O
memory O
and O
hippocampal O
long O
- O
term O
potentiation O
( O
LTP O
) O
as O
a O
key O
risk O
factor O
has O
been O
widely O
recognized O
and O
the O
oxidative O
damage O
has O
been O
proposed O
as O
a O
possible O
mechanism O
of O
lead O
neurotoxicity O
. O

Selenium B
( O
Se B
) O
is O
a O
nutritionally O
essential O
trace O
element O
with O
known O
antioxidant O
potential O
. O

In O
this O
study O
we O
investigated O
the O
effect O
and O
the O
underlying O
mechanisms O
of O
Se O
supplementary O
on O
Pb B
induced O
cognition O
and O
synaptic O
plasticity O
impairment O
. O

Lactating O
Sprague O
- O
Dawley O
rats O
( O
SD O
rats O
) O
were O
randomly O
divided O
to O
four O
groups O
: O
0ppm O
lead B
acetate I
( O
Pb B
) O
; O
0ppm O
Pb B
and O
0 O
. O
2ppm O
sodium B
selenite I
( O
Se B
) O
; O
100ppm O
Pb B
; O
100ppm O
Pb B
and O
0 O
. O
2ppm O
Se B
. O

Lactating O
rats O
were O
treated O
with O
or O
without O
Pb B
and O
/ O
or O
Se B
throughout O
lactation O
until O
weaning O
. O

The O
levels O
of O
hippocampal O
LTP O
, O
the O
spatial O
memory O
, O
the O
apoptosis O
of O
hippocampal O
neurons O
, O
the O
levels O
of O
lactate B
dehydrogenase O
( O
LDH O
) O
release O
, O
and O
the O
serum O
level O
of O
superoxide B
dismutase O
( O
SOD O
) O
and O
malondialdehyde B
( O
MDA B
) O
were O
assayed O
. O

It O
had O
been O
observed O
that O
in O
Pb B
group O
the O
spatial O
memory O
, O
the O
induce O
level O
of O
LTP O
, O
the O
serum O
SOD O
level O
decreased O
, O
the O
LDH O
release O
level O
, O
the O
neurons O
apoptosis O
level O
, O
the O
serum O
MDA B
level O
increased O
, O
while O
in O
the O
Se B
supplements O
groups O
, O
the O
spatial O
memory O
, O
the O
induce O
level O
of O
LTP O
increased O
significantly O
. O

Compared O
with O
the O
Pb B
group O
, O
Se B
supplements O
shown O
down O
regulated O
the O
level O
of O
LDH O
, O
the O
neurons O
apoptosis O
and O
the O
serum O
MDA B
, O
and O
up O
regulated O
the O
level O
of O
serum O
SOD O
. O

We O
could O
draw O
the O
conclusion O
that O
Se B
supplements O
could O
alleviate O
toxic O
effect O
of O
lead O
on O
hippocampal O
LTP O
and O
spatial O
memory O
. O

The O
treated O
with O
selenium B
around O
0 O
. O
2ppm O
may O
protect O
against O
spatial O
memory O
dysfunction O
induced O
by O
lead O
exposure O
. O

A O
critical O
examination O
of O
best O
dose O
analysis O
for O
determining O
cognitive O
- O
enhancing O
potential O
of O
drugs O
: O
studies O
with O
rhesus O
monkeys O
and O
computer O
simulations O
. O

RATIONALE O
: O
Best O
dose O
analysis O
involves O
identifying O
the O
dose O
associated O
with O
the O
greatest O
improvement O
in O
performance O
for O
each O
subject O
and O
comparing O
performances O
associated O
with O
these O
individually O
determined O
best O
doses O
to O
control O
performances O
. O

OBJECTIVES O
: O
The O
current O
experiments O
were O
conducted O
to O
examine O
whether O
significant O
best O
dose O
effects O
might O
result O
from O
the O
selective O
analysis O
of O
data O
rather O
than O
an O
actual O
drug O
effect O
. O

METHODS O
: O
Experiment O
1 O
examined O
the O
effects O
of O
nicotine B
and O
methylphenidate B
on O
delayed O
matching O
- O
to O
- O
sample O
( O
DMTS O
) O
and O
self O
- O
ordered O
spatial O
search O
( O
SOSS O
) O
performances O
in O
rhesus O
monkeys O
( O
DMTS O
: O
n O
= O
7 O
; O
SOSS O
: O
n O
= O
6 O
) O
to O
determine O
the O
validity O
and O
reliability O
of O
best O
dose O
effects O
. O

Experiment O
2 O
used O
Monte O
Carlo O
computer O
simulations O
to O
estimate O
the O
likelihood O
of O
obtaining O
a O
significant O
outcome O
when O
the O
best O
dose O
method O
was O
applied O
to O
randomly O
generated O
data O
sets O
for O
which O
no O
difference O
existed O
. O

RESULTS O
: O
Significant O
effects O
were O
obtained O
when O
the O
best O
dose O
analysis O
was O
applied O
to O
performances O
from O
nondrug O
sessions O
, O
and O
best O
dose O
performances O
were O
not O
significantly O
different O
from O
the O
best O
nondrug O
performances O
. O

The O
doses O
identified O
as O
best O
doses O
from O
two O
nicotine B
dose O
- O
response O
curve O
determinations O
were O
unrelated O
, O
and O
the O
improvement O
associated O
with O
the O
best O
dose O
observed O
during O
the O
first O
dose O
- O
response O
curve O
determination O
was O
not O
reliable O
when O
the O
dose O
was O
administered O
repeatedly O
. O

Finally O
, O
there O
was O
a O
high O
likelihood O
of O
obtaining O
a O
statistically O
significant O
difference O
when O
no O
real O
difference O
existed O
. O

CONCLUSIONS O
: O
Best O
dose O
analysis O
for O
the O
identification O
of O
potential O
therapeutic O
agents O
should O
be O
replaced O
by O
single O
- O
subject O
designs O
. O

Exposure O
of O
Bacillus O
subtilis O
to O
mercury B
induces O
accumulation O
of O
shorter O
tRNA O
Cys B
species O
. O

RNA O
processing O
is O
an O
essential O
pathway O
in O
the O
regulation O
of O
genetic O
expression O
in O
the O
cell O
. O

In O
this O
work O
, O
Bacillus O
subtilis O
was O
used O
to O
understand O
the O
effects O
of O
mercury B
on O
the O
mechanism O
of O
tRNA O
metabolism O
. O

The O
CVAAS O
( O
cold O
vapor O
atomic O
absorption O
spectroscopy O
) O
method O
revealed O
that O
from O
the O
addition O
of O
HgCl2 B
( O
0 O
. O
75 O
mu O
g O
ml O
( O
- O
1 O
) O
) O
during O
the O
bacterial O
exponential O
phase O
, O
ca O
. O

48 O
% O
of O
the O
added O
mercury B
was O
taken O
up O
by O
the O
cells O
. O

This O
led O
to O
an O
immediate O
reduction O
in O
the O
rate O
of O
cell O
division O
. O

During O
this O
response O
, O
we O
observed O
accumulation O
of O
species O
shorter O
than O
mature O
tRNA O
( O
Cys B
) O
over O
a O
10 O
h O
period O
. O

We O
did O
not O
observe O
this O
accumulation O
for O
another O
five O
tRNAs O
analyzed O
. O

tRNA O
processing O
is O
largely O
dependent O
on O
RNase O
R O
and O
PNPase O
in O
B O
. O
subtilis O
. O

Thus O
, O
when O
the O
exonuclease O
PNPase O
was O
absent O
, O
we O
found O
that O
the O
shorter O
tRNA O
( O
Cys B
) O
species O
increased O
and O
mature O
tRNA O
( O
Cys B
) O
decreased O
after O
mercury B
addition O
, O
but O
this O
proportion O
changed O
during O
the O
time O
analyzed O
. O

However O
, O
in O
the O
absence O
of O
RNase O
R O
and O
PNPase O
the O
accumulation O
of O
the O
shorter O
tRNA O
( O
Cys B
) O
was O
more O
pronounced O
and O
the O
mature O
form O
was O
not O
recovered O
. O

In O
the O
single O
rnr O
mutant O
strain O
the O
shorter O
tRNA O
( O
Cys O
) O
was O
not O
observed O
. O

All O
together O
, O
we O
provide O
in O
vivo O
evidence O
that O
PNPase O
and O
RNase O
R O
are O
indispensable O
in O
controlling O
tRNA O
( O
Cys O
) O
quality O
in O
the O
presence O
of O
mercury B
. O

Insights O
into O
the O
adsorption O
and O
energy O
transfer O
of O
Ag B
clusters O
on O
the O
AgCl B
( O
100 O
) O
surface O
. O

It O
is O
fundamental O
to O
uncover O
the O
real O
adsorption O
properties O
of O
Ag B
clusters O
on O
an O
AgCl B
surface O
and O
the O
energy O
transfer O
mechanisms O
at O
the O
interface O
to O
understand O
the O
highly O
active O
photocatalytic O
performance O
and O
the O
stability O
of O
the O
plasmonic O
photocatalyst O
Ag B
@ O
AgCl B
. O

Based O
on O
density O
functional O
theory O
calculations O
we O
provide O
valuable O
insights O
into O
the O
binding O
nature O
of O
Ag B
clusters O
on O
AgCl B
surface O
, O
where O
the O
binding O
between O
Ag B
atoms O
in O
the O
cluster O
and O
on O
the O
surface O
plays O
a O
decisive O
role O
in O
determining O
the O
most O
stable O
adsorption O
configurations O
. O

Our O
results O
demonstrate O
that O
there O
is O
energy O
transfer O
from O
the O
plasmonic O
metals O
to O
substrate O
. O

The O
hot O
holes O
excited O
by O
the O
decay O
of O
surface O
plasmon O
resonance O
on O
the O
metals O
can O
diffuse O
into O
the O
Cl B
ions O
in O
the O
outermost O
two O
layers O
of O
the O
surface O
producing O
highly O
oxidative O
Cl B
atoms O
. O

The O
dipole O
- O
dipole O
interaction O
between O
the O
plasmonic O
metal O
clusters O
and O
substrate O
Cl B
ions O
can O
also O
generate O
electron O
- O
hole O
pairs O
in O
the O
surface O
layers O
. O

It O
is O
deduced O
that O
the O
positively O
charged O
nature O
of O
adsorbed O
clusters O
acting O
as O
electron O
trapping O
centers O
and O
reduction O
sites O
plays O
a O
crucial O
role O
in O
keeping O
the O
stability O
of O
the O
Ag B
@ O
AgCl B
system O
during O
the O
photocatalytic O
process O
. O

Finally O
, O
the O
validity O
of O
the O
cluster O
adsorption O
model O
for O
energy O
transfer O
is O
verified O
with O
respect O
to O
the O
nucleation O
and O
aggregation O
process O
of O
Ag B
atoms O
on O
the O
AgCl B
surface O
and O
a O
detailed O
description O
of O
the O
formation O
and O
evolution O
of O
Ag B
nanoparticles O
on O
an O
AgCl B
surface O
is O
provided O
. O

The O
present O
study O
may O
be O
helpful O
for O
understanding O
and O
designing O
this O
novel O
plasmonic O
photocatalyst O
and O
can O
be O
useful O
for O
investigating O
other O
relevant O
photocatalysts O
as O
well O
. O

Diagnostic O
performance O
of O
( B
99m I
) I
Tc I
- O
MIBI O
scan O
in O
predicting O
the O
malignancy O
of O
thyroid O
nodules O
: O
a O
meta O
- O
analysis O
. O

Several O
studies O
have O
investigated O
the O
diagnostic O
performance O
of O
( B
99m I
) I
Tc I
- O
MIBI O
scan O
in O
the O
evaluation O
of O
thyroid O
nodules O
suspicious O
for O
malignancy O
with O
conflicting O
results O
. O

The O
aim O
of O
our O
study O
is O
to O
meta O
- O
analyze O
published O
data O
on O
this O
topic O
. O

A O
comprehensive O
literature O
search O
of O
studies O
published O
through O
December O
2012 O
regarding O
the O
diagnostic O
performance O
of O
( B
99m I
) I
Tc I
- I
MIBI I
scan O
in O
the O
evaluation O
of O
thyroid O
nodules O
suspicious O
for O
malignancy O
was O
carried O
out O
. O

Pooled O
sensitivity O
and O
specificity O
of O
( B
99m I
) I
Tc I
- O
MIBI O
scan O
on O
a O
per O
lesion O
- O
based O
analysis O
and O
the O
area O
under O
the O
ROC O
curve O
were O
calculated O
. O

Pathological O
reports O
of O
thyroid O
nodules O
were O
considered O
as O
reference O
standard O
. O

Twenty O
- O
one O
studies O
were O
included O
in O
the O
meta O
- O
analysis O
. O

Pooled O
sensitivity O
and O
specificity O
of O
( B
99m I
) I
Tc I
- O
MIBI O
scan O
in O
detecting O
malignant O
thyroid O
nodules O
were O
85 O
. O
1 O
% O
[ O
95 O
% O
confidence O
interval O
( O
95 O
% O
CI O
) O
: O
81 O
. O
1 O
- O
88 O
. O
5 O
% O
] O
and O
45 O
. O
7 O
% O
( O
95 O
% O
CI O
: O
42 O
. O
7 O
- O
48 O
. O
7 O
% O
) O
, O
respectively O
, O
on O
a O
per O
lesion O
- O
based O
analysis O
, O
irrespective O
of O
eventual O
results O
of O
previous O
technetium B
pertechnetate I
( O
( B
99m I
) I
TcO4 I
) O
or O
iodine B
- I
123 I
( O
( B
123 I
) I
I I
) O
scan O
. O

The O
area O
under O
the O
ROC O
curve O
was O
0 O
. O
78 O
. O

A O
sub O
- O
analysis O
restricted O
to O
data O
on O
hypofunctioning O
nodules O
on O
( B
99m I
) I
TcO4 I
or O
( B
123 I
) I
I I
scans O
was O
performed O
: O
pooled O
sensitivity O
and O
specificity O
of O
( B
99m I
) I
Tc I
- I
MIBI I
scan O
in O
these O
nodules O
were O
82 O
. O
1 O
% O
( O
95 O
% O
CI O
: O
77 O
. O
2 O
- O
86 O
. O
3 O
% O
) O
and O
62 O
. O
8 O
% O
( O
95 O
% O
CI O
: O
58 O
. O
9 O
- O
66 O
. O
7 O
% O
) O
, O
respectively O
, O
on O
a O
per O
lesion O
- O
based O
analysis O
. O

The O
area O
under O
the O
ROC O
curve O
was O
0 O
. O
81 O
. O

( B
99m I
) I
Tc I
- I
MIBI I
scan O
is O
a O
sensitive O
diagnostic O
tool O
in O
predicting O
the O
malignancy O
of O
thyroid O
nodules O
. O

Therefore O
, O
this O
imaging O
method O
could O
be O
helpful O
in O
patients O
with O
thyroid O
nodules O
in O
which O
malignancy O
is O
suspected O
on O
the O
basis O
of O
conventional O
diagnostic O
techniques O
. O

Higher O
specificity O
can O
be O
reached O
when O
hypofunctioning O
thyroid O
nodules O
are O
considered O
. O

Synthesis O
, O
antimicrobial O
evaluation O
and O
molecular O
modelling O
of O
novel O
sulfonamides B
carrying O
a O
biologically O
active O
quinazoline B
nucleus O
. O

A O
novel O
series O
of O
quinazolines B
5 O
- O
10 O
, O
triazoloquinazolines B
11 O
- O
17 O
and O
triazinoquinazoline B
19 O
bearing O
a O
biologically O
active O
sulfonamide B
moiety O
were O
synthesized O
, O
utilizing O
methyl B
2 I
- I
isothiocyanato I
benzoate I
2 O
. O

Some O
of O
the O
newly O
synthesized O
compounds O
revealed O
promising O
bacterial O
growth O
inhibition O
, O
compared O
with O
the O
ampicillin B
, O
as O
the O
reference O
drug O
. O

A O
LigandScout O
approach O
- O
generated O
pharmacophore O
model O
for O
the O
Staph O
aureus O
bacteria O
growth O
inhibition O
was O
done O
. O

The O
degree O
of O
fitting O
of O
the O
test O
set O
compounds O
( O
3 O
, O
4 O
, O
6 O
, O
8 O
, O
11 O
, O
17 O
) O
to O
the O
generated O
hypothetical O
model O
revealed O
a O
qualitative O
measure O
of O
the O
more O
or O
less O
microbial O
inhibition O
of O
Staphylococcus O
aureus O
. O

Compounds O
( O
7 O
, O
8 O
, O
10 O
, O
12 O
, O
15 O
, O
17 O
and O
22 O
) O
, O
which O
revealed O
significant O
activity O
, O
are O
able O
to O
effectively O
satisfy O
the O
proposed O
pharmacophore O
geometry O
, O
using O
the O
energy O
accessible O
conformers O
( O
E O
conf O
< O
20 O
kcal O
/ O
mol O
) O
. O

Agreement O
Between O
ICU O
Clinicians O
and O
Electrophysiology O
Cardiologists O
on O
the O
Decision O
to O
Initiate O
a O
QTc O
- O
interval O
Prolonging O
Medication O
in O
Critically O
Ill O
Patients O
with O
Potential O
Risk O
Factors O
for O
Torsade O
de O
Pointes O
: O
A O
Comparative O
, O
Case O
- O
Based O
Evaluation O
. O

STUDY O
OBJECTIVES O
: O
To O
measure O
concordance O
between O
different O
intensive O
care O
unit O
( O
ICU O
) O
clinicians O
and O
a O
consensus O
group O
of O
electrophysiology O
( O
EP O
) O
cardiologists O
for O
use O
of O
a O
common O
rate O
- O
corrected O
QT O
interval O
( O
QTc O
) O
- O
prolonging O
medication O
in O
cases O
containing O
different O
potential O
risk O
factor O
( O
s O
) O
for O
torsade O
de O
pointes O
( O
TdP O
) O
. O

DESIGN O
: O
Prospective O
case O
- O
based O
evaluation O
. O

SETTING O
: O
Academic O
medical O
center O
with O
320 O
beds O
. O

SUBJECTS O
: O
Medical O
house O
staff O
( O
MDs O
) O
and O
ICU O
nurses O
( O
RNs O
) O
from O
one O
center O
and O
select O
critical O
care O
pharmacists O
( O
PHs O
) O
. O

INTERVENTION O
: O
Completion O
of O
a O
survey O
containing O
10 O
hypothetical O
ICU O
cases O
in O
which O
patients O
had O
agitated O
delirium O
for O
which O
a O
psychiatrist O
recommended O
intravenous O
haloperidol B
5 O
mg O
every O
6 O
hours O
. O

Each O
case O
contained O
different O
potential O
risk O
factor O
( O
s O
) O
for O
TdP O
in O
specific O
combinations O
. O

A O
group O
of O
five O
EP O
cardiologists O
agreed O
that O
haloperidol B
use O
was O
safe O
in O
five O
cases O
and O
not O
safe O
in O
five O
cases O
. O

MEASUREMENTS O
AND O
MAIN O
RESULTS O
: O
For O
each O
case O
, O
participants O
were O
asked O
to O
document O
whether O
they O
would O
administer O
haloperidol B
, O
to O
provide O
a O
rationale O
for O
their O
decision O
, O
and O
to O
state O
their O
level O
of O
confidence O
in O
that O
decision O
. O

Most O
clinicians O
( O
92 O
of O
115 O
[ O
80 O
% O
] O
) O
invited O
to O
participate O
completed O
the O
cases O
. O

Among O
the O
five O
cases O
where O
EP O
cardiologists O
agreed O
that O
haloperidol B
was O
not O
safe O
, O
29 O
% O
of O
respondents O
felt O
that O
haloperidol B
was O
safe O
. O

Conversely O
, O
in O
the O
five O
cases O
where O
EP O
cardiologists O
felt O
haloperidol B
was O
safe O
, O
21 O
% O
of O
respondents O
believed O
that O
it O
was O
not O
safe O
. O

Overall O
respondent O
- O
EP O
cardiologist O
agreement O
for O
haloperidol B
use O
across O
the O
10 O
cases O
was O
moderate O
( O
kappa O
= O
0 O
. O
51 O
) O
. O

MDs O
and O
PHs O
were O
in O
agreement O
with O
the O
EP O
cardiologists O
more O
than O
RNs O
( O
p O
= O
0 O
. O
03 O
) O
. O

Interprofessional O
variability O
existed O
for O
the O
TdP O
risk O
factors O
each O
best O
identified O
. O

Clinician O
confidence O
correlated O
with O
EP O
cardiologist O
concordance O
for O
MDs O
( O
p O
= O
0 O
. O
002 O
) O
and O
PHs O
( O
p O
= O
0 O
. O
0002 O
) O
, O
but O
not O
for O
RNs O
( O
p O
= O
0 O
. O
69 O
) O
. O

CONCLUSION O
: O
When O
evaluating O
use O
of O
a O
QTc O
interval O
- O
prolonging O
medication O
, O
ICU O
clinicians O
often O
fail O
to O
identify O
the O
TdP O
risk O
factors O
that O
EP O
cardiologists O
feel O
should O
prevent O
its O
use O
. O

Clinician O
- O
EP O
cardiologist O
concordance O
varies O
by O
the O
specific O
risk O
factor O
( O
s O
) O
for O
TdP O
and O
the O
ICU O
professional O
conducting O
the O
assessment O
. O

High O
- O
Purity O
Prostate O
Circulating O
Tumor O
Cell O
Isolation O
by O
a O
Polymer O
Nanofiber O
- O
Embedded O
Microchip O
for O
Whole O
Exome O
Sequencing O
. O

Handpick O
single O
cancer O
cells O
: O
A O
modified O
NanoVelcro O
Chip O
is O
coupled O
with O
ArcturusXT O
laser O
capture O
microdissection O
( O
LCM O
) O
technology O
to O
enable O
the O
detection O
and O
isolation O
of O
single O
circulating O
tumor O
cells O
( O
CTCs O
) O
from O
patients O
with O
prostate O
cancer O
( O
PC O
) O
. O

This O
new O
approach O
paves O
the O
way O
for O
conducting O
next O
- O
generation O
sequencing O
( O
NGS O
) O
on O
single O
CTCs O
. O

Rapid O
Improvement O
of O
Diabetes O
After O
Gastric O
Bypass O
Surgery O
: O
Is O
It O
the O
Diet O
or O
Surgery O
? O

OBJECTIVEImprovement O
in O
diabetes O
after O
Roux O
- O
en O
- O
Y O
gastric O
bypass O
( O
RYGB O
) O
often O
occur O
days O
after O
surgery O
. O

Surgically O
induced O
hormonal O
changes O
and O
the O
restrictive O
postoperative O
diet O
are O
proposed O
mechanisms O
. O

We O
evaluated O
the O
contribution O
of O
caloric O
restriction O
versus O
surgically O
induced O
changes O
to O
glucose B
homeostasis O
in O
the O
immediate O
postoperative O
period O
. O
RESEARCH O
DESIGN O
AND O
METHODSPatients O
with O
type O
2 O
diabetes O
planning O
to O
undergo O
RYGB O
participated O
in O
a O
prospective O
two O
- O
period O
study O
( O
each O
period O
involved O
a O
10 O
- O
day O
inpatient O
stay O
and O
periods O
were O
separated O
by O
a O
minimum O
of O
6 O
weeks O
of O
wash O
- O
out O
) O
in O
which O
patients O
served O
as O
their O
own O
controls O
. O

The O
presurgery O
period O
consisted O
of O
diet O
alone O
. O

The O
postsurgery O
period O
was O
matched O
in O
all O
aspects O
( O
daily O
matched O
diet O
) O
and O
included O
RYGB O
surgery O
. O

Glucose B
measurements O
were O
performed O
every O
4 O
h O
throughout O
the O
study O
. O

A O
mixed O
meal O
challenge O
test O
was O
performed O
before O
and O
after O
each O
period O
. O
RESULTSTen O
patients O
completed O
the O
study O
and O
had O
the O
following O
characteristics O
: O
age O
, O
53 O
. O
2 O
years O
( O
95 O
% O
CI O
, O
48 O
. O
0 O
- O
58 O
. O
4 O
) O
; O
BMI O
, O
51 O
. O
2 O
kg O
/ O
m O
( O
2 O
) O
( O
46 O
. O
1 O
- O
56 O
. O
4 O
) O
; O
diabetes O
duration O
, O
7 O
. O
4 O
years O
( O
4 O
. O
8 O
- O
10 O
. O
0 O
) O
; O
and O
HbA1c O
, O
8 O
. O
52 O
% O
( O
7 O
. O
08 O
- O
9 O
. O
96 O
) O
. O

Patients O
lost O
7 O
. O
3 O
kg O
( O
8 O
. O
1 O
- O
6 O
. O
5 O
) O
during O
the O
presurgery O
period O
versus O
4 O
. O
0 O
kg O
( O
6 O
. O
2 O
- O
1 O
. O
7 O
) O
during O
the O
postsurgery O
period O
( O
P O
= O
0 O
. O
01 O
between O
periods O
) O
. O

Daily O
glycemia O
in O
the O
presurgery O
period O
was O
significantly O
lower O
( O
1 O
, O
293 O
. O
58 O
mg O
/ O
dL O
* O
day O
[ O
1 O
, O
096 O
. O
83 O
- O
1 O
, O
490 O
. O
33 O
) O
vs O
. O
1 O
, O
478 O
. O
80 O
mg O
/ O
dL O
* O
day O
[ O
1 O
, O
277 O
. O
47 O
- O
1 O
, O
680 O
. O
13 O
] O
) O
compared O
with O
the O
postsurgery O
period O
( O
P O
= O
0 O
. O
02 O
between O
periods O
) O
. O

The O
improvements O
in O
the O
fasting O
and O
maximum O
poststimulation O
glucose B
and O
6 O
- O
h O
glucose B
area O
under O
the O
curve O
( O
primary O
outcome O
) O
were O
similar O
during O
both O
periods O
. O
CONCLUSIONSGlucose O
homeostasis O
improved O
in O
response O
to O
a O
reduced O
caloric O
diet O
, O
with O
a O
greater O
effect O
observed O
in O
the O
absence O
of O
surgery O
as O
compared O
with O
after O
RYGB O
. O

These O
findings O
suggest O
that O
reduced O
calorie O
ingestion O
can O
explain O
the O
marked O
improvement O
in O
diabetes O
control O
observed O
after O
RYGB O
. O

Structural O
basis O
for O
activation O
of O
ZAP O
- O
70 O
by O
phosphorylation O
of O
the O
SH2 O
- O
kinase O
linker O
. O

Serial O
activation O
of O
the O
tyrosine B
kinases O
Lck O
and O
ZAP O
- O
70 O
initiates O
signaling O
downstream O
of O
the O
T O
- O
cell O
receptor O
. O

We O
had O
previously O
reported O
the O
structure O
of O
an O
autoinhibited O
ZAP O
- O
70 O
variant O
in O
which O
two O
regulatory O
tyrosine B
residues O
( O
315 O
and O
319 O
) O
in O
the O
SH2 O
- O
kinase O
linker O
were O
replaced O
by O
phenylalanine B
. O

We O
now O
present O
the O
crystal O
structure O
of O
ZAP O
- O
70 O
in O
which O
Tyr B
315 O
and O
Tyr B
319 O
are O
not O
mutated O
, O
leading O
to O
the O
recognition O
of O
a O
five O
- O
residue O
sequence O
register O
error O
in O
the O
SH2 O
- O
kinase O
linker O
of O
the O
original O
crystallographic O
model O
. O

The O
revised O
model O
identifies O
distinct O
roles O
for O
these O
two O
tyrosines B
. O

As O
seen O
in O
a O
recently O
reported O
structure O
of O
the O
related O
tyrosine B
kinase O
Syk O
, O
Tyr B
315 O
of O
ZAP O
- O
70 O
is O
part O
of O
a O
hydrophobic O
interface O
between O
the O
regulatory O
apparatus O
and O
the O
kinase O
domain O
, O
and O
the O
integrity O
of O
this O
interface O
would O
be O
lost O
upon O
engagement O
of O
doubly O
- O
phosphorylated O
peptides O
by O
the O
SH2 O
domains O
. O

Tyr B
319 O
is O
not O
necessarily O
dislodged O
by O
SH2 O
engagement O
, O
which O
activates O
ZAP O
- O
70 O
by O
only O
~ O
5 O
- O
fold O
in O
vitro O
. O

In O
contrast O
, O
phosphorylation O
by O
Lck O
activates O
ZAP O
- O
70 O
by O
~ O
100 O
- O
fold O
. O

This O
difference O
is O
due O
to O
the O
ability O
of O
Tyr B
319 O
to O
suppress O
ZAP O
- O
70 O
activity O
even O
when O
the O
SH2 O
domains O
are O
dislodged O
from O
the O
kinase O
domain O
, O
providing O
stringent O
control O
of O
ZAP O
- O
70 O
activity O
downstream O
of O
Lck O
. O

Laser O
welding O
of O
ruptured O
intestinal O
tissue O
using O
plasmonic O
polypeptide O
nanocomposite O
solders O
. O

Approximately O
1 O
. O
5 O
million O
people O
suffer O
from O
colorectal O
cancer O
and O
inflammatory O
bowel O
disease O
in O
the O
United O
States O
. O

Occurrence O
of O
leakage O
following O
standard O
surgical O
anastomosis O
in O
intestinal O
and O
colorectal O
surgery O
is O
common O
and O
can O
cause O
infection O
leading O
to O
life O
- O
threatening O
consequences O
. O

In O
this O
report O
, O
we O
demonstrate O
that O
plasmonic O
nanocomposites O
, O
generated O
from O
elastin O
- O
like O
polypeptides O
( O
ELPs O
) O
cross O
- O
linked O
with O
gold O
nanorods O
, O
can O
be O
used O
to O
weld O
ruptured O
intestinal O
tissue O
upon O
exposure O
to O
near O
- O
infrared O
( O
NIR O
) O
laser O
irradiation O
. O

Mechanical O
properties O
of O
these O
nanocomposites O
can O
be O
modulated O
based O
on O
the O
concentration O
of O
gold O
nanorods O
embedded O
within O
the O
ELP O
matrix O
. O

We O
employed O
photostable O
, O
NIR O
- O
absorbing O
cellularized O
and O
noncellularized O
GNR O
- O
ELP O
nanocomposites O
for O
ex O
vivo O
laser O
welding O
of O
ruptured O
porcine O
small O
intestines O
. O

Laser O
welding O
using O
the O
nanocomposites O
significantly O
enhanced O
the O
tensile O
strength O
, O
leakage O
pressure O
, O
and O
bursting O
pressure O
of O
ruptured O
intestinal O
tissue O
. O

This O
, O
in O
turn O
, O
provided O
a O
liquid O
- O
tight O
seal O
against O
leakage O
of O
luminal O
liquid O
from O
the O
intestine O
and O
resulting O
bacterial O
infection O
. O

This O
study O
demonstrates O
the O
utility O
of O
laser O
tissue O
welding O
using O
plasmonic O
polypeptide O
nanocomposites O
and O
indicates O
the O
translational O
potential O
of O
these O
materials O
in O
intestinal O
and O
colorectal O
repair O
. O

Bioinspired O
Water O
- O
Enhanced O
Mechanical O
Gradient O
Nanocomposite O
Films O
That O
Mimic O
the O
Architecture O
and O
Properties O
of O
the O
Squid O
Beak O
. O

Inspired O
by O
the O
water O
- O
enhanced O
mechanical O
gradient O
character O
of O
the O
squid O
beak O
, O
we O
herein O
report O
a O
nanocomposite O
that O
mimics O
both O
the O
architecture O
and O
properties O
of O
this O
interesting O
natural O
material O
. O

Similar O
to O
the O
squid O
beak O
, O
we O
have O
developed O
nanocomposites O
where O
the O
degree O
of O
cross O
- O
linking O
is O
controlled O
along O
the O
length O
of O
the O
film O
. O

In O
this O
study O
, O
we O
utilized O
tunicate O
cellulose O
nanocrystals O
as O
the O
nanofiller O
that O
are O
functionalized O
with O
allyl B
moieties O
. O

Using O
photoinduced O
thiol B
- I
ene I
chemistry O
, O
we O
have O
been O
able O
to O
cross O
- O
link O
the O
CNC O
nanofiller O
. O

In O
the O
dry O
state O
where O
strong O
CNC O
interactions O
can O
occur O
, O
only O
a O
small O
mechanical O
contrast O
is O
observed O
between O
the O
cross O
- O
linked O
and O
uncross O
- O
linked O
samples O
. O

However O
, O
when O
the O
films O
are O
exposed O
to O
water O
, O
which O
" O
switches O
off O
" O
the O
noncovalent O
CNC O
interactions O
, O
a O
significant O
mechanical O
contrast O
is O
observed O
between O
the O
same O
films O
. O

For O
example O
, O
at O
20 O
wt O
% O
CNC O
( O
in O
the O
dry O
film O
) O
, O
an O
increase O
in O
wet O
modulus O
from O
60 O
to O
300 O
MPa O
( O
~ O
500 O
% O
increase O
) O
is O
observed O
after O
photoirradiation O
. O

Furthermore O
, O
we O
show O
that O
the O
wet O
modulus O
can O
be O
controlled O
by O
altering O
the O
UV O
exposure O
time O
which O
allows O
access O
to O
mechanical O
gradient O
films O
. O

Multitarget O
Global O
Sensitivity O
Analysis O
of O
n B
- I
Butanol I
Combustion O
. O

A O
model O
for O
the O
combustion O
of O
butanol B
is O
studied O
using O
a O
recently O
developed O
theoretical O
method O
for O
the O
systematic O
improvement O
of O
the O
kinetic O
mechanism O
. O

The O
butanol B
mechanism O
includes O
1446 O
reactions O
, O
and O
we O
demonstrate O
that O
it O
is O
straightforward O
and O
computationally O
feasible O
to O
implement O
a O
full O
global O
sensitivity O
analysis O
incorporating O
all O
the O
reactions O
. O

In O
addition O
, O
we O
extend O
our O
previous O
analysis O
of O
ignition O
- O
delay O
targets O
to O
include O
species O
targets O
. O

The O
combination O
of O
species O
and O
ignition O
targets O
leads O
to O
multitarget O
global O
sensitivity O
analysis O
, O
which O
allows O
for O
a O
more O
complete O
mechanism O
validation O
procedure O
than O
we O
previously O
implemented O
. O

The O
inclusion O
of O
species O
sensitivity O
analysis O
allows O
for O
a O
direct O
comparison O
between O
reaction O
pathway O
analysis O
and O
global O
sensitivity O
analysis O
. O

Design O
, O
Synthesis O
, O
Biological O
Evaluation O
, O
and O
Docking O
Studies O
of O
( B
S I
) I
- I
Phenylalanine I
Derivatives O
with O
a O
2 B
- I
Cyanopyrrolidine I
Moiety O
as O
Potent O
Dipeptidyl O
Peptidase O
4 O
Inhibitors O
. O

A O
novel O
series O
of O
( B
S I
) I
- I
phenylalanine I
derivatives O
with O
a O
2 B
- I
cyanopyrrolidine I
moiety O
were O
designed O
and O
synthesized O
through O
a O
rational O
drug O
design O
strategy O
. O

Biological O
evaluation O
revealed O
that O
most O
tested O
compounds O
were O
potent O
dipeptidyl O
peptidase O
4 O
( O
DPP O
- O
4 O
) O
inhibitors O
, O
among O
them O
, O
the O
cyclopropyl B
- I
substituted I
phenylalanine I
derivative O
11h O
displayed O
the O
most O
potent O
DPP O
- O
4 O
inhibitory O
activity O
with O
an O
IC50 O
value O
of O
0 O
. O
247 O
mu O
M O
. O

In O
addition O
, O
molecular O
docking O
analysis O
of O
the O
representative O
compounds O
11h O
, O
11k O
, O
and O
15a O
were O
performed O
, O
which O
not O
only O
revealed O
the O
impact O
of O
binding O
modes O
on O
DPP O
- O
4 O
inhibitory O
activity O
, O
but O
also O
provided O
additional O
methodological O
values O
for O
design O
and O
optimization O
. O

( O
c O
) O
2013 O
John O
Wiley O
& O
Sons O
A O
/ O
S O
. O

HISTONE O
DEACETYLASE O
INHIBITION O
AFFECTS O
SODIUM B
IODIDE I
SYMPORTER O
( O
NIS O
) O
EXPRESSION O
AND O
INDUCES O
( O
1 O
) O
( O
3 O
) O
( O
1 O
) O
I O
CYTOTOXICITY O
IN O
ANAPLASTIC O
THYROID O
CANCER O
CELLS O
. O

Background O
: O
Anaplastic O
thyroid O
cancers O
( O
ATC O
) O
represent O
only O
1 O
- O
2 O
% O
of O
all O
thyroid O
tumors O
, O
but O
they O
account O
for O
up O
to O
50 O
% O
of O
the O
mortality O
. O

Treatment O
of O
differentiated O
thyroid O
carcinomas O
is O
well O
standardized O
and O
the O
use O
of O
radioiodine B
represents O
an O
essential O
step O
; O
in O
contrast O
, O
there O
is O
no O
standardized O
therapeutic O
approach O
for O
anaplastic O
tumors O
and O
their O
prognosis O
is O
poor O
. O

The O
resistance O
of O
anaplastic O
thyroid O
cancer O
to O
radioiodine B
treatment O
is O
principally O
due O
to O
the O
absence O
of O
expression O
of O
the O
sodium B
iodide I
symporter O
( O
NIS O
) O
, O
mainly O
due O
to O
epigenetic O
silencing O
. O

The O
acetylation O
status O
of O
histones O
is O
involved O
in O
the O
epigenetic O
control O
of O
gene O
expression O
and O
is O
usually O
disrupted O
in O
advanced O
thyroid O
cancer O
. O

Histone O
deacetylase O
inhibitors O
have O
been O
demonstrated O
as O
potent O
anticancer O
drugs O
with O
several O
different O
effects O
on O
cell O
viability O
and O
differentiation O
. O

Methods O
: O
Stabilized O
anaplastic O
thyroid O
cancer O
cell O
lines O
( O
BHT O
- O
101 O
and O
CAL O
- O
62 O
) O
and O
primary O
cultures O
from O
patients O
who O
underwent O
thyroidectomy O
for O
anaplastic O
thyroid O
cancer O
were O
treated O
with O
the O
histone O
deacetylase O
inhibitor O
LBH589 B
. O

After O
treatment O
, O
we O
evaluated O
the O
expression O
and O
function O
of O
NIS O
. O

Gene O
expression O
was O
evaluated O
by O
real O
- O
time O
PCR O
( O
RT O
- O
PCR O
) O
; O
NIS O
promoter O
activity O
was O
determined O
with O
a O
luciferase O
reporter O
assay O
; O
and O
protein O
expression O
was O
assessed O
through O
immunofluorescence O
. O

We O
tested O
the O
protein O
function O
by O
125I B
uptake O
and O
efflux O
experiments O
; O
finally O
the O
cytotoxic O
effect O
of O
131I B
was O
determined O
with O
a O
clonogenic O
assay O
. O

Results O
: O
Our O
results O
demonstrate O
that O
treatment O
with O
LBH589 B
leads O
to O
NIS O
RNA O
expression O
as O
shown O
by O
RT O
- O
PCR O
and O
luciferase O
assay O
, O
and O
to O
protein O
expression O
as O
determined O
by O
immunofluorescence O
in O
vitro O
and O
by O
immunohistochemistry O
in O
xenograft O
tumors O
. O

Moreover O
, O
125I B
uptake O
and O
efflux O
experiments O
show O
the O
correct O
protein O
function O
and O
iodine B
retention O
, O
that O
translate O
into O
cytotoxicity O
effects O
, O
as O
demonstrated O
by O
a O
clonogenic O
assay O
with O
131I B
. O

Conclusions O
: O
This O
study O
supplies O
a O
new O
potential O
strategy O
for O
the O
treatment O
of O
ATC O
by O
modifying O
gene O
expression O
with O
the O
aim O
of O
inducing O
responsiveness O
towards O
radioiodine B
therapy O
. O

Adhesion O
and O
Nanomechanics O
of O
Pili O
from O
the O
Probiotic O
Lactobacillus O
rhamnosus O
GG O
. O

Knowledge O
of O
the O
mechanisms O
by O
which O
bacterial O
pili O
adhere O
to O
host O
cells O
and O
withstand O
external O
forces O
is O
critical O
to O
our O
understanding O
of O
their O
functional O
roles O
and O
offers O
exciting O
avenues O
in O
biomedicine O
for O
controlling O
the O
adhesion O
of O
bacterial O
pathogens O
and O
probiotics O
. O

While O
much O
progress O
has O
been O
made O
in O
the O
nanoscale O
characterization O
of O
pili O
from O
Gram O
- O
negative O
bacteria O
, O
the O
adhesive O
and O
mechanical O
properties O
of O
Gram O
- O
positive O
bacterial O
pili O
remain O
largely O
unknown O
. O

Here O
, O
we O
use O
single O
- O
molecule O
atomic O
force O
microscopy O
to O
unravel O
the O
binding O
mechanism O
of O
pili O
from O
the O
probiotic O
Gram O
- O
positive O
bacterium O
Lactobacillus O
rhamnosus O
GG O
( O
LGG O
) O
. O

First O
, O
we O
show O
that O
SpaC O
, O
the O
key O
adhesion O
protein O
of O
the O
LGG O
pilus O
, O
is O
a O
multifunctional O
adhesin O
with O
broad O
specificity O
. O

SpaC O
forms O
homophilic O
trans O
- O
interactions O
engaged O
in O
bacterial O
aggregation O
and O
specifically O
binds O
mucin O
and O
collagen O
, O
two O
major O
extracellular O
components O
of O
host O
epithelial O
layers O
. O

Homophilic O
and O
heterophilic O
interactions O
display O
similar O
binding O
strengths O
and O
dissociation O
rates O
. O

Next O
, O
pulling O
experiments O
on O
living O
bacteria O
demonstrate O
that O
LGG O
pili O
exhibit O
two O
unique O
mechanical O
responses O
, O
that O
is O
, O
zipper O
- O
like O
adhesion O
involving O
multiple O
SpaC O
molecules O
distributed O
along O
the O
pilus O
length O
and O
nanospring O
properties O
enabling O
pili O
to O
resist O
high O
force O
. O

These O
mechanical O
properties O
may O
represent O
a O
generic O
mechanism O
among O
Gram O
- O
positive O
bacterial O
pili O
for O
strengthening O
adhesion O
and O
withstanding O
shear O
stresses O
in O
the O
natural O
environment O
. O

The O
single O
- O
molecule O
experiments O
presented O
here O
may O
help O
us O
to O
design O
molecules O
capable O
of O
promoting O
or O
inhibiting O
bacterial O
- O
host O
interactions O
. O

Using O
whole O
mount O
in O
situ O
hybridization O
to O
examine O
thyroid O
hormone O
deiodinase O
expression O
in O
embryonic O
and O
larval O
zebrafish O
: O
A O
tool O
for O
examining O
OH B
- I
BDE I
toxicity O
to O
early O
life O
stages O
. O

Polybrominated B
diphenyl I
ethers I
( O
PBDEs B
) O
and O
their O
oxidative O
metabolites O
( O
hydroxylated B
PBDEs I
; O
OH B
- I
BDEs I
) O
are O
known O
endocrine O
disrupting O
contaminants O
that O
have O
been O
shown O
to O
disrupt O
thyroid O
hormone O
regulation O
both O
in O
mammals O
and O
in O
fish O
. O

The O
purpose O
of O
this O
study O
was O
to O
determine O
the O
precise O
organ O
and O
tissue O
locations O
that O
express O
genes O
critical O
to O
thyroid O
hormone O
regulation O
in O
developing O
zebrafish O
( O
Danio O
rerio O
) O
, O
and O
to O
determine O
the O
effects O
of O
an O
OH B
- I
BDE I
on O
their O
expression O
. O

While O
RT O
- O
PCR O
can O
provide O
quantitative O
data O
on O
gene O
expression O
, O
it O
lacks O
spatial O
sensitivity O
to O
examine O
localized O
gene O
expression O
; O
and O
, O
isolation O
of O
organs O
from O
zebrafish O
embryos O
is O
technically O
difficult O
, O
if O
not O
impossible O
. O

For O
this O
reason O
, O
the O
present O
study O
used O
whole O
mount O
in O
situ O
hybridization O
to O
simultaneously O
localize O
and O
quantify O
gene O
expression O
in O
vivo O
. O

While O
PBDEs B
and O
OH B
- I
BDEs I
have O
been O
shown O
to O
inhibit O
the O
activity O
and O
expression O
of O
deiodionases O
, O
a O
family O
of O
enzymes O
that O
regulate O
thyroid O
hormone O
concentrations O
intracellularly O
, O
it O
is O
unclear O
whether O
or O
not O
they O
can O
affect O
regional O
expression O
of O
the O
different O
isoforms O
during O
early O
development O
. O

In O
this O
study O
we O
investigated O
deiodinase O
1 O
( O
Dio1 O
) O
, O
deiodinase O
2 O
( O
Dio2 O
) O
, O
and O
deiodinase O
3 O
( O
Dio3 O
) O
mRNA O
expression O
at O
the O
following O
life O
stages O
( O
2 O
, O
8 O
, O
and O
1k O
- O
cells O
; O
50 O
% O
- O
epiboly O
, O
6 O
and O
18 O
- O
somites O
, O
22 O
, O
24 O
, O
48 O
, O
72 O
hpf O
and O
/ O
or O
10 O
dpf O
) O
in O
zebrafish O
and O
found O
life O
stage O
specific O
expression O
of O
these O
genes O
that O
were O
highly O
localized O
. O

To O
demonstrate O
the O
use O
of O
this O
technique O
for O
investigating O
potential O
endocrine O
disrupting O
effects O
, O
zebrafish O
embryos O
were O
exposed O
to O
1 O
, O
10 O
and O
100nM O
6 B
- I
OH I
- I
BDE I
- I
47 I
. O

Significant O
increases O
in O
mean O
intensity O
of O
Dio1 O
and O
Dio3 O
expression O
in O
the O
periventricular O
zone O
of O
brain O
and O
pronephric O
duct O
, O
respectively O
( O
quantified O
by O
measuring O
intensity O
of O
coloration O
using O
ImageJ O
analysis O
software O
) O
were O
observed O
, O
suggesting O
localized O
response O
at O
the O
HPT O
axis O
with O
the O
possibility O
of O
impacting O
neurodevelopment O
. O

Our O
results O
demonstrate O
effects O
of O
OH B
- I
BDEs I
on O
thyroid O
regulating O
gene O
expression O
and O
provide O
more O
insight O
into O
potential O
sites O
of O
injury O
during O
early O
life O
stages O
. O

Transport O
Function O
and O
Transcriptional O
Regulation O
of O
a O
Liver O
- O
Enriched O
Human O
Organic O
Anion O
Transporting O
Polypeptide O
2B1 O
Transcriptional O
Start O
Site O
Variant O
. O

Human O
Organic O
Anion O
Transporting O
Polypeptide O
2B1 O
( O
OATP2B1 O
) O
is O
a O
membrane O
transporter O
that O
facilitates O
the O
cellular O
uptake O
of O
a O
number O
of O
endogenous O
compounds O
and O
drugs O
. O

OATP2B1 O
is O
widely O
expressed O
in O
tissues O
including O
the O
small O
intestine O
, O
liver O
, O
kidney O
, O
placenta O
, O
heart O
, O
skeletal O
muscle O
and O
platelets O
. O

Recently O
, O
it O
has O
been O
shown O
that O
differential O
promoter O
usage O
in O
tissues O
results O
in O
expression O
of O
five O
OATP2B1 O
transcriptional O
start O
site O
variants O
which O
utilize O
distinct O
first O
exons O
but O
share O
common O
subsequent O
exons O
. O

These O
variants O
are O
expected O
to O
encode O
either O
a O
full O
length O
( O
OATP2B1 O
- O
FL O
) O
or O
shortened O
protein O
lacking O
22 O
N B
- O
terminus O
amino B
acids I
( O
OATP2B O
- O
Short O
) O
. O

Little O
is O
known O
regarding O
the O
transport O
activity O
and O
regulation O
of O
OATP2B1 O
variants O
with O
N B
- O
terminus O
truncation O
. O

Here O
, O
using O
absolute O
quantitative O
polymerase O
chain O
reaction O
we O
find O
the O
full O
length O
variant O
is O
the O
major O
form O
expressed O
in O
duodenum O
but O
the O
short O
variant O
predominates O
in O
liver O
. O

Using O
a O
transient O
heterologous O
cell O
expression O
system O
, O
we O
find O
that O
the O
transport O
activities O
of O
the O
short O
OATP2B1 O
variant O
towards O
substrates O
estrone B
sulfate I
and O
rosuvastatin B
are O
similar O
to O
the O
well O
- O
characterized O
full O
length O
variant O
. O

Transcriptional O
activity O
screening O
of O
the O
liver O
enriched O
OATP2B1 O
variant O
promoter O
identified O
hepatocyte O
nuclear O
factor O
4 O
alpha O
( O
HNF4 O
alpha O
) O
as O
a O
novel O
transacting O
factor O
. O

With O
a O
combination O
of O
in O
silico O
screening O
, O
promoter O
mutation O
in O
cell O
- O
based O
reporter O
assays O
, O
siRNA O
knockdown O
and O
chromatin O
immunoprecipitation O
studies O
, O
we O
identified O
a O
functional O
HNF4 O
alpha O
binding O
site O
close O
to O
the O
transcription O
start O
site O
( O
- O
17 O
to O
- O
4 O
bp O
) O
. O

We O
conclude O
that O
the O
major O
OATP2B1 O
protein O
form O
in O
liver O
is O
transport O
competent O
and O
its O
hepatic O
expression O
is O
regulated O
by O
HNF4 O
alpha O
. O

Genome O
- O
wide O
association O
study O
in O
a O
Chinese O
population O
identifies O
a O
susceptibility O
locus O
for O
type O
2 O
diabetes O
at O
7q32 O
near O
PAX4 O
. O

AIMS O
/ O
HYPOTHESIS O
: O
Most O
genetic O
variants O
identified O
for O
type O
2 O
diabetes O
have O
been O
discovered O
in O
European O
populations O
. O

We O
performed O
genome O
- O
wide O
association O
studies O
( O
GWAS O
) O
in O
a O
Chinese O
population O
with O
the O
aim O
of O
identifying O
novel O
variants O
for O
type O
2 O
diabetes O
in O
Asians O
. O

METHODS O
: O
We O
performed O
a O
meta O
- O
analysis O
of O
three O
GWAS O
comprising O
684 O
patients O
with O
type O
2 O
diabetes O
and O
955 O
controls O
of O
Southern O
Han O
Chinese O
descent O
. O

We O
followed O
up O
the O
top O
signals O
in O
two O
independent O
Southern O
Han O
Chinese O
cohorts O
( O
totalling O
10 O
, O
383 O
cases O
and O
6 O
, O
974 O
controls O
) O
, O
and O
performed O
in O
silico O
replication O
in O
multiple O
populations O
. O

RESULTS O
: O
We O
identified O
CDKN2A O
/ O
B O
and O
four O
novel O
type O
2 O
diabetes O
association O
signals O
with O
p O
< O
1 O
x O
10 O
( O
- O
5 O
) O
from O
the O
meta O
- O
analysis O
. O

Thirteen O
variants O
within O
these O
four O
loci O
were O
followed O
up O
in O
two O
independent O
Chinese O
cohorts O
, O
and O
rs10229583 O
at O
7q32 O
was O
found O
to O
be O
associated O
with O
type O
2 O
diabetes O
in O
a O
combined O
analysis O
of O
11 O
, O
067 O
cases O
and O
7 O
, O
929 O
controls O
( O
p O
meta O
= O
2 O
. O
6 O
x O
10 O
( O
- O
8 O
) O
; O
OR O
[ O
95 O
% O
CI O
] O
1 O
. O
18 O
[ O
1 O
. O
11 O
, O
1 O
. O
25 O
] O
) O
. O

In O
silico O
replication O
revealed O
consistent O
associations O
across O
multiethnic O
groups O
, O
including O
five O
East O
Asian O
populations O
( O
p O
meta O
= O
2 O
. O
3 O
x O
10 O
( O
- O
10 O
) O
) O
and O
a O
population O
of O
European O
descent O
( O
p O
= O
8 O
. O
6 O
x O
10 O
( O
- O
3 O
) O
) O
. O

The O
rs10229583 O
risk O
variant O
was O
associated O
with O
elevated O
fasting O
plasma O
glucose B
, O
impaired O
beta O
cell O
function O
in O
controls O
, O
and O
an O
earlier O
age O
at O
diagnosis O
for O
the O
cases O
. O

The O
novel O
variant O
lies O
within O
an O
islet O
- O
selective O
cluster O
of O
open O
regulatory O
elements O
. O

There O
was O
significant O
heterogeneity O
of O
effect O
between O
Han O
Chinese O
and O
individuals O
of O
European O
descent O
, O
Malaysians O
and O
Indians O
. O

CONCLUSIONS O
/ O
INTERPRETATION O
: O
Our O
study O
identifies O
rs10229583 O
near O
PAX4 O
as O
a O
novel O
locus O
for O
type O
2 O
diabetes O
in O
Chinese O
and O
other O
populations O
and O
provides O
new O
insights O
into O
the O
pathogenesis O
of O
type O
2 O
diabetes O
. O

Disrupting O
the O
scaffold O
to O
improve O
focal O
adhesion O
kinase O
- O
targeted O
cancer O
therapeutics O
. O

Focal O
adhesion O
kinase O
( O
FAK O
) O
is O
emerging O
as O
a O
promising O
cancer O
target O
because O
it O
is O
highly O
expressed O
at O
both O
the O
transcriptional O
and O
translational O
level O
in O
cancer O
and O
is O
involved O
in O
many O
aspects O
of O
tumor O
growth O
, O
invasion O
, O
and O
metastasis O
. O

Existing O
FAK O
- O
based O
therapeutics O
focus O
on O
inhibiting O
the O
kinase O
' O
s O
catalytic O
function O
and O
not O
the O
large O
scaffold O
it O
creates O
that O
includes O
many O
oncogenic O
receptor O
tyrosine B
kinases O
and O
tumor O
suppressor O
proteins O
. O

Targeting O
the O
FAK O
scaffold O
is O
a O
feasible O
and O
promising O
approach O
for O
developing O
highly O
specific O
therapeutics O
that O
disrupt O
FAK O
signaling O
pathways O
in O
cancer O
. O

ERP O
evidence O
suggests O
executive O
dysfunction O
in O
ecstasy B
polydrug O
users O
. O

BACKGROUND O
: O
Deficits O
in O
executive O
functions O
such O
as O
access O
to O
semantic O
/ O
long O
- O
term O
memory O
have O
been O
shown O
in O
ecstasy B
users O
in O
previous O
research O
. O

Equally O
, O
there O
have O
been O
many O
reports O
of O
equivocal O
findings O
in O
this O
area O
. O

The O
current O
study O
sought O
to O
further O
investigate O
behavioural O
and O
electro O
- O
physiological O
measures O
of O
this O
executive O
function O
in O
ecstasy B
users O
. O

METHOD O
: O
Twenty O
ecstasy B
- O
polydrug O
users O
, O
20 O
non O
- O
ecstasy B
- O
polydrug O
users O
and O
20 O
drug O
- O
na O
i O
ve O
controls O
were O
recruited O
. O

Participants O
completed O
background O
questionnaires O
about O
their O
drug O
use O
, O
sleep O
quality O
, O
fluid O
intelligence O
and O
mood O
state O
. O

Each O
individual O
also O
completed O
a O
semantic O
retrieval O
task O
whilst O
64 O
channel O
Electroencephalograp O
( O
EEG O
) O
measures O
were O
recorded O
. O

RESULTS O
: O
Analysis O
of O
Variance O
( O
ANOVA O
) O
revealed O
no O
between O
- O
group O
differences O
in O
behavioural O
performance O
on O
the O
task O
. O

Mixed O
ANOVA O
on O
event O
- O
related O
potential O
( O
ERP O
) O
components O
P2 O
, O
N2 O
and O
P3 O
revealed O
significant O
between O
- O
group O
differences O
in O
the O
N2 O
component O
. O

Subsequent O
exploratory O
univariate O
ANOVAs O
on O
the O
N2 O
component O
revealed O
marginally O
significant O
between O
- O
group O
differences O
, O
generally O
showing O
greater O
negativity O
at O
occipito O
- O
parietal O
electrodes O
in O
ecstasy B
users O
compared O
to O
drug O
- O
na O
i O
ve O
controls O
. O

Despite O
absence O
of O
behavioural O
differences O
, O
differences O
in O
N2 O
magnitude O
are O
evidence O
of O
abnormal O
executive O
functioning O
in O
ecstasy B
- O
polydrug O
users O
. O

In O
vitro O
read O
- O
through O
of O
phenylalanine B
hydroxylase O
( O
PAH O
) O
nonsense O
mutations O
using O
aminoglycosides O
: O
a O
potential O
therapy O
for O
phenylketonuria O
. O

Phenylketonuria O
( O
PKU O
, O
OMIM O
261600 O
) O
is O
an O
autosomal O
recessive O
inborn O
error O
of O
phenylalanine B
metabolism O
, O
predominantly O
caused O
by O
mutations O
in O
the O
phenylalanine B
hydroxylase O
( O
PAH O
) O
gene O
. O

Approximately O
10 O
% O
of O
patients O
carry O
a O
nonsense O
mutation O
, O
which O
results O
in O
an O
inactive O
or O
unstable O
truncated O
protein O
. O

In O
some O
genetic O
disorders O
, O
including O
cystic O
fibrosis O
and O
Duchenne O
muscular O
dystrophy O
, O
restoration O
of O
full O
- O
length O
protein O
has O
been O
achieved O
by O
aminoglycoside B
antibiotics O
, O
such O
as O
gentamicin B
and O
G B
- I
418 I
( O
Geneticin B
) O
. O

More O
recently O
, O
nonsense O
read O
- O
through O
has O
been O
induced O
at O
greater O
rates O
using O
a O
non O
- O
aminoglycoside B
drug O
, O
PTC124 B
( O
Ataluren B
) O
, O
which O
has O
the O
advantage O
of O
being O
non O
- O
toxic O
in O
contrast O
to O
the O
antibiotics O
. O

The O
efficacy O
of O
read O
- O
through O
induced O
by O
three O
compounds O
, O
aminoglycosides B
G418 O
and O
gentamicin B
, O
and O
PTC124 O
were O
evaluated O
for O
four O
nonsense O
mutations O
of O
PAH O
in O
an O
in O
vitro O
expression O
system O
in O
two O
mammalian O
cell O
lines O
( O
COS O
- O
7 O
and O
HEK293 O
) O
. O

The O
production O
of O
full O
- O
length O
PAH O
was O
investigated O
using O
western O
blotting O
and O
the O
functionality O
confirmed O
by O
enzyme O
activity O
. O

Gentamicin B
and O
G B
- I
418 I
induced O
read O
- O
through O
of O
nonsense O
PAH O
mutations O
in O
HEK293 O
cells O
. O

The O
read O
- O
through O
product O
partially O
restored O
enzymatic O
activity O
, O
which O
was O
significantly O
less O
than O
that O
of O
wild O
- O
type O
, O
but O
comparable O
to O
a O
missense O
mutation O
of O
PAH O
associated O
with O
less O
severe O
forms O
of O
PKU O
. O

Treatment O
with O
PTC124 B
up O
to O
100 O
mu O
M O
did O
not O
result O
in O
full O
- O
length O
PAH O
polypeptide O
. O

Nonsense O
read O
- O
through O
drugs O
are O
a O
potential O
form O
of O
treatment O
for O
PKU O
, O
although O
the O
high O
dosage O
of O
aminoglycosides B
used O
is O
not O
appropriate O
in O
a O
clinical O
setting O
. O

In O
vitro O
studies O
with O
new O
non O
- O
toxic O
read O
- O
through O
agents O
as O
well O
as O
in O
vivo O
studies O
would O
also O
be O
essential O
to O
determine O
the O
extent O
of O
read O
- O
through O
required O
to O
restore O
normal O
phenylalanine B
levels O
. O

Implication O
of O
circulating O
omentin O
- O
1 O
level O
on O
the O
arterial O
stiffening O
in O
type O
2 O
diabetes O
mellitus O
. O

Omentin O
- O
1 O
is O
an O
adipokine O
implicated O
in O
diabetes O
, O
inflammation O
, O
and O
cardiovascular O
disease O
. O

However O
, O
no O
prospective O
studies O
have O
examined O
the O
impact O
of O
circulating O
omentin O
- O
1 O
levels O
on O
arterial O
stiffening O
in O
patients O
with O
type O
2 O
diabetes O
mellitus O
. O

For O
the O
purpose O
of O
this O
study O
, O
we O
recruited O
120 O
patients O
with O
type O
2 O
diabetes O
mellitus O
and O
measured O
serum O
omentin O
- O
1 O
, O
adiponectin O
, O
and O
high O
- O
sensitivity O
C O
- O
reactive O
protein O
levels O
as O
well O
as O
other O
cardiovascular O
risk O
factors O
. O

Arterial O
stiffness O
was O
assessed O
by O
brachial O
ankle O
pulse O
wave O
velocity O
( O
baPWV O
) O
. O

An O
increase O
in O
the O
level O
of O
circulating O
omentin O
- O
1 O
over O
a O
period O
of O
1 O
year O
was O
positively O
correlated O
with O
changes O
in O
levels O
of O
HbA1c O
and O
serum O
adiponectin O
as O
well O
as O
baPWV O
. O

Subjects O
with O
higher O
baseline O
serum O
omentin O
- O
1 O
levels O
tended O
to O
have O
a O
reduced O
arterial O
stiffness O
after O
1 O
year O
( O
P O
for O
linear O
trend O
= O
0 O
. O
03 O
) O
. O

In O
the O
group O
with O
increased O
baPWV O
after O
1 O
year O
, O
the O
magnitude O
of O
increase O
of O
circulating O
omentin O
- O
1 O
levels O
was O
significantly O
higher O
than O
in O
the O
group O
with O
a O
lower O
baPWV O
after O
1 O
year O
( O
134 O
. O
3 O
[ O
16 O
. O
6 O
, O
277 O
. O
1 O
] O
ng O
/ O
mL O
vs O
. O
15 O
. O
9 O
[ O
- O
67 O
. O
6 O
, O
145 O
. O
7 O
] O
ng O
/ O
mL O
, O
P O
< O
0 O
. O
01 O
) O
. O

Multiple O
stepwise O
logistic O
regression O
analysis O
revealed O
that O
an O
increase O
in O
systolic O
blood O
pressure O
and O
an O
increase O
in O
serum O
omentin O
- O
1 O
level O
were O
independently O
correlated O
with O
arterial O
stiffening O
, O
even O
after O
adjusting O
for O
other O
cardiovascular O
risk O
factors O
and O
medication O
history O
. O

Baseline O
serum O
omentin O
- O
1 O
levels O
can O
predict O
arterial O
stiffness O
changes O
occurring O
within O
a O
year O
. O

Furthermore O
, O
changes O
in O
serum O
omentin O
- O
1 O
levels O
after O
a O
year O
can O
function O
as O
independent O
markers O
of O
arterial O
stiffening O
in O
patients O
with O
type O
2 O
diabetes O
mellitus O
. O

High O
- O
Grade O
Prostatic O
Intraepithelial O
Neoplasia O
( O
HGPIN O
) O
and O
topographical O
distribution O
in O
1 O
, O
374 O
prostatectomy O
specimens O
: O
Existence O
of O
HGPIN O
near O
prostate O
cancer O
. O

PURPOSE O
: O
High O
- O
grade O
prostatic O
intraepithelial O
neoplasia O
( O
HGPIN O
) O
is O
believed O
to O
be O
a O
precursor O
of O
prostate O
cancer O
( O
PCa O
) O
. O

This O
study O
evaluated O
whether O
HGPIN O
was O
located O
close O
to O
PCa O
in O
whole O
radical O
prostatectomy O
specimens O
( O
RPSs O
) O
. O

MATERIALS O
AND O
METHODS O
: O
We O
evaluated O
1 O
, O
374 O
prostate O
specimens O
from O
1999 O
to O
2010 O
using O
a O
cMDX O
- O
based O
map O
model O
of O
the O
prostate O
. O

The O
distribution O
of O
10 O
, O
439 O
PCa O
foci O
was O
analyzed O
and O
visualized O
on O
a O
heat O
map O
. O

The O
color O
gradient O
of O
the O
heat O
map O
was O
reduced O
to O
six O
colors O
representing O
the O
frequency O
classification O
of O
the O
relative O
frequency O
of O
PCa O
using O
an O
image O
posterization O
effect O
. O

We O
defined O
22 O
regions O
in O
the O
prostate O
according O
to O
the O
frequency O
of O
PCa O
occurrence O
. O

Seven O
hundred O
ninety O
RPSs O
containing O
6 O
, O
374 O
PCa O
foci O
and O
4 O
, O
502 O
HGPIN O
foci O
were O
evaluated O
. O

The O
topographical O
association O
between O
PCa O
and O
HGPIN O
in O
the O
RPSs O
was O
analyzed O
by O
estimating O
the O
frequencies O
of O
PCa O
and O
HGPIN O
in O
22 O
regions O
. O

A O
logistic O
regression O
analysis O
was O
performed O
to O
assess O
the O
odds O
ratios O
of O
HGPIN O
for O
the O
presence O
of O
PCa O
in O
22 O
regions O
. O

RESULTS O
: O
Fifty O
- O
eight O
percent O
of O
PCa O
specimens O
included O
HGPIN O
and O
had O
significantly O
more O
favorable O
Gleason O
scores O
, O
lower O
PSA O
levels O
and O
smaller O
relative O
tumor O
volumes O
than O
isolated O
PCa O
specimens O
. O

HGPIN O
( O
68 O
% O
) O
and O
PCa O
( O
69 O
% O
) O
were O
predominantly O
localized O
to O
the O
apical O
half O
of O
the O
prostate O
. O

HGPIN O
was O
mainly O
concentrated O
in O
the O
peripheral O
zone O
medial O
to O
regions O
with O
high O
PCa O
frequencies O
. O

Upon O
logistic O
regression O
analysis O
, O
HGPIN O
was O
a O
significant O
predictor O
of O
PCa O
co O
- O
existence O
in O
11 O
regions O
. O

CONCLUSIONS O
: O
HGPIN O
was O
located O
adjacent O
to O
PCa O
in O
whole O
RPSs O
. O

PCa O
concomitant O
with O
HGPIN O
had O
more O
favorable O
pathologic O
features O
than O
isolated O
PCa O
. O

Prostate O
( O
c O
) O
2013 O
Wiley O
Periodicals O
, O
Inc O
. O

The O
Joubert O
Syndrome O
Associated O
Missense O
Mutation O
( O
V443D O
) O
in O
the O
Abelson O
- O
helper O
Integration O
Site O
1 O
( O
AHI1 O
) O
Protein O
Alters O
Its O
Localization O
and O
Protein O
- O
Protein O
Interactions O
. O

Mutations O
in O
AHI1 O
cause O
Joubert O
syndrome O
( O
JBTS O
) O
, O
a O
neurodevelopmental O
ciliopathy O
, O
characterized O
by O
midbrain O
- O
hindbrain O
malformations O
and O
motor O
/ O
cognitive O
deficits O
. O

Here O
, O
we O
show O
that O
primary O
cilia O
( O
PC O
) O
formation O
is O
decreased O
in O
fibroblasts O
from O
individuals O
with O
JBTS O
and O
AHI1 O
mutations O
. O

Most O
missense O
mutations O
in O
AHI1 O
, O
causing O
JBTS O
, O
occur O
in O
known O
protein O
domains O
, O
however O
, O
a O
common O
V443D O
mutation O
in O
AHI1 O
is O
found O
in O
a O
region O
with O
no O
known O
protein O
motifs O
. O

We O
show O
that O
cells O
transfected O
with O
AHI1 O
- O
V443D O
, O
or O
a O
new O
JBTS O
- O
causing O
mutation O
, O
AHI1 O
- O
R351L O
, O
have O
aberrant O
localization O
of O
AHI1 O
at O
the O
basal O
bodies O
of O
PC O
and O
at O
cell O
- O
cell O
junctions O
, O
likely O
through O
decreased O
binding O
of O
mutant O
AHI1 O
to O
NPHP1 O
( O
another O
JBTS O
- O
causing O
protein O
) O
. O

The O
AHI1 O
- O
V443D O
mutation O
causes O
decreased O
AHI1 O
stability O
, O
since O
there O
is O
a O
50 O
% O
reduction O
in O
AHI1 O
- O
V443D O
protein O
levels O
compared O
to O
wildtype O
AHI1 O
. O

Huntingtin O
- O
associated O
protein O
- O
1 O
( O
Hap1 O
) O
is O
a O
regulatory O
protein O
that O
binds O
Ahi1 O
, O
and O
Hap1 O
knockout O
mice O
have O
been O
reported O
to O
have O
JBTS O
- O
like O
phenotypes O
, O
suggesting O
a O
role O
for O
Hap1 O
in O
ciliogenesis O
. O

Fibroblasts O
and O
neurons O
with O
Hap1 O
deficiency O
form O
PC O
with O
normal O
growth O
factor O
- O
induced O
ciliary O
signaling O
, O
indicating O
that O
the O
Hap1 O
JBTS O
- O
phenotype O
is O
likely O
not O
through O
effects O
at O
PC O
. O

These O
results O
also O
suggest O
that O
the O
binding O
of O
Ahi1 O
and O
Hap1 O
may O
not O
be O
critical O
for O
ciliary O
function O
. O

However O
, O
we O
show O
that O
HAP1 O
has O
decreased O
binding O
to O
AHI1 O
- O
V443D O
indicating O
that O
this O
altered O
binding O
could O
be O
responsible O
for O
the O
JBTS O
- O
like O
phenotype O
through O
an O
unknown O
pathway O
. O

Thus O
, O
these O
JBTS O
- O
associated O
missense O
mutations O
alter O
their O
subcellular O
distribution O
and O
protein O
interactions O
, O
compromising O
functions O
of O
AHI1 O
in O
cell O
polarity O
and O
cilium O
- O
mediated O
signaling O
, O
thereby O
contributing O
to O
JBTS O
. O

Bioimaging O
real O
- O
time O
PXR O
- O
dependent O
mdr1a O
gene O
regulation O
in O
mdr1a O
. O
fLUC O
reporter O
mice O
. O

The O
MDR1 O
gene O
encodes O
P O
- O
glycoprotein O
, O
a O
transmembrane O
drug O
efflux O
transporter O
that O
confers O
multidrug O
resistance O
in O
cancer O
cells O
and O
affects O
drug O
pharmacokinetics O
by O
virtue O
of O
its O
expression O
in O
the O
liver O
, O
kidney O
, O
and O
colon O
. O

Nuclear O
receptors O
SXR O
and O
CAR O
are O
possible O
master O
regulators O
of O
xenobiotic O
- O
inducible O
MDR1 O
expression O
in O
drug O
processing O
organs O
, O
but O
the O
mechanism O
of O
MDR1 O
regulation O
has O
yet O
to O
be O
directly O
demonstrated O
in O
vivo O
. O

Moreover O
, O
it O
has O
previously O
been O
impossible O
to O
determine O
the O
sustained O
or O
cumulative O
effect O
of O
repeated O
doses O
of O
xenobiotics O
on O
in O
vivo O
MDR1 O
expression O
. O

We O
previously O
reported O
a O
mouse O
model O
containing O
firefly O
luciferase O
( O
fLUC O
) O
knocked O
into O
the O
mdr1a O
genomic O
locus O
, O
allowing O
non O
- O
invasive O
bioimaging O
of O
intestinal O
mdr1a O
gene O
expression O
in O
live O
animals O
. O

In O
the O
current O
study O
, O
we O
crossed O
mdr1a O
. O
fLUC O
mice O
into O
the O
pxr O
knockout O
( O
pxr O
( O
- O
/ O
- O
) O
) O
genetic O
background O
and O
injected O
mice O
with O
pregnenolone B
- I
16 I
alpha I
- I
carbonitrile I
( O
PCN B
) O
, O
a O
strong O
PXR O
ligand O
, O
and O
two O
therapeutically O
relevant O
taxanes B
, O
paclitaxel B
and O
docetaxel B
. O

All O
three O
agents O
induced O
mdr1a O
. O
fLUC O
expression O
( O
bioluminescence O
) O
, O
but O
only O
PCN B
and O
docetaxel B
appeared O
to O
act O
primarily O
via O
PXR O
. O

Luminescence O
returned O
to O
baseline O
by O
24 O
- O
48 O
hrs O
after O
drug O
injection O
and O
was O
re O
- O
inducible O
over O
two O
additional O
rounds O
of O
drug O
dosing O
in O
pxr O
( O
+ O
/ O
+ O
) O
mice O
. O

TCPOBOP B
, O
a O
CAR O
ligand O
, O
modestly O
induced O
mdr1a O
. O
fLUC O
in O
pxr O
( O
+ O
/ O
+ O
) O
and O
pxr O
( O
- O
/ O
- O
) O
strains O
, O
consistent O
with O
CAR O
' O
s O
minor O
role O
in O
mdr1a O
regulation O
. O

Collectively O
, O
these O
results O
demonstrate O
that O
the O
mdr1a O
. O
fLUC O
bioimaging O
model O
can O
capture O
changes O
in O
mdr1 O
gene O
expression O
under O
conditions O
of O
repeated O
xenobiotic O
treatment O
in O
vivo O
and O
that O
it O
can O
be O
used O
to O
probe O
the O
mechanism O
of O
gene O
regulation O
in O
response O
to O
different O
xenobiotic O
agents O
. O

SpecDis O
: O
quantifying O
the O
comparison O
of O
calculated O
and O
experimental O
electronic O
circular O
dichroism O
spectra O
. O

This O
article O
outlines O
theory O
and O
practice O
of O
the O
comparison O
of O
calculated O
and O
experimental O
electronic O
circular O
dichroism O
( O
ECD O
) O
curves O
to O
determine O
the O
absolute O
configuration O
of O
chiral O
molecules O
. O

The O
focus O
is O
on O
the O
evaluation O
of O
excited O
- O
state O
calculations O
giving O
hints O
at O
the O
identification O
of O
the O
correct O
bandwidth O
and O
the O
application O
of O
the O
so O
- O
called O
" O
UV O
shift O
" O
as O
a O
correction O
factor O
. O

A O
similarity O
factor O
is O
introduced O
, O
which O
helps O
to O
quantify O
the O
degree O
of O
matching O
of O
curves O
. O

In O
addition O
, O
a O
few O
common O
errors O
are O
described O
that O
can O
be O
made O
during O
the O
measurements O
of O
ECD O
and O
UV O
spectra O
- O
and O
advice O
is O
given O
of O
how O
to O
avoid O
these O
mistakes O
. O

All O
equations O
mentioned O
in O
the O
article O
are O
implemented O
in O
our O
SpecDis O
software O
, O
which O
has O
been O
developed O
to O
rapidly O
compare O
calculated O
ECD O
and O
UV O
curves O
with O
experimental O
ones O
, O
and O
to O
produce O
graphics O
in O
publication O
quality O
. O

O B
- I
heterocyclic I
embeurekols I
from O
Embellisia O
eureka O
, O
an O
endophyte O
of O
Cladanthus O
arabicus O
. O

Three O
new O
polyketides O
( O
( O
- O
) O
- O
1 O
, O
( O
+ O
) O
- O
1 O
, O
and O
2 O
) O
were O
isolated O
from O
the O
EtOAc B
extract O
of O
the O
fungus O
Embellisia O
eureka O
, O
an O
endophyte O
of O
the O
Moroccan O
plant O
Cladanthus O
arabicus O
( O
Asteraceae O
) O
. O

The O
structures O
of O
these O
new O
compounds O
were O
determined O
on O
the O
basis O
of O
one O
- O
and O
two O
- O
dimensional O
NMR O
spectroscopy O
as O
well O
as O
by O
high O
- O
resolution O
mass O
spectrometry O
. O

The O
absolute O
configurations O
of O
( O
- O
) O
- O
1 O
, O
( O
+ O
) O
- O
1 O
, O
and O
2 O
were O
determined O
by O
TDDFT O
ECD O
calculations O
of O
solution O
conformers O
, O
online O
HPLC O
- O
ECD O
analysis O
, O
and O
the O
modified O
Mosher O
method O
. O

Increased O
activin O
bioavailability O
enhances O
hepatic O
insulin O
sensitivity O
while O
inducing O
hepatic O
steatosis O
in O
male O
mice O
. O

The O
development O
of O
insulin O
resistance O
is O
tightly O
linked O
to O
fatty O
liver O
disease O
and O
is O
considered O
a O
major O
health O
concern O
worldwide O
, O
although O
their O
mechanistic O
relationship O
remains O
controversial O
. O

Activin O
has O
emerging O
roles O
in O
nutrient O
homeostasis O
but O
its O
metabolic O
effects O
on O
hepatocytes O
remain O
unknown O
. O

In O
this O
study O
, O
we O
investigated O
the O
effects O
of O
increased O
endogenous O
activin O
bioactivity O
on O
hepatic O
nutrient O
homeostasis O
by O
creating O
mice O
with O
inactivating O
mutations O
that O
deplete O
the O
circulating O
activin O
antagonists O
, O
follistatin O
like O
- O
3 O
( O
FSTL3 O
) O
or O
the O
follistatin O
315 O
isoform O
( O
FST315 O
; O
FST288 O
- O
only O
mice O
) O
. O

We O
investigated O
liver O
histology O
and O
lipid O
content O
, O
hepatic O
insulin O
sensitivity O
, O
and O
metabolic O
gene O
expression O
including O
the O
HepG2 O
cell O
and O
primary O
hepatocyte O
response O
to O
activin O
treatment O
. O

Both O
FSTL3KO O
and O
FST288 O
- O
only O
mice O
had O
extensive O
hepatic O
steatosis O
and O
elevated O
hepatic O
triglyceride B
( O
TG O
) O
content O
. O

Unexpectedly O
, O
insulin O
signaling O
, O
as O
assessed O
by O
phospho O
- O
AKT O
, O
was O
enhanced O
in O
both O
mouse O
models O
. O

Pretreatment O
of O
HepG2 O
cells O
with O
activin O
A O
increased O
their O
response O
to O
subsequent O
insulin O
challenge O
. O

Gene O
expression O
analysis O
suggests O
that O
increased O
lipid O
uptake O
, O
enhanced O
de O
novo O
lipid O
synthesis O
, O
decreased O
lipolysis O
and O
/ O
or O
enhanced O
glucose B
uptake O
contribute O
to O
increased O
hepatic O
TG O
content O
in O
these O
models O
. O

However O
, O
activin O
treatment O
recapitulated O
only O
some O
of O
these O
gene O
changes O
suggesting O
that O
increased O
activin O
bioactivity O
may O
be O
only O
partially O
responsible O
for O
this O
phenotype O
. O

Nevertheless O
, O
our O
results O
indicate O
that O
activin O
enhances O
hepatocyte O
insulin O
response O
which O
ultimately O
leads O
to O
hepatic O
steatosis O
despite O
the O
increased O
insulin O
sensitivity O
. O

Thus O
, O
regulation O
of O
activin O
bioactivity O
is O
critical O
for O
maintaining O
normal O
liver O
lipid O
homeostasis O
and O
response O
to O
insulin O
while O
activin O
agonists O
may O
be O
useful O
for O
increasing O
liver O
insulin O
sensitivity O
. O

Calculation O
of O
Electron O
Transfer O
Rates O
Using O
Mixed O
Quantum O
Classical O
Approaches O
: O
Nonadiabatic O
Limit O
and O
Beyond O
. O

We O
investigate O
the O
applicability O
of O
the O
Ehrenfest O
and O
surface O
hopping O
methods O
to O
calculate O
electron O
transfer O
rates O
using O
the O
spin O
- O
boson O
model O
with O
different O
parameters O
. O

Rate O
constants O
are O
obtained O
from O
short O
time O
dynamics O
performed O
in O
both O
the O
diabatic O
and O
adiabatic O
basis O
sets O
. O

Numerical O
results O
and O
theoretical O
analysis O
show O
that O
these O
two O
methods O
can O
be O
reasonably O
accurate O
in O
the O
nonadiabatic O
limit O
, O
by O
staying O
close O
to O
an O
approximate O
Fermi O
' O
s O
golden O
rule O
. O

Beyond O
the O
nonadiabatic O
limit O
, O
the O
calculated O
mixed O
quantum O
classical O
rates O
are O
compared O
with O
numerical O
exact O
results O
, O
and O
similar O
accuracy O
was O
found O
as O
in O
the O
nonadiabatic O
limit O
. O

The O
relation O
between O
the O
current O
finding O
and O
recent O
studies O
using O
the O
surface O
hopping O
method O
based O
on O
long O
time O
dynamics O
is O
also O
discussed O
. O

It O
is O
found O
that O
the O
short O
time O
dynamics O
could O
be O
more O
accurate O
in O
calculating O
rate O
constants O
using O
the O
mixed O
quantum O
classical O
methods O
. O

Effect O
of O
surface O
charge O
density O
on O
the O
affinity O
of O
oxide B
nanoparticles O
for O
the O
vapor O
- O
water O
interface O
. O

Using O
in O
- O
situ O
X O
- O
ray O
photoelectron O
spectroscopy O
at O
the O
vapor O
- O
water O
interface O
, O
the O
affinity O
of O
nanometer O
- O
sized O
silica B
colloids O
to O
adsorb O
at O
the O
interface O
is O
shown O
to O
depend O
on O
colloid O
surface O
charge O
density O
. O

In O
aqueous O
suspensions O
at O
pH O
10 O
corrected O
Debye O
- O
H O
u O
ckel O
theory O
for O
surface O
complexation O
calculations O
predict O
that O
smaller O
silica B
colloids O
have O
increased O
negative O
surface O
charge O
density O
that O
originates O
from O
enhanced O
screening O
of O
deprotonated O
silanol B
groups O
( O
= O
Si B
- I
O I
( I
- I
) I
) O
by O
counterions O
in O
the O
condensed O
ion O
layer O
. O

The O
increased O
negative O
surface O
charge O
density O
results O
in O
an O
electrostatic O
repulsion O
from O
the O
vapor O
- O
water O
interface O
that O
is O
seen O
to O
a O
lesser O
extent O
for O
larger O
particles O
that O
have O
a O
reduced O
charge O
density O
in O
the O
XPS O
measurements O
. O

We O
compare O
the O
results O
and O
interpretation O
of O
the O
in O
- O
situ O
XPS O
and O
corrected O
Debye O
- O
H O
u O
ckel O
theory O
for O
surface O
complexation O
calculations O
with O
traditional O
surface O
tension O
measurements O
. O

Our O
results O
show O
that O
controlling O
the O
surface O
charge O
density O
of O
colloid O
particles O
can O
regulate O
their O
adsorption O
to O
the O
interface O
between O
two O
dielectrics O
. O

Two O
- O
dimensional O
penning O
ionization O
electron O
spectroscopy O
of O
open O
- O
shell O
metallocenes B
: O
outer O
valence O
ionic O
States O
of O
vanadocene B
and O
nickelocene B
. O

In O
order O
to O
investigate O
outer O
valence O
ionic O
states O
of O
open O
- O
shell O
metallocenes B
, O
we O
have O
applied O
two O
- O
dimensional O
collision O
- O
energy O
/ O
electron O
- O
energy O
- O
resolved O
Penning O
ionization O
electron O
spectroscopy O
( O
2D O
- O
PIES O
) O
upon O
collision O
with O
metastable O
He B
* O
( O
2 O
( O
3 O
) O
S O
) O
excited O
atoms O
as O
well O
as O
a O
high O
level O
ab O
initio O
molecular O
orbital O
calculation O
( O
the O
partial O
third O
- O
order O
quasiparticle O
theory O
of O
the O
electron O
propagator O
( O
P3 O
) O
) O
to O
ionization O
from O
neutral O
ground O
states O
of O
vanadocene B
( O
( O
4 O
) O
A2g O
) O
and O
nickelocene B
( O
( O

3 O
) O
A2g O
) O
. O

Assignments O
of O
observed O
Penning O
ionization O
electron O
/ O
He B
I O
ultraviolet O
photoelectron O
spectra O
were O
consistent O
with O
the O
P3 O
calculation O
results O
for O
ionization O
of O
alpha O
and O
beta O
spin O
electrons O
except O
for O
electron O
correlation O
bands O
observed O
by O
PIES O
. O

Negative O
collision O
energy O
dependence O
of O
partial O
Penning O
ionization O
cross O
- O
sections O
( O
CEDPICS O
) O
indicate O
attractive O
interaction O
with O
He B
* O
( O
2 O
( O
3 O
) O
S O
) O
around O
the O
molecule O
. O

Results O
by O
model O
potential O
calculation O
utilizing O
Li B
( O
2 O
( O
2 O
) O
S O
) O
instead O
of O
He B
* O
( O
2 O
( O
3 O
) O
S O
) O
for O
interaction O
between O
He B
* O
( O
2 O
( O
3 O
) O
S O
) O
and O
open O
- O
shell O
metallocenes B
do O
not O
explain O
the O
strong O
negative O
CEDPICS O
of O
the O
bands O
observed O
in O
PIES O
. O

Antifreeze O
( O
Glyco O
) O
protein O
Mimetic O
Behavior O
of O
Poly B
( I
vinyl I
alcohol I
) I
: O
Detailed O
Structure O
Ice O
Recrystallization O
Inhibition O
Activity O
Study O
. O

This O
manuscript O
reports O
a O
detailed O
study O
on O
the O
ability O
of O
poly B
( I
vinyl I
alcohol I
) I
to O
act O
as O
a O
biomimetic O
surrogate O
for O
antifreeze O
( O
glyco O
) O
proteins O
, O
with O
a O
focus O
on O
the O
specific O
property O
of O
ice O
- O
recrystallization O
inhibition O
( O
IRI O
) O
. O

Despite O
over O
40 O
years O
of O
study O
, O
the O
underlying O
mechanisms O
that O
govern O
the O
action O
of O
biological O
antifreezes O
are O
still O
poorly O
understood O
, O
which O
is O
in O
part O
due O
to O
their O
limited O
availability O
and O
challenging O
synthesis O
. O

Poly B
( I
vinyl I
alcohol I
) I
( O
PVA B
) O
has O
been O
shown O
to O
display O
remarkable O
ice O
recrystallization O
inhibition O
activity O
despite O
its O
major O
structural O
differences O
to O
native O
antifreeze O
proteins O
. O

Here O
, O
controlled O
radical O
polymerization O
is O
used O
to O
synthesize O
well O
- O
defined O
PVA B
, O
which O
has O
enabled O
us O
to O
obtain O
the O
first O
quantitative O
structure O
- O
activity O
relationships O
, O
to O
probe O
the O
role O
of O
molecular O
weight O
and O
comonomers O
on O
IRI O
activity O
. O

Crucially O
, O
it O
was O
found O
that O
IRI O
activity O
is O
" O
switched O
on O
" O
when O
the O
polymer O
chain O
length O
increases O
from O
10 O
and O
20 O
repeat O
units O
. O

Substitution O
of O
the O
polymer O
side O
chains O
with O
hydrophilic O
or O
hydrophobic O
units O
was O
found O
to O
diminish O
activity O
. O

Hydrophobic O
modifications O
to O
the O
backbone O
were O
slightly O
more O
tolerated O
than O
side O
chain O
modifications O
, O
which O
implies O
an O
unbroken O
sequence O
of O
hydroxyl B
units O
is O
necessary O
for O
activity O
. O

These O
results O
highlight O
that O
, O
although O
hydrophobic O
domains O
are O
key O
components O
of O
IRI O
activity O
, O
the O
random O
inclusion O
of O
addition O
hydrophobic O
units O
does O
not O
guarantee O
an O
increase O
in O
activity O
and O
that O
the O
actual O
polymer O
conformation O
is O
important O
. O

Skin O
Sensitization O
of O
Epoxyaldehydes B
: O
Importance O
of O
Conjugation O
. O

Structure O
- O
activity O
relationship O
( O
SAR O
) O
models O
are O
important O
tools O
for O
predicting O
the O
skin O
sensitization O
potential O
of O
new O
compounds O
without O
animal O
testing O
. O

In O
compounds O
possessing O
a O
structural O
alert O
( O
aldehyde B
) O
and O
an O
activation O
alert O
( O
double O
bond O
) O
, O
it O
is O
important O
to O
consider O
bioactivation O
/ O
autoxidation O
( O
e O
. O
g O
. O
, O
epoxidation O
) O
. O

In O
the O
present O
study O
, O
we O
have O
explored O
a O
series O
of O
aldehydes B
with O
regard O
to O
contact O
allergy O
. O

The O
chemical O
reactivity O
of O
these O
6 O
aldehydes B
toward O
a O
model O
hexapeptide B
was O
investigated O
, O
and O
their O
skin O
sensitization O
potencies O
were O
evaluated O
using O
the O
local O
lymph O
node O
assay O
( O
LLNA O
) O
. O

Overall O
, O
we O
observed O
a O
similar O
trend O
for O
the O
in O
vitro O
reactivity O
and O
the O
in O
vivo O
sensitization O
potency O
for O
the O
structural O
analogues O
in O
this O
study O
. O

The O
highly O
reactive O
conjugated O
aldehydes B
( O
alpha B
, I
beta I
- I
unsaturated I
aldehydes I
and O
2 B
, I
3 I
- I
epoxyaldehydes I
) O
are O
sensitizing O
moieties O
, O
while O
nonconjugated O
aldehydes B
and O
nonterminal O
aliphatic I
epoxides I
show O
low O
reactivity O
and O
low O
sensitization O
potency O
. O

Our O
data O
show O
the O
importance O
of O
not O
only O
double O
bond O
conjugation O
to O
aldehyde B
but O
also O
epoxide B
- O
aldehyde B
conjugation O
. O

The O
observations O
indicate O
that O
the O
formation O
of O
nonconjugated O
epoxides B
by O
bioactivation O
or O
autoxidation O
is O
not O
sufficient O
to O
significantly O
increase O
the O
sensitization O
potency O
of O
weakly O
sensitizing O
parent O
compounds O
. O

Monomeric O
PcrA O
helicase O
processively O
unwinds O
plasmid O
lengths O
of O
DNA O
in O
the O
presence O
of O
the O
initiator O
protein O
RepD O
. O

The O
helicase O
PcrA O
unwinds O
DNA O
during O
asymmetric O
replication O
of O
plasmids O
, O
acting O
with O
an O
initiator O
protein O
, O
in O
our O
case O
RepD O
. O

Detailed O
kinetics O
of O
PcrA O
activity O
were O
measured O
using O
bulk O
solution O
and O
a O
single O
- O
molecule O
imaging O
technique O
to O
investigate O
the O
oligomeric O
state O
of O
the O
active O
helicase O
complex O
, O
its O
processivity O
and O
the O
mechanism O
of O
unwinding O
. O

By O
tethering O
either O
DNA O
or O
PcrA O
to O
a O
microscope O
coverslip O
surface O
, O
unwinding O
of O
both O
linear O
and O
natural O
circular O
plasmid O
DNA O
by O
PcrA O
/ O
RepD O
was O
followed O
in O
real O
- O
time O
using O
total O
internal O
reflection O
fluorescence O
microscopy O
. O

Visualization O
was O
achieved O
using O
a O
fluorescent O
single O
- O
stranded O
DNA O
- O
binding O
protein O
. O

The O
single O
- O
molecule O
data O
show O
that O
PcrA O
, O
in O
combination O
with O
RepD O
, O
can O
unwind O
plasmid O
lengths O
of O
DNA O
in O
a O
single O
run O
, O
and O
that O
PcrA O
is O
active O
as O
a O
monomer O
. O

Although O
the O
average O
rate O
of O
unwinding O
was O
similar O
in O
single O
- O
molecule O
and O
bulk O
solution O
assays O
, O
the O
single O
- O
molecule O
experiments O
revealed O
a O
wide O
distribution O
of O
unwinding O
speeds O
by O
different O
molecules O
. O

The O
average O
rate O
of O
unwinding O
was O
several O
- O
fold O
slower O
than O
the O
PcrA O
translocation O
rate O
on O
single O
- O
stranded O
DNA O
, O
suggesting O
that O
DNA O
unwinding O
may O
proceed O
via O
a O
partially O
passive O
mechanism O
. O

However O
, O
the O
fastest O
dsDNA O
unwinding O
rates O
measured O
in O
the O
single O
- O
molecule O
unwinding O
assays O
approached O
the O
PcrA O
translocation O
speed O
measured O
on O
ssDNA O
. O

Mechanisms O
of O
the O
anti O
- O
proliferative O
and O
anti O
- O
inflammatory O
effects O
of O
the O
herbal O
fixed O
combination O
STW B
5 I
( O
Iberogast B
( O
( O
R O
) O
) O
) O
on O
colon O
adenocarcinoma O
( O
HT29 O
) O
cells O
in O
vitro O
. O

INTRODUCTION O
: O
Several O
conventional O
pharmaceuticals O
like O
non O
- O
steroidal O
anti O
- O
inflammatory O
drugs O
( O
NSAIDS O
) O
or O
selective O
cyclooxygenase O
- O
2 O
( O
COX O
- O
2 O
) O
inhibitors O
have O
been O
demonstrated O
to O
exert O
anti O
- O
proliferative O
effects O
and O
to O
induce O
apoptosis O
in O
a O
variety O
of O
cell O
lines O
, O
e O
. O
g O
. O
colon O
, O
stomach O
, O
or O
prostate O
cancer O
cells O
. O

STW O
5 O
( O
Iberogast B
( O
( O
R O
) O
) O
) O
, O
a O
combination O
of O
nine O
plant O
extracts O
, O
is O
widely O
used O
in O
the O
treatment O
of O
gastrointestinal O
disorders O
, O
including O
functional O
dyspepsia O
and O
irritable O
bowel O
syndrome O
for O
which O
the O
involvement O
of O
an O
inflammatory O
etiology O
is O
discussed O
. O

To O
investigate O
the O
possible O
anti O
- O
proliferative O
effects O
, O
STW O
5 O
and O
its O
components O
have O
been O
tested O
by O
using O
the O
colon O
- O
carcinoma O
cell O
line O
HT O
- O
29 O
. O

The O
analyses O
have O
been O
performed O
in O
comparison O
to O
acetylsalicylic B
acid I
( O
ASA B
) O
and O
diclofenac B
( O
Diclo B
) O
, O
which O
are O
well O
- O
known O
to O
reduce O
colon O
carcinoma O
risk O
. O

RESULTS O
: O
STW O
5 O
showed O
significant O
anti O
- O
proliferative O
and O
pro O
- O
apoptotic O
effects O
on O
HT O
- O
29 O
cancer O
cells O
, O
similar O
to O
NSAIDs O
under O
test O
. O

However O
, O
using O
the O
LDH O
assay O
, O
STW O
5 O
revealed O
significantly O
lower O
cytotoxicity O
than O
Diclo B
at O
same O
concentrations O
. O

In O
contrast O
to O
NSAIDs O
, O
STW O
5 O
induced O
COX O
- O
1 O
/ O
COX O
- O
2 O
, O
caspase O
- O
3 O
and O
Bax O
mRNA O
expressions O
in O
HT O
- O
29 O
and O
blocked O
LPS O
mediated O
translocation O
of O
the O
NF O
- O
kappa O
B O
p65 O
from O
the O
cytoplasm O
into O
the O
nucleus O
in O
PMA B
- O
differentiated O
THP O
- O
1 O
macrophages O
. O

These O
effects O
might O
be O
relevant O
, O
e O
. O
g O
. O
for O
prevention O
of O
undesirable O
side O
effects O
like O
gastric O
erosions O
. O

CONCLUSION O
: O
Our O
data O
suggest O
that O
the O
pro O
- O
apoptotic O
effect O
of O
STW O
5 O
on O
HT O
- O
29 O
cells O
is O
involving O
multiple O
targets O
and O
is O
possibly O
due O
to O
an O
activation O
of O
the O
caspase O
cascade O
via O
mitochondrial O
destabilization O
. O

Active O
concentrations O
of O
STW O
5 O
are O
, O
in O
relation O
to O
therapeutic O
doses O
, O
comparable O
to O
those O
of O
ASA B
and O
Diclo B
, O
suggesting O
a O
similar O
favorable O
effect O
on O
colon O
carcinoma O
risk O
. O

Cajaninstilbene B
acid I
( O
CSA B
) O
exerts O
cytoprotective O
effects O
against O
oxidative O
stress O
through O
the O
Nrf2 O
- O
dependent O
antioxidant O
pathway O
. O

Cajaninstilbene B
acid I
( O
CSA B
) O
, O
an O
active O
compound O
separated O
from O
pigeon O
pea O
leaves O
, O
possesses O
the O
highly O
efficient O
antioxidant O
activities O
. O

Transcription O
factor O
nuclear O
factor O
- O
erythroid O
2 O
- O
related O
factor O
2 O
( O
Nrf2 O
) O
is O
an O
important O
regulator O
of O
cellular O
oxidative O
stress O
. O

This O
study O
examined O
the O
role O
of O
Nrf2 O
in O
CSA B
- O
mediated O
antioxidant O
effects O
on O
human O
hepatocarcinoma O
( O
HepG2 O
) O
cell O
line O
. O

The O
generation O
of O
reactive O
oxygen B
species O
( O
ROS O
) O
upon O
H2O2 B
and O
CSA O
treatment O
was O
lower O
than O
that O
of O
H2O2 B
alone O
. O

CSA B
activated O
Nrf2 O
as O
evaluated O
by O
Western O
blotting O
. O

A O
luciferase O
reporter O
assay O
also O
demonstrated O
that O
CSA B
- O
activated O
signaling O
resulted O
in O
the O
increased O
transcriptional O
activity O
of O
Nrf2 O
through O
binding O
to O
the O
antioxidant O
response O
element O
( O
ARE O
) O
enhancer O
sequence O
. O

Our O
study O
indicated O
that O
treatment O
of O
HepG2 O
cells O
with O
CSA B
induces O
Nrf2 O
- O
dependent O
ARE O
activity O
and O
gene O
expression O
of O
heme O
oxygenase O
- O
1 O
( O
HO O
- O
1 O
) O
, O
NAD B
( I
P I
) I
H I
quinone B
oxidoreductase O
1 O
( O
NQO1 O
) O
, O
and O
glutamate B
- O
cysteine B
ligase O
modifier O
subunits O
by O
activation O
of O
PI3K O
/ O
AKT O
, O
ERK O
and O
JNK O
signaling O
pathways O
. O

Inhibition O
of O
Nrf2 O
by O
siRNA O
reduced O
CSA B
- O
induced O
upregulation O
of O
these O
Nrf2 O
- O
related O
enzymes O
. O

These O
results O
suggest O
that O
the O
Nrf2 O
/ O
ARE O
pathway O
plays O
an O
important O
role O
in O
the O
regulation O
of O
CSA B
- O
mediated O
antioxidant O
effects O
in O
HepG2 O
cells O
. O

Enantiocomplementary O
access O
to O
carba B
- O
analogs O
of O
C B
- I
nucleoside I
derivatives O
by O
recombinant O
Baeyer O
- O
Villiger O
monooxygenases O
. O

A O
novel O
and O
stereoselective O
synthetic O
route O
towards O
carba B
- I
C I
- I
nucleosides I
was O
investigated O
applying O
an O
enantiodivergent O
biooxidation O
strategy O
by O
two O
different O
Baeyer O
- O
Villiger O
monooxygenases O
. O

Within O
only O
three O
chemo O
- O
enzymatic O
steps O
it O
was O
possible O
to O
introduce O
four O
chiral O
centers O
starting O
from O
commercially O
available O
non O
- O
chiral O
starting O
material O
. O

Use O
of O
asenapine B
in O
clinical O
practice O
for O
the O
management O
of O
bipolar O
mania O
. O

Bipolar O
disorder O
is O
a O
chronic O
mental O
illness O
associated O
with O
high O
levels O
of O
somatic O
morbidity O
, O
comorbidity O
and O
mortality O
. O

Treatment O
guidelines O
for O
bipolar O
mania O
generally O
recommend O
initiating O
first O
- O
line O
therapy O
with O
a O
second O
- O
generation O
antipsychotic O
or O
mood O
stabiliser O
, O
either O
alone O
or O
in O
combination O
. O

Asenapine B
is O
a O
second O
- O
generation O
antipsychotic O
with O
a O
unique O
receptor O
binding O
profile O
, O
licensed O
for O
the O
treatment O
of O
manic O
episodes O
in O
adults O
with O
bipolar O
I O
disorder O
. O

' O
Real O
- O
world O
' O
data O
are O
needed O
to O
complement O
evidence O
from O
clinical O
trials O
, O
in O
order O
to O
provide O
clinicians O
with O
pragmatic O
information O
regarding O
the O
likely O
risks O
and O
benefits O
of O
using O
a O
new O
agent O
in O
clinical O
practice O
. O

Evidence O
from O
real O
- O
world O
case O
reports O
demonstrates O
that O
- O
as O
in O
clinical O
trials O
- O
asenapine B
is O
effective O
in O
treating O
mania O
and O
mixed O
episodes O
associated O
with O
bipolar O
I O
disorder O
, O
whether O
used O
as O
monotherapy O
or O
in O
combination O
with O
a O
mood O
stabiliser O
. O

It O
has O
a O
rapid O
onset O
of O
antimanic O
effect O
and O
an O
early O
improvement O
is O
associated O
with O
treatment O
outcome O
. O

Asenapine B
also O
shows O
promise O
in O
controlling O
depressive O
symptoms O
and O
clinically O
challenging O
mixed O
states O
. O

Asenapine B
has O
a O
favourable O
tolerability O
profile O
, O
compared O
with O
other O
first O
- O
line O
agents O
, O
having O
a O
minimal O
impact O
on O
weight O
and O
metabolic O
parameters O
. O

Asenapine B
should O
be O
considered O
a O
first O
- O
line O
treatment O
option O
for O
adults O
with O
bipolar O
I O
disorder O
. O

Force O
nanoscopy O
of O
cell O
mechanics O
and O
cell O
adhesion O
. O

Cells O
are O
constantly O
exposed O
to O
mechanical O
stimuli O
in O
their O
environment O
and O
have O
several O
evolved O
mechanisms O
to O
sense O
and O
respond O
to O
these O
cues O
. O

It O
is O
becoming O
increasingly O
recognized O
that O
many O
cell O
types O
, O
from O
bacteria O
to O
mammalian O
cells O
, O
possess O
a O
diverse O
set O
of O
proteins O
to O
translate O
mechanical O
cues O
into O
biochemical O
signalling O
and O
to O
mediate O
cell O
surface O
interactions O
such O
as O
cell O
adhesion O
. O

Moreover O
, O
the O
mechanical O
properties O
of O
cells O
are O
involved O
in O
regulating O
cell O
function O
as O
well O
as O
serving O
as O
indicators O
of O
disease O
states O
. O

Importantly O
, O
the O
recent O
development O
of O
biophysical O
tools O
and O
nanoscale O
methods O
has O
facilitated O
a O
deeper O
understanding O
of O
the O
role O
that O
physical O
forces O
play O
in O
modulating O
cell O
mechanics O
and O
cell O
adhesion O
. O

Here O
, O
we O
discuss O
how O
atomic O
force O
microscopy O
( O
AFM O
) O
has O
recently O
been O
used O
to O
investigate O
cell O
mechanics O
and O
cell O
adhesion O
at O
the O
single O
- O
cell O
and O
single O
- O
molecule O
levels O
. O

This O
knowledge O
is O
critical O
to O
our O
understanding O
of O
the O
molecular O
mechanisms O
that O
govern O
mechanosensing O
, O
mechanotransduction O
, O
and O
mechanoresponse O
in O
living O
cells O
. O

While O
pushing O
living O
cells O
with O
the O
AFM O
tip O
provides O
a O
means O
to O
quantify O
their O
mechanical O
properties O
and O
examine O
their O
response O
to O
nanoscale O
forces O
, O
pulling O
single O
surface O
proteins O
with O
a O
functionalized O
tip O
allows O
one O
to O
understand O
their O
role O
in O
sensing O
and O
adhesion O
. O

The O
combination O
of O
these O
nanoscale O
techniques O
with O
modern O
molecular O
biology O
approaches O
, O
genetic O
engineering O
and O
optical O
microscopies O
provides O
a O
powerful O
platform O
for O
understanding O
the O
sophisticated O
functions O
of O
the O
cell O
surface O
machinery O
, O
and O
its O
role O
in O
the O
onset O
and O
progression O
of O
complex O
diseases O
. O

Geographical O
differences O
in O
the O
prevalence O
of O
chronic O
polypharmacy O
in O
older O
people O
: O
eleven O
years O
of O
the O
EPIFARM O
- O
Elderly O
Project O
. O

PURPOSE O
: O
To O
compare O
the O
geographical O
differences O
in O
the O
prevalence O
of O
chronic O
polypharmacy O
in O
community O
- O
dwelling O
older O
people O
over O
11 O
years O
. O

METHODS O
: O
This O
study O
analyzed O
nearly O
two O
million O
patients O
aged O
65 O
- O
94 O
years O
recorded O
in O
the O
Drug O
Administrative O
Database O
of O
the O
Lombardy O
Region O
( O
Northern O
Italy O
) O
from O
2000 O
to O
2010 O
. O

Chronic O
polypharmacy O
was O
defined O
as O
taking O
five O
or O
more O
drugs O
in O
1 O
month O
for O
at O
least O
6 O
months O
( O
consecutive O
or O
not O
) O
in O
a O
year O
. O

RESULTS O
: O
There O
was O
a O
significant O
spatial O
autocorrelation O
that O
increased O
at O
the O
municipality O
level O
from O
2000 O
( O
Moran O
' O
s O
I O
Index O
= O
0 O
. O
26 O
, O
z O
score O
= O
16 O
. O
91 O
, O
p O
< O
0 O
. O
0001 O
) O
to O
2010 O
( O
Moran O
' O
s O
I O
Index O
= O
0 O
. O
36 O
, O
z O
score O
= O
23 O
. O
78 O
, O
p O
< O
0 O
. O
0001 O
) O
. O

Clusters O
of O
high O
( O
Z O
( O
G O
) O
> O
1 O
. O
96 O
) O
and O
low O
( O
Z O
( O
G O
) O
< O
- O
1 O
. O
96 O
) O
prevalence O
rates O
of O
chronic O
polypharmacy O
were O
found O
and O
were O
not O
influenced O
by O
age O
. O

Chronic O
polypharmacy O
weakly O
correlated O
with O
hospital O
admission O
( O
2000 O
: O
rho O
= O
0 O
. O
08 O
, O
p O
= O
0 O
. O
0032 O
; O
2005 O
: O
rho O
= O
0 O
. O
11 O
, O
p O
< O
0 O
. O
0001 O
; O
2010 O
: O
rho O
= O
0 O
. O
18 O
, O
p O
< O
0 O
. O
0001 O
) O
, O
but O
not O
with O
mortality O
. O

CONCLUSIONS O
: O
There O
were O
geographical O
differences O
in O
the O
prevalence O
of O
older O
people O
with O
chronic O
polypharmacy O
that O
were O
only O
partly O
explained O
by O
health O
indicators O
. O

Targeted O
activities O
on O
prescription O
practice O
to O
ensure O
that O
the O
prescribing O
of O
chronic O
polypharmacy O
is O
appropriate O
are O
required O
. O

The O
effects O
of O
gender O
difference O
on O
monocrotaline B
- O
induced O
pulmonary O
hypertension O
in O
rats O
. O

The O
present O
study O
aimed O
to O
compare O
the O
effect O
of O
gender O
difference O
on O
hemodynamic O
consequences O
in O
the O
development O
of O
monocrotaline B
( O
MCT B
) O
- O
induced O
pulmonary O
hypertension O
in O
rat O
. O

The O
effect O
of O
antioxidant O
enzyme O
systems O
on O
the O
development O
of O
pulmonary O
hypertension O
mediated O
by O
the O
phytotoxin O
MCT O
and O
the O
effect O
of O
gender O
on O
these O
antioxidant O
systems O
were O
also O
investigated O
. O

For O
this O
purpose O
, O
the O
right O
ventricular O
pressures O
( O
RVPs O
) O
and O
right O
ventricular O
/ O
heart O
weight O
( O
HW O
) O
ratios O
were O
compared O
between O
groups O
and O
the O
glutathione B
( O
GSH B
) O
level O
and O
superoxide B
dismutase O
( O
SOD O
) O
, O
catalase O
( O
CAT O
) O
and O
glutathione B
- O
S B
- O
transferase O
( O
GST O
) O
activities O
were O
determined O
in O
lung O
and O
liver O
tissue O
samples O
of O
rats O
. O

RVP O
and O
right O
ventricular O
/ O
HW O
ratios O
significantly O
increased O
in O
the O
MCT B
group O
compared O
to O
the O
control O
group O
. O

In O
the O
MCT O
group O
, O
RVP B
was O
significantly O
higher O
in O
males O
than O
females O
. O

MCT B
- O
induced O
pulmonary O
hypertension O
resulted O
in O
decreased O
GSH B
level O
, O
decreased O
GST O
and O
SOD O
activities O
and O
increased O
CAT O
activity O
in O
lung O
and O
liver O
tissues O
of O
both O
male O
and O
female O
rats O
. O

In O
addition O
, O
the O
lung O
and O
liver O
GSH B
level O
and O
GST O
and O
SOD O
levels O
were O
higher O
in O
female O
control O
rats O
compared O
to O
male O
control O
rats O
. O

The O
results O
of O
the O
present O
study O
, O
that O
antioxidant O
enzyme O
activities O
were O
different O
between O
the O
groups O
, O
highlight O
the O
possible O
role O
of O
oxidative O
stress O
in O
the O
pathogenesis O
of O
MCT B
- O
induced O
pulmonary O
hypertension O
in O
rats O
. O

Moreover O
, O
the O
lower O
antioxidant O
defense O
capacity O
of O
male O
rats O
than O
female O
rats O
may O
be O
considered O
as O
a O
cause O
of O
more O
aggressive O
course O
of O
MCT B
- O
induced O
pulmonary O
hypertension O
in O
males O
compared O
to O
females O
. O

Injection O
of O
ropivacaine B
into O
the O
subarachnoid O
changes O
the O
ultrastructure O
and O
proteome O
of O
the O
rat O
spinal O
cord O
. O

Abstract O
1 O
. O

In O
the O
present O
study O
, O
we O
investigated O
the O
impact O
of O
1 O
. O
0 O
% O
ropivacaine B
on O
the O
ultrastructure O
and O
proteome O
of O
the O
rat O
spinal O
cord O
. O

2 O
. O

Rats O
received O
three O
injections O
( O
90 O
- O
min O
intervals O
, O
0 O
. O
2 O
mL O
/ O
kg O
) O
of O
0 O
. O
9 O
% O
NaCl B
, O
0 O
. O
5 O
% O
ropivacaine B
or O
1 O
. O
0 O
% O
ropivacaine B
via O
an O
implanted O
intrathecal O
catheter O
. O

Transmission O
electron O
microscopy O
was O
performed O
to O
exam O
the O
ultrastructure O
of O
the O
spinal O
cord O
. O

Two O
- O
dimensional O
electrophoresis O
followed O
by O
mass O
spectrometry O
identification O
were O
carried O
out O
to O
investigate O
the O
proteome O
. O

3 O
. O

In O
the O
rats O
administered O
1 O
. O
0 O
% O
ropivacaine B
, O
deformed O
organelles O
, O
detached O
myelinated O
nerve O
fiber O
layer O
, O
and O
incomplete O
inner O
and O
outer O
shaft O
membranes O
were O
observed O
in O
the O
spinal O
cord O
and O
posterior O
root O
shrunken O
nuclei O
. O

Furthermore O
, O
in O
the O
rat O
spinal O
cord O
1 O
. O
0 O
% O
ropivacaine B
induced O
the O
down O
- O
regulation O
of O
voltage O
- O
dependent O
anion O
channel O
2 O
( O
VDAC2 O
) O
and O
mitochondrial O
pyruvate B
dehydrogenase O
subunit O
alpha O
( O
ODPA O
) O
, O
the O
upregulation O
of O
myelin O
basic O
protein O
( O
MBP O
) O
, O
the O
disappearance O
of O
myelin O
transcription O
factor O
1 O
( O
MYT1 O
) O
and O
the O
appearance O
of O
heat O
shock O
protein O
25 O
( O
HSP25 O
) O
. O

Little O
change O
was O
observed O
in O
the O
0 O
. O
5 O
% O
ropivacaine B
or O
control O
groups O
. O

4 O
. O

Our O
results O
suggest O
that O
1 O
. O
0 O
% O
ropivacaine B
treatment O
led O
to O
neurotoxicity O
, O
as O
shown O
by O
ultrastructural O
and O
proteomic O
changes O
in O
the O
rat O
spinal O
cord O
. O

Specific O
proteins O
were O
identified O
that O
are O
implicated O
in O
1 O
. O
0 O
% O
ropivacaine B
- O
induced O
neurotoxicity O
. O

Temperature O
Dependence O
and O
Energetics O
of O
Single O
Ions O
at O
the O
Aqueous O
Liquid O
- O
Vapor O
Interface O
. O

We O
investigate O
temperature O
- O
dependence O
of O
free O
energetics O
with O
two O
single O
halide B
anions O
, O
I B
- I
and O
Cl B
- I
, O
crossing O
the O
aqueous O
liquid O
- O
vapor O
interface O
through O
molecular O
dynamics O
simulations O
. O

The O
result O
shows O
that O
I B
- I
has O
a O
modest O
surface O
stability O
of O
0 O
. O
5 O
kcal O
/ O
mol O
at O
300 O
K O
and O
the O
stability O
decreases O
as O
the O
temperature O
increases O
, O
indicating O
the O
surface O
adsorption O
process O
for O
the O
anion O
is O
entropically O
disfavored O
. O

In O
contrast O
, O
Cl B
- I
shows O
no O
such O
surface O
state O
at O
all O
temperatures O
. O

Decomposition O
of O
free O
energetics O
reveals O
that O
water O
- O
water O
interactions O
provide O
a O
favorable O
enthalpic O
contribution O
, O
while O
the O
desolvation O
of O
ion O
induces O
an O
increase O
in O
free O
energy O
. O

Calculations O
of O
surface O
fluctuations O
demonstrate O
that O
I B
- I
generates O
significantly O
greater O
interfacial O
fluctuations O
compared O
to O
Cl B
- I
. O

The O
fluctuation O
is O
attributed O
to O
the O
malleability O
of O
the O
solvation O
shells O
, O
which O
allows O
for O
more O
long O
- O
ranged O
perturbations O
and O
solvent O
density O
redistribution O
induced O
by O
I B
- I
as O
the O
anion O
approaches O
the O
liquid O
- O
vapor O
interface O
. O

The O
increase O
in O
temperature O
of O
the O
solvent O
enhances O
the O
inherent O
thermally O
- O
excited O
fluctuations O
and O
consequently O
reduces O
the O
relative O
contribution O
from O
anion O
to O
surface O
fluctuations O
, O
which O
is O
consistent O
with O
the O
decrease O
in O
surface O
- O
stability O
of O
I B
- I
. O

Our O
results O
indicate O
a O
strong O
correlation O
with O
induced O
interfacial O
fluctuations O
and O
anion O
surface O
stability O
; O
moreover O
, O
resulting O
temperature O
dependent O
behavior O
of O
induced O
fluctuations O
suggests O
the O
possibility O
of O
a O
critical O
level O
of O
induced O
fluctuations O
associated O
with O
surface O
stability O
. O

Molecular O
Mechanism O
of O
the O
Inhibition O
of O
EGCG B
on O
the O
Alzheimer O
A O
beta O
1 O
- O
42 O
Dimer O
. O

Growing O
evidence O
supports O
that O
amyloid O
beta O
( O
A O
beta O
) O
oligomers O
are O
the O
major O
causative O
agents O
leading O
to O
neural O
cell O
death O
in O
Alzheimer O
' O
s O
disease O
. O

The O
polyphenol B
( B
- I
) I
- I
epigallocatechin I
gallate I
( O
EGCG B
) O
was O
recently O
reported O
to O
inhibit O
A O
beta O
fibrillization O
and O
redirect O
A O
beta O
aggregation O
into O
unstructured O
, O
off O
- O
pathway O
oligomers O
. O

Given O
the O
experimental O
challenge O
to O
characterize O
the O
structures O
of O
A O
beta O
/ O
EGCG B
complexes O
, O
we O
performed O
extensive O
atomistic O
replica O
exchange O
molecular O
dynamics O
simulations O
of O
A O
beta O
1 O
- O
42 O
dimer O
in O
the O
present O
and O
absence O
of O
EGCG B
in O
explicit O
solvent O
. O

Our O
equilibrium O
A O
beta O
dimeric O
structures O
free O
of O
EGCG B
are O
consistent O
with O
the O
collision O
cross O
section O
from O
ion O
- O
mobility O
mass O
spectrometry O
and O
the O
secondary O
structure O
composition O
from O
circular O
dichroism O
experiment O
. O

In O
the O
presence O
of O
EGCG B
, O
the O
A O
beta O
structures O
are O
characterized O
by O
increased O
inter O
- O
center O
- O
of O
- O
mass O
distances O
, O
reduced O
interchain O
and O
intrachain O
contacts O
, O
reduced O
beta O
- O
sheet O
content O
, O
and O
increased O
coil O
and O
alpha O
- O
helix O
contents O
. O

Analysis O
of O
the O
free O
energy O
surfaces O
reveals O
that O
the O
A O
beta O
dimer O
with O
EGCG B
adopts O
new O
conformations O
, O
affecting O
therefore O
its O
propensity O
to O
adopt O
fibril O
- O
prone O
states O
. O

Overall O
, O
this O
study O
provides O
, O
for O
the O
first O
time O
, O
insights O
on O
the O
equilibrium O
structures O
of O
A O
beta O
1 O
- O
42 O
dimer O
in O
explicit O
aqueous O
solution O
and O
an O
atomic O
picture O
of O
the O
EGCG B
- O
mediated O
conformational O
change O
on O
A O
beta O
dimer O
. O

Lipopolysaccharide O
Interactions O
of O
C B
- O
Terminal O
Peptides O
from O
Human O
Thrombin O
. O

Interactions O
with O
bacterial O
lipopolysaccharide O
( O
LPS O
) O
, O
both O
in O
aqueous O
solution O
and O
in O
lipid O
membranes O
, O
were O
investigated O
for O
a O
series O
of O
amphiphilic O
peptides O
derived O
from O
the O
C B
- O
terminal O
region O
of O
human O
thrombin O
, O
using O
ellipsometry O
, O
dual O
polarization O
interferometry O
, O
fluorescence O
spectroscopy O
, O
circular O
dichroism O
( O
CD O
) O
, O
dynamic O
light O
scattering O
, O
and O
z O
- O
potential O
measurements O
. O

The O
ability O
of O
these O
peptides O
to O
block O
endotoxic O
effects O
caused O
by O
LPS O
, O
monitored O
through O
NO B
production O
in O
macrophages O
, O
was O
compared O
to O
peptide O
binding O
to O
LPS O
and O
its O
endotoxic O
component O
lipid B
A I
, O
and O
to O
size O
, O
charge O
, O
and O
secondary O
structure O
of O
peptide O
/ O
LPS O
complexes O
. O

While O
the O
antiendotoxic O
peptide O
GKY25 B
( O
GKYGFYTHVFRLKKWIQKVI O
) O
displayed O
significant O
binding O
to O
both O
LPS O
and O
lipid O
A O
, O
so O
did O
two O
control O
peptides O
with O
either O
selected O
D B
- I
amino I
acid I
substitutions O
or O
with O
maintained O
composition O
but O
scrambled O
sequence O
, O
both O
displaying O
strongly O
attenuated O
antiendotoxic O
effects O
. O

Hence O
, O
the O
extent O
of O
LPS O
or O
lipid B
A I
binding O
is O
not O
the O
sole O
discriminant O
for O
the O
antiendotoxic O
effect O
of O
these O
peptides O
. O

In O
contrast O
, O
helix O
formation O
in O
peptide O
/ O
LPS O
complexes O
correlates O
to O
the O
antiendotoxic O
effect O
of O
these O
peptides O
and O
is O
potentially O
linked O
to O
this O
functionality O
. O

Preferential O
binding O
to O
LPS O
over O
lipid O
membrane O
was O
furthermore O
demonstrated O
for O
these O
peptides O
and O
preferential O
binding O
to O
the O
lipid B
A I
moiety O
within O
LPS O
inferred O
. O

Structural O
Changes O
in O
Cytochrome O
c O
Oxidase O
Induced O
by O
Binding O
of O
Sodium B
and O
Calcium B
Ions O
: O
An O
ATR O
- O
FTIR O
Study O
. O

Attenuated O
total O
reflection O
Fourier O
transform O
infrared O
( O
ATR O
- O
FTIR O
) O
spectroscopy O
was O
used O
to O
investigate O
the O
binding O
of O
Na B
( I
+ I
) I
and O
Ca B
( I
2 I
+ I
) I
cations O
to O
bovine O
cytochrome O
c O
oxidase O
in O
its O
fully O
oxidized O
and O
partially O
reduced O
, O
cyanide B
- O
ligated O
( O
a B
( I
2 I
+ I
) I
a3 I
( I
3 I
+ I
) I
- O
CN B
) O
( O
mixed O
valence O
) O
forms O
. O

These O
ions O
induced O
distinctly O
different O
IR O
binding O
spectra O
, O
indicating O
that O
the O
induced O
structural O
changes O
are O
different O
. O

Despite O
this O
, O
their O
binding O
spectra O
were O
mutually O
exclusive O
, O
confirming O
their O
known O
competitive O
binding O
behavior O
. O

Dissociation O
constants O
for O
Na B
( I
+ I
) I
and O
Ca B
( I
2 I
+ I
) I
with O
the O
oxidized O
enzyme O
were O
1 O
. O
2 O
mM O
and O
11 O
mu O
M O
, O
respectively O
and O
Na B
( I
+ I
) I
binding O
appeared O
to O
involve O
cooperative O
binding O
of O
two O
Na B
( I
+ I
) I
. O

Ca B
( I
2 I
+ I
) I
binding O
induced O
a O
large O
IR O
spectrum O
, O
with O
prominent O
amide B
I O
/ O
II O
polypeptide O
changes O
, O
bandshifts O
assigned O
to O
carboxylate B
and O
an O
arginine B
, O
and O
a O
number O
of O
bandshifts O
of O
heme B
a O
. O

The O
Na B
( I
+ I
) I
- O
induced O
binding O
spectrum O
showed O
much O
weaker O
amide B
I O
/ O
II O
and O
heme B
a O
changes O
but O
had O
similar O
shifts O
assignable O
to O
carboxylate B
and O
arginine B
residues O
. O

Yeast O
CcO O
also O
displayed O
a O
calcium B
- O
induced O
IR O
and O
UV O
/ O
visible O
binding O
spectra O
, O
though O
of O
lower O
intensities O
. O

This O
was O
attributed O
to O
the O
difficulty O
in O
fully O
depleting O
Ca B
( I
2 I
+ I
) I
from O
its O
binding O
site O
, O
as O
has O
been O
found O
with O
bacterial O
CcOs O
. O

The O
implications O
of O
Ca B
( I
2 I
+ I
) I
/ O
Na B
( I
+ I
) I
ion O
binding O
are O
discussed O
in O
terms O
of O
structure O
and O
possible O
modulation O
of O
core O
catalytic O
function O
. O

NMDA B
receptor O
- O
dependent O
function O
and O
plasticity O
in O
inhibitory O
circuits O
. O

NMDA B
receptors O
have O
been O
known O
to O
play O
a O
central O
role O
in O
long O
- O
term O
potentiation O
at O
glutamatergic O
synapses O
in O
principal O
cells O
for O
thirty O
years O
. O

In O
contrast O
, O
their O
roles O
in O
the O
development O
and O
activity O
- O
dependent O
plasticity O
of O
synapses O
in O
inhibitory O
circuits O
have O
only O
recently O
begun O
to O
be O
understood O
. O

Progress O
has O
, O
to O
a O
great O
extent O
, O
been O
hampered O
by O
the O
extensive O
diversity O
of O
GABAergic O
cell O
types O
in O
the O
CNS O
. O

However O
, O
anatomical O
, O
immunohistochemical O
and O
electrophysiological O
methods O
have O
allowed O
distinct O
types O
to O
be O
identified O
, O
with O
the O
result O
that O
consistent O
patterns O
of O
synaptic O
plasticity O
have O
begun O
to O
emerge O
. O

This O
review O
summarizes O
recent O
evidence O
on O
the O
role O
of O
NMDA B
receptors O
in O
the O
development O
and O
plasticity O
of O
GABAergic O
synapses O
on O
principal O
cells O
and O
of O
glutamatergic O
synapses O
on O
identified O
interneurons O
. O

A O
major O
challenge O
is O
to O
understand O
how O
NMDA B
receptors O
affect O
the O
routing O
of O
information O
in O
healthy O
inhibitory O
circuits O
, O
and O
how O
changes O
in O
NMDA B
receptor O
function O
may O
contribute O
to O
altered O
circuit O
function O
in O
disorders O
such O
as O
schizophrenia O
. O

This O
article O
is O
part O
of O
a O
Special O
Issue O
entitled O
" O
Glutamate B
receptor O
- O
dependent O
synaptic O
plasticity O
" O
. O

Nanocarrier O
systems O
for O
oral O
drug O
delivery O
: O
Do O
we O
really O
need O
them O
? O

In O
particular O
since O
the O
last O
two O
decades O
there O
is O
constantly O
increasing O
interest O
in O
nanocarrier O
systems O
. O

They O
are O
utilized O
in O
order O
to O
overcome O
the O
major O
challenges O
being O
associated O
with O
this O
route O
of O
administration O
- O
namely O
poor O
solubility O
( O
I O
) O
, O
poor O
permeability O
( O
II O
) O
and O
poor O
GI O
- O
stability O
( O
III O
) O
. O

In O
order O
to O
improve O
drug O
solubility O
nanonization O
of O
the O
API O
, O
the O
use O
of O
solid O
lipid O
nanoparticles O
and O
porous O
adsorbent O
particles O
have O
shown O
great O
potential O
. O

Nanocrystals O
and O
selfnanoemulsifying O
drug O
delivery O
systems O
( O
SNEDDS O
) O
resulted O
already O
in O
numerous O
marketed O
drug O
products O
. O

Moreover O
, O
proof O
- O
of O
- O
principle O
studies O
for O
nanocarrier O
systems O
providing O
enhanced O
oral O
drug O
uptake O
are O
available O
. O

By O
providing O
a O
comparatively O
more O
intimate O
contact O
with O
the O
absorption O
membrane O
, O
a O
prolonged O
GI O
- O
residence O
time O
and O
/ O
or O
exhibiting O
permeation O
enhancing O
properties O
, O
oral O
absorption O
can O
be O
strongly O
improved O
. O

Likely O
because O
of O
safety O
considerations O
and O
because O
of O
insufficiently O
high O
bioavailability O
improvements O
( O
< O
5 O
- O
fold O
) O
, O
however O
, O
a O
commercial O
interest O
in O
these O
systems O
is O
limited O
. O

Poor O
GI O
- O
stability O
can O
be O
overcome O
by O
incorporating O
the O
drug O
in O
nanocarrier O
systems O
providing O
a O
protective O
effect O
towards O
an O
enzymatic O
attack O
in O
the O
GI O
- O
tract O
. O

Furthermore O
, O
as O
nanocarrier O
systems O
can O
at O
least O
to O
some O
extent O
diffuse O
into O
the O
mucus O
gel O
layer O
releasing O
their O
payload O
there O
, O
a O
presystemic O
metabolism O
of O
the O
drug O
on O
the O
way O
between O
the O
delivery O
system O
and O
the O
absorption O
membrane O
can O
be O
excluded O
. O

Future O
trends O
are O
mainly O
focusing O
on O
carrier O
systems O
capable O
of O
not O
just O
improving O
solubility O
but O
providing O
also O
controlled O
drug O
release O
as O
well O
as O
on O
nanocarrier O
systems O
capable O
of O
efficiently O
permeating O
the O
mucus O
gel O
layer O
without O
destroying O
it O
. O

Amino B
acids I
as O
co O
- O
amorphous O
stabilizers O
for O
poorly O
water O
soluble O
drugs O
- O
Part O
1 O
: O
Preparation O
, O
stability O
and O
dissolution O
enhancement O
. O

Poor O
aqueous O
solubility O
of O
an O
active O
pharmaceutical O
ingredient O
( O
API O
) O
is O
one O
of O
the O
most O
pressing O
problems O
in O
pharmaceutical O
research O
and O
development O
because O
up O
to O
90 O
% O
of O
new O
API O
candidates O
under O
development O
are O
poorly O
water O
soluble O
. O

These O
drugs O
usually O
have O
a O
low O
and O
variable O
oral O
bioavailability O
, O
and O
therefore O
an O
unsatisfactory O
therapeutic O
effect O
. O

One O
of O
the O
most O
promising O
approaches O
to O
increase O
dissolution O
rate O
and O
solubility O
of O
these O
drugs O
is O
the O
conversion O
of O
a O
crystalline O
form O
of O
the O
drug O
into O
its O
respective O
amorphous O
form O
, O
usually O
by O
incorporation O
into O
hydrophilic O
polymers O
, O
forming O
glass O
solutions O
. O

However O
, O
this O
strategy O
only O
led O
to O
a O
small O
number O
of O
marketed O
products O
usually O
because O
of O
inadequate O
physical O
stability O
of O
the O
drug O
( O
crystallization O
) O
. O

In O
this O
study O
, O
we O
investigated O
a O
fundamentally O
different O
approach O
to O
stabilize O
the O
amorphous O
form O
of O
drugs O
, O
namely O
the O
use O
of O
amino B
acids I
as O
small O
molecular O
weight O
excipients O
that O
form O
specific O
molecular O
interactions O
with O
the O
drug O
resulting O
in O
co O
- O
amorphous O
forms O
. O

The O
two O
poorly O
water O
soluble O
drugs O
carbamazepine B
and O
indomethacin B
were O
combined O
with O
amino B
acids I
from O
the O
binding O
sites O
of O
the O
biological O
receptors O
of O
these O
drugs O
. O

Mixtures O
of O
drug O
and O
the O
amino O
acids O
arginine B
, O
phenylalanine B
, O
tryptophan B
and O
tyrosine B
were O
prepared O
by O
vibrational O
ball O
milling O
. O

Solid O
- O
state O
characterization O
with O
X O
- O
ray O
powder O
diffraction O
( O
XRPD O
) O
and O
differential O
scanning O
calorimetry O
( O
DSC O
) O
revealed O
that O
the O
various O
blends O
could O
be O
prepared O
as O
homogeneous O
, O
single O
phase O
co O
- O
amorphous O
formulations O
indicated O
by O
the O
appearance O
of O
an O
amorphous O
halo O
in O
the O
XRPD O
diffractograms O
and O
a O
single O
glass O
transition O
temperature O
( O
Tg O
) O
in O
the O
DSC O
measurements O
. O

In O
addition O
, O
the O
Tgs O
of O
the O
co O
- O
amorphous O
mixtures O
were O
significantly O
increased O
over O
those O
of O
the O
individual O
drugs O
. O

The O
drugs O
remained O
chemically O
stable O
during O
the O
milling O
process O
and O
the O
co O
- O
amorphous O
formulations O
were O
generally O
physically O
stable O
over O
at O
least O
6months O
at O
40 O
degrees O
C O
under O
dry O
conditions O
. O

The O
dissolution O
rate O
of O
all O
co O
- O
amorphous O
drug O
- O
amino B
acid I
mixtures O
was O
significantly O
increased O
over O
that O
of O
the O
respective O
crystalline O
and O
amorphous O
pure O
drugs O
. O

Amino B
acids I
thus O
appear O
as O
promising O
excipients O
to O
solve O
challenges O
connected O
with O
the O
stability O
and O
dissolution O
of O
amorphous O
drugs O
. O

Dysfunctions O
of O
the O
translational O
machinery O
in O
digestive O
glands O
of O
mussels O
exposed O
to O
mercury B
ions O
. O

Mercury B
is O
an O
element O
naturally O
occurring O
in O
the O
biosphere O
, O
but O
is O
also O
released O
into O
the O
environment O
by O
human O
activities O
, O
such O
as O
mining O
, O
smelting O
, O
and O
industrial O
discharge O
. O

Mercury B
is O
a O
biologically O
harmful O
element O
and O
any O
exposure O
of O
living O
organisms O
mainly O
due O
to O
contamination O
, O
can O
cause O
severe O
or O
even O
lethal O
side O
effects O
. O

In O
every O
form O
detected O
, O
elemental O
, O
inorganic O
, O
or O
organic O
, O
mercury B
exhibits O
toxicity O
associated O
with O
induced O
oxidative O
stress O
. O

Although O
the O
genotoxicity O
of O
mercury B
has O
been O
well O
demonstrated O
in O
mussels O
, O
little O
is O
known O
about O
its O
toxic O
effects O
on O
the O
translational O
machinery O
at O
the O
molecular O
level O
. O

To O
investigate O
possible O
effects O
, O
we O
exposed O
the O
common O
mussel O
Mytilus O
galloprovincialis O
in O
seawater O
supplemented O
by O
30 O
mu O
g O
/ O
L O
Hg B
( I
2 I
+ I
) I
for O
15 O
days O
. O

We O
observed O
that O
Hg B
( I
2 I
+ I
) I
was O
significantly O
accumulated O
in O
the O
digestive O
glands O
of O
mussels O
, O
reaching O
a O
level O
around O
80 O
mu O
g O
/ O
g O
tissue O
( O
dry O
weight O
) O
at O
the O
15th O
day O
of O
exposure O
. O

Exposure O
of O
mussels O
to O
Hg B
( I
2 I
+ I
) I
resulted O
in O
failure O
of O
redox O
homeostasis O
, O
as O
reflected O
on O
lipid O
peroxidation O
levels O
and O
superoxide B
dismutase O
activity O
in O
glands O
, O
and O
micronucleus O
frequency O
in O
gills O
. O

Extracts O
from O
digestive O
glands O
after O
15 O
- O
day O
exposure O
to O
Hg B
( I
2 I
+ I
) I
exhibited O
decreased O
tRNA O
aminoacylation O
ability O
and O
, O
moreover O
, O
a O
70 O
% O
reduction O
in O
the O
ability O
of O
40S O
ribosomal O
subunits O
to O
form O
the O
48S O
initiation O
ribosomal O
complex O
. O

A O
similar O
reduction O
was O
detected O
in O
the O
ability O
of O
ribosomes O
to O
translocate O
peptidyl O
- O
tRNA O
from O
the O
A O
- O
site O
to O
the O
P O
- O
site O
, O
an O
observation O
coinciding O
with O
the O
notion O
that O
regulation O
of O
protein O
synthesis O
by O
Hg B
( I
2 I
+ I
) I
mainly O
occurs O
at O
the O
initiation O
and O
elongation O
stages O
of O
translation O
. O

A O
- O
site O
binding O
, O
peptidyl O
transferase O
activity O
, O
and O
termination O
of O
peptide O
chain O
synthesis O
underwent O
less O
pronounced O
but O
measurable O
reductions O
, O
a O
finding O
which O
explains O
why O
poly B
( I
Phe I
) I
- O
synthesis O
in O
ribosomes O
isolated O
from O
exposed O
mussels O
is O
reduced O
by O
70 O
% O
. O

In O
conclusion O
, O
Hg B
( I
2 I
+ I
) I
apart O
from O
being O
a O
genotoxic O
ion O
acts O
as O
a O
modulator O
of O
protein O
synthesis O
in O
mussels O
, O
an O
observation O
probably O
related O
with O
its O
ability O
to O
induce O
oxidative O
stress O
. O

Analysis O
of O
MC B
- I
LR I
and O
MC B
- I
RR I
in O
tissue O
from O
freshwater O
fish O
( O
Tinca O
tinca O
) O
and O
crayfish O
( O
Procambarus O
clarkii O
) O
in O
tench O
ponds O
( O
C O
a O
ceres O
, O
Spain O
) O
by O
liquid O
chromatography O
- O
mass O
spectrometry O
( O
LC O
- O
MS O
) O
. O

In O
the O
present O
study O
a O
new O
method O
has O
been O
developed O
and O
validated O
for O
detecting O
free O
microcystins B
( O
MCs O
) O
( O
MC B
- I
RR I
, O
MC B
- I
LR I
and O
MC B
- I
YR I
) O
by O
liquid O
chromatography O
- O
mass O
spectrometry O
( O
LC O
- O
MS O
) O
in O
the O
cyprinid O
Tinca O
tinca O
and O
in O
the O
crayfish O
Procambarus O
clarkii O
collected O
from O
three O
ponds O
in O
Extremadura O
( O
Spain O
) O
where O
the O
presence O
of O
the O
cyanobacteria O
species O
Microcystis O
aeruginosa O
and O
Anabaena O
spiroides O
has O
been O
confirmed O

. O

Once O
the O
method O
had O
been O
validated O
, O
free O
MCs O
were O
determined O
in O
fish O
( O
tench O
, O
T O
. O
tinca O
) O
and O
crayfish O
from O
different O
ponds O
in O
order O
to O
understand O
how O
they O
are O
bioaccumulated O
through O
the O
food O
web O
. O

MCs O
were O
not O
detected O
in O
any O
of O
the O
fish O
samples O
analyzed O
. O

It O
was O
confirmed O
that O
P O
. O
clarkii O
accumulated O
MCs O
in O
their O
tissues O
without O
losing O
their O
organoleptic O
characteristics O
, O
with O
MC B
- I
LR I
( O
2 O
. O
3 O
- O
18 O
. O
1 O
mu O
g O
MC B
- I
LR I
/ O
g O
body O
weight O
) O
being O
the O
predominant O
MC O
variant O
detected O
in O
all O
the O
crayfish O
samples O
. O

MC B
- I
RR I
was O
measured O
in O
50 O
% O
of O
the O
samples O
analyzed O
, O
ranging O
between O
1 O
. O
4 O
and O
7 O
. O
8 O
mu O
g O
MC B
- I
RR I
/ O
g O
body O
weight O
and O
no O
MC B
- I
YR I
was O
detected O
. O

The O
results O
indicated O
that O
crayfish O
can O
accumulate O
free O
MCs O
in O
higher O
quantities O
than O
tench O
that O
live O
in O
ponds O
contaminated O
by O
toxic O
cyanobacteria O
species O
, O
and O
emphasized O
the O
need O
for O
regular O
monitoring O
if O
the O
health O
risks O
associated O
with O
their O
consumption O
are O
to O
be O
avoided O
. O

Lead O
, O
mercury B
, O
and O
cadmium B
in O
blood O
and O
their O
relation O
to O
diet O
among O
Swedish O
adults O
. O

The O
aim O
of O
the O
present O
study O
was O
to O
examine O
the O
body O
burden O
of O
lead O
( O
Pb B
) O
, O
mercury B
( O
Hg B
) O
, O
and O
cadmium B
( O
Cd B
) O
in O
blood O
among O
Swedish O
adults O
and O
the O
association O
between O
blood O
levels O
, O
diet O
and O
other O
lifestyle O
factors O
. O

The O
study O
was O
based O
on O
a O
subgroup O
( O
n O
= O
273 O
) O
of O
the O
national O
survey O
Riksmaten O
2010 O
- O
2011 O
( O
4 O
- O
day O
food O
records O
and O
questionnaire O
) O
. O

Lead O
, O
Hg B
, O
and O
Cd B
were O
measured O
in O
whole O
blood O
, O
and O
Cd B
additionally O
in O
urine O
, O
by O
mass O
or O
fluorescence O
spectrometry O
methods O
. O

The O
median O
values O
( O
5 O
- O
95th O
percentiles O
) O
of O
the O
metals O
in O
blood O
were O
as O
follows O
; O
Pb B
: O
13 O
. O
4 O
( O
5 O
. O
8 O
- O
28 O
. O
6 O
) O
mu O
g O
/ O
L O
, O
Hg B
: O
1 O
. O
13 O
( O
0 O
. O
31 O
- O
3 O
. O
45 O
) O
mu O
g O
/ O
L O
, O
and O
Cd B
: O
0 O
. O
19 O
( O
0 O
. O
09 O
- O
1 O
. O
08 O
) O
mu O
g O
/ O
L O
. O

All O
three O
metals O
increased O
with O
increasing O
age O
. O

Lead O
levels O
in O
blood O
were O
positively O
associated O
with O
intakes O
of O
game O
and O
alcohol B
, O
Hg B
was O
related O
to O
fish O
intake O
, O
and O
blood O
Cd B
related O
to O
smoking O
and O
low O
iron B
stores O
and O
to O
a O
low O
meat O
intake O
. O

Body O
burdens O
of O
the O
studied O
metals O
were O
generally O
below O
health O
based O
reference O
values O
, O
but O
several O
individuals O
had O
blood O
Pb B
levels O
above O
the O
reference O
point O
for O
possible O
nephrotoxic O
and O
developmental O
neurotoxic O
effects O
. O

As O
health O
effects O
cannot O
be O
excluded O
, O
individuals O
with O
high O
Pb B
exposure O
should O
aim O
at O
decreasing O
their O
body O
burden O
, O
both O
from O
food O
and O
from O
other O
exposure O
routes O
. O

The O
involvement O
of O
heme B
oxygenase O
1 O
but O
not O
nitric B
oxide I
synthase O
2 O
in O
a O
hepatoprotective O
action O
of O
quercetin B
in O
lipopolysaccharide O
- O
induced O
hepatotoxicity O
of O
d B
- I
galactosamine I
sensitized O
rats O
. O

The O
objective O
of O
this O
study O
was O
to O
evaluate O
potential O
hepatoprotective O
capabilities O
of O
quercetin B
in O
relation O
to O
its O
modulation O
of O
the O
HO O
- O
1 O
and O
NOS O
- O
2 O
activities O
in O
an O
experimental O
model O
of O
fulminant O
liver O
failure O
. O

Liver O
insult O
was O
induced O
by O
in O
vivo O
administration O
of O
d B
- I
galactosamine I
( O
d B
- I
GalN I
, O
400mg O
/ O
kg O
, O
i O
. O
p O
. O
) O
and O
lipopolysaccharide O
( O
LPS O
, O
10 O
mu O
g O
/ O
kg O
, O
i O
. O
p O
. O
) O
. O

The O
effects O
of O
quercetin B
( O
50mg O
/ O
kg O
, O
i O
. O
p O
) O
on O
d B
- I
GalN I
toxicity O
was O
evaluated O
by O
standard O
biochemical O
, O
RT O
- O
PCR O
and O
Western O
blot O
methods O
. O

Administration O
of O
d B
- I
GalN I
/ O
LPS O
combination O
resulted O
in O
significantly O
higher O
plasma O
levels O
of O
aminotransferases O
, O
as O
well O
as O
increased O
mRNA O
and O
protein O
expressions O
of O
both O
HO O
- O
1 O
and O
NOS O
- O
2 O
enzymes O
. O

Quercetin B
exhibited O
cytoprotective O
effects O
on O
the O
liver O
, O
as O
evidenced O
by O
decreased O
aminotransferase O
plasma O
levels O
. O

Additionally O
, O
quercetin B
treatment O
in O
d B
- I
GalN I
/ O
LPS O
treated O
rats O
significantly O
increased O
HO O
- O
1 O
mRNA O
and O
its O
protein O
expressions O
. O

On O
the O
contrary O
, O
quercetin B
did O
not O
exhibit O
any O
significant O
effects O
on O
the O
levels O
of O
nitrites B
, O
and O
NOS O
- O
2 O
mRNA O
and O
protein O
expressions O
in O
d B
- I
GalN I
/ O
LPS O
treated O
rats O
. O

Quercetin B
when O
given O
alone O
did O
not O
have O
any O
significant O
changes O
on O
liver O
enzymes O
nor O
HO O
- O
1 O
and O
NOS O
- O
2 O
mRNA O
and O
protein O
expressions O
. O

It O
can O
be O
concluded O
that O
the O
quercetin B
' O
s O
induction O
of O
HO O
- O
1 O
and O
its O
byproducts O
, O
without O
concomitant O
NOS O
- O
2 O
activity O
reduction O
, O
is O
among O
mechanisms O
contributing O
to O
the O
hepatoprotective O
effect O
in O
d B
- I
GalN I
/ O
LPS O
hepatotoxicity O
. O

Apoptotic O
and O
proinflammatory O
effect O
of O
combustion O
- O
generated O
organic O
nanoparticles O
in O
endothelial O
cells O
. O

Air O
pollution O
exposure O
in O
industrialized O
cities O
is O
associated O
with O
an O
increased O
risk O
of O
morbidity O
and O
mortality O
attributed O
to O
cardiovascular O
diseases O
. O

Combustion O
exhausts O
emitted O
from O
motor O
vehicles O
and O
industries O
represent O
a O
major O
source O
of O
nanoparticles O
in O
the O
atmosphere O
. O

Flame O
- O
generated O
organic O
carbon B
nanoparticles O
( O
OC O
NPs O
) O
provide O
interesting O
model O
nanoparticles O
that O
simulate O
fresh O
combustion O
emissions O
near O
roadways O
or O
combustion O
sources O
. O

These O
model O
nanoparticles O
can O
be O
produced O
by O
controlling O
flame O
operating O
conditions O
and O
used O
to O
test O
possible O
toxicological O
mechanisms O
responsible O
for O
the O
observed O
health O
effects O
. O

OC O
NPs O
were O
used O
to O
investigate O
their O
possible O
effect O
on O
endothelial O
cells O
( O
EC O
) O
growth O
and O
production O
of O
proinflammatory O
lipid O
mediators O
. O

Results O
indicated O
a O
dose O
and O
time O
- O
dependent O
reduction O
in O
cell O
viability O
following O
incubation O
of O
EC O
with O
OC O
NPs O
for O
24 O
and O
48h O
. O

Fluorescence O
- O
activated O
cell O
sorting O
revealed O
that O
EC O
treated O
with O
OC O
NPs O
showed O
a O
cell O
proliferation O
index O
significantly O
lower O
than O
that O
of O
control O
cells O
and O
an O
increased O
apoptotic O
cell O
death O
. O

The O
annexin O
assay O
confirmed O
the O
increased O
apoptotic O
cell O
death O
. O

Moreover O
, O
OC O
NPs O
also O
induced O
a O
time O
- O
dependent O
increase O
of O
proinflammatory O
lysophospholipid B
production O
. O

These O
results O
, O
establishing O
that O
OC O
NPs O
induce O
EC O
proinflammatory O
lysophosholipid B
production O
and O
apoptotic O
cell O
death O
, O
provide O
the O
first O
evidence O
of O
the O
detrimental O
effect O
of O
OC O
NPs O
on O
EC O
. O

Discovery O
of O
adamantane B
based O
highly O
potent O
HDAC O
inhibitors O
. O

Herein O
, O
we O
report O
the O
development O
of O
highly O
potent O
HDAC O
inhibitors O
for O
the O
treatment O
of O
cancer O
. O

A O
series O
of O
adamantane B
and O
nor B
- I
adamantane I
based O
HDAC O
inhibitors O
were O
designed O
, O
synthesized O
and O
screened O
for O
the O
inhibitory O
activity O
of O
HDAC O
. O

A O
number O
of O
compounds O
exhibited O
GI50 O
of O
10 O
- O
100 O
nM O
in O
human O
HCT116 O
, O
NCI O
- O
H460 O
and O
U251 O
cancer O
cells O
, O
in O
vitro O
. O

Compound O
32 O
displays O
efficacy O
in O
human O
tumour O
animal O
xenograft O
model O
. O

EZETIMIBE B
INCREASES O
HEPATIC O
IRON B
LEVELS O
IN O
MICE O
FED O
A O
HIGH O
- O
FAT O
DIET O
. O

Accumulating O
evidence O
suggests O
that O
ezetimibe B
may O
be O
a O
promising O
agent O
for O
treatment O
of O
non O
- O
alcoholic O
fatty O
liver O
disease O
and O
steatohepatitis O
( O
NAFLD O
/ O
NASH O
) O
. O

Phlebotomy O
and O
dietary O
iron B
restriction O
reduces O
serum O
transaminase O
in O
NAFLD O
/ O
NASH O
patients O
. O

Recent O
studies O
showed O
that O
mutual O
effects O
exist O
between O
lipid O
metabolism O
and O
iron B
metabolism O
. O

Accordingly O
, O
the O
effects O
of O
ezetimibe B
on O
iron B
metabolism O
were O
examined O
in O
mice O
fed O
a O
high O
- O
fat O
diet O
with O
or O
without O
iron B
. O

C57BL O
/ O
6 O
mice O
were O
fed O
the O
following O
diets O
for O
12 O
weeks O
. O

Experiment O
1 O
: O
1 O
) O
a O
control O
diet O
; O
C O
2 O
) O
C O
plus O
ezetimibe B
( O
0 O
. O
3mg O
/ O
day O
; O
4 O
weeks O
) O
; O
CE O
3 O
) O
a O
high O
- O
fat O
diet O
; O
H O
4 O
) O
H O
plus O
ezetimibe B
; O
HE O
. O

Experiment O
2 O
: O
1 O
) O
C O
containing O
carbonyl B
iron I
( O
average O
; O
22 O
. O
4mg O
/ O
day O
; O
6 O
weeks O
) O
; O
CI O
2 O
) O
CI O
plus O
ezetimibe B
; O
CIE O
3 O
) O
H O
containing O
carbonyl B
iron I
; O
HI O
4 O
) O
HI O
plus O
ezetimibe B
; O
HIE O
. O

Blood O
, O
livers O
, O
and O
duodenum O
were O
removed O
after O
12 O
weeks O
. O

In O
Experiment O
1 O
, O
hepatic O
iron B
levels O
were O
higher O
in O
HE O
than O
H O
, O
whereas O
there O
was O
no O
difference O
between O
C O
and O
CE O
. O

Hepatic O
mRNA O
expression O
of O
transferrin O
receptor O
1 O
and O
2 O
, O
ferritins O
, O
and O
hepcidin O
were O
increased O
more O
in O
CE O
than O
C O
, O
and O
in O
HE O
than O
H O
. O

In O
duodenum O
, O
DMT1 O
, O
ferritinH O
, O
and O
hephaestin O
mRNA O
levels O
were O
increased O
in O
CE O
compared O
to O
C O
. O

In O
Experiment O
2 O
, O
hepatic O
iron B
concentrations O
were O
higher O
in O
HIE O
than O
HI O
. O

Hepatic O
mRNA O
expression O
of O
ferritinL O
and O
hepcidin O
were O
increased O
in O
HIE O
compared O
to O
HI O
. O

In O
duodenum O
, O
ferritinL O
mRNA O
was O
increased O
in O
HIE O
compared O
to O
CIE O
. O

Ezetimibe B
induced O
hepatic O
iron B
uptake O
transporter O
expression O
in O
mice O
fed O
a O
high O
- O
fat O
diet O
, O
causing O
increased O
hepatic O
iron B
concentrations O
. O

Astaxanthin B
Suppresses O
MPP B
+ I
- O
Induced O
Oxidative O
Damage O
in O
PC12 O
Cells O
through O
a O
Sp1 O
/ O
NR1 O
Signaling O
Pathway O
. O

Objective O
: O
To O
investigate O
astaxanthin B
( O
ATX B
) O
neuroprotection O
, O
and O
its O
mechanism O
, O
on O
a O
1 B
- I
methyl I
- I
4 I
- I
phenyl I
- I
pyridine I
ion O
( O
MPP B
+ I
) O
- O
induced O
cell O
model O
of O
Parkinson O
' O
s O
disease O
. O

Methods O
: O
Mature O
, O
differentiated O
PC12 O
cells O
treated O
with O
MPP B
+ I
were O
used O
as O
an O
in O
vitro O
cell O
model O
. O

The O
MTT B
assay O
was O
used O
to O
investigate O
cell O
viability O
after O
ATX B
treatment O
, O
and O
western O
blot O
analysis O
was O
used O
to O
observe O
Sp1 O
( O
activated O
transcription O
factor O
1 O
) O
and O
NR1 O
( O
NMDA B
receptor O
subunit O
1 O
) O
protein O
expression O
, O
real O
- O
time O
PCR O
was O
used O
to O
monitor O
Sp1 O
and O
NR1 O
mRNA O
, O
and O
cell O
immunofluorescence O
was O
used O
to O
determine O
the O
location O
of O
Sp1 O
and O
NR1 O
protein O
and O
the O
nuclear O
translocation O
of O
Sp1 O
. O

Results O
: O
PC12 O
cell O
viability O
was O
significantly O
reduced O
by O
MPP B
+ I
treatment O
. O

The O
expression O
of O
Sp1 O
and O
NR1 O
mRNA O
and O
protein O
were O
increased O
compared O
with O
the O
control O
( O
p O
< O
0 O
. O
01 O
) O
. O

Following O
co O
- O
treatment O
with O
ATX B
and O
MPP B
+ I
, O
cell O
viability O
was O
significantly O
increased O
, O
and O
Sp1 O
and O
NR1 O
mRNA O
and O
protein O
were O
decreased O
, O
compared O
with O
the O
MPP B
+ I
groups O
( O
p O
< O
0 O
. O
01 O
) O
. O

In O
addition O
, O
mithracycin B
A I
protected O
PC12 O
cells O
from O
oxidative O
stress O
caused O
by O
MPP B
+ I
by O
specifically O
inhibiting O
the O
expression O
of O
Sp1 O
. O

Moreover O
, O
cell O
immunofluorescence O
revealed O
that O
ATX O
could O
suppress O
Sp1 O
nuclear O
transfer O
. O

Conclusion O
: O
ATX B
inhibited O
oxidative O
stress O
induced O
by O
MPP B
+ I
in O
PC12 O
cells O
, O
via O
the O
SP1 O
/ O
NR1 O
signaling O
pathway O
. O

p38 O
Mitogen O
Activated O
Protein O
Kinase O
Regulates O
the O
Nuclear O
Receptor O
CAR O
to O
Activate O
the O
CYP2B6 O
Gene O
. O

The O
constitutive O
active O
/ O
androstane B
receptor O
( O
CAR O
) O
regulates O
hepatic O
drug O
metabolism O
by O
activating O
genes O
such O
as O
cytochrome O
P450 O
( O
CYP O
) O
and O
certain O
transferases O
. O

p38 O
mitogen O
activated O
protein O
kinase O
( O
MAPK O
) O
is O
highly O
activated O
in O
human O
primary O
hepatocytes O
but O
barely O
in O
human O
hepatoma O
cell O
- O
lines O
including O
HepG2 O
cells O
. O

Liganded O
- O
CAR O
induced O
CYP2B6 O
mRNA O
in O
human O
primary O
hepatocytes O
far O
more O
effectively O
than O
in O
HepG2 O
cells O
ectopically O
expressing O
CAR O
. O

Here O
, O
we O
have O
now O
found O
that O
activation O
of O
p38 O
MAPK O
by O
anisomycin B
potentiated O
induction O
of O
CYP2B6 O
mRNA O
by O
CAR O
ligand O
in O
HepG2 O
cells O
to O
levels O
observed O
in O
ligand O
- O
treated O
human O
primary O
hepatocytes O
. O

siRNA O
knockdown O
of O
p38 O
MAPK O
abrogated O
the O
ability O
of O
anisomycin B
to O
synergistically O
induce O
CYP2B6 O
mRNA O
. O

In O
addition O
to O
CYP2B6 O
, O
anisomycin B
co O
- O
treatment O
potentiated O
an O
increase O
in O
CYP2A7 O
and O
CYP2C9 O
mRNAs O
but O
not O
CYP3A4 O
or O
UDP B
- O
glucuronosyltransfer O
1A1 O
mRNAs O
. O

Thus O
, O
activated O
p38 O
MAPK O
is O
required O
for O
liganded O
- O
CAR O
to O
selectively O
activate O
a O
set O
of O
genes O
that O
encode O
drug O
metabolizing O
enzymes O
. O

Our O
present O
results O
suggest O
that O
CAR O
- O
mediated O
induction O
of O
these O
enzymes O
can O
not O
be O
understood O
by O
ligand O
binding O
alone O
because O
the O
specificity O
and O
magnitude O
of O
induction O
are O
co O
- O
determined O
by O
a O
given O
cell O
signaling O
such O
as O
p38 O
MAPK O
; O
both O
physiological O
and O
pathophysiological O
states O
of O
cell O
signaling O
may O
have O
a O
strong O
impact O
in O
hepatic O
drug O
metabolizing O
capability O
during O
therapeutic O
treatments O
. O

Insulin O
- O
like O
Factor O
3 O
promotes O
wound O
healing O
at O
the O
ocular O
surface O
. O

Tear O
fluid O
is O
known O
to O
contain O
many O
different O
hormones O
with O
relevance O
for O
ocular O
surface O
homeostasis O
. O

We O
studied O
the O
presence O
and O
functional O
role O
of O
insulin O
- O
like O
factor O
3 O
( O
INSL3 O
) O
and O
its O
cognate O
receptor O
RXFP2 O
at O
the O
ocular O
surface O
and O
in O
tears O
. O

Expression O
of O
human O
INSL3 O
and O
RXFP2 O
was O
determined O
in O
tissues O
of O
the O
ocular O
surface O
, O
lacrimal O
apparatus O
, O
in O
human O
corneal O
( O
HCE O
) O
, O
conjunctival O
( O
HCjE O
) O
, O
sebaceous O
( O
SC O
) O
epithelial O
cell O
lines O
and O
in O
human O
tears O
by O
RT O
- O
PCR O
and O
ELISA O
. O

We O
investigated O
effects O
of O
human O
recombinant O
( O
hr O
) O
INSL3 O
on O
cell O
proliferation O
and O
cell O
migration O
and O
the O
influence O
of O
hrINSL3 O
on O
the O
expression O
of O
MMP2 O
, O
- O
9 O
, O
- O
13 O
and O
TIMP1 O
and O
- O
2 O
was O
quantified O
by O
real O
- O
time O
PCR O
and O
ELISA O
in O
HCE O
, O
HCjE O
and O
SC O
cells O
. O

We O
used O
a O
C57BL O
/ O
6 O
mouse O
corneal O
defect O
model O
to O
elucidate O
the O
effect O
of O
topical O
application O
of O
hrINSL3 O
on O
corneal O
wound O
healing O
. O

INSL3 O
and O
RXFP2 O
transcripts O
and O
INSL3 O
protein O
were O
detected O
in O
all O
tissues O
and O
cell O
lines O
investigated O
. O

Significantly O
higher O
concentrations O
of O
INSL3 O
were O
detected O
in O
tears O
from O
male O
vs O
. O
female O
volunteers O
. O

Stimulation O
of O
HCE O
, O
HCjE O
and O
SC O
with O
hrINSL3 O
significantly O
increased O
cell O
proliferation O
in O
HCjE O
and O
SC O
and O
migration O
of O
HCjE O
. O

Treatment O
with O
hrINSL3 O
for O
24 O
h O
regulated O
MMP2 O
, O
TIMP1 O
and O
TIMP2 O
expression O
. O

The O
local O
application O
of O
hrINSL3 O
onto O
denuded O
corneal O
surface O
resulted O
in O
significantly O
accelerated O
corneal O
wound O
healing O
in O
mice O
. O

These O
findings O
suggest O
a O
novel O
and O
gender O
specific O
role O
for O
INSL3 O
and O
cognate O
receptor O
RXFP2 O
signaling O
in O
ocular O
surface O
homeostasis O
and O
determined O
a O
novel O
role O
for O
hrINSL3 O
in O
corneal O
wound O
healing O
. O

Amphetamine B
, O
past O
and O
present O
- O
a O
pharmacological O
and O
clinical O
perspective O
. O

Amphetamine B
was O
discovered O
over O
100 O
years O
ago O
. O

Since O
then O
, O
it O
has O
transformed O
from O
a O
drug O
that O
was O
freely O
available O
without O
prescription O
as O
a O
panacea O
for O
a O
broad O
range O
of O
disorders O
into O
a O
highly O
restricted O
Controlled O
Drug O
with O
therapeutic O
applications O
restricted O
to O
attention O
deficit O
hyperactivity O
disorder O
( O
ADHD O
) O
and O
narcolepsy O
. O

This O
review O
describes O
the O
relationship O
between O
chemical O
structure O
and O
pharmacology O
of O
amphetamine B
and O
its O
congeners O
. O

Amphetamine B
' O
s O
diverse O
pharmacological O
actions O
translate O
not O
only O
into O
therapeutic O
efficacy O
, O
but O
also O
into O
the O
production O
of O
adverse O
events O
and O
liability O
for O
recreational O
abuse O
. O

Accordingly O
, O
the O
balance O
of O
benefit O
/ O
risk O
is O
the O
key O
challenge O
for O
its O
clinical O
use O
. O

The O
review O
charts O
advances O
in O
pharmaceutical O
development O
from O
the O
introduction O
of O
once O
- O
daily O
formulations O
of O
amphetamine B
through O
to O
lisdexamfetamine B
, O
which O
is O
the O
first O
d B
- I
amphetamine I
prodrug O
approved O
for O
the O
management O
of O
ADHD O
in O
children O
, O
adolescents O
and O
adults O
. O

The O
unusual O
metabolic O
route O
for O
lisdexamfetamine B
to O
deliver O
d B
- I
amphetamine I
makes O
an O
important O
contribution O
to O
its O
pharmacology O
. O

How O
lisdexamfetamine B
' O
s O
distinctive O
pharmacokinetic O
/ O
pharmacodynamic O
profile O
translates O
into O
sustained O
efficacy O
as O
a O
treatment O
for O
ADHD O
and O
its O
reduced O
potential O
for O
recreational O
abuse O
is O
also O
discussed O
. O

Strategic O
use O
of O
conformational O
bias O
and O
structure O
based O
design O
to O
identify O
potent O
JAK3 O
inhibitors O
with O
improved O
selectivity O
against O
the O
JAK O
family O
and O
the O
kinome O
. O

Using O
a O
structure O
based O
design O
approach O
we O
have O
identified O
a O
series O
of O
indazole B
substituted O
pyrrolopyrazines B
, O
which O
are O
potent O
inhibitors O
of O
JAK3 O
. O

Intramolecular O
electronic O
repulsion O
was O
used O
as O
a O
strategy O
to O
induce O
a O
strong O
conformational O
bias O
within O
the O
ligand O
. O

Compounds O
bearing O
this O
conformation O
participated O
in O
a O
favorable O
hydrophobic O
interaction O
with O
a O
cysteine B
residue O
in O
the O
JAK3 O
binding O
pocket O
, O
which O
imparted O
high O
selectivity O
versus O
the O
kinome O
and O
improved O
selectivity O
within O
the O
JAK O
family O
. O

Copper B
- O
catalyzed O
diastereoselective O
arylation O
of O
tryptophan B
derivatives O
: O
total O
synthesis O
of O
( B
+ I
) I
- I
naseseazines I
a I
and I
B I
. O

A O
copper B
- O
catalyzed O
arylation O
of O
tryptophan B
derivatives O
is O
reported O
. O

The O
reaction O
proceeds O
with O
high O
site O
- O
and O
diastereoselectivity O
to O
provide O
aryl B
pyrroloindoline I
products O
in O
one O
step O
from O
simple O
starting O
materials O
. O

The O
utility O
of O
this O
transformation O
is O
highlighted O
in O
the O
five O
- O
step O
syntheses O
of O
the O
natural O
products O
( B
+ I
) I
- I
naseseazine I
A I
and I
B I
. O

Surface O
Engineering O
of O
Ultrafine O
Cellulose O
Nanofibrils O
toward O
Polymer O
Nanocomposite O
Materials O
. O

Surface O
grafting O
of O
crystalline O
and O
ultrafine O
cellulose O
nanofibrils O
with O
poly B
( I
ethylene I
glycol I
) I
( O
PEG B
) O
chains O
via O
ionic O
bonds O
was O
achieved O
by O
a O
simple O
ion O
- O
exchange O
treatment O
. O

The O
PEG B
- O
grafted O
cellulose O
nanofibrils O
exhibited O
nanodispersibility O
in O
organic O
solvents O
such O
as O
chloroform B
, O
toluene B
, O
and O
tetrahydrofuran B
. O

Then O
, O
the O
PEG B
- O
grafted O
cellulose O
nanofibril O
/ O
chloroform B
dispersion O
and O
poly B
( I
l I
- I
lactide I
) I
( O
PLLA B
) O
/ O
chloroform B
solution O
were O
mixed O
, O
and O
the O
PEG B
- O
grafted O
cellulose O
nanofibril O
/ O
PLLA B
composite O
films O
with O
various O
blend O
ratios O
were O
prepared O
by O
casting O
the O
mixtures O
on O
a O
plate O
and O
drying O
. O

The O
tensile O
strength O
, O
Young O
' O
s O
modulus O
, O
and O
work O
of O
fracture O
of O
the O
composite O
films O
were O
remarkably O
improved O
, O
despite O
low O
cellulose O
addition O
levels O
( O
< O
1 O
wt O
% O
) O
. O

The O
highly O
efficient O
nanocomposite O
effect O
was O
explained O
in O
terms O
of O
achievement O
of O
nanodispersion O
states O
of O
the O
PEG B
- O
grafted O
cellulose O
nanofibrils O
in O
the O
PLLA B
matrix O
. O

Moreover O
, O
some O
attractive O
interactions O
mediated O
by O
the O
PEG B
chains O
were O
likely O
to O
be O
formed O
between O
the O
cellulose O
nanofibrils O
and O
PLLA B
molecules O
in O
the O
composites O
, O
additionally O
enhancing O
the O
efficient O
nanocomposite O
effect O
. O

Small O
Molecule O
Regulation O
of O
Protein O
Conformation O
by O
Binding O
in O
the O
Flap O
of O
HIV O
Protease O
. O

The O
fragment O
indole B
- I
6 I
- I
carboxylic I
acid I
( O
1F1 O
) O
, O
previously O
identified O
as O
a O
flap O
site O
binder O
in O
a O
fragment O
- O
based O
screen O
against O
HIV O
protease O
( O
PR O
) O
, O
has O
been O
cocrystallized O
with O
pepstatin B
- O
inhibited O
PR O
and O
with O
apo O
- O
PR O
. O

Another O
fragment O
, O
3 B
- I
indolepropionic I
acid I
( O
1F1 O
- O
N O
) O
, O
predicted O
by O
AutoDock O
calculations O
and O
confirmed O
in O
a O
novel O
inhibition O
of O
nucleation O
crystallization O
assay O
, O
exploits O
the O
same O
interactions O
in O
the O
flap O
site O
in O
two O
crystal O
structures O
. O

Both O
1F1 O
and O
1F1 O
- O
N O
bind O
to O
the O
closed O
form O
of O
apo O
- O
PR O
and O
to O
pepstatin O
: O
PR O
. O

In O
solution O
, O
1F1 O
and O
1F1 O
- O
N O
raise O
the O
Tm O
of O
apo O
- O
PR O
by O
3 O
. O
5 O
- O
5 O
degrees O
C O
as O
assayed O
by O
differential O
scanning O
fluorimetry O
( O
DSF O
) O
and O
show O
equivalent O
low O
- O
micromolar O
binding O
constants O
to O
both O
apo O
- O
PR O
and O
pepstatin O
: O
PR O
, O
assayed O
by O
backscattering O
interferometry O
( O
BSI O
) O
. O

The O
observed O
signal O
intensities O
in O
BSI O
are O
greater O
for O
each O
fragment O
upon O
binding O
to O
apo O
- O
PR O
than O
to O
pepstatin B
- O
bound O
PR O
, O
consistent O
with O
greater O
conformational O
change O
in O
the O
former O
binding O
event O
. O

Together O
, O
these O
data O
indicate O
that O
fragment O
binding O
in O
the O
flap O
site O
favors O
a O
closed O
conformation O
of O
HIV O
PR O
. O

Improving O
the O
Catalytic O
Activity O
of O
Semiconductor O
Nanocrystals O
through O
Selective O
Domain O
Etching O
. O

Colloidal O
chemistry O
offers O
an O
assortment O
of O
synthetic O
tools O
for O
tuning O
the O
shape O
of O
semiconductor O
nanocrystals O
. O

While O
many O
nanocrystal O
architectures O
can O
be O
obtained O
directly O
via O
colloidal O
growth O
, O
other O
nanoparticle O
morphologies O
require O
alternative O
processing O
strategies O
. O

Here O
, O
we O
show O
that O
chemical O
etching O
of O
colloidal O
nanoparticles O
can O
facilitate O
the O
realization O
of O
nanocrystal O
shapes O
that O
are O
topologically O
inaccessible O
by O
hot O
- O
injection O
techniques O
alone O
. O

The O
present O
methodology O
is O
demonstrated O
by O
synthesizing O
a O
two O
- O
component O
CdSe B
/ O
CdS B
nanoparticle O
dimer O
, O
constructed O
in O
a O
way O
that O
both O
CdSe B
and O
CdS B
semiconductor O
domains O
are O
exposed O
to O
the O
external O
environment O
. O

This O
structural O
morphology O
is O
highly O
desirable O
for O
catalytic O
applications O
as O
it O
enables O
both O
reductive O
and O
oxidative O
reactions O
to O
occur O
simultaneously O
on O
dissimilar O
nanoparticle O
surfaces O
. O

Hydrogen B
production O
tests O
confirmed O
the O
improved O
catalytic O
activity O
of O
CdSe B
/ O
CdS B
dimers O
, O
which O
was O
enhanced O
3 O
- O
4 O
times O
upon O
etching O
treatment O
. O

We O
expect O
that O
the O
demonstrated O
application O
of O
etching O
to O
shaping O
of O
colloidal O
heteronanocrystals O
can O
become O
a O
common O
methodology O
in O
the O
synthesis O
of O
charge O
- O
separating O
nanocrystals O
, O
leading O
to O
advanced O
nanoparticles O
architectures O
for O
applications O
in O
areas O
of O
photocatalysis O
, O
photovoltaics O
, O
and O
light O
detection O
. O

Synergistic O
effects O
of O
diosmetin B
with O
erythromycin B
against O
ABC O
transporter O
over O
- O
expressed O
methicillin B
- O
resistant O
Staphylococcus O
aureus O
( O
MRSA O
) O
RN4220 O
/ O
pUL5054 O
and O
inhibition O
of O
MRSA O
pyruvate B
kinase O
. O

Increasing O
prevalence O
of O
methicillin B
- O
resistant O
Staphylococcus O
aureus O
( O
MRSA O
) O
worldwide O
with O
limited O
therapeutic O
options O
is O
a O
growing O
public O
health O
concern O
. O

Natural O
products O
have O
been O
shown O
to O
possess O
antibacterial O
actions O
against O
MRSA O
. O

Flavonoids B
from O
natural O
products O
have O
been O
shown O
to O
possess O
antibacterial O
actions O
against O
MRSA O
by O
antagonizing O
its O
resistance O
mechanisms O
. O

Diosmin B
and O
diosmetin B
are O
natural O
flavonoids B
found O
in O
a O
variety O
of O
citrus O
fruits O
. O

The O
aim O
of O
this O
study O
was O
to O
investigate O
whether O
diosmin B
and O
diosmetin B
could O
inhibit O
the O
growth O
of O
MRSA O
and O
the O
in O
vitro O
enzymatic O
activity O
of O
a O
newly O
discovered O
MRSA O
drug O
target O
, O
pyruvate B
kinase O
( O
PK O
) O
. O

By O
using O
a O
panel O
of O
MRSA O
strains O
with O
known O
resistant O
mechanisms O
, O
neither O
diosmin B
nor O
diosmetin B
was O
shown O
to O
possess O
direct O
antibacterial O
activities O
against O
all O
tested O
MRSA O
strains O
. O

However O
, O
in O
checkerboard O
assay O
, O
we O
found O
that O
diosmetin B
together O
with O
erythromycin B
, O
could O
synergistically O
inhibit O
the O
growth O
of O
ABC O
- O
pump O
overexpressed O
MRSA O
- O
RN4220 O
/ O
pUL5054 O
, O
and O
time O
kill O
assay O
also O
showed O
that O
the O
antibacterial O
activities O
of O
diosmetin B
with O
erythromycin B
were O
bactericidal O
. O

Diosmetin B
was O
further O
shown O
to O
significantly O
suppress O
the O
MRSA O
PK O
activities O
in O
a O
dose O
dependent O
manner O
. O

In O
conclusion O
, O
the O
inhibition O
of O
MRSA O
PK O
by O
diosmetin B
could O
lead O
to O
a O
deficiency O
of O
ATP B
and O
affect O
the O
bacterial O
efflux O
pump O
which O
might O
contribute O
to O
the O
antibacterial O
actions O
of O
diosmetin B
against O
MRSA O
. O

Endothelin O
- O
3 O
Expression O
in O
the O
Subfornical O
Organ O
Enhances O
the O
Sensitivity O
of O
Nax O
, O
the O
Brain O
Sodium B
- O
Level O
Sensor O
, O
to O
Suppress O
Salt O
Intake O
. O

Salt O
homeostasis O
is O
essential O
to O
survival O
, O
but O
brain O
mechanisms O
for O
salt O
- O
intake O
control O
have O
not O
been O
fully O
elucidated O
. O

Here O
, O
we O
found O
that O
the O
sensitivity O
of O
Nax O
channels O
to O
[ O
Na B
( I
+ I
) I
] I
o O
is O
dose O
- O
dependently O
enhanced O
by O
endothelin O
- O
3 O
( O
ET O
- O
3 O
) O
. O

Nax O
channels O
began O
to O
open O
when O
[ O
Na B
( I
+ I
) I
] O
o O
exceeded O
~ O
150 O
mM O
without O
ET O
- I
3 I
, O
but O
opened O
fully O
at O
a O
physiological O
[ O
Na B
( I
+ I
) I
] O
o O
( O
135 O
- O
145 O
mM O
) O
with O
1 O
nM O
ET B
- I
3 I
. O

Importantly O
, O
ET O
- O
3 O
was O
expressed O
in O
the O
subfornical O
organ O
( O
SFO O
) O
along O
with O
Nax O
, O
and O
the O
level O
was O
robustly O
increased O
by O
dehydration O
. O

Pharmacological O
experiments O
revealed O
that O
endothelin O
receptor O
B O
( O
ETBR O
) O
signaling O
is O
involved O
in O
this O
modulation O
of O
Nax O
gating O
through O
protein O
kinase O
C O
and O
ERK1 O
/ O
2 O
activation O
. O
ETBR O
agonists O
increased O
the O
firing O
rate O
of O
GABAergic O
neurons O
via O
lactate B
in O
the O
SFO O
, O
and O
an O
ETBR O
antagonist O
attenuated O
salt O
aversion O
during O
dehydration O
. O

These O
results O
indicate O
that O
ET O
- O
3 O
expression O
in O
the O
SFO O
is O
tightly O
coupled O
with O
body O
- O
fluid O
homeostasis O
through O
modulation O
of O
the O
[ B
Na I
( I
+ I
) I
] I
o I
sensitivity O
of O
Nax O
. O

Pharmacological O
study O
of O
a O
new O
Asp49 O
phospholipase O
A2 O
( O
Bbil O
- O
TX O
) O
isolated O
from O
Bothriopsis O
bilineata O
smargadina O
( O
forest O
viper O
) O
venom O
in O
vertebrate O
neuromuscular O
preparations O
. O

The O
neuromuscular O
activity O
of O
Bbil O
- O
TX O
, O
a O
PLA2 O
with O
catalytic O
activity O
isolated O
from O
Bothriopsis O
bilineata O
smargadina O
venom O
, O
was O
examined O
in O
chick O
biventer O
cervicis O
( O
BC O
) O
and O
mouse O
phrenic O
nerve O
- O
diaphragm O
( O
PND O
) O
preparations O
. O

In O
BC O
preparations O
, O
Bbil B
- I
TX I
( O
0 O
. O
5 O
- O
10 O
mu O
g O
/ O
ml O
) O
caused O
time O
- O
and O
concentration O
- O
dependent O
blockade O
that O
was O
not O
reversed O
by O
washing O
; O
the O
times O
for O
50 O
% O
blockade O
were O
87 O
+ O
/ O
- O
7 O
, O
41 O
+ O
/ O
- O
7 O
and O
19 O
+ O
/ O
- O
2 O
min O
( O
mean O
+ O
/ O
- O
SEM O
; O
n O
= O
4 O
- O
6 O
) O
for O
1 O
, O
5 O
and O
10 O
mu O
g O
/ O
ml O
, O
respectively O
. O

Muscle O
contractures O
to O
exogenous O
ACh B
and O
KCl B
were O
unaffected O
. O

The O
toxin O
( O
10 O
mu O
g O
/ O
ml O
) O
also O
did O
not O
affect O
the O
twitch O
- O
tension O
of O
directly O
- O
stimulated O
, O
curarized O
( O
10 O
mu O
g O
/ O
ml O
) O
BC O
preparations O
. O

However O
, O
Bbil O
- O
TX O
( O
10 O
mu O
g O
/ O
ml O
) O
produced O
mild O
morphological O
alterations O
( O
edematous O
and O
/ O
or O
hyperchromic O
fibers O
) O
in O
BC O
; O
there O
was O
also O
a O
progressive O
release O
of O
CK O
( O
from O
116 O
+ O
/ O
- O
17 O
IU O
/ O
ml O
( O
basal O
) O
to O
710 O
+ O
/ O
- O
91 O
IU O
/ O
ml O
after O
45 O
min O
) O
. O

Bbil O
- O
TX O
( O
5 O
mu O
g O
/ O
ml O
) O
- O
induced O
blockade O
was O
markedly O
inhibited O
at O
22 O
- O
24 O
degrees O
C O
and O
pretreatment O
with O
p B
- I
bromophenacyl I
bromide I
( O
p B
- I
BPB I
) O
abolished O
the O
neuromuscular O
blockade O
. O

Bbil O
- O
TX O
( O
3 O
- O
30 O
mu O
g O
/ O
ml O
, O
n O
= O
4 O
- O
6 O
) O
caused O
partial O
time O
- O
and O
concentration O
- O
dependent O
blockade O
in O
PND O
preparations O
( O
52 O
+ O
/ O
- O
2 O
% O
at O
the O
highest O
concentration O
) O
. O

Bbil O
- O
TX O
( O
30 O
mu O
g O
/ O
ml O
) O
also O
markedly O
reduced O
the O
MEPPs O
frequency O
[ O
from O
26 O
+ O
/ O
- O
2 O
. O
5 O
( O
basal O
) O
to O
10 O
+ O
/ O
- O
1 O
after O
60 O
min O
; O
n O
= O
5 O
; O
p O
< O
0 O
. O
05 O
] O
and O
the O
quantal O
content O
[ O
from O
94 O
+ O
/ O
- O
14 O
( O
basal O
) O
to O
24 O
+ O
/ O
- O
3 O
after O
60 O
min O
; O
n O
= O
5 O
; O
p O
< O
0 O
. O
05 O
] O
of O
PND O
preparations O
, O
but O
caused O
only O
minor O
depolarization O
of O
the O
membrane O
resting O
potential O
[ O
from O
- O
80 O
+ O
/ O
- O
1 O
mV O
( O
basal O
) O
to O
- O
66 O
+ O
/ O

- O
2 O
mV O
after O
120 O
min O
; O
n O
= O
5 O
; O
p O
< O
0 O
. O
05 O
] O
, O
with O
no O
significant O
change O
in O
the O
depolarizing O
response O
to O
exogenous O
carbachol B
. O

These O
results O
show O
that O
Bbil O
- O
TX O
is O
a O
presynaptic O
PLA2 O
that O
contributes O
to O
the O
neuromuscular O
blockade O
caused O
by O
B O
. O

b O
. O
smargadina O
venom O
. O

Selenium B
and O
mercury B
molar O
ratios O
in O
commercial O
fish O
from O
New O
Jersey O
and O
Illinois O
: O
Variation O
within O
species O
and O
relevance O
to O
risk O
communication O
. O

There O
is O
an O
emerging O
consensus O
that O
people O
consuming O
large O
amounts O
of O
fish O
with O
selenium B
: O
mercury B
ratios O
below O
1 O
are O
at O
higher O
risk O
from O
mercury B
toxicity O
. O

As O
the O
relative O
amount O
of O
selenium B
increases O
compared O
to O
mercury B
, O
risk O
may O
be O
lowered O
, O
but O
it O
is O
unclear O
how O
much O
excess O
selenium B
is O
required O
. O

It O
would O
be O
useful O
if O
the O
selenium B
: O
mercury B
ratio O
was O
relatively O
consistent O
within O
a O
species O
, O
but O
this O
has O
not O
been O
the O
case O
in O
our O
studies O
of O
wild O
- O
caught O
fish O
. O

Since O
most O
people O
in O
developed O
countries O
and O
urban O
areas O
obtain O
their O
fish O
and O
other O
seafood O
commercially O
, O
we O
examined O
selenium B
: O
mercury B
molar O
ratios O
in O
commercial O
fish O
purchased O
in O
stores O
and O
fish O
markets O
in O
central O
New O
Jersey O
and O
Chicago O
. O

There O
was O
substantial O
interspecific O
and O
intraspecific O
variation O
in O
molar O
ratios O
. O

Across O
species O
the O
selenium B
: O
mercury B
molar O
ratio O
decreased O
with O
increasing O
mean O
mercury B
levels O
, O
but O
selenium B
variation O
also O
contributed O
to O
the O
ratio O
. O

Few O
samples O
had O
selenium B
: O
mercury B
molar O
ratios O
below O
1 O
, O
but O
there O
was O
a O
wide O
range O
in O
ratios O
, O
complicating O
the O
interpretation O
for O
use O
in O
risk O
management O
and O
communication O
. O

Before O
ratios O
can O
be O
used O
in O
risk O
management O
, O
more O
information O
is O
needed O
on O
mercury B
: O
selenium B
interactions O
and O
mutual O
bioavailability O
, O
and O
on O
the O
relationship O
between O
molar O
ratios O
and O
health O
outcomes O
. O

Further O
, O
people O
who O
are O
selenium B
deficient O
may O
be O
more O
at O
risk O
from O
mercury B
toxicity O
than O
others O
. O

Synthesis O
and O
biological O
evaluation O
of O
prodrugs O
of O
2 B
- I
fluoro I
- I
2 I
- I
deoxyribose I
- I
1 I
- I
phosphate I
and O
2 B
, I
2 I
- I
difluoro I
- I
2 I
- I
deoxyribose I
- I
1 I
- I
phosphate I
. O

We O
report O
in O
this O
Letter O
the O
synthesis O
of O
prodrugs O
of O
2 B
- I
fluoro I
- I
2 I
- I
deoxyarabinose I
- I
1 I
- I
phosphate I
and O
2 B
, I
2 I
- I
difluoro I
- I
2 I
- I
deoxyribose I
- I
1 I
- I
phosphate I
. O

We O
demonstrate O
the O
difficulty O
of O
realising O
a O
phosphorylation O
step O
on O
the O
anomeric O
position O
of O
2 B
- I
deoxyribose I
, O
and O
we O
discover O
that O
introduction O
of O
fluorine B
atoms O
on O
the O
2 O
position O
of O
2 B
- I
deoxyribose I
enables O
the O
phosphorylation O
step O
: O
in O
fact O
, O
the O
stability O
of O
the O
prodrugs O
increases O
with O
the O
degree O
of O
2 O
- O
fluorination O
. O

Stability O
studies O
of O
produgs O
of O
2 B
- I
fluoro I
- I
2 I
- I
deoxyribose I
- I
1 I
- I
phosphate I
and O
2 B
, I
2 I
- I
difluoro I
- I
2 I
- I
deoxyribose I
- I
1 I
- I
phosphate I
in O
acidic O
and O
neutral O
conditions O
were O
conducted O
to O
confirm O
our O
observation O
. O

Biological O
evaluation O
of O
prodrugs O
of O
2 B
, I
2 I
- I
difluoro I
- I
2 I
- I
deoxyribose I
- I
1 I
- I
phosphate I
for O
antiviral O
and O
cytotoxic O
activity O
is O
reported O
. O

Oxidation O
- O
specific O
epitopes O
and O
immunological O
responses O
: O
Translational O
biotheranostic O
implications O
for O
atherosclerosis O
. O

Oxidation O
- O
specific O
epitopes O
( O
OSE O
) O
, O
present O
on O
oxidized O
LDL O
( O
OxLDL O
) O
, O
apoptotic O
cells O
, O
cell O
debris O
and O
modified O
proteins O
in O
the O
vessel O
wall O
, O
accumulate O
in O
response O
to O
hypercholesterolemia O
, O
and O
generate O
potent O
pro O
- O
inflammatory O
, O
disease O
- O
specific O
antigens O
. O

They O
represent O
an O
important O
class O
of O
' O
danger O
associated O
molecular O
patterns O
' O
( O
DAMPs O
) O
, O
against O
which O
a O
concerted O
innate O
immune O
response O
is O
directed O
. O

OSE O
are O
recognized O
by O
innate O
' O
pattern O
recognition O
receptors O
' O
, O
such O
as O
scavenger O
receptors O
present O
on O
dendritic O
cells O
and O
monocyte O
/ O
macrophages O
, O
as O
well O
as O
by O
innate O
proteins O
, O
such O
as O
IgM O
natural O
antibodies O
and O
soluble O
proteins O
, O
such O
as O
C O
- O
reactive O
protein O
and O
complement O
factor O
H O
. O

These O
innate O
immune O
responses O
provide O
a O
first O
line O
of O
defense O
against O
atherosclerosis O
- O
specific O
DAMPs O
, O
and O
engage O
adaptive O
immune O
responses O
, O
provided O
by O
T O
and O
B O
- O
2 O
cells O
, O
which O
provide O
a O
more O
specific O
and O
definitive O
response O
. O

Such O
immune O
responses O
are O
ordinarily O
directed O
to O
remove O
foreign O
pathogens O
, O
such O
as O
those O
found O
on O
microbial O
pathogens O
, O
but O
when O
persistent O
or O
maladaptive O
, O
lead O
to O
host O
damage O
. O

In O
this O
context O
, O
atherosclerosis O
can O
be O
considered O
as O
a O
systemic O
chronic O
inflammatory O
disease O
initiated O
by O
the O
accumulation O
of O
OSE O
type O
DAMPs O
and O
perpetuated O
by O
maladaptive O
response O
of O
the O
innate O
and O
adaptive O
immune O
system O
. O

Understanding O
this O
paradigm O
leads O
to O
new O
approaches O
to O
defining O
cardiovascular O
risk O
and O
suggests O
new O
modes O
of O
therapy O
. O

Therefore O
, O
OSE O
have O
become O
potential O
targets O
of O
diagnostic O
and O
therapeutic O
agents O
. O

Human O
and O
murine O
OSE O
- O
targeting O
antibodies O
have O
been O
developed O
and O
are O
now O
being O
used O
as O
biomarkers O
in O
human O
studies O
and O
experimentally O
in O
translational O
applications O
of O
non O
- O
invasive O
molecular O
imaging O
of O
oxidation O
- O
rich O
plaques O
and O
immunotherapeutics O
. O

Posttranslational O
mechanisms O
modulating O
the O
expression O
of O
the O
cytochrome O
P450 O
1A1 O
gene O
by O
methylmercury B
in O
HepG2 O
cells O
: O
A O
role O
of O
heme B
oxygenase O
- O
1 O
. O

Recently O
we O
demonstrated O
the O
ability O
of O
mercuric B
chloride I
( O
Hg B
( I
2 I
+ I
) I
) O
in O
human O
hepatoma O
HepG2 O
cells O
to O
significantly O
decrease O
the O
TCDD B
- O
mediated O
induction O
of O
Cytochrome O
P450 O
1A1 O
( O
CYP1A1 O
) O
mRNA O
, O
protein O
, O
and O
catalytic O
activity O
levels O
. O

In O
this O
study O
we O
investigated O
the O
effect O
of O
methylmercury B
( O
MeHg B
) O
on O
CYP1A1 O
in O
HepG2 O
cells O
. O

For O
this O
purpose O
, O
cells O
were O
co O
- O
exposed O
to O
MeHg B
and O
TCDD B
and O
the O
expression O
of O
CYP1A1 O
mRNA O
, O
protein O
, O
and O
catalytic O
activity O
levels O
were O
determined O
. O

Our O
results O
showed O
that O
MeHg B
did O
not O
alter O
the O
TCDD B
- O
mediated O
induction O
of O
CYP1A1 O
mRNA O
, O
or O
protein O
levels O
; O
however O
it O
was O
able O
to O
significantly O
decrease O
CYP1A1 O
catalytic O
activity O
levels O
in O
a O
concentration O
- O
dependent O
manner O
. O

Importantly O
, O
this O
inhibition O
was O
specific O
to O
CYP1A1and O
was O
not O
radiated O
to O
other O
aryl B
hydrocarbon I
receptor O
( O
AhR O
) O
- O
regulated O
genes O
, O
as O
MeHg B
induced O
NAD B
( I
P I
) I
H I
: O
quinone B
oxidoreductase O
1 O
mRNA O
and O
protein O
levels O
. O

Mechanistically O
, O
the O
inhibitory O
effect O
of O
MeHg B
on O
the O
induction O
of O
CYP1A1 O
coincided O
with O
an O
increase O
in O
heme O
oxygenase O
- O
1 O
( O
HO O
- O
1 O
) O
mRNA O
levels O
. O

Furthermore O
, O
the O
inhibition O
of O
HO O
- O
1 O
activity O
, O
by O
tin B
mesoporphyrin I
, O
caused O
a O
complete O
restoration O
of O
MeHg B
- O
mediated O
inhibition O
of O
CYP1A1 O
activity O
, O
induced O
by O
TCDD B
. O

In O
addition O
, O
transfection O
of O
HepG2 O
cells O
with O
siRNA O
targeting O
the O
human O
HO O
- O
1 O
gene O
reversed O
the O
MeHg B
- O
mediated O
inhibition O
of O
TCDD B
- O
induced O
CYP1A1 O
. O

In O
conclusion O
, O
this O
study O
demonstrated O
that O
MeHg B
inhibited O
the O
TCDD B
- O
mediated O
induction O
of O
CYP1A1 O
through O
a O
posttranslational O
mechanism O
and O
confirms O
the O
role O
of O
HO O
- O
1 O
in O
a O
MeHg B
- O
mediated O
effect O
. O

Molecular O
Basis O
of O
SMC O
ATPase O
Activation O
: O
Role O
of O
Internal O
Structural O
Changes O
of O
the O
Regulatory O
Subcomplex O
ScpAB O
. O

In O
many O
bacteria O
, O
a O
homodimer O
of O
structural O
- O
maintenance O
- O
of O
- O
chromosomes O
proteins O
associates O
with O
two O
regulatory O
subunits O
( O
known O
as O
ScpA O
and O
ScpB O
) O
, O
assembling O
a O
protein O
complex O
that O
plays O
a O
crucial O
role O
in O
chromosome O
organization O
and O
segregation O
. O

It O
remains O
poorly O
understood O
, O
however O
, O
how O
this O
complex O
might O
work O
at O
the O
mechanistic O
level O
. O

Here O
, O
we O
report O
crystal O
structures O
of O
the O
ScpAB O
core O
complex O
that O
display O
a O
highly O
unusual O
structure O
in O
which O
the O
central O
segment O
of O
ScpA O
winds O
around O
an O
asymmetrically O
oriented O
ScpB O
dimer O
. O

The O
two O
C B
- O
terminal O
domains O
of O
the O
ScpB O
dimer O
primarily O
interact O
with O
different O
regions O
of O
ScpA O
with O
different O
affinities O
. O

Moreover O
, O
flexible O
interdomain O
regions O
of O
ScpB O
contribute O
to O
a O
dynamic O
folding O
process O
of O
the O
ScpAB O
subcomplex O
. O

Together O
with O
other O
genetic O
and O
biochemical O
assays O
, O
we O
provide O
evidence O
that O
internal O
structural O
changes O
of O
the O
ScpAB O
subcomplex O
are O
tightly O
coupled O
with O
activation O
of O
the O
structural O
- O
maintenance O
- O
of O
- O
chromosomes O
ATPase O
. O

Osteochondral O
tissue O
regeneration O
using O
a O
bilayered O
composite O
hydrogel O
with O
modulating O
dual O
growth O
factor O
release O
kinetics O
in O
a O
rabbit O
model O
. O

Biodegradable O
oligo B
( I
poly I
( I
ethylene I
glycol I
) I
fumarate I
) I
( O
OPF B
) O
composite O
hydrogels O
have O
been O
investigated O
for O
the O
delivery O
of O
growth O
factors O
( O
GFs O
) O
with O
the O
aid O
of O
gelatin O
microparticles O
( O
GMPs O
) O
and O
stem O
cell O
populations O
for O
osteochondral O
tissue O
regeneration O
. O

In O
this O
study O
, O
a O
bilayered O
OPF O
composite O
hydrogel O
that O
mimics O
the O
distinctive O
hierarchical O
structure O
of O
native O
osteochondral O
tissue O
was O
utilized O
to O
investigate O
the O
effect O
of O
transforming O
growth O
factor O
- O
beta O
3 O
( O
TGF O
- O
beta O
3 O
) O
with O
varying O
release O
kinetics O
and O
/ O
or O
insulin O
- O
like O
growth O
factor O
- O
1 O
( O
IGF O
- O
1 O
) O
on O
osteochondral O
tissue O
regeneration O
in O
a O
rabbit O
full O
- O
thickness O
osteochondral O
defect O
model O
. O

The O
four O
groups O
investigated O
included O
( O
i O
) O
a O
blank O
control O
( O
no O
GFs O
) O
, O
( O
ii O
) O
GMP B
- O
loaded O
IGF O
- O
1 O
alone O
, O
( O
iii O
) O
GMP B
- O
loaded O
IGF O
- O
1 O
and O
gel O
- O
loaded O
TGF O
- O
beta O
3 O
, O
and O
( O
iv O
) O
GMP B
- O
loaded O
IGF O
- O
1 O
and O
GMP B
- O
loaded O
TGF O
- O
beta O
3 O
in O
OPF O
composite O
hydrogels O
. O

The O
results O
of O
an O
in O
vitro O
release O
study O
demonstrated O
that O
TGF O
- O
beta O
3 O
release O
kinetics O
could O
be O
modulated O
by O
the O
GF O
incorporation O
method O
. O

At O
12weeks O
post O
- O
implantation O
, O
the O
quality O
of O
tissue O
repair O
in O
both O
chondral O
and O
subchondral O
layers O
was O
analyzed O
based O
on O
quantitative O
histological O
scoring O
. O

All O
groups O
incorporating O
GFs O
resulted O
in O
a O
significant O
improvement O
in O
cartilage O
morphology O
compared O
to O
the O
control O
. O

Single O
delivery O
of O
IGF O
- O
1 O
showed O
higher O
scores O
in O
subchondral O
bone O
morphology O
as O
well O
as O
chondrocyte O
and O
glycosaminoglycan O
amount O
in O
adjacent O
cartilage O
tissue O
when O
compared O
to O
a O
dual O
delivery O
of O
IGF O
- O
1 O
and O
TGF O
- O
beta O
3 O
, O
independent O
of O
the O
TGF O
- O
beta O
3 O
release O
kinetics O
. O

The O
results O
suggest O
that O
although O
the O
dual O
delivery O
of O
TGF O
- O
beta O
3 O
and O
IGF O
- O
1 O
may O
not O
synergistically O
enhance O
the O
quality O
of O
engineered O
tissue O
, O
the O
delivery O
of O
IGF O
- O
1 O
alone O
from O
bilayered O
composite O
hydrogels O
positively O
affects O
osteochondral O
tissue O
repair O
and O
holds O
promise O
for O
osteochondral O
tissue O
engineering O
applications O
. O

Fishing O
and O
knockout O
of O
bioactive O
compounds O
using O
a O
combination O
of O
high O
- O
speed O
counter O
- O
current O
chromatography O
( O
HSCCC O
) O
and O
preparative O
HPLC O
for O
evaluating O
the O
holistic O
efficacy O
and O
interaction O
of O
the O
components O
of O
Herba O
Epimedii O
. O

Due O
to O
the O
complex O
chemical O
compositions O
and O
pharmacological O
effects O
of O
traditional O
Chinese O
medicines O
, O
we O
developed O
a O
strategy O
based O
on O
fishing O
and O
knockout O
of O
bioactive O
compounds O
using O
a O
combination O
of O
high O
- O
speed O
counter O
- O
current O
chromatography O
( O
HSCCC O
) O
and O
preparative O
HPLC O
for O
evaluating O
the O
holistic O
activity O
and O
interaction O
of O
the O
components O
of O
Herba O
Epimedii O
. O

First O
, O
osteoblast O
target O
cell O
extraction O
was O
used O
for O
preliminary O
screening O
of O
the O
potential O
bioactive O
compounds O
of O
Herba O
Epimedii O
. O

Second O
, O
the O
bioactive O
compounds O
identified O
( O
epimedin B
A I
, O
epimedin B
B I
, O
epimedin B
C I
and O
icariin B
) O
were O
fished O
and O
knocked O
out O
using O
high O
- O
speed O
counter O
- O
current O
chromatography O
and O
preparative O
HPLC O
. O

Third O
, O
the O
bioactivity O
of O
resulting O
fractions O
was O
assessed O
by O
determining O
their O
influence O
on O
cell O
proliferation O
and O
differentiation O
, O
thereby O
allowing O
for O
an O
evaluation O
of O
their O
interaction O
. O
The O
pharmacodynamic O
contribution O
ratio O
of O
each O
bioactive O
compound O
to O
the O
efficacy O
of O
the O
herbal O
medicine O
could O
then O
be O
comprehensively O
and O
intuitively O
determined O
based O
on O
the O
spectra O
- O
activity O
correlations O
( O
VIP O
values O
) O
of O
the O
tested O
compositions O
using O
partial O
least O
- O
squares O
regression O
( O
PLS O
- O
R O
) O
, O
through O
which O
the O
reliability O
of O
the O
screening O
and O
isolation O
of O
bioactive O
compounds O
by O
the O
target O
cell O
extraction O
technique O
were O
verified O
. O

The O
proposed O
strategy O
is O
a O
useful O
approach O
with O
potential O
application O
in O
other O
traditional O
Chinese O
medicines O
. O

Potential O
diagnostic O
applications O
of O
side O
chain O
oxysterols B
analysis O
in O
plasma O
and O
cerebrospinal O
fluid O
. O

The O
neurospecific O
cholesterol B
24 O
- O
hydroxylase O
converts O
excess O
brain O
cholesterol B
into O
24S B
- I
hydroxycholesterol I
( O
24OHC B
) O
which O
, O
via O
the O
liver O
X O
receptor O
( O
LXR O
) O
, O
can O
increase O
the O
expression O
and O
synthesis O
of O
astrocyte O
ApoE O
. O

24OHC B
effluxes O
directly O
from O
brain O
into O
plasma O
where O
it O
is O
considered O
an O
indicator O
of O
brain O
cholesterol B
turnover O
. O

It O
is O
reduced O
in O
neurodegenerative O
disease O
states O
proportionally O
to O
the O
severity O
of O
disease O
and O
the O
degree O
of O
brain O
atrophy O
. O

In O
the O
early O
phases O
of O
active O
disease O
, O
a O
higher O
rate O
of O
turnover O
may O
result O
in O
transitory O
increases O
in O
plasma O
24OHC B
. O

Less O
than O
1 O
% O
of O
the O
total O
brain O
excretion O
of O
24OHC B
occurs O
via O
the O
cerebrospinal O
fluid O
( O
CSF O
) O
whereas O
almost O
all O
27 B
- I
hydroxycholesterol I
( O
27OHC B
) O
excretion O
is O
dependent O
on O
the O
function O
of O
the O
blood O
- O
cerebrospinal O
fluid O
barrier O
. O

Iincreased O
CSF O
oxysterols B
were O
found O
in O
patients O
with O
neurodegenerative O
and O
neuroinflammatory O
diseases O
in O
the O
presence O
of O
barrier O
dysfunction O
. O

In O
neurodegeneration O
, O
free O
cholesterol B
released O
from O
dying O
cells O
may O
engulf O
neurons O
. O

Cholesterol B
also O
increases O
Amyloid O
beta O
( O
A O
beta O
) O
deposition O
and O
tau O
pathology O
. O

ApoE O
, O
24OHC O
, O
tau O
and O
soluble O
APP O
were O
correlated O
in O
Alzheimer O
disease O
( O
AD O
) O
samples O
. O

Excess O
of O
cholesterol B
converted O
into O
24OHC B
may O
up O
- O
regulate O
ApoE O
synthesis O
which O
is O
a O
scavenger O
for O
A O
beta O
and O
Tau O
. O

In O
AD O
this O
protective O
mechanism O
seems O
to O
be O
inefficient O
, O
probably O
due O
to O
the O
presence O
of O
high O
concentrations O
of O
27OHC B
, O
microvascular O
dysfunction O
and O
the O
decreased O
efficiency O
of O
ApoE4 O
as O
lipid O
transporter O
and O
A O
beta O
scavenger O
. O

24OHC B
itself O
was O
cytotoxic O
. O

Analysis O
of O
side O
chain O
oxysterols B
in O
the O
CSF O
is O
likely O
to O
provided O
useful O
information O
about O
cholesterol B
metabolism O
and O
ApoE O
function O
in O
the O
pathogenesis O
of O
AD O
. O

Anti O
- O
inflammatory O
and O
antioxidant O
properties O
of O
hydroalcoholic O
crude O
extract O
from O
Casearia O
sylvestris O
Sw O
. O

( O
Salicaceae O
) O
. O

ETHNOPHARMACOLOGICAL O
RELEVANCE O
: O
Casearia O
sylvestris O
Sw O
. O

is O
widely O
used O
in O
popular O
medicine O
to O
treat O
inflammatory O
conditions O
. O

AIM O
OF O
THE O
STUDY O
: O
To O
investigate O
the O
anti O
- O
inflammatory O
and O
antioxidant O
properties O
of O
hydroalcoholic O
crude O
extract O
( O
HCE O
) O
taken O
from O
Casearia O
sylvestris O
Sw O
. O

( O
Salicaceae O
) O
. O

METHODS O
AND O
RESULTS O
: O
The O
effect O
of O
the O
HCE O
from O
this O
plant O
( O
3 O
- O
300mg O
/ O
kg O
) O
on O
the O
reduction O
of O
inflammatory O
response O
to O
carrageenan O
was O
investigated O
in O
pleurisy O
in O
rats O
( O
intrapleural O
, O
2 O
% O
in O
0 O
. O
2mL O
) O
or O
paw O
edema O
in O
mice O
( O
intraplantar O
, O
300 O
mu O
g O
/ O
20 O
mu O
L O
, O
right O
hind O
paw O
) O
. O

The O
plant O
anti O
- O
inflammatory O
action O
was O
assessed O
by O
its O
capability O
in O
inhibiting O
cell O
migration O
, O
enzymatic O
activity O
of O
myeloperoxidase O
( O
MPO O
) O
and O
production O
of O
nitrite B
/ O
nitrate B
or O
edema O
. O

The O
in O
vitro O
antioxidant O
activity O
of O
this O
extract O
against O
lipid O
peroxidation O
and O
damage O
to O
proteins O
was O
assessed O
as O
possible O
pathways O
to O
contribute O
as O
anti O
- O
inflammatory O
mechanisms O
. O

Carrageenan O
- O
induced O
hind O
paw O
edema O
( O
739 O
. O
3 O
+ O
/ O
- O
11 O
. O
9 O
mu O
m O
) O
was O
reduced O
by O
HCE O
( O
30mg O
/ O
kg O
: O
462 O
. O
8 O
+ O
/ O
- O
28 O
. O
38 O
mu O
m O
) O
to O
similar O
extents O
as O
dexametasone B
( O
365 O
. O
1 O
+ O
/ O
- O
16 O
. O
7 O
) O
. O

In O
pleurisy O
, O
treatment O
of O
the O
animals O
with O
HCE O
( O
100mg O
/ O
kg O
: O
0 O
. O
010 O
+ O
/ O
- O
0 O
. O
001mU O
/ O
mg O
of O
protein O
) O
also O
reduced O
MPO O
activity O
augmented O
by O
carrageenan O
( O
0 O
. O
020 O
+ O
/ O
- O
0 O
. O
001mU O
/ O
mg O
of O
protein O
) O
as O
well O
as O
leukocytes O
migration O
( O
carrageenan O
: O
17 O
. O
8890 O
+ O
/ O
- O
2 O
. O
3900leukocytes O
/ O
mL O
, O
HCE O
100mg O
/ O
kg O
: O
7 O
. O
0880 O
+ O
/ O
- O
9631leukocytes O
/ O
mL O
) O
. O

Significant O
effects O
were O
also O
observed O
in O
animals O
treated O
with O
different O
doses O
of O
HCE O
in O
biochemical O
tests O
for O
oxidative O
stress O
analysis O
. O

CONCLUSION O
: O
The O
anti O
- O
inflammatory O
and O
antioxidant O
effects O
of O
HCE O
from O
Casearia O
sylvestris O
Sw O
. O
suggests O
a O
potential O
therapeutic O
benefit O
of O
this O
plant O
in O
treatment O
of O
inflammatory O
conditions O
. O

Ethanol B
extract O
of O
Adiantum O
capillus O
- O
veneris O
L O
. O
suppresses O
the O
production O
of O
inflammatory O
mediators O
by O
inhibiting O
NF O
- O
kappa O
B O
activation O
. O

ETHNOPHARMACOLOGICAL O
RELEVANCE O
: O
Adiantum O
capillus O
- O
veneris O
L O
. O

is O
a O
wildly O
distributed O
plant O
species O
and O
has O
been O
extensively O
used O
in O
south O
of O
China O
as O
traditional O
folk O
medicine O
for O
the O
treatment O
of O
inflammatory O
diseases O
. O

AIM O
OF O
THE O
STUDY O
: O
To O
investigate O
the O
anti O
- O
inflammatory O
effect O
of O
ethanolic O
extracts O
of O
Adiantum O
capillus O
- O
veneris O
L O
. O
and O
the O
involvement O
of O
NF O
- O
kappa O
B O
signaling O
in O
the O
regulation O
of O
inflammation O
. O

MATERIALS O
AND O
METHODS O
: O
The O
plant O
ethanolic O
extracts O
were O
initially O
tested O
against O
lipopolysaccharide O
( O
LPS O
) O
- O
induced O
prostaglandin B
E2 I
( O
PGE2 B
) O
production O
in O
RAW264 O
. O
7 O
mouse O
macrophages O
, O
and O
interleukin O
6 O
( O
IL O
- O
6 O
) O
and O
tumor O
necrosis O
factor O
( O
TNF O
) O
production O
in O
human O
U937 O
monocytes O
. O

The O
effect O
of O
the O
plant O
extracts O
on O
the O
transcription O
factor O
nuclear O
factor O
kappa O
B O
( O
NF O
- O
kappa O
B O
) O
pathway O
was O
evaluated O
in O
TNF O
- O
alpha O
stimulated O
HepG2 O
cells O
by O
luciferase O
gene O
reporter O
assay O
and O
Western O
blotting O
at O
the O
transcriptional O
and O
translational O
levels O
. O

Subsequently O
, O
the O
inhibition O
of O
NF O
- O
kappa O
B O
downstream O
gene O
expression O
( O
IL O
- O
8 O
and O
ICAM O
- O
1 O
) O
by O
the O
plant O
extracts O
was O
assessed O
via O
quantitative O
real O
time O
polymerase O
chain O
reaction O
( O
qPCR O
) O
. O

Lastly O
, O
the O
anti O
- O
inflammatory O
activities O
of O
the O
plant O
extracts O
in O
vivo O
were O
evaluated O
by O
testing O
spleen O
index O
and O
NF O
- O
kappa O
B O
related O
protein O
expression O
in O
LPS O
- O
stimulated O
CD1 O
mice O
. O

RESULTS O
: O
The O
plant O
ethanolic O
extracts O
effectively O
suppressed O
PGE2 B
, O
IL O
- O
6 O
and O
TNF O
release O
with O
an O
IC50 O
less O
than O
50 O
mu O
g O
/ O
ml O
. O

Moreover O
, O
luciferase O
expression O
could O
be O
specifically O
blocked O
in O
HepG2 O
cells O
, O
not O
in O
HEK293 O
cells O
, O
showing O
that O
the O
plant O
extracts O
displayed O
a O
cell O
- O
specific O
pattern O
on O
NF O
- O
kappa O
B O
gene O
transcription O
. O

The O
assayed O
biological O
activity O
also O
depended O
on O
the O
order O
of O
adding O
TNF O
- O
alpha O
and O
the O
plant O
extracts O
because O
the O
plant O
extracts O
could O
only O
block O
the O
NF O
- O
kappa O
B O
activation O
if O
added O
earlier O
but O
were O
unable O
to O
stop O
the O
signal O
when O
added O
after O
TNF O
- O
alpha O
. O

However O
, O
the O
plant O
extracts O
did O
not O
exert O
any O
effect O
on O
ubiquitination O
which O
regulates O
several O
steps O
in O
the O
NF O
- O
kappa O
B O
pathway O
. O

Additionally O
, O
the O
plant O
extracts O
down O
- O
regulated O
phosphorylation O
of O
IKK O
alpha O
/ O
beta O
at O
S176 O
/ O
180 O
, O
p38 O
at O
T180 O
/ O
Y182 O
and O
p65 O
at O
S536 O
, O
but O
not O
p65 O
at O
S276 O
. O

This O
was O
confirmed O
by O
their O
ability O
to O
selectively O
abrogate O
the O
induction O
of O
IL O
- O
8 O
transcription O
, O
whereas O
the O
ICAM O
- O
1 O
gene O
, O
which O
is O
not O
transcribed O
selectively O
by O
an O
NF O
- O
kappa O
B O
complex O
containing O
a O
form O
of O
p65 O
phosphorylated O
on O
Ser536 B
, O
did O
not O
change O
. O

Finally O
, O
the O
plant O
extracts O
at O
200 O
mu O
g O
/ O
mg O
could O
normalize O
the O
LPS O
- O
induced O
elevation O
of O
spleen O
index O
as O
well O
as O
NF O
- O
kappa O
B O
and O
p38 O
activations O
in O
CD1 O
mice O
. O

CONCLUSION O
: O
The O
present O
studies O
presents O
the O
potential O
utilization O
of O
this O
plant O
extracts O
, O
as O
a O
natural O
resources O
for O
the O
development O
of O
an O
anti O
- O
inflammatory O
medicine O
. O

Neuroprotection O
by O
steroids B
after O
neurotrauma O
in O
organotypic O
spinal O
cord O
cultures O
: O
A O
key O
role O
for O
progesterone B
receptors O
and O
steroidal B
modulators O
of O
GABAA O
receptors O
. O

Progesterone B
is O
neuroprotective O
after O
spinal O
cord O
injury O
, O
however O
its O
mechanism O
of O
action O
remains O
unexplored O
. O

Here O
we O
used O
organotypic O
spinal O
cord O
slice O
cultures O
from O
3 O
weeks O
- O
old O
mice O
to O
evaluate O
the O
mechanisms O
of O
neuroprotection O
by O
progesterone B
and O
its O
5 O
alpha O
- O
reduced O
metabolites O
. O

In O
vitro O
spinal O
cord O
injury O
, O
using O
a O
weight O
drop O
model O
, O
induced O
a O
decrease O
in O
the O
number O
of O
motoneurons O
. O

This O
was O
correlated O
with O
an O
increase O
in O
the O
number O
of O
dying O
cells O
( O
PI O
( O
+ O
) O
cells O
) O
and O
in O
LDH O
release O
. O

Addition O
of O
10 O
mu O
M O
of O
progesterone B
, O
5 B
alpha I
- I
dihydroprogesterone I
( O
5 B
alpha I
- I
DHP I
) O
or O
allopregnanolone B
( O
3 B
alpha I
, I
5 I
alpha I
- I
tetrahydroprogestero I
) O
to O
the O
medium O
at O
the O
time O
of O
injury O
rescued O
the O
spinal O
cord O
slices O
from O
the O
effects O
of O
damage O
. O

Progesterone B
prevented O
membrane O
cell O
damage O
, O
motoneuron O
loss O
and O
cell O
death O
. O

These O
effects O
were O
not O
due O
to O
its O
bioconversion O
to O
5 B
alpha I
- I
DHP I
nor O
to O
allopregnanolone B
, O
as O
supported O
by O
the O
finasteride B
, O
an O
inhibitor O
of O
5 O
alpha O
- O
reductase O
enzymes O
, O
and O
by O
the O
absence O
of O
5 B
alpha I
- I
reduced I
progesterone I
metabolites O
in O
the O
slices O
analyzed O
by O
gas O
chromatography O
- O
mass O
spectrometry O
. O

The O
neuroprotective O
effects O
of O
progesterone B
required O
PR O
as O
they O
could O
not O
be O
observed O
in O
slices O
from O
homozygous O
knockout O
PR O
( O
- O
/ O
- O
) O
mice O
. O

Allopregnanolone B
treatment O
was O
also O
neuroprotective O
. O

Its O
effects O
were O
not O
due O
to O
its O
bioconversion O
back O
to O
5 B
alpha I
- I
DHP I
, O
which O
can O
activate O
gene O
transcription O
via O
PR O
, O
because O
they O
were O
still O
observed O
in O
slices O
from O
knockout O
PR O
( O
- O
/ O
- O
) O
mice O
. O

Allopregnanolone B
effects O
involved O
GABAA O
receptors O
, O
as O
they O
were O
inhibited O
by O
the O
selective O
GABAA O
receptor O
antagonist O
Gabazine B
, O
in O
both O
PR O
( O
+ O
/ O
+ O
) O
and O
PR O
( O
- O
/ O
- O
) O
mice O
. O

Altogether O
, O
these O
findings O
identify O
both O
PR O
and O
GABAA O
receptors O
as O
important O
targets O
for O
neuroprotection O
by O
progestagens B
after O
spinal O
cord O
injury O
. O

Central O
functional O
response O
to O
the O
novel O
peptide O
cannabinoid O
, O
hemopressin B
. O

Hemopressin O
is O
the O
first O
peptide O
ligand O
to O
be O
described O
for O
the O
CB1 O
cannabinoid O
receptor O
. O

Hemopressin O
acts O
as O
an O
inverse O
agonist O
in O
vivo O
and O
can O
cross O
the O
blood O
- O
brain O
barrier O
to O
both O
inhibit O
appetite O
and O
induce O
antinociception O
. O

Despite O
being O
highly O
effective O
, O
synthetic O
CB1 O
inverse O
agonists O
are O
limited O
therapeutically O
due O
to O
unwanted O
, O
over O
dampening O
of O
central O
reward O
pathways O
. O

However O
, O
hemopressin B
appears O
to O
have O
its O
effect O
on O
appetite O
by O
affecting O
satiety O
rather O
than O
reward O
, O
suggesting O
an O
alternative O
mode O
of O
action O
which O
might O
avoid O
adverse O
side O
effects O
. O

Here O
, O
to O
resolve O
the O
neuronal O
circuitry O
mediating O
hemopressin B
' O
s O
actions O
, O
we O
have O
combined O
blood O
- O
oxygen B
- O
level O
- O
dependent O
, O
pharmacological O
- O
challenge O
magnetic O
resonance O
imaging O
with O
c O
- O
Fos O
functional O
activity O
mapping O
to O
compare O
brain O
regions O
responsive O
to O
systemic O
administration O
of O
hemopressin B
and O
the O
synthetic O
CB1 O
inverse O
agonist O
, O
AM251 B
. O

Using O
these O
complementary O
methods O
, O
we O
demonstrate O
that O
hemopressin B
activates O
distinct O
neuronal O
substrates O
within O
the O
brain O
, O
focused O
mainly O
on O
the O
feeding O
- O
related O
circuits O
of O
the O
mediobasal O
hypothalamus O
and O
in O
nociceptive O
regions O
of O
the O
periaqueductal O
grey O
( O
PAG O
) O
and O
dorsal O
raphe O
( O
DR O
) O
. O

In O
contrast O
to O
AM251 B
, O
there O
is O
a O
distinct O
lack O
of O
activation O
of O
the O
brain O
reward O
centres O
, O
such O
as O
the O
ventral O
tegmental O
area O
, O
nucleus O
accumbens O
and O
orbitofrontal O
cortex O
, O
which O
normally O
form O
a O
functional O
activity O
signature O
for O
the O
central O
action O
of O
synthetic O
CB1 O
receptor O
inverse O
agonists O
. O

Thus O
, O
hemopressin B
modulates O
the O
function O
of O
key O
feeding O
- O
related O
brain O
nuclei O
of O
the O
mediobasal O
hypothalamus O
, O
and O
descending O
pain O
pathways O
of O
the O
PAG O
and O
DR O
, O
and O
not O
higher O
limbic O
structures O
. O

Thus O
, O
hemopressin B
may O
offer O
behaviourally O
selective O
effects O
on O
nociception O
and O
appetite O
, O
without O
engaging O
reward O
pathways O
. O

A O
novel O
method O
for O
preparing O
complete O
antigens O
of O
gonyautoxin B
2 I
, I
3 I
and O
their O
feature O
of O
immunogenicity O
. O

In O
this O
paper O
, O
a O
novel O
method O
was O
proposed O
to O
prepare O
artificial O
antigens O
of O
gonyaulax O
parlaytic O
shellfish O
toxin O
2 O
and O
3 O
( O
GTX2 O
, O
3 O
) O
. O

An O
intermediate O
GTX2 O
, O
3 B
- I
aldehyde I
was O
first O
synthesized O
by O
activating O
the O
NH2 B
group O
of O
the O
2nd O
and O
8th O
amino B
acid I
residues O
with O
three O
different O
aldehydes B
and O
two O
artificial O
complete O
antigens O
GTX2 O
, O
3 B
- I
aldehyde I
- O
bovine O
serum O
albumin O
( O
BSA O
) O
and O
GTX2 O
, O
3 B
- I
aldehyde I
- O
keyhole O
limpet O
hemocyanin O
( O
KLH O
) O
were O
then O
prepared O
by O
cross O
- O
linking O
the O
intermediate O
with O
BSA O
or O
KLH O
. O

The O
successful O
preparation O
of O
the O
two O
complete O
antigens O
was O
confirmed O
by O
UV O
spectral O
scanning O
, O
HPLC O
, O
production O
of O
antibodies O
with O
titer O
of O
1 O
. O
28 O
x O
10 O
( O
4 O
) O
from O
mice O
immunized O
with O
the O
two O
complete O
antigens O
, O
indirect O
ELISA O
and O
Western O
- O
blot O
. O

In O
conclusion O
, O
the O
synthesized O
complete O
antigens O
have O
strong O
immunogenicity O
, O
which O
provides O
a O
solid O
foundation O
for O
preparing O
GTX2 O
, O
3 O
monoclonal O
antibody O
and O
rapid O
detection O
kit O
. O

A O
GLUE O
uncertainty O
analysis O
of O
a O
drying O
model O
of O
pharmaceutical O
granules O
. O

A O
shift O
from O
batch O
processing O
towards O
continuous O
processing O
is O
of O
interest O
in O
the O
pharmaceutical O
industry O
. O

However O
, O
this O
transition O
requires O
detailed O
knowledge O
and O
process O
understanding O
of O
all O
consecutive O
unit O
operations O
in O
a O
continuous O
manufacturing O
line O
to O
design O
adequate O
control O
strategies O
. O

This O
can O
be O
facilitated O
by O
developing O
mechanistic O
models O
of O
the O
multi O
- O
phase O
systems O
in O
the O
process O
. O

Since O
modelling O
efforts O
only O
started O
recently O
in O
this O
field O
, O
uncertainties O
about O
the O
model O
predictions O
are O
generally O
neglected O
. O

However O
, O
model O
predictions O
have O
an O
inherent O
uncertainty O
( O
i O
. O
e O
. O
prediction O
uncertainty O
) O
originating O
from O
uncertainty O
in O
input O
data O
, O
model O
parameters O
, O
model O
structure O
, O
boundary O
conditions O
and O
software O
. O

In O
this O
paper O
, O
the O
model O
prediction O
uncertainty O
is O
evaluated O
for O
a O
model O
describing O
the O
continuous O
drying O
of O
single O
pharmaceutical O
wet O
granules O
in O
a O
six O
- O
segmented O
fluidized O
bed O
drying O
unit O
, O
which O
is O
part O
of O
the O
full O
continuous O
from O
- O
powder O
- O
to O
- O
tablet O
manufacturing O
line O
( O
Consigma O
( O
TM O
) O
, O
GEA O
Pharma O
Systems O
) O
. O

A O
validated O
model O
describing O
the O
drying O
behaviour O
of O
a O
single O
pharmaceutical O
granule O
in O
two O
consecutive O
phases O
is O
used O
. O

First O
of O
all O
, O
the O
effect O
of O
the O
assumptions O
at O
the O
particle O
level O
on O
the O
prediction O
uncertainty O
is O
assessed O
. O

Secondly O
, O
the O
paper O
focuses O
on O
the O
influence O
of O
the O
most O
sensitive O
parameters O
in O
the O
model O
. O

Finally O
, O
a O
combined O
analysis O
( O
particle O
level O
plus O
most O
sensitive O
parameters O
) O
is O
performed O
and O
discussed O
. O

To O
propagate O
the O
uncertainty O
originating O
from O
the O
parameter O
uncertainty O
to O
the O
model O
output O
, O
the O
Generalized O
Likelihood O
Uncertainty O
Estimation O
( O
GLUE O
) O
method O
is O
used O
. O

This O
method O
enables O
a O
modeller O
to O
incorporate O
the O
information O
obtained O
from O
the O
experimental O
data O
in O
the O
assessment O
of O
the O
uncertain O
model O
predictions O
and O
to O
find O
a O
balance O
between O
model O
performance O
and O
data O
precision O
. O

A O
detailed O
evaluation O
of O
the O
obtained O
uncertainty O
analysis O
results O
is O
made O
with O
respect O
to O
the O
model O
structure O
, O
interactions O
between O
parameters O
and O
uncertainty O
boundaries O
. O

Liver O
X O
receptors O
: O
Emerging O
therapeutic O
targets O
for O
Alzheimer O
' O
s O
disease O
. O

Alzheimer O
' O
s O
disease O
( O
AD O
) O
is O
a O
complex O
neurodegenerative O
disorder O
, O
typified O
by O
the O
pathological O
accumulation O
of O
beta O
- O
amyloid O
peptides O
( O
A O
beta O
) O
and O
neurofibrillary O
tangles O
within O
the O
brain O
, O
culminating O
to O
cognitive O
impairment O
. O

Epidemiological O
and O
biochemical O
data O
have O
suggested O
a O
link O
between O
cholesterol B
content O
, O
APP O
( O
amyloid O
precursor O
protein O
) O
processing O
, O
A O
beta O
, O
inflammation O
and O
AD O
. O

The O
intricacy O
of O
the O
disease O
presents O
considerable O
challenges O
for O
the O
development O
of O
newer O
therapeutic O
agents O
. O

Liver O
X O
receptors O
( O
LXRa O
and O
LXR O
beta O
) O
are O
oxysterol B
activated O
nuclear O
receptors O
that O
play O
essential O
role O
in O
lipid O
and O
glucose B
homeostasis O
, O
steroidogenesis O
and O
inflammatory O
responses O
. O

LXR O
signalling O
impacts O
the O
development O
of O
AD O
pathology O
through O
multiple O
pathways O
. O

Reports O
indicate O
that O
genetic O
loss O
of O
either O
lxra O
or O
lxr O
beta O
in O
APP O
/ O
PS1 O
transgenic O
mice O
results O
in O
increased O
amyloid O
plaque O
load O
. O

Studies O
also O
suggest O
that O
ligand O
activation O
of O
LXRs O
in O
Tg2576 O
mice O
enhanced O
, O
the O
expression O
of O
genes O
linked O
with O
cholesterol B
efflux O
e O
. O
g O
. O
apoe O
, O
abca O
- O
1 O
, O
down O
regulated O
APP O
processing O
and O
A O
beta O
production O
with O
significant O
improvement O
in O
memory O
functions O
. O

LXR O
agonists O
have O
also O
depicted O
to O
inhibit O
neuroinflammation O
through O
modulation O
of O
microglial O
phagocytosis O
and O
by O
repressing O
the O
expression O
of O
cox2 O
, O
mcp1 O
and O
iNos O
in O
glial O
cells O
. O

This O
review O
summarizes O
in O
brief O
the O
biology O
of O
LXRs O
, O
with O
an O
emphasis O
on O
their O
probable O
pathophysiological O
mechanisms O
that O
may O
elicit O
the O
defending O
role O
of O
these O
receptors O
in O
brains O
of O
AD O
patients O
. O

Mitochondrial O
complex O
I O
dysfunction O
induced O
by O
cocaine B
and O
cocaine B
plus O
morphine B
in O
brain O
and O
liver O
mitochondria O
. O

Mitochondrial O
function O
and O
energy O
metabolism O
are O
affected O
in O
brains O
of O
human O
cocaine B
abusers O
. O

Cocaine B
is O
known O
to O
induce O
mitochondrial O
dysfunction O
in O
cardiac O
and O
hepatic O
tissues O
, O
but O
its O
effects O
on O
brain O
bioenergetics O
are O
less O
documented O
. O

Furthermore O
, O
the O
combination O
of O
cocaine B
and O
opioids O
( O
speedball O
) O
was O
also O
shown O
to O
induce O
mitochondrial O
dysfunction O
. O

In O
this O
work O
, O
we O
compared O
the O
effects O
of O
cocaine B
and O
/ O
or O
morphine B
on O
the O
bioenergetics O
of O
isolated O
brain O
and O
liver O
mitochondria O
, O
to O
understand O
their O
specific O
effects O
in O
each O
tissue O
. O

Upon O
energization O
with O
complex O
I O
substrates O
, O
cocaine B
decreased O
state O
- O
3 O
respiration O
in O
brain O
( O
but O
not O
in O
liver O
) O
mitochondria O
and O
decreased O
uncoupled O
respiration O
and O
mitochondrial O
potential O
in O
both O
tissues O
, O
through O
a O
direct O
effect O
on O
complex O
I O
. O

Morphine B
presented O
only O
slight O
effects O
on O
brain O
and O
liver O
mitochondria O
, O
and O
the O
combination O
cocaine B
+ O
morphine B
had O
similar O
effects O
to O
cocaine B
alone O
, O
except O
for O
a O
greater O
decrease O
in O
state O
- O
3 O
respiration O
. O

Brain O
and O
liver O
mitochondrial O
respirations O
were O
differentially O
affected O
, O
and O
liver O
mitochondria O
were O
more O
prone O
to O
proton O
leak O
caused O
by O
the O
drugs O
or O
their O
combination O
. O

This O
was O
possibly O
related O
with O
a O
different O
dependence O
on O
complex O
I O
in O
mitochondrial O
populations O
from O
these O
tissues O
. O

In O
summary O
, O
cocaine B
and O
cocaine B
+ O
morphine B
induce O
mitochondrial O
complex O
I O
dysfunction O
in O
isolated O
brain O
and O
liver O
mitochondria O
, O
with O
specific O
effects O
in O
each O
tissue O
. O

In O
vitro O
characterisation O
of O
the O
anti O
- O
intravasative O
properties O
of O
the O
marine O
product O
heteronemin O
. O

Metastases O
destroy O
the O
function O
of O
infested O
organs O
and O
are O
the O
main O
reason O
of O
cancer O
- O
related O
mortality O
. O

Heteronemin O
, O
a O
natural O
product O
derived O
from O
a O
marine O
sponge O
, O
was O
tested O
in O
vitro O
regarding O
its O
properties O
to O
prevent O
tumour O
cell O
intravasation O
through O
the O
lymph O
- O
endothelial O
barrier O
. O

In O
three O
- O
dimensional O
( O
3D O
) O
cell O
cultures O
consisting O
of O
MCF O
- O
7 O
breast O
cancer O
cell O
spheroids O
that O
were O
placed O
on O
lymph O
- O
endothelial O
cell O
( O
LEC O
) O
monolayers O
, O
tumour O
cell O
spheroids O
induce O
" O
circular O
chemorepellent O
- O
induced O
defects O
" O
( O
CCIDs O
) O
in O
the O
LEC O
monolayer O
; O
12 B
( I
S I
) I
- I
Hydroxyeicosatetraen I
acid I
( O
12 B
( I
S I
) I
- I
HETE I
) O
and O
NF O
- O
kappa O
B O
activity O
are O
major O
factors O
inducing O
CCIDs O
, O
which O
are O
entry O
gates O
for O
tumour O
emboli O

intravasating O
the O
vasculature O
. O

This O
3D O
co O
- O
culture O
is O
a O
validated O
model O
for O
the O
investigation O
of O
intravasation O
mechanisms O
and O
of O
drugs O
preventing O
CCID O
formation O
and O
hence O
lymph O
node O
metastasis O
. O

Furthermore O
, O
Western O
blot O
analyses O
, O
NF O
- O
kappa O
B O
reporter O
, O
EROD O
, O
SELE O
, O
12 B
( I
S I
) I
- I
HETE I
, O
and O
adhesion O
assays O
were O
performed O
to O
investigate O
the O
properties O
of O
heteronemin O
. O

Five O
micromolar O
heteronemin O
inhibited O
the O
directional O
movement O
of O
LECs O
and O
, O
therefore O
, O
the O
formation O
of O
CCIDs O
, O
which O
were O
induced O
by O
MCF O
- O
7 O
spheroids O
. O

Furthermore O
, O
heteronemin O
reduced O
the O
adhesion O
of O
MCF O
- O
7 O
cells O
to O
LECs O
and O
suppressed O
12 B
( I
S I
) I
- I
HETE I
- O
induced O
expression O
of O
the O
EMT O
marker O
paxillin O
, O
which O
is O
a O
regulator O
of O
directional O
cell O
migration O
. O

The O
activity O
of O
CYP1A1 O
, O
which O
contributed O
to O
CCID O
formation O
, O
was O
also O
inhibited O
by O
heteronemin O
. O

Hence O
, O
heteronemin O
inhibits O
important O
mechanisms O
contributing O
to O
tumour O
intravasation O
in O
vitro O
and O
should O
be O
tested O
in O
vivo O
. O

Nicotine B
- O
Induced O
Structural O
Plasticity O
in O
Mesencephalic O
Dopaminergic O
Neurons O
Is O
Mediated O
by O
Dopamine B
D3 O
Receptors O
and O
Akt O
- O
mTORC1 O
Signalling O
. O

Though O
long O
- O
term O
exposure O
to O
nicotine B
is O
highly O
addictive O
, O
one O
" O
beneficial O
" O
consequence O
of O
chronic O
tobacco O
use O
is O
a O
reduced O
risk O
for O
Parkinson O
' O
s O
disease O
. O

Interestingly O
, O
these O
effects O
both O
reflect O
structural O
and O
functional O
plasticity O
of O
brain O
circuits O
controlling O
reward O
and O
motor O
behavior O
, O
and O
specifically O
recruitment O
of O
nicotinic O
acetylcholine B
receptors O
( O
nAChR O
) O
in O
mesencephalic O
dopaminergic O
neurons O
. O

Since O
the O
underlying O
cellular O
mechanisms O
are O
poorly O
understood O
, O
we O
addressed O
this O
issue O
employing O
primary O
cultures O
of O
mouse O
mesencephalic O
dopaminergic O
neurons O
. O

Exposure O
to O
nicotine B
( O
1 O
- O
10 O
mu O
M O
) O
for O
72 O
hr O
in O
vitro O
increased O
dendritic O
arborization O
and O
soma O
size O
in O
primary O
cultures O
. O

These O
effects O
were O
blocked O
by O
mecamylamine B
and O
dihydro B
- I
beta I
- I
erythroidine I
, O
but O
not O
methyllycaconitine B
. O

The O
involvement O
of O
alpha O
4 O
beta O
2 O
nAChR O
was O
supported O
by O
the O
lack O
of O
nicotine B
- O
induced O
structural O
remodeling O
in O
neurons O
from O
alpha O
4 O
null O
mutant O
mice O
( O
KO O
) O
. O

Challenge O
with O
nicotine B
triggered O
phosphorylation O
of O
the O
extracellular O
signal O
- O
regulated O
kinase O
( O
ERK O
) O
and O
the O
thymoma O
viral O
proto O
- O
oncogene O
( O
Akt O
) O
followed O
by O
activation O
of O
the O
mTORC1 O
- O
dependent O
p70 O
ribosomal O
S6 O
protein O
kinase O
. O

Upstream O
pathway O
blockade O
using O
the O
phosphatidylinositol B
3 O
- O
kinase O
inhibitor O
LY294002 B
resulted O
in O
suppression O
of O
nicotine B
- O
induced O
phosphorylations O
and O
structural O
plasticity O
. O

These O
effects O
were O
dependent O
upon O
functional O
DA O
D3 O
receptor O
( O
D3R O
) O
since O
nicotine B
was O
inactive O
both O
in O
cultures O
from O
D3R O
KO O
mice O
and O
following O
pharmacologic O
blockade O
with O
D3R O
antagonist O
SB B
- I
277011 I
- I
A I
( O
50 O
nM O
) O
. O

Finally O
, O
exposure O
to O
nicotine B
in O
utero O
( O
5 O
mg O
/ O
kg O
/ O
day O
for O
5 O
days O
) O
resulted O
in O
increased O
soma O
area O
of O
DAergic O
neurons O
of O
newborn O
mice O
, O
effects O
not O
observed O
in O
D3KO O
mice O
. O

These O
findings O
indicate O
that O
nicotine B
- O
induced O
structural O
plasticity O
in O
mesencephalic O
dopaminergic O
neurons O
involves O
alpha O
4 O
beta O
2 O
nAChRs O
together O
with O
dopamine B
D3R O
- O
mediated O
recruitment O
of O
ERK O
/ O
Akt O
- O
mTORC1 O
signaling O
. O

Macroprolactinemia O
in O
hyperprolactinemic O
infertile O
women O
. O

Hyperprolactinemia O
occurs O
in O
15 O
- O
20 O
% O
of O
women O
with O
menstrual O
disturbances O
and O
30 O
- O
40 O
% O
of O
infertile O
women O
and O
it O
can O
adversely O
affect O
the O
fertility O
. O

High O
molecular O
weight O
prolactin O
( O
macroprolactin O
) O
has O
long O
been O
known O
in O
hyperprolactinemic O
fertile O
women O
. O

However O
, O
the O
prevalence O
of O
macroprolactinemia O
in O
hyperprolactinemic O
infertile O
women O
is O
not O
known O
. O

This O
cross O
- O
sectional O
study O
was O
carried O
out O
during O
the O
period O
of O
June O
2010 O
and O
June O
2011 O
at O
a O
single O
tertiary O
care O
centre O
. O

All O
women O
who O
attended O
the O
infertility O
clinic O
during O
this O
period O
were O
screened O
for O
hyperprolactinemia O
and O
only O
women O
with O
hyperprolactinemia O
and O
infertility O
were O
further O
studied O
for O
the O
presence O
of O
macroprolactin O
by O
polyethylene B
glycol I
precipitation O
assay O
. O

We O
compared O
the O
clinical O
, O
hormonal O
profile O
and O
fertility O
outcome O
of O
infertile O
women O
with O
true O
hyperprolactinemia O
and O
macroprolacinemia O
using O
appropriate O
statistical O
tests O
. O

Of O
1 O
, O
163 O
infertile O
women O
, O
183 O
( O
15 O
. O
7 O
% O
) O
had O
hyperprolactinemia O
[ O
134 O
( O
73 O
% O
) O
had O
primary O
infertility O
and O
49 O
( O
27 O
% O
) O
had O
secondary O
infertility O
] O
. O

Out O
of O
these O
183 O
women O
with O
hyperprolactinemia O
, O
one O
had O
microadenoma O
, O
161 O
had O
true O
idiopathic O
hyperprolactinemia O
and O
21 O
( O
11 O
. O
5 O
% O
) O
women O
had O
macroprolactinemia O
. O

The O
prevalence O
of O
oligomenorrhea O
and O
galactorrhea O
were O
significantly O
higher O
in O
patients O
with O
true O
hyperprolactinemia O
than O
macroprolactinemia O
( O
46 O
vs O
. O
14 O
% O
, O
p O
< O
0 O
. O
008 O
and O
30 O
vs O
. O
5 O
% O
, O
p O
= O
0 O
. O
01 O
respectively O
) O
. O

Twenty O
- O
two O
patients O
( O
13 O
. O
5 O
% O
) O
of O
true O
hyperprolactinemia O
and O
two O
( O
9 O
% O
) O
in O
macroprolactinemia O
became O
pregnant O
during O
the O
study O
period O
. O

Prolactin O
measurement O
should O
be O
a O
part O
of O
routine O
evaluation O
of O
couples O
referred O
to O
infertility O
clinics O
. O

Macroprolactin O
screening O
is O
mandatory O
when O
clinical O
features O
and O
serum O
PRL O
assay O
results O
are O
conflicting O
. O

Patients O
with O
macroprolactinemia O
should O
be O
investigated O
for O
causes O
of O
infertility O
other O
than O
hyperprolactinemia O
. O

Theoretical O
Considerations O
and O
Practical O
Approaches O
to O
Address O
the O
Effect O
of O
Anti O
- O
drug O
Antibody O
( O
ADA O
) O
on O
Quantification O
of O
Biotherapeutics O
in O
Circulation O
. O

Continuous O
improvement O
in O
bioanalytical O
method O
development O
is O
desired O
in O
order O
to O
ensure O
the O
quality O
of O
the O
data O
and O
to O
better O
support O
pharmacokinetic O
( O
PK O
) O
and O
safety O
studies O
of O
biotherapeutics O
. O

One O
area O
that O
has O
been O
getting O
increasing O
attention O
recently O
is O
in O
the O
assessment O
of O
" O
free O
" O
and O
" O
total O
" O
analyte O
and O
the O
impact O
of O
the O
assay O
format O
on O
those O
assessments O
. O

To O
compliment O
these O
considerations O
, O
the O
authors O
provide O
a O
critical O
review O
of O
available O
literature O
and O
prospectively O
explore O
methods O
to O
mitigate O
the O
potential O
impact O
of O
anti O
- O
drug O
antibody O
on O
PK O
assay O
measurement O
. O

This O
challenge O
is O
of O
particular O
interest O
and O
importance O
since O
biotherapeutic O
drugs O
often O
elicit O
an O
immune O
response O
, O
and O
thus O
may O
have O
a O
direct O
impact O
on O
quantification O
of O
the O
drug O
for O
its O
PK O
and O
safety O
evaluations O
. O

Pharmacokinetic O
characterization O
of O
CK2 O
inhibitor O
CX B
- I
4945 I
. O

Over O
- O
expression O
of O
protein O
kinase O
CK2 O
is O
highly O
linked O
to O
the O
survival O
of O
cancer O
cells O
and O
the O
poor O
prognosis O
of O
patients O
with O
cancers O
. O

CX B
- I
4945 I
, O
a O
potent O
and O
selective O
orally O
bioavailable O
ATP B
- O
competitive O
inhibitor O
of O
CK2 O
, O
inhibits O
the O
oncogenic O
cellular O
events O
such O
as O
proliferation O
and O
angiogenesis O
, O
and O
the O
increase O
of O
tumor O
growth O
in O
mouse O
xenograft O
model O
. O

In O
this O
study O
, O
the O
pharmacokinetic O
information O
about O
CX B
- I
4945 I
was O
provided O
; O
at O
10 O
mu O
M O
, O
CX B
- I
4945 I
with O
high O
stability O
in O
human O
and O
rat O
liver O
microsome O
exhibited O
low O
percentage O
of O
inhibition O
( O
< O
10 O
% O
) O
in O
CYP450 O
isoforms O
( O
1A2 O
, O
2C19 O
, O
3A4 O
) O
, O
but O
considerable O
inhibition O
( O
~ O
70 O
% O
) O
in O
CYP450 O
2C9 O
and O
2D6 O
. O

In O
hERG O
potassium B
channel O
inhibition O
assay O
, O
CX B
- I
4945 I
exhibited O
relatively O
low O
inhibition O
rate O
. O

Additionally O
, O
CX B
- I
4945 I
showed O
high O
MDCK O
cell O
permeability O
( O
> O
10 O
x O
10 O
( O
- O
6 O
) O
cm O
/ O
s O
) O
and O
above O
98 O
% O
of O
plasma O
protein O
binding O
in O
the O
rat O
. O

After O
intravenous O
administration O
, O
Vss O
( O
1 O
. O
39 O
l O
/ O
kg O
) O
and O
extremely O
low O
CL O
( O
0 O
. O
08 O
l O
/ O
kg O
/ O
h O
) O
were O
observed O
. O

Moreover O
, O
orally O
administrated O
CX B
- I
4945 I
showed O
high O
bioavailability O
( O
> O
70 O
% O
) O
and O
these O
data O
might O
be O
related O
to O
the O
MDCK O
cell O
permeability O
results O
. O

Novel O
4 B
- I
substituted I
- I
2 I
( I
1H I
) I
- I
phthalazinone I
derivatives O
: O
synthesis O
, O
molecular O
modeling O
study O
and O
their O
effects O
on O
alpha O
- O
receptors O
. O

Novel O
4 B
- I
( I
4 I
- I
bromophenyl I
) I
phthalazine I
derivatives O
connected O
via O
an O
alkyl O
spacer O
to O
amine B
or O
N B
- I
substituted I
piperazine I
were O
designed O
and O
synthesized O
as O
promising O
alpha O
- O
adrenoceptor O
antagonists O
. O

The O
structures O
of O
the O
phthalazine B
derivatives O
were O
established O
using O
elemental O
and O
spectral O
analyses O
. O

Twelve O
of O
the O
tested O
compounds O
displayed O
significant O
alpha O
- O
blocking O
activity O
. O

Molecular O
modeling O
studies O
were O
performed O
to O
rationalize O
the O
biological O
results O
. O

Among O
the O
tested O
compounds O
, O
7j O
displayed O
the O
best O
- O
fitting O
score O
and O
the O
highest O
in O
vitro O
activity O
. O

Nickel B
and O
Cobalt B
- O
Catalyzed O
Coupling O
of O
Alkyl B
Halides I
with O
Alkenes B
via O
Heck O
Reactions O
and O
Radical O
Conjugate O
Addition O
. O

Cross O
- O
coupling O
of O
alkyl B
halides I
with O
alkenes B
leading O
to O
Heck O
- O
type O
and O
addition O
products O
is O
summarized O
. O

The O
development O
of O
Heck O
reaction O
with O
aliphatic B
halides I
although O
has O
made O
significant O
progress O
in O
the O
past O
decade O
and O
particularly O
recently O
, O
it O
was O
much O
less O
explored O
in O
comparison O
with O
the O
aryl B
halides I
. O

The O
use O
of O
Ni B
- O
and O
Co B
- O
catalyzed O
protocols O
allowed O
efficient O
Heck O
coupling O
of O
activated O
and O
unactivated O
alkenes B
with O
1 B
( I
o I
) I
, I
2 I
( I
o I
) I
and I
3 I
( I
o I
) I
alkyl I
halides I
. O

In O
addition O
, O
radical O
conjugate O
addition O
to O
activated O
alkenes B
has O
become O
a O
well O
- O
established O
method O
that O
has O
led O
to O
efficient O
construction O
of O
many O
natural O
products O
. O

The O
utilization O
of O
Ni B
- O
and O
Co B
- O
catalyzed O
strategies O
would O
avoid O
toxic O
tin B
reagents O
, O
and O
therefore O
worth O
exploring O
. O

The O
recent O
development O
of O
Ni B
- O
and O
Co B
- O
catalyzed O
addition O
of O
alkyl B
halides I
to O
alkenes B
displays O
much O
improved O
reactivity O
and O
functional O
group O
tolerance O
. O

In O
this O
mini O
- O
review O
, O
we O
also O
attempt O
to O
overview O
the O
mechanisms O
that O
are O
proposed O
in O
the O
reactions O
, O
aiming O
at O
providing O
insight O
into O
the O
nickel B
and O
cobalt B
- O
catalyzed O
coupling O
of O
alkyl B
halides I
with O
alkenes B
. O

Pyrazolines B
: O
a O
biological O
review O
. O

Pyrazoline B
is O
an O
important O
five O
membered O
nitrogen B
heterocycle O
, O
which O
has O
been O
extensively O
researched O
upon O
. O

The O
ring O
is O
quite O
stable O
and O
has O
inspired O
chemists O
to O
carry O
out O
various O
structural O
variations O
in O
the O
ring O
. O

This O
has O
propelled O
the O
development O
of O
distinct O
pyrazolines B
with O
an O
array O
of O
pharmacological O
activities O
viz O
. O
anti O
- O
inflammatory O
, O
analgesic O
, O
antimicrobial O
, O
anticancer O
, O
antidepressant O
etc O
. O

The O
review O
aims O
at O
highlighting O
this O
pharmacological O
diversity O
of O
pyrazolines B
. O

The O
review O
is O
a O
gist O
of O
latest O
work O
done O
describing O
the O
pharmacological O
aspects O
and O
potential O
of O
pyrazoline B
ring O
. O

Nanoscale O
Imaging O
of O
Neutral O
Atoms O
with O
a O
Pulsed O
Magnetic O
Lens O
. O

We O
present O
a O
scheme O
for O
imaging O
of O
neutral O
atoms O
to O
the O
nanoscale O
with O
a O
pulsed O
magnetic O
lens O
and O
show O
its O
viability O
through O
numerical O
calculations O
. O

This O
scheme O
achieves O
focal O
lengths O
on O
the O
order O
of O
several O
centimeters O
and O
focal O
spots O
of O
less O
than O
10 O
nm O
. O

With O
these O
results O
, O
it O
is O
possible O
to O
create O
sub O
- O
10 O
nm O
structures O
on O
surfaces O
in O
a O
parallel O
and O
time O
- O
efficient O
manner O
. O

When O
used O
with O
metastable O
noble O
gas O
atoms O
, O
and O
in O
combination O
with O
electron O
spectroscopy O
, O
this O
scheme O
can O
create O
a O
chemically O
sensitive O
microscope O
which O
can O
probe O
surfaces O
on O
the O
nanometer O
scale O
. O

In O
Vitro O
Fertilization O
outcomes O
in O
treated O
hypothyroidism O
. O

Background O
: O
Levothyroxine B
has O
been O
shown O
to O
enhance O
pregnancy O
outcomes O
in O
women O
with O
hypothyroidism O
requiring O
In O
Vitro O
Fertilization O
( O
IVF O
) O
. O

However O
, O
the O
precise O
magnitude O
of O
these O
benefits O
remains O
to O
be O
determined O
. O

In O
particular O
, O
it O
has O
yet O
to O
be O
clarified O
whether O
levothyroxine B
may O
fully O
overcome O
the O
detrimental O
effects O
of O
hypothyroidism O
or O
, O
conversely O
, O
whether O
affected O
women O
remain O
at O
reduced O
prognosis O
for O
pregnancy O
outcomes O
. O

Methods O
: O
Patients O
who O
underwent O
IVF O
- O
ICSI O
( O
IVF O
- O
intracytoplasmic O
sperm O
injection O
) O
over O
a O
three O
- O
year O
period O
were O
reviewed O
. O

Cases O
were O
deemed O
eligible O
if O
they O
were O
diagnosed O
with O
clinical O
or O
subclinical O
hypothyroidism O
and O
were O
receiving O
levothyroxine B
. O

Controls O
were O
two O
subsequently O
age O
- O
matched O
euthyroid O
women O
for O
every O
case O
. O

Both O
cases O
and O
controls O
were O
selected O
only O
if O
serum O
TSH O
was O
< O
= O
2 O
. O
5 O
mIU O
/ O
L O
. O

Results O
: O
One O
hundred O
thirty O
- O
seven O
women O
with O
treated O
hypothyroidism O
and O
274 O
controls O
were O
included O
. O

Baseline O
characteristics O
of O
the O
two O
study O
groups O
were O
similar O
with O
the O
exception O
of O
BMI O
, O
which O
was O
slightly O
higher O
among O
the O
cases O
( O
22 O
. O
9 O
+ O
/ O
- O
3 O
. O
9 O
versus O
21 O
. O
9 O
+ O
/ O
- O
3 O
. O
3 O
Kg O
/ O
m2 O
, O
p O
= O
0 O
. O
013 O
) O
. O

Most O
IVF O
- O
ICSI O
cycle O
outcome O
variables O
were O
also O
similar O
with O
the O
exception O
of O
a O
higher O
rate O
of O
cancellation O
for O
poor O
response O
( O
3 O
. O
6 O
% O
versus O
0 O
. O
7 O
% O
, O
p O
= O
0 O
. O
04 O
) O
, O
a O
longer O
duration O
of O
stimulation O
( O
10 O
. O
9 O
+ O
/ O
- O
2 O
. O
2 O
versus O
10 O
. O
1 O
+ O
/ O
- O
2 O
. O
0 O
days O
, O
p O
= O
0 O
. O
001 O
) O
, O
a O
higher O
proportion O
of O
women O
failing O
to O
obtain O
viable O
embryos O
( O
17 O
% O
versus O
7 O
% O
, O
p O
= O
0 O
. O
006 O
) O
, O
and O
a O
lower O
fertilization O
rate O
( O
75 O
% O
versus O
86 O
% O
, O
p O
= O
0 O
. O
017 O

) O
among O
cases O
. O

Conversely O
, O
the O
clinical O
pregnancy O
rate O
per O
started O
cycle O
, O
the O
implantation O
rate O
and O
the O
live O
birth O
rate O
per O
started O
cycle O
did O
not O
differ O
; O
they O
were O
36 O
% O
and O
34 O
% O
( O
p O
= O
0 O
. O
93 O
) O
, O
28 O
% O
and O
22 O
% O
( O
p O
= O
0 O
. O
11 O
) O
and O
30 O
% O
and O
27 O
% O
( O
p O
= O
0 O
. O
50 O
) O
in O
cases O
and O
controls O
, O
respectively O
. O

Subgroup O
analyses O
comparing O
women O
with O
( O
n O
= O
79 O
) O
and O
without O
( O
n O
= O
58 O
) O
thyroid O
autoimmunity O
and O
comparing O
women O
who O
were O
diagnosed O
with O
overt O
hypothyroidism O
( O
n O
= O
70 O
) O
or O
subclinical O
hypothyroidism O
( O
n O
= O
67 O
) O
failed O
to O
identify O
relevant O
differences O
. O

Conclusions O
: O
In O
our O
population O
, O
IVF O
- O
ICSI O
outcome O
was O
not O
significantly O
hampered O
in O
women O
with O
adequately O
treated O
hypothyroidism O
. O

The O
magnitude O
of O
the O
detected O
differences O
in O
cycle O
outcome O
was O
mild O
and O
we O
failed O
to O
document O
any O
differences O
for O
the O
most O
relevant O
outcomes O
, O
i O
. O
e O
. O
pregnancy O
rate O
, O
implantation O
rate O
and O
delivery O
rate O
. O

In O
conclusion O
, O
adequate O
levothyroxine B
treatment O
maintaining O
TSH O
serum O
levels O
below O
2 O
. O
5 O
mIU O
/ O
L O
may O
overcome O
the O
detrimental O
effects O
of O
hypothyroidism O
. O

Chronic O
dietary O
exposure O
to O
chlorpyrifos B
causes O
behavioral O
impairments O
, O
low O
activity O
of O
brain O
membrane O
- O
bound O
acetylcholinesterase O
, O
and O
increased O
brain O
acetylcholinesterase O
- O
R O
mRNA O
. O

Chlorpyrifos B
( O
CPF B
) O
is O
an O
organophosphate B
( O
OP O
) O
insecticide O
that O
is O
metabolically O
activated O
to O
the O
highly O
toxic O
chlorpyrifos B
oxon I
. O

Dietary O
exposure O
is O
the O
main O
route O
of O
intoxication O
for O
non O
- O
occupational O
exposures O
. O

However O
, O
only O
limited O
behavioral O
effects O
of O
chronic O
dietary O
exposure O
have O
been O
investigated O
. O

Therefore O
, O
male O
Wistar O
rats O
were O
fed O
a O
dose O
of O
5mg O
/ O
kg O
/ O
day O
of O
CPF B
for O
thirty O
- O
one O
weeks O
. O

Animals O
were O
evaluated O
in O
spatial O
learning O
and O
impulsivity O
tasks O
after O
21 O
weeks O
of O
CPF B
dietary O
exposure O
and O
one O
week O
after O
exposure O
ended O
, O
respectively O
. O

In O
addition O
, O
the O
degree O
of O
inhibition O
of O
brain O
acetylcholinesterase O
( O
AChE O
) O
was O
evaluated O
for O
both O
the O
soluble O
and O
particulate O
forms O
of O
the O
enzyme O
, O
as O
well O
as O
AChE O
gene O
expression O
. O

Also O
, O
brain O
acylpeptide B
hydrolase O
( O
APH O
) O
was O
investigated O
as O
an O
alternative O
target O
for O
OP O
- O
mediated O
effects O
. O

All O
variables O
were O
evaluated O
at O
various O
time O
points O
in O
response O
to O
CPF B
diet O
and O
after O
exposure O
ended O
. O

Results O
from O
behavioral O
procedures O
suggest O
cognitive O
and O
emotional O
disorders O
. O

Moreover O
, O
low O
levels O
of O
activity O
representing O
membrane O
- O
bound O
oligomeric O
forms O
( O
tetramers O
) O
were O
also O
observed O
. O

In O
addition O
, O
increased O
brain O
AChE O
- O
R O
mRNA O
levels O
were O
detected O
after O
four O
weeks O
of O
CPF B
dietary O
exposure O
. O

However O
, O
no O
changes O
in O
levels O
of O
brain O
APH O
were O
observed O
among O
groups O
. O

In O
conclusion O
, O
our O
data O
point O
to O
a O
relationship O
between O
cognitive O
impairments O
and O
changes O
in O
AChE O
forms O
, O
specifically O
to O
a O
high O
inhibition O
of O
the O
particulate O
form O
and O
a O
modification O
of O
alternative O
splicing O
of O
mRNA O
during O
CPF B
dietary O
exposure O
. O

In O
vitro O
intestinal O
and O
hepatic O
metabolism O
of O
Di B
( I
2 I
- I
ethylhexyl I
) I
phthalate I
( O
DEHP B
) O
in O
human O
and O
rat O
. O

Species O
and O
organ O
differences O
in O
the O
intrinsic O
clearance O
and O
the O
enzymes O
involved O
in O
the O
metabolism O
of O
DEHP B
were O
examined O
in O
subcellular O
fractions O
of O
the O
intestine O
and O
liver O
as O
well O
as O
by O
recombinant O
cytochrome O
P450 O
( O
CYP O
) O
isoforms O
of O
human O
and O
rat O
. O

Estimated O
clearance O
( O
CLint O
) O
of O
DEHP B
via O
esterase O
- O
mediated O
pathway O
in O
human O
intestine O
was O
2 O
. O
4 O
- O
fold O
greater O
than O
that O
in O
human O
liver O
while O
its O
value O
in O
rat O
intestine O
was O
1 O
. O
7 O
- O
fold O
less O
than O
that O
in O
rat O
liver O
. O

Ranks O
of O
CLint O
for O
CYP O
- O
mediated O
oxidation O
/ O
dealkylation O
of O
MEHP B
were O
human O
liver O
> O
rat O
liver O
> O
human O
intestine O
> O
rat O
intestine O
. O

Estimates O
of O
CLint O
for O
the O
production O
of O
mono B
( I
2 I
- I
ethyl I
- I
5 I
- I
hydroxyhexyl I
) I
phthalate I
and O
mono B
( I
2 I
- I
ethyl I
- I
5 I
- I
oxohexyl I
) I
phthalate I
by O
human O
CYP2C9 O
( O
* O
) O
1 O
were O
4 O
. O
2 O
- O
and O
2 O
. O
6 O
- O
fold O
greater O
than O
those O
by O
rat O
CYP2C6 O
, O
respectively O
. O

Total O
CLint O
via O
hCYP2C9 B
( O
* O
) O
3 O
- O
mediated O
oxidation O
was O
1 O
. O
9 O
- O
and O
2 O
. O
6 O
- O
fold O
less O
than O
those O
by O
hCYP2C9 B
( O
* O
) O
2 O
and O
2C9 O
( O
* O
) O
1 O
, O
respectively O
. O

Estimated O
CLint O
for O
phthalic B
acid I
production O
by O
hCYP3A4 B
was O
24 O
. O
5 O
mu O
LnmolCYP O
( O
- O
1 O
) O
min O
( O
- O
1 O
) O
while O
it O
was O
continuously O
produced O
by O
rCYP2C6 O
and O
3A2 O
via O
passive O
mechanism O
. O

These O
species O
/ O
organ O
differences O
in O
major O
metabolic O
pathway O
and O
CYP O
isoforms O
should O
be O
considered O
for O
appraisal O
of O
the O
potential O
adverse O
health O
effects O
of O
DEHP B
. O

Electroactive O
nanoparticle O
directed O
assembly O
of O
functionalized O
graphene B
nanosheets O
into O
hierarchical O
structures O
with O
hybrid O
compositions O
for O
flexible O
supercapacitors O
. O

Hierarchical O
structures O
of O
hybrid O
materials O
with O
the O
controlled O
compositions O
have O
been O
shown O
to O
offer O
a O
breakthrough O
for O
energy O
storage O
and O
conversion O
. O

Here O
, O
we O
report O
the O
integrative O
assembly O
of O
chemically O
modified O
graphene B
( O
CMG O
) O
building O
blocks O
into O
hierarchical O
complex O
structures O
with O
the O
hybrid O
composition O
for O
high O
performance O
flexible O
pseudocapacitors O
. O

The O
formation O
mechanism O
of O
hierarchical O
CMG O
/ O
Nafion B
/ O
RuO2 B
( O
CMGNR O
) O
microspheres O
, O
which O
is O
triggered O
by O
the O
cooperative O
interplay O
during O
the O
in O
situ O
synthesis O
of O
RuO2 B
nanoparticles O
( O
NPs O
) O
, O
was O
extensively O
investigated O
. O

In O
particular O
, O
the O
hierarchical O
CMGNR O
microspheres O
consisting O
of O
the O
aggregates O
of O
CMG O
/ O
Nafion B
( O
CMGN O
) O
nanosheets O
and O
RuO2 B
NPs O
provided O
large O
surface O
area O
and O
facile O
ion O
accessibility O
to O
storage O
sites O
, O
while O
the O
interconnected O
nanosheets O
offered O
continuous O
electron O
pathways O
and O
mechanical O
integrity O
. O

The O
synergistic O
effect O
of O
CMGNR O
hybrids O
on O
the O
supercapacitor O
( O
SC O
) O
performance O
was O
derived O
from O
the O
hybrid O
composition O
of O
pseudocapacitive O
RuO2 B
NPs O
with O
the O
conductive O
CMGNs O
as O
well O
as O
from O
structural O
features O
. O

Consequently O
, O
the O
CMGNR O
- O
SCs O
showed O
a O
specific O
capacitance O
as O
high O
as O
160 O
F O
g O
( O
- O
1 O
) O
, O
three O
- O
fold O
higher O
than O
that O
of O
conventional O
graphene B
SCs O
, O
and O
a O
capacitance O
retention O
of O
> O
95 O
% O
of O
the O
maximum O
value O
even O
after O
severe O
bending O
and O
1000 O
charge O
- O
discharge O
tests O
due O
to O
the O
structural O
and O
compositional O
features O
. O

Beneficial O
influence O
of O
topical O
extra O
virgin O
olive O
oil O
application O
on O
an O
experimental O
model O
of O
penile O
fracture O
in O
rats O
. O

Penile O
fracture O
( O
PF O
) O
is O
known O
as O
a O
traumatic O
rupture O
of O
the O
tunica O
albuginea O
of O
corpus O
cavernosum O
. O

In O
this O
study O
, O
we O
aimed O
to O
investigate O
the O
healing O
influence O
of O
topical O
extra O
virgin O
olive O
oil O
( O
EVOO O
) O
on O
PF O
through O
evaluating O
levels O
of O
some O
oxidative O
stress O
biomarkers O
for O
the O
first O
time O
. O

Histopathological O
evaluation O
was O
also O
realized O
. O

A O
total O
of O
18 O
male O
Sprague O
- O
Dawley O
albino O
rats O
were O
divided O
into O
three O
groups O
of O
six O
rats O
each O
as O
control O
group O
, O
in O
PF O
( O
alone O
) O
group O
, O
and O
PF O
+ O
EVOO O
group O
. O

Experimental O
PF O
was O
formed O
via O
incising O
from O
the O
proximal O
dorsal O
side O
of O
the O
penis O
in O
the O
rats O
of O
all O
groups O
except O
control O
. O

While O
in O
PF O
( O
alone O
) O
group O
, O
fracture O
was O
formed O
and O
the O
incision O
was O
primarily O
closed O
, O
in O
PF O
+ O
EVOO O
group O
in O
addition O
to O
foregoing O
processes O
, O
EVOO O
was O
also O
administrated O
topically O
twice O
a O
day O
for O
3 O
weeks O
. O

At O
the O
end O
of O
the O
experiment O
, O
all O
rats O
were O
killed O
and O
penectomy O
was O
carried O
out O
. O

While O
malondialdehyde B
, O
myeloperoxidase O
, O
lipid O
hyroperoxide O
, O
and O
total O
oxidant O
status O
significantly O
( O
p O
< O
0 O
. O
05 O
) O
increased O
, O
reduced B
glutathione I
and O
total O
free O
sulfhydryl B
groups O
markedly O
( O
p O
< O
0 O
. O
05 O
) O
decreased O
in O
PF O
( O
alone O
) O
group O
when O
compared O
with O
PF O
+ O
EVOO O
group O
. O

Levels O
of O
these O
parameters O
were O
reversed O
to O
nearly O
normal O
values O
by O
topical O
EVOO O
application O
. O

Protection O
by O
EVOO B
is O
further O
substantiated O
via O
the O
improved O
histological O
findings O
in O
PF O
+ O
EVOO B
group O
as O
against O
degenerative O
changes O
in O
the O
rats O
of O
PF O
( O
alone O
) O
group O
. O

Our O
data O
revealed O
that O
EVOO O
has O
protective O
effect O
in O
penile O
cavernosal O
tissue O
through O
probably O
its O
antioxidant O
, O
free O
radical O
defusing O
, O
anti O
- O
inflammatory O
, O
and O
antimicrobial O
effects O
. O

Design O
, O
Synthesis O
and O
Antiviral O
Activity O
of O
2 B
- I
( I
3 I
- I
Amino I
- I
4 I
- I
piperazinylphenyl I
) I
chromone I
Derivatives O
. O

Previously O
, O
we O
have O
confirmed O
that O
the O
antiviral O
activities O
of O
the O
chromone B
derivatives O
were O
controlled O
by O
the O
type O
as O
well O
as O
the O
position O
of O
the O
substituents O
attached O
to O
the O
chromone B
core O
structure O
. O

In O
the O
course O
of O
our O
ongoing O
efforts O
to O
optimize O
the O
antiviral O
activity O
of O
the O
chromone B
derivatives O
, O
we O
have O
been O
attempting O
to O
derivatize O
the O
chromone B
scaffold O
via O
introduction O
of O
various O
substituents O
. O

In O
this O
proof O
- O
of O
- O
concept O
study O
, O
we O
introduced O
a O
3 B
- I
amino I
- I
4 I
- I
piperazinylphenyl I
functionality O
to O
the O
chromone B
scaffold O
and O
evaluated O
the O
antiviral O
activities O
of O
the O
resulting O
chromone B
derivatives O
. O

The O
synthesized O
2 B
- I
( I
3 I
- I
amino I
- I
4 I
- I
piperazinylphenyl I
) I
- I
chromones I
showed O
severe O
acute O
respiratory O
syndrome O
- O
corona O
virus O
( O
SARS O
- O
CoV O
) O
- O
specific O
antiviral O
activity O
. O

In O
particular O
, O
the O
2 B
- I
pyridinylpiperazinyl I
substituents O
provided O
the O
resulting O
chromone B
derivatives O
with O
selective O
antiviral O
activity O
. O

Taken O
together O
, O
this O
result O
indicates O
the O
possible O
pharmacophoric O
role O
of O
the O
2 B
- I
pyridinylpiperazine I
functionality O
attached O
to O
the O
chromone O
scaffold O
, O
which O
warrants O
further O
in O
- O
depth O
structure O
- O
activity O
relationship O
study O
. O

Randomly O
amplified O
polymorphic O
- O
DNA O
analysis O
for O
detecting O
genotoxic O
effects O
of O
Boron B
on O
maize O
( O
Zea O
mays O
L O
. O
) O
. O

This O
study O
was O
carried O
out O
to O
investigate O
the O
genotoxic O
effect O
of O
boron B
( O
B O
) O
on O
maize O
using O
randomly O
amplified O
polymorphic O
DNA O
( O
RAPD O
) O
method O
. O

Experimental O
design O
was O
conducted O
under O
0 O
, O
5 O
, O
10 O
, O
25 O
, O
50 O
, O
100 O
, O
125 O
, O
and O
150 O
ppm O
B O
exposures O
, O
and O
physiological O
changes O
have O
revealed O
a O
sharp O
decrease O
in O
root O
growth O
rates O
from O
28 O
% O
to O
85 O
% O
, O
starting O
from O
25 O
ppm O
to O
150 O
ppm O
, O
respectively O
. O

RAPD O
- O
polymerase O
chain O
reaction O
( O
PCR O
) O
analysis O
shows O
that O
DNA O
alterations O
are O
clearly O
observed O
from O
beginning O
to O
100 O
ppm O
. O

B O
- O
induced O
inhibition O
in O
root O
growth O
had O
a O
positive O
correlation O
with O
DNA O
alterations O
. O

Total O
soluble O
protein O
, O
root O
and O
stem O
lengths O
, O
and O
B B
content O
analysis O
in O
root O
and O
leaves O
encourage O
these O
results O
as O
a O
consequence O
. O

These O
preliminary O
findings O
reveal O
that O
B O
causes O
chromosomal O
aberration O
and O
genotoxic O
effects O
on O
maize O
. O

Meanwhile O
, O
usage O
of O
RAPD O
- O
PCR O
technique O
is O
a O
suitable O
biomarker O
to O
detect O
genotoxic O
effect O
of O
B O
on O
maize O
and O
other O
crops O
for O
the O
future O
. O

PTHrP O
is O
endogenous O
relaxant O
for O
spontaneous O
smooth O
muscle O
contraction O
in O
urinary O
bladder O
of O
female O
rat O
. O

Acute O
bladder O
distension O
causes O
various O
morphological O
and O
functional O
changes O
, O
in O
part O
through O
altered O
gene O
expression O
. O

We O
aimed O
to O
investigate O
the O
physiological O
role O
of O
PTHrP O
, O
which O
is O
upregulated O
in O
an O
acute O
bladder O
distension O
model O
in O
female O
rats O
. O

In O
the O
control O
Empty O
group O
, O
bladders O
were O
kept O
empty O
for O
6 O
h O
, O
and O
in O
the O
Distension O
group O
, O
bladders O
were O
kept O
distended O
for O
3 O
h O
after O
an O
artificial O
storing O
- O
voiding O
cycle O
for O
3 O
h O
. O

In O
the O
Distention O
group O
bladder O
, O
upregulation O
of O
transcripts O
was O
noted O
for O
three O
genes O
reported O
to O
be O
upregulated O
by O
stretch O
in O
the O
cultured O
bladder O
smooth O
muscle O
cells O
( O
BSMC O
) O
in O
vitro O
. O

Further O
transcriptome O
analysis O
by O
microarray O
identified O
PTHrP O
as O
the O
2second O
highest O
gene O
upregulated O
in O
Distension O
group O
bladder O
, O
among O
more O
than O
27 O
, O
000 O
genes O
. O

Localization O
of O
PTHrP O
and O
its O
functional O
receptor O
, O
PTH O
/ O
PTHrP O
receptor O
1 O
( O
PTH1R O
) O
, O
were O
analyzed O
in O
the O
untreated O
rat O
bladders O
and O
cultured O
bladder O
cells O
using O
real O
- O
time O
RT O
- O
PCR O
and O
immunoblotting O
, O
which O
revealed O
that O
PTH1R O
and O
PTHrP O
were O
more O
predominantly O
expressed O
in O
smooth O
muscle O
than O
in O
urothelium O
. O

Exogenous O
PTHrP O
peptide O
( O
1 O
- O
34 O
) O
increased O
intracellular O
cAMP B
level O
in O
cultured O
BSMC O
. O

In O
organ O
bath O
study O
using O
bladder O
strips O
, O
the O
PTHrP O
peptide O
caused O
a O
marked O
reduction O
in O
the O
amplitude O
of O
spontaneous O
contraction O
, O
but O
caused O
only O
modest O
suppression O
for O
carbachol B
- O
induced O
contraction O
. O

In O
in O
vivo O
functional O
study O
by O
cystometrogram O
, O
the O
PTHrP O
peptide O
decreased O
voiding O
pressure O
and O
increased O
bladder O
compliance O
. O

Thus O
, O
PTHrP O
is O
a O
potent O
endogenous O
relaxant O
of O
bladder O
contraction O
, O
and O
autocrine O
or O
paracrine O
mechanism O
of O
PTHrP O
- O
PTH1R O
axis O
is O
a O
physiologically O
relevant O
pathway O
functioning O
in O
the O
bladder O
. O

17 B
beta I
- I
estradiol I
activates O
glucose B
uptake O
via O
GLUT4 O
translocation O
and O
PI3K O
/ O
Akt O
signaling O
pathway O
in O
MCF O
- O
7 O
cells O
. O

The O
relationship O
between O
estrogen B
and O
some O
types O
of O
breast O
cancer O
has O
been O
clearly O
established O
. O

However O
, O
although O
several O
studies O
have O
demonstrated O
the O
relationship O
between O
estrogen B
and O
glucose B
uptake O
via O
PI3K O
/ O
Akt O
in O
other O
tissues O
, O
not O
too O
much O
is O
known O
about O
the O
possible O
cross O
talk O
between O
them O
for O
development O
and O
maintenance O
of O
breast O
cancer O
. O

This O
study O
was O
designed O
to O
test O
the O
rapid O
effects O
of O
17 B
beta I
- I
estradiol I
( O
E2 O
) O
or O
its O
membrane O
- O
impermeable O
form O
conjugated O
with O
bovine O
serum O
albumin O
( O
E2BSA O
) O
on O
glucose B
uptake O
in O
a O
positive O
estrogen B
receptor O
( O
ER O
) O
breast O
cancer O
cell O
line O
, O
through O
the O
possible O
relationship O
between O
key O
components O
of O
the O
PI3K O
/ O
Akt O
signaling O
pathway O
and O
acute O
steroid O
treatment O
. O

MCF O
- O
7 O
human O
breast O
cancer O
cells O
were O
cultured O
in O
standard O
conditions O
. O

Then O
10nM O
of O
17 B
beta I
- I
estradiol I
or O
estradiol B
BSA O
conjugated O
were O
administrated O
before O
obtaining O
the O
cell O
lysates O
. O

To O
study O
the O
glucose B
uptake O
, O
the O
glucose B
fluorescent O
analogue O
2 B
- I
[ I
N I
- I
( I
7 I
- I
nitrobenz I
- I
2 I
- I
oxa I
- I
1 I
, I
3 I
- I
diazol I
- I
4 I
- I
yl I
) I
amino I
] I
- I
2 I
- I
deoxy I
- I
d I
- I
glucose I
was O
used O
. O

We O
report O
an O
ER O
- O
dependent O
activation O
of O
some O
of O
the O
key O
steps O
of O
the O
PI3K O
/ O
Akt O
signaling O
pathway O
cascade O
that O
leads O
cells O
to O
improve O
some O
mechanisms O
that O
finally O
increase O
glucose B
uptake O
capacity O
. O

Our O
data O
suggest O
that O
both O
E2 O
and O
E2BSA B
enhance O
the O
entrance O
of O
the O
fluorescent O
glucose B
analogue O
2 B
- I
NBDG I
, O
and O
also O
activates O
s O
PI3K O
/ O
Akt O
signaling O
pathway O
, O
leading O
to O
translocation O
of O
GLUT4 O
to O
the O
plasma O
membrane O
in O
an O
ER O
alpha O
dependent O
manner O
. O

E2 O
enhances O
ER O
- O
dependent O
rapid O
signaling O
triggered O
, O
partially O
in O
the O
plasma O
membrane O
, O
allowing O
ER O
alpha O
- O
positive O
MCF O
- O
7 O
breast O
cancer O
cells O
to O
increase O
glucose B
uptake O
, O
which O
could O
be O
essential O
to O
meet O
the O
energy O
demands O
of O
the O
high O
rate O
of O
proliferation O
. O

The O
consumption O
of O
n O
- O
3 O
polyunsaturated B
fatty I
acids I
differentially O
modulates O
gene O
expression O
of O
peroxisome O
proliferator O
- O
activated O
receptor O
alpha O
and O
gamma O
and O
hypoxia O
- O
inducible O
factor O
1 O
alpha O
in O
subcutaneous O
adipose O
tissue O
of O
obese O
adolescents O
. O

The O
aim O
of O
this O
study O
was O
to O
evaluate O
the O
effect O
of O
long O
- O
chain O
omega B
- I
3 I
polyunsaturated I
fatty I
acid I
( O
n O
- O
3 O
PUFA B
) O
supplementation O
on O
metabolic O
state O
and O
gene O
expression O
in O
subcutaneous O
adipose O
tissues O
of O
obese O
adolescents O
. O

Obese O
adolescents O
( O
n O
= O
26 O
, O
10 O
girls O
and O
16 O
boys O
) O
aged O
12 O
. O
4 O
+ O
/ O
- O
2 O
. O
1 O
years O
were O
assigned O
to O
a O
12 O
- O
week O
regimen O
of O
n O
- O
3 O
PUFA B
intake O
. O

Five O
times O
per O
day O
, O
subjects O
received O
a O
food O
supplement O
consisting O
of O
eicosapentaenoic B
acid I
( O
EPA B
) O
and O
docosahexaenoic B
acid I
( O
DHA B
) O
( O
3 O
g O
per O
day O
, O
944 O
mg O
EPA B
, O
and O
2 O
, O
088 O
mg O
DHA B
) O
. O

Blood O
parameters O
were O
measured O
, O
and O
subcutaneous O
adipose O
tissue O
biopsies O
were O
analyzed O
to O
determine O
gene O
expression O
at O
baseline O
and O
after O
12 O
weeks O
. O

Student O
' O
s O
t O
test O
and O
the O
Wilcoxon O
signed O
- O
rank O
test O
were O
used O
to O
estimate O
differences O
in O
arithmetic O
means O
of O
pre O
- O
and O
post O
- O
dietary O
supplementation O
for O
various O
anthropometric O
, O
biochemical O
, O
clinical O
, O
and O
gene O
expression O
parameters O
. O

After O
12 O
weeks O
, O
n O
- O
3 O
PUFA B
consumption O
was O
associated O
with O
decreased O
body O
mass O
index O
( O
29 O
. O
7 O
+ O
/ O
- O
4 O
. O
6 O
vs O
. O
27 O
. O
8 O
+ O
/ O
- O
4 O
. O
4 O
kg O
/ O
m O
( O
2 O
) O
; O
P O
< O
0 O
. O
001 O
) O
, O
waist O
circumference O
( O
93 O
. O
2 O
+ O
/ O
- O
9 O
. O
9 O
vs O
. O
90 O
. O
5 O
+ O
/ O
- O
10 O
. O
0 O
cm O
; O
P O
< O
0 O
. O
003 O
) O
, O
hip O
circumference O
( O
102 O
. O
9 O
+ O
/ O
- O
10 O
. O
9 O
vs O
. O
101 O
. O
1 O
+ O
/ O
- O
10 O
. O
9 O
cm O
; O
P O
< O
0 O
. O
014 O
) O
, O

and O
blood O
triglyceride B
levels O
( O
220 O
. O
8 O
+ O
/ O
- O
27 O
. O
4 O
vs O
. O
99 O
. O
7 O
+ O
/ O
- O
32 O
. O
7 O
mg O
/ O
dL O
; O
P O
< O
0 O
. O
001 O
) O
. O

Fatty B
acid I
supplementation O
/ O
n3 O
PUFA B
supplementation O
was O
associated O
with O
a O
downregulated O
expression O
of O
the O
genes O
encoding O
PPAR O
gamma O
and O
PGC O
- O
1 O
alpha O
( O
P O
< O
0 O
. O
001 O
) O
, O
and O
an O
upregulated O
expression O
of O
the O
genes O
encoding O
PPAR O
alpha O
( O
P O
< O
0 O
. O
007 O
) O
and O
SREBP1 O
( O
P O
< O
0 O
. O
021 O
) O
. O

The O
expressions O
of O
SOD2 O
( O
P O
< O
0 O
. O
04 O
) O
, O
CAT O
( O
P O
< O
0 O
. O
001 O
) O
, O
GPX3 O
( O
P O
< O
0 O
. O
032 O
) O
and O
HIF O
- O
1 O
alpha O
protein O
also O
decreased O
. O

Our O
study O
demonstrated O
that O
n O
- O
3 O
PUFA B
consumption O
and O
dietary O
restriction O
improved O
the O
anthropometric O
parameters O
and O
decreased O
the O
triglycerides B
levels O
of O
the O
adolescents O
, O
suggesting O
a O
reduction O
in O
hypoxia O
in O
subcutaneous O
adipose O
tissue O
. O

Structure O
of O
Bradyrhizobium O
japonicum O
transcription O
factor O
FixK2 O
unveils O
sites O
of O
DNA O
binding O
and O
oxidation O
. O

FixK2 O
is O
an O
important O
regulatory O
protein O
that O
helps O
activating O
a O
large O
number O
of O
genes O
for O
the O
anoxic O
and O
microoxic O
, O
endosymbiotic O
and O
nitrogen B
- O
fixing O
life O
styles O
of O
the O
alpha O
- O
proteobacterium O
Bradyrhizobium O
japonicum O
. O

FixK2 O
belongs O
to O
the O
cyclic B
AMP I
receptor O
protein O
( O
CRP O
) O
superfamily O
. O

While O
most O
CRP O
- O
family O
members O
are O
co O
- O
regulated O
by O
effector O
molecules O
, O
the O
activity O
of O
FixK2 O
is O
negatively O
controlled O
by O
oxidation O
of O
its O
single O
cysteine B
( O
C183 O
) O
located O
next O
to O
the O
DNA O
binding O
domain O
, O
and O
possibly O
also O
by O
proteolysis O
. O

Here O
we O
report O
the O
three O
- O
dimensional O
X O
- O
ray O
structure O
of O
FixK2 O
, O
a O
representative O
of O
the O
FixK O
subgroup O
of O
the O
CRP O
superfamily O
. O

Crystallization O
succeeded O
only O
( O
i O
) O
when O
an O
oxidation O
- O
and O
protease O
- O
insensitive O
protein O
variant O
( O
C183S O
- O
FixK2His6 O
) O
was O
used O
, O
in O
which O
C183 O
was O
replaced O
by O
serine B
and O
the O
C B
- O
terminus O
fused O
with O
a O
hexa B
- I
histidine I
tag O
, O
and O
( O
ii O
) O
when O
this O
protein O
was O
allowed O
to O
form O
a O
complex O
with O
a O
30mer O
double O
- O
strand O
target O
DNA O
. O

The O
structure O
of O
the O
FixK2 O
- O
DNA O
complex O
was O
solved O
at O
a O
resolution O
of O
1 O
. O
77 O
A O
in O
which O
the O
protein O
formed O
a O
homodimer O
. O

The O
precise O
protein O
- O
DNA O
contacts O
were O
identified O
which O
led O
to O
an O
affirmation O
of O
the O
canonical O
target O
sequence O
, O
the O
so O
- O
called O
FixK2 O
box O
. O

The O
C B
- O
terminus O
is O
surface O
- O
exposed O
which O
might O
explain O
its O
sensitivity O
to O
specific O
cleavage O
and O
degradation O
. O

The O
oxidation O
- O
sensitive O
C183 O
is O
also O
surface O
- O
exposed O
and O
in O
close O
proximity O
to O
DNA O
. O

Therefore O
, O
we O
propose O
a O
mechanism O
whereby O
the O
oxo B
- I
acids I
generated O
after O
oxidation O
of O
the O
cysteine B
thiol B
cause O
an O
electrostatic O
repulsion O
, O
thus O
preventing O
specific O
DNA O
binding O
. O

Nanostructured O
potential O
of O
optical O
trapping O
using O
a O
plasmonic O
nanoblock O
pair O
. O

We O
performed O
two O
- O
dimensional O
mapping O
of O
optical O
trapping O
potentials O
experienced O
by O
a O
100 O
nm O
dielectric O
particle O
above O
a O
plasmon O
- O
resonant O
gold O
nanoblock O
pair O
with O
a O
gap O
of O
several O
nanometers O
. O

Our O
results O
demonstrate O
that O
the O
potentials O
have O
nanoscale O
spatial O
structures O
that O
reflect O
the O
near O
- O
field O
landscape O
of O
the O
nanoblock O
pair O
. O

When O
an O
incident O
polarization O
parallel O
to O
the O
pair O
axis O
is O
rotated O
by O
90 O
degrees O
, O
a O
single O
potential O
well O
turns O
into O
multiple O
potential O
wells O
separated O
by O
a O
distance O
smaller O
than O
the O
diffraction O
limit O
; O
this O
is O
associated O
with O
super O
- O
resolution O
optical O
trapping O
. O

In O
addition O
, O
we O
show O
that O
the O
trap O
stiffness O
can O
be O
enhanced O
by O
approximately O
3 O
orders O
of O
magnitude O
compared O
to O
that O
with O
conventional O
far O
- O
field O
trapping O
. O

Photoinduced O
and O
Thermal O
Denitrogenation O
of O
Bulky O
Triazoline B
Crystals O
: O
Insights O
into O
Solid O
- O
to O
- O
Solid O
Transformation O
. O

The O
photoinduced O
and O
thermal O
denitrogenation O
of O
crystalline O
triazolines B
with O
bulky O
substituents O
leads O
to O
the O
quantitative O
formation O
of O
aziridines B
in O
clean O
solid O
- O
to O
- O
solid O
reactions O
despite O
very O
large O
structural O
changes O
in O
the O
transition O
from O
reactant O
to O
product O
. O

Analysis O
of O
the O
reaction O
progress O
by O
powder O
X O
- O
ray O
diffraction O
, O
solid O
- O
state O
( B
13 I
) I
C I
CPMAS O
NMR O
, O
solid O
- O
state O
FTIR O
spectroscopy O
, O
and O
thermal O
analysis O
has O
revealed O
that O
solid O
- O
to O
- O
solid O
reactions O
proceed O
either O
through O
metastable O
phases O
susceptible O
to O
amorphization O
or O
by O
mechanisms O
that O
involve O
a O
reconstructive O
phase O
transition O
that O
culminates O
in O
the O
formation O
of O
the O
stable O
phase O
of O
the O
product O
. O

While O
the O
key O
for O
a O
solid O
- O
to O
- O
solid O
transformation O
is O
that O
the O
reaction O
occurs O
below O
the O
eutectic O
temperature O
of O
the O
reactant O
and O
product O
two O
- O
component O
system O
, O
experimental O
evidence O
suggests O
that O
those O
reactions O
will O
undergo O
a O
reconstructive O
phase O
transition O
when O
they O
take O
place O
above O
the O
glass O
transition O
temperature O
. O

Genetics O
of O
serotonin B
receptors O
and O
depression O
: O
state O
of O
the O
art O
. O

Major O
depression O
( O
MD O
) O
is O
a O
major O
health O
problem O
, O
partly O
due O
to O
the O
incomplete O
understanding O
of O
the O
pathogenic O
mechanisms O
of O
the O
disease O
. O

Research O
efforts O
have O
mainly O
focused O
on O
alterations O
in O
monoaminergic O
neurotransmission O
, O
especially O
in O
relation O
to O
the O
serotonergic O
system O
, O
due O
to O
its O
key O
role O
in O
the O
regulation O
of O
mood O
and O
related O
biological O
functions O
. O

Given O
the O
high O
heritability O
of O
MD O
( O
estimated O
between O
31 O
% O
and O
42 O
% O
for O
unipolar O
depression O
) O
, O
genes O
coding O
for O
key O
regulators O
of O
the O
serotonergic O
neurotransmission O
have O
been O
considered O
as O
optimal O
candidates O
. O

The O
present O
review O
is O
focused O
on O
the O
role O
of O
genes O
coding O
for O
serotonin B
receptors O
in O
MD O
pathogenesis O
, O
since O
the O
serotonin B
transporter O
and O
enzymes O
involved O
in O
serotonin B
metabolism O
have O
been O
reviewed O
elsewhere O
. O

Despite O
the O
large O
number O
of O
candidate O
gene O
studies O
focusing O
on O
genes O
coding O
for O
serotonin B
receptors O
, O
results O
have O
been O
inconsistent O
. O

The O
most O
replicated O
findings O
are O
the O
associations O
between O
rs6295 O
( O
HTR1A O
gene O
) O
G O
allele O
or O
G O
/ O
G O
genotype O
and O
rs6311 O
( O
HTR2A O
gene O
) O
A O
allele O
or O
A O
/ O
A O
genotype O
and O
MD O
or O
depressive O
symptoms O
. O

Preclinical O
and O
imaging O
/ O
post O
- O
mortem O
studies O
in O
humans O
provide O
strong O
support O
for O
the O
involvement O
of O
HTR1A O
and O
HTR2A O
genes O
in O
MD O
. O

Nevertheless O
, O
the O
inconsistency O
across O
previous O
studies O
clearly O
suggests O
that O
innovative O
approaches O
should O
be O
designed O
in O
order O
to O
overcome O
the O
limitations O
of O
candidate O
gene O
studies O
. O

To O
date O
, O
the O
most O
appealing O
methodologies O
seem O
to O
be O
full O
exome O
or O
genome O
sequencing O
, O
genome O
- O
wide O
pathway O
analyses O
, O
endophenotypes O
, O
and O
epigenetic O
biomarkers O
. O

The O
reported O
tools O
may O
assist O
in O
the O
detection O
of O
multiple O
- O
loci O
models O
, O
which O
could O
potentially O
explain O
the O
high O
percentage O
of O
MD O
susceptibility O
ascribed O
to O
genetic O
factors O
. O

Key O
targets O
and O
relevant O
inhibitors O
for O
the O
drug O
discovery O
of O
tuberculosis O
. O

Tuberculosis O
( O
TB O
) O
is O
an O
infectious O
disease O
caused O
by O
the O
pathogen O
Mycobacterium O
tuberculosis O
( O
M O
. O
tuberculosis O
) O
, O
killing O
about O
two O
million O
people O
worldwide O
each O
year O
. O

An O
increase O
in O
the O
prevalence O
of O
drug O
- O
resistant O
strains O
of O
M O
. O
tuberculosis O
in O
the O
past O
decades O
has O
renewed O
focus O
on O
the O
development O
of O
new O
drugs O
that O
can O
treat O
both O
drug O
- O
sensitive O
and O
resistant O
TB O
infections O
. O

M O
. O
tuberculosis O
evades O
the O
host O
immune O
system O
and O
drug O
regimes O
by O
entering O
dormant O
phase O
within O
macrophage O
. O

As O
a O
consequence O
, O
there O
is O
a O
pressing O
need O
for O
new O
vaccines O
and O
antimicrobials O
to O
treat O
persistent O
infections O
. O

As O
clinically O
used O
antibiotics O
target O
very O
few O
essential O
functions O
of O
mycobacterium O
, O
it O
is O
rational O
that O
identification O
of O
new O
targets O
that O
are O
essential O
for O
bacterial O
growth O
and O
survival O
can O
serve O
as O
starting O
point O
for O
designing O
of O
novel O
drugs O
to O
cure O
both O
drug O
- O
sensitive O
and O
resistant O
TB O
infections O
. O

With O
the O
development O
of O
molecular O
biology O
and O
structural O
biology O
and O
the O
availability O
of O
the O
genome O
sequence O
of O
M O
. O
tuberculosis O
, O
some O
success O
has O
been O
achieved O
in O
the O
identification O
of O
new O
targets O
in O
M O
. O
tuberculosis O
and O
their O
relevant O
inhibitors O
. O

This O
review O
summarizes O
about O
ninety O
important O
targets O
that O
participate O
in O
a O
range O
of O
diverse O
physiological O
processes O
in O
M O
. O
tuberculosis O
and O
seven O
new O
drugs O
currently O
in O
clinical O
phase O
2 O
or O
3 O
trials O
. O

In O
addition O
, O
promising O
inhibitors O
with O
novel O
mechanisms O
of O
action O
and O
clinical O
vaccine O
candidates O
are O
highlighted O
. O

Discovery O
of O
the O
First O
C B
- I
Nucleoside I
HCV O
Polymerase O
Inhibitor O
( O
GS B
- I
6620 I
) O
with O
Demonstrated O
Antiviral O
Response O
in O
HCV O
Infected O
Patients O
. O

Hepatitis O
C O
virus O
( O
HCV O
) O
infection O
presents O
an O
unmet O
medical O
need O
requiring O
more O
effective O
treatment O
options O
. O

Nucleoside B
inhibitors O
( O
NI O
) O
of O
HCV O
polymerase O
( O
NS5B O
) O
have O
demonstrated O
pan O
- O
genotypic O
activity O
and O
durable O
antiviral O
response O
in O
the O
clinic O
, O
and O
they O
are O
likely O
to O
become O
a O
key O
component O
of O
future O
treatment O
regimens O
. O

NI O
candidates O
that O
have O
entered O
clinical O
development O
thus O
far O
have O
all O
been O
N B
- I
nucleoside I
derivatives O
. O

Herein O
, O
we O
report O
the O
discovery O
of O
a O
C B
- I
nucleoside I
class O
of O
NS5B O
inhibitors O
. O

Exploration O
of O
adenosine B
analogs O
in O
this O
class O
identified O
1 B
' I
- I
cyano I
- I
2 I
' I
- I
C I
- I
methyl I
4 I
- I
aza I
- I
7 I
, I
9 I
- I
dideaza I
adenosine I
as O
a O
potent O
and O
selective O
inhibitor O
of O
NS5B O
. O

A O
monophosphate B
prodrug O
approach O
afforded O
a O
series O
of O
compounds O
showing O
submicromolar O
activity O
in O
HCV O
replicon O
assays O
. O

Further O
pharmacokinetic O
optimization O
for O
sufficient O
oral O
absorption O
and O
liver O
triphosphate B
loading O
led O
to O
identification O
of O
a O
clinical O
development O
candidate O
GS B
- I
6620 I
. O

In O
a O
phase O
I O
clinical O
study O
, O
the O
potential O
for O
potent O
activity O
was O
demonstrated O
but O
with O
high O
intra O
- O
and O
interpatient O
pharmacokinetic O
and O
pharmacodynamic O
variability O
. O

Cytotoxicity O
and O
Modulation O
of O
Cancer O
- O
Related O
Signaling O
by O
( B
Z I
) I
- I
and I
( I
E I
) I
- I
3 I
, I
4 I
, I
3 I
' I
, I
5 I
' I
- I
Tetramethoxystilbene I
Isolated O
from O
Eugenia O
rigida O
. O

Bioassay O
- O
guided O
fractionation O
of O
the O
leaves O
of O
Eugenia O
rigida O
yielded O
three O
stilbenes B
, O
( B
Z I
) I
- I
3 I
, I
4 I
, I
3 I
' I
, I
5 I
' I
- I
tetramethoxystilbene I
( O
1 O
) O
, O
( B
E I
) I
- I
3 I
, I
4 I
, I
3 I
' I
, I
5 I
' I
- I
tetramethoxystilbene I
( O
2 O
) O
, O
and O
( B
E I
) I
- I
3 I
, I
5 I
, I
4 I
' I
- I
trimethoxystilbene I
( O
3 O
) O
. O

Their O
structures O
were O
determined O
using O
1D O
- O
and O
2D O
- O
NMR O
spectroscopy O
and O
HRESIMS O
. O

The O
sterically O
hindered O
Z O
- O
stereoisomer O
1 O
, O
a O
new O
natural O
product O
, O
was O
prepared O
by O
time O
- O
dependent O
photoisomerization O
of O
the O
E O
- O
isomer O
( O
2 O
) O
under O
UV O
irradiation O
at O
lambda O
254 O
nm O
, O
while O
2 B
, I
3 I
, I
5 I
, I
7 I
- I
tetramethoxyphenanth I
( O
5 O
) O
was O
identified O
at O
lambda O
365 O
nm O
by O
UHPLC O
/ O
APCI O
- O
MS O
and O
NMR O
spectroscopy O
. O

Compounds O
1 O
- O
3 O
were O
tested O
against O
a O
panel O
of O
luciferase O
reporter O
gene O
assays O
that O
assess O
the O
activity O
of O
many O
cancer O
- O
related O
signaling O
pathways O
, O
and O
the O
Z O
- O
isomer O
( O
1 O
) O
was O
found O
to O
be O
more O
potent O
than O
the O
E O
- O
isomer O
( O
2 O
) O
in O
inhibiting O
the O
activation O
of O
Stat3 O
, O
Smad3 O
/ O
4 O
, O
myc O
, O
Ets O
, O
Notch O
, O
and O
Wnt O
signaling O
, O
with O
IC50 O
values O
between O
40 O
and O
80 O
mu O
M O
. O

However O
, O
both O
compounds O
showed O
similar O
inhibition O
against O
Ap O
- O
1 O
and O
NF O
- O
kappa O
B O
signaling O
. O

In O
addition O
, O
1 O
demonstrated O
cytotoxic O
activity O
toward O
human O
leukemia O
cells O
, O
solid O
tumor O
cells O
of O
epidermal O
, O
breast O
, O
and O
cervical O
carcinomas O
, O
and O
skin O
melanoma O
, O
with O
IC50 O
values O
between O
3 O
. O
6 O
and O
4 O
. O
3 O
mu O
M O
, O
while O
2 O
was O
weakly O
active O
against O
leukemia O
, O
cervical O
carcinoma O
, O
and O
skin O
melanoma O
cells O
. O

Interestingly O
, O
2 O
showed O
antioxidant O
activity O
by O
inhibition O
of O
ROS O
generation O
to O
50 O
% O
at O
33 O
. O
3 O
mu O
M O
in O
PMA B
- O
induced O
HL O
- O
60 O
cells O
, O
while O
1 O
was O
inactive O
at O
100 O
mu O
M O
( O
vs O
Trolox B
1 O
. O
4 O
mu O
M O
) O
. O

Neoclerodanes B
as O
Atypical O
Opioid O
Receptor O
Ligands O
. O

The O
neoclerodane B
diterpene I
salvinorin B
A I
is O
the O
major O
active O
component O
of O
the O
hallucinogenic O
mint O
plant O
Salvia O
divinorum O
Epling O
and O
J O
a O
tiva O
( O
Lamiaceae O
) O
. O

Since O
the O
finding O
that O
salvinorin B
A I
exerts O
its O
potent O
psychotropic O
actions O
through O
the O
activation O
of O
opioid O
receptors O
, O
the O
site O
of O
action O
of O
morphine B
and O
related O
analogues O
, O
there O
has O
been O
much O
interest O
in O
elucidating O
the O
underlying O
mechanisms O
behind O
its O
effects O
. O

These O
effects O
are O
particularly O
remarkable O
because O
( O
1 O
) O
salvinorin B
A I
is O
the O
first O
reported O
non O
- O
nitrogenous O
opioid O
receptor O
agonist O
and O
( O
2 O
) O
its O
effects O
are O
not O
mediated O
through O
the O
previously O
investigated O
targets O
of O
psychotomimetics O
. O

This O
Perspective O
outlines O
our O
research O
program O
, O
illustrating O
a O
new O
direction O
to O
the O
development O
of O
tools O
to O
further O
elucidate O
the O
biological O
mechanisms O
of O
drug O
tolerance O
and O
dependence O
. O

The O
information O
gained O
from O
these O
efforts O
is O
expected O
to O
facilitate O
the O
design O
of O
novel O
agents O
to O
treat O
pain O
, O
drug O
abuse O
, O
and O
other O
central O
nervous O
system O
disorders O
. O

Formation O
of O
a O
tyrosine B
adduct O
involved O
in O
lignin O
degradation O
by O
Trametopsis O
cervina O
lignin O
peroxidase O
: O
A O
novel O
peroxidase O
activation O
mechanism O
. O

Lignin O
peroxidase O
( O
LiP O
) O
from O
Trametopsis O
cervina O
has O
an O
exposed O
catalytic O
tyrosine B
( O
Tyr B
- O
181 O
) O
instead O
of O
the O
conserved O
tryptophan B
of O
other O
lignin O
- O
degrading O
peroxidases O
. O

Pristine O
LiP O
showed O
a O
lag O
period O
in O
veratryl B
alcohol I
( O
VA O
) O
oxidation O
. O

However O
, O
LiP O
after O
turnover O
with O
H2O2 B
/ O
VA O
( O
VA O
- O
LiP O
) O
lacked O
this O
lag O
, O
and O
H2O2 B
- O
pretreated O
LiP O
( O
H2O2 B
- O
LiP O
) O
was O
inactive O
. O

MS O
analyses O
revealed O
that O
VA O
- O
LiP O
includes O
one O
VA O
molecule O
covalently O
bound O
to O
the O
side O
- O
chain O
of O
Tyr B
- O
181 O
, O
whereas O
H2O2 B
- O
LiP O
contains O
hydroxylated O
Tyr B
- O
181 O
. O

No O
adduct O
is O
formed O
by O
the O
Y171N O
variant O
. O

Molecular O
docking O
showed O
that O
VA O
binding O
is O
favored O
by O
sandwich O
pi O
stacking O
with O
Tyr B
- O
181 O
and O
Phe B
- O
89 O
. O

EPR O
spectroscopy O
after O
peroxide B
activation O
of O
the O
pretreated O
LiPs O
showed O
other O
protein O
radicals O
than O
the O
tyrosine B
radical O
found O
in O
pristine O
LiP O
, O
which O
were O
assigned O
to O
a O
tyrosine B
/ O
VA O
adduct O
radical O
in O
VA O
- O
LiP O
and O
a O
dihydroxyphenyalanin B
radical O
in O
H2O2 B
- O
LiP O
. O

Both O
radicals O
are O
able O
to O
oxidize O
large O
low O
redox O
- O
potential O
substrates O
, O
but O
H2O2 B
- O
LiP O
is O
unable O
to O
oxidize O
high O
redox O
- O
potential O
substrates O
. O

Transient O
- O
state O
kinetics O
showed O
that O
the O
tyrosine B
/ O
VA O
adduct O
strongly O
promotes O
( O
> O
100 O
- O
fold O
) O
substrate O
oxidation O
by O
compound O
II O
, O
the O
rate O
- O
limiting O
step O
in O
catalysis O
. O

The O
novel O
activation O
mechanism O
is O
involved O
in O
ligninolysis O
, O
as O
demonstrated O
using O
lignin O
model O
substrates O
. O

This O
is O
the O
first O
report O
on O
autocatalytic O
modification O
, O
resulting O
in O
functional O
alteration O
, O
among O
class O
- O
II O
peroxidases O
. O

Nrf2 O
- O
dependent O
neuroprotective O
activity O
of O
diterpenoids B
isolated O
from O
Sideritis O
spp O
. O

ETHNOPHARMACOLOGICAL O
RELEVANCE O
: O
The O
species O
of O
the O
genus O
Sideritis O
are O
extensively O
used O
in O
the O
Mediterranean O
area O
in O
folk O
medicine O
for O
their O
digestive O
, O
antimicrobial O
, O
anti O
- O
inflammatory O
and O
antioxidant O
properties O
, O
among O
others O
. O

Moreover O
, O
Sideritis O
species O
as O
tea O
infusions O
are O
popularly O
known O
for O
improving O
memory O
function O
and O
cognitive O
ability O
. O

Diterpenoids B
are O
one O
of O
the O
most O
abundant O
and O
important O
pharmacological O
interest O
of O
the O
classes O
of O
natural O
products O
presented O
in O
these O
medicinal O
plants O
. O

AIM O
OF O
THE O
STUDY O
: O
To O
determine O
for O
the O
first O
time O
the O
neuroprotective O
effects O
, O
based O
on O
their O
antioxidant O
properties O
, O
of O
the O
three O
isolated O
major O
diterpenoids B
andalusol B
, O
conchitriol B
and O
lagascatriol B
in O
an O
oxidative O
stress O
model O
. O

MATERIALS O
AND O
METHODS O
: O
H2O2 B
was O
used O
as O
oxidant O
inductor O
and O
rat O
adrenal O
pheochromocytoma O
PC12 O
cells O
as O
cellular O
model O
. O

Cell O
viability O
was O
measured O
using O
MTT B
and O
LDH O
assays O
, O
lipid O
peroxidation O
was O
determined O
by O
HPLC O
, O
GSH B
and O
GSSG B
levels O
assessed O
by O
fluorometric O
techniques O
, O
enzymatic O
activity O
and O
protein O
expression O
were O
determined O
by O
spectrofometric O
techniques O
and O
Western O
blot O
, O
respectively O
. O

RESULTS O
: O
Pretreatments O
with O
the O
three O
diterpenoids B
significantly O
attenuated O
H2O2 B
- O
induced O
changes O
in O
mitochondrial O
integrity O
and O
activity O
( O
MTT B
assay O
) O
, O
in O
cell O
membrane O
integrity O
( O
LDH O
assay O
) O
and O
in O
cell O
morphology O
. O

Moreover O
, O
these O
diterpenoids B
inhibited O
intracellular O
ROS O
production O
H2O2 B
- O
induced O
, O
reduced O
lipid O
peroxidation O
and O
counteracted O
GSH B
/ O
GSSG B
changes O
. O

Furthermore O
, O
both O
activities O
and O
protein O
expression O
of O
the O
endogenous O
antioxidant O
enzymes O
( O
CAT O
, O
SOD O
, O
GR O
, O
GPx O
and O
HO O
- O
1 O
) O
were O
increased O
. O

The O
Nrf2 O
pathway O
was O
involved O
, O
at O
least O
in O
part O
, O
in O
the O
protective O
effects O
of O
these O
diterpenoids B
. O

CONCLUSION O
: O
These O
findings O
suggest O
that O
these O
natural O
compounds O
provide O
significant O
antioxidant O
effects O
in O
PC12 O
under O
for O
counteracting O
the O
oxidative O
damage O
H2O2 B
- O
induced O
and O
their O
potential O
role O
as O
useful O
agents O
for O
the O
prevention O
of O
those O
oxidative O
stress O
- O
mediated O
dementia O
disorders O
. O

Andalusol B
was O
the O
most O
active O
compound O
among O
the O
studied O
diterpenoids B
. O

The O
putative O
JAK O
- O
STAT O
inhibitor O
AG490 B
exacerbates O
LPS O
- O
fever O
, O
reduces O
sickness O
behavior O
, O
and O
alters O
the O
expression O
of O
pro O
- O
and O
anti O
- O
inflammatory O
genes O
in O
the O
rat O
brain O
. O

The O
functional O
significance O
for O
activation O
of O
inflammatory O
transcription O
factors O
, O
such O
as O
signal O
transducer O
and O
activator O
of O
transcription O
( O
STAT3 O
) O
, O
nuclear O
factor O
( O
NF O
) O
kappa O
B O
or O
NF O
- O
interleukin O
( O
IL O
) O
6 O
and O
their O
contribution O
to O
the O
induction O
of O
brain O
controlled O
sickness O
responses O
, O
such O
as O
fever O
, O
during O
infection O
and O
inflammation O
is O
unknown O
. O

Using O
AG490 B
, O
previously O
shown O
to O
inhibit O
the O
STAT3 O
- O
and O
NF O
- O
IL6 O
- O
signaling O
pathway O
, O
we O
therefore O
investigated O
the O
central O
involvement O
of O
these O
two O
signaling O
pathways O
in O
mediating O
sickness O
behavior O
, O
fever O
and O
accompanying O
brain O
inflammation O
induced O
by O
peripheral O
lipopolysaccharide O
( O
LPS O
) O
- O
stimulation O
. O

Rats O
pre O
- O
treated O
i O
. O
c O
. O
v O
. O
with O
AG490 B
1 O
h O
before O
the O
i O
. O
p O
. O

LPS O
- O
challenge O
( O
100 O
mu O
g O
/ O
kg O
) O
showed O
a O
modestly O
exaggerated O
fever O
, O
attenuated O
adipsia O
and O
almost O
unimpaired O
locomotor O
activity O
compared O
to O
LPS O
- O
controls O
receiving O
vehicle O
( O
i O
. O
c O
. O
v O
. O
) O
. O

The O
LPS O
- O
induced O
anorexia O
was O
not O
altered O
and O
AG490 B
did O
not O
have O
any O
effect O
on O
rats O
receiving O
PBS O
( O
i O
. O
p O
. O
) O
. O

We O
did O
observe O
effects O
of O
AG490 B
on O
STAT3 O
- O
signaling O
at O
4 O
h O
, O
while O
AG490 B
- O
mediated O
changes O
in O
brain O
activity O
of O
inflammatory O
transcription O
factors O
at O
8 O
h O
were O
not O
significant O
. O

Increased O
NF O
- O
IL6 O
and O
suppressor O
of O
cytokines O
3 O
mRNA O
- O
expression O
in O
AG490 B
/ O
LPS O
- O
treated O
rats O
were O
indicative O
of O
a O
compensative O
activation O
at O
24 O
h O
. O

Moreover O
, O
a O
significant O
decrease O
in O
hypothalamic O
anti O
- O
inflammatory O
IL O
- O
10 O
- O
expression O
and O
an O
increase O
in O
inflammatory O
microsomal O
prostaglandin B
E I
synthase O
( O
mPGES O
) O
mRNA O
- O
expression O
8 O
h O
after O
LPS O
- O
injection O
was O
revealed O
in O
AG490 B
pre O
- O
treated O
animals O
compared O
to O
solvent O
- O
treated O
LPS O
- O
controls O
. O

In O
summary O
, O
we O
have O
shown O
a O
dissociation O
between O
the O
effects O
of O
central O
AG490 B
treatment O
on O
fever O
and O
components O
of O
sickness O
behavior O
, O
which O
appears O
to O
be O
related O
to O
reduced O
IL O
- O
10 O
and O
increased O
mPGES O
- O
expression O
in O
the O
brain O
. O

Thus O
, O
AG490 B
might O
have O
therapeutic O
potential O
to O
reduce O
sickness O
behavior O
. O

Distinct O
signaling O
cascades O
elicited O
by O
different O
formyl B
Peptide O
receptor O
2 O
( O
FPR2 O
) O
agonists O
. O

The O
formyl B
peptide O
receptor O
2 O
( O
FPR2 O
) O
is O
a O
remarkably O
versatile O
transmembrane O
protein O
belonging O
to O
the O
G O
- O
protein O
coupled O
receptor O
( O
GPCR O
) O
family O
. O

FPR2 O
is O
activated O
by O
an O
array O
of O
ligands O
, O
which O
include O
structurally O
unrelated O
lipids O
and O
peptide O
/ O
proteins O
agonists O
, O
resulting O
in O
different O
intracellular O
responses O
in O
a O
ligand O
- O
specific O
fashion O
. O

In O
addition O
to O
the O
anti O
- O
inflammatory O
lipid O
, O
lipoxin B
A4 I
, O
several O
other O
endogenous O
agonists O
also O
bind O
FPR2 O
, O
including O
serum O
amyloid O
A O
, O
glucocorticoid O
- O
induced O
annexin O
1 O
, O
urokinase O
and O
its O
receptor O
, O
suggesting O
that O
the O
activation O
of O
FPR2 O
may O
result O
in O
potent O
pro O
- O
or O
anti O
- O
inflammatory O
responses O
. O

Other O
endogenous O
ligands O
, O
also O
present O
in O
biological O
samples O
, O
include O
resolvins B
, O
amyloidogenic O
proteins O
, O
such O
as O
beta O
amyloid O
( O
A O
beta O
) O
- O
42 O
and O
prion O
protein O
( O
Prp O
) O
106 O
- O
126 O
, O
the O
neuroprotective O
peptide O
, O
humanin O
, O
antibacterial O
peptides O
, O
annexin O
1 O
- O
derived O
peptides O
, O
chemokine O
variants O
, O
the O
neuropeptides O
, O
vasoactive O
intestinal O
peptide O
( O
VIP O
) O
and O
pituitary O
adenylate O
cyclase O
activating O
polypeptide O
( O

PACAP O
) O
- O
27 O
, O
and O
mitochondrial O
peptides O
. O

Upon O
activation O
, O
intracellular O
domains O
of O
FPR2 O
mediate O
signaling O
to O
G O
- O
proteins O
, O
which O
trigger O
several O
agonist O
- O
dependent O
signal O
transduction O
pathways O
, O
including O
activation O
of O
phospholipase O
C O
( O
PLC O
) O
, O
protein O
kinase O
C O
( O
PKC O
) O
isoforms O
, O
the O
phosphoinositide O
3 O
- O
kinase O
( O
PI3K O
) O
/ O
protein O
kinase O
B O
( O
Akt O
) O
pathway O
, O
the O
mitogen O
- O
activated O
protein O
kinase O
( O
MAPK O
) O
pathway O
, O
p38MAPK O
, O
as O
well O
as O
the O
phosphorylation O
of O
cytosolic O
tyrosine B
kinases O
, O

tyrosine B
kinase O
receptor O
transactivation O
, O
phosphorylation O
and O
nuclear O
translocation O
of O
regulatory O
transcriptional O
factors O
, O
release O
of O
calcium B
and O
production O
of O
oxidants O
. O

FPR2 O
is O
an O
attractive O
therapeutic O
target O
, O
because O
of O
its O
involvement O
in O
a O
range O
of O
normal O
physiological O
processes O
and O
pathological O
diseases O
. O

Here O
, O
we O
review O
and O
discuss O
the O
most O
significant O
findings O
on O
the O
intracellular O
pathways O
and O
on O
the O
cross O
- O
communication O
between O
FPR2 O
and O
tyrosine B
kinase O
receptors O
triggered O
by O
different O
FPR2 O
agonists O
. O

Isolation O
and O
Structure O
Elucidation O
of O
Three O
New O
Dolastanes B
from O
the O
Brown O
Alga O
Dilophus O
spiralis O
. O

Three O
new O
dolastane B
diterpenes B
( O
1 O
- O
3 O
) O
and O
five O
previously O
reported O
perhydroazulenes B
were O
isolated O
from O
the O
organic O
extracts O
of O
the O
brown O
alga O
Dilophus O
spiralis O
. O

The O
structure O
elucidation O
and O
the O
assignment O
of O
the O
relative O
configurations O
of O
the O
isolated O
natural O
products O
were O
based O
on O
extensive O
analyses O
of O
their O
spectroscopic O
data O
, O
whereas O
the O
absolute O
configuration O
of O
metabolite O
2 O
was O
determined O
through O
its O
chemical O
conversion O
to O
a O
previously O
isolated O
compound O
of O
known O
configuration O
. O

A O
Distal O
Enhancer O
Controls O
Cytokine O
- O
dependent O
Human O
cPLA2 O
alpha O
Gene O
Expression O
. O

Specific O
control O
of O
group O
IVA O
cytosolic O
phospholipase O
A2 O
( O
cPLA2 O
alpha O
or O
PLA2G4A O
) O
expression O
modulates O
arachidonic B
acid I
production O
, O
thus O
tightly O
regulating O
the O
downstream O
effects O
of O
pro O
- O
and O
anti O
- O
inflammatory O
eicosanoids B
. O

The O
significance O
of O
this O
pathway O
in O
human O
disease O
is O
apparent O
in O
a O
range O
of O
pathologies O
from O
inflammation O
to O
tumorigenesis O
. O

While O
much O
of O
the O
regulation O
of O
cPLA2 O
alpha O
has O
focused O
on O
post O
- O
translational O
phosphorylation O
of O
the O
protein O
, O
studies O
on O
transcriptional O
regulation O
of O
this O
gene O
have O
focused O
only O
on O
proximal O
promoter O
regions O
. O

We O
have O
identified O
a O
DNase O
I O
hypersensitive O
site O
encompassing O
a O
5 O
' O
distal O
enhancer O
element O
containing O
a O
highly O
conserved O
consensus O
AP O
- O
1 O
site O
involved O
in O
transcriptional O
activation O
of O
cPLA2 O
alpha O
by O
IL O
- O
1 O
beta O
. O

ChIP O
, O
knockdown O
, O
knockout O
and O
overexpression O
analyses O
have O
shown O
that O
c O
- O
Jun O
acts O
both O
in O
a O
negative O
and O
positive O
regulatory O
role O
. O

Transcriptional O
activation O
of O
cPLA2 O
alpha O
occurs O
through O
the O
phosphorylation O
of O
c O
- O
Jun O
in O
conjunction O
with O
increased O
association O
of O
C O
/ O
EBP O
beta O
with O
the O
distal O
novel O
enhancer O
. O

The O
association O
of O
C O
/ O
EBP O
beta O
with O
the O
transcriptional O
activation O
complex O
does O
not O
require O
an O
obvious O
DNA O
binding O
site O
. O

These O
data O
provide O
new O
and O
important O
contributions O
to O
the O
understanding O
of O
cPLA2 O
alpha O
regulation O
at O
the O
transcriptional O
level O
with O
implications O
to O
eicosanoid B
metabolism O
, O
cellular O
signaling O
and O
disease O
pathogenesis O
. O

Ultrahigh O
- O
efficiency O
photocatalysts O
based O
on O
mesoporous O
Pt B
- O
WO3 B
nanohybrids O
. O

A O
reliable O
nanocasting O
method O
has O
been O
developed O
to O
synthesize O
mesoporous O
hybrids O
of O
platinum B
( O
Pt B
) O
nanoparticles O
decorating O
tungsten B
trioxide I
( O
WO3 B
) O
. O

The O
process O
began O
with O
modification O
of O
the O
SBA O
- I
15 I
template O
with O
carbon B
polymers O
and O
Pt B
nanoparticles O
accompanied O
by O
adsorption O
of O
W B
( I
6 I
+ I
) I
, O
which O
was O
then O
converted O
into O
m O
- O
Pt B
- O
WO3 B
composites O
by O
heat O
treatment O
and O
subsequent O
template O
removal O
. O

The O
synthetic O
strategy O
can O
be O
easily O
extended O
to O
prepare O
other O
mesoporous O
nanohybrids O
with O
metal B
oxide I
loaded O
precious O
metal O
composites O
. O

Comprehensive O
characterizations O
suggest O
that O
the O
as O
- O
developed O
m O
- O
Pt B
- O
WO3 B
nanohybrid O
exhibits O
unique O
properties O
with O
mesoporous O
structure O
, O
excellent O
crystalline O
structure O
, O
and O
high O
surface O
area O
. O

When O
the O
photocatalytic O
properties O
of O
m O
- O
Pt B
- O
WO3 B
nanohybrids O
were O
systematically O
investigated O
, O
it O
was O
revealed O
that O
the O
m O
- O
Pt B
- O
WO3 B
nanohybrids O
showed O
great O
promise O
for O
degrading O
the O
organic O
dye O
under O
visible O
light O
irradiation O
, O
which O
shows O
an O
excellent O
photocatalytic O
activity O
that O
far O
exceeded O
those O
of O
pure O
phase O
mesoporous O
WO3 B
and O
commercial O
TiO2 B
( O
P25 B
) O
, O
and O
was O
10 O
- O
fold O
more O
active O
than O
that O
of O
the O
bulk O
Pt B
- O
WO3 B
catalyst O
. O

The O
as O
- O
developed O
synthetic O
route O
opens O
up O
a O
new O
avenue O
for O
designing O
mesoporous O
hybrid O
materials O
for O
various O
applications O
benefiting O
from O
the O
unique O
porous O
structure O
, O
high O
surface O
area O
, O
and O
synergistic O
effects O
among O
constituents O
. O

An O
Active O
Role O
for O
Steroid B
- O
binding O
Globulins O
: O
An O
Update O
. O

It O
has O
been O
7 O
years O
( O
can O
it O
really O
be O
that O
long O
? O
) O
since O
we O
co O
- O
edited O
a O
volume O
( O
# O
38 O
) O
of O
Hormone O
and O
Metabolic O
Research O
that O
focused O
on O
evidence O
that O
steroid B
- O
binding O
globulins O
play O
an O
active O
role O
in O
the O
actions O
of O
steroids B
. O

There O
has O
been O
considerable O
progress O
in O
identifying O
the O
location O
, O
the O
physiological O
actions O
, O
and O
of O
determining O
the O
role O
of O
binding O
globulins O
in O
the O
actions O
of O
steroids B
and O
identifying O
a O
membrane O
- O
associated O
receptor O
for O
a O
binding O
protein O
since O
then O
and O
this O
review O
will O
discuss O
this O
progress O
. O

Mechanisms O
of O
metal O
- O
catalyzed O
dehydrocoupling O
reactions O
. O

This O
review O
summarizes O
selected O
mechanistic O
insight O
garnered O
from O
reactions O
that O
form O
bonds O
between O
main O
group O
elements O
with O
liberation O
of O
hydrogen B
, O
dehydrocoupling O
or O
dehydropolymerizatio O
reactions O
. O

Focus O
has O
been O
made O
where O
mechanistic O
study O
has O
been O
done O
or O
provides O
unique O
insight O
as O
compared O
to O
previous O
work O
. O

Thus O
, O
a O
limited O
number O
of O
catalysts O
and O
substrates O
will O
be O
discussed O
, O
but O
a O
broad O
range O
of O
mechanistic O
features O
will O
be O
noted O
. O

A O
comparative O
approach O
considering O
dehydrocoupling O
reactions O
that O
appear O
to O
proceed O
by O
certain O
mechanistic O
steps O
is O
taken O
here O
, O
beginning O
with O
steps O
that O
are O
well O
established O
and O
general O
then O
moving O
to O
those O
that O
are O
newer O
, O
at O
least O
to O
this O
application O
. O

Dominant O
role O
of O
molybdenum B
in O
the O
electrochemical O
deposition O
of O
biological O
macromolecules O
on O
metallic O
surfaces O
. O

The O
corrosion O
of O
CoCrMo B
, O
an O
alloy O
frequently O
used O
in O
orthopedic O
implants O
, O
was O
studied O
with O
an O
electrochemical O
quartz B
crystal O
microbalance O
( O
QCM O
) O
in O
three O
physiologically O
relevant O
solutions O
. O

Mass O
changes O
were O
measured O
during O
potentiodynamic O
tests O
, O
showing O
material O
deposition O
in O
protein O
solutions O
at O
potential O
levels O
that O
caused O
mass O
loss O
when O
the O
proteins O
were O
not O
present O
. O

X O
- O
ray O
photoelectron O
spectroscopy O
( O
XPS O
) O
data O
indicated O
that O
the O
deposited O
material O
was O
primarily O
organic O
and O
therefore O
was O
most O
likely O
derived O
from O
proteins O
in O
the O
electrolyte O
. O

Material O
deposition O
consistently O
occurred O
at O
a O
critical O
potential O
and O
was O
not O
dependent O
on O
the O
current O
density O
or O
total O
charge O
released O
into O
solution O
. O

Corrosion O
studies O
on O
pure O
Co B
, O
Cr B
, O
and O
Mo B
in O
protein O
solutions O
found O
material O
deposition O
only O
on O
Mo B
. O

We O
hypothesize O
that O
organic O
deposition O
results O
from O
the O
interaction O
of O
Mo B
( I
VI I
) I
with O
proteins O
in O
the O
surrounding O
solution O
. O

The O
organic O
layer O
is O
reminiscent O
of O
tribochemical O
reaction O
layers O
that O
form O
on O
the O
surface O
of O
CoCrMo O
hip O
bearings O
, O
suggesting O
that O
these O
types O
of O
layers O
can O
be O
formed O
by O
purely O
electrochemical O
means O
. O

Spontaneous O
formation O
of O
hydrophobic O
domains O
in O
isolated O
peptides O
. O

Aromatic B
amino I
acids I
are O
known O
for O
their O
hydrophobicity O
and O
the O
active O
role O
they O
play O
in O
protein O
folding O
. O

Here O
, O
we O
investigate O
the O
intrinsic O
propensity O
of O
small O
peptides O
to O
form O
hydrophobic O
domains O
in O
the O
absence O
of O
solvent O
water O
molecules O
. O

The O
structures O
of O
three O
aromatic O
- O
rich O
isolated O
peptides O
, O
Ac B
- I
Phe I
- I
Phe I
- I
NH2 I
( O
FF O
) O
, O
Ac B
- I
Trp I
- I
Tyr I
- I
NH2 I
( O
WY O
) O
, O
and O
Ac B
- I
Phe I
- I
Phe I
- I
Phe I
- I
NH2 I
( O
FFF O
) O
, O
all O
in O
the O
gas O
phase O
, O
have O
been O
studied O
by O
infrared O
- O
ultraviolet O
( O
IR O
/ O
UV O
) O
double O
resonance O
laser O
spectroscopy O
, O
aided O
by O
dispersion O
- O
corrected O
density O
functional O
theory O
( O
DFT O
- O
D O
) O
calculations O
. O

Spontaneous O
formation O
of O
hydrophobic O
domains O
is O
systematically O
observed O
, O
whatever O
the O
secondary O
structure O
adopted O
by O
the O
backbone O
. O

Various O
types O
of O
aromatic O
- O
aromatic O
arrangements O
have O
been O
identified O
and O
associated O
to O
specific O
secondary O
structures O
, O
illustrating O
the O
interplay O
between O
the O
hydrophobic O
clusters O
and O
the O
backbone O
. O

Backbone O
NH B
amide B
groups O
surrounded O
by O
aromatic O
rings O
have O
also O
been O
evidenced O
and O
are O
found O
to O
contribute O
significantly O
to O
the O
stabilization O
of O
aromatic O
pairs O
. O

These O
results O
suggest O
that O
the O
formation O
of O
aromatic O
clusters O
involving O
contiguous O
residues O
might O
be O
a O
very O
efficient O
process O
leading O
to O
the O
formation O
of O
hydrophobic O
domains O
in O
the O
early O
stages O
of O
protein O
folding O
, O
well O
before O
a O
hydrophobic O
collapse O
into O
the O
tertiary O
structure O
. O

Using O
genomic O
data O
to O
revisit O
an O
early O
example O
of O
reproductive O
character O
displacement O
in O
Haitian O
Anolis O
lizards O
. O

The O
pattern O
of O
reproductive O
character O
displacement O
( O
RCD O
) O
- O
in O
which O
traits O
associated O
with O
reproductive O
isolation O
are O
more O
different O
where O
two O
species O
occur O
together O
than O
where O
they O
occur O
in O
isolation O
- O
is O
frequently O
attributed O
to O
reinforcement O
, O
a O
process O
during O
which O
natural O
selection O
acting O
against O
maladaptive O
mating O
events O
leads O
to O
enhanced O
prezygotic O
isolation O
between O
species O
or O
incipient O
species O
. O

One O
of O
the O
first O
studies O
of O
RCD O
to O
include O
molecular O
genetic O
data O
was O
described O
40 O
years O
ago O
in O
a O
complex O
of O
Haitian O
trunk O
anole O
lizards O
using O
a O
small O
number O
of O
allozyme O
loci O
. O

In O
this O
example O
, O
Anolis O
caudalis O
appears O
to O
experience O
divergence O
in O
the O
color O
and O
pattern O
of O
an O
extensible O
throat O
fan O
, O
or O
dewlap O
, O
in O
areas O
of O
contact O
with O
closely O
related O
species O
at O
the O
northern O
and O
southern O
limits O
of O
its O
range O
. O

However O
, O
this O
case O
study O
has O
been O
largely O
overlooked O
for O
decades O
; O
meanwhile O
, O
explanations O
for O
geographic O
variation O
in O
dewlap O
color O
and O
pattern O
have O
focused O
primarily O
on O
adaptation O
to O
local O
signalling O
environments O
. O

We O
reinvestigate O
this O
example O
using O
amplified O
fragment O
length O
polymorphism O
( O
AFLP O
) O
genome O
scans O
, O
mtDNA O
sequence O
data O
, O
information O
on O
dewlap O
phenotypes O
and O
GIS O
data O
on O
environmental O
variation O
to O
test O
the O
hypothesis O
of O
RCD O
generated O
by O
reinforcement O
in O
Haitian O
trunk O
anoles O
. O

Together O
, O
our O
phenotypic O
and O
genetic O
results O
are O
consistent O
with O
RCD O
at O
the O
southern O
and O
northern O
limits O
of O
the O
range O
of O
A O
. O
caudalis O
. O

We O
evaluate O
the O
evidence O
for O
reinforcement O
as O
the O
explanation O
for O
RCD O
in O
Haitian O
trunk O
anoles O
, O
consider O
alternative O
explanations O
and O
provide O
suggestions O
for O
future O
work O
on O
the O
relationship O
between O
dewlap O
variation O
and O
speciation O
in O
Haitian O
trunk O
anoles O
. O

Sensitive O
determination O
of O
lead O
, O
cadmium B
and O
nickel B
in O
soil O
, O
water O
, O
vegetable O
and O
fruit O
samples O
using O
STAT O
- O
FAAS O
after O
preconcentration O
with O
activated O
carbon B
. O

In O
this O
study O
, O
lead O
( O
Pb B
) O
, O
cadmium B
( O
Cd B
) O
and O
nickel B
( O
Ni B
) O
were O
determined O
in O
soil O
, O
water O
, O
vegetable O
and O
fruit O
samples O
taken O
from O
around O
oil O
refinery O
region O
in O
Batman O
, O
Turkey O
. O

Digestion O
procedures O
for O
samples O
were O
optimized O
and O
all O
optimum O
parameters O
were O
used O
both O
in O
digestion O
and O
in O
determination O
steps O
. O

In O
order O
to O
determine O
Pb B
and O
Cd B
, O
slotted O
tube O
atom O
trap O
( O
STAT O
) O
was O
used O
to O
increase O
the O
sensitivity O
in O
atomic O
absorption O
spectrophotometry O
. O

Preconcentration O
procedure O
under O
the O
optimum O
conditions O
was O
applied O
to O
water O
, O
vegetable O
and O
fruit O
samples O
to O
determine O
Pb B
, O
Cd B
and O
Ni B
in O
trace O
levels O
. O

In O
soil O
samples O
, O
concentrations O
of O
analytes O
were O
found O
in O
the O
range O
of O
4 O
. O
0 O
+ O
/ O
- O
0 O
. O
2 O
- O
12 O
, O
000 O
+ O
/ O
- O
60 O
mg O
/ O
kg O
for O
Pb B
, O
0 O
. O
15 O
+ O
/ O
- O
0 O
. O
01 O
- O
3 O
. O
0 O
+ O
/ O
- O
0 O
. O
1 O
mg O
/ O
kg O
for O
Cd B
and O
21 O
+ O
/ O
- O
1 O
- O
65 O
+ O
/ O
- O
3 O
. O
4 O
mg O
/ O
kg O
for O
Ni B
. O

In O
all O
water O
samples O
, O
concentration O
of O
Ni B
was O
expressed O
as O
nanogram O
per O
milliliter O
( O
ng O
/ O
mL O
) O
and O
found O
to O
be O
higher O
than O
Pb B
and O
Cd B
levels O
. O

It O
was O
observed O
that O
Pb B
, O
Cd B
and O
Ni B
concentrations O
varied O
from O
both O
plant O
to O
plant O
and O
in O
same O
plants O
at O
different O
experimental O
sites O
. O

Pb B
concentrations O
in O
vegetable O
and O
fruit O
samples O
interested O
varied O
between O
20 O
+ O
/ O
- O
2 O
and O
160 O
+ O
/ O
- O
12 O
ng O
/ O
g O
, O
and O
the O
highest O
level O
of O
Pb B
was O
found O
to O
be O
in O
green O
pepper O
taken O
from O
1000 O
m O
away O
from O
refinery O
. O

UVA O
photoirradiation O
of O
benzo B
[ I
a I
] I
pyrene I
metabolites O
: O
induction O
of O
cytotoxicity O
, O
reactive O
oxygen B
species O
, O
and O
lipid O
peroxidation O
. O

Benzo B
[ I
a I
] I
pyrene I
( O
BaP B
) O
is O
a O
prototype O
for O
studying O
carcinogenesis O
of O
polycyclic B
aromatic I
hydrocarbons I
( O
PAHs B
) O
. O

We O
have O
long O
been O
interested O
in O
studying O
the O
phototoxicity O
of O
PAHs B
. O

In O
this O
study O
, O
we O
determined O
that O
metabolism O
of O
BaP B
by O
human O
skin O
HaCaT O
keratinocytes O
resulted O
in O
six O
identified O
phase O
I O
metabolites O
, O
for O
example O
, O
BaP B
trans I
- I
7 I
, I
8 I
- I
dihydrodiol I
( O
BaP B
t I
- I
7 I
, I
8 I
- I
diol I
) O
, O
BaP B
t I
- I
4 I
, I
5 I
- I
diol I
, O
BaP B
t I
- I
9 I
, I
10 I
- I
diol I
, O
3 B
- I
hydroxybenzo I
[ I
a I
] I
pyrene I
( O
3 B
- I
OH I
- I
BaP I
) O
, O
BaP B
( I
7 I
, I
10 I
/ I
8 I
, I
9 I
) I
tetrol I
, O
and O
BaP B
( O
7 O

/ I
8 I
, I
9 I
, I
10 I
) I
tetrol I
. O

The O
photocytotoxicity O
of O
BaP B
, O
3 B
- I
OH I
- I
BaP I
, O
BaP B
t I
- I
7 I
, I
8 I
- I
diol I
, O
BaP B
trans I
- I
7 I
, I
8 I
- I
diol I
- I
anti I
- I
9 I
, I
10 I
- I
epoxide I
( O
BPDE B
) O
, O
and O
BaP B
( I
7 I
, I
10 I
/ I
8 I
, I
9 I
) I
tetrol I
in O
the O
HaCaT O
keratinocytes O
was O
examined O
. O

When O
irradiated O
with O
1 O
. O
0 O
J O
/ O
cm O
( O
2 O
) O
UVA O
light O
, O
these O
compounds O
when O
tested O
at O
doses O
of O
0 O
. O
1 O
, O
0 O
. O
2 O
, O
and O
0 O
. O
5 O
mu O
M O
, O
all O
induced O
photocytotoxicity O
in O
a O
dose O
- O
dependent O
manner O
. O

When O
photoirradiation O
was O
conducted O
in O
the O
presence O
of O
a O
lipid O
( O
methyl B
linoleate I
) O
, O
BaP B
metabolites O
, O
BPDE B
, O
and O
three O
related O
PAHs B
, O
pyrene B
, O
7 B
, I
8 I
, I
9 I
, I
10 I
- I
tetrahydro I
- I
BaP I
trans I
- I
7 I
, I
8 I
- I
diol I
, O
and O
7 B
, I
8 I
, I
9 I
, I
10 I
- I
tetrahydro I
- I
BaP I
trans I
- I
9 I
, I
10 I
- I
diol I
, O
all O
induced O
lipid O
peroxidation O
. O

The O
formation O
of O
lipid O
peroxides B
by O
BaP B
t I
- I
7 I
, I
8 I
- I
diol I
was O
inhibited O
by O
NaN3 B
and O
enhanced O
by O
deuterated B
methanol I
, O
which O
suggests O
that O
singlet O
oxygen B
may O
be O
involved O
in O
the O
generation O
of O
lipid O
peroxides B
. O

The O
formation O
of O
lipid O
hydroperoxides B
was O
partially O
inhibited O
by O
superoxide B
dismutase O
( O
SOD O
) O
. O

Electron O
spin O
resonance O
spin O
trapping O
experiments O
indicated O
that O
both O
singlet O
oxygen B
and O
superoxide B
radical O
anion O
were O
generated O
from O
UVA O
photoirradiation O
of O
BPDE B
in O
a O
light O
dose O
responding O
manner O
. O

Rapid O
self O
- O
healable O
poly B
( I
ethylene I
glycol I
) I
hydrogels O
formed O
by O
selective O
metal O
- O
phosphate B
interactions O
. O

Rapid O
self O
- O
healable O
and O
biocompatible O
hydrogels O
were O
prepared O
using O
the O
selective O
formation O
of O
metal O
- O
ligand O
interactions O
between O
selected O
metal O
ions O
and O
phosphate B
end O
groups O
of O
poly B
( I
ethylene I
glycol I
) I
( O
PEG B
) O
. O

The O
phosphate B
- O
terminated O
branch O
of O
PEG B
was O
synthesized O
via O
a O
substitution O
reaction O
of O
the O
hydroxyl B
end O
groups O
using O
phosphoryl B
chloride I
. O

The O
gelation O
and O
gel O
properties O
including O
rheological O
properties O
can O
be O
tuned O
by O
the O
careful O
selection O
of O
metal O
ions O
, O
branch O
numbers O
, O
and O
temperature O
. O

Especially O
, O
the O
gels O
rapidly O
formed O
by O
trivalent O
metal O
ions O
such O
as O
Fe B
( I
3 I
+ I
) I
, O
V B
( I
3 I
+ I
) I
, O
Al B
( I
3 I
+ I
) I
, O
Ti B
( I
3 I
+ I
) I
, O
and O
Ga B
( I
3 I
+ I
) I
have O
relatively O
small O
ionic O
radii O
. O

The O
ligand O
substitution O
rates O
also O
affected O
the O
repeatable O
autonomic O
healing O
ability O
. O

We O
have O
also O
demonstrated O
a O
gel O
- O
sol O
/ O
sol O
- O
gel O
transition O
by O
switching O
the O
redox O
states O
of O
Fe B
( I
3 I
+ I
) I
/ O
Fe B
( I
2 I
+ I
) I
ions O
. O

Learning O
from O
biological O
systems O
, O
the O
proposed O
phosphate B
- O
metal O
ion O
based O
self O
- O
healable O
hydrogels O
could O
become O
an O
attractive O
candidate O
for O
various O
biomedical O
and O
environmental O
applications O
. O

Soluble O
Receptor O
for O
Advanced O
Glycation O
End O
- O
Product O
( O
sRAGE O
) O
/ O
Pentosidine B
Ratio O
: O
A O
Potential O
Risk O
Factor O
Determinant O
for O
Type O
2 O
Diabetic O
Retinopathy O
. O

This O
study O
aims O
to O
investigate O
potential O
diabetic O
retinopathy O
( O
DR O
) O
risk O
factors O
by O
evaluating O
the O
circulating O
levels O
of O
pentosidine B
, O
soluble O
receptor O
for O
advanced O
glycation O
end O
- O
product O
( O
sRAGE O
) O
, O
advanced O
oxidation O
protein O
product O
( O
AOPP O
) O
as O
well O
as O
glutathione B
peroxidase O
( O
GPx O
) O
and O
superoxide B
dismutase O
( O
SOD O
) O
activities O
in O
DR O
patients O
. O

A O
total O
of O
235 O
healthy O
controls O
, O
171 O
type O
2 O
diabetic O
without O
retinopathy O
( O
DNR O
) O
and O
200 O
diabetic O
retinopathy O
( O
DR O
) O
patients O
were O
recruited O
. O

Plasma O
was O
extracted O
for O
the O
estimation O
of O
pentosidine B
, O
sRAGE O
, O
AOPP O
levels O
and O
GPx O
activity O
whereas O
peripheral O
blood O
mononuclear O
cells O
were O
disrupted O
for O
SOD O
activity O
measurement O
. O

DNR O
and O
DR O
patients O
showed O
significantly O
higher O
levels O
of O
plasma O
pentosidine B
, O
sRAGE O
and O
AOPP O
but O
lower O
GPx O
and O
SOD O
activities O
when O
compared O
to O
healthy O
controls O
. O

The O
sRAGE O
/ O
pentosidine B
ratio O
in O
DR O
patients O
was O
significantly O
lower O
than O
the O
ratio O
detected O
in O
DNR O
patients O
. O

Proliferative O
DR O
patients O
had O
significantly O
higher O
levels O
of O
plasma O
pentosidine B
, O
sRAGE O
, O
AOPP O
and O
sRAGE O
/ O
pentosidine B
ratio O
than O
non O
- O
proliferative O
DR O
patients O
. O

High O
HbA1c O
level O
, O
long O
duration O
of O
diabetes O
and O
low O
sRAGE O
/ O
pentosidine B
ratio O
were O
determined O
as O
the O
risk O
factors O
for O
DR O
. O

This O
study O
suggests O
that O
sRAGE O
/ O
pentosidine B
ratio O
could O
serve O
as O
a O
risk O
factor O
determinant O
for O
type O
2 O
DR O
as O
it O
has O
a O
positive O
correlation O
with O
the O
severity O
of O
DR O
. O

Dioscin B
- O
induced O
autophagy O
mitigates O
cell O
apoptosis O
through O
modulation O
of O
PI3K O
/ O
Akt O
and O
ERK O
and O
JNK O
signaling O
pathways O
in O
human O
lung O
cancer O
cell O
lines O
. O

Our O
previous O
study O
has O
revealed O
that O
dioscin B
, O
a O
compound O
with O
anti O
- O
inflammatory O
, O
lipid O
- O
lowering O
, O
anticancer O
and O
hepatoprotective O
effects O
, O
may O
induce O
autophagy O
in O
hepatoma O
cells O
. O

Autophagy O
is O
a O
lysosomal O
degradation O
pathway O
that O
is O
essential O
for O
cell O
survival O
and O
tissue O
homeostasis O
. O

In O
this O
study O
, O
the O
role O
of O
autophagy O
and O
related O
signaling O
pathways O
during O
dioscin B
- O
induced O
apoptosis O
in O
human O
lung O
cancer O
cells O
was O
investigated O
. O

Results O
from O
4 B
' I
- I
6 I
- I
diamidino I
- I
2 I
- I
phenylindole I
and O
annexin O
- O
V O
/ O
PI O
double O
- O
staining O
assay O
showed O
that O
caspase O
- O
3 O
- O
and O
caspase O
- O
8 O
- O
dependent O
, O
and O
dose O
- O
dependent O
apoptoses O
were O
detected O
after O
a O
24 O
- O
h O
dioscin B
treatment O
. O

Meanwhile O
, O
autophagy O
was O
detected O
as O
early O
as O
12 O
h O
after O
an O
exposure O
to O
low O
- O
dose O
dioscin B
, O
as O
indicated O
by O
an O
up O
- O
regulated O
expression O
of O
LC3 O
- O
II O
and O
beclin O
- O
1 O
proteins O
. O

Blockade O
of O
autophagy O
with O
bafilomycin B
A1 I
or O
3 B
- I
methyladenine I
sensitized O
the O
A549 O
and O
H1299 O
cells O
to O
apoptosis O
. O

Treatment O
of O
A549 O
and O
H1299 O
cells O
with O
dioscin B
caused O
a O
dose O
- O
dependent O
increase O
in O
ERK1 O
/ O
2 O
and O
JNK1 O
/ O
2 O
activity O
, O
accompanied O
with O
a O
decreased O
PI3K O
expression O
and O
decreased O
phosphorylation O
of O
Akt O
and O
mTOR O
. O

Taken O
together O
, O
this O
study O
demonstrated O
for O
the O
first O
time O
that O
autophagy O
occurred O
earlier O
than O
apoptosis O
during O
dioscin B
- O
induced O
human O
lung O
cancer O
cell O
line O
apoptosis O
. O

Dioscin B
- O
induced O
autophagy O
via O
ERK1 O
/ O
2 O
and O
JNK1 O
/ O
2 O
pathways O
may O
provide O
a O
protective O
mechanism O
for O
cell O
survival O
against O
dioscin B
- O
induced O
apoptosis O
to O
act O
as O
a O
cytoprotective O
reaction O
. O

Cytotoxic O
and O
Antibacterial O
Cembranoids B
from O
a O
South O
China O
Sea O
Soft O
Coral O
, O
Lobophytum O
sp O
. O

Chemical O
examination O
of O
a O
South O
China O
Sea O
soft O
coral O
Lobophytum O
sp O
. O
led O
to O
the O
isolation O
of O
three O
new O
alpha B
- I
methylene I
- I
gamma I
- I
lactone I
- O
containing O
cembranoids B
, O
( B
1R I
* I
, I
3R I
* I
, I
4R I
* I
, I
14R I
* I
, I
7E I
, I
11E I
) I
- I
3 I
, I
4 I
- I
epoxycembra I
- I
7 I
, I
11 I
, I
15 I
( I
17 I
) I
- I
trien I
- I
16 I
, I
14 I
- I
olide I
( O
1 O
) O
, O
( B
1R I
* I
, I
7S I
* I
, I
14S I
* I
, I
3E I
, I
11E I
) I
- I
7 I
- I

hydroperoxycembra I
- I
3 I
, I
8 I
( I
19 I
) I
, I
11 I
, I
15 I
( I
17 I
) I
- I
tetraen I
- I
16 I
, I
14 I
- I
olide I
( O
2 O
) O
, O
and O
( B
1R I
* I
, I
7S I
* I
, I
14S I
* I
, I
3E I
, I
11E I
) I
- I
18 I
- I
acetoxy I
- I
7 I
- I
hydroperoxycembra I
- I
3 I
, I
8 I
( I
19 I
) I
, I
11 I
, I
15 I
( I
17 I
) I
- I
tetraen I
- I
16 I
, I
14 I
- I
olide I
( O
3 O
) O
, O
along O
with O
eleven O
known O
analogues O
4 O
- O
14 O
. O

The O
structures O
of O
the O
new O
compounds O
were O
elucidated O
through O
extensive O
spectroscopic O
analysis O
, O
including O
1D O
and O
2D O
NMR O
data O
. O

Compounds O
1 O
- O
3 O
exhibited O
moderate O
cytotoxic O
activity O
against O
the O
selected O
tumor O
cell O
lines O
. O

Moreover O
, O
2 O
and O
3 O
were O
found O
to O
be O
moderate O
inhibitors O
against O
the O
bacteria O
S O
. O
aureus O
and O
S O
. O
pneumoniae O
. O

Atypical O
antipsychotics O
in O
the O
treatment O
of O
children O
and O
adolescents O
with O
pervasive O
developmental O
disorders O
. O

RATIONALE O
: O
Autism O
and O
related O
pervasive O
developmental O
disorders O
( O
PDD O
) O
are O
characterized O
by O
impairments O
in O
social O
interaction O
and O
communication O
, O
restricted O
interests O
, O
and O
repetitive O
and O
stereotyped O
patterns O
of O
behavior O
. O

Individuals O
with O
PDD O
frequently O
display O
irritability O
and O
disruptive O
behaviors O
including O
tantrums O
, O
self O
- O
injurious O
behavior O
, O
and O
aggression O
. O

Atypical O
antipsychotics O
are O
currently O
the O
most O
efficacious O
pharmacological O
interventions O
available O
for O
treatment O
of O
irritability O
associated O
with O
PDD O
. O

OBJECTIVES O
: O
This O
article O
aims O
to O
review O
the O
body O
of O
literature O
pertaining O
to O
the O
use O
of O
atypical O
antipsychotics O
in O
the O
treatment O
of O
patients O
with O
PDD O
. O

METHODS O
: O
A O
PubMed O
literature O
search O
was O
conducted O
using O
the O
following O
key O
words O
: O
autism O
, O
pervasive O
developmental O
disorders O
, O
atypical O
antipsychotics O
, O
risperidone B
, O
aripiprazole B
, O
quetiapine B
, O
ziprasidone B
, O
olanzapine B
, O
clozapine B
, O
paliperidone B
, O
iloperidone B
, O
asenapine B
, O
and O
lurasidone B
. O

Search O
terms O
were O
limited O
to O
English O
language O
, O
human O
subjects O
, O
and O
publication O
from O
1999 O
to O
present O
. O

Relevant O
references O
from O
identified O
articles O
were O
also O
reviewed O
. O

RESULTS O
: O
The O
efficacy O
and O
tolerability O
of O
risperidone B
and O
aripiprazole B
for O
the O
treatment O
of O
irritability O
in O
autism O
have O
been O
established O
with O
multi O
- O
site O
, O
randomized O
, O
controlled O
trials O
. O

Studies O
supporting O
the O
use O
of O
other O
atypical O
antipsychotics O
are O
either O
limited O
in O
scope O
or O
less O
robust O
in O
their O
findings O
, O
though O
newer O
agents O
such O
as O
ziprasidone B
and O
paliperidone B
show O
promise O
. O

CONCLUSIONS O
: O
Atypical O
antipsychotics O
are O
currently O
first O
- O
line O
pharmacological O
agents O
for O
the O
treatment O
of O
irritability O
and O
associated O
behaviors O
in O
children O
with O
PDD O
. O

Further O
placebo O
- O
controlled O
studies O
are O
warranted O
to O
characterize O
the O
efficacy O
and O
tolerability O
of O
the O
majority O
of O
these O
medications O
. O

There O
is O
also O
a O
need O
for O
the O
development O
of O
novel O
, O
targeted O
drugs O
with O
more O
favorable O
long O
- O
term O
side O
effect O
profiles O
. O

Development O
and O
Regulation O
of O
Biosimilars O
: O
Current O
Status O
and O
Future O
Challenges O
. O

Biologic O
medicinal O
products O
developed O
via O
rDNA O
technology O
as O
recombinant O
protein O
- O
based O
medicines O
that O
have O
been O
in O
clinical O
use O
since O
the O
early O
1980s O
as O
original O
biopharmaceuticals O
have O
greatly O
contributed O
to O
the O
therapy O
of O
severe O
metabolic O
and O
degenerative O
diseases O
. O

The O
recent O
expiration O
of O
the O
data O
protection O
or O
patents O
for O
most O
of O
them O
created O
opportunities O
for O
the O
development O
of O
copy O
versions O
of O
original O
biopharmaceuticals O
with O
similar O
biologic O
activity O
( O
termed O
biosimilars O
) O
. O

Production O
of O
these O
new O
products O
is O
expected O
to O
meet O
worldwide O
demand O
, O
promote O
market O
competition O
, O
maintain O
the O
incentives O
for O
innovation O
, O
and O
sustain O
the O
healthcare O
systems O
. O

The O
licencing O
of O
these O
products O
, O
however O
, O
relies O
on O
the O
experience O
gained O
with O
the O
original O
biopharmaceuticals O
. O

Critical O
issues O
related O
to O
this O
class O
of O
medicinal O
products O
include O
their O
terminology O
( O
to O
avoid O
confusion O
with O
generics O
and O
non O
- O
innovator O
copy O
versions O
that O
have O
not O
been O
tested O
according O
to O
the O
biosimilar O
guidelines O
) O
, O
manufacturing O
, O
and O
regulation O
. O

The O
European O
Union O
( O
EU O
) O
has O
been O
the O
first O
to O
establish O
a O
regulatory O
framework O
for O
marketing O
authorization O
application O
( O
MAA O
) O
and O
has O
named O
these O
products O
biosimilars O
, O
a O
term O
also O
recently O
adopted O
by O
the O
US O
FDA O
. O

Unlike O
the O
conventional O
, O
more O
common O
small O
molecular O
weight O
human O
medicines O
and O
chemical O
generics O
, O
protein O
- O
based O
medicines O
exhibit O
higher O
molecular O
weight O
, O
complexity O
in O
structure O
and O
function O
that O
can O
be O
affected O
by O
changes O
in O
the O
manufacturing O
process O
. O

Therefore O
, O
biosimilars O
represent O
a O
relatively O
heterogeneous O
class O
of O
medicinal O
products O
that O
make O
their O
regulation O
quite O
challenging O
. O

According O
to O
the O
current O
understanding O
in O
the O
EU O
, O
a O
biosimilar O
is O
a O
copy O
version O
of O
an O
already O
authorized O
biopharmaceutical O
( O
or O
reference O
product O
) O
with O
similar O
biologic O
activity O
, O
physicochemical O
characteristics O
, O
efficacy O
, O
and O
safety O
, O
based O
on O
a O
full O
comparability O
exercise O
at O
quality O
, O
preclinical O
and O
clinical O
level O
to O
ensure O
similar O
efficacy O
and O
safety O
. O

Guidance O
has O
been O
provided O
through O
several O
Committee O
for O
Medicinal O
Products O
for O
Human O
Use O
( O
CHMP O
) O
guidelines O
as O
well O
as O
individual O
scientific O
advice O
requested O
from O
the O
European O
Medicines O
Agency O
( O
EMA O
) O
by O
various O
companies O
for O
the O
development O
and O
regulation O
of O
biosimilars O
. O

This O
review O
is O
mainly O
focused O
on O
the O
current O
status O
of O
regulation O
of O
biosimilars O
in O
the O
EU O
as O
well O
as O
on O
future O
challenges O
lying O
ahead O
for O
the O
improvement O
of O
the O
requirements O
needed O
for O
the O
marketing O
authorization O
of O
biosimilars O
. O

Emphasis O
is O
given O
on O
the O
quality O
requirements O
concerning O
these O
medicinal O
products O
( O
biologics O
) O
. O

The O
evolving O
role O
of O
antifungal O
susceptibility O
testing O
. O

Although O
increasing O
numbers O
of O
hospital O
microbiology O
laboratories O
are O
performing O
antifungal O
susceptibility O
testing O
( O
AST O
) O
, O
its O
routine O
use O
is O
uncommon O
. O

The O
utility O
of O
AST O
is O
founded O
on O
the O
belief O
that O
susceptibility O
( O
or O
resistance O
) O
of O
an O
agent O
allows O
some O
prediction O
of O
clinical O
outcome O
. O

This O
review O
provides O
an O
overview O
of O
the O
development O
of O
antifungal O
susceptibility O
testing O
methodology O
, O
including O
wild O
- O
type O
minimum O
inhibitory O
concentration O
( O
MIC O
) O
distributions O
, O
epidemiologic O
breakpoints O
, O
and O
Interpretive O
Clinical O
Breakpoints O
for O
antifungal O
agents O
. O

In O
addition O
, O
we O
examine O
the O
current O
clinical O
utility O
of O
AST O
and O
the O
clinical O
data O
support O
utilized O
in O
the O
development O
of O
clinical O
breakpoints O
( O
CBP O
) O
for O
common O
pathogens O
causing O
invasive O
fungal O
infections O
. O

In O
the O
treatment O
of O
fungal O
infections O
, O
identifying O
consistent O
correlations O
between O
MICs O
- O
or O
susceptibility O
category O
- O
and O
clinical O
outcomes O
is O
an O
ongoing O
challenge O
, O
and O
current O
data O
sets O
are O
insufficient O
for O
many O
drugs O
and O
pathogens O
to O
enable O
the O
development O
, O
revision O
, O
or O
confirmation O
of O
CBPs O
. O

Antifungal O
susceptibility O
testing O
is O
of O
current O
value O
, O
but O
further O
research O
in O
many O
areas O
is O
needed O
before O
MICs O
are O
independently O
used O
to O
guide O
treatment O
decisions O
. O

Role O
of O
Interleukin O
- O
1 O
Inhibitors O
in O
the O
Management O
of O
Gout O
. O

Interleukin O
- O
1 O
( O
IL O
- O
1 O
) O
inhibitors O
potentially O
have O
a O
role O
as O
antiinflammatory O
agents O
in O
refractory O
gout O
or O
for O
patients O
who O
are O
unable O
to O
tolerate O
conventional O
therapy O
, O
such O
as O
nonsteroidal O
antiinflammatory O
drugs O
( O
NSAIDs O
) O
, O
colchicine B
, O
or O
glucocorticoids O
, O
for O
acute O
attacks O
. O

Additionally O
, O
IL O
- O
1 O
inhibitors O
may O
also O
help O
patients O
with O
polyarticular O
and O
tophaceous O
gout O
by O
making O
them O
less O
vulnerable O
to O
breakthrough O
attacks O
during O
initiation O
of O
chronic O
urate O
- O
lowering O
treatment O
, O
the O
mainstay O
of O
gout O
therapy O
. O

Because O
evidence O
highlights O
the O
role O
of O
proinflammatory O
cytokine O
IL O
- O
1 O
in O
the O
inflammation O
process O
during O
an O
acute O
gouty O
attack O
, O
IL O
- O
1 O
inhibitors O
are O
used O
to O
modulate O
the O
pathogenesis O
of O
a O
variety O
of O
autoinflammatory O
diseases O
, O
providing O
support O
for O
its O
potential O
role O
in O
the O
inflammatory O
process O
of O
gout O
. O

After O
NSAIDs O
, O
colchicine B
, O
and O
steroids B
, O
IL O
- O
1 O
inhibitors O
are O
beneficial O
as O
fourth O
- O
line O
therapy O
for O
acute O
gout O
attacks O
due O
to O
their O
high O
cost O
and O
limited O
clinical O
experience O
. O

The O
IL O
- O
1 O
inhibitors O
used O
in O
gout O
are O
anakinra O
, O
canakinumab O
, O
and O
rilonacept O
. O

Based O
on O
published O
evidence O
, O
anakinra O
has O
limited O
support O
in O
the O
form O
of O
anecdotal O
case O
reports O
to O
justify O
its O
use O
for O
treating O
gout O
. O

Canakinumab O
' O
s O
toxic O
profile O
in O
clinical O
trials O
precludes O
its O
use O
in O
treating O
patients O
for O
gout O
, O
and O
rilonacept O
shows O
promise O
with O
a O
few O
well O
- O
designed O
studies O
to O
support O
its O
use O
in O
gout O
patients O
initiating O
urate O
- O
lowering O
treatment O
. O

When O
combined O
with O
current O
traditional O
therapies O
, O
these O
newer O
agents O
present O
clinicians O
and O
patients O
with O
more O
potential O
treatment O
options O
in O
the O
difficult O
- O
to O
- O
treat O
gout O
population O
. O

Incidence O
and O
costs O
of O
adverse O
drug O
reactions O
in O
a O
tertiary O
care O
pediatric O
intensive O
care O
unit O
. O

Adverse O
drug O
reactions O
( O
ADRs O
) O
increase O
morbidity O
, O
mortality O
, O
and O
hospital O
costs O
in O
children O
treated O
in O
the O
Pediatric O
Intensive O
Care O
Unit O
( O
PICU O
) O
. O

Few O
studies O
have O
reported O
the O
incidence O
and O
risk O
factors O
of O
ADRs O
in O
PICU O
. O

Our O
study O
aimed O
to O
evaluate O
incidence O
, O
risk O
factors O
, O
and O
economic O
burden O
of O
ADRs O
in O
PICU O
. O

An O
intensive O
ADR O
surveillance O
was O
conducted O
at O
the O
PICU O
of O
Children O
' O
s O
Hospital O
of O
Michigan O
between O
November O
1 O
, O
2010 O
and O
May O
31 O
, O
2011 O
. O

A O
trigger O
list O
was O
used O
to O
screen O
for O
suspected O
ADR O
cases O
. O

Of O
the O
697 O
consecutive O
PICU O
admissions O
reviewed O
, O
13 O
. O
1 O
% O
experienced O
at O
least O
one O
episode O
of O
ADR O
. O

The O
ADR O
incidence O
was O
22 O
% O
in O
patients O
with O
cardiovascular O
( O
CV O
) O
surgery O
and O
11 O
. O
5 O
% O
in O
other O
patients O
. O

The O
most O
frequently O
detected O
ADR O
was O
electrolyte O
imbalance O
associated O
with O
diuretic O
exposure O
. O

Mean O
age O
at O
admission O
was O
4 O
years O
( O
interquartile O
range O
: O
9 O
months O
- O
13 O
years O
) O
. O

Risk O
factors O
for O
ADR O
included O
young O
age O
( O
< O
1 O
year O
) O
, O
Pediatric O
Risk O
of O
Mortality O
( O
PRISM O
) O
score O
upon O
admission O
> O
= O
3 O
, O
and O
administration O
of O
> O
= O
16 O
medications O
. O

ADRs O
increased O
total O
ICU O
costs O
by O
3 O
. O
5 O
- O
fold O
and O
length O
of O
ICU O
stay O
by O
3 O
. O
8 O
- O
fold O
. O

Increased O
ADR O
surveillance O
of O
high O
risk O
patients O
in O
conjunction O
with O
early O
intervention O
may O
reduce O
drug O
related O
morbidity O
and O
costs O
in O
the O
PICU O
. O

A O
comparison O
of O
bone O
quality O
at O
the O
distal O
radius O
between O
Asian O
and O
Caucasian O
adolescents O
and O
young O
adults O
: O
An O
HR O
- O
pQCT O
study O
. O

Paradoxically O
, O
Asians O
have O
lower O
areal O
bone O
mineral O
density O
, O
but O
their O
rates O
of O
hip O
and O
wrist O
fractures O
are O
lower O
than O
Caucasians O
. O

Therefore O
, O
we O
used O
high O
- O
resolution O
pQCT O
( O
HR O
- O
pQCT O
) O
to O
determine O
whether O
differences O
in O
bone O
macro O
- O
and O
microstructure O
, O
BMD O
and O
bone O
strength O
at O
the O
distal O
radius O
are O
apparent O
in O
Asian O
( O
n O
= O
91 O
, O
53 O
males O
, O
38 O
females O
, O
17 O
. O
3 O
+ O
/ O
- O
1 O
. O
5 O
yrs O
) O
and O
Caucasian O
( O
n O
= O
89 O
, O
46 O
males O
, O
43 O
females O
, O
18 O
. O
1 O
+ O
/ O
- O
1 O
. O
8 O
yrs O
) O
adolescents O
and O
young O
adults O
. O

HR O
- O
pQCT O
outcomes O
included O
total O
BMD O
( O
Tt O
. O
BMD O
) O
, O
trabecular O
bone O
volume O
fraction O
( O
BV O
/ O
TV O
) O
, O
trabecular O
number O
( O
Tb O
. O
N O
) O
, O
thickness O
( O
Tb O
. O
Th O
) O
and O
separation O
( O
Tb O
. O
Sp O
) O
. O

We O
used O
an O
automated O
segmentation O
algorithm O
to O
determine O
total O
bone O
area O
( O
Tt O
. O
Ar O
) O
, O
cortical O
BMD O
( O
Ct O
. O
BMD O
) O
, O
porosity O
( O
Ct O
. O
Po O
) O
and O
thickness O
( O
Ct O
. O
Th O
) O
, O
and O
we O
applied O
finite O
element O
analysis O
to O
HR O
- O
pQCT O
scans O
to O
estimate O
bone O
strength O
. O

We O
fit O
sex O
- O
specific O
multivariable O
regression O
models O
to O
compare O
bone O
outcomes O
between O
Asians O
and O
Caucasians O
, O
adjusting O
for O
age O
, O
age O
at O
menarche O
( O
girls O
) O
, O
lean O
mass O
, O
ulnar O
length O
, O
dietary O
calcium B
intake O
and O
physical O
activity O
. O

In O
males O
, O
after O
adjusting O
for O
covariates O
, O
Asians O
had O
11 O
% O
greater O
Tt O
. O
BMD O
, O
8 O
% O
greater O
Ct O
. O
BMD O
and O
25 O
% O
lower O
Ct O
. O
Po O
than O
Caucasians O
( O
p O
< O
0 O
. O
05 O
) O
. O

Also O
, O
Asians O
had O
9 O
% O
smaller O
Tt O
. O
Ar O
and O
27 O
% O
greater O
Ct O
. O
Th O
( O
p O
< O
0 O
. O
01 O
) O
. O

In O
females O
, O
Asians O
had O
smaller O
Tt O
. O
Ar O
than O
Caucasians O
( O
16 O
% O
, O
p O
< O
0 O
. O
001 O
) O
, O
but O
this O
difference O
was O
not O
significant O
after O
adjusting O
for O
covariates O
. O

Asian O
females O
had O
5 O
% O
greater O
Ct O
. O
BMD O
, O
12 O
% O
greater O
Ct O
. O
Th O
and O
11 O
% O
lower O
Tb O
. O
Sp O
than O
Caucasians O
after O
adjusting O
for O
covariates O
( O
p O
< O
0 O
. O
05 O
) O
. O

Estimated O
bone O
strength O
did O
not O
differ O
between O
Asian O
and O
Caucasian O
males O
or O
females O
. O

Our O
study O
supports O
the O
notion O
of O
compensatory O
elements O
of O
bone O
structure O
that O
sustain O
bone O
strength O
; O
smaller O
bones O
as O
observed O
between O
those O
of O
Asian O
compared O
with O
Caucasian O
origin O
, O
have O
, O
on O
average O
, O
more O
dense O
, O
less O
porous O
and O
thicker O
cortices O
. O

Longitudinal O
studies O
are O
needed O
to O
determine O
whether O
ethnic O
differences O
in O
bone O
structure O
exist O
in O
childhood O
, O
persist O
into O
old O
age O
and O
whether O
they O
influence O
fracture O
risk O
. O

( O
c O
) O
2013 O
American O
Society O
for O
Bone O
and O
Mineral O
Research O
. O

Impact O
of O
Phytolacca O
americana O
Extracts O
on O
Gene O
Expression O
of O
Colon O
Cancer O
Cells O
. O

Native O
Americans O
have O
used O
Phytolacca O
americana O
to O
treat O
breast O
ailments O
, O
gastrointestinal O
disorders O
, O
rashes O
, O
and O
inflammation O
. O

Some O
anti O
- O
cancer O
and O
anti O
- O
viral O
research O
has O
been O
reported O
on O
this O
perennial O
herb O
, O
but O
none O
has O
been O
published O
concerning O
the O
effects O
of O
its O
extracts O
on O
cancer O
cell O
genes O
. O

In O
this O
study O
, O
changes O
in O
gene O
expression O
at O
the O
transcription O
level O
were O
evaluated O
in O
HCT O
- O
116 O
colon O
cancer O
cells O
after O
exposure O
to O
P O
. O
americana O
ethanol B
extract O
and O
its O
water O
fraction O
using O
the O
Human O
Cancer O
Pathway O
Finder O
PCR O
Array O
. O

Of O
the O
genes O
significantly O
affected O
in O
HCT O
- O
116 O
cells O
exposed O
to O
the O
ethanol B
extract O
at O
3200 O
micro O
g O
/ O
ml O
, O
changes O
in O
expression O
of O
MYC O
, O
PLAU O
, O
and O
TEK O
may O
benefit O
the O
treatment O
of O
colon O
cancer O
. O

Exposing O
the O
cells O
to O
1600 O
micro O
g O
/ O
ml O
of O
the O
water O
fraction O
resulted O
in O
several O
gene O
changes O
that O
may O
also O
be O
beneficial O
in O
the O
treatment O
of O
colon O
cancer O
: O
NME4 O
, O
TEK O
, O
and O
THBS1 O
. O

A O
few O
genes O
on O
this O
array O
that O
are O
known O
to O
play O
a O
specific O
role O
in O
colon O
cancer O
had O
activities O
changed O
in O
a O
way O
that O
may O
be O
detrimental O
in O
the O
treatment O
of O
colon O
cancer O
. O

Further O
studies O
should O
be O
performed O
to O
understand O
how O
these O
changes O
would O
impact O
colon O
cancer O
treatment O
. O

Copyright O
( O
c O
) O
2013 O
John O
Wiley O
& O
Sons O
, O
Ltd O
. O

Furanodiene B
Presents O
Synergistic O
Anti O
- O
proliferative O
Activity O
With O
Paclitaxel B
Via O
Altering O
Cell O
Cycle O
and O
Integrin O
Signaling O
in O
95 O
- O
D O
Lung O
Cancer O
Cells O
. O

Furanodiene B
( O
FUR B
) O
is O
a O
natural O
terpenoid B
isolated O
from O
Rhizoma O
Curcumae O
, O
a O
well O
- O
known O
Chinese O
medicinal O
herb O
that O
presents O
anti O
- O
proliferative O
activities O
in O
several O
cancer O
cell O
lines O
. O

Recently O
, O
we O
found O
that O
the O
combined O
treatment O
of O
FUR B
with O
paclitaxel B
( O
TAX B
) O
showed O
synergetic O
anti O
- O
proliferative O
activities O
in O
95 O
- O
D O
lung O
cancer O
cells O
. O

Herein O
, O
we O
showed O
that O
FUR B
reduced O
the O
cell O
numbers O
distributed O
in O
mitosis O
phase O
induced O
by O
TAX B
while O
increased O
those O
in O
G1 O
phase O
. O

The O
protein O
levels O
of O
cyclin O
D1 O
, O
cyclin O
B1 O
, O
CDK6 O
and O
c O
- O
Myc O
were O
all O
down O
- O
regulated O
in O
the O
group O
of O
combined O
treatment O
. O

The O
dramatically O
down O
- O
regulated O
expression O
of O
integrin O
beta O
4 O
, O
focal O
adhesion O
kinase O
and O
paxillin O
might O
partially O
contribute O
to O
the O
synergic O
effect O
. O

Though O
FUR B
alone O
obviously O
induced O
endoplasmic O
reticulum O
stress O
, O
this O
signaling O
pathway O
may O
not O
contribute O
to O
the O
synergetic O
anti O
- O
proliferative O
effect O
as O
the O
protein O
expression O
of O
CHOP O
and O
BIP O
was O
similar O
in O
FUR B
alone O
and O
combined O
treatment O
group O
. O

Copyright O
( O
c O
) O
2013 O
John O
Wiley O
& O
Sons O
, O
Ltd O
. O

A O
Mineral O
Extract O
from O
red O
Algae O
Ameliorates O
Chronic O
Spontaneous O
Colitis O
in O
IL O
- O
10 O
Deficient O
Mice O
in O
a O
Mouse O
Strain O
Dependent O
Manner O
. O

Inflammatory O
bowel O
disease O
is O
an O
urgent O
public O
health O
problem O
with O
a O
high O
incidence O
in O
developed O
countries O
. O

Alterations O
of O
lifestyle O
or O
dietary O
interventions O
may O
attenuate O
the O
disease O
progression O
and O
increase O
the O
efficacy O
of O
current O
therapies O
. O

Here O
we O
tested O
the O
effect O
of O
chronic O
supplementation O
with O
a O
mineral O
extract O
from O
red O
marine O
algae O
- O
rich O
in O
calcium B
( O
34 O
% O
) O
, O
magnesium B
, O
phosphorus B
, O
selenium B
and O
other O
trace O
minerals O
- O
in O
a O
clinically O
relevant O
model O
of O
spontaneous O
enterocolitis O
, O
interleukin O
( O
IL O
) O
- O
10 O
( O
- O
/ O
- O
) O
mice O
. O

The O
mineral O
extract O
was O
administered O
in O
the O
drinking O
water O
of O
Il10 O
( O
- O
/ O
- O
) O
mice O
on O
C57BL O
/ O
6 O
J O
and O
BALB O
/ O
c O
strain O
backgrounds O
for O
25 O
weeks O
commencing O
from O
3 O
to O
4 O
weeks O
of O
age O
. O

The O
mineral O
extract O
ameliorated O
the O
spontaneous O
development O
of O
colitis O
and O
severity O
of O
disease O
in O
Il10 O
( O
- O
/ O
- O
) O
mice O
on O
a O
C57BL O
/ O
6 O
J O
background O
. O

Mineral O
extract O
- O
treated O
Il10 O
( O
- O
/ O
- O
) O
C57BL O
/ O
6 O
J O
strain O
mice O
had O
significantly O
reduced O
mortality O
, O
circulating O
levels O
of O
serum O
Amyloid O
A O
and O
reduced O
colonic O
tissue O
damage O
. O

In O
contrast O
, O
comparable O
treatment O
of O
Il10 O
( O
- O
/ O
- O
) O
mice O
on O
a O
BALB O
/ O
c O
background O
with O
the O
mineral O
extract O
did O
not O
alter O
the O
course O
of O
colitis O
. O

These O
data O
demonstrate O
that O
chronic O
supplementation O
with O
a O
natural O
mineral O
extract O
selectively O
ameliorates O
spontaneous O
mild O
- O
moderate O
colitis O
in O
Il10 O
( O
- O
/ O
- O
) O
mice O
on O
a O
C57BL O
/ O
6 O
J O
, O
but O
does O
not O
attenuate O
more O
moderate O
- O
severe O
colitis O
in O
BALB O
/ O
c O
strain O
animals O
. O

Copyright O
( O
c O
) O
2013 O
John O
Wiley O
& O
Sons O
, O
Ltd O
. O

Expression O
, O
purification O
and O
proteomic O
analysis O
of O
recombinant O
histone O
H4 O
acetylated O
at O
lysine B
16 O
. O

Many O
histone O
covalent O
modifications O
have O
been O
identified O
and O
shown O
to O
play O
key O
regulatory O
roles O
in O
eukaryotic O
transcription O
, O
DNA O
damage O
repair O
, O
and O
replication O
. O

In O
vitro O
experiments O
designed O
to O
understand O
the O
mechanistic O
role O
of O
individual O
modifications O
require O
the O
availability O
of O
substantial O
quantities O
of O
pure O
histones O
, O
homogeneously O
modified O
at O
specific O
residues O
. O

We O
have O
applied O
the O
amber O
stop O
codon O
/ O
suppressor O
tRNA O
strategy O
to O
the O
production O
of O
histone O
H4 O
acetylated O
at O
lysine B
16 O
, O
a O
particularly O
important O
isoform O
of O
this O
histone O
. O

Our O
success O
relies O
on O
adapting O
the O
H4 O
DNA O
sequence O
to O
the O
codon O
preference O
of O
E O
. O
coli O
and O
on O
preventing O
the O
premature O
decay O
of O
the O
H4 O
mRNA O
. O

These O
modifications O
to O
the O
original O
procedure O
render O
it O
easily O
applicable O
to O
the O
generation O
of O
any O
covalently O
modified O
histone O
H4 O
isoform O
. O

SiCN B
: O
SiCN B
Nanofibers O
with O
a O
Diameter O
Below O
100 O
nm O
Synthesized O
via O
Concerted O
Block O
Copolymer O
Formation O
, O
Microphase O
Separation O
, O
and O
Crosslinking O
( O
Small O
7 O
/ O
2013 O
) O
. O

SiCN B
fibers O
with O
a O
mean O
diameter O
of O
50 O
nm O
and O
an O
aspect O
ratio O
of O
up O
to O
100 O
are O
produced O
in O
a O
two O
- O
step O
process O
by O
R O
. O

Kempe O
and O
co O
- O
workers O
. O

The O
key O
step O
to O
fabricate O
the O
longitudinal O
and O
crosssectional O
views O
of O
the O
mesofibers O
shown O
here O
is O
a O
concerted O
block O
- O
copolymer O
synthesis O
, O
microphase O
separation O
, O
and O
cross O
linking O
at O
140 O
degrees O
C O
followed O
by O
pyrolysis O
at O
1100 O
degrees O
C O
. O

Inexpensive O
components O
like O
a O
commercially O
available O
silazane B
and O
polyethylene B
are O
linked O
. O

The O
fibers O
may O
find O
application O
in O
electronic O
devices O
, O
as O
components O
of O
ceramic O
matrix O
composites O
, O
as O
fiber O
beds O
in O
hightemperature O
nano O
- O
filtering O
like O
diesel O
fine O
dust O
removal O
, O
or O
as O
thermally O
robust O
and O
chemically O
inert O
catalyst O
supports O
. O

Furthermore O
, O
the O
SiCN B
nanofibers O
introduced O
on O
page O
984 O
are O
a O
promising O
alternative O
to O
ultrathin O
carbon B
fibers O
, O
due O
to O
their O
oxidation O
resistance O
. O

Graphene B
in O
Light O
: O
Design O
, O
Synthesis O
and O
Applications O
of O
Photo O
- O
active O
Graphene B
and O
Graphene B
- O
Like O
Materials O
. O

Graphene B
functionalized O
with O
photo O
- O
active O
units O
has O
become O
one O
of O
the O
most O
exciting O
topics O
of O
research O
in O
the O
last O
few O
years O
, O
which O
remarkably O
sustains O
and O
expands O
the O
graphene B
boom O
. O

The O
rise O
of O
photo O
- O
active O
graphene B
in O
photonics O
and O
optoelectronics O
is O
evidenced O
by O
a O
spate O
of O
recent O
reports O
on O
topics O
ranging O
from O
photodetectors O
, O
photovoltaics O
, O
and O
optoelectronics O
to O
photocatalysis O
. O

For O
these O
applications O
, O
the O
fabrication O
of O
photo O
- O
active O
graphene B
through O
appropriate O
chemical O
functionalization O
strategies O
is O
essential O
as O
pristine O
graphene B
has O
zero O
bandgap O
and O
only O
weak O
absorption O
of O
photons O
. O

Written O
from O
the O
chemists O
' O
point O
of O
view O
, O
up O
- O
to O
- O
date O
chemical O
functionalization O
of O
graphene B
with O
various O
small O
organic O
molecules O
, O
conjugated O
polymers O
, O
rare O
- O
earth O
components O
, O
and O
inorganic O
semiconductors O
is O
reviewed O
. O

Particular O
attention O
is O
paid O
to O
the O
development O
of O
graphene B
functionalized O
with O
light O
- O
harvesting O
moieties O
, O
including O
materials O
synthesis O
, O
characterization O
, O
energy O
/ O
charge O
- O
transfer O
processes O
, O
and O
applications O
in O
photovoltaics O
. O

Challenges O
currently O
faced O
by O
researchers O
and O
future O
perspectives O
in O
this O
field O
are O
also O
discussed O
. O

Potent O
Agonists O
of O
a O
Hematopoietic O
Stem O
Cell O
Cytokine O
Receptor O
, O
c O
- O
Mpl O
. O

Several O
growth O
factors O
feature O
prominently O
in O
the O
control O
of O
hematopoiesis O
. O

Thrombopoietin O
, O
a O
class O
I O
hematopoietic O
cytokine O
, O
plays O
critical O
roles O
in O
regulating O
hematopoietic O
stem O
cell O
numbers O
and O
also O
stimulates O
the O
production O
and O
differentiation O
of O
megakaryocytes O
, O
the O
bone O
marrow O
cells O
that O
ultimately O
produce O
platelets O
. O

Thrombopoietin O
interacts O
with O
the O
c O
- O
Mpl O
cell O
- O
surface O
receptor O
. O

Recently O
, O
several O
peptide O
and O
small O
- O
molecule O
agonists O
and O
antagonists O
of O
c O
- O
Mpl O
have O
been O
reported O
. O

We O
conducted O
a O
bioinformatics O
and O
molecular O
modeling O
study O
aimed O
at O
understanding O
the O
agonist O
activities O
of O
peptides O
that O
bind O
to O
c O
- O
Mpl O
, O
and O
developed O
new O
potent O
peptide O
agonists O
with O
low O
nanomolar O
activity O
. O

These O
agonists O
also O
show O
very O
high O
activity O
in O
human O
CD34 O
( O
+ O
) O
primary O
cell O
cultures O
, O
and O
doubled O
the O
mean O
blood O
platelet O
counts O
when O
injected O
into O
mice O
. O

Amorphous O
Ni B
( I
OH I
) I
2 I
Nanoboxes O
: O
Fast O
Fabrication O
and O
Enhanced O
Sensing O
for O
Glucose B
. O

Inspired O
by O
Pearson O
' O
s O
hard O
and O
soft O
acid O
- O
base O
( O
HSAB O
) O
principle O
, O
uniform O
amorphous O
Ni B
( I
OH I
) I
2 I
nanoboxes O
with O
intact O
shell O
structures O
and O
various O
sizes O
are O
quickly O
fabricated O
by O
deliberately O
selecting O
S2 B
O3 I
( I
2 I
- I
) I
as O
the O
coordinating O
etchant O
toward O
Cu2 B
O I
templates O
and O
optimizing O
the O
reaction O
conditions O
. O

It O
is O
found O
that O
not O
only O
the O
solvent O
system O
but O
also O
the O
employing O
of O
a O
surfactant O
is O
vital O
for O
the O
fabrication O
of O
the O
nanoboxes O
. O

Ni B
( I
OH I
) I
2 I
nanoboxes O
, O
as O
an O
example O
, O
demonstrate O
an O
improved O
electrochemical O
sensing O
ability O
for O
glucose B
, O
which O
might O
be O
due O
to O
their O
amorphous O
and O
hollow O
structural O
features O
. O

A O
Thyroxine B
Absorption O
Test O
Followed O
by O
Weekly O
Thyroxine B
Administration O
: O
A O
Method O
to O
Assess O
Non O
- O
Adherence O
to O
Treatment O
. O

OBJECTIVE O
: O
For O
patients O
, O
who O
remain O
hypothyroid O
despite O
the O
administration O
of O
what O
would O
seem O
adequate O
doses O
of O
levothyroxine B
, O
the O
underlying O
cause O
can O
be O
difficult O
to O
determine O
. O

The O
possibility O
of O
a O
biological O
cause O
should O
first O
be O
explored O
; O
however O
, O
in O
the O
majority O
of O
cases O
poor O
adherence O
to O
medication O
is O
likely O
to O
be O
the O
main O
cause O
of O
treatment O
failure O
. O

When O
non O
- O
adherence O
is O
suspected O
but O
not O
volunteered O
, O
options O
to O
confirm O
the O
suspicion O
are O
limited O
. O

In O
this O
study O
we O
identified O
patients O
for O
whom O
known O
drug O
and O
pathological O
causes O
of O
levothyroxine B
malabsorption O
were O
excluded O
and O
despite O
often O
high O
doses O
of O
levothyroxine B
, O
the O
patients O
remained O
hypothyroid O
. O

DESIGN O
: O
Using O
a O
weight O
- O
determined O
oral O
levothyroxine B
bolus O
administration O
, O
absorption O
was O
initially O
assessed O
in O
twenty O
- O
three O
patients O
. O

In O
nearly O
all O
patients O
this O
was O
shown O
to O
be O
maximal O
at O
120mins O
post O
ingestion O
. O

This O
was O
then O
followed O
by O
the O
continued O
administration O
of O
a O
weekly O
thyroxine B
bolus O
for O
a O
four O
- O
week O
period O
after O
which O
TSH O
and O
free O
T4 O
levels O
were O
recorded O
. O

RESULTS O
: O
All O
patients O
showed O
a O
rise O
in O
free O
T4 O
at O
120mins O
following O
the O
administration O
of O
the O
levothyroxine B
bolus O
, O
with O
a O
mean O
increase O
of O
54 O
+ O
/ O
- O
3 O
% O
from O
baseline O
. O

Following O
the O
treatment O
period O
, O
using O
an O
equivalent O
weekly O
levothyroxine B
dose O
which O
was O
significantly O
less O
than O
that O
of O
the O
daily O
dose O
taken O
by O
the O
patients O
before O
the O
test O
, O
the O
TSH O
reduced O
from O
baseline O
in O
~ O
75 O
% O
of O
cases O
. O

CONCLUSION O
: O
Using O
this O
combination O
of O
tests O
allows O
significant O
malabsorptive O
problems O
to O
be O
first O
identified O
, O
then O
potential O
non O
- O
adherence O
to O
be O
demonstrated O
. O

A O
management O
plan O
can O
then O
be O
implemented O
to O
increase O
adherence O
, O
aiming O
to O
improve O
treatment O
outcomes O
. O

Pressor O
and O
renal O
regional O
hemodynamic O
effects O
of O
urotensin O
II O
in O
neonatal O
pigs O
. O

Renal O
expression O
of O
the O
peptide O
hormone O
urotensin O
II O
( O
UII O
) O
and O
its O
receptor O
( O
UTR O
) O
are O
dependent O
on O
kidney O
maturation O
and O
anatomical O
regions O
. O

However O
, O
renal O
regional O
hemodynamic O
effects O
of O
UII O
in O
neonates O
are O
unclear O
. O

Here O
, O
we O
investigated O
regional O
hemodynamic O
responses O
to O
acute O
intrarenal O
arterial O
administration O
of O
UII O
in O
newborn O
pigs O
. O

Western O
immunoblotting O
and O
immunofluorescence O
confirmed O
UTR O
expression O
and O
membrane O
localization O
in O
newborn O
pig O
renal O
afferent O
arterioles O
and O
afferent O
arteriolar O
smooth O
muscle O
cells O
respectively O
. O

Intrarenal O
arterial O
bolus O
injections O
of O
human O
UII O
( O
hUII O
; O
1 O
- O
100 O
ng O
/ O
kg O
) O
resulted O
in O
a O
dose O
- O
dependent O
decrease O
in O
total O
renal O
blood O
flow O
( O
RBF O
) O
and O
an O
increase O
in O
mean O
arterial O
pressure O
( O
MAP O
) O
and O
renal O
vascular O
resistance O
( O
RVR O
) O
in O
newborn O
pigs O
. O

Moreover O
, O
hUII O
dose O
dependently O
reduced O
cortical O
blood O
flow O
( O
CBF O
) O
but O
increased O
medullary O
blood O
flow O
( O
MBF O
) O
in O
the O
piglets O
. O

hUII O
- O
induced O
MAP O
elevation O
and O
hemodynamic O
changes O
were O
inhibited O
by O
urantide B
, O
a O
UTR O
antagonist O
, O
but O
not O
losartan B
, O
a O
type O
1 O
angiotensin O
II O
receptor O
antagonist O
. O

U B
- I
73122 I
, O
a O
phospholipase O
C O
( O
PLC O
) O
inhibitor O
, O
and O
2 B
- I
aminoethoxydiphenyl I
borate I
, O
an O
inositol B
1 I
, I
4 I
, I
5 I
trisphosphate I
( O
IP3 O
) O
receptor O
antagonist O
, O
attenuated O
hUII O
- O
induced O
MAP O
and O
RVR O
elevations O
, O
RBF O
and O
CBF O
reductions O
, O
but O
not O
MBF O
increase O
. O

These O
findings O
indicate O
that O
intrarenal O
arterial O
administration O
of O
hUII O
elevates O
blood O
pressure O
and O
induces O
region O
- O
selective O
renal O
hemodynamic O
changes O
in O
newborn O
pigs O
. O

Our O
data O
also O
suggest O
that O
the O
PLC O
/ O
IP3 B
signaling O
pathway O
contributes O
to O
hUII O
- O
induced O
alterations O
in O
MAP O
, O
RBF O
, O
RVR O
, O
and O
CBF O
but O
not O
MBF O
in O
newborn O
pigs O
. O

Neuronal O
expression O
of O
glucosylceramide B
synthase O
in O
central O
nervous O
system O
regulates O
body O
weight O
and O
energy O
homeostasis O
. O

Hypothalamic O
neurons O
are O
main O
regulators O
of O
energy O
homeostasis O
. O

Neuronal O
function O
essentially O
depends O
on O
plasma O
membrane O
- O
located O
gangliosides O
. O

The O
present O
work O
demonstrates O
that O
hypothalamic O
integration O
of O
metabolic O
signals O
requires O
neuronal O
expression O
of O
glucosylceramide B
synthase O
( O
GCS O
; O
UDP B
- O
glucose B
: O
ceramide B
glucosyltransferase O
) O
. O

As O
a O
major O
mechanism O
of O
central O
nervous O
system O
( O
CNS O
) O
metabolic O
control O
, O
we O
demonstrate O
that O
GCS O
- O
derived O
gangliosides B
interacting O
with O
leptin O
receptors O
( O
ObR O
) O
in O
the O
neuronal O
membrane O
modulate O
leptin O
- O
stimulated O
formation O
of O
signaling O
metabolites O
in O
hypothalamic O
neurons O
. O

Furthermore O
, O
ganglioside B
- O
depleted O
hypothalamic O
neurons O
fail O
to O
adapt O
their O
activity O
( O
c O
- O
Fos O
) O
in O
response O
to O
alterations O
in O
peripheral O
energy O
signals O
. O

Consequently O
, O
mice O
with O
inducible O
forebrain O
neuron O
- O
specific O
deletion O
of O
the O
UDP B
- O
glucose B
: O
ceramide B
glucosyltransferase O
gene O
( O
Ugcg O
) O
display O
obesity O
, O
hypothermia O
, O
and O
lower O
sympathetic O
activity O
. O

Recombinant O
adeno O
- O
associated O
virus O
( O
rAAV O
) O
- O
mediated O
Ugcg O
delivery O
to O
the O
arcuate O
nucleus O
( O
Arc O
) O
significantly O
ameliorated O
obesity O
, O
specifying O
gangliosides B
as O
seminal O
components O
for O
hypothalamic O
regulation O
of O
body O
energy O
homeostasis O
. O

Dose O
- O
dependent O
pharmacokinetics O
of O
bulleyaconitine B
A I
in O
rats O
. O

This O
study O
was O
conducted O
to O
determine O
the O
pharmacokinetic O
characteristics O
of O
bulleyaconitine B
A I
( O
BLA B
) O
after O
oral O
gavage O
and O
intravenous O
administration O
of O
BLA B
at O
a O
single O
dose O
of O
0 O
. O
04 O
, O
0 O
. O
12 O
, O
0 O
. O
36 O
mg O
/ O
kg O
( O
oral O
) O
or O
0 O
. O
02 O
mg O
/ O
kg O
( O
i O
. O
v O
. O
) O
in O
male O
Sprague O
- O
Dawley O
rats O
. O

Plasma O
concentration O
profiles O
were O
analysed O
using O
a O
non O
- O
compartmental O
pharmacokinetic O
method O
. O

Following O
i O
. O
v O
. O
0 O
. O
02 O
mg O
/ O
kg O
and O
oral O
administration O
0 O
. O
04 O
, O
0 O
. O
12 O
or O
0 O
. O
36 O
mg O
/ O
kg O
, O
the O
geometric O
mean O
Cmax O
values O
were O
19 O
. O
97 O
, O
2 O
. O
11 O
, O
5 O
. O
11 O
and O
11 O
. O
47 O
ng O
/ O
ml O
, O
respectively O
; O
the O
corresponding O
geometric O
mean O
AUC O
( O
0 O
- O
t O
) O
values O
were O
10 O
. O
50 O
, O
3 O
. O
19 O
, O
9 O
. O
59 O
and O
18 O
. O
10 O
ng O
x O
h O
/ O
ml O
, O
respectively O
. O

The O
median O
Tmax O
values O
were O
0 O
. O
033 O
, O
0 O
. O
167 O
, O
0 O
. O
167 O
and O
0 O
. O
167 O
h O
, O
respectively O
. O

The O
terminal O
elimination O
half O
- O
lives O
( O
t1 O
/ O
2 O
) O
were O
1 O
. O
23 O
, O
2 O
. O
48 O
, O
1 O
. O
93 O
and O
2 O
. O
17h O
, O
respectively O
. O

The O
results O
showed O
that O
Cmax O
and O
AUC O
( O
0 O
- O
t O
) O
increased O
with O
increasing O
doses O
of O
BLA B
. O

The O
increase O
in O
exposure O
with O
increasing O
dose O
was O
lower O
than O
expected O
under O
conditions O
of O
strict O
proportionality O
. O

Anticancer O
activity O
of O
the O
liposome O
- O
encapsulated O
cyclic B
dipeptides I
, O
cyclo B
( I
His I
- I
Gly I
) I
and O
cyclo B
( I
His I
- I
Ala I
) I
. O

Cyclic B
dipeptides I
have O
been O
well O
characterized O
for O
their O
biological O
activity O
, O
including O
antimicrobial O
and O
anticancer O
activities O
. O

Cyclo B
( I
His I
- I
Gly I
) I
and O
cyclo B
( I
His I
- I
Ala I
) I
have O
also O
recently O
demonstrated O
significant O
anticancer O
activity O
against O
a O
range O
of O
cell O
lines O
, O
however O
, O
as O
a O
result O
of O
their O
physicochemistry O
, O
namely O
high O
solubility O
and O
low O
lipophilicity O
, O
it O
can O
be O
predicted O
that O
cellular O
permeability O
would O
be O
low O
, O
making O
them O
ideal O
candidates O
for O
liposome O
drug O
delivery O
. O

Liposomes O
were O
composed O
of O
phosphatidylcholine B
, O
hydrogenated O
soy O
phosphatidylcholine B
( O
HSPC O
) O
, O
stearylamine B
, O
alpha B
- I
tocopherol I
and O
1 B
, I
2 I
- I
distearoyl I
- I
sn I
- I
glycero I
- I
3 I
- I
phosphoethanolamine I
- I
N I
- I
[ I
amino I
( I
polyethylene I
glycol I
) I
- I
2000 I
] I
( O
PEG B
- I
DSPE I
) O
or O
folate B
- O
polyethylene B
glycol I
- I
cholesteryl I
hemisuccinate I
( O
F O
- I

PEG B
- O
CHEMS O
) O
using O
the O
thin O
- O
film O
hydration O
method O
and O
characterized O
for O
size O
and O
encapsulation O
. O

The O
cytotoxic O
activity O
of O
the O
encapsulated O
cyclic B
dipeptides I
was O
tested O
against O
HeLa O
, O
low O
folate B
HeLa O
and O
MCF O
- O
7 O
cells O
and O
found O
to O
have O
limited O
improvement O
in O
activity O
. O

However O
, O
modification O
of O
the O
polyethylene B
glycol I
with O
folic B
acid I
to O
target O
folate B
receptors O
significantly O
decreased O
the O
IC50 O
values O
recorded O
in O
all O
cells O
lines O
tested O
, O
particularly O
HeLa O
cells O
cultured O
in O
media O
containing O
physiological O
concentrations O
of O
folic B
acid I
with O
the O
lowest O
IC50 O
being O
recorded O
as O
0 O
. O
0962 O
mM O
for O
folate B
- O
targeted O
cyclo B
( I
His I
- I
Ala I
) I
. O

Therefore O
, O
hydrophilic O
cyclic B
dipeptides I
are O
ideal O
candidates O
for O
inclusion O
into O
targeted O
drug O
delivery O
systems O
such O
as O
liposomes O
. O

Biological O
activities O
of O
selected O
basidiomycetes O
from O
Yemen O
. O

In O
a O
previous O
paper O
we O
demonstrated O
the O
results O
of O
biological O
screening O
of O
Yemeni O
basidiomycetes O
. O

The O
present O
study O
was O
aimed O
to O
investigate O
the O
antimicrobial O
and O
the O
antioxidant O
activity O
of O
further O
basidiomycetes O
collected O
in O
Yemen O
. O

Dichloromethane B
, O
methanol B
and O
aqueous O
extracts O
of O
the O
fruiting O
bodies O
of O
25 O
species O
were O
screened O
in O
vitro O
for O
their O
antibacterial O
activities O
against O
three O
Gram O
- O
positive O
bacteria O
( O
Staphyloccocus O
aureus O
, O
Bacillus O
subtilis O
, O
Micrococcus O
flavus O
) O
and O
two O
Gram O
- O
negative O
bacteria O
( O
Escherichia O
coli O
, O
Pseudomonas O
aeruginosa O
) O
, O
against O
six O
human O
fungal O
pathogens O
( O
Candida O
albicans O
, O
Candida O
krusei O
, O
Aspergillus O
fumigatus O
, O

Mucor O
sp O
. O
, O
Microsporum O
gypseum O
, O
Trichophyton O
mentagrophytes O
) O
and O
against O
one O
non O
human O
pathogenic O
fungus O
( O
Candida O
maltosa O
) O
. O

The O
results O
indicated O
that O
75 O
extracts O
exhibited O
activity O
against O
one O
or O
more O
of O
the O
bacteria O
. O

The O
methanol B
extracts O
of O
Agaricus O
cf O
. O
bernardii O
, O
Agrocybe O
pediades O
, O
Chlorophyllum B
molybdites O
, O
Coriolopsis O
polyzona O
, O
Ganoderma O
xylonoides O
, O
Pycnoporus O
sanguineus O
, O
Trametes O
lactinea O
and O
Trametes O
cingulata O
showed O
activity O
against O
all O
tested O
bacteria O
. O

The O
highest O
antibacterial O
activity O
was O
exhibited O
by O
methanol B
extracts O
from O
Chlorophyllum O
molybdites O
, O
Ganoderma O
xylonoides O
and O
Trametes O
cingulata O
and O
Agaricus O
cf O
. O
bernardii O
, O
Agrocybe O
pediades O
, O
Coriolopsis O
polyzona O
, O
Pycnoporus O
sanguineus O
and O
Trametes O
lactinea O
. O

The O
methanol B
extracts O
of O
Chlorophyllum O
molybdites O
, O
Ganoderma O
xylonoides O
and O
Pycnoporus O
sanguineus O
showed O
considerable O
antifungal O
activities O
against O
the O
tested O
fungal O
strains O
. O

Strong O
antioxidative O
effects O
employing O
the O
DPPH B
assay O
were O
exhibited O
by O
methanol B
extracts O
from O
Chlorophyllum O
molybdites O
, O
Ganoderma O
xylonoides O
, O
Hexagonia O
velutina O
, O
Pycnoporus O
sanguineus O
, O
Trametes O
lactinea O
and O
Trametes O
cingulata O
. O

Our O
previous O
and O
presented O
studies O
about O
48 O
basidiomycetes O
collected O
in O
Yemen O
provide O
evidence O
that O
basidiomycetes O
from O
the O
Arabic O
region O
so O
far O
should O
attract O
more O
attention O
as O
potential O
source O
for O
new O
biologically O
active O
agents O
. O

Rovibrational O
Energies O
of O
the O
Hydrocarboxyl B
Radical O
from O
a O
RCCSD O
( O
T O
) O
Study O
. O

A O
RCCSD O
( O
T O
) O
/ O
cc O
- O
pVQZ O
potential O
energy O
surface O
is O
constructed O
for O
the O
HOCO B
radical O
in O
the O
ground O
electronic O
state O
and O
used O
to O
compute O
rotation O
- O
vibration O
levels O
of O
HOCO B
and O
DOCO B
. O

Two O
numerical O
strategies O
are O
employed O
to O
study O
in O
detail O
the O
wave O
function O
properties O
. O

The O
importance O
of O
stretch O
- O
bend O
coupling O
, O
such O
as O
nu O
4 O
/ O
nu O
5 O
and O
nu O
3 O
/ O
nu O
4 O
, O
for O
the O
internal O
dynamics O
is O
demonstrated O
. O

The O
rotational O
constants O
computed O
for O
the O
vibrational O
ground O
state O
of O
trans O
and O
cis O
conformers O
are O
in O
good O
agreement O
with O
experimental O
values O
. O

Institutional O
Profile O
: O
Jayne O
Haines O
Center O
for O
Pharmacogenomics O
and O
Drug O
Safety O
: O
educating O
future O
generations O
of O
healthcare O
professionals O
. O

The O
Jayne O
Haines O
Center O
for O
Pharmacogenomics O
and O
Drug O
Safety O
operates O
in O
the O
Temple O
University O
School O
of O
Pharmacy O
and O
serves O
as O
an O
educational O
and O
research O
facility O
for O
professional O
pharmacy O
students O
, O
graduate O
students O
, O
residents O
, O
postdoctoral O
fellows O
and O
faculties O
. O

The O
Center O
is O
involved O
in O
educational O
and O
investigational O
projects O
in O
a O
setting O
that O
includes O
an O
inner O
city O
research O
/ O
teaching O
hospital O
and O
the O
Temple O
University O
Schools O
of O
Pharmacy O
, O
Medicine O
, O
Dentistry O
and O
Health O
Professions O
. O

The O
mission O
of O
the O
Haines O
Center O
is O
to O
facilitate O
the O
basic O
science O
approach O
to O
the O
problems O
of O
pharmacotherapy O
, O
and O
to O
provide O
education O
for O
future O
healthcare O
professionals O
in O
the O
genetics O
of O
drug O
response O
. O

With O
the O
expanding O
role O
of O
genetic O
analysis O
in O
preventing O
adverse O
effects O
of O
pharmacotherapy O
, O
we O
are O
working O
towards O
truly O
personalized O
pharmacotherapy O
that O
fully O
exploits O
the O
advances O
of O
modern O
biomedical O
science O
. O

Antioxidant O
activity O
of O
Tunisian O
Geranium O
robertianum O
L O
. O

( O
Geraniaceae O
) O
. O

The O
present O
investigation O
focuses O
on O
the O
methanolic O
extract O
obtained O
from O
Geranium O
robertianum O
L O
. O

( O
Geraniaceae O
) O
( O
Herb O
Robert O
) O
, O
a O
herbal O
plant O
used O
in O
traditional O
medicine O
for O
the O
treatment O
of O
human O
and O
animal O
diseases O
. O

The O
antioxidant O
capacities O
of O
the O
extract O
were O
evaluated O
using O
1 B
, I
1 I
- I
diphenyl I
- I
2 I
- I
picrylhydrazyl I
radical O
, O
beta B
- I
carotene I
/ O
linoleic B
acid I
and O
reducing O
power O
and O
metal O
chelating O
activity O
assays O
. O

The O
amount O
of O
total O
phenolic O
content O
, O
flavonoids B
and O
condensed B
tannins I
was O
very O
high O
, O
and O
the O
correlation O
between O
the O
antioxidant O
activity O
potential O
and O
total O
phenolic B
level O
of O
the O
extract O
was O
pointed O
out O
. O

Galactose B
- O
Based O
Amphiphilic O
Block O
Copolymers O
: O
Synthesis O
, O
Micellization O
, O
and O
Bioapplication O
. O

Redox O
- O
responsive O
amphiphilic O
diblock O
copolymers O
, O
poly B
( I
6 I
- I
O I
- I
methacryloyl I
- I
d I
- I
galactopyranose I
- I
co I
- I
2 I
- I
( I
N I
, I
N I
- I
dimethylaminoethyl I
) I
methacrylate I
) I
- I
b I
- I
poly I
( I
pyridyl I
disulfide I
ethyl I
methylacrylate I
) I
( O
P B
( I
MAGP I
- I
co I
- I
DMAEMA I
) I
- I
b I
- I
PPDSMA I
) O
were O
obtained O
by O
deprotection O
of O
poly B
( I
( I
6 I
- I
O I
- I
methacryloyl I

- I
1 I
, I
2 I
: I
3 I
, I
4 I
- I
di I
- I
O I
- I
isopropylidene I
- I
d I
- I
galactopyranose I
) I
- I
co I
- I
DMAEMA I
) I
- I
b I
- I
PPDSMA I
[ O
P B
( I
MAlpGP I
- I
co I
- I
DMAEMA I
) I
- I
b I
- I
PPDSMA I
] O
, O
which O
were O
prepared O
via O
reversible O
addition O
- O
fragmentation O
chain O
transfer O
( O
RAFT O
) O
polymerization O
of O
PDSMA B
using O
P B
( I
MAlpGP I
- I
co I
- I
DMAEMA I
) I
as O
macro O
- O
RAFT O
agent O
. O

Dynamic O
light O
scattering O
( O
DLS O
) O
and O
transmission O
electron O
microscopy O
( O
TEM O
) O
studies O
showed O
that O
diblock O
copolymers O
P B
( I
MAGP I
- I
co I
- I
DMAEMA I
) I
- I
b I
- I
PPDSMA I
can O
self O
- O
assemble O
into O
micelles O
. O

Doxorubicin B
( O
DOX B
) O
could O
be O
encapsulated O
by O
P B
( I
MAGP I
- I
co I
- I
DMAEMA I
) I
- I
b I
- I
PPDSMA I
upon O
micellization O
and O
released O
upon O
adding O
glutathione B
( O
GSH B
) O
into O
the O
micelle O
solution O
. O

The O
galactose B
functional O
groups O
in O
the O
PMAGP O
block O
had O
specific O
interaction O
with O
HepG2 O
cells O
, O
and O
P B
( I
MAGP I
- I
co I
- I
DMAEMA I
) I
- I
b I
- I
PPDSMA I
can O
act O
as O
gene O
delivery O
vehicle O
. O

So O
, O
this O
kind O
of O
polymer O
has O
potential O
applications O
in O
hepatoma O
- O
targeting O
drug O
and O
gene O
delivery O
and O
biodetection O
. O

Effects O
of O
prediabetes O
and O
diabetes O
on O
left O
ventricular O
and O
coronary O
microvascular O
functions O
. O

BACKGROUND O
: O
Coronary O
flow O
reserve O
( O
CFR O
) O
provides O
independent O
prognostic O
information O
in O
diabetic O
patients O
with O
known O
or O
suspected O
coronary O
artery O
disease O
. O

However O
, O
there O
have O
been O
no O
substantial O
data O
to O
evaluate O
CFR O
in O
prediabetics O
. O

Accordingly O
, O
we O
aimed O
to O
evaluate O
CFR O
in O
subjects O
with O
prediabetes O
using O
second O
harmonic O
transthoracic O
Doppler O
echocardiography O
. O

METHODS O
AND O
RESULTS O
: O
We O
measured O
CFR O
of O
65 O
subjects O
with O
prediabetes O
, O
45 O
patients O
with O
overt O
type O
2 O
diabetes O
, O
and O
43 O
sex O
and O
age O
matched O
normoglycemic O
healthy O
subjects O
with O
normal O
glucose B
tolerance O
. O

Ages O
, O
gender O
, O
existence O
of O
hypertension O
or O
hypercholesterolemia O
, O
smoking O
status O
were O
similar O
among O
the O
groups O
. O

CFR O
was O
significantly O
lower O
in O
diabetics O
( O
2 O
. O
15 O
+ O
/ O
- O
0 O
. O
39 O
) O
than O
in O
prediabetics O
( O
2 O
. O
39 O
+ O
/ O
- O
0 O
. O
45 O
) O
and O
controls O
( O
2 O
. O
75 O
+ O
/ O
- O
0 O
. O
35 O
) O
; O
in O
addition O
, O
it O
was O
significantly O
lower O
in O
prediabetics O
than O
controls O
. O

Only O
2 O
( O
5 O
% O
) O
of O
control O
subjects O
had O
abnormal O
CFR O
( O
< O
2 O
) O
but O
11 O
( O
17 O
% O
) O
prediabetic O
subjects O
and O
19 O
( O
42 O
% O
) O
diabetic O
patients O
had O
abnormal O
CFR O
. O

We O
found O
that O
only O
age O
( O
beta O
= O
- O
0 O
. O
31 O
, O
P O
< O
0 O
. O
01 O
) O
and O
presence O
of O
the O
diabetes O
( O
beta O
= O
- O
0 O
. O
57 O
, O
P O
< O
0 O
. O
01 O
) O
were O
significant O
predictors O
of O
lower O
CFR O
in O
a O
multivariable O
model O
that O
adjusted O
for O
other O
variables O
. O

CFR O
was O
significantly O
and O
inversely O
correlated O
with O
age O
( O
r O
= O
- O
0 O
. O
15 O
, O
P O
= O
0 O
. O
04 O
) O
, O
fasting O
glucose B
level O
( O
r O
= O
- O
0 O
. O
27 O
, O
P O
= O
0 O
. O
001 O
) O
, O
postprandial O
glucose B
level O
( O
r O
= O
0 O
. O
43 O
, O
P O
< O
0 O
. O
001 O
) O
, O
hemoglobin O
A1C O
level O
( O
r O
= O
- O
0 O
. O
34 O
, O
P O
< O
0 O
. O
001 O
) O
, O
LDL O
cholesterol B
level O
( O
r O
= O
0 O
. O
22 O
, O
P O
= O
0 O
. O
009 O
) O
, O
mitral O
A O
velocity O
( O
r O
= O
- O
0 O
. O
27 O
, O
P O
= O

0 O
. O
001 O
) O
and O
Tei O
index O
( O
r O
= O
- O
0 O
. O
19 O
, O
P O
= O
0 O
. O
02 O
) O
, O
whereas O
mitral O
E O
/ O
A O
ratio O
, O
mitral O
Em O
( O
r O
= O
0 O
. O
18 O
, O
P O
= O
0 O
. O
02 O
) O
, O
mitral O
Em O
/ O
Am O
ratio O
( O
r O
= O
0 O
. O
23 O
, O
P O
= O
0 O
. O
004 O
) O
were O
significantly O
and O
positively O
correlated O
with O
CFR O
. O

CONCLUSION O
: O
CFR O
is O
impaired O
in O
subjects O
with O
prediabetics O
, O
but O
this O
impairment O
is O
not O
as O
severe O
as O
that O
in O
diabetics O
. O

Does O
4 B
- I
tert I
- I
octylphenol I
affect O
estrogen B
signaling O
pathways O
in O
bank O
vole O
Leydig O
cells O
and O
tumor O
mouse O
Leydig O
cells O
in O
vitro O
? O

Primary O
Leydig O
cells O
obtained O
from O
bank O
vole O
testes O
and O
the O
established O
tumor O
Leydig O
cell O
line O
( O
MA O
- O
10 O
) O
have O
been O
used O
to O
explore O
the O
effects O
of O
4 B
- I
tert I
- I
octylphenol I
( O
OP O
) O
. O

Leydig O
cells O
were O
treated O
with O
two O
concentrations O
of O
OP O
( O
10 O
( O
- O
4 O
) O
M O
, O
10 O
( O
- O
8 O
) O
M O
) O
alone O
or O
concomitantly O
with O
anti O
- O
estrogen B
ICI B
182 I
, I
780 I
( O
1 O
mu O
M O
) O
. O

In O
OP O
- O
treated O
bank O
vole O
Leydig O
cells O
, O
inhomogeneous O
staining O
of O
estrogen B
receptor O
alpha O
( O
ER O
alpha O
) O
within O
cell O
nuclei O
was O
found O
, O
whereas O
it O
was O
of O
various O
intensity O
among O
MA O
- O
10 O
Leydig O
cells O
. O

The O
expression O
of O
ER O
alpha O
mRNA O
and O
protein O
decreased O
in O
both O
primary O
and O
immortalized O
Leydig O
cells O
independently O
of O
OP O
dose O
. O

ICI B
partially O
reversed O
these O
effects O
at O
mRNA O
level O
while O
at O
protein O
level O
abrogation O
was O
found O
only O
in O
vole O
cells O
. O

Dissimilar O
action O
of O
OP O
on O
cAMP B
and O
androgen B
production O
was O
also O
observed O
. O

This O
study O
provides O
further O
evidence O
that O
OP O
shows O
estrogenic O
properties O
acting O
on O
Leydig O
cells O
. O

However O
, O
its O
effect O
is O
diverse O
depending O
on O
the O
cellular O
origin O
. O

mTOR O
Regulates O
Nox4 O
- O
Mediated O
Podocyte O
Depletion O
in O
Diabetic O
Renal O
Injury O
. O

Podocyte O
apoptosis O
is O
a O
critical O
mechanism O
for O
excessive O
loss O
of O
urinary O
albumin O
that O
eventuates O
in O
kidney O
fibrosis O
. O

Pharmacological O
doses O
of O
the O
mTOR O
inhibitor O
rapamycin B
reduce O
albuminura O
in O
diabetes O
. O

We O
explored O
the O
hypothesis O
that O
mTOR O
mediates O
podocyte O
injury O
in O
diabetes O
. O

High O
glucose B
( O
HG O
) O
induces O
apoptosis O
of O
podocytes O
, O
inhibits O
AMPK O
activation O
, O
inactivates O
tuberin O
and O
activates O
mTOR O
. O

HG B
also O
increases O
the O
levels O
of O
Nox4 O
and O
Nox1 O
and O
NADPH B
oxidase O
activity O
. O

Inhibition O
of O
mTOR O
by O
low O
dose O
rapamycin B
decreases O
HG B
- O
induced O
Nox4 O
and O
Nox1 O
, O
NADPH B
oxidase O
activity O
and O
podocyte O
apoptosis O
. O

Inhibition O
of O
mTOR O
had O
no O
effect O
on O
AMPK O
or O
tuberin O
phosphorylation O
indicating O
that O
mTOR O
is O
downstream O
of O
these O
signaling O
molecules O
. O

In O
isolated O
glomeruli O
of O
OVE26 O
mice O
, O
there O
is O
similar O
decrease O
in O
the O
activation O
of O
AMPK O
and O
tuberin O
and O
activation O
of O
mTOR O
with O
increase O
in O
Nox4 O
and O
NADPH B
oxidase O
activity O
. O

Inhibition O
of O
mTOR O
by O
small O
dose O
of O
rapamycin B
reduces O
podocyte O
apoptosis O
, O
attenuates O
glomerular O
injury O
and O
albuminuria O
. O

Our O
data O
provide O
evidence O
for O
a O
novel O
function O
of O
mTOR O
in O
Nox4 O
- O
derived O
ROS O
generation O
and O
podocyte O
apoptosis O
that O
contributes O
to O
urinary O
albumin O
excretion O
in O
type O
1 O
diabetes O
. O

Thus O
mTOR O
and O
or O
NADPH B
oxidase O
inhibition O
may O
represent O
a O
therapeutic O
modality O
of O
diabetic O
kidney O
disease O
. O

Application O
of O
Target O
- O
Mediated O
Drug O
Disposition O
Model O
to O
Small O
Molecule O
Heat O
Shock O
Protein O
90 O
Inhibitors O
. O

Replacement O
of O
hydrogen B
with O
fluorine B
within O
three O
pairs O
of O
structurally O
similar O
small O
molecule O
inhibitors O
of O
heat O
shock O
protein O
90 O
( O
HSP90 O
) O
resulted O
in O
differences O
in O
inhibition O
constants O
( O
Ki O
) O
in O
vitro O
as O
well O
as O
marked O
differences O
in O
rat O
intravenous O
pharmacokinetic O
profiles O
. O

The O
difference O
in O
pharmacokinetic O
profiles O
between O
lower O
and O
higher O
affinity O
inhibitors O
( O
LAIs O
and O
HAIs O
, O
respectively O
) O
was O
characterized O
by O
remarkably O
different O
estimates O
for O
steady O
- O
state O
volumes O
of O
distribution O
( O
Vss O
: O
1 O
. O
8 O
to O
2 O
. O
0 O
versus O
10 O
to O
13 O
L O
/ O
kg O
) O
with O
comparable O
clearance O
estimates O
( O
3 O
. O
2 O
to O
3 O
. O
5 O
L O
/ O
h O
/ O
kg O
) O
. O

When O
the O
observed O
Vss O
estimates O
were O
compared O
to O
the O
values O
predicted O
with O
the O
tissue O
- O
composition O
- O
based O
model O
, O
the O
observed O
Vss O
estimates O
for O
HAIs O
were O
4 O
to O
8 O
- O
fold O
larger O
than O
the O
predicted O
values O
whereas O
the O
Vss O
values O
for O
LAIs O
were O
comparable O
each O
other O
. O

Accordingly O
, O
a O
negative O
relationship O
between O
in O
vitro O
HSP90 O
Ki O
versus O
in O
vivo O
Vss O
estimates O
was O
observed O
among O
these O
inhibitors O
. O

We O
therefore O
hypothesized O
that O
pharmacokinetic O
profiles O
of O
these O
inhibitors O
could O
be O
characterized O
by O
target O
- O
mediated O
drug O
disposition O
( O
TMDD O
) O
model O
. O

In O
vivo O
equilibrium O
dissociation O
constant O
( O
KD O
) O
estimates O
for O
HAIs O
due O
to O
target O
binding O
by O
TMDD O
model O
with O
rapid O
binding O
approximation O
were O
1 O
to O
6 O
nM O
( O
equivalent O
to O
0 O
. O
3 O
to O
2 O
nM O
free O
drug O
) O
, O
which O
appeared O
comparable O
to O
the O
in O
vitro O
Ki O
estimates O
( O
2 O
to O
3 O
nM O
) O
. O

In O
vivo O
KD O
values O
of O
LAIs O
were O
not O
accurately O
determined O
by O
the O
TMDD O
model O
, O
likely O
due O
to O
non O
- O
specific O
binding O
dependent O
- O
tissue O
distribution O
obscuring O
TMDD O
profiles O
. O

Overall O
, O
these O
results O
suggest O
that O
the O
observed O
large O
Vss O
estimates O
for O
potent O
HSP90 O
inhibitors O
are O
likely O
due O
to O
pharmacological O
target O
binding O
. O

1 B
, I
3 I
, I
4 I
- I
Oxadiazol I
- I
2 I
- I
ones I
as O
fatty B
- I
acid I
amide I
hydrolase O
and O
monoacylglycerol B
lipase O
inhibitors O
: O
Synthesis O
, O
in O
vitro O
evaluation O
and O
insight O
into O
potency O
and O
selectivity O
determinants O
by O
molecular O
modelling O
. O

Inhibition O
of O
the O
key O
hydrolytic O
enzymes O
of O
the O
endocannabinoid O
system O
, O
fatty B
acid I
amide B
hydrolase O
( O
FAAH O
) O
and O
monoacylglycerol B
lipase O
( O
MAGL O
) O
, O
has O
been O
proposed O
as O
potential O
mode O
of O
action O
for O
various O
therapeutic O
applications O
. O

Continuing O
our O
previous O
work O
, O
we O
take O
the O
first O
steps O
of O
structure O
- O
activity O
relationship O
exploration O
and O
show O
that O
1 B
, I
3 I
, I
4 I
- I
oxadiazol I
- I
2 I
- I
ones I
can O
serve O
as O
scaffold O
for O
both O
selective O
FAAH O
and O
MAGL O
inhibitors O
, O
and O
also O
function O
as O
a O
dual O
FAAH O
/ O
MAGL O
inhibitor O
at O
sub O
- O
micromolar O
IC50 O
values O
. O

Moreover O
, O
10 O
- O
fold O
selectivity O
against O
MAGL O
over O
FAAH O
was O
achieved O
with O
compound O
3d O
( O
FAAH O
and O
MAGL O
IC50 O
; O
2 O
. O
0 O
and O
0 O
. O
22 O
mu O
M O
) O
. O

Lastly O
, O
enzyme O
and O
ligand O
features O
contributing O
to O
the O
potency O
and O
selectivity O
differences O
are O
analysed O
by O
molecular O
docking O
. O

Development O
of O
solid O
lipid O
nanoparticles O
based O
controlled O
release O
system O
for O
topical O
delivery O
of O
terbinafine B
hydrochloride I
. O

The O
study O
describes O
the O
development O
and O
evaluation O
of O
solid O
lipid O
nanoparticles O
( O
SLNs O
) O
of O
terbinafine B
hydrochloride I
( O
TH O
) O
for O
sustained O
release O
and O
skin O
targeting O
. O

TH O
- O
loaded O
SLNs O
were O
prepared O
by O
solvent O
- O
injection O
technique O
and O
optimized O
using O
3 O
( O
3 O
) O
full O
- O
factorial O
design O
. O

Effect O
of O
drug O
: O
lipid O
ratio O
, O
surfactant O
concentration O
and O
volume O
of O
organic O
solvent O
were O
studied O
on O
% O
entrapment O
efficiency O
( O
% O
EE O
) O
and O
particle O
size O
( O
PS O
) O
. O

The O
optimum O
formulation O
based O
on O
desirability O
( O
0 O
. O
945 O
) O
exhibited O
% O
EE O
of O
73 O
. O
74 O
% O
and O
PS O
of O
300nm O
. O

Optimized O
SLNs O
were O
incorporated O
into O
Carbopol B
gel O
and O
evaluated O
for O
drug O
content O
, O
pH O
, O
in O
vitro O
release O
, O
ex O
vivo O
retention O
, O
in O
vivo O
pharmacodynamic O
and O
stability O
studies O
. O

Drug O
release O
from O
SLNs O
dispersion O
followed O
Korsmeyer O
- O
Peppas O
model O
, O
indicating O
Fickian O
drug O
release O
, O
while O
that O
from O
the O
gel O
followed O
Higuchi O
model O
. O

The O
ex O
vivo O
studies O
through O
rat O
abdominal O
skin O
indicated O
skin O
retention O
ability O
of O
SLNs O
as O
compared O
to O
commercial O
product O
. O

In O
vivo O
pharmacodynamic O
studies O
showed O
that O
the O
SLNs O
based O
gel O
reduced O
fungal O
burden O
of O
Candida O
albicans O
in O
rats O
as O
compared O
to O
commercial O
product O
in O
shorter O
duration O
of O
time O
. O

The O
SLNs O
dispersion O
and O
gel O
exhibited O
physicochemical O
stability O
under O
refrigeration O
upto O
3months O
. O

It O
was O
concluded O
that O
SLNs O
incorporated O
Carbopol B
gel O
had O
skin O
targeting O
ability O
and O
may O
serve O
as O
a O
promising O
carrier O
in O
treatment O
of O
fungal O
skin O
infections O
. O

Antitumor O
effect O
of O
5 B
- I
fluorouracil I
is O
enhanced O
by O
rosemary O
extract O
in O
both O
drug O
sensitive O
and O
resistant O
colon O
cancer O
cells O
. O

5 B
- I
Fluorouracil I
( O
5 B
- I
FU I
) O
is O
the O
most O
used O
chemotherapeutic O
agent O
in O
colorectal O
cancer O
. O

However O
, O
resistance O
to O
this O
drug O
is O
relatively O
frequent O
, O
and O
new O
strategies O
to O
overcome O
it O
are O
urgently O
needed O
. O

The O
aim O
of O
this O
work O
was O
to O
determine O
the O
antitumor O
properties O
of O
a O
supercritical O
fluid O
rosemary O
extract O
( O
SFRE O
) O
, O
alone O
and O
in O
combination O
with O
5 B
- I
FU I
, O
as O
a O
potential O
adjuvant O
therapy O
useful O
for O
colon O
cancer O
patients O
. O

This O
extract O
has O
been O
recognized O
as O
a O
healthy O
component O
by O
the O
European O
Food O
Safety O
Authority O
( O
EFSA O
) O
. O

The O
effects O
of O
SFRE B
both O
alone O
and O
in O
combination O
with O
5 B
- I
FU I
were O
evaluated O
in O
different O
human O
colon O
cancer O
cells O
in O
terms O
of O
cell O
viability O
, O
cytotoxicity O
, O
and O
cell O
transformation O
. O

Additionally O
, O
colon O
cancer O
cells O
resistant O
to O
5 B
- I
FU I
were O
used O
to O
assay O
the O
effects O
of O
SFRE B
on O
drug O
resistance O
. O

Finally O
, O
qRT O
- O
PCR O
was O
performed O
to O
ascertain O
the O
mechanism O
by O
which O
SFRE B
potentiates O
the O
effect O
of O
5 B
- I
FU I
. O

Our O
results O
show O
that O
SFRE B
displays O
dose O
- O
dependent O
antitumor O
activities O
and O
exerts O
a O
synergistic O
effect O
in O
combination O
with O
5 B
- I
FU I
on O
colon O
cancer O
cells O
. O

Furthermore O
, O
SFRE O
sensitizes O
5 B
- I
FU I
- O
resistant O
cells O
to O
the O
therapeutic O
activity O
of O
this O
drug O
, O
constituting O
a O
beneficial O
agent O
against O
both O
5 B
- I
FU I
sensitive O
and O
resistant O
tumor O
cells O
. O

Gene O
expression O
analysis O
indicates O
that O
the O
enhancement O
of O
the O
effect O
of O
5 B
- I
FU I
by O
SFRE B
might O
be O
explained O
by O
the O
downregulation O
of O
TYMS O
and O
TK1 O
, O
enzymes O
related O
to O
5 B
- I
FU I
resistance O
. O

A O
new O
method O
for O
stranded O
whole O
transcriptome O
RNA O
- O
seq O
. O

This O
report O
describes O
an O
improved O
protocol O
to O
generate O
stranded O
, O
barcoded O
RNA O
- O
seq O
libraries O
to O
capture O
the O
whole O
transcriptome O
. O

By O
optimizing O
the O
use O
of O
duplex O
specific O
nuclease O
( O
DSN O
) O
to O
remove O
ribosomal O
RNA O
reads O
from O
stranded O
barcoded O
libraries O
, O
we O
demonstrate O
improved O
efficiency O
of O
multiplexed O
next O
generation O
sequencing O
( O
NGS O
) O
. O

This O
approach O
detects O
expression O
profiles O
of O
all O
RNA O
types O
, O
including O
miRNA O
( O
microRNA O
) O
, O
piRNA O
( O
Piwi O
- O
interacting O
RNA O
) O
, O
snoRNA O
( O
small O
nucleolar O
RNA O
) O
, O
lincRNA O
( O
long O
non O
- O
coding O
RNA O
) O
, O
mtRNA O
( O
mitochondrial O
RNA O
) O
and O
mRNA O
( O
messenger O
RNA O
) O
without O
the O
use O
of O
gel O
electrophoresis O
. O

The O
improved O
protocol O
generates O
high O
quality O
data O
that O
can O
be O
used O
to O
identify O
differential O
expression O
in O
known O
and O
novel O
coding O
and O
non O
- O
coding O
transcripts O
, O
splice O
variants O
, O
mitochondrial O
genes O
and O
SNPs O
( O
single O
nucleotide O
polymorphisms O
) O
. O

A O
diarylheptanoid B
phytoestrogen O
from O
Curcuma O
comosa O
, O
1 B
, I
7 I
- I
diphenyl I
- I
4 I
, I
6 I
- I
heptadien I
- I
3 I
- I
ol I
, O
accelerates O
human O
osteoblast O
proliferation O
and O
differentiation O
. O

Curcuma O
comosa O
Roxb O
. O

is O
ginger O
- O
family O
plant O
used O
to O
relieve O
menopausal O
symptoms O
. O

Previous O
work O
showed O
that O
C O
. O
comosa O
extracts O
protect O
mice O
from O
ovariectomy O
- O
induced O
osteopenia O
with O
minimal O
effects O
on O
reproductive O
organs O
, O
and O
identified O
the O
diarylheptanoid B
( B
3R I
) I
- I
1 I
, I
7 I
- I
diphenyl I
- I
( I
4E I
, I
6E I
) I
- I
4 I
, I
6 I
- I
heptadien I
- I
3 I
- I
ol I
( O
DPHD B
) O
as O
the O
major O
active O
component O
of O
C O
. O
comosa O
rhizomes O
. O

At O
1 O
- O
10 O
mu O
M O
, O
DPHD B
increased O
differentiation O
in O
transformed O
mouse O
osteoblasts O
, O
but O
the O
effect O
of O
DPHD B
on O
normal O
bone O
cells O
was O
unknown O
. O

We O
examined O
the O
concentration O
dependency O
and O
mechanism O
of O
action O
of O
DPHD B
relative O
to O
17 B
beta I
- I
estradiol I
in O
nontransformed O
human O
osteoblasts O
( O
h O
- O
OB O
) O
. O

The O
h O
- O
OB O
were O
10 O
- O
100 O
fold O
more O
sensitive O
to O
DPHD B
than O
transformed O
osteoblasts O
: O
DPHD B
increased O
h O
- O
OB O
proliferation O
at O
10nM O
and O
, O
at O
100nM O
, O
activated O
MAP O
kinase O
signaling O
within O
30min O
. O

In O
long O
- O
term O
differentiation O
assays O
, O
responses O
of O
h O
- O
OB O
to O
DPHD B
were O
significant O
at O
10nM O
, O
and O
optimal O
response O
in O
most O
cases O
was O
at O
100nM O
. O

At O
7 O
- O
21 O
days O
, O
DPHD B
accelerated O
osteoblast O
differentiation O
, O
indicated O
by O
alkaline O
phosphatase O
activity O
and O
osteoblast O
- O
specific O
mRNA O
production O
. O

Effects O
of O
DPHD B
were O
eliminated O
by O
the O
estrogen B
receptor O
antagonist O
ICI182780 B
. O

During O
differentiation O
, O
DPHD B
promoted O
early O
expression O
of O
osteoblast O
transcription O
factors O
, O
RUNX2 O
and O
osterix O
. O

Subsequently O
, O
DPHD B
accelerated O
production O
of O
bone O
structural O
genes O
, O
including O
COL1A1 O
and O
osteocalcin O
comparably O
to O
17 B
beta I
- I
estradiol I
. O

In O
h O
- O
OB O
, O
DPHD O
increased O
the O
osteoprotegerin O
to O
RANKL O
ratio O
and O
supported O
mineralization O
more O
efficiently O
than O
10nM O
17 B
beta I
- I
estradiol I
. O

We O
conclude O
that O
DPHD B
promotes O
human O
osteoblast O
function O
in O
vitro O
effectively O
at O
nanomolar O
concentrations O
, O
making O
it O
a O
promising O
compound O
to O
protect O
bone O
in O
menopausal O
women O
. O

Cyclohexanone B
derivatives O
with O
cytotoxicity O
from O
the O
fungus O
Penicillium O
commune O
. O

Four O
new O
cyclohexanone B
derivatives O
( O
2 O
- O
5 O
) O
and O
one O
known O
analog O
, O
( B
- I
) I
- I
Palitantin I
( O
1 O
) O
were O
isolated O
from O
the O
EtOAc B
extract O
of O
Penicillium O
commune O
, O
a O
fungal O
strain O
of O
low O
- O
temperature O
habitats O
. O

The O
structures O
of O
2 O
- O
5 O
were O
determined O
on O
the O
basis O
of O
extensive O
spectroscopic O
analysis O
. O

Furthermore O
, O
the O
absolute O
configuration O
of O
2 O
was O
assigned O
by O
electronic O
circular O
dichroism O
( O
ECD O
) O
calculations O
, O
whereas O
that O
3 O
- O
5 O
were O
deduced O
via O
the O
CD O
data O
. O

Cytotoxicities O
of O
2 O
- O
5 O
against O
five O
human O
carcinoma O
cell O
lines O
( O
Hela O
, O
A549 O
, O
MCF7 O
, O
HCT116 O
, O
T24 O
) O
were O
evaluated O
. O

Biological O
Therapies O
for O
Rheumatoid O
Arthritis O
: O
Progress O
to O
Date O
. O

Biologic O
drugs O
for O
the O
management O
of O
rheumatoid O
arthritis O
( O
RA O
) O
have O
revolutionized O
the O
therapeutic O
armamentarium O
with O
the O
development O
of O
several O
novel O
monoclonal O
antibodies O
, O
which O
include O
murine O
, O
chimeric O
, O
humanized O
, O
fully O
human O
antibodies O
and O
fusion O
proteins O
. O

These O
biologics O
bind O
to O
their O
targets O
with O
high O
affinity O
and O
specificity O
. O

Since O
1998 O
, O
nine O
different O
biologics O
have O
been O
approved O
by O
the O
US O
Food O
and O
Drug O
Administration O
( O
FDA O
) O
and O
European O
Medicines O
Agency O
( O
EMA O
) O
for O
the O
treatment O
of O
RA O
, O
and O
several O
others O
are O
in O
different O
stages O
of O
clinical O
trials O
. O

This O
field O
is O
in O
continuous O
evolution O
and O
new O
biologics O
are O
tested O
every O
year O
. O

Therefore O
a O
precise O
analysis O
is O
required O
in O
order O
to O
have O
a O
detailed O
and O
updated O
state O
of O
the O
art O
of O
this O
field O
. O

In O
this O
review O
, O
our O
main O
aim O
is O
to O
analyse O
all O
available O
biological O
therapies O
that O
are O
FDA O
and O
EMA O
approved O
for O
the O
treatment O
of O
RA O
and O
also O
those O
that O
are O
in O
clinical O
trials O
for O
the O
management O
of O
RA O
patients O
. O

Lixisenatide O
: O
first O
global O
approval O
. O

The O
selective O
once O
- O
daily O
prandial O
glucagon O
- O
like O
peptide O
- O
1 O
( O
GLP O
- O
1 O
) O
receptor O
agonist O
lixisenatide O
( O
Lyxumia O
( O
( O
R O
) O
) O
) O
is O
under O
development O
with O
Sanofi O
for O
the O
treatment O
of O
type O
2 O
diabetes O
mellitus O
. O

Lixisenatide O
belongs O
to O
a O
class O
of O
GLP O
- O
1 O
compounds O
designed O
to O
mimic O
the O
endogenous O
hormone O
GLP O
- O
1 O
. O

Native O
GLP O
- O
1 O
stimulates O
insulin O
secretion O
in O
a O
glucose B
- O
dependent O
manner O
, O
as O
well O
as O
suppressing O
glucagon O
production O
and O
slowing O
gastric O
emptying O
. O

A O
once O
- O
daily O
subcutaneous O
formulation O
of O
lixisenatide O
has O
been O
approved O
in O
the O
EU O
, O
Iceland O
, O
Liechtenstein O
, O
Norway O
and O
Mexico O
for O
the O
treatment O
of O
type O
2 O
diabetes O
, O
and O
is O
under O
regulatory O
review O
in O
the O
USA O
, O
Switzerland O
, O
Brazil O
, O
Canada O
, O
Ukraine O
, O
South O
Africa O
, O
Japan O
and O
Australia O
. O

This O
article O
summarizes O
the O
milestones O
in O
the O
development O
of O
lixisenatide O
, O
leading O
to O
this O
first O
approval O
for O
use O
in O
adults O
with O
type O
2 O
diabetes O
. O

Annexin O
A2 O
regulates O
beta O
1 O
integrin O
internalization O
and O
intestinal O
epithelial O
cell O
migration O
. O

The O
gastrointestinal O
epithelium O
functions O
as O
an O
important O
barrier O
that O
separates O
luminal O
contents O
from O
the O
underlying O
tissue O
compartment O
and O
is O
vital O
in O
maintaining O
mucosal O
homeostasis O
. O

Mucosal O
wounds O
in O
inflammatory O
disorders O
compromise O
the O
critical O
epithelial O
barrier O
. O

In O
response O
to O
injury O
, O
intestinal O
epithelial O
cells O
( O
IECs O
) O
rapidly O
migrate O
to O
reseal O
wounds O
. O

We O
have O
previously O
observed O
that O
a O
membrane O
associated O
, O
Actin O
binding O
protein O
, O
Annexin O
A2 O
( O
AnxA2 O
) O
, O
is O
up O
- O
regulated O
in O
migrating O
IECs O
and O
plays O
an O
important O
role O
in O
promoting O
wound O
closure O
. O

To O
identify O
the O
mechanisms O
by O
which O
AnxA2 O
promotes O
IEC O
movement O
and O
wound O
closure O
we O
used O
a O
loss O
of O
function O
approach O
. O

AnxA2 O
specific O
shRNA O
was O
utilized O
to O
generate O
IECs O
with O
stable O
down O
- O
regulation O
of O
AnxA2 O
. O

Loss O
of O
AnxA2 O
inhibited O
IEC O
migration O
while O
promoting O
enhanced O
cell O
- O
matrix O
adhesion O
. O

These O
functional O
effects O
were O
associated O
with O
increased O
levels O
of O
beta O
1 O
integrin O
protein O
, O
which O
is O
reported O
to O
play O
an O
important O
role O
in O
mediating O
the O
cell O
- O
matrix O
adhesive O
properties O
of O
epithelial O
cells O
. O

Since O
cell O
migration O
requires O
dynamic O
turnover O
of O
integrin O
based O
adhesions O
, O
we O
tested O
if O
AnxA2 O
modulates O
internalization O
of O
cell O
surface O
beta O
1 O
integrin O
required O
for O
forward O
cell O
movement O
. O

Indeed O
, O
pulse O
- O
chase O
biotinylation O
experiments O
in O
IECs O
lacking O
AnxA2 O
demonstrated O
a O
significant O
increase O
in O
cell O
surface O
beta O
1 O
integrin O
that O
was O
accompanied O
by O
decreased O
beta O
1 O
integrin O
internalization O
and O
degradation O
. O

These O
findings O
support O
an O
important O
role O
of O
AnxA2 O
in O
controlling O
dynamics O
of O
beta O
1 O
integrin O
at O
the O
cell O
surface O
that O
in O
turn O
is O
required O
for O
the O
active O
turnover O
of O
cell O
- O
matrix O
associations O
, O
cell O
migration O
and O
wound O
closure O
. O

Human O
polymerase O
kappa O
uses O
a O
template O
- O
slippage O
deletion O
mechanism O
, O
but O
can O
realign O
the O
slipped O
strands O
to O
favour O
base O
substitution O
mutations O
over O
deletions O
. O

Polymerases O
belonging O
to O
the O
DinB O
class O
of O
the O
Y O
- O
family O
translesion O
synthesis O
DNA O
polymerases O
have O
a O
preference O
for O
accurately O
and O
efficiently O
bypassing O
damaged O
guanosines B
. O

These O
DinB O
polymerases O
also O
generate O
single O
- O
base O
( O
- O
1 O
) O
deletions O
at O
high O
frequencies O
with O
most O
occurring O
on O
repetitive O
' O
deletion O
hotspot O
' O
sequences O
. O

Human O
DNA O
polymerase O
kappa O
( O
hPol O
kappa O
) O
, O
the O
eukaryotic O
DinB O
homologue O
, O
displays O
an O
unusual O
efficiency O
for O
to O
extend O
from O
mispaired O
primer O
termini O
, O
either O
by O
extending O
directly O
from O
the O
mispair O
or O
by O
primer O
- O
template O
misalignment O
. O

This O
latter O
property O
explains O
how O
hPol O
kappa O
creates O
single O
- O
base O
deletions O
in O
non O
- O
repetitive O
sequences O
, O
but O
does O
not O
address O
how O
deletions O
occur O
in O
repetitive O
deletion O
hotspots O
. O

Here O
, O
we O
show O
that O
hPol O
kappa O
uses O
a O
classical O
Streisinger O
template O
- O
slippage O
mechanism O
to O
generate O
- O
1 O
deletions O
in O
repetitive O
sequences O
, O
as O
do O
the O
bacterial O
and O
archaeal O
homologues O
. O

After O
the O
first O
nucleotide B
is O
added O
by O
template O
slippage O
, O
however O
, O
hPol O
kappa O
can O
efficiently O
realign O
the O
primer O
- O
template O
duplex O
before O
continuing O
DNA O
synthesis O
. O

Strand O
realignment O
results O
in O
a O
base O
- O
substitution O
mutation O
, O
minimizing O
generation O
of O
more O
deleterious O
frameshift O
mutations O
. O

On O
non O
- O
repetitive O
sequences O
, O
we O
find O
that O
nucleotide B
misincorporation O
is O
slower O
if O
the O
incoming O
nucleotide B
can O
correctly O
basepair O
with O
the O
nucleotide B
immediately O
5 O
' O
to O
the O
templating O
base O
, O
thereby O
competing O
against O
the O
mispairing O
with O
the O
templating O
base O
. O

Exploring O
the O
zebrafish O
embryo O
as O
an O
alternative O
model O
for O
the O
evaluation O
of O
liver O
toxicity O
by O
histopathology O
and O
expression O
profiling O
. O

The O
whole O
zebrafish O
embryo O
model O
( O
ZFE O
) O
has O
proven O
its O
applicability O
in O
developmental O
toxicity O
testing O
. O

Since O
functional O
hepatocytes O
are O
already O
present O
from O
36 O
h O
post O
fertilization O
onwards O
, O
whole O
ZFE O
have O
been O
proposed O
as O
an O
attractive O
alternative O
to O
mammalian O
in O
vivo O
models O
in O
hepatotoxicity O
testing O
. O

The O
goal O
of O
the O
present O
study O
is O
to O
further O
underpin O
the O
applicability O
of O
whole O
ZFE O
for O
hepatotoxicity O
testing O
by O
combining O
histopathology O
and O
next O
- O
generation O
sequencing O
- O
based O
gene O
expression O
profiling O
. O

To O
this O
aim O
, O
whole O
ZFE O
and O
adult O
zebrafish O
were O
exposed O
to O
a O
set O
of O
hepatotoxic O
reference O
compounds O
. O

Histopathology O
revealed O
compound O
and O
life O
- O
stage O
- O
specific O
effects O
indicative O
of O
toxic O
injury O
in O
livers O
of O
whole O
ZFE O
and O
adult O
zebrafish O
. O

Next O
- O
generation O
sequencing O
( O
NGS O
) O
was O
used O
to O
compare O
transcript O
profiles O
in O
pooled O
individual O
RNA O
samples O
of O
whole O
ZFE O
and O
livers O
of O
adult O
zebrafish O
. O

This O
revealed O
that O
hepatotoxicity O
- O
associated O
expression O
can O
be O
detected O
beyond O
the O
overall O
transcription O
noise O
in O
the O
whole O
embryo O
. O

In O
situ O
hybridization O
verified O
liver O
specificity O
of O
selected O
highly O
expressed O
markers O
in O
whole O
ZFE O
. O

Finally O
, O
cyclosporine B
A I
( O
CsA B
) O
was O
used O
as O
an O
illustrative O
case O
to O
support O
applicability O
of O
ZFE O
in O
hepatotoxicity O
testing O
by O
comparing O
CsA B
- O
induced O
gene O
expression O
between O
ZFE O
, O
in O
vivo O
mouse O
liver O
and O
HepaRG O
cells O
on O
the O
levels O
of O
single O
genes O
, O
pathways O
and O
transcription O
factors O
. O

While O
there O
was O
no O
clear O
overlap O
on O
single O
gene O
level O
between O
the O
whole O
ZFE O
and O
in O
vivo O
mouse O
liver O
, O
strong O
similarities O
were O
observed O
between O
whole O
ZFE O
and O
in O
vivo O
mouse O
liver O
in O
regulated O
pathways O
related O
to O
hepatotoxicity O
, O
as O
well O
as O
in O
relevant O
overrepresented O
transcription O
factors O
. O

In O
conclusion O
, O
both O
the O
use O
of O
NGS O
of O
pooled O
RNA O
extracts O
analysis O
combined O
with O
histopathology O
and O
traditional O
microarray O
in O
single O
case O
showed O
the O
potential O
to O
detect O
liver O
- O
related O
genes O
and O
processes O
within O
the O
transcriptome O
of O
a O
whole O
zebrafish O
embryo O
. O

This O
supports O
the O
applicability O
of O
the O
whole O
ZFE O
model O
for O
compound O
- O
induced O
hepatotoxicity O
screening O
. O

Synthesis O
and O
Cytostatic O
and O
Antiviral O
Activities O
of O
2 B
' I
- I
Deoxy I
- I
2 I
' I
, I
2 I
' I
- I
difluororibo I
- I
and I
2 I
' I
- I
Deoxy I
- I
2 I
' I
- I
fluororibonucleoside I
Derived O
from O
7 B
- I
( I
Het I
) I
aryl I
- I
7 I
- I
deazaadenines I
. O

A O
series O
of O
sugar B
- O
modified O
derivatives O
of O
cytostatic O
7 B
- I
heteroaryl I
- I
7 O
- O
deazaadenosines O
( O
2 B
' I
- I
deoxy I
- I
2 I
' I
- I
fluororibo I
- I
and I
2 I
' I
- I
deoxy I
- I
2 I
' I
, I
2 I
' I
- I
difluororibonucleosi I
) O
bearing O
an O
aryl O
or O
heteroaryl O
group O
at O
position O
7 O
was O
prepared O
and O
screened O
for O
biological O
activity O
. O

The O
difluororibonucleosi B
were O
prepared O
by O
non O
- O
stereoselective O
glycosidation O
of O
6 B
- I
chloro I
- I
7 O
- O
deazapurine O
with O
benzoyl B
- I
protected I
2 I
- I
deoxy I
- I
2 I
, I
2 I
- I
difluoro I
- I
D I
- I
erythro I
- I
pentofuranosyl I
- I
1 I
- I
mesylate I
, O
followed O
by O
amination O
and O
aqueous O
Suzuki O
cross O
- O
couplings O
with O
( O
het O
) O
arylboronic B
acids I
. O

The O
fluororibo B
derivatives O
were O
prepared O
by O
aqueous O
palladium B
- O
catalyzed O
cross O
- O
coupling O
reactions O
of O
the O
corresponding O
7 B
- I
iodo I
- I
7 O
- O
deazaadenine O
2 B
' I
- I
deoxy I
- I
2 I
' I
- I
fluororibonucleoside I
20 O
with O
( O
het O
) O
arylboronic B
acids I
. O

The O
key O
intermediate O
20 O
was O
prepared O
by O
a O
six O
- O
step O
sequence O
from O
the O
corresponding O
arabinonucleoside B
by O
selective O
protection O
of O
3 B
' I
- I
and I
5 I
' I
- I
hydroxy I
groups O
with O
acid O
- O
labile O
groups O
, O
followed O
by O
stereoselective O
SN O
2 O
fluorination O
and O
deprotection O
. O

Some O
of O
the O
title O
nucleosides B
and O
7 B
- I
iodo I
- I
7 O
- O
deazaadenine O
intermediates O
showed O
micromolar O
cytostatic O
or O
anti O
- O
HCV O
activity O
. O

The O
most O
active O
were O
7 B
- I
iodo I
and O
7 B
- I
ethynyl I
derivatives O
. O

The O
corresponding O
2 B
' I
- I
deoxy I
- I
2 I
' I
, I
2 I
' I
- I
difluororibonucleosi I
5 I
' I
- I
O I
- I
triphosphates I
were O
found O
to O
be O
good O
substrates O
for O
bacterial O
DNA O
polymerases O
, O
but O
are O
inhibitors O
of O
human O
polymerase O
alpha O
. O

Tissue O
Factor O
Activity O
and O
ECM O
- O
Related O
Gene O
Expression O
in O
Human O
Aortic O
Endothelial O
Cells O
Grown O
on O
Electrospun O
Biohybrid O
Scaffolds O
. O

All O
blood O
vessels O
are O
lined O
with O
a O
quiescent O
endothelium O
, O
which O
aids O
in O
regulating O
regular O
blood O
flow O
and O
avoiding O
thrombus O
formation O
. O

Current O
attempts O
at O
replacing O
diseased O
blood O
vessels O
frequently O
fail O
due O
to O
the O
intrinsic O
thrombogenicity O
of O
the O
materials O
used O
as O
vascular O
grafts O
. O

In O
extending O
our O
previous O
work O
where O
we O
introduced O
a O
new O
candidate O
scaffolds O
for O
vascular O
grafts O
electrospun O
from O
a O
blend O
solution O
of O
PLGA B
, O
gelatin O
, O
and O
elastin O
( O
PGE O
) O
, O
this O
study O
aimed O
to O
evaluate O
the O
potential O
of O
PGE B
scaffolds O
to O
support O
nonthrombogenic O
monolayers O
of O
primary O
isolates O
of O
human O
aortic O
endothelial O
cells O
( O
HAECs O
) O
, O
as O
assessed O
by O
a O
combination O
of O
biochemical O
, O
molecular O
, O
and O
bioinformatics O
- O
based O
analyses O
. O

After O
24 O
h O
of O
culture O
on O
3 O
- O
D O
fibrous O
PGE B
scaffolds O
, O
HAECs O
formed O
a O
confluent O
, O
nonthrombogenic O
, O
and O
physiologically O
competent O
monolayer O
, O
as O
assessed O
by O
tissue O
factor O
( O
TF O
) O
gene O
expression O
and O
protein O
activity O
assays O
. O

The O
levels O
of O
TF O
mRNA O
/ O
protein O
activity O
in O
HAECs O
grown O
on O
PGE B
scaffolds O
were O
similar O
to O
those O
on O
gelatin O
or O
collagen O
IV O
- O
coated O
2 O
- O
D O
surfaces O
. O

In O
addition O
, O
bioinformatics O
- O
based O
analysis O
of O
a O
focused O
microarray O
containing O
84 O
ECM O
- O
related O
cDNA O
probes O
demonstrated O
that O
HAECs O
essentially O
expressed O
a O
histotypic O
ECM O
- O
related O
" O
transcriptome O
" O
on O
PGE B
scaffolds O
, O
where O
cells O
were O
more O
quiescent O
than O
cells O
cultured O
on O
2 O
- O
D O
coverslips O
coated O
with O
gelatin O
( O
a O
well O
- O
known O
" O
inert O
" O
substrate O
for O
conventional O
EC O
culture O
) O
, O
but O
less O
so O
than O
on O
2 O
- O
D O
PGE B
films O
. O

These O
data O
suggest O
an O
important O
role O
for O
nanorough O
substrates O
( O
PGE B
films O
) O
in O
passivating O
endothelial O
cells O
and O
confirm O
the O
crucial O
effect O
of O
substrate O
composition O
in O
this O
process O
. O

Principal O
component O
analysis O
of O
microarray O
data O
on O
the O
above O
substrates O
( O
including O
collagen O
IV O
) O
implied O
that O
substrate O
composition O
plays O
a O
greater O
role O
than O
surface O
topography O
in O
affecting O
the O
endothelial O
ECM O
- O
related O
" O
transcriptome O
" O
. O

Taken O
together O
, O
our O
findings O
suggest O
that O
electrospun O
PGE O
scaffolds O
are O
potentially O
suitable O
for O
application O
in O
small O
diameter O
vascular O
tissue O
engineering O
. O

Pressure O
modulation O
of O
ras O
- O
membrane O
interactions O
and O
intervesicle O
transfer O
. O

Proteins O
attached O
to O
the O
plasma O
membrane O
frequently O
encounter O
mechanical O
stresses O
, O
including O
high O
hydrostatic O
pressure O
( O
HHP O
) O
stress O
. O

Signaling O
pathways O
involving O
membrane O
- O
associated O
small O
GTPases O
( O
e O
. O
g O
. O
, O
Ras O
) O
have O
been O
identified O
as O
critical O
loci O
for O
pressure O
perturbation O
. O

However O
, O
the O
impact O
of O
mechanical O
stimuli O
on O
biological O
outputs O
is O
still O
largely O
terra O
incognita O
. O

The O
present O
study O
explores O
the O
effect O
of O
HHP O
on O
the O
membrane O
association O
, O
dissociation O
, O
and O
intervesicle O
transfer O
process O
of O
N O
- O
Ras O
by O
using O
a O
FRET O
- O
based O
assay O
to O
obtain O
the O
kinetic O
parameters O
and O
volumetric O
properties O
along O
the O
reaction O
path O
of O
these O
processes O
. O

Notably O
, O
membrane O
association O
is O
fostered O
upon O
pressurization O
. O

Conversely O
, O
depending O
on O
the O
nature O
and O
lateral O
organization O
of O
the O
lipid O
membrane O
, O
acceleration O
or O
retardation O
is O
observed O
for O
the O
dissociation O
step O
. O

In O
addition O
, O
HHP O
can O
be O
inferred O
as O
a O
positive O
regulator O
of O
N O
- O
Ras O
clustering O
, O
in O
particular O
in O
heterogeneous O
membranes O
. O

The O
susceptibility O
of O
membrane O
interaction O
to O
pressure O
raises O
the O
idea O
of O
a O
role O
of O
lipidated O
signaling O
molecules O
as O
mechanosensors O
, O
transducing O
mechanical O
stimuli O
to O
chemical O
signals O
by O
regulating O
their O
membrane O
binding O
and O
dissociation O
. O

Finally O
, O
our O
results O
provide O
first O
insights O
into O
the O
influence O
of O
pressure O
on O
membrane O
- O
associated O
Ras O
- O
controlled O
signaling O
events O
in O
organisms O
living O
under O
extreme O
environmental O
conditions O
such O
as O
those O
that O
are O
encountered O
in O
the O
deep O
sea O
and O
sub O
- O
seafloor O
environments O
, O
where O
pressures O
reach O
the O
kilobar O
( O
100 O
MPa O
) O
range O
. O

Modeling O
the O
Conformational O
Preference O
of O
the O
Carbon B
- O
Bonded O
Covalent O
Adduct O
Formed O
upon O
Exposure O
of O
2 B
' I
- I
Deoxyguanosine I
to O
Ochratoxin B
A I
. O

The O
conformational O
flexibility O
of O
the O
C8 O
- O
linked O
guanine B
adduct O
formed O
from O
attachment O
of O
ochratoxin B
A I
( O
OTA B
) O
was O
analyzed O
using O
a O
systematic O
computational O
approach O
and O
models O
ranging O
from O
the O
nucleobase B
to O
the O
adducted O
DNA O
helix O
. O

A O
focus O
was O
placed O
on O
the O
influence O
of O
the O
C8 O
- O
modification O
of O
2 B
' I
- I
deoxyguanosine I
( O
dG O
) O
on O
the O
preferred O
relative O
arrangement O
of O
the O
nucleobase B
and O
the O
C8 O
- O
substituent O
and O
, O
more O
importantly O
, O
the O
anti O
/ O
syn O
conformational O
preference O
with O
respect O
to O
the O
glycosidic O
bond O
. O

Although O
OTA B
is O
twisted O
with O
respect O
to O
the O
base O
in O
the O
nucleobase B
model O
, O
addition O
of O
the O
deoxyribose B
sugar B
induces O
a O
further O
twist O
and O
restricts O
rotation O
about O
the O
C B
- I
C I
linkage O
due O
to O
close O
contacts O
between O
OTA B
and O
the O
sugar B
. O

The O
nucleoside B
model O
preferentially O
adpots B
a O
syn O
orientation O
( O
by O
10 O
- O
20 O
kJ O
mol O
( O
- O
1 O
) O
depending O
on O
the O
OTA B
conformation O
) O
due O
to O
the O
presence O
of O
an O
O5 B
' I
- I
H I
. O
. O
. O
N3 O
interaction O
. O

However O
, O
when O
this O
hydrogen B
bond O
is O
eliminated O
, O
which O
better O
mimics O
the O
DNA O
environment O
, O
a O
small O
( O
< O
5 O
kJ O
mol O
( O
- O
1 O
) O
) O
anti O
/ O
syn O
energy O
difference O
is O
predicted O
. O

Inclusion O
of O
the O
5 B
' I
- I
monophosphate I
group O
leads O
to O
an O
up O
to O
20 O
kJ O
mol O
( O
- O
1 O
) O
preference O
for O
the O
syn O
( O
nucleotide B
) O
conformation O
due O
to O
stabilizing O
base O
- O
phosphate B
interactions O
involving O
the O
amino B
group O
of O
guanine B
. O

Nevertheless O
, O
MD O
simulations O
and O
free O
energy O
analysis O
predict O
that O
both O
syn O
- O
and O
anti O
- O
conformations O
of O
OTB B
- O
dG O
are O
equally O
stable O
in O
helices O
when O
paired O
opposite O
cytosine B
. O

These O
results O
indicate O
that O
the O
adduct O
will O
likely O
adopt O
a O
syn O
conformation O
in O
an O
isolated O
nucleoside B
and O
nucleotide B
, O
while O
a O
mixture O
of O
syn O
and O
anti O
conformations O
will O
be O
observed O
in O
DNA O
duplexes O
. O

Since O
the O
syn O
conformation O
could O
stabilize O
base O
mismatches O
upon O
DNA O
replication O
or O
Z O
- O
DNA O
structures O
with O
varied O
biological O
outcomes O
, O
future O
computational O
and O
experimental O
work O
should O
elucidate O
the O
consequences O
of O
the O
conformational O
preference O
of O
this O
potentially O
harmful O
DNA O
lesion O
. O

Synthesis O
and O
Biological O
Evaluation O
of O
a O
New O
Series O
of O
Hexahydro B
- I
2H I
- I
pyrano I
[ I
3 I
, I
2 I
- I
c I
] I
quinolines I
as O
Novel O
Selective O
sigma O
1 O
Receptor O
Ligands O
. O

The O
synthesis O
and O
pharmacological O
activity O
of O
a O
new O
series O
of O
hexahydro B
- I
2H I
- I
pyrano I
[ I
3 I
, I
2 I
- I
c I
] I
quinoline I
derivatives O
as O
potent O
sigma O
1 O
receptor O
( O
sigma O
1R O
) O
ligands O
are O
reported O
. O

This O
family O
, O
which O
does O
not O
contain O
the O
highly O
basic O
amino B
group O
usually O
present O
in O
other O
sigma O
1R O
ligands O
, O
showed O
high O
selectivity O
over O
the O
sigma O
2 O
receptor O
( O
sigma O
2R O
) O
. O

The O
activity O
was O
shown O
to O
reside O
in O
only O
one O
of O
the O
four O
possible O
diastereoisomers O
, O
which O
exhibited O
a O
perfect O
match O
with O
known O
sigma O
1R O
pharmacophores O
. O

A O
hit O
to O
lead O
program O
based O
on O
a O
high O
- O
throughput O
screening O
hit O
( O
8a O
) O
led O
to O
the O
identification O
of O
compound O
32c O
, O
with O
substantially O
improved O
activity O
and O
physicochemical O
properties O
. O

Compound O
32c O
also O
exhibited O
a O
good O
ADMET O
( O
absorption O
, O
distribution O
, O
metabolism O
, O
excretion O
, O
toxicity O
) O
profile O
and O
was O
identified O
as O
a O
sigma O
1R O
antagonist O
on O
the O
basis O
of O
its O
analgesic O
activity O
in O
the O
mouse O
capsaicin B
and O
formalin B
models O
of O
neurogenic O
pain O
. O

Mycoleptodiscins B
A I
and I
B I
, O
Cytotoxic O
Alkaloids O
from O
the O
Endophytic O
Fungus O
Mycoleptodiscus O
sp O
. O

F0194 O
. O

Two O
novel O
reddish O
- O
orange O
alkaloids O
, O
mycoleptodiscin B
A I
( O
1 O
) O
and O
mycoleptodiscin B
B I
( O
2 O
) O
, O
were O
isolated O
from O
liquid O
cultures O
of O
the O
endophytic O
fungus O
Mycoleptodiscus O
sp O
. O
that O
had O
been O
isolated O
from O
Desmotes O
incomparabilis O
in O
Panama O
. O

Elucidation O
of O
their O
structures O
was O
accomplished O
using O
1D O
and O
2D O
NMR O
spectroscopy O
in O
combination O
with O
IR O
spectroscopic O
and O
MS O
data O
. O

These O
compounds O
are O
indole B
- O
terpenes B
with O
a O
new O
skeleton O
uncommon O
in O
nature O
. O

Mycoleptodiscin B
B I
( O
2 O
) O
was O
active O
in O
inhibiting O
the O
growth O
of O
cancer O
cell O
lines O
with O
IC50 O
values O
in O
the O
range O
0 O
. O
60 O
- O
0 O
. O
78 O
mu O
M O
. O

Altering O
colloidal O
surface O
functionalization O
using O
DNA O
encapsulated O
inside O
monodisperse O
gelatin O
microsphere O
templates O
. O

Soluble O
oligonucleotides O
are O
typically O
introduced O
to O
bulk O
solution O
to O
promote O
hybridization O
activity O
on O
DNA O
- O
functionalized O
surfaces O
. O

Here O
, O
an O
alternative O
approach O
is O
explored O
by O
encapsulating O
secondary O
target O
strands O
inside O
semipermeable O
colloidal O
satellite O
assemblies O
, O
then O
triggering O
their O
release O
at O
37 O
degrees O
C O
for O
subsequent O
surface O
hybridization O
activity O
. O

To O
prepare O
DNA O
- O
loaded O
satellite O
assemblies O
, O
uniform O
gelatin O
microspheres O
are O
fabricated O
using O
microfluidics O
, O
loaded O
with O
15 O
base O
- O
long O
secondary O
DNA O
targets O
, O
capped O
with O
a O
polyelectrolyte O
bilayer O
, O
and O
finally O
coated O
with O
a O
monolayer O
of O
polystyrene B
microspheres O
functionalized O
with O
duplexes O
comprised O
of O
immobilized O
probes O
and O
soluble O
, O
13 O
base O
- O
long O
hybridization O
partner O
strands O
. O

Once O
warmed O
to O
37 O
degrees O
C O
, O
secondary O
DNA O
targets O
are O
released O
from O
the O
gelatin O
template O
and O
then O
competitively O
displace O
the O
shorter O
, O
original O
hybridization O
partners O
on O
the O
polystyrene B
microspheres O
. O

Quantitating O
the O
Lattice O
Strain O
Dependence O
of O
Monolayer O
Pt B
Shell O
Activity O
toward O
Oxygen B
Reduction O
. O

Lattice O
strain O
of O
Pt B
- O
based O
catalysts O
reflecting O
d O
- O
band O
status O
is O
the O
decisive O
factor O
of O
their O
catalytic O
activity O
toward O
oxygen B
reduction O
reaction O
( O
ORR O
) O
. O

For O
the O
newly O
arisen O
monolayer O
Pt B
system O
, O
however O
, O
no O
general O
strategy O
to O
isolate O
the O
lattice O
strain O
has O
been O
achieved O
due O
to O
the O
short O
- O
range O
ordering O
structure O
of O
monolayer O
Pt B
shells O
on O
different O
facets O
of O
core O
nanoparticles O
. O

Herein O
, O
based O
on O
the O
extended O
X O
- O
ray O
absorption O
fine O
structure O
of O
monolayer O
Pt B
atoms O
on O
various O
single O
crystal O
facets O
, O
we O
propose O
an O
effective O
methodology O
for O
evaluating O
the O
lattice O
strain O
of O
monolayer O
Pt B
shells O
on O
core O
nanoparticles O
. O

The O
quantitative O
lattice O
strain O
establishes O
a O
direct O
correlation O
to O
monolayer O
Pt B
shell O
ORR O
activity O
. O

Antioxidant O
capacity O
of O
anthocyanins B
from O
Rhodomyrtus O
tomentosa O
( O
Ait O
. O
) O
and O
identification O
of O
the O
major O
anthocyanins B
. O

The O
anthocyanins B
in O
the O
fruits O
of O
Rhodomyrtus O
tomentosa O
( O
ACN O
) O
were O
extracted O
by O
1 O
% O
TFA B
in O
methanol B
, O
and O
then O
purified O
by O
X O
- O
5 O
resin O
column O
and O
C18 O
( O
SPE O
) O
cartridges O
. O

The O
purified O
anthocyanin B
extract O
( O
ART O
) O
from O
the O
fruits O
of O
R O
. O
tomentosa O
showed O
strong O
antioxidant O
activities O
, O
including O
DPPH B
radical O
- O
scavenging O
capacity O
, O
ABTS B
radical O
scavenging O
capacity O
, O
reducing O
power O
and O
oxygen B
radical O
absorbance O
capacity O
( O
ORAC O
) O
. O

The O
purified O
anthocyanin B
extract O
was O
analyzed O
by O
high O
performance O
liquid O
chromatography O
( O
HPLC O
) O
. O

The O
major O
anthocyanins B
were O
purified O
by O
semi O
- O
preparative O
HPLC O
and O
Sephadex O
LH O
- O
20 O
column O
chromatography O
, O
and O
were O
identified O
as O
cyanidin B
- I
3 I
- I
O I
- I
glucoside I
, O
peonidin B
- I
3 I
- I
O I
- I
glucoside I
, O
malvidin B
- I
3 I
- I
O I
- I
glucoside I
, O
petunidin B
- I
3 I
- I
O I
- I
glucoside I
, O
delphinidin B
- I
3 I
- I
O I
- I
glucoside I
and O
pelargonidin B
- I
3 I
- I
glucoside I
by O
HPLC O
- O
ESI O
/ O
MS O
and O
nuclear O

magnetic O
resonance O
spectroscopy O
( O
NMR O
) O
. O

Cyanidin B
- I
3 I
- I
O I
- I
glucoside I
was O
considered O
as O
the O
most O
abundant O
anthocyanin B
, O
which O
was O
29 O
. O
4mg O
/ O
100g O
dry O
weight O
of O
R O
. O
tomentosa O
fruits O
. O

Additionally O
, O
all O
the O
major O
anthocyanins B
were O
identified O
from O
R O
. O
tomentosa O
fruit O
for O
the O
first O
time O
. O

Dummy O
- O
template O
molecularly O
imprinted O
solid O
phase O
extraction O
for O
selective O
analysis O
of O
ractopamine B
in O
pork O
. O

Molecularly O
imprinted O
polymers O
( O
MIPs O
) O
for O
selective O
adsorption O
of O
ractopamine B
hydrochloride I
( O
RAC B
) O
were O
synthesised O
by O
an O
in O
situ O
method O
, O
in O
which O
salbutamol B
( O
SAL B
) O
was O
used O
as O
the O
dummy O
- O
template O
to O
avoid O
the O
template O
leakage O
. O

Scanning O
electron O
microscopy O
( O
SEM O
) O
, O
mercury B
porosimerty O
and O
Fourier O
transform O
infrared O
spectroscopy O
( O
FTIR O
) O
were O
used O
to O
investigate O
the O
physical O
and O
morphological O
characteristics O
of O
the O
dummy O
- O
template O
MIPs O
. O

The O
test O
of O
adsorption O
selectivity O
indicated O
that O
the O
dummy O
- O
template O
MIPs O
exhibited O
high O
selectivity O
to O
RAC O
. O

The O
saturated O
adsorption O
capacity O
for O
RAC B
on O
dummy O
- O
template O
MIPs O
was O
90 O
. O
9 O
mu O
gg O
( O
- O
1 O
) O
. O

Based O
on O
the O
dummy O
- O
template O
polymers O
, O
a O
liquid O
chromatography O
- O
mass O
spectrometry O
( O
LC O
- O
MS O
) O
method O
was O
developed O
for O
the O
selective O
analysis O
of O
RAC B
in O
real O
pork O
samples O
. O

The O
averages O
of O
intra O
- O
and O
inter O
- O
day O
accuracy O
ranged O
from O
78 O
. O
9 O
% O
to O
92 O
. O
2 O
% O
and O
from O
90 O
. O
7 O
% O
to O
93 O
. O
1 O
% O
, O
respectively O
. O

The O
RSD O
% O
of O
repeatability O
ranged O
from O
1 O
. O
9 O
% O
to O
6 O
. O
3 O
% O
, O
and O
the O
RSD O
% O
of O
intermediate O
precision O
ranged O
from O
3 O
. O
5 O
% O
to O
9 O
. O
2 O
% O
, O
while O
the O
limit O
of O
detection O
( O
LOD O
) O
was O
0 O
. O
02 O
mu O
gkg B
( O
- O
1 O
) O
. O

Plums O
( O
Prunus O
domestica O
L O
. O
) O
are O
a O
good O
source O
of O
yeasts O
producing O
organic O
acids O
of O
industrial O
interest O
from O
glycerol B
. O

The O
production O
of O
organic O
acids O
from O
several O
yeasts O
isolated O
from O
mature O
plums O
on O
media O
containing O
glycerol B
as O
carbon B
source O
was O
analysed O
by O
HPLC O
- O
UV O
. O

The O
yeasts O
isolated O
were O
identified O
by O
sequencing O
the O
5 O
. O
8S O
internal O
transcribed O
spacer O
as O
Pichia O
fermentans O
, O
Wickerhamomyces O
anomalus O
and O
Candida O
oleophila O
. O

The O
organic O
acid O
profiles O
of O
these O
strains O
comprise O
acetic B
, I
citric I
, I
succinic I
and I
malic I
acids I
that O
qualitatively O
and O
quantitatively O
vary O
between O
different O
species O
as O
well O
as O
among O
strains O
from O
the O
same O
species O
. O

The O
production O
from O
glycerol B
of O
succinic B
, I
acetic I
, I
citric I
, I
malic I
and I
oxalic I
acids I
from O
C O
. O
oleophila O
and O
W O
. O
anomalus O
, O
and O
that O
of O
succinic B
, I
oxalic I
and I
acetic I
acids I
by O
P O
. O
fermentans O
is O
reported O
for O
the O
first O
time O
in O
this O
work O
, O
as O
is O
the O
production O
of O
oxalic B
acid I
from O
glycerol B
in O
yeasts O
. O

Our O
results O
also O
showed O
that O
mature O
fruits O
can O
be O
a O
good O
source O
of O
new O
yeasts O
able O
to O
metabolise O
glycerol B
, O
producing O
different O
organic O
acids O
with O
industrial O
and O
biotechnological O
interest O
. O

Active O
films O
based O
on O
cocoa O
extract O
with O
antioxidant O
, O
antimicrobial O
and O
biological O
applications O
. O

Novel O
films O
of O
ethylene B
- I
vinyl I
alcohol I
copolymer O
( O
EVOH B
) O
containing O
flavonoid B
- O
rich O
cocoa O
were O
developed O
. O

To O
understand O
their O
potential O
application O
as O
active O
packaging O
material O
, O
antioxidant O
and O
antimicrobial O
properties O
of O
the O
films O
were O
determined O
as O
well O
as O
the O
antioxidant O
activity O
of O
the O
release O
compounds O
in O
Caco O
- O
2 O
human O
epithelial O
colorectal O
adenocarcinoma O
cells O
. O

Exposure O
of O
the O
films O
to O
aqueous O
food O
simulant O
showed O
antioxidant O
capacity O
. O

The O
release O
of O
cocoa O
extract O
components O
was O
dependent O
on O
the O
antioxidant O
concentration O
incorporated O
in O
the O
film O
and O
on O
temperature O
. O

Cocoa O
extract O
and O
the O
fraction O
obtained O
after O
in O
vitro O
gastrointestinal O
digestion O
presented O
antioxidant O
activity O
against O
oxidative O
stress O
induced O
by O
hydrogen B
peroxide I
in O
Caco O
- O
2 O
cells O
. O

Films O
with O
10 O
% O
, O
15 O
% O
, O
and O
20 O
% O
cocoa O
extract O
produced O
bactericidal O
effect O
against O
Staphylococcus O
aureus O
, O
Listeria O
monocytogenes O
, O
Escherichia O
coli O
and O
Salmonella O
enterica O
. O

The O
application O
of O
films O
to O
an O
infant O
milk O
formula O
, O
previously O
inoculated O
with O
L O
. O
monocytogenes O
, O
inhibited O
the O
growth O
of O
bacteria O
1 O
. O
5log O
units O
the O
first O
day O
and O
showed O
sustained O
release O
, O
inhibiting O
0 O
. O
52 O
and O
0 O
. O
76log O
units O
, O
respectively O
, O
by O
the O
sixth O
day O
, O
while O
cocoa O
powder O
added O
directly O
did O
not O
produce O
any O
effect O
. O

In O
vivo O
and O
in O
vitro O
antioxidant O
activity O
and O
alpha O
- O
glucosidase O
, O
alpha O
- O
amylase O
inhibitory O
effects O
of O
flavonoids B
from O
Cichorium O
glandulosum O
seeds O
. O

The O
aim O
of O
this O
study O
was O
to O
investigate O
the O
antioxidant O
, O
anti O
- O
glucosidase O
and O
anti O
- O
amylase O
activities O
of O
total O
flavonoids B
( O
TFs O
) O
from O
Cichorium O
glandulosum O
seeds O
, O
and O
to O
analyse O
its O
chemical O
composition O
by O
HPLC O
- O
ESI O
/ O
MS O
. O

In O
vitro O
study O
, O
radical O
scavenging O
IC50 O
values O
of O
TFs O
were O
7 O
. O
33 O
+ O
/ O
- O
0 O
. O
093 O
, O
9 O
. O
24 O
+ O
/ O
- O
0 O
. O
100 O
, O
154 O
. O
33 O
+ O
/ O
- O
11 O
. O
38 O
and O
256 O
. O
7 O
+ O
/ O
- O
4 O
. O
86 O
mu O
g O
/ O
ml O
for O
DPPH B
, O
ABTS B
, O
hydroxyl B
radicals O
, O
and O
superoxide B
anion O
, O
respectively O
. O

In O
the O
8 O
- O
64mg O
/ O
ml O
range O
, O
alpha O
- O
glucosidase O
and O
alpha O
- O
amylase O
were O
inhibited O
by O
TFs B
to O
a O
certain O
extent O
. O

In O
vivo O
, O
the O
treatment O
groups O
with O
TFs O
( O
100 O
, O
200 O
, O
400mg O
/ O
kg O
) O
showed O
a O
significant O
decrease O
in O
the O
malondialdehyde B
level O
, O
the O
superoxide B
dismutase O
and O
glutathione B
levels O
were O
restored O
to O
almost O
normal O
levels O
, O
and O
the O
catalase O
and O
glutathione B
peroxidase O
levels O
significantly O
increased O
compared O
to O
the O
CCl4 B
- O
intoxicated O
group O
in O
rats O
. O

The O
present O
study O
suggests O
that O
C O
. O
glandulosum O
seeds O
should O
be O
given O
special O
attention O
because O
of O
their O
antioxidant O
and O
anti O
- O
glucosidase O
, O
anti O
- O
amylase O
activity O
. O

Distribution O
, O
antioxidant O
and O
characterisation O
of O
phenolic B
compounds O
in O
soybeans O
, O
flaxseed O
and O
olives O
. O

The O
distribution O
of O
free O
and O
bound O
phenolic B
compounds O
present O
in O
soybean O
, O
flaxseed O
and O
olive O
were O
investigated O
. O

The O
phenolic B
compounds O
were O
fractionated O
on O
the O
basis O
on O
their O
solubility O
characteristics O
in O
water O
, O
alcohol B
, O
dilute O
base O
and O
dilute O
acid O
. O

Reversed O
phase O
high O
pressure O
liquid O
chromatography O
( O
RP O
- O
HPLC O
) O
and O
mass O
spectrometry O
( O
MS O
) O
were O
used O
for O
identification O
of O
individual O
components O
of O
phenolic B
compounds O
. O

Antioxidant O
activity O
( O
AA O
% O
) O
of O
free O
and O
bound O
phenolic B
compounds O
was O
measured O
using O
the O
linoleic B
acid I
/ O
beta B
- I
carotene I
assay O
. O

The O
water O
- O
soluble O
phenolic O
compound O
fractions O
represented O
68 O
- O
81 O
% O
, O
50 O
- O
72 O
% O
and O
46 O
- O
56 O
% O
of O
the O
total O
phenolic B
compounds O
measured O
in O
full O
- O
fat O
soybean O
, O
olive O
and O
flaxseed O
, O
respectively O
. O

Methanolic O
extraction O
of O
free O
phenolic O
compounds O
without O
heat O
, O
solubilised O
21 O
- O
56 O
% O
, O
42 O
- O
62 O
% O
and O
34 O
- O
51 O
% O
of O
the O
total O
phenolic B
compounds O
measured O
in O
soybean O
, O
olive O
and O
flaxseed O
, O
respectively O
; O
methanol B
extraction O
of O
free O
phenolic O
compounds O
with O
heat O
solubilised O
a O
further O
24 O
- O
34 O
% O
, O
31 O
- O
37 O
% O
and O
36 O
- O
37 O
% O
of O
phenolic O
compounds O
from O
soybean O
, O
olive O
and O
flaxseed O
, O
respectively O
. O

Further O
dilute O
alkali O
and O
dilute O
acid O
solubilised O
the O
remaining O
10 O
- O
40 O
% O
, O
1 O
- O
21 O
% O
and O
12 O
- O
29 O
% O
of O
the O
total O
phenolic B
compounds O
from O
soybean O
, O
olive O
and O
flaxseed O
, O
respectively O
. O

Results O
indicated O
that O
the O
full O
- O
fat O
meals O
of O
soybean O
, O
flaxseed O
and O
olive O
showed O
higher O
antioxidant O
activity O
compared O
to O
defatted O
meals O
. O

RP O
- O
HPLC O
and O
LC O
- O
MS O
/ O
MS O
profil1 O
for O
soybean O
, O
flaxseed O
and O
olive O
indicate O
two O
classes O
of O
phenolic B
compounds O
designated O
as O
free O
and O
bound O
phenolic B
compounds O
. O

Maqui O
berry O
( O
Aristotelia O
chilensis O
) O
and O
the O
constituent O
delphinidin B
glycoside I
inhibit O
photoreceptor O
cell O
death O
induced O
by O
visible O
light O
. O

The O
protective O
effects O
of O
maqui O
berry O
( O
Aristotelia O
chilensis O
) O
extract O
( O
MBE O
) O
and O
its O
major O
anthocyanins B
[ O
delphinidin B
3 I
, I
5 I
- I
O I
- I
diglucoside I
( O
D3G5G B
) O
and O
delphinidin B
3 I
- I
O I
- I
sambubioside I
- I
5 I
- I
O I
- I
glucoside I
( O
D3S5G B
) O
] O
against O
light O
- O
induced O
murine O
photoreceptor O
cells O
( O
661W O
) O
death O
were O
evaluated O
. O

Viability O
of O
661W O
after O
light O
treatment O
for O
24h O
, O
assessed O
by O
the O
tetrazolium B
salt I
( O
WST O
- O
8 O
) O
assay O
and O
Hoechst B
33342 I
nuclear O
staining O
, O
was O
improved O
by O
addition O
of O
MBE O
, O
D3G5G O
, O
and O
D3S5G O
. O

Intracellular O
radical O
activation O
in O
661W O
, O
evaluated O
using O
the O
reactive O
oxygen B
species O
( O
ROS O
) O
- O
sensitive O
probe O
5 B
- I
( I
and I
- I
6 I
) I
- I
chloromethyl I
- I
2 I
, I
7 I
- I
dichlorodihydro I
fluorescein I
diacetate I
acetyl I
ester I
( O
CM B
- I
H2DCFDA I
) O
, O
was O
reduced O
by O
MBE O
and O
its O
anthocyanins B
. O

The O
anti O
- O
apoptosis O
mechanism O
of O
MBE O
was O
evaluated O
by O
light O
- O
induced O
phosphorylation O
of O
p38 O
. O

MBE O
significantly O
suppressed O
the O
light O
- O
induced O
phosphorylation O
of O
p38 O
. O

These O
findings O
indicate O
that O
MBE O
and O
its O
anthocyanidins B
suppress O
the O
light O
- O
induced O
photoreceptor O
cell O
death O
by O
inhibiting O
ROS O
production O
, O
suggesting O
that O
the O
inhibition O
of O
phosphorylated O
- O
p38 O
may O
be O
involved O
in O
the O
underlying O
mechanism O
. O

Encapsulation O
of O
indole B
- I
3 I
- I
carbinol I
and O
3 B
, I
3 I
' I
- I
diindolylmethane I
in O
zein O
/ O
carboxymethyl B
chitosan O
nanoparticles O
with O
controlled O
release O
property O
and O
improved O
stability O
. O

Indole B
- I
3 I
- I
carbinol I
( O
I3C B
) O
and O
3 B
, I
3 I
' I
- I
diindolylmethane I
( O
DIM B
) O
are O
two O
bioactive O
compounds O
from O
Cruciferous O
vegetables O
. O

The O
stability O
of O
these O
compounds O
is O
a O
major O
challenge O
for O
their O
pharmaceutical O
applications O
. O

In O
this O
study O
, O
zein O
and O
zein O
/ O
carboxymethyl B
chitosan O
( O
CMCS O
) O
nanoparticles O
were O
prepared O
to O
encapsulate O
I3C B
and O
DIM B
by O
a O
combined O
liquid O
- O
liquid O
phase O
separation O
and O
ionic O
gelation O
method O
. O

After O
zein O
nanoparticles O
were O
coated O
with O
CMCS O
, O
the O
zeta O
potential O
was O
decreased O
from O
around O
- O
10 O
to O
- O
20mV O
, O
and O
encapsulation O
efficiency O
was O
greatly O
improved O
. O

Both O
nanoparticle O
formulations O
provided O
controlled O
release O
of O
I3C B
and O
DIM B
in O
PBS O
medium O
. O

Zein O
and O
zein O
/ O
CMCS O
nanoparticles O
demonstrated O
similar O
protection O
for O
both O
I3C O
and O
DIM O
against O
ultraviolet O
( O
UV O
) O
light O
, O
attributed O
mainly O
to O
the O
contribution O
of O
the O
zein O
protein O
. O

Compared O
with O
zein O
nanoparticles O
, O
zein O
/ O
CMCS O
nanoparticles O
exhibited O
better O
protection O
of O
I3C B
against O
degradation O
and O
better O
inhibition O
against O
its O
oligomerization O
to O
DIM O
under O
thermal O
condition O
( O
37 O
degrees O
C O
) O
. O

Based O
on O
our O
results O
, O
the O
encapsulation O
of O
hydrophobic O
bioactives O
in O
zein O
/ O
CMCS O
nanoparticles O
is O
a O
promising O
approach O
to O
improve O
their O
stability O
against O
harsh O
conditions O
and O
provide O
controlled O
release O
for O
food O
/ O
pharmaceutical O
applications O
. O

Sonicated O
pineapple O
juice O
as O
substrate O
for O
L O
. O
casei O
cultivation O
for O
probiotic O
beverage O
development O
: O
Process O
optimisation O
and O
product O
stability O
. O

The O
aim O
of O
this O
study O
was O
to O
evaluate O
the O
use O
of O
sonicated O
pineapple O
juice O
as O
substrate O
for O
producing O
a O
probiotic O
beverage O
by O
Lactobacillus O
casei O
NRRL O
B442 O
. O

Maximal O
microbial O
viability O
was O
found O
by O
cultivating O
L O
. O
casei O
at O
31 O
degrees O
C O
and O
pH O
5 O
. O
8 O
( O
optimised O
conditions O
) O
. O

After O
fermentation O
, O
samples O
of O
sweetened O
and O
non O
- O
sweetened O
juice O
were O
stored O
. O

After O
42days O
of O
storage O
under O
refrigeration O
( O
4 O
degrees O
C O
) O
, O
the O
microbial O
viability O
was O
6 O
. O
03LogCFU O
/ O
mL O
in O
the O
non O
- O
sweetened O
sample O
and O
4 O
. O
77LogCFU O
/ O
mL O
in O
the O
sweetened O
sample O
. O

The O
pH O
of O
both O
samples O
decreased O
during O
storage O
due O
to O
lactic B
acid I
production O
( O
post O
acidification O
) O
. O

The O
characteristic O
colour O
of O
the O
juice O
was O
maintained O
throughout O
the O
shelf O
life O
and O
no O
browning O
was O
observed O
. O

Sonicated O
pineapple O
juice O
was O
shown O
to O
be O
a O
suitable O
substrate O
for O
L O
. O
casei O
cultivation O
and O
for O
the O
development O
of O
an O
alternative O
non O
- O
dairy O
probiotic O
beverage O
. O

Ligands O
affecting O
silver B
antimicrobial O
efficacy O
on O
Listeria O
monocytogenes O
and O
Salmonella O
enterica O
. O

Although O
silver B
is O
being O
extensively O
used O
in O
food O
or O
other O
applications O
as O
the O
key O
component O
to O
control O
microbial O
proliferation O
, O
many O
factors O
affecting O
its O
real O
potential O
are O
still O
unknown O
. O

In O
the O
present O
work O
, O
the O
presence O
of O
specific O
ligands O
or O
the O
contents O
in O
organic O
matter O
was O
correlated O
with O
silver B
speciation O
and O
its O
antibacterial O
performance O
. O

Silver B
was O
found O
to O
be O
only O
active O
in O
form O
of O
free O
silver B
ions O
( O
FSI O
) O
. O

The O
presence O
of O
chloride B
ions O
produced O
an O
equilibrium O
of O
stable O
silver B
chloride I
complexes O
which O
were O
void O
of O
antimicrobial O
efficacy O
. O

However O
, O
even O
at O
relatively O
high O
concentrations O
of O
chlorides B
, O
a O
small O
fraction O
of O
FSI O
may O
still O
be O
present O
, O
producing O
a O
bactericidal O
effect O
with O
concentrations O
at O
the O
nanomolar O
level O
under O
optimum O
conditions O
. O

Low O
concentrations O
of O
thiol B
groups O
completely O
inactivated O
silver B
, O
while O
methylsulphur B
groups O
only O
affected O
its O
efficacy O
at O
very O
high O
concentrations O
. O

Antibacterial O
performance O
revealed O
differences O
of O
about O
1000 O
- O
fold O
between O
results O
for O
environments O
with O
high O
organic O
matter O
content O
and O
results O
for O
aqueous O
salt O
buffers O
. O

Thiol B
groups O
were O
nonetheless O
not O
found O
directly O
associated O
with O
the O
decrease O
in O
antimicrobial O
performance O
in O
a O
nutrient O
rich O
environment O
. O

These O
results O
point O
out O
the O
complexity O
of O
the O
antimicrobial O
systems O
based O
on O
silver B
and O
can O
have O
relevance O
in O
food O
or O
other O
applications O
of O
silver B
as O
an O
antimicrobial O
. O

Antioxidant O
capacity O
, O
polyphenolic O
content O
and O
tandem O
HPLC O
- O
DAD O
- O
ESI O
/ O
MS O
profiling O
of O
phenolic B
compounds O
from O
the O
South O
American O
berries O
Luma O
apiculata O
and O
L O
. O
chequ O
e O
n O
. O

Native O
Myrtaceae O
fruits O
were O
gathered O
by O
South O
American O
Amerindians O
as O
a O
food O
source O
. O

At O
present O
, O
there O
is O
still O
some O
regional O
consume O
of O
the O
small O
berries O
from O
trees O
belonging O
to O
genus O
Luma O
that O
occurs O
in O
southern O
Chile O
and O
Argentina O
. O

The O
aerial O
parts O
and O
berries O
from O
Luma O
apiculata O
and O
Luma O
chequen O
were O
investigated O
for O
phenolic B
constituents O
and O
antioxidant O
capacity O
. O

A O
high O
performance O
electrospray O
ionisation O
mass O
spectrometry O
method O
was O
developed O
for O
the O
rapid O
identification O
of O
phenolics B
in O
polar O
extracts O
from O
both O
species O
. O

Thirty O
- O
one O
phenolic B
compounds O
were O
detected O
and O
27 O
were O
identified O
or O
tentatively O
characterised O
based O
on O
photodiode O
array O
UV O
- O
vis O
spectra O
( O
DAD O
) O
, O
ESI O
- O
MS O
- O
MS O
spectrometric O
data O
and O
spiking O
experiments O
with O
authentic O
standards O
. O

Twelve O
phenolic B
compounds O
were O
detected O
in O
L O
. O
apiculata O
fruits O
and O
12 O
in O
the O
aerial O
parts O
while O
L O
. O
chequen O
yielded O
10 O
compounds O
in O
fruits O
and O
16 O
in O
aerial O
parts O
, O
respectively O
. O

From O
the O
compounds O
occurring O
in O
both O
Luma O
species O
, O
seven O
were O
identified O
as O
tannins B
or O
their O
monomers O
, O
15 O
were O
flavonol B
derivatives O
and O
five O
were O
anthocyanins B
. O

The O
whole O
berry O
and O
aerial O
parts O
extracts O
presented O
high O
antioxidant O
capacity O
in O
the O
DPPH B
assay O
( O
IC50 O
of O
10 O
. O
41 O
+ O
/ O
- O
0 O
. O
02 O
and O
2 O
. O
44 O
+ O
/ O
- O
0 O
. O
03 O
mu O
g O
/ O
mL O
for O
L O
. O
apiculata O
, O
12 O
. O
89 O
+ O
/ O
- O
0 O
. O
05 O
and O
3 O
. O
22 O
+ O
/ O
- O
0 O
. O
05 O
for O
L O
. O
chequen O
, O
respectively O
) O
, O
which O
can O
be O
related O
to O
the O
diverse O
range O
of O
phenolics B
detected O
. O

The O
antioxidant O
capacity O
together O
with O
the O
high O
polyphenolic O
contents O
and O
compounds O
identified O
can O
support O
at O
least O
in O
part O
, O
their O
use O
as O
botanical O
drugs O
. O

From O
the O
compounds O
identified O
in O
both O
species O
, O
3 B
- I
O I
- I
( I
6 I
' I
' I
- I
O I
- I
galloyl I
) I
- I
hexose I
derivatives O
of O
myricetin B
, O
quercetin B
, O
laricitrin B
and O
isorhamnetin B
are O
reported O
for O
the O
first O
time O
for O
the O
genus O
Luma O
. O

Structural O
characterisation O
of O
partially O
glycosylated O
whey O
protein O
as O
influenced O
by O
pH O
and O
heat O
using O
surface O
- O
enhanced O
Raman O
spectroscopy O
. O

Maillard O
- O
induced O
glycosylation O
of O
whey O
protein O
improves O
solubility O
and O
thermal O
stability O
over O
a O
wide O
pH O
range O
. O

However O
, O
the O
relationship O
between O
structural O
changes O
and O
functional O
enhancement O
upon O
glycosylation O
is O
not O
well O
- O
characterized O
. O

Therefore O
, O
our O
objective O
was O
to O
characterise O
these O
structural O
changes O
and O
determine O
the O
protein O
conformation O
at O
various O
pH O
and O
thermal O
treatments O
, O
using O
surface O
- O
enhanced O
Raman O
- O
spectroscopy O
. O

The O
spectra O
of O
glycosylated O
protein O
revealed O
a O
new O
peak O
at O
983cm O
( O
- O
1 O
) O
that O
can O
be O
used O
as O
a O
Raman O
marker O
for O
the O
early O
stage O
glycosylation O
. O

Upon O
glycosylation O
, O
structural O
variations O
were O
significant O
at O
the O
disulfide B
, O
hydrophobic O
, O
amide B
III O
, O
amide B
II O
, O
and O
amide B
I O
regions O
. O

Ionisation O
of O
carboxyl B
groups O
at O
all O
tested O
pH O
values O
, O
and O
increased O
beta O
- O
sheet O
configuration O
were O
also O
observed O
. O

The O
noted O
structural O
modifications O
imparted O
molecular O
rigidity O
and O
a O
consequent O
resistance O
to O
denaturation O
upon O
thermal O
treatment O
over O
a O
wide O
pH O
range O
. O

These O
findings O
can O
be O
used O
to O
explain O
various O
functional O
enhancements O
of O
whey O
protein O
upon O
glycosylation O
. O

Changes O
in O
urocanic B
acid I
, O
histamine B
, O
putrescine B
and O
cadaverine B
levels O
in O
Indian O
mackerel O
( O
Rastrelliger O
kanagurta O
) O
during O
storage O
at O
different O
temperatures O
. O

Histamine B
, O
putrescine B
cadaverine I
and O
cis B
- I
urocanic I
acid I
( O
UCA B
) O
have O
all O
been O
implicated O
or O
suggested O
in O
scombroid O
fish O
poisoning O
. O

However O
, O
there O
is O
little O
information O
on O
UCA O
especially O
during O
storage O
. O

Changes O
in O
their O
contents O
during O
storage O
of O
whole O
Indian O
mackerel O
at O
0 O
, O
3 O
+ O
/ O
- O
1 O
, O
10 O
+ O
/ O
- O
1 O
for O
up O
to O
15days O
and O
23 O
+ O
/ O
- O
2 O
degrees O
C O
for O
up O
to O
2days O
were O
monitored O
. O

Fresh O
muscles O
contained O
14 O
. O
83mg O
/ O
kg O
trans B
- I
UCA I
, O
2 O
. O
23mg O
/ O
kg O
cis B
- I
UCA I
and O
1 O
. O
86mg O
/ O
kg O
cadaverine B
. O

Histamine B
and O
putrescine B
were O
not O
detected O
. O

After O
15days O
at O
0 O
and O
3 O
degrees O
C O
, O
trans B
- I
UCA I
content O
increased O
to O
52 O
. O
83 O
and O
189 O
. O
51mg O
/ O
kg O
, O
respectively O
, O
and O
decreased O
to O
< O
2mg O
/ O
kg O
at O
the O
other O
two O
temperatures O
. O

Storage O
at O
10 O
degrees O
C O
also O
resulted O
in O
an O
increase O
in O
trans B
- I
UCA I
after O
3days O
, O
only O
to O
decrease O
after O
6days O
. O

The O
concentration O
of O
cis B
- I
UCA I
increased O
nearly O
13 O
- O
fold O
after O
15days O
at O
0 O
and O
3 O
degrees O
C O
, O
decreased O
at O
10 O
degrees O
C O
and O
remained O
unchanged O
at O
23 O
degrees O
C O
. O

Histamine B
, O
putrescine B
and O
cadaverine B
levels O
increased O
significantly O
( O
P O
value O
< O
0 O
. O
05 O
) O
at O
all O
temperatures O
especially O
at O
23 O
degrees O
C O
. O

Fundamental O
studies O
on O
the O
structural O
functionality O
of O
whey O
protein O
isolate O
in O
the O
presence O
of O
small O
polyhydroxyl B
compounds O
as O
co O
- O
solute O
. O

The O
present O
work O
deals O
with O
the O
changing O
network O
morphology O
of O
whey O
protein O
isolate O
( O
15 O
% O
, O
w O
/ O
w O
) O
in O
the O
presence O
of O
glucose B
syrup O
( O
co O
- O
solute O
) O
with O
concentrations O
ranging O
from O
0 O
% O
to O
65 O
% O
( O
w O
/ O
w O
) O
in O
10mM O
CaCl2 B
solution O
, O
thus O
producing O
formulations O
with O
a O
total O
level O
of O
solids O
of O
up O
to O
80 O
% O
( O
w O
/ O
w O
) O
. O

Denaturation O
behaviour O
and O
aggregation O
of O
whey O
protein O
systems O
were O
investigated O
using O
small O
deformation O
dynamic O
oscillation O
on O
shear O
, O
micro O
and O
modulated O
differential O
scanning O
calorimetry O
, O
and O
confocal O
laser O
scanning O
microscopy O
. O

A O
progression O
in O
the O
mechanical O
strength O
of O
protein O
aggregates O
was O
observed O
resulting O
from O
enhanced O
protein O
- O
protein O
interactions O
in O
the O
presence O
of O
glucose B
syrup O
. O

Addition O
of O
the O
co O
- O
solute O
resulted O
in O
better O
thermal O
stability O
of O
protein O
molecules O
by O
shifting O
the O
process O
of O
denaturation O
to O
higher O
temperature O
, O
as O
observed O
by O
calorimetry O
. O

Observations O
are O
supported O
by O
micrographs O
showing O
coherent O
networks O
with O
reduced O
size O
of O
whey O
protein O
aggregates O
in O
the O
presence O
of O
high O
levels O
of O
glucose B
syrup O
, O
as O
opposed O
to O
thick O
and O
random O
clusters O
for O
systems O
of O
whey O
protein O
by O
itself O
. O

Glass O
transition O
phenomenon O
was O
observed O
for O
condensed O
protein O
/ O
co O
- O
solute O
systems O
, O
which O
were O
treated O
with O
theoretical O
concepts O
adapted O
from O
synthetic O
polymer O
research O
to O
pinpoint O
the O
mechanical O
glass O
transition O
temperature O
. O

Croton O
lechleri O
M O
u O
ll O
. O

Arg O
. O

( O
Euphorbiaceae O
) O
stem O
bark O
essential O
oil O
as O
possible O
mutagen O
- O
protective O
food O
ingredient O
against O
heterocyclic B
amines I
from O
cooked O
food O
. O

The O
Amazonian O
Croton O
lechleri O
stem O
bark O
essential O
oil O
was O
tested O
for O
its O
anti O
- O
mutagenic O
potential O
by O
performing O
the O
Ames O
test O
against O
heterocyclic B
amines I
( O
HCAs B
) O
, O
in O
continuing O
research O
on O
applicative O
functional O
profile O
of O
this O
phytocomplex O
as O
food O
ingredient O
( O
Rossi O
et O
al O
. O
, O
2011 O
) O
. O

Salmonella O
typhimurium O
strain O
TA98 O
was O
used O
with O
and O
without O
metabolic O
activation O
( O
S9 O
mix O
) O
. O

The O
anti O
- O
mutagenic O
properties O
was O
assayed O
with O
the O
following O
HCAs O
: O
2 B
- I
amino I
- I
3 I
- I
methylimidazo I
- I
[ I
4 I
, I
5 I
- I
f I
] I
quinoline I
( O
IQ O
) O
, O
2 B
- I
amino I
- I
3 I
, I
4 I
- I
dimethylimidazo I
- I
[ I
4 I
, I
5 I
- I
f I
] I
quinoline I
( O
MeIQ B
) O
, O
2 B
- I
amino I
- I
3 I
, I
8 I
- I
dimethylimidazo I
- I
[ I
4 I
, I
5 I
- I
f I
] I
quinoxaline I
( O
MeIQx B
) O
, O
the O
imidazoles O
2 B
- I
amino I
- I
6 I
- I

methyldipyrido I
- I
[ I
1 I
, I
2 I
- I
a I
: I
3 I
' I
, I
2 I
' I
- I
d I
] I
imidazole I
( O
Glu B
- I
P I
- I
1 I
) O
and O
2 B
- I
aminodipirydo I
- I
[ I
1 I
, I
2 I
- I
a I
: I
3 I
' I
, I
2 I
' I
- I
d I
] I
imidazole I
( O
Glu B
- I
P I
- I
2 I
) O
. O

All O
HCAs B
with O
S9 O
induced O
mutagenicity O
at O
10 O
( O
- O
10 O
) O
mol O
/ O
plate O
. O

Without O
S9 O
, O
IQ O
and O
MeIQ B
showed O
mutagenicity O
at O
10 O
( O
- O
8 O
) O
mol O
/ O
plate O
, O
MeIQx B
and O
Glu B
- I
P I
- I
1 I
at O
10 O
( O
- O
5 O
) O
mol O
/ O
plate O
, O
while O
Glu B
- I
P I
- I
2 I
was O
inactive O
. O

In O
presence O
of O
HACs O
( O
10 O
( O
- O
9 O
) O
mol O
/ O
plate O
) O
, O
C O
. O
lechleri O
essential O
oil O
was O
tested O
for O
mutagen O
- O
protective O
properties O
( O
concentration O
range O
: O
0 O
. O
01 O
- O
0 O
. O
10mg O
/ O
plate O
) O
taking O
the O
Highest O
Uneffective O
Dose O
( O
HUD O
) O
as O
threshold O
reference O
. O

With O
S9 O
mix O
, O
C O
. O
lechleri O
essential O
oil O
displayed O
a O
significant O
reduction O
of O
revertants O
at O
0 O
. O
05mg O
/ O
plate O
, O
from O
21 O
% O
to O
34 O
% O
. O

The O
essential O
oil O
showed O
mutagen O
- O
protective O
efficacy O
against O
IQ O
and O
MeIQ B
tested O
as O
direct O
mutagens O
( O
10 O
( O
- O
7 O
) O
mol O
/ O
plate O
) O
, O
with O
a O
revertants O
percentage O
reduction O
of O
39 O
% O
and O
40 O
% O
, O
respectively O
. O

No O
anti O
- O
mutagen O
capacity O
was O
noted O
for O
MeIQx B
and O
Glu B
- I
P I
- I
1 I
( O
10 O
( O
- O
5 O
) O
mol O
/ O
plate O
) O
. O

Since O
HACs O
are O
known O
as O
possible O
colon O
and O
liver O
cancer O
inducers O
, O
C O
. O
lechleri O
essential O
oil O
was O
tested O
for O
its O
cytotoxicity O
and O
anti O
- O
proliferative O
capacity O
against O
LoVo O
and O
HepG2 O
cancer O
cell O
lines O
showing O
IC50 O
of O
74 O
. O
95 O
+ O
/ O
- O
0 O
. O
05 O
mu O
g O
/ O
ml O
( O
LoVo O
) O
and O
82 O
. O
28 O
+ O
/ O
- O
0 O
. O
03 O
mu O
g O
/ O
ml O
( O
HepG2 O
) O
, O
displaying O
a O
promising O
role O
of O
this O
essential O
oil O
as O
a O
functional O
food O
ingredient O
with O
interesting O
mutagen O
preventing O
properties O
. O

Characterisation O
of O
non O
- O
polar O
dimers O
formed O
during O
thermo O
- O
oxidative O
degradation O
of O
beta B
- I
sitosterol I
. O

Thermo O
- O
oxidative O
degradation O
of O
sterols B
at O
temperature O
typical O
for O
frying O
leads O
to O
the O
formation O
of O
oxidised O
derivatives O
, O
fragmented O
sterols B
and O
oligomers O
. O

Recent O
research O
on O
sterol B
oxidation O
focuses O
mainly O
on O
the O
oxysterol B
derivatives O
formation O
to O
the O
exclusion O
of O
compounds O
with O
high O
molecular O
mass O
. O

The O
aim O
of O
this O
work O
was O
to O
decipher O
the O
chemical O
structure O
of O
non O
- O
polar O
dimers O
formed O
during O
beta B
- I
sitosterol I
oxidation O
at O
180 O
degrees O
C O
in O
the O
presence O
of O
oxygen B
. O

The O
dimer O
fraction O
was O
separated O
by O
size O
- O
exclusion O
chromatography O
( O
SEC O
) O
after O
pre O
- O
fractionation O
on O
silica B
gel I
. O

The O
chemical O
structure O
of O
the O
dimers O
was O
assessed O
by O
1D O
and O
2D O
NMR O
, O
IR O
, O
Raman O
and O
MS O
spectroscopies O
. O

NMR O
data O
confirmed O
that O
the O
predominant O
non O
- O
polar O
dimer O
formed O
during O
beta B
- I
sitosterol I
oxidative O
degradation O
has O
a O
configuration O
of O
3 B
beta I
, I
3 I
beta I
' I
- I
disitosteryl I
ether I
. O

Data O
from O
IR O
and O
Raman O
spectroscopies O
further O
proved O
it O
chemical O
structure O
. O

Applied O
analytical O
techniques O
also O
confirmed O
presence O
of O
dimers O
with O
different O
configuration O
than O
disteryl B
ethers I
. O

Proportions O
of O
A1 O
, O
A2 O
, O
B O
and O
C O
beta O
- O
casein O
protein O
variants O
in O
retail O
milk O
in O
the O
UK O
. O

The O
A1 O
variant O
protein O
of O
the O
beta O
- O
casein O
family O
has O
been O
implicated O
in O
various O
disease O
states O
although O
much O
evidence O
is O
weak O
or O
contradictory O
. O

The O
primary O
objective O
was O
to O
measure O
, O
for O
the O
first O
time O
, O
the O
proportions O
of O
the O
key O
beta O
- O
casein O
variant O
proteins O
in O
UK O
retail O
milk O
over O
the O
course O
of O
one O
year O
. O

In O
total O
, O
55 O
samples O
of O
semi O
- O
skimmed O
milk O
were O
purchased O
from O
five O
supermarkets O
over O
the O
course O
of O
a O
year O
and O
the O
proportions O
of O
the O
A1 O
, O
A2 O
, O
B O
and O
C O
casein O
variant O
proteins O
were O
measured O
, O
using O
high O
resolution O
HPLC O
- O
MS O
. O

The O
results O
showed O
that O
beta O
- O
casein O
in O
UK O
retail O
milk O
comprises O
approximately O
0 O
. O
58 O
, O
0 O
. O
31 O
, O
0 O
. O
07 O
and O
0 O
. O
03 O
A2 O
, O
A1 O
, O
B O
and O
C O
protein O
variants O
, O
respectively O
. O

The O
proportion O
of O
A2 O
is O
higher O
than O
some O
early O
studies O
would O
predict O
although O
the O
reasons O
for O
this O
and O
any O
implications O
for O
health O
are O
unclear O
. O

RP O
- O
HPLC O
and O
chemometrics O
for O
wheat O
flour O
protein O
characterisation O
in O
an O
industrial O
bread O
- O
making O
process O
monitoring O
context O
. O

In O
the O
baking O
industry O
, O
a O
difficult O
task O
is O
to O
keep O
the O
quality O
perceived O
by O
the O
consumer O
as O
constant O
as O
possible O
, O
given O
the O
inner O
variability O
of O
flour O
, O
e O
. O
g O
. O
due O
to O
different O
wheat O
mixtures O
, O
harvesting O
time O
, O
etc O
. O

Here O
, O
we O
evaluated O
the O
influence O
of O
flour O
batches O
properties O
on O
bread O
quality O
, O
considering O
an O
industrial O
bread O
making O
process O
. O

In O
particular O
, O
flour O
composition O
in O
terms O
of O
protein O
fractions O
( O
gliadins O
, O
glutenins O
) O
has O
been O
determined O
by O
means O
of O
RP O
- O
HPLC O
, O
to O
assess O
the O
inter O
- O
and O
intra O
- O
batch O
variability O
of O
flour O
mixtures O
deliveries O
at O
a O
baking O
plant O
. O

Multivariate O
data O
analysis O
allowed O
evaluation O
of O
correlation O
between O
flour O
protein O
composition O
and O
technological O
properties O
. O

A O
great O
variability O
within O
different O
deliveries O
of O
a O
same O
flour O
batch O
emerged O
, O
as O
well O
as O
a O
considerable O
seasonal O
variability O
. O

Correlation O
models O
among O
protein O
sub O
- O
fractions O
, O
technological O
properties O
and O
bread O
quality O
are O
difficult O
to O
establish O
; O
however O
, O
the O
role O
of O
the O
protein O
profile O
on O
flour O
behaviour O
in O
bread O
making O
could O
be O
highlighted O
. O

Anthocyanins B
in O
the O
ripe O
fruits O
of O
Rubus O
coreanus O
Miquel O
and O
their O
protective O
effect O
on O
neuronal O
PC O
- O
12 O
cells O
. O

Phenolics B
of O
the O
fresh O
ripe O
fruits O
of O
Rubus O
coreanus O
Miquel O
were O
extracted O
and O
separated O
into O
anthocyanin B
and O
the O
non O
- O
anthocyanin B
fractions O
, O
which O
were O
used O
for O
the O
evaluation O
for O
antioxidant O
capacity O
and O
neuroprotective O
effects O
. O

The O
anthocyanin B
fraction O
accounted O
for O
approximately O
47 O
- O
55 O
% O
of O
the O
total O
antioxidant O
capacity O
of O
the O
whole O
extract O
and O
had O
significantly O
higher O
free O
radical O
- O
scavenging O
capacity O
than O
the O
non O
- O
anthocyanin B
fraction O
. O

Furthermore O
, O
the O
anthocyanins B
alleviated O
intracellular O
oxidative O
stress O
, O
as O
assayed O
by O
in O
vitro O
fluorescent O
measurements O
. O

The O
anthocyanins B
showed O
neuroprotective O
effects O
on O
PC O
- O
12 O
cells O
in O
vitro O
against O
oxidative O
stress O
in O
a O
dose O
- O
dependent O
manner O
. O

Triple O
quadrupole O
LC O
/ O
MS O
and O
Q O
- O
TOF O
LC O
/ O
MS O
analyses O
revealed O
four O
major O
anthocyanins B
; O
cyanidin B
3 I
- I
O I
- I
sambubioside I
, O
cyanidin B
3 I
- I
O I
- I
glucoside I
, O
cyanidin B
3 I
- I
O I
- I
xylosylrutinoside I
, O
and O
cyanidin B
3 I
- I
O I
- I
rutinoside I
in O
increasing O
order O
of O
amounts O
. O

These O
results O
demonstrated O
that O
anthocyanins B
are O
the O
major O
components O
and O
contributors O
to O
the O
antioxidant O
capacity O
of O
ripe O
R O
. O
coreanus O
Miquel O
fruits O
. O

Further O
studies O
are O
warranted O
to O
determine O
whether O
consumption O
of O
the O
fruits O
reduces O
oxidative O
stress O
in O
the O
brain O
and O
promotes O
health O
. O

Extraction O
and O
structural O
characterisation O
of O
rhamnogalacturonan O
I O
- O
type O
pectic O
polysaccharides O
from O
potato O
cell O
wall O
. O

Cell O
wall O
material O
from O
potato O
pulp O
by O
- O
product O
was O
used O
for O
the O
extraction O
of O
galactan O
- O
rich O
rhamnogalacturonan O
I O
( O
RG O
- O
I O
) O
type O
pectic O
polysaccharides O
using O
alkaline O
( O
NaOH B
and O
KOH B
) O
and O
enzymatic O
( O
endopolygalacturonas O
from O
Aspergillus O
niger O
) O
methods O
. O

The O
extraction O
yield O
increased O
as O
the O
concentration O
of O
alkaline O
solution O
was O
increased O
from O
0 O
. O
5M O
( O
22 O
- O
24 O
% O
) O
to O
2M O
( O
53 O
- O
56 O
% O
) O
. O

The O
yield O
of O
38 O
% O
obtained O
upon O
the O
enzymatic O
treatment O
was O
similar O
to O
those O
observed O
with O
1M O
alkaline O
solutions O
. O

The O
results O
reveal O
the O
high O
debranching O
of O
arabinan O
side O
chains O
of O
RG O
I O
as O
compared O
to O
the O
galactan O
ones O
under O
harsh O
alkaline O
conditions O
. O

The O
molecular O
weight O
distribution O
shows O
that O
the O
enzymatic O
extraction O
led O
to O
the O
highest O
proportion O
of O
high O
- O
molecular O
weight O
polysaccharides O
( O
> O
500kDa O
; O
62 O
. O
2 O
% O
) O
. O

According O
to O
monosaccharide B
pattern O
, O
the O
weak O
acidic O
fractions O
of O
high O
alkaline O
( O
1 O
- O
2M O
) O
- O
based O
polysaccharide O
extracts O
was O
the O
most O
enriched O
with O
galactan O
- O
rich O
RG O
I O
. O

Using O
milder O
conditions O
( O
enzyme O
and O
weak O
alkaline O
) O
, O
two O
RG O
I O
populations O
with O
low O
and O
high O
linked O
homogalacturonan O
fragments O
were O
recovered O
in O
the O
weak O
and O
strong O
acidic O
fractions O
, O
respectively O
. O

The O
structure O
of O
galactan O
- O
rich O
RG O
I O
was O
confirmed O
by O
H B
( O
1 O
) O
NMR O
spectroscopy O
analysis O
. O

Distribution O
of O
carotenoids O
in O
endosperm O
, O
germ O
, O
and O
aleurone O
fractions O
of O
cereal O
grain O
kernels O
. O

To O
compare O
the O
distribution O
of O
carotenoids O
across O
the O
grain O
, O
non O
- O
corn O
and O
corn O
cereals O
were O
hand O
dissected O
into O
endosperm O
, O
germ O
and O
aleurone O
fractions O
. O

Total O
carotenoid O
content O
( O
TCC O
) O
and O
carotenoid O
composition O
were O
analysed O
using O
spectrophotometry O
and O
HPLC O
. O

Cereal O
carotenoid O
composition O
was O
similar O
; O
however O
, O
concentrations O
varied O
significantly O
( O
p O
< O
0 O
. O
05 O
) O
. O

Endosperm O
fractions O
had O
TCC O
ranging O
from O
0 O
. O
88 O
to O
2 O
. O
27 O
and O
14 O
. O
17 O
to O
31 O
. O
35mg O
/ O
kg O
in O
non O
- O
corn O
cereals O
and O
corn O
, O
respectively O
. O

TCC B
, O
lutein B
and O
zeaxanthin B
in O
germ O
fractions O
were O
higher O
in O
non O
- O
corn O
cereals O
than O
in O
corn O
. O

Lutein B
and O
zeaxanthin B
contents O
were O
lower O
in O
non O
- O
corn O
cereal O
endosperms O
. O

The O
aleurone O
layer O
had O
zeaxanthin B
levels O
2 O
- O
to O
5 O
- O
fold O
higher O
than O
lutein B
among O
the O
cereals O
. O

Positive O
significant O
correlations O
( O
p O
< O
0 O
. O
05 O
) O
were O
found O
between O
TCC O
, O
carotenoids O
analysed O
by O
HPLC O
and O
DPPH B
results O
. O

This O
study O
is O
the O
first O
to O
report O
on O
carotenoid O
composition O
of O
the O
aleurone O
layer O
. O

Our O
findings O
suggest O
that O
the O
aleurone O
of O
wheat O
, O
oat O
, O
corn O
and O
germ O
of O
barley O
have O
significantly O
enhanced O
carotenoid O
levels O
. O

Aluminium B
and O
other O
elements O
in O
selected O
herbal O
tea O
plant O
species O
and O
their O
infusions O
. O

The O
determination O
of O
Al B
, O
B B
, O
Cu B
, O
Fe B
, O
Mn B
, O
Ni B
, O
P B
, O
Zn B
and O
Ca B
, O
K B
, O
Mg B
by O
inductively O
coupled O
plasma O
optical O
emission O
spectrometry O
( O
ICP O
- O
OES O
) O
and O
flame O
atomic O
absorption O
spectroscopy O
( O
FAAS O
) O
, O
respectively O
, O
in O
digests O
and O
infusions O
of O
Hibiscus O
sabdariffa O
( O
petals O
) O
, O
Rosa O
canina O
( O
receptacles O
) O
, O
Ginkgo O
biloba O
( O
leaves O
) O
, O
Cymbopogon O
citratus O
( O
leaves O
) O
, O
Aloe O
vera O
( O
leaves O
) O
and O
Panax O

ginseng O
( O
roots O
) O
was O
carried O
out O
in O
this O
study O
. O

Particular O
attention O
has O
been O
given O
to O
Al B
and O
heavy O
metals O
for O
the O
identification O
of O
possible O
raw O
material O
contaminants O
, O
their O
transformation O
into O
the O
infusion O
and O
for O
predicting O
their O
eventual O
role O
in O
the O
human O
diet O
during O
daily O
consumption O
. O

Additionally O
, O
Ion O
Chromatography O
( O
IC O
) O
speciation O
of O
Al B
in O
the O
leachates O
was O
carried O
out O
. O

In O
dry O
herbs O
, O
hibiscus O
and O
ginkgo O
appeared O
to O
contain O
the O
greatest O
contents O
of O
Al B
, O
Fe B
, O
K B
, O
Mn B
, O
Ni B
, O
Zn B
and O
B B
, O
Mg B
, O
P B
, O
respectively O
. O

A O
. O
vera O
contained O
the O
highest O
amount O
of O
Ca B
and O
highest O
values O
of O
Cu B
and O
P B
were O
observed O
in O
ginseng O
. O

In O
infusions O
, O
the O
topmost O
concentrations O
of O
Al B
, O
B B
, O
Cu B
, O
Fe B
, O
P B
, O
K B
, O
Mn B
, O
Ni B
, O
Zn B
were O
detected O
in O
those O
prepared O
from O
hibiscus O
petals O
, O
Ca B
from O
aloe O
leaves O
and O
Mg B
from O
leaves O
of O
ginkgo O
. O

According O
to O
a O
possible O
daily O
consumption O
exceeding O
1L O
, O
hibiscus O
decoction O
was O
identified O
as O
potentially O
dietetically O
significant O
in O
the O
content O
of O
certain O
elements O
. O

It O
seems O
to O
be O
possibly O
one O
of O
the O
top O
contributors O
of O
B O
from O
food O
( O
up O
to O
5 O
. O
5 O
+ O
/ O
- O
0 O
. O
2mg O
/ O
L O
) O
. O

The O
Mg O
contained O
in O
the O
infusion O
( O
up O
to O
106 O
+ O
/ O
- O
5mg O
/ O
L O
) O
may O
be O
a O
contributor O
in O
the O
attenuation O
of O
blood O
pressure O
. O

A O
high O
amount O
of O
accessible O
Mn B
( O
up O
to O
17 O
. O
4 O
+ O
/ O
- O
1 O
. O
1mg O
/ O
L O
) O
can O
probably O
have O
an O
adverse O
effect O
in O
humans O
. O

The O
total O
Al B
allowance O
( O
up O
to O
1 O
. O
2 O
+ O
/ O
- O
0 O
. O
1mg O
/ O
L O
) O
suggests O
that O
no O
more O
than O
1L O
of O
the O
hibiscus O
infusion O
should O
be O
consumed O
per O
day O
by O
sensitive O
individuals O
including O
pregnant O
women O
and O
should O
be O
completely O
excluded O
from O
the O
diet O
of O
children O
under O
6months O
of O
age O
and O
children O
with O
chronic O
renal O
failure O
. O

Cultivar O
variations O
in O
antioxidant O
and O
antihyperlipidemic O
properties O
of O
pomelo O
pulp O
( O
Citrus O
grandis O
[ O
L O
. O
] O
Osbeck O
) O
in O
Thailand O
. O

Pomelo O
( O
Citrus O
grandis O
L O
. O
Osbeck O
) O
is O
a O
native O
fruit O
of O
great O
economic O
importance O
in O
Southeast O
Asia O
. O

To O
provide O
experimental O
evidence O
for O
the O
antioxidant O
and O
antihyperlipidemic O
properties O
of O
pomelo O
, O
6 O
cultivars O
, O
including O
Kao O
- O
Yai O
( O
KY O
) O
, O
Thong O
- O
dee O
( O
TD O
) O
, O
Kao O
- O
Tangkwa O
( O
KT O
) O
, O
Kao O
- O
Numpueng O
( O
KN O
) O
, O
Ta O
- O
Koi O
( O
TK O
) O
, O
and O
Tubtim O
Siam O
( O
TS O
) O
were O
evaluated O
. O

KY O
had O
the O
highest O
phenolic O
content O
, O
and O
the O
strongest O
1 B
, I
1 I
- I
diphenyl I
- I
2 I
- I
pireyhydrazyl I
radical O
scavenging O
capacity O
and O
hydroxyl B
radical O
scavenging O
activity O
. O

From O
the O
high O
- O
performance O
liquid O
chromatography O
analysis O
, O
naringin B
and O
naringenin B
were O
the O
major O
flavonoids B
in O
the O
KT O
and O
TK O
cultivars O
. O

Six O
pomelo O
cultivars O
had O
antihyperlipidemic O
activities O
including O
the O
inhibition O
of O
pancreatic O
lipase O
and O
cholesterol B
esterase O
, O
as O
well O
as O
cholesterol B
micelle O
formation O
and O
bile B
acid I
binding O
. O

Hierarchical O
clustering O
analysis O
showed O
that O
the O
6 O
cultivars O
were O
separated O
into O
2 O
classifications O
. O

In O
addition O
, O
the O
total O
phenolics B
of O
the O
pomelo O
cultivars O
were O
significantly O
correlated O
with O
ferric B
reducing O
antioxidant O
power O
and O
Trolox B
equivalent O
antioxidant O
capacity O
. O

The O
results O
suggest O
that O
pomelo O
provides O
significant O
health O
benefits O
and O
may O
be O
used O
for O
developing O
functional O
foods O
. O

Identification O
and O
quantification O
of O
active O
alkaloids O
in O
Catharanthus O
roseus O
by O
liquid O
chromatography O
- O
ion O
trap O
mass O
spectrometry O
. O

Catharanthus O
roseus O
is O
an O
important O
dicotyledonous O
medicinal O
plant O
that O
produces O
anticancer O
compounds O
. O

The O
active O
alkaloids O
vinblastine B
, O
vindoline B
, O
ajmalicine B
, O
catharanthine B
, O
and O
vinleurosine B
were O
identified O
by O
direct O
- O
injection O
ion O
trap O
- O
mass O
spectrometry O
( O
IT O
- O
MS O
) O
for O
collecting O
MS O
( O
1 O
- O
2 O
) O
spectra O
. O

The O
determinations O
of O
five O
alkaloids O
were O
accomplished O
by O
liquid O
chromatography O
( O
LC O
) O
with O
UV O
and O
MS O
detections O
. O

The O
analytes O
provided O
good O
signals O
corresponding O
to O
the O
protonated O
molecular O
ions O
[ O
M O
+ O
H B
] O
( O
+ O
) O
and O
product O
ions O
. O

The O
precursor O
ions O
and O
product O
ions O
for O
quantification O
of O
vinblastine B
, O
vindoline B
, O
ajmalicine B
, O
catharanthine B
, O
and O
vinleurosine B
were O
m O
/ O
z O
825 O
- O
- O
> O
807 O
, O
457 O
- O
- O
> O
397 O
, O
353 O
- O
- O
> O
144 O
, O
337 O
- O
- O
> O
144 O
and O
809 O
- O
- O
> O
748 O
by O
LC O
- O
IT O
- O
MS O
, O
respectively O
. O

Two O
methods O
were O
used O
to O
evaluate O
a O
number O
of O
validation O
characteristics O
( O
repeatability O
, O
LOD O
, O
calibration O
range O
, O
and O
recovery O
) O
. O

MS O
provided O
a O
high O
selectivity O
and O
sensitivity O
for O
determination O
of O
five O
alkaloids O
in O
positive O
mode O
. O

After O
optimisation O
of O
the O
methods O
, O
separation O
, O
identification O
and O
quantification O
of O
the O
five O
components O
in O
C O
. O
roseus O
were O
comprehensively O
accomplished O
by O
HPLC O
with O
UV O
and O
MS O
detection O
. O

Structures O
and O
reactions O
of O
compounds O
involved O
in O
pink O
discolouration O
of O
onion O
. O

In O
" O
pinking O
" O
of O
onion O
, O
E B
- I
( I
+ I
) I
- I
S I
- I
( I
1 I
- I
propenyl I
) I
- I
l I
- I
cysteine I
sulfoxide I
is O
first O
cleaved O
by O
alliinase O
to O
yield O
colour O
developers O
( O
CDs O
) O
, O
which O
react O
with O
amino B
acids I
, O
such O
as O
valine B
, O
to O
form O
pigment O
precursors O
( O
PPs O
) O
. O

The O
PPs O
react O
with O
naturally O
occurring O
carbonyls B
( O
NOCs O
) O
to O
form O
pigments O
. O

By O
inducing O
a O
PP O
from O
previously O
isolated O
cepathiolanes B
and O
l B
- I
valine I
, O
it O
was O
confirmed O
that O
cepathiolanes B
constitute O
at O
least O
a O
part O
of O
the O
CDs O
. O

From O
the O
PP O
and O
formaldehyde B
as O
a O
NOC O
, O
two O
colourless O
and O
two O
pink O
compounds O
were O
derived O
. O

The O
structure O
of O
one O
of O
the O
colourless O
compounds O
was O
established O
as O
2 B
- I
( I
2 I
- I
( I
1 I
- I
( I
1 I
- I
carboxy I
- I
2 I
- I
methylpropyl I
) I
- I
3 I
, I
4 I
- I
dimethyl I
- I
1H I
- I
pyrrol I
- I
2 I
- I
yl I
) I
methyl I
- I
3 I
, I
4 I
- I
dimethyl I
- I
1H I
- I
pyrrol I
- I
1 I
- I
yl I
) I
- I
3 I
- I
methylbutanoic I
acid I
. O

The O
structures O
of O
the O
other O
colourless O
compound O
and O
the O
pink O
pigments O
were O
predicted O
based O
on O
their O
molecular O
formula O
and O
the O
MS O
( O
n O
) O
spectral O
data O
. O

A O
trimeric O
pigment O
structure O
was O
predicted O
for O
one O
of O
the O
pink O
pigments O
, O
which O
was O
believed O
to O
be O
the O
first O
to O
be O
reported O
in O
the O
literature O
. O

With O
these O
, O
a O
new O
reaction O
scheme O
for O
" O
pinking O
" O
of O
onion O
is O
proposed O
. O

Effect O
of O
floral O
sources O
on O
the O
antioxidant O
, O
antimicrobial O
, O
and O
anti O
- O
inflammatory O
activities O
of O
honeys O
in O
Taiwan O
. O

We O
evaluated O
the O
antioxidant O
, O
antibacterial O
, O
and O
anti O
- O
inflammatory O
activities O
of O
honey O
made O
from O
different O
floral O
sources O
, O
including O
the O
medicinal O
herb O
Bidens O
pilosa O
, O
fruit O
trees O
, O
Dimocarpus O
longan O
, O
Litchi O
chinensis O
, O
and O
Citrus O
maxima O
, O
the O
Taiwanese O
endemic O
plant O
Aglaia O
formosana O
, O
and O
a O
multifloral O
forest O
. O

The O
total O
phenolic B
and O
flavonoid B
contents O
of O
the O
honey O
made O
from O
B O
. O
pilosa O
were O
significantly O
higher O
than O
those O
of O
the O
other O
honeys O
. O

The O
honey O
from O
B O
. O
pilosa O
also O
had O
significantly O
greater O
scavenging O
activities O
for O
1 B
, I
1 I
- I
diphenyl I
- I
2 I
- I
picrylhydrazyl I
( O
DPPH B
. I
) O
and O
hydroxyl B
radical O
, O
and O
substantially O
more O
reducing O
power O
. O

In O
addition O
, O
the O
honey O
from O
B O
. O
pilosa O
showed O
greater O
antibacterial O
activity O
against O
Gram O
- O
positive O
and O
Gram O
- O
negative O
bacteria O
. O

However O
, O
B O
. O
pilosa O
honey O
showed O
little O
inhibitory O
activity O
against O
IL O
- O
8 O
secretion O
, O
whereas O
the O
other O
honeys O
did O
. O

These O
findings O
suggest O
that O
the O
levels O
of O
antioxidant O
and O
antibacterial O
activities O
are O
attributable O
to O
the O
total O
phenolic B
and O
flavonoid B
contents O
of O
honeys O
, O
while O
the O
IL O
- O
8 O
inhibition O
is O
attributable O
to O
components O
other O
than O
phenols B
. O

Fatty B
acid I
profiling O
of O
the O
seed O
oils O
of O
some O
varieties O
of O
field O
peas O
( O
Pisum O
sativum O
) O
by O
RP O
- O
LC O
/ O
ESI O
- O
MS O
/ O
MS O
: O
Towards O
the O
development O
of O
an O
oilseed O
pea O
. O

Reversed O
- O
phase O
liquid O
chromatography O
coupled O
to O
negative O
- O
ion O
electrospray O
tandem O
mass O
spectrometry O
( O
RP O
- O
LC O
/ O
ESI O
- O
MS O
/ O
MS O
) O
was O
used O
to O
study O
the O
fatty B
acid I
profile O
from O
the O
oil O
of O
harvested O
field O
pea O
( O
Pisum O
sativum O
) O
varieties O
as O
part O
of O
a O
research O
project O
to O
develop O
this O
legume O
as O
a O
commercial O
oilseed O
for O
Canada O
. O

The O
seed O
oils O
from O
pea O
samples O
contained O
palmitic B
and I
stearic I
acids I
as O
major O
saturated B
fatty I
acids I
. O

Oleic B
, I
linoleic I
and I
linolenic I
acids I
were O
the O
major O
unsaturated B
fatty I
acids I
found O
. O

Small O
percentages O
of O
other O
long O
chain O
fatty B
acids I
were O
also O
detected O
. O

This O
profile O
suggests O
that O
the O
species O
of O
field O
pea O
investigated O
might O
have O
the O
potential O
to O
be O
used O
as O
raw O
materials O
to O
develop O
a O
future O
new O
oilseed O
crop O
for O
the O
food O
industry O
. O

Fatty B
acid I
extracts O
did O
not O
require O
further O
manipulation O
before O
final O
analysis O
by O
RP O
- O
LC O
/ O
ESI O
- O
MS O
/ O
MS O
, O
indicating O
the O
utility O
and O
relative O
simplicity O
of O
this O
technique O
for O
future O
screening O
studies O
. O

Tert B
- I
butylhydroquinone I
recognition O
of O
molecular O
imprinting O
electrochemical O
sensor O
based O
on O
core O
- O
shell O
nanoparticles O
. O

One O
novel O
electrochemistry O
- O
molecular O
imprinting O
sensor O
for O
determining O
tert B
- I
butylhydroquinone I
( O
TBHQ B
) O
in O
foodstuff O
was O
developed O
. O

TBHQ B
- O
imprinted O
core O
- O
shell O
nanoparticles O
( O
TICSNs O
) O
were O
fabricated O
using O
silica B
nanoparticles O
as O
core O
material O
. O

The O
silica B
nanoparticles O
were O
modified O
with O
( B
3 I
- I
chloropropyl I
) I
trimethoxysilan I
and O
polyethylenimine B
, O
respectively O
, O
and O
polymerised O
to O
form O
the O
TICSNs O
with O
ethylene B
glycol I
dimethacrylate I
as O
cross O
- O
linker O
. O

The O
specific O
core O
- O
shell O
structure O
demonstrates O
extremely O
high O
specific O
surface O
area O
which O
greatly O
increases O
the O
effective O
binding O
sites O
and O
improves O
the O
recognition O
capability O
for O
model O
molecules O
. O

Under O
the O
optimal O
conditions O
, O
the O
linear O
range O
of O
the O
calibration O
curve O
was O
0 O
. O
1 O
- O
50 O
. O
0mgkg O
( O
- O
1 O
) O
with O
the O
detection O
limit O
of O
0 O
. O
27mgkg O
( O
- O
1 O
) O
. O

The O
sensor O
has O
been O
successfully O
applied O
to O
the O
determination O
of O
TBHQ B
in O
food O
samples O
and O
achieved O
high O
sensitivity O
and O
selectivity O
. O

Curcumin B
inhibits O
invasion O
and O
metastasis O
in O
K1 O
papillary O
thyroid O
cancer O
cells O
. O

Curcumin B
, O
the O
active O
constituent O
of O
dietary O
spice O
turmeric O
, O
possesses O
a O
strong O
potential O
for O
cancer O
prevention O
and O
treatment O
. O

However O
, O
there O
is O
no O
study O
to O
address O
the O
effects O
of O
curcumin B
on O
invasion O
and O
metastasis O
of O
thyroid O
cancers O
. O

Thyroid O
cancer O
is O
the O
most O
common O
malignancy O
of O
endocrine O
organs O
, O
and O
its O
incidence O
rates O
have O
steadily O
increased O
over O
recent O
decades O
. O

Although O
most O
indolent O
tumours O
can O
be O
effectively O
managed O
, O
metastatic O
tumours O
at O
distant O
secondary O
sites O
behave O
aggressively O
and O
currently O
there O
is O
no O
effective O
form O
of O
treatment O
. O

Here O
, O
for O
the O
first O
time O
it O
has O
been O
reported O
that O
curcumin B
inhibit O
multiple O
metastasis O
steps O
of O
K1 O
papillary O
thyroid O
cancer O
cells O
. O

Curcumin B
dose O
- O
dependently O
suppressed O
viability O
of O
K1 O
cells O
as O
well O
as O
its O
cell O
attachment O
, O
spreading O
, O
migration O
and O
invasion O
abilities O
. O

Moreover O
, O
curcumin B
could O
also O
down O
- O
regulate O
the O
expression O
and O
activity O
of O
matrix O
metalloproteinase O
- O
9 O
( O
MMP O
- O
9 O
) O
. O

The O
findings O
showed O
that O
curcumin B
might O
be O
an O
effective O
tumouristatic O
agent O
for O
the O
treatment O
of O
aggressive O
papillary O
thyroid O
carcinomas O
. O

The O
potential O
of O
solvent O
- O
minimized O
extraction O
methods O
in O
the O
determination O
of O
polycyclic B
aromatic I
hydrocarbons I
in O
fish O
oils O
. O

Fish O
oil O
has O
been O
identified O
as O
one O
of O
the O
most O
important O
contributors O
to O
the O
level O
of O
Persistent O
Organic O
Pollutants O
( O
POPs O
) O
in O
feed O
products O
. O

The O
determination O
of O
polycyclic B
aromatic I
hydrocarbons I
( O
PAHs B
) O
in O
fish O
oils O
is O
complicated O
due O
to O
the O
fat O
matrix O
, O
which O
affects O
both O
extraction O
efficiency O
and O
analytical O
quality O
. O

This O
article O
reviews O
and O
addresses O
two O
of O
the O
most O
relevant O
analytical O
methods O
for O
determining O
11 O
mutagenic O
and O
carcinogenic O
PAHs B
, O
as O
well O
as O
two O
EPA O
indicator O
PAHs B
in O
fish O
oils O
. O

We O
discuss O
and O
critically O
evaluate O
two O
different O
extraction O
procedures O
, O
such O
as O
ultrasound O
- O
assisted O
solvent O
extraction O
( O
USAE O
) O
and O
ultrasound O
- O
assisted O
emulsification O
- O
microextraction O
( O
USAEME O
) O
. O

Clean O
- O
up O
of O
extracts O
was O
performed O
by O
solid O
- O
phase O
extraction O
using O
C18 O
and O
glass O
columns O
containing O
silica B
gel I
and O
florisil B
for O
USAE O
or O
only O
C18 O
for O
USAEME O
. O

Detection O
of O
the O
selected O
PAHs B
was O
carried O
out O
by O
high O
- O
performance O
liquid O
chromatography O
coupled O
with O
fluorescence O
detection O
for O
determination O
. O

Optimization O
of O
the O
variables O
affecting O
extraction O
by O
the O
selected O
extraction O
techniques O
was O
conducted O
and O
recoveries O
ranged O
from O
70 O
% O
to O
100 O
% O
by O
USAE O
and O
from O
70 O
% O
to O
108 O
% O
by O
USAEME O
with O
estimated O
quantification O
limits O
between O
0 O
. O
020 O
and O
2 O
. O
6 O
mu O
g O
/ O
kg O
were O
achieved O
. O

Moreover O
, O
the O
applicability O
of O
the O
selected O
methods O
was O
evaluated O
by O
the O
analysis O
of O
real O
samples O
. O

To O
our O
knowledge O
, O
this O
is O
the O
first O
time O
that O
USAEME O
has O
been O
applied O
to O
the O
determination O
of O
PAHs B
in O
food O
matrices O
, O
such O
as O
oil O
fish O
samples O
. O

The O
methods O
proposed O
were O
applied O
to O
the O
determination O
of O
the O
target O
PAHs B
in O
fish O
samples O
from O
different O
countries O
, O
and O
it O
was O
found O
that O
the O
low O
PAH B
contamination O
of O
the O
selected O
fish O
oils O
could O
mainly O
occur O
by O
atmospheric O
sources O
. O

Non O
- O
enzymatic O
glycation O
of O
natural O
actomyosin O
( O
NAM O
) O
with O
glucosamine B
in O
a O
liquid O
system O
at O
moderate O
temperatures O
. O

Muscle O
protein O
functionality O
plays O
an O
important O
role O
in O
routine O
applications O
in O
the O
food O
industry O
. O

Glycation O
by O
the O
Maillard O
reaction O
is O
a O
naturally O
occurring O
process O
, O
which O
can O
be O
used O
to O
develop O
new O
ingredients O
with O
improved O
functionality O
using O
a O
food O
grade O
approach O
. O

Actomyosin O
was O
conjugated O
with O
glucose B
or O
glucosamine B
in O
a O
liquid O
system O
at O
moderate O
temperatures O
( O
40 O
degrees O
C O
) O
. O

Sugar B
to O
protein O
conjugation O
was O
evident O
by O
UV O
- O
Vis O
spectral O
changes O
, O
with O
the O
glycation O
level O
determined O
by O
matrix O
assisted O
laser O
desorption O
/ O
ionisation O
mass O
spectrometry O
. O

Parameters O
for O
glycation O
of O
muscle O
protein O
were O
optimised O
using O
the O
bidimensional O
hierarchical O
clustering O
analyses O
. O

The O
best O
glycation O
conditions O
were O
40 O
degrees O
C O
for O
8h O
at O
1 O
: O
3 O
protein O
: O
sugar B
ratio O
. O

Solubility O
and O
emulsifying O
properties O
of O
glycoconjugates O
were O
significantly O
improved O
as O
compared O
to O
non O
- O
glycated O
proteins O
. O

At O
pH O
7 O
glycated O
actomyosin O
was O
on O
average O
31 O
% O
more O
soluble O
compared O
to O
non O
- O
treated O
protein O
. O

Glucosamine B
was O
found O
to O
be O
more O
effective O
for O
glycation O
and O
provided O
higher O
protein O
functionality O
as O
compared O
to O
glucose B
. O

Mechanisms O
of O
saccharide B
protection O
against O
epigallocatechin B
- I
3 I
- I
gallate I
deterioration O
in O
aqueous O
solutions O
. O

We O
investigated O
the O
mechanisms O
of O
the O
protection O
conferred O
by O
sugars B
to O
epigallocatechin B
- I
3 I
- I
gallate I
( O
EGCG B
) O
against O
deterioration O
. O

Additionally O
, O
we O
present O
a O
rapid O
method O
for O
evaluating O
the O
deterioration O
rate O
of O
EGCG B
using O
absorbance O
spectroscopy O
. O

We O
found O
that O
various O
sugars B
provided O
different O
levels O
of O
protection O
at O
identical O
weight O
percentage O
, O
and O
the O
combination O
of O
sugars B
and O
beta O
- O
lactoglobulin O
nanocomplexes O
provided O
greater O
protection O
for O
EGCG B
than O
each O
protective O
component O
alone O
. O

We O
suggest O
that O
the O
concentration O
- O
dependent O
protection O
by O
sugars B
resulted O
from O
a O
combination O
of O
mechanisms O
, O
including O
: O
( O
1 O
) O
reduced O
aqueous O
O2 B
solubility O
, O
( O
2 O
) O
scavenging O
of O
reactive O
oxygen B
species O
, O
and O
( O
3 O
) O
chelation O
of O
traces O
of O
transition B
metal I
ions O
, O
which O
is O
suggested O
to O
be O
the O
main O
reason O
for O
the O
differences O
among O
the O
sugars B
. O

The O
observed O
protective O
effect O
of O
sugars B
can O
be O
easily O
applied O
by O
the O
industry O
in O
proper O
selection O
of O
sugars B
for O
enrichment O
of O
syrups O
or O
concentrates O
with O
EGCG B
and O
for O
the O
preparation O
of O
enriched O
beverages O
and O
foods O
for O
health O
promotion O
. O

Combined O
impact O
of O
Bacillus O
stearothermophilus O
maltogenic O
alpha O
- O
amylase O
and O
surfactants O
on O
starch O
pasting O
and O
gelation O
properties O
. O

In O
baking O
applications O
involving O
starch O
gelatinisation O
, O
surfactants O
such O
as O
sodium B
stearoyl I
lactylate I
( O
SSL B
) O
and O
monoacylglycerols B
( O
MAG B
) O
and O
Bacillus O
stearothermophilus O
maltogenic O
alpha O
- O
amylase O
( O
BStA O
) O
can O
be O
used O
jointly O
. O

We O
here O
showed O
that O
SSL O
but O
not O
MAG O
delays O
wheat O
starch O
hydrolysis O
by O
BStA O
. O

The O
effects O
were O
explained O
in O
terms O
of O
different O
degrees O
of O
adsorption O
of O
the O
surfactants O
on O
the O
starch O
granule O
surface O
, O
retarded O
and O
/ O
or O
decreased O
water O
uptake O
and O
delayed O
availability O
of O
gelatinised O
starch O
for O
hydrolysis O
by O
BStA B
. O

Additional O
experiments O
with O
waxy O
maize O
starch O
led O
to O
the O
conclusion O
that O
SSL O
impacts O
swelling O
power O
and O
carbohydrate B
leaching O
more O
by O
covering O
the O
starch O
granule O
surface O
than O
by O
forming O
amylose O
- O
lipid O
complexes O
. O

SSL O
postponed O
starch O
hydrolysis O
by O
BStA B
, O
but O
this O
did O
not O
influence O
subsequent O
starch O
gelation O
. O

Finally O
, O
when O
adding O
SSL O
or O
MAG O
on O
top O
of O
BStA B
to O
starch O
suspensions O
, O
the O
effect O
of O
the O
surfactants O
on O
gel O
strength O
predominated O
over O
that O
of O
BStA B
. O

Polyphasic O
approach O
to O
the O
identification O
of O
Aspergillus O
section O
Flavi O
isolated O
from O
Brazil O
nuts O
. O

The O
aim O
of O
this O
study O
was O
to O
use O
a O
polyphasic O
approach O
to O
identify O
Aspergillus O
section O
Flavi O
isolated O
from O
Brazil O
nuts O
collected O
in O
the O
Amazon O
forest O
: O
investigation O
of O
macro O
- O
and O
microscopic O
morphology O
, O
production O
of O
extrolites O
, O
heat O
- O
resistance O
fungi O
, O
and O
sequencing O
of O
DNA O
regions O
. O

The O
following O
Aspergillus O
section O
Flavi O
species O
were O
identified O
: O
Aspergillus O
flavus O
( O
75 O
. O
5 O
% O
) O
, O
Aspergillus O
nomius O
( O
22 O
. O
3 O
% O
) O
, O
and O
Aspergillus O
parasiticus O
( O
2 O
. O
2 O
% O
) O
. O

All O
A O
. O
nomius O
and O
A O
. O
parasiticus O
isolates O
produced O
aflatoxins B
B I
and I
G I
, O
but O
not O
cyclopiazonic B
acid I
( O
CPA B
) O
. O

A O
. O
flavus O
isolates O
were O
more O
diversified O
and O
a O
high O
frequency O
of O
mycotoxigenic O
strains O
was O
observed O
. O

The O
polyphasic O
approach O
permitted O
the O
reliable O
identification O
of O
section O
Flavi O
species O
. O

The O
rate O
of O
mycotoxigenic O
strains O
was O
high O
( O
92 O
. O
7 O
% O
) O
and O
mainly O
included O
A O
. O
flavus O
strains O
producing O
elevated O
levels O
of O
aflatoxins B
and O
CPA B
. O

These O
results O
highlight O
the O
possibility O
of O
co O
- O
occurrence O
of O
both O
toxins O
, O
increasing O
their O
potential O
toxic O
effect O
in O
this O
commodity O
. O

Flavour O
profiles O
of O
three O
novel O
acidic O
varieties O
of O
muskmelon O
( O
Cucumis O
melo O
L O
. O
) O
. O

Novel O
acidic O
varieties O
of O
muskmelon O
( O
Cucumis O
melo O
L O
. O
) O
are O
emerging O
onto O
the O
UK O
market O
. O

These O
melons O
contain O
almost O
twice O
the O
amount O
of O
citric B
acid I
compared O
to O
standard O
melons O
and O
are O
described O
as O
' O
zesty O
and O
fresh O
' O
. O

This O
study O
compared O
the O
flavour O
components O
of O
three O
acidic O
varieties O
with O
a O
standard O
Galia O
- O
type O
melon O
. O

The O
volatile O
and O
semivolatile O
compounds O
were O
extracted O
, O
using O
dynamic O
headspace O
extraction O
( O
DHE O
) O
or O
solid O
- O
phase O
microextraction O
( O
SPME O
) O
and O
solid O
phase O
extraction O
( O
SPE O
) O
, O
respectively O
, O
followed O
by O
gas O
chromatography O
- O
mass O
spectrometry O
( O
GC O
- O
MS O
) O
and O
gas O
chromatography O
- O
olfactometry O
( O
GC O
- O
O O
) O
. O

More O
than O
50 O
volatile O
and O
50 O
semivolatile O
compounds O
were O
identified O
in O
the O
headspace O
and O
the O
SPE O
extracts O
, O
respectively O
. O

GC O
- O
O O
revealed O
15 O
odour O
- O
active O
components O
in O
the O
headspace O
, O
with O
esters B
being O
consistently O
higher O
in O
the O
acidic O
variety O
. O

This O
study O
showed O
quantitative O
and O
qualitative O
differences O
among O
all O
four O
varieties O
and O
key O
differences O
between O
acidic O
varieties O
and O
standard O
melons O
. O

Ostreol B
A I
: O
A O
new O
cytotoxic O
compound O
isolated O
from O
the O
epiphytic O
dinoflagellate O
Ostreopsis O
cf O
. O
ovata O
from O
the O
coastal O
waters O
of O
Jeju O
Island O
, O
Korea O
. O

Ostreol B
A I
was O
isolated O
from O
cultures O
of O
the O
epiphytic O
dinoflagellate O
Ostreopsis O
cf O
. O
ovata O
from O
the O
coastal O
waters O
of O
Jeju O
Island O
, O
Korea O
. O

The O
compound O
, O
a O
non O
- O
palytoxin B
derivative O
, O
has O
a O
polyhydroxy B
chain O
ending O
with O
the O
primary B
amino I
group O
and O
contains O
an O
amide B
bond O
, O
along O
with O
two O
tetrahydropyran B
rings O
in O
the O
chain O
. O

Its O
chemical O
structure O
was O
elucidated O
by O
nuclear O
magnetic O
resonance O
( O
NMR O
) O
spectroscopy O
methods O
and O
confirmed O
by O
mass O
analysis O
. O

The O
compound O
exhibited O
significant O
cytotoxicity O
in O
the O
brine O
shrimp O
lethality O
test O
at O
a O
concentration O
of O
0 O
. O
9 O
mu O
g O
/ O
mL O
. O

Arylsulfonamide B
pyrimidines I
as O
VLA O
- O
4 O
antagonists O
. O

A O
series O
of O
( B
S I
) I
- I
2 I
- I
( I
2 I
- I
( I
diethylamino I
) I
- I
5 I
- I
( I
N I
- I
alkyl I
- I
N I
- I
sulfonamido I
) I
pyrimidin I
- I
4 I
- I
ylamino I
) I
- I
3 I
- I
( I
4 I
- I
( I
carbamoyloxy I
) I
phenyl I
) I
propanoic I
acid I
is O
discovered O
as O
orally O
available O
VLA O
- O
4 O
antagonists O
. O

Representative O
compounds O
11b O
and O
11p O
showed O
efficacy O
in O
multiple O
in O
vivo O
animal O
models O
. O

The O
in O
vitro O
selectivity O
of O
11p O
is O
also O
described O
. O

The O
fibroblast O
as O
a O
therapeutic O
target O
in O
rheumatoid O
arthritis O
. O

Significant O
advances O
have O
been O
made O
in O
the O
last O
5 O
years O
that O
have O
finally O
allowed O
investigators O
to O
start O
targeting O
stromal O
cells O
such O
as O
fibroblasts O
in O
inflammatory O
disease O
. O

Rheumatoid O
arthritis O
is O
a O
prototype O
inflammatory O
disease O
, O
in O
which O
fibroblasts O
maintain O
the O
persistence O
of O
inflammation O
in O
the O
joint O
underpinned O
by O
a O
unique O
pathological O
phenotype O
driven O
by O
multiple O
epigenetic O
modifications O
. O

The O
step O
changes O
that O
are O
enabling O
the O
development O
of O
such O
therapies O
are O
an O
improved O
understanding O
of O
the O
mechanisms O
by O
which O
fibroblasts O
mediate O
persistence O
and O
the O
discovery O
of O
new O
markers O
that O
identify O
discrete O
functional O
subsets O
of O
fibroblast O
cells O
that O
have O
potential O
as O
disease O
- O
specific O
therapeutic O
targets O
. O

Melittin O
peptide O
kills O
Trypanosoma O
cruzi O
parasites O
by O
inducing O
different O
cell O
death O
pathways O
. O

Antimicrobial O
peptides O
( O
AMPs O
) O
are O
components O
of O
the O
innate O
immune O
response O
that O
represent O
desirable O
alternatives O
to O
conventional O
pharmaceuticals O
, O
as O
they O
have O
a O
fast O
mode O
of O
action O
, O
a O
low O
likelihood O
of O
resistance O
development O
and O
can O
act O
in O
conjunction O
with O
existing O
drug O
regimens O
. O

AMPs B
exhibit O
strong O
inhibitory O
activity O
against O
both O
Gram O
- O
positive O
and O
Gram O
- O
negative O
bacteria O
, O
fungi O
, O
viruses O
, O
metazoans O
and O
other O
parasites O
, O
such O
as O
the O
protozoan O
Leishmania O
. O

Melittin O
is O
a O
naturally O
occurring O
AMP O
, O
which O
comprises O
40 O
- O
50 O
% O
of O
the O
dry O
weight O
of O
Apis O
mellifera O
venom O
. O

Our O
group O
has O
recently O
shown O
that O
crude O
A O
. O
mellifera O
venom O
is O
lethal O
to O
Trypanosoma O
cruzi O
, O
the O
Chagas O
disease O
etiologic O
agent O
, O
and O
generates O
a O
variety O
of O
cell O
death O
phenotypes O
among O
treated O
parasites O
. O

Here O
, O
we O
demonstrate O
that O
the O
melittin O
affected O
all O
of O
T O
. O
cruzi O
developmental O
forms O
, O
including O
the O
intracellular O
amastigotes O
. O

The O
ultrastructural O
changes O
induced O
by O
melittin B
suggested O
the O
occurrence O
of O
different O
programmed O
cell O
death O
pathways O
, O
as O
was O
observed O
in O
A O
. O
mellifera O
- O
treated O
parasites O
. O

Autophagic O
cell O
death O
appeared O
to O
be O
the O
main O
death O
mechanism O
in O
epimastigotes O
. O

In O
contrast O
, O
melittin B
- O
treated O
trypomastigotes O
appeared O
to O
be O
dying O
via O
an O
apoptotic O
mechanism O
. O

Our O
findings O
confirm O
the O
great O
potential O
of O
AMPs O
, O
including O
melittin B
, O
as O
a O
potential O
source O
of O
new O
drugs O
for O
the O
treatment O
of O
neglected O
diseases O
, O
such O
as O
Chagas O
disease O
. O

TRP O
and O
ASIC O
channels O
mediate O
the O
antinociceptive O
effect O
of O
citronellyl B
acetate I
. O

Background O
Citronellyl B
acetate I
( O
CAT B
) O
, O
a O
monoterpene B
product O
of O
the O
secondary O
metabolism O
of O
plants O
, O
has O
been O
shown O
in O
the O
literature O
to O
possess O
several O
different O
biological O
activities O
. O

However O
, O
no O
antinociceptive O
abilities O
have O
yet O
been O
discussed O
. O

Here O
, O
we O
used O
acute O
pain O
animal O
models O
to O
describe O
the O
antinociceptive O
action O
of O
CAT O
. O

Methods O
The O
acetic B
acid I
- O
induced O
writhing O
test O
and O
the O
paw O
- O
licking O
test O
, O
in O
which O
paw O
licking O
was O
induced O
by O
glutamate B
and O
formalin B
, O
were O
performed O
to O
evaluate O
the O
antinociceptive O
action O
of O
CAT O
and O
to O
determine O
the O
involvement O
of O
PKC O
, O
PKA O
, O
TRPV1 O
, O
TRPA1 O
, O
TRPM8 O
and O
ASIC O
in O
its O
antinociceptive O
mechanism O
. O

To O
do O
so O
, O
we O
induced O
paw O
- O
linking O
using O
agonists O
. O

Results O
CAT O
was O
administered O
intragastrically O
( O
25 O
, O
50 O
, O
75 O
, O
100 O
and O
200mg O
/ O
kg O
) O
, O
and O
the O
two O
higher O
doses O
caused O
antinociceptive O
effects O
in O
the O
acetic B
acid I
model O
; O
the O
highest O
dose O
reduced O
pain O
for O
4h O
after O
it O
was O
administered O
( O
200mg O
/ O
kg O
) O
. O

In O
the O
formalin B
test O
, O
two O
doses O
of O
CAT O
promoted O
antinociception O
in O
both O
the O
early O
and O
later O
phases O
of O
the O
test O
. O

The O
glutamate B
test O
showed O
that O
its O
receptors O
are O
involved O
in O
the O
antinociceptive O
mechanism O
of O
CAT O
. O

Pretreatment O
with O
CAT O
did O
not O
alter O
locomotor O
activity O
or O
motor O
coordination O
. O

In O
an O
investigation O
into O
the O
participation O
of O
TRP O
channels O
and O
ASICs O
in O
CAT O
' O
s O
antinociceptive O
mechanism O
, O
we O
used O
capsaicin B
( O
2 O
. O
2 O
mu O
g O
/ O
paw O
) O
, O
cinnamaldehyde B
( O
10mmol O
/ O
paw O
) O
, O
menthol B
( O
1 O
. O
2mmol O
/ O
paw O
) O
and O
acidified O
saline O
( O
2 O
% O
acetic B
acid I
, O
pH O
1 O
. O
98 O
) O
. O

The O
results O
showed O
that O
TRPV1 O
, O
TRPM8 O
and O
ASIC O
, O
but O
not O
TRPA1 O
, O
are O
involved O
in O
the O
antinociceptive O
mechanism O
. O

Finally O
, O
the O
involvement O
of O
PKC O
and O
PKA O
was O
also O
studied O
, O
and O
we O
showed O
that O
both O
play O
a O
role O
in O
the O
antinociceptive O
mechanism O
of O
CAT O
. O

Conclusion O
The O
results O
of O
this O
work O
contribute O
information O
regarding O
the O
antinociceptive O
properties O
of O
CAT O
on O
acute O
pain O
and O
show O
that O
, O
at O
least O
in O
part O
, O
TRPV1 O
, O
TRPM8 O
, O
ASIC O
, O
glutamate B
receptors O
, O
PKC O
and O
PKA O
participate O
in O
CAT O
' O
s O
antinociceptive O
mechanism O
. O

Discovering O
and O
targeting O
the O
basic O
mechanism O
of O
neurodegeneration O
: O
The O
role O
of O
peptides O
from O
the O
C B
- O
terminus O
of O
acetylcholinesterase O
: O
Non O
- O
hydrolytic O
effects O
of O
ache O
: O
The O
actions O
of O
peptides O
derived O
from O
the O
C B
- O
terminal O
and O
their O
relevance O
to O
neurodegeneration O
. O

Acetylcholinesterase O
( O
AChE O
) O
is O
now O
well O
- O
established O
widely O
as O
a O
signalling O
molecule O
with O
non O
- O
hydrolytic O
functions O
including O
trophic O
activity O
in O
a O
diverse O
variety O
of O
situations O
in O
both O
neural O
and O
non O
- O
neural O
tissues O
. O

We O
have O
focussed O
on O
the O
observation O
that O
AChE O
, O
operating O
as O
a O
trophic O
agent O
independent O
of O
its O
enzymatic O
action O
, O
does O
indeed O
trigger O
calcium B
entry O
into O
neurons O
. O

It O
is O
possible O
that O
AChE O
has O
a O
dual O
non O
- O
classical O
action O
that O
ranges O
along O
a O
trophic O
- O
toxic O
axis O
, O
depending O
on O
amount O
, O
duration O
of O
availability O
and O
, O
most O
significantly O
, O
age O
. O

The O
neurodegenerative O
diseases O
could O
therefore O
be O
viewed O
as O
aberrant O
activation O
of O
developmental O
mechanisms O
with O
' O
non O
- O
cholinergic O
' O
AChE O
as O
a O
, O
perhaps O
the O
, O
pivotal O
molecule O
. O

We O
have O
identified O
two O
peptides O
that O
could O
be O
cleaved O
from O
the O
C B
- O
terminus O
of O
T O
- O
AChE O
, O
one O
( O
T14 O
) O
, O
within O
the O
other O
( O
T30 O
) O
, O
and O
which O
have O
a O
strong O
sequence O
homology O
to O
the O
comparable O
region O
of O
beta O
- O
amyloid O
whilst O
the O
inert O
residue O
within O
the O
T30 O
sequence O
( O
' O
T15 O
' O
) O
acts O
as O
a O
control O
, O
and O
is O
without O
effect O
. O

We O
have O
subsequently O
been O
able O
to O
ascribe O
the O
trophic O
- O
toxic O
actions O
of O
the O
both O
T14 O
and O
T30 O
peptides O
to O
the O
modulation O
of O
calcium B
influx O
via O
an O
allosteric O
site O
on O
the O
alpha O
- O
7 O
nicotinic O
acetylcholine B
receptor O
( O
alpha O
7 O
- O
nAChR O
) O
. O

If O
the O
scenario O
described O
here O
is O
indeed O
the O
primary O
mechanism O
of O
neurodegeneration O
, O
then O
interception O
of O
the O
actions O
of O
the O
' O
non O
- O
cholinergic O
' O
AChE O
- O
peptides O
T14 O
and O
T30 O
at O
the O
alpha O
7 O
- O
nAChR O
, O
would O
be O
a O
promising O
novel O
therapy O
for O
arresting O
and O
stabilising O
cell O
loss O
in O
Alzheimer O
' O
s O
disease O
, O
whereas O
detection O
of O
the O
peptides O
ideally O
in O
the O
blood O
, O
could O
provide O
a O
sensitive O
surrogate O
marker O
. O

If O
the O
marker O
was O
sensitive O
enough O
to O
be O
detected O
pre O
- O
symptomatically O
in O
a O
routine O
blood O
test O
, O
then O
the O
medication O
for O
arresting O
further O
cell O
loss O
could O
be O
initiated O
at O
that O
time O
, O
and O
the O
symptoms O
would O
never O
appear O
. O

This O
dual O
approach O
of O
identifying O
the O
marker O
and O
then O
intercepting O
its O
further O
action O
, O
could O
thus O
amount O
to O
an O
effective O
treatment O
for O
Alzheimer O
' O
s O
and O
other O
neurodegenerative O
diseases O
. O

Poly B
( I
N I
- I
isopropylacrylamide I
- I
co I
- I
hydroxyethylacrylami I
) I
thermosensitive O
microspheres O
: O
The O
size O
of O
microgels O
dictates O
the O
pulsatile O
release O
mechanism O
. O

Poly B
( I
N I
- I
isopropylacrylamide I
- I
co I
- I
N I
- I
hydroxyethylacrylami I
) I
( O
poly B
( I
NIPAAm I
- I
co I
- I
HEAAm I
) I
) O
was O
prepared O
as O
a O
new O
thermosensitive O
copolymer O
possessing O
a O
sharp O
phase O
transition O
around O
the O
human O
body O
temperature O
. O

The O
effect O
of O
the O
copolymer O
concentration O
on O
the O
lower O
critical O
solution O
temperature O
( O
LCST O
) O
was O
determined O
under O
physiological O
conditions O
by O
cloud O
point O
( O
CP O
) O
and O
differential O
scanning O
calorimetric O
( O
DSC O
) O
methods O
. O

Then O
, O
thermosensitive O
microspheres O
were O
prepared O
from O
preformed O
copolymers O
by O
chemical O
cross O
- O
linking O
of O
hydroxyl B
groups O
with O
glutaraldehyde B
at O
a O
temperature O
situated O
slightly O
below O
LCST O
of O
the O
copolymer O
solution O
. O

The O
volume O
phase O
transition O
temperature O
( O
VPTT O
) O
of O
corresponding O
cross O
- O
linked O
microspheres O
was O
determined O
from O
swelling O
degree O
- O
temperature O
curve O
. O

The O
microspheres O
were O
loaded O
with O
model O
drug O
indomethacin B
by O
the O
solvent O
evaporation O
method O
. O

The O
DSC O
analysis O
proved O
that O
the O
drug O
is O
molecularly O
dispersed O
in O
the O
polymer O
network O
. O

Finally O
, O
the O
influence O
of O
the O
microsphere O
size O
on O
drug O
release O
was O
investigated O
. O

It O
was O
established O
that O
microspheres O
with O
the O
diameter O
ranging O
between O
5 O
and O
60 O
mu O
m O
release O
the O
drug O
with O
almost O
the O
same O
rate O
below O
( O
in O
the O
swollen O
state O
) O
and O
above O
the O
VPTT B
( O
in O
the O
collapsed O
state O
) O
. O

On O
the O
contrary O
, O
microspheres O
with O
the O
diameter O
ranging O
between O
125 O
and O
220 O
mu O
m O
release O
a O
significantly O
higher O
amount O
of O
indomethacin B
below O
than O
above O
the O
VPTT B
. O

This O
different O
behavior O
is O
enough O
to O
assure O
a O
pulsatile O
release O
mechanism O
when O
the O
temperature O
changes O
cyclically O
below O
and O
above O
the O
VPTT O
. O

However O
, O
both O
small O
and O
large O
microspheres O
release O
a O
large O
amount O
of O
the O
drug O
during O
the O
collapsing O
process O
. O

Carboxymethyl B
starch O
and O
lecithin B
complex O
as O
matrix O
for O
targeted O
drug O
delivery O
: O
I O
. O

Monolithic O
Mesalamine B
forms O
for O
colon O
delivery O
. O

For O
drugs O
expected O
to O
act O
locally O
in O
the O
colon O
, O
and O
for O
successful O
treatment O
, O
a O
delivery O
device O
is O
necessary O
, O
in O
order O
to O
limit O
the O
systemic O
absorption O
which O
decreases O
effectiveness O
and O
causes O
important O
side O
effects O
. O

Various O
delayed O
release O
systems O
are O
currently O
commercialized O
; O
most O
of O
them O
based O
on O
pH O
- O
dependent O
release O
which O
is O
sensitive O
to O
gastrointestinal O
pH O
variation O
. O

This O
study O
proposes O
a O
novel O
excipient O
for O
colon O
delivery O
. O

This O
new O
preparation O
consists O
in O
the O
complexation O
between O
carboxymethyl B
starch O
( O
CMS O
) O
and O
Lecithin O
( O
L O
) O
. O

As O
opposed O
to O
existing O
excipients O
, O
the O
new O
complex O
is O
pH O
- O
independent O
, O
inexpensive O
, O
and O
easy O
to O
manufacture O
and O
allows O
a O
high O
drug O
loading O
. O

FTIR O
, O
X O
- O
ray O
, O
and O
SEM O
structural O
analysis O
all O
support O
the O
hypothesis O
of O
the O
formation O
of O
a O
complex O
. O

By O
minor O
variation O
of O
the O
excipient O
content O
within O
the O
tablet O
, O
it O
is O
possible O
to O
modulate O
the O
release O
time O
and O
delivery O
at O
specific O
sites O
of O
the O
gastrointestinal O
tract O
. O

This O
study O
opens O
the O
door O
to O
a O
new O
pH O
- O
independent O
delivery O
system O
for O
mesalamine B
targeted O
administration O
. O

Our O
novel O
formulation O
fits O
well O
with O
the O
posology O
of O
mesalamine B
, O
used O
in O
the O
treatment O
of O
Inflammatory O
Bowel O
Disease O
( O
IBD O
) O
, O
which O
requires O
repeated O
administrations O
( O
1g O
orally O
four O
times O
a O
day O
) O
to O
maintain O
a O
good O
quality O
of O
life O
. O

Crystallization O
of O
poly B
( I
ethylene I
oxide I
) I
with O
acetaminophen B
- O
A O
study O
on O
solubility O
, O
spherulitic O
growth O
, O
and O
morphology O
. O

A O
simple O
, O
sensitive O
, O
efficient O
, O
and O
novel O
method O
analyzing O
the O
number O
of O
spherulitic O
nuclei O
was O
proposed O
to O
estimate O
the O
solubility O
of O
a O
model O
drug O
acetaminophen B
( O
APAP B
) O
in O
poly B
( I
ethylene I
oxide I
) I
( O
PEO B
) O
. O

At O
high O
crystallization O
temperature O
( O
323K O
) O
, O
10 O
% O
APAP B
- I
PEO I
had O
the O
same O
low O
number O
of O
spherulitic O
nuclei O
as O
pure O
PEO B
, O
indicating O
that O
APAP B
and O
PEO B
were O
fully O
miscible O
. O

At O
low O
crystallization O
temperature O
( O
303K O
) O
, O
the O
number O
of O
nuclei O
for O
10 O
% O
APAP B
- I
PEO I
was O
significantly O
higher O
, O
suggesting O
that O
APAP B
was O
oversaturated O
and O
therefore O
recrystallized O
and O
acted O
as O
a O
nucleating O
agent O
. O

Based O
on O
the O
results O
obtained O
, O
the O
solubility O
of O
APAP B
in O
PEO B
is O
possibly O
between O
the O
concentration O
of O
0 O
. O
1 O
% O
and O
1 O
% O
at O
303K O
. O

The O
spherulitic O
growth O
rate O
G O
of O
PEO B
was O
found O
to O
decrease O
with O
increasing O
APAP B
concentration O
, O
suggesting O
that O
APAP B
is O
most O
likely O
functioning O
as O
a O
chemical O
defect O
and O
is O
either O
rejected O
from O
or O
included O
in O
the O
PEO B
crystals O
during O
chain O
folding O
. O

APAP B
could O
possibly O
locate O
in O
the O
inter O
- O
spherulitic O
, O
inter O
- O
fibrillar O
, O
inter O
- O
lamellar O
, O
or O
intra O
- O
lamellar O
regions O
of O
PEO B
. O

At O
323K O
, O
the O
morphology O
of O
10 O
% O
APAP B
- I
PEO I
is O
more O
dendritic O
than O
spherulitic O
with O
large O
unfilled O
space O
in O
between O
dendrites O
and O
spherulites O
, O
which O
is O
a O
sign O
of O
one O
or O
the O
combination O
of O
the O
four O
modes O
of O
segregation O
. O

An O
extensive O
spherulitic O
nucleation O
and O
growth O
kinetics O
study O
using O
the O
classical O
theoretical O
relationships O
, O
for O
example O
, O
the O
Hoffman O
- O
Lauritzen O
( O
HL O
) O
and O
Avrami O
theories O
, O
was O
conducted O
. O

Both O
microscopic O
and O
differential O
scanning O
calorimetric O
( O
DSC O
) O
analysis O
yielded O
similar O
values O
for O
the O
nucleation O
constant O
Kg O
as O
well O
as O
the O
fold O
surface O
free O
energy O
sigma O
e O
and O
work O
of O
chain O
folding O
q O
. O

The O
values O
of O
sigma O
e O
and O
q O
increased O
with O
APAP B
concentration O
, O
indicating O
that O
the O
chain O
folding O
of O
PEO B
was O
hindered O
by O
APAP B
. O

Hyaluronic O
acid O
/ O
chitosan O
multilayer O
coatings O
on O
neuronal O
implants O
for O
localized O
delivery O
of O
siRNA O
nanoplexes O
. O

Binding O
, O
stabilizing O
and O
promoting O
cellular O
uptake O
of O
siRNA O
are O
all O
critical O
efforts O
in O
creating O
matrices O
for O
the O
localized O
delivery O
of O
siRNA O
molecules O
to O
target O
cells O
. O

In O
this O
study O
, O
we O
describe O
the O
generation O
of O
chitosan O
imidazole B
/ O
siRNA O
nanoplexes O
( O
NPs O
) O
embedded O
in O
nano O
scope O
polyelectrolyte O
multilayers O
( O
PEMs O
) O
composed O
of O
hyaluronic O
acid O
and O
chitosan O
for O
sustained O
and O
localized O
drug O
delivery O
. O

Regular O
PEM O
build O
- O
up O
, O
successful O
integration O
of O
NPs O
and O
controlled O
release O
under O
physiological O
conditions O
were O
shown O
. O

Biological O
efficacy O
was O
evaluated O
in O
neuronal O
cell O
culture O
concerning O
cell O
adhesion O
, O
viability O
, O
NPs O
uptake O
and O
gene O
silencing O
. O

The O
additionally O
shown O
biological O
functionalization O
of O
neuronal O
implants O
possesses O
potential O
for O
future O
applications O
in O
the O
field O
of O
regenerative O
medicine O
and O
treatment O
of O
spinal O
cord O
injuries O
. O

Medicinal O
plants O
of O
genus O
Curculigo O
: O
Traditional O
uses O
and O
a O
phytochemical O
and O
ethnopharmacological O
review O
. O

ETHNOPHARMACOLOGICAL O
RELEVANCE O
: O
In O
the O
genus O
Curculigo O
, O
Curculigo O
orchioides O
Gaertn O
, O
Curculigo O
capitulata O
( O
Lour O
) O
O O
. O

Ktze O
and O
Curculigo O
pilosa O
( O
Schumach O
. O
& O
Thonn O
. O
) O
Engl O
are O
often O
used O
in O
traditional O
medicine O
. O

Curculigo O
orchioides O
is O
used O
for O
the O
treatment O
of O
impotence O
, O
limb O
limpness O
, O
arthritis O
of O
the O
lumbar O
and O
knee O
joints O
, O
and O
watery O
diarrhea O
in O
traditional O
Chinese O
medicine O
, O
and O
also O
used O
as O
a O
potent O
immunomodulator O
and O
aphrodisiac O
in O
the O
Ayurvedic O
medical O
system O
. O

Curculigo O
capitulata O
is O
used O
for O
the O
treatment O
of O
consumptive O
cough O
, O
kidney O
asthenia O
, O
impotence O
and O
spermatorrhea O
, O
hemorrhoids O
, O
asthma O
, O
jaundice O
, O
diarrhea O
, O
colic O
and O
gonorrhea O
in O
traditional O
Chinese O
and O
India O
medicine O
, O
and O
to O
treat O
urinary O
tract O
infection O
, O
acute O
renal O
pelvis O
and O
nephritis O
, O
nephritis O
- O
edema O
, O
cystitis O
, O
nephrolithiasis O
, O
hypertension O
and O
rheumatic O
arthritis O
in O
traditional O
Dai O
medicine O
. O

Curculigo O
pilosa O
are O
applied O
to O
treat O
gastrointestinal O
and O
heart O
diseases O
in O
Africa O
. O

AIM O
OF O
THE O
REVIEW O
: O
This O
review O
aims O
to O
exhibit O
up O
- O
to O
- O
date O
and O
comprehensive O
information O
about O
traditional O
uses O
, O
phytochemistry O
, O
pharmacology O
and O
toxicology O
of O
medicinal O
plants O
in O
the O
genus O
Curculigo O
, O
and O
has O
an O
insight O
into O
the O
opportunities O
for O
the O
future O
research O
and O
development O
of O
Curculigo O
plant O
. O

METHODS O
: O
A O
bibliographic O
investigation O
was O
performed O
by O
analyzing O
the O
information O
available O
on O
Curculigo O
plant O
from O
worldwide O
accepted O
scientific O
databases O
( O
Pubmed O
, O
Scopus O
and O
Web O
of O
Science O
, O
SciFinder O
, O
Google O
Scholar O
, O
Yahoo O
) O
. O

Furthermore O
, O
information O
also O
was O
obtained O
from O
some O
local O
and O
foreign O
books O
on O
ethnobotany O
and O
ethnomedicines O
. O

RESULTS O
: O
Curculigo O
orchioides O
, O
Curculigo O
capitulata O
and O
Curculigo O
pilosa O
have O
been O
used O
as O
traditional O
medicine O
to O
treat O
kinds O
of O
diseases O
such O
as O
impotence O
, O
limb O
limpness O
, O
gastrointestinal O
and O
heart O
diseases O
, O
etc O
. O

Phytochemical O
investigation O
of O
eight O
species O
of O
the O
genus O
Curculigo O
has O
resulted O
in O
identification O
of O
more O
than O
110 O
compounds O
. O

The O
content O
of O
curculigoside B
is O
used O
as O
an O
indicator O
to O
evaluate O
the O
quality O
of O
rhizome O
of O
Curculigo O
orchioides O
. O

The O
medicinal O
plants O
have O
showed O
a O
wide O
spectrum O
pharmacological O
activities O
, O
including O
adaptive O
, O
immunostimulatory O
, O
taste O
- O
modifying O
and O
sweet O
- O
tasting O
, O
antioxidant O
, O
mast O
cell O
stabilization O
, O
antihistaminic O
and O
antiasthmatic O
, O
hepatoprotective O
and O
neuroprotective O
activity O
. O

Toxicological O
test O
indicated O
that O
Curculigo O
orchioides O
at O
the O
dose O
of O
120g O
/ O
kg O
after O
administrating O
rats O
for O
180 O
days O
may O
cause O
injury O
of O
liver O
and O
kidney O
. O

CONCLUSION O
: O
The O
medicinal O
plants O
of O
genus O
Curculigo O
have O
emerged O
as O
a O
good O
source O
of O
the O
traditional O
medicines O
. O

Some O
uses O
of O
these O
plants O
in O
the O
traditional O
medicines O
have O
been O
validated O
by O
pharmacological O
investigation O
. O

However O
, O
the O
mechanism O
of O
their O
actions O
should O
be O
further O
elucidated O
; O
the O
particular O
constituent O
responsible O
for O
toxicity O
should O
be O
isolated O
and O
identified O
, O
and O
the O
target O
tissue O
and O
mechanism O
of O
toxic O
ingredients O
also O
deserve O
to O
be O
further O
investigated O
; O
more O
reference O
substances O
should O
be O
prepared O
, O
and O
sophisticated O
analytical O
technologies O
should O
be O
developed O
to O
comprehensively O
assess O
the O
quality O
of O
Curculigo O
herbs O
. O

These O
investigations O
will O
be O
helpful O
for O
further O
utilization O
of O
the O
plants O
of O
genus O
Curculigo O
. O

Anti O
- O
inflammatory O
activity O
of O
hexane B
extracts O
from O
bones O
and O
internal O
organs O
of O
Anguilla O
japonica O
suppresses O
cyclooxygenase O
- O
2 O
- O
dependent O
prostaglandin B
D2 I
generation O
in O
mast O
cells O
and O
anaphylaxis O
in O
mice O
. O

The O
purpose O
of O
this O
study O
is O
to O
investigate O
the O
effects O
of O
n B
- I
hexane I
extracts O
from O
bones O
and O
internal O
organs O
of O
Japanese O
eel O
, O
Anguilla O
japonica O
( O
HEE O
) O
, O
on O
cyclooxygenase O
- O
2 O
( O
COX O
- O
2 O
) O
- O
dependent O
prostaglandin B
D2 I
( O
PGD2 B
) O
generation O
in O
stem O
cell O
factor O
( O
SCF O
) O
, O
IL O
- O
10 O
, O
plus O
LPS O
- O
induced O
mouse O
bone O
marrow O
- O
derived O
mast O
cells O
( O
BMMCs O
) O
and O
on O
passive O
cutaneous O
anaphylaxis O
( O
PCA O
) O
in O
mice O
. O

HEE O
suppressed O
SCF O
/ O
IL O
- O
10 O
/ O
LPS O
- O
induced O
PGD2 B
generation O
, O
and O
concomitantly O
reduced O
COX O
- O
2 O
protein O
expression O
dose O
- O
dependently O
. O

To O
understand O
the O
mechanistic O
basis O
for O
the O
inhibition O
of O
PGD2 B
generation O
by O
HEE O
, O
we O
examined O
the O
effects O
of O
HEE O
on O
upstream O
signaling O
pathways O
essential O
for O
COX O
- O
2 O
induction O
. O

HEE O
was O
found O
to O
inhibit O
the O
translocation O
of O
nuclear O
factor O
- O
kappa O
B O
( O
NF O
- O
kappa O
B O
) O
p65 O
subunit O
to O
the O
nucleus O
and O
its O
DNA O
- O
binding O
ability O
through O
the O
inhibition O
of O
TAK1 O
, O
IKK O
and O
I O
kappa O
B O
phosphorylation O
. O

Furthermore O
, O
HEE O
also O
attenuated O
mitogen O
- O
activated O
protein O
kinase O
( O
MAPK O
) O
- O
mediated O
regulation O
of O
DNA O
binding O
of O
activator O
protein O
- O
1 O
( O
AP O
- O
1 O
) O
. O

Moreover O
, O
oral O
administration O
of O
HEE O
inhibited O
anti O
- O
dinitrophenyl B
( O
DNP B
) O
IgE O
- O
induced O
PCA O
in O
a O
dose O
dependent O
manner O
. O

Taken O
together O
, O
the O
present O
study O
provides O
new O
insights O
into O
the O
anti O
- O
inflammatory O
activity O
of O
HEE O
, O
which O
could O
be O
a O
promising O
candidate O
to O
be O
used O
for O
an O
inflammatory O
therapy O
. O

Vinblastine B
- O
induced O
apoptosis O
of O
melanoma O
cells O
is O
mediated O
by O
Ras O
homologous O
A O
protein O
( O
Rho O
A O
) O
via O
mitochondrial O
and O
non O
- O
mitochondrial O
- O
dependent O
mechanisms O
. O

Despite O
the O
availability O
of O
melanoma O
treatment O
at O
the O
primary O
site O
, O
the O
recurrence O
of O
local O
melanoma O
can O
metastasize O
to O
any O
distant O
organ O
. O

Currently O
, O
the O
available O
therapies O
for O
the O
treatment O
of O
metastatic O
melanoma O
are O
of O
limited O
benefit O
. O

Thus O
, O
the O
functional O
analysis O
of O
conventional O
therapies O
may O
help O
to O
improve O
their O
efficiency O
in O
the O
treatment O
of O
metastatic O
melanoma O
. O

In O
the O
present O
study O
, O
the O
exposure O
of O
melanoma O
cells O
to O
vinblastine B
was O
found O
to O
trigger O
apoptosis O
as O
evidenced O
by O
the O
loss O
of O
mitochondrial O
membrane O
potential O
, O
the O
release O
of O
both O
cytochrome O
c O
and O
apoptosis O
inducing O
factor O
, O
activation O
of O
caspase O
- O
9 O
and O
3 O
, O
and O
cleavage O
of O
Poly B
( I
ADP I
- I
ribose I
) I
- O
Polymerase O
. O

Also O
, O
vinblastine B
enhances O
the O
phosphorylation O
of O
Ras O
homologous O
protein O
A O
, O
the O
accumulation O
of O
reactive O
oxygen B
species O
, O
the O
release O
of O
intracellular O
Ca B
( I
2 I
+ I
) I
, O
as O
well O
as O
the O
activation O
of O
apoptosis O
signal O
- O
regulating O
kinase O
1 O
, O
c O
- O
jun O
- O
N B
- O
terminal O
kinase O
, O
p38 O
, O
inhibitor O
of O
kappaB O
alpha O
( O
I O
kappa O
B O
alpha O
) O
kinase O
, O
and O
inositol B
requiring O
enzyme O
1 O
alpha O
. O

In O
addition O
, O
vinblastine B
induces O
the O
DNA O
- O
binding O
activities O
of O
the O
transcription O
factor O
NF O
- O
kappa O
B O
, O
HSF1 O
, O
AP O
- O
1 O
, O
and O
ATF O
- O
2 O
, O
together O
with O
the O
expression O
of O
HSP70 O
and O
Bax O
proteins O
. O

Moreover O
, O
inhibitory O
experiments O
addressed O
a O
central O
role O
for O
Rho O
A O
in O
the O
regulation O
of O
vinblastine B
- O
induced O
apoptosis O
of O
melanoma O
cells O
via O
mitochondrial O
and O
non O
- O
mitochondrial O
- O
dependent O
mechanisms O
. O

In O
conclusion O
, O
the O
present O
study O
addresses O
for O
the O
first O
time O
a O
central O
role O
for O
Rho O
A O
in O
the O
modulation O
of O
vinblastine B
- O
induced O
apoptosis O
of O
melanoma O
cells O
and O
thereby O
provides O
an O
insight O
into O
the O
molecular O
action O
of O
vinblastine B
in O
melanoma O
treatment O
. O

Gene O
expression O
profiling O
of O
three O
different O
stressors O
in O
the O
water O
flea O
Daphnia O
magna O
. O

Microarrays O
are O
an O
ideal O
tool O
to O
screen O
for O
differences O
in O
gene O
expression O
of O
thousands O
of O
genes O
simultaneously O
. O

However O
, O
often O
commercial O
arrays O
are O
not O
available O
. O

In O
this O
study O
, O
we O
performed O
microarray O
analyses O
to O
evaluate O
patterns O
of O
gene O
transcription O
following O
exposure O
to O
two O
natural O
and O
one O
anthropogenic O
stressor O
. O

cDNA O
microarrays O
compiled O
of O
three O
life O
stage O
specific O
and O
three O
stressor O
- O
specific O
EST O
libraries O
, O
yielding O
1734 O
different O
EST O
sequences O
, O
were O
used O
. O

We O
exposed O
juveniles O
of O
the O
water O
flea O
Daphnia O
magna O
for O
48 O
, O
96 O
and O
144 O
h O
to O
three O
stressors O
known O
to O
exert O
strong O
selection O
in O
natural O
populations O
of O
this O
species O
i O
. O
e O
. O
a O
sublethal O
concentration O
of O
the O
pesticide O
carbaryl B
, O
infective O
spores O
of O
the O
endoparasite O
Pasteuria O
ramosa O
, O
and O
fish O
predation O
risk O
mimicked O
by O
exposure O
to O
fish O
kairomones O
. O

A O
total O
of O
148 O
gene O
fragments O
were O
differentially O
expressed O
compared O
to O
the O
control O
. O

Based O
on O
a O
PCA O
, O
the O
exposure O
treatments O
were O
separated O
into O
two O
main O
groups O
based O
on O
the O
extent O
of O
the O
transcriptional O
response O
: O
a O
low O
and O
a O
high O
( O
144 O
h O
of O
fish O
or O
carbaryl B
exposure O
and O
96 O
h O
of O
parasite O
exposure O
) O
stress O
group O
. O

Firstly O
, O
we O
observed O
a O
general O
stress O
- O
related O
transcriptional O
expression O
profile O
independent O
of O
the O
treatment O
characterized O
by O
repression O
of O
transcripts O
involved O
in O
transcription O
, O
translation O
, O
signal O
transduction O
and O
energy O
metabolism O
. O

Secondly O
, O
we O
observed O
treatment O
- O
specific O
responses O
including O
signs O
of O
migration O
to O
deeper O
water O
layers O
in O
response O
to O
fish O
predation O
, O
structural O
challenge O
of O
the O
cuticle O
in O
response O
to O
carbaryl B
exposure O
, O
and O
disturbance O
of O
the O
ATP B
production O
in O
parasite O
exposure O
. O

A O
third O
important O
conclusion O
is O
that O
transcription O
expression O
patterns O
exhibit O
stress O
- O
specific O
changes O
over O
time O
. O

Parasite O
exposure O
shows O
the O
most O
differentially O
expressed O
gene O
fragments O
after O
96 O
h O
. O

The O
peak O
of O
differentially O
expressed O
transcripts O
came O
only O
after O
144 O
h O
of O
fish O
exposure O
, O
while O
carbaryl B
exposure O
induced O
a O
more O
stable O
number O
of O
differently O
expressed O
gene O
fragments O
over O
time O
. O

Structure O
- O
Property O
Investigations O
of O
Substituted O
Triarylamines B
and O
Their O
Applications O
as O
Fluorescent O
pH O
Sensors O
. O

Fourteen O
triphenylamine B
derivatives O
functionalized O
with O
fluorophenyl B
, O
methoxyphenyl B
, O
and O
pyridinyl B
groups O
as O
respective O
donors O
and O
acceptors O
were O
synthesized O
and O
characterized O
. O

Their O
photophysical O
properties O
were O
systematically O
investigated O
in O
various O
solvents O
with O
different O
polarities O
. O

The O
solvent O
- O
dependent O
Stokes O
shifts O
of O
these O
compounds O
were O
observed O
and O
analyzed O
by O
the O
Lippert O
- O
Mataga O
equation O
. O

The O
synthesized O
compounds O
, O
especially O
tris B
( I
4 I
- I
( I
pyridin I
- I
4 I
- I
yl I
) I
phenyl I
) I
amine I
, O
presented O
pH O
- O
dependent O
absorptions O
and O
emissions O
, O
indicating O
that O
these O
compounds O
might O
be O
used O
as O
pH O
sensors O
. O

Twisted O
Signatures O
of O
GC O
- O
Biased O
Gene O
Conversion O
Embedded O
in O
an O
Evolutionary O
Stable O
Karyotype O
. O

The O
genomes O
of O
many O
vertebrates O
show O
a O
characteristic O
heterogeneous O
distribution O
of O
GC O
content O
, O
the O
so O
- O
called O
GC O
isochore O
structure O
. O

The O
origin O
of O
isochores O
has O
been O
explained O
via O
the O
mechanism O
of O
GC O
- O
biased O
gene O
conversion O
( O
gBGC O
) O
. O

However O
, O
although O
the O
isochore O
structure O
is O
declining O
in O
many O
mammalian O
genomes O
, O
the O
heterogeneity O
in O
GC O
content O
is O
being O
reinforced O
in O
the O
avian O
genome O
. O

Despite O
this O
discrepancy O
, O
which O
remains O
unexplained O
, O
examinations O
of O
individual O
substitution O
frequencies O
in O
mammals O
and O
birds O
are O
both O
consistent O
with O
the O
gBGC O
model O
of O
isochore O
evolution O
. O

On O
the O
other O
hand O
, O
a O
negative O
correlation O
between O
substitution O
and O
recombination O
rate O
found O
in O
the O
chicken O
genome O
is O
inconsistent O
with O
the O
gBGC O
model O
. O

It O
should O
therefore O
be O
important O
to O
consider O
along O
with O
gBGC O
other O
consequences O
of O
recombination O
on O
the O
origin O
and O
fate O
of O
mutations O
, O
as O
well O
as O
to O
account O
for O
relationships O
between O
recombination O
rate O
and O
other O
genomic O
features O
. O

We O
therefore O
developed O
an O
analytical O
model O
to O
describe O
the O
substitution O
patterns O
found O
in O
the O
chicken O
genome O
, O
and O
further O
investigated O
the O
relationships O
between O
substitution O
patterns O
and O
several O
genomic O
features O
in O
a O
rigorous O
statistical O
framework O
. O

Our O
analysis O
indicates O
that O
GC O
content O
itself O
, O
either O
directly O
or O
indirectly O
via O
interrelations O
to O
other O
genomic O
features O
, O
has O
an O
impact O
on O
the O
substitution O
pattern O
. O

Further O
, O
we O
suggest O
that O
this O
phenomenon O
is O
particularly O
visible O
in O
avian O
genomes O
due O
to O
their O
unusually O
low O
rate O
of O
chromosomal O
evolution O
. O

Because O
of O
this O
, O
interrelations O
between O
GC O
content O
and O
other O
genomic O
features O
are O
being O
reinforced O
, O
and O
are O
as O
such O
more O
pronounced O
in O
avian O
genomes O
as O
compared O
with O
other O
vertebrate O
genomes O
with O
a O
less O
stable O
karyotype O
. O

Combinatorial O
Treatment O
of O
Tart O
Cherry O
Extract O
and O
Essential O
Fatty B
Acids I
Reduces O
Cognitive O
Impairments O
and O
Inflammation O
in O
the O
mu O
- O
p75 O
Saporin O
- O
Induced O
Mouse O
Model O
of O
Alzheimer O
' O
s O
Disease O
. O

Abstract O
Alzheimer O
' O
s O
disease O
( O
AD O
) O
is O
a O
progressive O
neurodegenerative O
disorder O
that O
affects O
more O
than O
five O
million O
Americans O
and O
is O
characterized O
by O
a O
progressive O
loss O
of O
memory O
, O
loss O
of O
cholinergic O
neurons O
in O
the O
basal O
forebrain O
, O
formation O
of O
amyloid O
plaques O
and O
neurofibrillary O
tangles O
, O
and O
an O
increase O
in O
oxidative O
stress O
. O

Recent O
studies O
indicate O
that O
dietary O
supplements O
of O
antioxidants O
and O
omega B
- I
3 I
and I
omega I
- I
6 I
fatty I
acids I
may O
reduce O
the O
cognitive O
deficits O
in O
AD O
patients O
. O

The O
current O
study O
tested O
a O
combinatorial O
treatment O
of O
antioxidants O
from O
tart O
cherry O
extract O
and O
essential O
fatty B
acids I
from O
Nordic O
fish O
and O
emu O
oils O
for O
reducing O
cognitive O
deficits O
in O
the O
mu O
- O
p75 O
saporin O
( O
SAP O
) O
- O
induced O
mouse O
model O
of O
AD O
. O

Mice O
were O
given O
daily O
gavage O
treatments O
of O
Cerise O
( O
( O
R O
) O
) O
Total O
- O
Body O
- O
Rhythm O
( O
TM O
) O
( O
TBR O
; O
containing O
tart O
cherry O
extract O
, O
Nordic O
fish O
oil O
, O
and O
refined O
emu O
oil O
) O
or O
vehicle O
( O
methylcellulose O
) O
for O
2 O
weeks O
before O
intracerebroventricu O
injections O
of O
the O
cholinergic O
toxin O
, O
mu O
- O
p75 O
SAP O
, O
or O
phosphate B
- O
buffered O
saline O
. O

The O
TBR B
treatments O
continued O
for O
an O
additional O
17 O
days O
, O
when O
the O
mice O
were O
tested O
on O
a O
battery O
of O
cognitive O
and O
motor O
tasks O
. O

Results O
indicate O
that O
TBR B
decreased O
the O
SAP O
- O
induced O
cognitive O
deficits O
assessed O
by O
the O
object O
- O
recognition O
, O
place O
- O
recognition O
, O
and O
Morris O
- O
water O
- O
maze O
tasks O
. O

Histological O
examination O
of O
the O
brain O
tissue O
indicated O
that O
TBR B
protected O
against O
SAP O
- O
induced O
inflammatory O
response O
and O
loss O
of O
cholinergic O
neurons O
in O
the O
area O
around O
the O
medial O
septum O
. O

These O
findings O
indicate O
that O
TBR B
has O
the O
potential O
to O
serve O
as O
an O
adjunctive O
treatment O
which O
may O
help O
reduce O
the O
severity O
of O
cognitive O
deficits O
in O
disorders O
involving O
cholinergic O
deficits O
, O
such O
as O
AD O
. O

Zhizhu O
decoction O
promotes O
gastric O
emptying O
and O
protects O
the O
gastric O
mucosa O
. O

Abstract O
The O
aim O
of O
this O
study O
was O
to O
evaluate O
the O
effects O
of O
the O
Zhizhu O
decoction O
on O
gastric O
emptying O
and O
gastric O
mucosal O
protection O
. O

The O
Zhizhu O
decoction O
is O
composed O
of O
Aurantii O
fructus O
and O
Atractylodes O
macrocephala O
Rhizoma O
. O

Results O
showed O
that O
oral O
administration O
of O
the O
Zhizhu O
decoction O
accelerated O
gastric O
emptying O
in O
mouse O
and O
protected O
gastric O
mucosa O
from O
ethanol B
- O
induced O
ulcers O
in O
rat O
. O

Our O
investigations O
demonstrated O
that O
the O
Zhizhu O
decoction O
accelerated O
gastric O
emptying O
, O
at O
least O
in O
part O
, O
by O
activating O
the O
muscarinic O
and O
5 O
- O
HT3 O
receptors O
. O

The O
gastroprotective O
effect O
is O
involved O
in O
its O
antioxidant O
effects O
and O
increased O
vascular O
endothelial O
growth O
factor O
expression O
. O

The O
immunomodulation O
effect O
of O
aronia O
extract O
lacks O
association O
with O
its O
antioxidant O
anthocyanins B
. O

Abstract O
Polyphenols B
comprise O
a O
diverse O
group O
of O
molecules O
with O
antioxidative O
and O
anti O
- O
inflammatory O
activities O
. O

To O
compare O
the O
antioxidative O
and O
anti O
- O
inflammatory O
capacity O
of O
Aronia O
melanocarpa O
berries O
( O
chokeberries O
) O
, O
recognized O
for O
their O
high O
content O
of O
anthocyanins B
, O
a O
noncytotoxic O
isolation O
method O
was O
developed O
to O
obtain O
high O
- O
purity O
anthocyanins B
in O
the O
extract O
. O

The O
antioxidative O
activity O
of O
the O
extract O
, O
the O
anthocyanin B
- O
rich O
fraction O
( O
AF O
) O
was O
determined O
by O
1 B
, I
1 I
- I
diphenyl I
- I
2 I
- I
picrylhydrazyl I
radical O
and O
ferric B
- O
reducing O
ability O
of O
plasma O
along O
with O
resveratrol B
as O
a O
reference O
. O

The O
immunomodulation O
properties O
were O
assessed O
in O
lipopolysaccharide O
( O
LPS O
) O
- O
stimulated O
human O
monocytes O
mono O
mac O
6 O
. O

The O
isolated O
AF O
, O
containing O
six O
different O
anthocyanins B
, O
exhibited O
a O
stronger O
antioxidative O
capacity O
compared O
to O
resveratrol B
. O

Resveratrol B
enhanced O
tumor O
necrosis O
factor O
- O
alpha O
and O
reduced O
interleukin O
- O
10 O
( O
IL O
- O
10 O
) O
production O
by O
LPS O
, O
whereas O
AF O
only O
had O
a O
slight O
effect O
in O
reducing O
IL O
- O
10 O
. O

These O
results O
demonstrated O
that O
there O
was O
no O
major O
relationship O
between O
the O
antioxidative O
effect O
and O
immunomodulation O
capacities O
of O
AF O
and O
resveratrol B
. O

The O
immunomodulatory O
activity O
of O
the O
extract O
is O
associated O
with O
bioactive O
compounds O
in O
Aronia O
other O
than O
its O
anthocyanins B
. O

Novel O
sulfonamide B
compounds O
for O
inhibition O
of O
metastatic O
tumor O
growth O
( O
WO2012021963 O
) O
. O

A O
series O
of O
novel O
ureido B
- I
sulfonamides I
was O
prepared O
by O
reaction O
of O
aminobenzenesulfonam B
with O
alkyl B
/ I
aryl I
isocyanate I
. O

These O
compounds O
are O
claimed O
for O
use O
as O
therapeutic O
agents O
of O
metastatic O
tumors O
, O
which O
are O
poorly O
responsive O
to O
classical O
chemotherapies O
and O
constitute O
a O
conceptually O
novel O
approach O
for O
cancer O
treatment O
. O

High O
glucose B
, O
insulin O
and O
free O
fatty B
acid I
concentrations O
synergistically O
enhance O
perilipin O
3 O
expression O
and O
lipid O
accumulation O
in O
macrophages O
. O

OBJECTIVE O
: O
Perilipin O
( O
PLIN O
) O
3 O
, O
an O
intracellular O
lipid O
droplet O
( O
LD O
) O
- O
associated O
protein O
, O
is O
implicated O
in O
foam O
cell O
formation O
. O

Since O
metabolic O
derangements O
found O
in O
metabolic O
syndrome O
, O
such O
as O
high O
serum O
levels O
of O
glucose B
, O
insulin O
and O
free O
fatty B
acids I
( O
FFAs O
) O
, O
are O
major O
risk O
factors O
promoting O
atherosclerosis O
, O
we O
investigated O
whether O
PLIN3 O
expression O
is O
affected O
by O
glucose B
, O
insulin O
and O
oleic B
acid I
( O
OA O
) O
using O
RAW264 O
. O
7 O
cells O
. O

METHODS O
: O
Real O
- O
time O
PCR O
and O
Western O
blotting O
were O
performed O
to O
detect O
PLIN3 O
or O
PLIN2 O
expression O
. O

Oil O
- O
red O
O O
staining O
and O
Lipid O
Analysis O
were O
employed O
to O
measure O
cellular O
content O
of O
triacylglycerides B
( O
TAG B
) O
and O
cholesterol B
. O

RESULTS O
: O
PLIN3 O
mRNA O
was O
stimulated O
by O
high O
glucose B
or O
insulin O
concentrations O
individually O
, O
but O
not O
by O
OA O
. O

A O
combination O
of O
any O
two O
factors O
did O
not O
enhance O
PLIN3 O
expression O
any O
more O
than O
that O
evoked O
by O
glucose B
alone O
at O
24h O
. O

Interestingly O
, O
however O
, O
simultaneous O
addition O
of O
all O
three O
factors O
synergistically O
enhanced O
the O
PLIN3 O
expression O
. O

This O
synergistic O
effect O
was O
not O
apparent O
for O
PLIN2 O
mRNA O
expression O
. O

Inhibitors O
of O
Src O
family O
tyrosine B
kinase O
and O
/ O
or O
phosphatidylinositol B
3 O
- O
kinase O
, O
both O
of O
which O
are O
activated O
by O
insulin O
and O
FFA O
signaling O
, O
partially O
suppressed O
PLIN3 O
expression O
induced O
by O
the O
combination O
of O
the O
three O
factors O
. O

While O
simultaneous O
addition O
of O
glucose B
, O
insulin O
and O
OA O
remarkably O
increased O
the O
cellular O
content O
of O
TAG B
and O
cholesterol B
, O
knocking O
- O
down O
of O
PLIN3 O
predominantly O
reduced O
TAG B
content O
. O

CONCLUSIONS O
: O
These O
results O
indicate O
that O
PLIN3 O
expression O
is O
synergistically O
stimulated O
by O
high O
glucose B
, O
insulin O
and O
FFA O
concentrations O
, O
in O
parallel O
with O
TAG B
accumulation O
in O
macrophages O
. O

This O
finding O
raises O
new O
evidence O
of O
PLIN3 O
involvement O
in O
conversion O
of O
macrophages O
into O
foam O
cells O
. O

( B
1 I
) I
H I
NMR O
- O
based O
metabonomic O
analysis O
of O
the O
serum O
and O
urine O
of O
rats O
following O
subchronic O
exposure O
to O
dichlorvos B
, O
deltamethrin B
, O
or O
a O
combination O
of O
these O
two O
pesticides O
. O

Metabonomic O
analysis O
, O
clinical O
chemical O
analysis O
and O
histopathology O
were O
used O
to O
investigate O
the O
toxic O
effects O
of O
subchronic O
exposure O
to O
dichlorvos B
, O
deltamethrin B
, O
and O
a O
combination O
of O
these O
two O
pesticides O
, O
in O
rats O
. O

Weight O
loss O
, O
hind O
limb O
weakness O
and O
histopathological O
changes O
in O
kidney O
tissue O
were O
only O
observed O
in O
rats O
exposed O
to O
high O
doses O
of O
deltamethrin B
, O
or O
a O
combination O
of O
deltamethrin B
and O
dichlorvos B
. O

Urinary O
metabonomic O
analysis O
indicated O
that O
exposure O
to O
a O
mixture O
of O
dichlorvos B
and O
deltamethrin B
was O
followed O
by O
increases O
in O
urinary O
lactate B
, O
dimethylamine B
, O
N B
- O
glycoprotein O
( O
NAC B
) O
and O
glycine B
similar O
to O
those O
observed O
in O
rats O
treated O
with O
either O
dichlorvos B
or O
deltamethrin B
alone O
. O

Serum O
metabonomic O
analysis O
suggests O
that O
dichlorvos B
induced O
an O
increase O
in O
lactate B
and O
alanine B
and O
a O
decrease O
in O
dimethylglycine B
( O
DMG B
) O
, O
NAC B
and O
very O
low O
- O
and O
low O
- O
density O
lipoprotein O
( O
VLDL O
/ O
LDL O
) O
. O

High O
levels O
of O
lactate B
and O
low O
levels O
of O
NAC B
and O
VLDL O
/ O
LDL O
were O
observed O
in O
the O
deltamethrin B
treatment O
group O
. O

Treating O
rats O
with O
a O
mixture O
of O
dichlorvos B
and O
deltamethrin B
caused O
an O
increase O
in O
serum O
lactate B
, O
trimethylamine B
- I
N I
- I
oxide I
( O
TMAO B
) O
, O
choline B
and O
alanine B
, O
with O
the O
highest O
levels O
of O
these O
metabolites O
observed O
in O
those O
that O
received O
the O
highest O
dose O
. O

Exposure O
to O
a O
mixture O
of O
dichlorvos B
and O
deltamethrin B
also O
resulted O
in O
a O
decrease O
in O
serum O
acetone B
, O
DMG B
, O
NAC B
, O
and O
VLDL O
/ O
LDL O
. O

Changes O
in O
serum O
TMAO B
, O
alanine B
, O
choline B
and O
acetone B
in O
this O
treatment O
group O
were O
higher O
than O
in O
rats O
treated O
with O
either O
dichlorvos B
or O
deltamethrin B
. O

These O
results O
suggest O
that O
exposing O
rats O
to O
subchronic O
doses O
of O
dichlorvos B
, O
deltamethrin B
, O
or O
a O
combination O
of O
these O
pesticides O
, O
disrupted O
the O
energy O
metabolism O
of O
the O
liver O
and O
reduced O
kidney O
function O
. O

Identification O
of O
active O
compounds O
from O
Caesalpinia O
sappan O
L O
. O
extracts O
suppressing O
IL O
- O
6 O
production O
in O
RAW O
264 O
. O
7 O
cells O
by O
PLS O
. O

ETHNOPHARMACOLOGICAL O
RELEVANCE O
: O
Caesalpinia O
sappan O
L O
. O

is O
distributed O
in O
Southeast O
Asia O
and O
also O
used O
as O
herbal O
medicine O
for O
the O
treatment O
of O
various O
diseases O
such O
as O
burning O
sensations O
, O
leprosy O
, O
dysentery O
, O
osteoarthritis O
and O
rheumatoid O
arthritis O
( O
RA O
) O
. O

The O
overproduction O
of O
IL O
- O
6 O
plays O
an O
important O
role O
in O
the O
prognosis O
of O
RA O
, O
but O
the O
active O
compounds O
from O
the O
extracts O
of O
Caesalpinia O
sappan O
L O
. O
suppressing O
IL O
- O
6 O
production O
remain O
unknown O
. O

AIMS O
OF O
THE O
STUDY O
: O
Identifying O
the O
main O
active O
compounds O
of O
Caesalpinia O
sappan O
L O
. O
extracts O
inhibiting O
the O
IL O
- O
6 O
production O
in O
LPS O
- O
stimulated O
RAW O
264 O
. O
7 O
cells O
by O
partial O
least O
squares O
( O
PLS O
) O
. O

MATERIALS O
AND O
METHODS O
: O
Sixty O
- O
four O
samples O
with O
different O
proportions O
of O
compounds O
were O
prepared O
from O
Caesalpinia O
sappan O
L O
. O
by O
supercritical O
CO2 B
fluid O
extraction O
( O
SCFE O
) O
and O
refluxing O
. O

Each O
of O
64 O
samples O
was O
applied O
to O
RAW O
264 O
. O
7 O
cells O
with O
LPS O
to O
evaluate O
whether O
IL O
- O
6 O
production O
by O
LPS O
is O
affected O
by O
addition O
of O
each O
sample O
. O

The O
IL O
- O
6 O
production O
in O
medium O
was O
determined O
by O
ELISA O
and O
the O
inhibitory O
activity O
of O
each O
sample O
was O
analyzed O
. O

In O
addition O
, O
the O
fingerprints O
of O
these O
64 O
samples O
were O
also O
established O
by O
ultra O
- O
performance O
liquid O
chromatography O
electrospray O
ionization O
tandem O
mass O
spectrometry O
( O
UPLC O
- O
MS O
) O
. O

We O
used O
the O
PLS O
, O
a O
simplified O
method O
, O
to O
evaluate O
the O
results O
from O
IL O
- O
6 O
production O
and O
fingerprints O
. O

RESULTS O
: O
Each O
of O
64 O
samples O
markedly O
suppressed O
LPS O
- O
induced O
IL O
- O
6 O
production O
in O
RAW O
cells O
. O

The O
fingerprints O
by O
UPLC O
- O
MS O
clearly O
revealed O
variations O
among O
64 O
samples O
produced O
in O
different O
extract O
conditions O
. O

The O
PLS O
analysis O
with O
IL O
- O
6 O
production O
and O
fingerprints O
by O
UPLC O
- O
MS O
suggested O
that O
the O
peaks O
71 O
, O
93 O
, O
150 O
, O
157 O
, O
168 O
have O
more O
influence O
on O
the O
inhibitory O
activity O
of O
Caesalpinia O
sappan O
L O
. O
extracts O
. O

The O
peaks O
71 O
, O
93 O
, O
150 O
are O
likely O
representing O
sappanone B
A I
, O
protosappanin B
E I
and O
neoprotosappanin B
, O
respectively O
. O

The O
peaks O
157 O
and O
168 O
are O
still O
at O
large O
. O

CONCLUSION O
: O
This O
is O
the O
first O
report O
that O
sappanone B
A I
, O
protosappanin B
E I
, O
neoprotosappanin B
and O
two O
unidentified O
compounds O
can O
be O
considered O
as O
possible O
active O
compounds O
that O
might O
inhibit O
IL O
- O
6 O
production O
. O

Further O
studies O
are O
needed O
to O
confirm O
the O
effectiveness O
of O
these O
five O
compounds O
on O
IL O
- O
6 O
production O
and O
possible O
mechanism O
. O

Commonly O
used O
metal O
and O
crystalline O
salts O
in O
South O
African O
traditional O
medicine O
. O

ETHNOPHARMACOLOGICAL O
RELEVANCE O
: O
Traditional O
medicines O
in O
the O
form O
of O
plants O
, O
animals O
and O
/ O
or O
minerals O
are O
used O
by O
millions O
of O
South O
Africans O
. O

There O
is O
currently O
no O
data O
regarding O
the O
commonly O
used O
mineral O
elements O
thus O
the O
potential O
benefits O
or O
hazards O
of O
such O
products O
remain O
unclear O
. O

MATERIALS O
AND O
METHODS O
: O
Metal O
and O
crystalline O
salts O
were O
purchased O
from O
a O
rural O
market O
( O
Nongoma O
, O
Zululand O
, O
South O
Africa O
) O
. O

Information O
regarding O
the O
colloquial O
name O
, O
price O
and O
weight O
was O
recorded O
. O

Energy O
dispersive O
X O
- O
ray O
spectroscopy O
( O
EDX O
) O
was O
used O
to O
quantatively O
determine O
the O
unknown O
salts O
. O

RESULTS O
: O
Six O
widely O
available O
salts O
were O
analyzed O
. O

Ndonya O
, O
as O
it O
is O
colloquially O
known O
, O
refers O
to O
two O
products O
which O
look O
identical O
to O
the O
untrained O
eye O
- O
one O
is O
dyed O
table O
salt O
and O
the O
other O
is O
hexavalent B
chromium I
. O

A O
further O
product O
used O
medicinally O
, O
although O
not O
widely O
available O
, O
was O
identified O
as O
iron B
chromite I
ore O
. O

CONCLUSIONS O
: O
The O
array O
of O
substances O
documented O
, O
ranging O
from O
benign O
to O
carcinogenic O
, O
stresses O
the O
importance O
of O
documenting O
components O
used O
in O
traditional O
medicine O
and O
confirms O
the O
necessity O
to O
regulate O
South O
Africa O
traditional O
medicine O
. O

Healthcare O
workers O
should O
be O
aware O
of O
the O
complexities O
of O
using O
such O
metal O
salt O
. O

Real O
- O
time O
imaging O
and O
kinetics O
measurements O
of O
focused O
ultrasound O
- O
induced O
extravasation O
in O
skeletal O
muscle O
using O
SPECT O
/ O
CT O
. O

Drugs O
need O
to O
overcome O
several O
biological O
barriers O
such O
as O
the O
endothelium O
and O
cellular O
membranes O
in O
order O
to O
reach O
their O
target O
. O

Promising O
new O
therapeutics O
, O
many O
of O
which O
are O
charged O
and O
macromolecular O
, O
are O
not O
able O
to O
passively O
extravasate O
, O
let O
alone O
cross O
cell O
membranes O
, O
and O
stay O
mainly O
in O
the O
blood O
pool O
upon O
intravenous O
injection O
until O
clearance O
. O

Using O
focused O
ultrasound O
( O
fUS O
) O
in O
combination O
with O
circulating O
microbubbles O
( O
MBs O
) O
leads O
to O
temporary O
localized O
tissue O
permeabilization O
allowing O
extravasation O
of O
( O
macro O
) O
molecules O
from O
the O
vascular O
system O
. O

Thus O
, O
fUS O
is O
a O
promising O
approach O
for O
localized O
drug O
delivery O
. O

However O
, O
little O
is O
known O
about O
the O
permeabilization O
kinetics O
in O
skeletal O
muscle O
. O

In O
this O
study O
, O
we O
used O
single O
photon O
emission O
computed O
tomography O
( O
SPECT O
) O
to O
characterize O
the O
kinetics O
of O
extravasation O
of O
( B
111 I
) I
In I
- O
labeled O
bovine O
serum O
albumin O
( O
BSA O
) O
, O
a O
model O
macromolecular O
drug O
, O
in O
muscle O
treated O
with O
fUS O
and O
MBs O
. O

The O
same O
fUS O
protocol O
was O
applied O
to O
6 O
groups O
of O
mice O
with O
different O
times O
, O
increment O
t O
, O
between O
fUS O
application O
and O
BSA O
injection O
( O
increment O
t O
= O
- O
10 O
, O
2 O
. O
5 O
, O
10 O
, O
30 O
, O
60 O
, O
90min O
) O
followed O
by O
SPECT O
imaging O
. O

For O
increment O
t O
< O
= O
30min O
we O
observed O
an O
exponential O
accumulation O
of O
activity O
in O
an O
area O
of O
the O
treated O
muscle O
which O
extended O
to O
a O
volume O
larger O
than O
the O
fUS O
pattern O
with O
highest O
accumulation O
for O
short O
waiting O
times O
increment O
t O
. O

The O
extent O
of O
extravasation O
decreased O
exponentially O
with O
increasing O
increment O
t O
, O
with O
a O
calculated O
half O
- O
life O
of O
ca O
. O

21min O
, O
defining O
the O
time O
window O
of O
extravasation O
. O

The O
same O
treatment O
without O
MBs O
did O
not O
induce O
extravasation O
of O
BSA O
thus O
supporting O
MBs O
and O
drug O
co O
- O
injection O
strategies O
. O

These O
results O
provide O
essential O
information O
for O
the O
development O
of O
fUS O
based O
strategies O
for O
localized O
drug O
delivery O
. O

Comparative O
study O
on O
transcriptional O
activity O
of O
17 O
parabens B
mediated O
by O
estrogen B
receptor O
alpha O
and O
beta O
and O
androgen B
receptor O
. O

The O
structure O
- O
activity O
relationships O
of O
parabens B
which O
are O
widely O
used O
as O
preservatives O
for O
transcriptional O
activities O
mediated O
by O
human O
estrogen B
receptor O
alpha O
( O
hER O
alpha O
) O
, O
hER O
beta O
and O
androgen B
receptor O
( O
hAR O
) O
were O
investigated O
. O

Fourteen O
of O
17 O
parabens B
exhibited O
hER O
alpha O
and O
/ O
or O
hER O
beta O
agonistic O
activity O
at O
concentrations O
of O
> O
= O
1 O
x O
10 O
( O
- O
5 O
) O
M O
, O
whereas O
none O
of O
the O
17 O
parabens B
showed O
AR O
agonistic O
or O
antagonistic O
activity O
. O

Among O
12 O
parabens B
with O
linear O
alkyl O
chains O
ranging O
in O
length O
from O
C1 O
to O
C12 O
, O
heptylparaben B
( O
C7 O
) O
and O
pentylparaben B
( O
C5 O
) O
showed O
the O
most O
potent O
ER O
alpha O
and O
ER O
beta O
agonistic O
activity O
in O
the O
order O
of O
10 O
( O
- O
7 O
) O
M O
and O
10 O
( O
- O
8 O
) O
M O
, O
respectively O
, O
and O
the O
activities O
decreased O
in O
a O
stepwise O
manner O
as O
the O
alkyl O
chain O
was O
shortened O
to O
C1 O
or O
lengthened O
to O
C12 O
. O

Most O
parabens B
showing O
estrogenic O
activity O
exhibited O
ER O
beta O
- O
agonistic O
activity O
at O
lower O
concentrations O
than O
those O
inducing O
ER O
alpha O
- O
agonistic O
activity O
. O

The O
estrogenic O
activity O
of O
butylparaben B
was O
markedly O
decreased O
by O
incubation O
with O
rat O
liver O
microsomes O
, O
and O
the O
decrease O
of O
activity O
was O
blocked O
by O
a O
carboxylesterase O
inhibitor O
. O

These O
results O
indicate O
that O
parabens B
are O
selective O
agonists O
for O
ER O
beta O
over O
ER O
alpha O
; O
their O
interactions O
with O
ER O
alpha O
/ O
beta O
are O
dependent O
on O
the O
size O
and O
bulkiness O
of O
the O
alkyl O
groups O
; O
and O
they O
are O
metabolized O
by O
carboxylesterases O
, O
leading O
to O
attenuation O
of O
their O
estrogenic O
activity O
. O

DICO B
, O
a O
novel O
nonaromatic O
B O
- O
ring O
flavonoid B
, O
induces O
G2 O
/ O
M O
cell O
cycle O
arrest O
and O
apoptosis O
in O
human O
hepatoma O
cells O
. O

DICO B
was O
a O
novel O
nonaromatic O
B O
- O
ring O
flavonoid B
obtained O
from O
Macrothelypteris O
torresiana O
. O

In O
the O
present O
work O
, O
we O
investigated O
the O
antitumor O
activity O
and O
the O
antineoplastic O
mechanism O
of O
DICO B
. O

Our O
study O
showed O
that O
DICO B
inhibited O
the O
growth O
of O
HepG2 O
cells O
in O
dose O
and O
time O
- O
dependent O
manners O
. O

As O
well O
as O
DICO B
induced O
G2 O
/ O
M O
cell O
cycle O
arrest O
and O
apoptosis O
via O
a O
ROS O
- O
mediated O
mitochondrial O
pathway O
. O

Western O
blot O
assay O
demonstrated O
that O
DICO B
decreased O
Bcl O
- O
2 O
level O
and O
induced O
Bax O
translocation O
to O
cause O
cytochrome O
c O
release O
. O

Subsequently O
, O
caspase O
- O
9 O
and O
caspase O
- O
3 O
were O
activated O
. O

Meanwhile O
, O
the O
alterations O
of O
cyclin O
A O
and O
B1 O
, O
p O
- O
CDK1 O
and O
p O
- O
cdc25c O
levels O
were O
also O
observed O
in O
response O
to O
DICO B
treatment O
. O

Taken O
together O
, O
DICO B
displayed O
a O
significant O
antitumor O
effect O
through O
G2 O
/ O
M O
cell O
cycle O
arrest O
and O
apoptosis O
induction O
, O
which O
suggested O
DICO B
might O
have O
therapeutic O
potential O
against O
tumors O
. O

Chloroquine B
causes O
similar O
electroretinogram O
modifications O
, O
neuronal O
phospholipidosis O
and O
marked O
impairment O
of O
synaptic O
vesicle O
transport O
in O
Albino O
and O
Pigmented O
Rats O
. O

Retinal O
toxicity O
of O
chloroquine B
has O
been O
known O
for O
several O
years O
, O
but O
the O
mechanism O
( O
s O
) O
of O
toxicity O
remain O
controversial O
; O
some O
author O
support O
the O
idea O
that O
the O
binding O
of O
chloroquine B
to O
melanin O
pigments O
in O
the O
retinal O
pigmented O
epithelium O
( O
RPE O
) O
play O
a O
major O
toxic O
role O
by O
concentrating O
the O
drug O
in O
the O
eye O
. O

In O
our O
study O
, O
12 O
albinos O
Sprague O
- O
Dawley O
( O
SD O
) O
and O
12 O
pigmented O
Brown O
Norway O
( O
BN O
) O
rats O
were O
treated O
orally O
for O
3 O
months O
with O
chloroquine B
to O
compare O
functional O
and O
pathological O
findings O
. O

On O
Flash O
electroretinograms O
( O
ERG O
) O
performed O
in O
scotopic O
conditions O
, O
similar O
and O
progressive O
( O
time O
- O
dependent O
) O
delayed O
onset O
and O
decreased O
amplitudes O
of O
oscillatory O
potentials O
( O
from O
Day O
71 O
) O
and O
b O
- O
waves O
( O
on O
Day O
92 O
) O
were O
identified O
in O
both O
BN O
and O
SD O
rats O
. O

In O
both O
strains O
, O
identical O
morphological O
changes O
consisted O
of O
neuronal O
phospholipidosis O
associated O
with O
UV O
auto O
- O
fluorescence O
without O
evidence O
of O
retinal O
degeneration O
and O
gliosis O
; O
the O
RPE O
did O
not O
show O
any O
morphological O
lesions O
or O
autofluorescence O
. O

IHC O
analyses O
demonstrated O
a O
decrease O
in O
GABA B
expression O
in O
the O
inner O
nuclear O
layer O
. O

In O
addition O
, O
a O
marked O
accumulation O
of O
synaptic O
vesicles O
coupled O
with O
a O
marked O
disruption O
of O
neurofilaments O
in O
the O
optic O
nerve O
fibers O
was O
identified O
. O

In O
conclusion O
, O
ERG O
observations O
were O
very O
similar O
to O
those O
described O
in O
humans O
. O

Comparable O
ERG O
modifications O
, O
histopathology O
and O
immunohistochemistry O
findings O
were O
observed O
in O
the O
retina O
of O
both O
rat O
strains O
suggesting O
that O
melanin O
pigment O
is O
unlikely O
involved O
. O
chloroquine B
- O
induced O
impairment O
of O
synaptic O
vesicle O
transport O
, O
likely O
related O
to O
disruption O
of O
neurofilaments O
was O
identified O
and O
non O
- O
previously O
reported O
. O

This O
new O
mechanism O
of O
toxicity O
may O
also O
be O
responsible O
for O
the O
burry O
vision O
described O
in O
humans O
chronically O
treated O
with O
chloroquine B
. O

Thiazolidin B
- I
4 I
- I
one I
and O
thiazinan B
- I
4 I
- I
one I
derivatives O
analogous O
to O
rosiglitazone B
as O
potential O
antihyperglycemic O
and O
antidyslipidemic O
agents O
. O

A O
number O
of O
thiazolidin B
- I
4 I
- I
one I
and O
thiazinan B
- I
4 I
- I
one I
derivatives O
were O
prepared O
by O
three O
component O
condensation O
in O
one O
pot O
reaction O
method O
. O

These O
compounds O
were O
evaluated O
for O
anti O
- O
hyperglycemic O
activity O
by O
in O
vitro O
and O
in O
vivo O
assay O
systems O
. O

The O
compounds O
with O
thiazolidin B
- I
4 I
- I
one I
and O
thiazinan B
- I
4 I
- I
one I
moieties O
exhibited O
significant O
anti O
- O
hyperglycemic O
activity O
. O

A O
few O
compounds O
( O
3a O
, O
3b O
, O
4a O
and O
4b O
) O
have O
exhibited O
both O
anti O
- O
hyperglycemic O
and O
anti O
- O
dyslipidemic O
activities O
. O

Among O
them O
the O
thiazinan B
- I
4 I
- I
one I
derivative O
4a O
showed O
maximal O
( O
45 O
% O
) O
improvement O
in O
oral O
glucose B
tolerance O
test O
in O
db O
/ O
db O
mice O
at O
30 O
mg O
/ O
kg O
oral O
dose O
. O

Synthesis O
and O
biological O
evaluation O
of O
novel O
aliphatic B
amido I
- I
quaternary I
ammonium I
salts I
for O
anticancer O
chemotherapy O
: O
Part O
II O
. O

A O
series O
of O
novel O
aliphatic B
amido I
- I
quaternary I
ammonium I
salts I
were O
synthesized O
and O
evaluated O
for O
their O
anticancer O
effects O
involving O
induction O
of O
RhoB O
. O

Most O
of O
these O
compounds O
, O
featuring O
open O
- O
ring O
forms O
of O
aliphatic B
amido I
- I
quaternary I
ammonium I
salts I
, O
exhibited O
potent O
anti O
- O
proliferative O
activities O
in O
human O
cancer O
cell O
lines O
, O
including O
PC O
- O
3 O
, O
NUGC O
- O
3 O
, O
MDA O
- O
MB O
- O
231 O
, O
ACHN O
, O
HCT O
- O
15 O
, O
and O
NCI O
- O
H23 O
. O

In O
further O
evaluation O
, O
the O
representative O
compound O
N B
, I
N I
- I
diethyl I
- I
N I
- I
( I
2 I
- I
( I
N I
- I
methyltetradecanamid I
) I
ethyl I
) I
prop I
- I
2 I
- I
en I
- I
1 I
- I
aminium I
bromide I
( O
3b O
) O
exhibited O
potent O
pro O
- O
apoptotic O
activity O
, O
through O
RhoB O
activation O
, O
in O
HeLa O
cells O
. O

Identification O
of O
novel O
FLT3 O
kinase O
inhibitors O
. O

FLT3 O
and O
PDGFR O
tyrosine B
kinases O
are O
important O
targets O
for O
therapy O
of O
different O
types O
of O
leukemia O
. O

Several O
FLT3 O
/ O
PDGFR O
inhibitors O
are O
currently O
under O
clinical O
investigation O
for O
combination O
with O
standard O
therapy O
for O
treatment O
of O
acute O
myeloid O
leukemia O
( O
AML O
) O
, O
however O
these O
agents O
only O
induce O
partial O
remission O
and O
development O
of O
resistance O
has O
been O
reported O
. O

In O
this O
work O
we O
describe O
the O
identification O
of O
potent O
and O
novel O
dual O
FLT3 O
/ O
PDGFR O
inhibitors O
that O
resulted O
from O
our O
efforts O
to O
screen O
a O
library O
of O
25 O
, O
607 O
small O
molecules O
against O
the O
FLT3 O
dependent O
cell O
line O
MOLM O
- O
13 O
and O
the O
PDGFR O
dependent O
cell O
line O
EOL O
- O
1 O
. O

This O
effort O
led O
to O
the O
identification O
of O
five O
compounds O
that O
were O
confirmed O
to O
be O
active O
on O
additional O
FLT3 O
dependent O
cell O
lines O
( O
cellular O
EC50 O
values O
between O
35 O
and O
700 O
nM O
) O
, O
while O
having O
no O
significant O
effect O
on O
24 O
other O
tyrosine B
kinases O
. O

Preparation O
and O
antimalarial O
activity O
of O
semisynthetic O
lycorenine B
derivatives O
. O

A O
set O
of O
twenty O
one O
lycorenine B
derivatives O
has O
been O
prepared O
from O
the O
alkaloid O
hippeastrine B
( O
1 O
) O
. O

The O
modifications O
performed O
on O
hippeastrine B
included O
some O
functional O
group O
transformations O
, O
structural O
simplification O
and O
preparation O
of O
dimers O
. O

All O
alkaloids O
were O
tested O
as O
potential O
antimalarial O
agents O
, O
being O
the O
hippeastrine B
dimers O
the O
most O
active O
compounds O
. O

Transport O
of O
gabapentin B
by O
LAT1 O
( O
SLC7A5 O
) O
. O

Gabapentin B
is O
used O
in O
the O
treatment O
of O
epilepsy O
and O
neuropathic O
pain O
. O

Gabapentin B
has O
high O
and O
saturable O
permeability O
across O
the O
BBB O
, O
but O
no O
mechanistic O
studies O
underpinning O
this O
process O
have O
been O
reported O
. O

The O
aim O
of O
the O
current O
study O
was O
to O
investigate O
the O
transport O
of O
gabapentin B
in O
a O
model O
of O
the O
BBB O
, O
identify O
the O
important O
drug O
transporter O
( O
s O
) O
and O
to O
use O
mathematical O
modelling O
to O
quantify O
the O
processes O
involved O
. O

A O
human O
brain O
endothelial O
cell O
line O
( O
hCMEC O
/ O
D3 O
) O
was O
utilised O
as O
an O
in O
- O
vitro O
model O
of O
the O
BBB O
. O

Uptake O
of O
radiolabeled O
gabapentin B
into O
cells O
in O
the O
presence O
of O
chemical O
inhibitors O
, O
siRNA O
or O
overexpressed O
drug O
transporters O
of O
interest O
was O
investigated O
. O

Gabapentin B
was O
demonstrated O
to O
be O
a O
LAT1 O
substrate O
in O
brain O
endothelial O
cells O
( O
LAT1 O
- O
process O
; O
Km O
= O
530 O
mu O
M O
and O
Vmax O
= O
7039pmoles O
/ O
million O
cells O
/ O
min O
versus O
other O
- O
processes O
; O
Km O
= O
923 O
mu O
M O
and O
Vmax O
= O
3656pmoles O
/ O
million O
cells O
/ O
min O
) O
and O
in O
transfected O
HEK O
293 O
LAT1 O
cells O
( O
LAT1 O
- O
process O
; O
Km O
= O
217 O
mu O
M O
and O
Vmax O
= O
5192pmoles O
/ O
million O
cells O
/ O
min O
versus O
otherprocesses O
; O

Km O
= O
1546 O
mu O
M O
and O
Vmax O
= O
3375pmoles O
/ O
million O
cells O
/ O
min O
) O
. O

At O
physiological O
concentrations O
of O
gabapentin B
, O
LAT1 O
mediated O
transport O
was O
3 O
or O
~ O
10 O
- O
fold O
higher O
than O
the O
other O
transport O
processes O
in O
the O
two O
systems O
, O
respectively O
, O
demonstrating O
clear O
selectivity O
for O
gabapentin B
. O

In O
- O
silico O
structural O
homology O
modelling O
confirmed O
that O
LAT1 O
could O
have O
the O
LeuT O
conserved O
fold O
and O
functions O
by O
the O
alternative O
access O
mechanism O
. O

Mathematical O
modelling O
of O
this O
mechanism O
revealed O
revised O
significance O
of O
Vmax O
and O
Km O
so O
that O
a O
low O
Km O
may O
not O
necessarily O
imply O
a O
high O
affinity O
transport O
process O
. O

Gabapentin B
was O
negative O
for O
OCT O
like O
transport O
and O
LAT2 O
activity O
in O
the O
hCMEC O
/ O
D3 O
and O
OCT1 O
transfected O
cells O
. O

Our O
data O
shows O
that O
gabapentin B
is O
a O
substrate O
for O
the O
influx O
transporter O
LAT1 O
at O
therapeutic O
concentrations O
. O

Single O
- O
photon O
sources O
: O
non O
- O
blinking O
single O
- O
photon O
generation O
with O
anisotropic O
colloidal O
nanocrystals O
: O
towards O
room O
- O
temperature O
, O
efficient O
, O
colloidal O
quantum O
sources O
( O
adv O
. O
Mater O
. O
14 O
/ O
2013 O
) O
. O

High O
- O
quality O
core O
/ O
shell O
CdSe B
/ O
CdS B
colloidal O
nanocrystals O
are O
demonstrated O
to O
be O
efficient O
sources O
of O
non O
- O
classical O
light O
. O

As O
shown O
by O
Ferruccio O
Pisanello O
and O
co O
- O
workers O
on O
page O
1974 O
, O
the O
intrinsic O
anisotropy O
of O
these O
nanoparticles O
allows O
an O
independent O
tuning O
of O
shell O
length O
and O
thickness O
, O
resulting O
in O
a O
full O
control O
of O
photon O
statistics O
. O

This O
can O
be O
exploited O
to O
obtain O
non O
- O
blinking O
, O
room O
- O
temperature O
single O
- O
photon O
generation O
, O
thus O
bringing O
colloidal O
nanocrystals O
one O
step O
closer O
to O
non O
- O
classical O
light O
sources O
for O
quantum O
applications O
. O

Light O
- O
Emitting O
Field O
- O
Effect O
Transistors O
Having O
Combined O
Organic O
Semiconductor O
and O
Metal B
Oxide I
Layers O
. O

A O
new O
organic O
light O
- O
emitting O
field O
- O
effect O
transistor O
characterized O
by O
a O
metal B
oxide I
layer O
inserted O
between O
the O
organic O
layer O
and O
the O
gate O
insulator O
is O
proposed O
. O

The O
metal B
oxide I
is O
indirectly O
connected O
with O
source O
and O
drain O
electrodes O
through O
the O
organic O
layer O
. O

Upon O
increasing O
the O
potential O
difference O
between O
the O
source O
and O
drain O
electrodes O
, O
the O
emission O
becomes O
exceedingly O
strong O
and O
the O
emission O
region O
encompasses O
the O
whole O
channel O
zone O
. O

Patterned O
Growth O
of O
Crystalline O
Organic O
Heterostructures O
. O

Organic O
droplet O
epitaxy O
is O
presented O
as O
a O
method O
for O
growing O
nanopatterned O
crystalline O
heterostructures O
, O
thanks O
to O
the O
transport O
of O
molecules O
of O
an O
amorphous O
first O
- O
layer O
on O
top O
of O
a O
crystalline O
second O
- O
layer O
, O
where O
they O
form O
an O
epitaxial O
interface O
. O

Such O
heterostructures O
may O
be O
transferred O
to O
any O
substrates O
, O
raising O
particular O
interest O
for O
applications O
( O
e O
. O
g O
. O
, O
for O
organic O
photovoltaics O
) O
, O
where O
crystallinity O
and O
nanopatterning O
constitute O
well O
recognized O
advantages O
. O

Decreased O
consumption O
of O
sweet O
fluids O
in O
mu O
opioid O
receptor O
knockout O
mice O
: O
a O
microstructural O
analysis O
of O
licking O
behavior O
. O

RATIONALE O
: O
Evidence O
suggests O
that O
the O
palatability O
of O
food O
( O
i O
. O
e O
. O
, O
the O
hedonic O
impact O
produced O
by O
its O
sensory O
features O
) O
can O
promote O
feeding O
and O
may O
underlie O
compulsive O
eating O
, O
leading O
to O
obesity O
. O

Pharmacological O
studies O
implicate O
opioid O
transmission O
in O
the O
hedonic O
control O
of O
feeding O
, O
though O
these O
studies O
often O
rely O
on O
agents O
lacking O
specificity O
for O
particular O
opioid O
receptors O
. O

OBJECTIVES O
: O
Here O
, O
we O
investigated O
the O
role O
of O
mu O
opioid O
receptors O
( O
MORs O
) O
specifically O
in O
determining O
hedonic O
responses O
to O
palatable O
sweet O
stimuli O
. O

METHODS O
: O
In O
Experiment O
1 O
, O
licking O
microstructure O
when O
consuming O
sucrose B
solution O
( O
2 O
to O
20 O
% O
) O
was O
compared O
in O
MOR O
knockout O
and O
wildtype O
mice O
as O
a O
function O
of O
sucrose B
concentration O
and O
level O
of O
food O
deprivation O
. O

In O
Experiment O
2 O
, O
a O
similar O
examination O
was O
conducted O
using O
the O
palatable O
but O
calorie O
- O
free O
stimulus O
sucralose B
( O
0 O
. O
001 O
to O
1 O
% O
) O
, O
allowing O
study O
of O
licking O
behavior O
independent O
of O
homeostatic O
variables O
. O

RESULTS O
: O
In O
Experiment O
1 O
, O
MOR O
knockout O
mice O
exhibited O
several O
alterations O
in O
sucrose B
licking O
. O

Although O
wildtype O
mice O
exhibited O
a O
twofold O
increase O
in O
the O
burst O
length O
when O
food O
deprived O
, O
relative O
to O
the O
nondeprived O
test O
, O
this O
aspect O
of O
sucrose B
licking O
was O
generally O
insensitive O
to O
manipulations O
of O
food O
deprivation O
for O
MOR O
knockout O
mice O
. O

Furthermore O
, O
during O
concentration O
testing O
, O
their O
rate O
of O
sucrose B
licking O
was O
less O
than O
half O
that O
of O
wildtype O
mice O
. O

During O
sucralose O
testing O
( O
Experiment O
2 O
) O
, O
MOR O
knockout O
mice O
licked O
at O
approximately O
half O
the O
wildtype O
rate O
, O
providing O
more O
direct O
evidence O
that O
MOR O
knockout O
mice O
were O
impaired O
in O
processing O
stimulus O
palatability O
. O

CONCLUSIONS O
: O
These O
results O
suggest O
that O
transmission O
through O
MORs O
mediates O
hedonic O
responses O
to O
palatable O
stimuli O
, O
and O
therefore O
likely O
contributes O
to O
normal O
and O
pathological O
eating O
. O

Non O
- O
classical O
Pharmacology O
of O
the O
Dopamine B
Transporter O
: O
Atypical O
Inhibitors O
, O
Allosteric O
Modulators O
and O
Partial O
Substrates O
. O

The O
dopamine B
transporter O
( O
DAT O
) O
is O
a O
sodium B
- O
coupled O
symporter O
protein O
responsible O
for O
modulating O
the O
concentration O
of O
extraneuronal O
dopamine B
in O
the O
brain O
. O

The O
DAT O
is O
a O
principle O
target O
of O
various O
psychostimulant O
, O
nootropic O
and O
antidepressant O
drugs O
, O
as O
well O
as O
certain O
drugs O
used O
recreationally O
, O
including O
the O
notoriously O
addictive O
stimulant O
cocaine B
. O

DAT O
ligands O
have O
traditionally O
been O
divided O
into O
two O
categories O
: O
cocaine B
- O
like O
inhibitors O
and O
amphetamine B
- O
like O
substrates O
. O

Whereas O
inhibitors O
block O
monoamine B
uptake O
by O
the O
DAT O
, O
but O
are O
not O
translocated O
across O
the O
membrane O
, O
substrates O
are O
actively O
translocated O
and O
trigger O
DAT O
- O
mediated O
release O
of O
dopamine B
by O
reversal O
of O
the O
translocation O
cycle O
. O

As O
both O
inhibitors O
and O
substrates O
increase O
extraneuronal O
dopamine B
levels O
, O
it O
is O
often O
assumed O
that O
all O
DAT O
ligands O
posses O
an O
addictive O
liability O
equivalent O
to O
cocaine B
. O

However O
, O
the O
recent O
development O
of O
novel O
' O
atypical O
' O
inhibitors O
and O
' O
partial O
substrate O
' O
ligands O
with O
reduced O
or O
even O
a O
complete O
lack O
of O
cocaine B
- O
like O
rewarding O
effects O
suggests O
that O
addictiveness O
is O
not O
a O
constant O
property O
of O
DAT O
- O
affecting O
compounds O
. O

These O
atypical O
ligands O
do O
not O
conform O
to O
the O
classical O
preconception O
that O
all O
DAT O
inhibitors O
( O
or O
substrates O
) O
are O
functionally O
and O
mechanistically O
alike O
. O

Instead O
, O
they O
suggest O
the O
possibility O
that O
the O
DAT O
exhibits O
some O
of O
the O
ligand O
- O
specific O
' O
pleiotropic O
' O
functional O
qualities O
inherent O
to O
G O
- O
protein O
- O
coupled O
receptors O
. O

That O
is O
, O
ligands O
with O
different O
chemical O
structures O
induce O
specific O
conformational O
changes O
in O
the O
transporter O
protein O
, O
which O
can O
be O
differentially O
transduced O
by O
the O
cell O
, O
ultimately O
eliciting O
unique O
behavioral O
and O
psychical O
effects O
. O

The O
present O
overview O
discusses O
compounds O
with O
conformation O
- O
specific O
activity O
, O
useful O
not O
only O
as O
tools O
for O
studying O
the O
mechanics O
of O
dopamine B
transport O
, O
but O
also O
as O
leads O
for O
medication O
development O
in O
addictive O
disorders O
. O

Molecular O
Identification O
and O
Characterization O
of O
an O
Essential O
Pyruvate B
Transporter O
from O
Trypanosoma O
brucei O
. O

Pyruvate B
export O
is O
an O
essential O
physiological O
process O
for O
the O
bloodstream O
form O
of O
T O
. O
brucei O
as O
the O
parasite O
would O
otherwise O
accumulate O
this O
end O
product O
of O
glucose B
metabolism O
to O
toxic O
levels O
. O

In O
the O
studies O
reported O
here O
genetic O
complementation O
in O
Saccharomyces O
cerevisiae O
has O
been O
employed O
to O
identify O
a O
gene O
( O
TbPT0 O
) O
that O
encodes O
this O
vital O
pyruvate B
transporter O
from O
T O
. O
brucei O
. O

Expression O
of O
TbPT0 O
in O
S O
. O
cerevisiae O
reveals O
that O
TbPT0 O
is O
a O
high O
affinity O
pyruvate B
transporter O
. O

TbPT0 O
belongs O
to O
a O
clustered O
multigene O
family O
consisting O
of O
five O
members O
, O
whose O
expression O
is O
up O
- O
regulated O
in O
the O
bloodstream O
form O
. O

Interestingly O
, O
TbPT O
family O
permeases O
are O
related O
to O
polytopic O
proteins O
from O
plants O
but O
not O
to O
characterized O
monocarboxylate B
transporters O
from O
mammals O
. O

Remarkably O
, O
inhibition O
of O
the O
TbPT O
gene O
family O
expression O
in O
bloodstream O
parasites O
by O
RNAi O
is O
lethal O
, O
confirming O
the O
physiological O
relevance O
of O
these O
transporters O
. O

The O
discovery O
of O
TbPT0 O
reveals O
for O
the O
first O
time O
the O
identity O
of O
the O
essential O
pyruvate B
transporter O
and O
provides O
a O
potential O
drug O
target O
against O
the O
mammalian O
life O
cycle O
stage O
of O
T O
. O
brucei O
. O

DNA O
repair O
and O
cytotoxic O
drugs O
: O
the O
potential O
role O
of O
RAD51 O
in O
clinical O
outcome O
of O
non O
- O
small O
- O
cell O
lung O
cancer O
patients O
. O

Many O
of O
the O
cytotoxic O
drugs O
used O
in O
the O
treatment O
of O
non O
- O
small O
- O
cell O
lung O
carcinoma O
patients O
can O
interfere O
with O
DNA O
activity O
and O
the O
definition O
of O
an O
individual O
DNA O
repair O
profile O
could O
be O
a O
key O
strategy O
to O
achieve O
better O
response O
to O
chemotherapeutic O
treatment O
. O

Although O
DNA O
repair O
mechanisms O
are O
important O
factors O
in O
the O
prevention O
of O
carcinogenesis O
, O
these O
molecular O
pathways O
are O
also O
involved O
in O
therapy O
response O
. O

RAD51 O
is O
a O
crucial O
element O
in O
DNA O
repair O
by O
homologous O
recombination O
and O
has O
been O
shown O
to O
interfere O
with O
the O
prognosis O
of O
patients O
treated O
with O
chemoradiotherapy O
. O

There O
is O
increasing O
evidence O
that O
genetic O
polymorphisms O
in O
repair O
enzymes O
can O
influence O
DNA O
repair O
capacity O
and O
, O
consequently O
, O
affect O
chemotherapy O
efficacy O
. O

We O
conducted O
this O
review O
to O
show O
the O
possible O
influence O
of O
the O
RAD51 O
genetic O
variants O
in O
damage O
repair O
capacity O
and O
treatment O
response O
in O
non O
- O
small O
- O
cell O
lung O
carcinoma O
patients O
. O

Extracellular O
Signal O
- O
Regulated O
Kinases O
( O
ERK O
) O
Inhibitors O
from O
Aristolochia O
yunnanensis O
. O

Six O
new O
sesquiterpenoids B
, O
aristoyunnolins B
A I
- I
F I
( O
1 O
- O
6 O
) O
, O
an O
artifact O
of O
isolation O
[ O
7 B
- I
O I
- I
ethyl I
madolin I
W I
( O
7 O
) O
] O
, O
and O
12 O
known O
analogues O
were O
isolated O
from O
stems O
of O
Aristolochia O
yunnanensis O
. O

The O
structures O
were O
determined O
by O
combined O
chemical O
and O
spectral O
methods O
, O
and O
the O
absolute O
configurations O
of O
compounds O
2 O
, O
3 O
, O
5 O
- O
7 O
, O
9 O
, O
14 O
, O
and O
17 O
were O
determined O
by O
the O
modified O
Mosher O
' O
s O
method O
and O
CD O
analysis O
. O

Compounds O
1 O
- O
19 O
were O
screened O
using O
a O
bioassay O
system O
designed O
to O
evaluate O
the O
effect O
on O
mitogen O
- O
activated O
protein O
kinases O
( O
MAPKs O
) O
signaling O
pathways O
. O

Among O
three O
MAPKs O
( O
ERK1 O
/ O
2 O
, O
JNK O
, O
and O
p38 O
) O
, O
compounds O
1 O
, O
4 O
, O
10 O
- O
13 O
, O
16 O
, O
18 O
, O
and O
19 O
exhibited O
selective O
inhibition O
of O
the O
phosphorylation O
of O
ERK1 O
/ O
2 O
. O

Compounds O
16 O
and O
19 O
were O
more O
active O
than O
the O
positive O
control O
PD98059 B
, O
a O
known O
inhibitor O
of O
the O
ERK1 O
/ O
2 O
signaling O
pathway O
. O

Different O
levels O
of O
prenatal O
zinc B
and O
selenium B
had O
different O
effects O
on O
neonatal O
neurobehavioral O
development O
. O

Either O
deficient O
or O
excessive O
of O
essential O
nutrients O
had O
adverse O
effects O
. O

Effects O
of O
different O
levels O
of O
prenatal O
zinc B
( O
Zn B
) O
and O
selenium B
( O
Se B
) O
on O
fetal O
neurobehavioral O
development O
remain O
unclear O
. O

To O
determine O
the O
effects O
of O
different O
cord O
serum O
levels O
of O
Zn B
and O
Se B
on O
neurobehavioral O
development O
in O
neonates O
and O
to O
explore O
possible O
threshold O
level O
of O
Zn B
and O
Se B
based O
on O
fetal O
neurodevelopment O
, O
we O
conducted O
this O
epidemiological O
research O
. O

In O
the O
multi O
- O
center O
study O
, O
we O
investigated O
these O
questions O
in O
927 O
mother O
- O
newborn O
pairs O
in O
Shanghai O
, O
China O
, O
from O
2008 O
through O
2009 O
. O

Umbilical O
cord O
serum O
concentrations O
of O
Zn B
and O
Se B
were O
measured O
and O
Neonatal O
Behavioral O
Neurological O
Assessment O
( O
NBNA O
) O
tests O
were O
conducted O
. O

The O
median O
cord O
serum O
Zn B
and O
Se B
concentrations O
were O
794 O
. O
3 O
mu O
g O
/ O
L O
and O
63 O
. O
1 O
mu O
g O
/ O
L O
, O
respectively O
. O

A O
nonlinear O
relationship O
was O
observed O
between O
cord O
serum O
Zn B
and O
NBNA O
after O
adjusting O
for O
potential O
confounders O
. O

NBNA O
score O
decreased O
with O
increasing O
Zn B
levels O
after O
794 O
. O
3 O
mu O
g O
/ O
L O
( O
adjusted O
beta O
= O
- O
3 O
. O
0 O
, O
95 O
% O
CI O
: O
- O
3 O
. O
6 O
to O
- O
2 O
. O
4 O
, O
p O
< O
0 O
. O
001 O
) O
. O

Additionally O
, O
an O
invert O
U O
- O
shape O
with O
a O
threshold O
Se O
of O
100 O
mu O
g O
/ O
L O
was O
observed O
between O
cord O
serum O
Se O
and O
NBNA O
. O

The O
adjusted O
regression O
coefficient O
was O
4 O
. O
4 O
( O
95 O
% O
CI O
: O
3 O
. O
6 O
- O
5 O
. O
2 O
, O
p O
< O
0 O
. O
001 O
) O
for O
Se B
< O
100 O
mu O
g O
/ O
L O
while O
- O
3 O
. O
6 O
( O
95 O
% O
CI O
: O
- O
6 O
. O
1 O
to O
- O
1 O
. O
1 O
, O
p O
< O
0 O
. O
01 O
) O
for O
Se B
> O
= O
100 O
mu O
g O
/ O
L O
. O

Of O
the O
927 O
infants O
, O
50 O
% O
had O
a O
high O
level O
Zn B
( O
> O
= O
794 O
. O
3 O
mu O
g O
/ O
L O
) O
and O
8 O
. O
6 O
% O
had O
a O
high O
level O
Se B
( O
> O
= O
100 O
mu O
g O
/ O
L O
) O
. O

High O
levels O
of O
both O
Zn B
and O
Se B
mainly O
had O
adverse O
effects O
on O
behavior O
and O
passive O
tone O
( O
p O
< O
0 O
. O
001 O
) O
. O

Taken O
together O
, O
our O
study O
suggested O
that O
a O
threshold O
of O
cord O
blood O
Zn B
and O
Se B
was O
existed O
for O
fetal O
neurodevelopment O
and O
the O
prevalence O
of O
excessive O
Zn B
was O
high O
. O

Thus O
, O
the O
supplementation O
of O
Zn B
during O
pregnancy O
should O
be O
considered O
with O
caution O
in O
Shanghai O
, O
China O
. O

Substituted O
imidazopyridazines B
are O
potent O
and O
selective O
inhibitors O
of O
Plasmodium O
falciparum O
calcium B
- O
dependent O
protein O
kinase O
1 O
( O
PfCDPK1 O
) O
. O

A O
series O
of O
imidazopyridazines B
which O
are O
potent O
inhibitors O
of O
Plasmodium O
falciparum O
calcium B
- O
dependent O
protein O
kinase O
1 O
( O
PfCDPK1 O
) O
was O
identified O
from O
a O
high O
- O
throughput O
screen O
against O
the O
isolated O
enzyme O
. O

Subsequent O
exploration O
of O
the O
SAR O
and O
optimisation O
has O
yielded O
leading O
members O
which O
show O
promising O
in O
vitro O
anti O
- O
parasite O
activity O
along O
with O
good O
in O
vitro O
ADME O
and O
selectivity O
against O
human O
kinases O
. O

Initial O
in O
vivo O
testing O
has O
revealed O
good O
oral O
bioavailability O
in O
a O
mouse O
PK O
study O
and O
modest O
in O
vivo O
efficacy O
in O
a O
Plasmodium O
berghei O
mouse O
model O
of O
malaria O
. O

Development O
and O
evaluation O
of O
novel O
solid O
nanodispersion O
system O
for O
oral O
delivery O
of O
poorly O
water O
- O
soluble O
drugs O
. O

The O
aim O
of O
the O
present O
study O
was O
to O
develop O
and O
evaluate O
a O
novel O
drug O
solubilization O
platform O
( O
so O
- O
called O
solid O
nanodispersion O
) O
prepared O
by O
a O
simple O
co O
- O
grinding O
and O
solvent O
- O
free O
process O
. O

Using O
structurally O
diverse O
model O
compounds O
from O
the O
Pfizer O
drug O
library O
, O
including O
ingliforib B
, O
furosemide B
and O
celecoxib B
, O
we O
successfully O
prepared O
stable O
solid O
nanodispersions O
( O
SNDs O
) O
without O
the O
use O
of O
solvent O
or O
heat O
. O

Stable O
colloidal O
particles O
( O
< O
350nm O
) O
containing O
drug O
, O
polyvinylpyrrolidone B
( O
PVP B
) O
K12 O
and O
sodium B
dodecyl I
sulfate I
( O
SDS B
) O
in O
1 O
: O
2 O
. O
75 O
: O
0 O
. O
25 O
ratio O
were O
produced O
after O
2h O
of O
co O
- O
grinding O
. O

The O
composition O
and O
particle O
size O
of O
SNDs O
were O
optimized O
by O
varying O
the O
grinding O
media O
size O
, O
powder O
- O
to O
- O
grinding O
media O
ratio O
, O
milling O
speed O
and O
milling O
time O
. O

The O
resulting O
formulations O
contained O
crystalline O
drug O
and O
were O
stable O
at O
room O
temperature O
for O
over O
one O
month O
. O

Greater O
than O
80 O
% O
of O
the O
drug O
was O
released O
from O
the O
SND O
in O
less O
than O
30min O
, O
with O
sustained O
supersaturation O
over O
4h O
. O

Using O
furosemide B
( O
BCS O
class O
IV O
compound O
) O
as O
a O
model O
compound O
, O
we O
conducted O
transport O
studies O
with O
Madin O
- O
Darby O
canine O
kidney O
cells O
transfected O
with O
human O
MDR1 O
gene O
( O
MDCK O
/ O
MDR1 O
) O
, O
followed O
by O
pharmacokinetics O
studies O
in O
rats O
. O

Results O
showed O
that O
the O
SND O
formulation O
enhanced O
the O
absorptive O
flux O
of O
furosemide B
by O
more O
than O
3 O
- O
fold O
. O

In O
the O
pharmacokinetics O
studies O
, O
the O
SND O
formulation O
increased O
Cmax O
and O
AUC O
of O
furosemide B
by O
36 O
. O
6 O
and O
43 O
. O
2 O
fold O
respectively O
, O
relative O
to O
Methocel O
formulation O
. O

Interestingly O
, O
physical O
mixture O
containing O
furosemide B
, O
PVP B
K12 I
and O
SDS B
produced O
a O
similar O
level O
of O
oral O
exposure O
as O
the O
SNDs O
, O
albeit O
with O
a O
longer O
Tmax O
than O
the O
SND O
formulation O
. O

The O
results O
suggest O
that O
PVP B
K12 I
and O
SDS B
were O
able O
to O
increase O
the O
furosemide B
free O
fraction O
available O
for O
oral O
absorption O
. O

Low O
solubility O
, O
poor O
permeability O
, O
and O
high O
first O
- O
pass O
effect O
of O
furosemide B
may O
also O
have O
produced O
the O
effect O
that O
small O
improvements O
in O
solubilization O
resulted O
in O
significant O
potentiation O
of O
the O
oral O
exposure O
of O
the O
physical O
mixture O
. O

However O
the O
use O
of O
a O
physical O
mixture O
of O
drug O
, O
polymer O
and O
surfactant O
, O
to O
increase O
drug O
bioavailability O
cannot O
be O
generalized O
to O
all O
drugs O
. O

There O
are O
only O
a O
few O
reported O
cases O
of O
such O
phenomenon O
. O

While O
SNDs O
may O
not O
be O
the O
only O
option O
to O
solubilize O
compounds O
in O
every O
case O
, O
SNDs O
are O
expected O
to O
be O
applicable O
to O
a O
broader O
chemical O
space O
of O
pharmaceutical O
compounds O
compared O
to O
a O
physical O
mixture O
. O

Ultimately O
, O
formulation O
scientists O
have O
to O
exercise O
judgment O
in O
choosing O
the O
appropriate O
formulation O
strategy O
for O
the O
compound O
of O
interest O
. O

SNDs O
represent O
a O
significant O
improvement O
over O
current O
enabling O
technologies O
such O
as O
nanocrystal O
and O
spray O
- O
dried O
dispersion O
technologies O
, O
in O
that O
SNDs O
are O
simple O
, O
do O
not O
require O
solvent O
or O
heat O
, O
are O
applicable O
to O
a O
structurally O
diverse O
chemical O
space O
, O
and O
are O
amenable O
to O
the O
development O
of O
solid O
dosage O
forms O
. O

In O
vivo O
and O
in O
vitro O
anti O
- O
inflammatory O
potential O
of O
pentahydroxy B
- I
pregn I
- I
14 I
- I
ol I
, O
20 B
- I
one I
- I
beta I
- I
d I
- I
thevetopyranoside I
in O
rats O
. O

Polyhydroxy B
pregnane I
glycoside I
( O
PPG B
) O
, O
a O
steroidal B
glycoside I
was O
isolated O
from O
Wattakaka O
volubilis O
Linn O
. O

( O
Stap O
. O
f O
. O
) O
. O

PPG O
was O
evaluated O
for O
in O
vivo O
and O
in O
vitro O
anti O
- O
inflammatory O
activity O
using O
acute O
inflammation O
and O
chronic O
model O
of O
inflammation O
in O
rats O
and O
LPS O
- O
induced O
RAW O
264 O
. O
7 O
macrophage O
cells O
. O

PPG O
seemed O
to O
be O
responsible O
for O
the O
anti O
- O
inflammatory O
activity O
in O
the O
studied O
models O
. O

PPG O
at O
dose O
level O
of O
both O
5 O
and O
10mg O
/ O
kg O
significantly O
reduced O
the O
edema O
induced O
by O
the O
carrageenan O
in O
acute O
model O
of O
inflammation O
. O

It O
also O
showed O
significant O
anti O
- O
proliferative O
effect O
( O
dry O
pellet O
weight O
basis O
) O
in O
chronic O
model O
of O
inflammation O
. O

Cellular O
content O
of O
granuloma O
was O
measured O
by O
assaying O
activity O
of O
N B
- I
acetyl I
glucosaminidase O
( O
NAG O
) O
and O
total O
nucleic O
acid O
content O
. O

PPG B
at O
5 O
and O
10mg O
/ O
kg O
significantly O
suppressed O
the O
cellular O
infiltration O
measured O
by O
total O
nucleic O
acid O
content O
. O

In O
contrast O
, O
NAG O
activity O
decreased O
over O
a O
period O
of O
10 O
days O
resulting O
in O
inhibition O
of O
granuloma O
weight O
gain O
. O

PPG O
had O
a O
more O
effective O
response O
than O
the O
reference O
drug O
diclofenac B
sodium I
in O
both O
the O
models O
of O
inflammation O
. O

Wattakaka O
volubilis O
steroidal B
glycoside I
mixture O
( O
WVSM O
) O
and O
PPG O
( O
1 O
- O
50 O
mu O
M O
) O
significantly O
inhibited O
the O
COX O
- O
2 O
and O
iNOS O
enzymes O
resulting O
in O
low O
levels O
of O
PGE2 B
and O
NO B
in O
LPS O
- O
induced O
RAW O
264 O
. O
7 O
macrophage O
cells O
. O

Hence O
the O
study O
supports O
the O
traditional O
use O
of O
Wattakaka O
volubilis O
and O
its O
constituent O
PPG O
in O
treatment O
of O
inflammatory O
disorders O
. O

DNA O
repair O
activity O
in O
fish O
and O
interest O
in O
ecotoxicology O
: O
A O
review O
. O

The O
knowledge O
of O
DNA O
repair O
in O
a O
target O
species O
is O
of O
first O
importance O
as O
it O
is O
the O
primary O
line O
of O
defense O
against O
genotoxicants O
, O
and O
a O
better O
knowledge O
of O
DNA O
repair O
capacity O
in O
fish O
could O
help O
to O
interpret O
genotoxicity O
data O
and O
/ O
or O
assist O
in O
the O
choice O
of O
target O
species O
, O
developmental O
stage O
and O
tissues O
to O
focus O
on O
, O
both O
for O
environmental O
biomonitoring O
studies O
and O
DNA O
repair O
testing O
. O

This O
review O
focuses O
in O
a O
first O
part O
on O
what O
is O
presently O
known O
on O
a O
mechanistic O
basis O
, O
about O
the O
various O
DNA O
repair O
systems O
in O
fish O
, O
in O
vivo O
and O
in O
established O
cell O
lines O
. O

Data O
on O
base O
excision O
repair O
( O
BER O
) O
, O
direct O
reversal O
with O
O B
( I
6 I
) I
- I
alkylguanine I
transferase O
and O
double O
strand O
breaks O
repair O
, O
although O
rather O
scarce O
, O
are O
being O
reviewed O
, O
as O
well O
as O
nucleotide B
excision O
repair O
( O
NER O
) O
and O
photoreactivation O
repair O
( O
PER O
) O
, O
which O
are O
by O
far O
the O
most O
studied O
repair O
mechanisms O
in O
fish O
. O

Most O
of O
these O
repair O
mechanisms O
seem O
to O
be O
strongly O
species O
and O
tissue O
dependent O
; O
they O
also O
depend O
on O
the O
developmental O
stage O
of O
the O
organisms O
. O

BER O
is O
efficient O
in O
vivo O
, O
although O
no O
data O
has O
been O
found O
on O
in O
vitro O
models O
. O

NER O
activity O
is O
quite O
low O
or O
even O
inexistent O
depending O
on O
the O
studies O
; O
however O
this O
lack O
is O
partly O
compensated O
by O
a O
strong O
PER O
activity O
, O
especially O
in O
early O
developmental O
stage O
. O

In O
a O
second O
part O
, O
a O
survey O
of O
the O
ecotoxicological O
studies O
integrating O
DNA O
repair O
as O
a O
parameter O
responding O
to O
single O
or O
mixture O
of O
contaminant O
is O
realized O
. O

Three O
main O
approaches O
are O
being O
used O
: O
the O
measurement O
of O
DNA O
repair O
gene O
expression O
after O
exposure O
, O
although O
it O
has O
not O
yet O
been O
clearly O
established O
whether O
gene O
expression O
is O
indicative O
of O
repair O
capacity O
; O
the O
monitoring O
of O
DNA O
damage O
removal O
by O
following O
DNA O
repair O
kinetics O
; O
and O
the O
modulation O
of O
DNA O
repair O
activity O
following O
exposure O
in O
situ O
, O
in O
order O
to O
assess O
the O
impact O
of O
exposure O
history O
on O
DNA O
repair O
capacity O
. O

Since O
all O
DNA O
repair O
processes O
are O
possible O
targets O
for O
environmental O
pollutants O
, O
we O
can O
also O
wonder O
at O
which O
extent O
such O
a O
modulation O
of O
repair O
capacities O
in O
fish O
could O
be O
the O
base O
for O
the O
development O
of O
new O
biomarkers O
of O
genotoxicity O
. O

Knowing O
the O
importance O
of O
the O
germ O
cell O
DNA O
integrity O
in O
the O
reproductive O
success O
of O
aquatic O
organisms O
, O
the O
DNA O
repair O
capacity O
of O
such O
cells O
deserve O
to O
be O
more O
studied O
, O
as O
well O
as O
DNA O
repair O
capacities O
of O
established O
fish O
cell O
lines O
. O

The O
limited O
amount O
of O
available O
data O
, O
which O
shows O
low O
/ O
slow O
DNA O
repair O
capacities O
of O
fish O
cell O
lines O
compared O
with O
mammalian O
cell O
lines O
, O
concerned O
mainly O
the O
NER O
system O
; O
thus O
this O
point O
merits O
to O
be O
explored O
more O
deeply O
. O

Additionally O
, O
since O
some O
of O
the O
DNA O
repair O
systems O
appear O
more O
efficient O
in O
embryo O
larval O
stages O
, O
it O
would O
be O
of O
interest O
to O
consider O
embryonic O
cell O
lineages O
more O
closely O
. O

The O
Ras O
- O
GTPase O
activity O
of O
neurofibromin O
restrains O
ERK O
- O
dependent O
FGFR O
signaling O
during O
endochondral O
bone O
formation O
. O

The O
severe O
defects O
in O
growth O
plate O
development O
caused O
by O
chondrocyte O
extracellular O
signal O
- O
regulated O
protein O
kinases O
1 O
and O
2 O
( O
ERK1 O
/ O
2 O
) O
gain O
or O
loss O
- O
of O
- O
function O
suggest O
that O
tight O
spatial O
and O
temporal O
regulation O
of O
mitogen O
- O
activated O
protein O
kinase O
signaling O
is O
necessary O
to O
achieve O
harmonious O
growth O
plate O
elongation O
and O
structure O
. O

We O
provide O
here O
evidence O
that O
neurofibromin O
, O
via O
its O
Ras O
guanosine O
triphosphatase O
- O
activating O
activity O
, O
controls O
ERK1 O
/ O
2 O
- O
dependent O
fibroblast O
growth O
factor O
receptor O
( O
FGFR O
) O
signaling O
in O
chondrocytes O
. O

We O
show O
first O
that O
neurofibromin O
is O
expressed O
in O
FGFR O
- O
positive O
prehypertrophic O
and O
hypertrophic O
chondrocytes O
during O
growth O
plate O
endochondral O
ossification O
. O

Using O
mice O
lacking O
neurofibromin O
1 O
( O
Nf1 O
) O
in O
type O
II O
collagen O
- O
expressing O
cells O
, O
( O
Nf1col2 O
( O
- O
/ O
- O
) O
mutant O
mice O
) O
, O
we O
then O
show O
that O
lack O
of O
neurofibromin O
in O
post O
- O
mitotic O
chondrocytes O
triggers O
a O
number O
of O
phenotypes O
reminiscent O
of O
the O
ones O
observed O
in O
mice O
characterized O
by O
FGFR O
gain O
- O
of O
- O
function O
mutations O
. O

Those O
include O
dwarfism O
, O
constitutive O
ERK1 O
/ O
2 O
activation O
, O
strongly O
reduced O
Ihh O
expression O
and O
decreased O
chondrocyte O
proliferation O
and O
maturation O
, O
increased O
chondrocytic O
expression O
of O
Rankl O
, O
matrix O
metalloproteinase O
9 O
( O
Mmp9 O
) O
and O
Mmp13 O
and O
enhanced O
growth O
plate O
osteoclastogenesis O
, O
as O
well O
as O
increased O
sensitivity O
to O
caspase O
- O
9 O
mediated O
apoptosis O
. O

Using O
wildtype O
( O
WT O
) O
and O
Nf1 O
( O
- O
/ O
- O
) O
chondrocyte O
cultures O
in O
vitro O
, O
we O
show O
that O
FGF2 O
pulse O
- O
stimulation O
triggers O
rapid O
ERK1 O
/ O
2 O
phosphorylation O
in O
both O
genotypes O
, O
but O
that O
return O
to O
the O
basal O
level O
is O
delayed O
in O
Nf1 O
( O
- O
/ O
- O
) O
chondrocytes O
. O

Importantly O
, O
in O
vivo O
ERK1 O
/ O
2 O
inhibition O
by O
daily O
injection O
of O
a O
recombinant O
form O
of O
C O
- O
type O
natriuretic O
peptide O
to O
post O
- O
natal O
pups O
for O
18 O
days O
was O
able O
to O
correct O
the O
short O
stature O
of O
Nf1col2 O
( O
- O
/ O
- O
) O
mice O
. O

Together O
, O
these O
results O
underscore O
the O
requirement O
of O
neurofibromin O
and O
ERK1 O
/ O
2 O
for O
normal O
endochondral O
bone O
formation O
and O
support O
the O
notion O
that O
neurofibromin O
, O
by O
restraining O
RAS O
- O
ERK1 O
/ O
2 O
signaling O
, O
is O
a O
negative O
regulator O
of O
FGFR O
signaling O
in O
differentiating O
chondrocytes O
. O

Stereoselective O
Glucuronidation O
of O
Ornidazole B
in O
Humans O
: O
Predominant O
Contribution O
of O
UDP B
- O
Glucuronosyltransfer O
1A9 O
and O
2B7 O
. O

Ornidazole B
[ O
R B
, I
S I
- I
1 I
- I
chloro I
- I
3 I
- I
( I
2 I
- I
methyl I
- I
5 I
- I
nitro I
- I
1H I
- I
imidazol I
- I
1 I
- I
yl I
) I
propan I
- I
2 I
- I
ol I
] O
is O
a O
chiral O
5 B
- I
nitroimidazole I
class O
antimicrobial O
agent O
. O

This O
study O
aimed O
to O
investigate O
the O
principal O
metabolic O
pathway O
of O
ornidazole B
in O
humans O
and O
identify O
the O
major O
enzymes O
involved O
. O

A O
total O
of O
19 O
metabolites O
were O
identified O
in O
human O
urine O
collected O
from O
patients O
with O
hepatobiliary O
diseases O
after O
an O
intravenous O
drip O
infusion O
of O
500 O
mg O
of O
racemic B
ornidazole I
. O

Stereoselective O
glucuronidation O
, O
followed O
by O
renal O
excretion O
, O
was O
the O
principal O
metabolic O
pathway O
of O
ornidazole B
in O
humans O
, O
accounting O
for O
37 O
. O
3 O
% O
of O
the O
administered O
dose O
. O

Screening O
assays O
with O
12 O
available O
human O
recombinant O
UDP B
- O
glucuronosyltransfer O
( O
UGTs O
) O
demonstrated O
that O
UGT1A9 O
was O
the O
predominant O
UGT O
isoform O
involved O
in O
R B
- I
ornidazole I
glucuronidation O
, O
whereas O
S B
- I
ornidazole I
glucuronidation O
was O
almost O
exclusively O
catalyzed O
by O
UGT2B7 O
. O

Chemical O
inhibition O
study O
with O
niflumic B
acid I
and O
flurbiprofen B
supported O
these O
findings O
. O

Enzyme O
kinetic O
parameters O
were O
then O
determined O
in O
human O
liver O
microsomes O
( O
HLMs O
) O
, O
human O
kidney O
microsomes O
( O
HKMs O
) O
, O
UGT1A9 O
and O
2B7 O
. O

The O
Km O
values O
for O
UGT1A9 O
( O
15 O
. O
6 O
+ O
/ O
- O
1 O
. O
6 O
mM O
for O
R B
- I
ornidazole I
) O
and O
2B7 O
( O
3 O
. O
8 O
+ O
/ O
- O
0 O
. O
9 O
mM O
for O
S B
- I
ornidazole I
) O
were O
quite O
similar O
to O
those O
determined O
in O
HLMs O
and O
HKMs O
( O
20 O
. O
1 O
+ O
/ O
- O
1 O
. O
4 O
and O
17 O
. O
7 O
+ O
/ O
- O
4 O
. O
0 O
mM O
for O
R B
- I
ornidazole I
; O
6 O
. O
6 O
+ O
/ O
- O
1 O
. O
3 O
and O
3 O
. O
2 O
+ O
/ O
- O
0 O
. O
4 O
mM O
for O
S B
- I

ornidazole B
) O
. O

The O
in O
vitro O
intrinsic O
clearance O
( O
CLint O
) O
ratios O
of O
S B
- I
and I
R I
- I
ornidazole I
were O
approximately O
4 O
. O
3 O
in O
HLMs O
and O
6 O
. O
5 O
in O
HKMs O
, O
respectively O
. O

The O
hepatic O
and O
renal O
clearances O
were O
estimated O
based O
on O
the O
well O
- O
stirred O
model O
. O

Overall O
, O
stereoselective O
glucuronidation O
was O
the O
principal O
metabolic O
pathway O
of O
ornidazole B
in O
humans O
. O

Furthermore O
, O
UGT1A9 O
and O
2B7 O
were O
the O
predominant O
UGT O
isoforms O
responsible O
for O
R B
- I
and I
S I
- I
ornidazole I
glucuronidation O
in O
humans O
, O
respectively O
. O

Ion O
Mobility O
Spectrometry O
- O
Mass O
Spectrometry O
Analysis O
for O
the O
Site O
of O
Aromatic O
Hydroxylation O
. O

Hydroxylated O
metabolites O
often O
retain O
the O
pharmacological O
activity O
of O
parent O
compound O
, O
and O
the O
position O
of O
hydroxylation O
determines O
the O
formation O
of O
chemically O
reactive O
intermediates O
such O
as O
quinones B
and O
analogues O
from O
para O
- O
and O
/ O
or O
ortho O
- O
hydroxylation O
of O
phenols B
or O
arylamines B
. O

Therefore O
, O
the O
identification O
of O
exact O
position O
of O
hydroxylation O
is O
often O
required O
at O
the O
early O
development O
stage O
of O
new O
drug O
candidates O
. O

In O
many O
cases O
, O
liquid O
chromatography O
- O
tandem O
mass O
spectrometry O
( O
LC O
- O
MS O
/ O
MS O
) O
provides O
identical O
MS O
/ O
MS O
spectra O
among O
isomeric O
hydroxylated O
metabolites O
, O
and O
therefore O
, O
it O
alone O
cannot O
unequivocally O
identify O
the O
exact O
position O
( O
s O
) O
of O
hydroxylation O
. O

Ion O
mobility O
spectrometry O
( O
IMS O
) O
, O
integrated O
with O
LC O
- O
MS O
/ O
MS O
, O
recently O
demonstrates O
the O
capability O
of O
separating O
isomeric O
species O
based O
on O
differences O
in O
their O
drift O
times O
from O
IMS O
, O
which O
are O
linearly O
proportional O
to O
the O
collision O
cross O
- O
section O
( O
CCS O
) O
reflecting O
physical O
size O
and O
shape O
. O

In O
the O
present O
study O
, O
a O
chemical O
derivatization O
of O
isomeric O
hydroxylated O
metabolites O
with O
2 B
- I
fluoro I
- I
N I
- I
methyl I
pyridinium I
p I
- I
toluenesulfonate I
was O
found O
to O
confer O
distinct O
theoretical O
CCS O
value O
on O
each O
isomer O
by O
forming O
corresponding O
N B
- I
methyl I
pyridine I
( O
NMP B
) O
derivative O
. O

The O
regression O
lines O
established O
by O
the O
comparison O
between O
theoretical O
CCS O
values O
and O
observed O
drift O
times O
from O
IMS O
for O
each O
set O
of O
parent O
compound O
( O
labetalol B
, O
ezetimibe B
, O
atorvastatin B
and O
warfarin B
) O
and O
its O
MS O
/ O
MS O
product O
ions O
accurately O
and O
selectively O
projected O
the O
actual O
drift O
times O
of O
NMP B
derivatives O
of O
corresponding O
aromatic O
or O
isomeric O
hydroxylated O
metabolites O
. O

The O
established O
method O
was O
used O
for O
the O
accurate O
assignment O
of O
predominant O
formation O
of O
2 O
- O
hydroxylated O
metabolite O
from O
imipramine B
in O
NADPH B
- O
fortified O
human O
liver O
microsomes O
. O

The O
present O
application O
expands O
the O
versatility O
of O
LC O
- O
IMS O
- O
MS O
technique O
to O
the O
structure O
identification O
of O
isomeric O
hydroxylated O
metabolites O
at O
the O
early O
stage O
for O
drug O
development O
. O

Pharmacovigilance O
Using O
Clinical O
Notes O
. O

With O
increasing O
adoption O
of O
electronic O
health O
records O
( O
EHRs O
) O
, O
there O
is O
an O
opportunity O
to O
use O
the O
free O
- O
text O
portion O
of O
EHRs O
for O
pharmacovigilance O
. O

We O
present O
novel O
methods O
that O
annotate O
the O
unstructured O
clinical O
notes O
and O
transform O
them O
into O
a O
deidentified O
patient O
- O
feature O
matrix O
encoded O
using O
medical O
terminologies O
. O

We O
demonstrate O
the O
use O
of O
the O
resulting O
high O
- O
throughput O
data O
for O
detecting O
drug O
- O
adverse O
event O
associations O
and O
adverse O
events O
associated O
with O
drug O
- O
drug O
interactions O
. O

We O
show O
that O
these O
methods O
flag O
adverse O
events O
early O
( O
in O
most O
cases O
before O
an O
official O
alert O
) O
, O
allow O
filtering O
of O
spurious O
signals O
by O
adjusting O
for O
potential O
confounding O
, O
and O
compile O
prevalence O
information O
. O

We O
argue O
that O
analyzing O
large O
volumes O
of O
free O
- O
text O
clinical O
notes O
enables O
drug O
safety O
surveillance O
using O
a O
yet O
untapped O
data O
source O
. O

Such O
data O
mining O
can O
be O
used O
for O
hypothesis O
generation O
and O
for O
rapid O
analysis O
of O
suspected O
adverse O
event O
risk O
. O
Clinical O
Pharmacology O
& O
Therapeutics O
( O
2013 O
) O
; O
advance O
online O
publication O
10 O
April O
2013 O
. O
doi O
: O
10 O
. O
1038 O
/ O
clpt O
. O
2013 O
. O
47 O
. O

Attenuation O
of O
erythrocytic O
actylcholinesterase O
by O
antidepressants O
: O
Evidence O
in O
an O
in O
vitro O
experiment O
. O

The O
current O
study O
was O
aimed O
to O
scrutinize O
acetylcholinesterase O
( O
AchE O
) O
inhibitory O
profile O
of O
two O
antidepressants O
, O
diazepam B
and O
phenobarbitone B
. O

The O
experimental O
designed O
was O
based O
on O
Michaelis O
- O
Menten O
parameters O
( O
apparent O
Michaelis O
constant O
( O
aKm O
) O
and O
apparent O
maximum O
velocity O
( O
aVm O
) O
) O
that O
estimate O
inhibition O
( O
% O
) O
as O
well O
as O
the O
type O
of O
inhibition O
( O
mechanism O
) O
. O

The O
results O
showed O
marked O
inhibition O
of O
AchE O
by O
diazepam B
and O
the O
values O
of O
aKm O
and O
aVm B
were O
65 O
. O
5 O
% O
and O
52 O
. O
63 O
% O
, O
respectively O
. O

These O
values O
suggested O
a O
competitive O
type O
of O
antagonism O
for O
diazepam B
. O

Similar O
trend O
of O
antagonism O
was O
shown O
by O
phenobarbitone B
when O
it O
was O
subjected O
to O
the O
challenge O
of O
AchE O
with O
aKm O
and O
aVm B
values O
of O
51 O
. O
99 O
% O
and O
71 O
. O
80 O
% O
, O
respectively O
. O

It O
is O
concluded O
that O
diazepam B
and O
phenobarbitone B
exhibited O
prominent O
AchE O
attenuation O
apart O
from O
their O
well O
- O
established O
antidepressant O
activity O
, O
which O
could O
be O
more O
useful O
in O
related O
diseased O
conditions O
. O

A O
Role O
for O
Cargo O
in O
the O
Activation O
of O
ADP B
- O
Ribosylation O
Factors O
( O
Arf O
) O
and O
Adaptor O
Recruitment O
. O

Membrane O
traffic O
requires O
the O
specific O
concentration O
of O
protein O
cargos O
and O
exclusion O
of O
other O
proteins O
into O
nascent O
carriers O
. O

Critical O
components O
of O
this O
selectivity O
are O
the O
protein O
adaptors O
that O
bind O
to O
short O
, O
linear O
motifs O
in O
the O
cytoplasmic O
tails O
of O
transmembrane O
protein O
cargos O
and O
sequester O
them O
into O
nascent O
carriers O
. O

The O
recruitment O
of O
the O
adaptors O
is O
mediated O
by O
activated O
Arf O
GTPases O
and O
the O
Arf O
- O
adaptor O
complexes O
mark O
sites O
of O
carrier O
formation O
. O

However O
, O
the O
nature O
of O
the O
signal O
( O
s O
) O
that O
initiate O
carrier O
biogenesis O
remains O
unknown O
. O

We O
examined O
the O
specificity O
and O
initial O
sites O
of O
recruitment O
of O
Arf O
- O
dependent O
adaptors O
( O
AP O
- O
1 O
and O
GGAs O
) O
in O
response O
to O
the O
Golgi O
or O
endosomal O
localization O
of O
specific O
cargo O
proteins O
( O
furin O
, O
mannose B
- I
6 I
- I
phosphate I
receptor O
( O
M6PR O
) O
and O
M6PR O
lacking O
a O
C B
- O
terminal O
domain O
M6PR O
Delta O
C O
) O
. O

We O
find O
that O
cargo O
promotes O
the O
recruitment O
of O
specific O
adaptors O
, O
suggesting O
that O
it O
is O
part O
of O
an O
upstream O
signaling O
event O
. O

Cargos O
do O
not O
promote O
adaptor O
recruitment O
to O
all O
compartments O
in O
which O
they O
reside O
and O
thus O
additional O
factors O
regulate O
the O
cargo O
' O
s O
ability O
to O
promote O
Arf O
activation O
and O
adaptor O
recruitment O
. O

We O
document O
that O
within O
a O
given O
compartment O
different O
cargos O
recruit O
different O
adaptors O
suggesting O
that O
there O
is O
little O
or O
no O
free O
, O
activated O
Arf O
at O
the O
membrane O
and O
that O
Arf O
activation O
is O
spatially O
and O
temporally O
coupled O
to O
the O
cargo O
and O
the O
adaptor O
. O

Using O
temperature O
block O
, O
Brefeldin B
A I
, O
and O
recovery O
from O
each O
, O
we O
found O
that O
the O
cytoplasmic O
tail O
of O
M6PR O
causes O
the O
recruitment O
of O
AP O
- O
1 O
and O
GGAs O
to O
recycling O
endosomes O
and O
not O
at O
the O
Golgi O
, O
as O
predicted O
by O
steady O
state O
staining O
profiles O
. O

These O
results O
are O
discussed O
with O
respect O
to O
the O
generation O
of O
novel O
models O
for O
cargo O
- O
dependent O
regulation O
of O
membrane O
traffic O
. O

Gelation O
- O
induced O
visible O
supramolecular O
chiral O
recognition O
by O
fluorescent O
metal O
complexes O
of O
quinolinol B
- O
glutamide B
. O

Three O
metal O
complexes O
consisting O
of O
Li B
( I
+ I
) I
, O
Zn B
( I
2 I
+ I
) I
, O
and O
Al B
( I
3 I
+ I
) I
and O
quinolinol B
- O
functionalized O
l B
- I
glutamides I
( O
HQLG O
) O
, O
( O
abbreviated O
as O
LiHQLG O
, O
Zn B
( O
HQLG O
) O
2 O
, O
and O
Al B
( O
HQLG O
) O
3 O
) O
were O
found O
to O
form O
fluorescent O
metallogels O
in O
several O
organic O
solvents O
. O

In O
solution O
, O
these O
chiral O
complexes O
showed O
neither O
any O
CD O
signal O
in O
the O
chromophore O
region O
nor O
chiral O
recognition O
of O
the O
chiral O
species O
. O

However O
, O
upon O
gel O
formation O
, O
the O
supramolecular O
chirality O
emerged O
because O
of O
the O
self O
- O
assembled O
nanostructures O
, O
which O
provided O
an O
opportunity O
for O
the O
chiral O
recognition O
of O
enantiomeric O
ligands O
. O

The O
metallogels O
showed O
different O
fluorescence O
changes O
when O
they O
met O
with O
enantiomeric O
( B
R I
, I
R I
) I
- I
or I
( I
S I
, I
S I
) I
- I
1 I
, I
2 I
- I
diaminocyclohexane I
. O

Among O
them O
, O
the O
Al B
( I
HQLG O
) O
3 O
metallogels O
did O
not O
show O
any O
change O
whereas O
the O
LiHQLG O
gels O
exhibited O
the O
same O
decrease O
in O
fluorescence O
. O

Interestingly O
, O
the O
Zn B
( I
HQLG I
) I
2 I
gels O
showed O
obviously O
different O
fluorescent O
color O
with O
respect O
to O
( B
R I
, I
R I
) I
- I
and I
( I
S I
, I
S I
) I
- I
1 I
, I
2 I
- I
diaminocyclohexane I
, O
thus O
providing O
visible O
chiral O
recognition O
via O
the O
naked O
eye O
. O

Such O
different O
recognition O
ability O
was O
discussed O
on O
the O
basis O
of O
the O
assembled O
chiral O
nanostructures O
and O
the O
primary O
molecular O
structures O
of O
the O
metal O
complexes O
. O

It O
was O
shown O
that O
both O
of O
them O
played O
important O
roles O
in O
chiral O
recognition O
. O

JNK O
inhibitors O
as O
anti O
- O
inflammatory O
and O
neuroprotective O
agents O
. O

JNK O
is O
involved O
in O
a O
broad O
range O
of O
physiological O
processes O
. O

Several O
inflammatory O
and O
neurodegenerative O
diseases O
, O
such O
as O
multiple O
sclerosis O
, O
Alzheimer O
' O
s O
and O
Parkinson O
' O
s O
disease O
have O
been O
linked O
with O
the O
dysregulated O
JNK O
pathway O
. O

Research O
on O
disease O
models O
using O
the O
relevant O
knockout O
mice O
has O
highlighted O
the O
importance O
of O
specific O
JNK O
isoformsin O
- O
particular O
disorders O
and O
has O
stimulated O
further O
efforts O
in O
the O
drug O
- O
discovery O
area O
. O

However O
, O
most O
of O
the O
experimental O
evidence O
for O
the O
efficacy O
of O
JNK O
inhibition O
in O
animal O
models O
is O
from O
studies O
using O
JNK O
inhibitors O
, O
which O
are O
not O
isoform O
selective O
. O

Some O
of O
the O
more O
recent O
compounds O
exhibit O
good O
oral O
bioavailability O
, O
CNS O
penetration O
and O
selectivity O
against O
the O
rest O
of O
the O
kinome O
. O

Efforts O
to O
design O
isoform O
- O
selective O
inhibitors O
have O
produced O
a O
number O
of O
examples O
with O
various O
selectivity O
profiles O
. O

This O
article O
presents O
recent O
progress O
in O
this O
area O
and O
comment O
on O
the O
role O
of O
isoform O
selectivity O
for O
efficacy O
. O

Effects O
of O
17 B
alpha I
- I
ethynylestradiol I
- O
induced O
cholestasis O
on O
the O
pharmacokinetics O
of O
doxorubicin B
in O
rats O
: O
reduced O
biliary O
excretion O
and O
hepatic O
metabolism O
of O
doxorubicin B
. O

Abstract O
1 O
. O

Since O
the O
prevalent O
hormonal O
combination O
therapy O
with O
estrogen B
analogues O
in O
cancer O
patients O
has O
frequency O
and O
possibility O
to O
induce O
the O
cholestasis O
, O
the O
frequent O
combination O
therapy O
with O
17 B
alpha I
- I
ethynylestradiol I
( O
EE O
, O
an O
oral O
contraceptive O
) O
and O
doxorubicin B
( O
an O
anticancer O
drug O
) O
might O
be O
monitored O
in O
aspect O
of O
efficacy O
and O
safety O
. O

Doxorubicin B
is O
mainly O
excreted O
into O
the O
bile O
via O
P O
- O
glycoprotein O
( O
P O
- O
gp O
) O
and O
multidrug O
resistance O
- O
associated O
protein O
2 O
( O
Mrp2 O
) O
in O
hepatobiliary O
route O
and O
metabolized O
via O
cytochrome O
P450 O
( O
CYP O
) O
3A O
subfamily O
. O

Also O
the O
hepatic O
Mrp2 O
( O
not O
P O
- O
gp O
) O
and O
CYP3A O
subfamily O
levels O
were O
reduced O
in O
EE O
- O
induced O
cholestatic O
( O
EEC O
) O
rats O
. O

Thus O
, O
we O
herein O
report O
the O
pharmacokinetic O
changes O
of O
doxorubicin B
with O
respect O
to O
the O
changes O
in O
its O
biliary O
excretion O
and O
hepatic O
metabolism O
in O
EEC O
rats O
. O

2 O
. O

The O
pharmacokinetic O
study O
of O
doxorubicin B
after O
intravenous O
administration O
of O
its O
hydrochloride O
was O
conducted O
along O
with O
the O
investigation O
of O
bile O
flow O
rate O
and O
hepatobiliary O
excretion O
of O
doxorubicin B
in O
control O
and O
EEC O
rats O
. O

3 O
. O

The O
significantly O
greater O
AUC O
( O
58 O
. O
7 O
% O
increase O
) O
of O
doxorubicin B
in O
EEC O
rats O
was O
due O
to O
the O
slower O
CL O
( O
32 O
. O
9 O
% O
decrease O
) O
. O

The O
slower O
CL O
was O
due O
to O
the O
reduction O
of O
hepatic O
biliary O
excretion O
( O
67 O
. O
0 O
% O
decrease O
) O
and O
hepatic O
CYP3A O
subfamily O
- O
mediated O
metabolism O
( O
21 O
. O
9 O
% O
decrease O
) O
of O
doxorubicin B
. O

These O
results O
might O
have O
broader O
implications O
to O
understand O
the O
altered O
pharmacokinetics O
and O
/ O
or O
pharmacologic O
effects O
of O
doxorubicin B
via O
biliary O
excretion O
and O
hepatic O
metabolism O
in O
experimental O
and O
clinical O
estrogen B
- O
induced O
cholestasis O
. O

Oxidation O
of O
CO B
by O
Nickel B
Oxide I
Clusters O
Revealed O
by O
Post O
Heating O
. O

Reactions O
of O
nickel B
oxide I
cluster O
ions O
, O
NinOn B
+ O
x I
( I
+ I
) I
( O
n O
= O
4 O
- O
10 O
, O
x O
= O
- O
1 O
~ O
+ O
3 O
) O
, O
with O
CO B
in O
a O
He B
buffer O
gas O
were O
investigated O
using O
mass O
spectrometry O
. O

When O
the O
cluster O
ions O
react O
at O
room O
temperature O
, O
a O
CO B
molecule O
tends O
to O
attach O
readily O
to O
NinOn B
+ I
x I
( I
+ I
) I
for O
all O
of O
the O
cluster O
ions O
with O
different O
stoichiometry O
, O
although O
rate O
constants O
of O
the O
CO B
attachment O
reaction O
are O
more O
or O
less O
stoichiometry O
- O
dependent O
. O

However O
, O
CO B
was O
found O
to O
be O
released O
from O
the O
cluster O
ions O
when O
the O
cluster O
ions O
were O
heated O
up O
to O
523 O
K O
after O
the O
reaction O
. O

This O
finding O
is O
interpreted O
such O
that O
the O
CO B
molecule O
that O
physisorbs O
weakly O
to O
NinOn B
+ I
x I
( I
+ I
) I
at O
room O
temperature O
desorbs O
into O
the O
gas O
phase O
by O
the O
post O
heating O
. O

In O
addition O
, O
we O
found O
that O
an O
oxygen B
extraction O
reaction O
by O
a O
CO B
molecule O
actually O
occurs O
for O
oxygen B
- O
rich O
clusters O
such O
as O
Ni6O7 B
( I
+ I
) I
and O
Ni8O9 B
( I
+ I
) I
. O

As O
the O
oxygen B
extraction O
reaction O
is O
one O
order O
of O
magnitude O
slower O
than O
physisorption O
, O
it O
lies O
hidden O
underneath O
of O
the O
faster O
physisorption O
processes O
in O
the O
mass O
spectrum O
but O
is O
revealed O
by O
the O
elimination O
of O
physisorption O
through O
the O
post O
heating O
. O

Antigen O
presentation O
by O
dendritic O
cells O
in O
rheumatoid O
arthritis O
. O

Rheumatoid O
Arthritis O
( O
RA O
) O
is O
a O
chronic O
autoimmune O
inflammatory O
disease O
that O
affects O
largely O
synovial O
joints O
. O

It O
has O
been O
postulated O
that O
activated O
autoreactive O
CD4 O
T O
cells O
play O
a O
key O
role O
in O
triggering O
and O
/ O
or O
maintaining O
the O
chronic O
inflammatory O
process O
in O
RA O
. O

Dendritic O
cells O
( O
DCs O
) O
are O
antigen O
- O
presenting O
cells O
that O
activate O
cognate O
clonal O
CD4 O
T O
cells O
in O
the O
lymph O
nodes O
. O

The O
activation O
process O
involves O
the O
formation O
of O
a O
molecular O
structure O
at O
the O
DC O
- O
CD4 O
T O
cell O
contact O
zone O
called O
immunological O
synapse O
( O
IS O
) O
. O

In O
RA O
, O
the O
synovium O
, O
a O
thin O
layer O
of O
tissue O
below O
the O
capsule O
in O
the O
joints O
, O
shows O
a O
massive O
infiltration O
of O
DCs O
and O
CD4 O
T O
cells O
. O

Subjects O
bearing O
HLA O
- O
DRB1 O
alleles O
of O
the O
Major O
Histocompatibility O
Complex O
II O
gene O
displaying O
a O
motif O
called O
RA O
" O
shared O
epitope O
( O
SE O
) O
" O
, O
have O
an O
enhanced O
susceptibility O
to O
suffer O
RA O
. O

Interestingly O
, O
the O
SE O
- O
containing O
HLA O
- O
DRB1 O
molecules O
display O
a O
pocket O
with O
a O
high O
affinity O
for O
citrullinated O
antigens O
, O
which O
are O
found O
at O
higher O
levels O
in O
subjects O
prone O
to O
develop O
RA O
. O

Thus O
, O
it O
is O
possible O
that O
the O
DCs O
of O
susceptible O
individuals O
may O
form O
IS O
with O
particular O
features O
that O
may O
present O
citrullinated O
peptides O
to O
autorreactive O
na O
i O
ve O
CD4 O
T O
clones O
that O
, O
after O
being O
activated O
, O
contribute O
to O
the O
initiation O
or O
development O
of O
the O
disease O
. O

Herein O
I O
put O
forward O
a O
model O
of O
RA O
initiation O
based O
on O
current O
information O
on O
the O
immune O
response O
and O
RA O
. O

Citrullinated O
peptides O
in O
the O
diagnosis O
of O
rheumatoid O
arthritis O
. O

Antibodies O
directed O
against O
citrullinated O
proteins O
and O
peptides O
( O
ACPAs O
) O
are O
the O
most O
specific O
serological O
markers O
available O
for O
diagnosing O
rheumatoid O
arthritis O
( O
RA O
) O
. O

ACPAs O
may O
be O
detected O
several O
years O
before O
symptoms O
of O
RA O
appear O
, O
and O
their O
presence O
at O
disease O
onset O
is O
a O
good O
predictor O
of O
the O
development O
of O
erosive O
joint O
lesions O
. O

RA O
patients O
can O
be O
classified O
into O
two O
major O
groups O
: O
those O
who O
have O
ACPAs O
and O
those O
who O
do O
not O
. O

The O
presence O
of O
ACPAs O
at O
early O
stages O
of O
RA O
predicts O
the O
development O
of O
earlier O
and O
more O
widespread O
joint O
erosions O
, O
and O
low O
remission O
rates O
. O
Synthetic O
peptides O
can O
replace O
cognate O
proteins O
in O
solid O
- O
phase O
assays O
for O
specific O
autoantibody O
recognition O
in O
RA O
patients O
. O

The O
use O
of O
synthetic O
peptides O
instead O
of O
proteins O
represents O
an O
advantage O
in O
terms O
of O
the O
reproducibility O
of O
such O
immunoassays O
. O

Proteins O
also O
contain O
non O
- O
citrullinated O
epitopes O
that O
are O
recognized O
by O
non O
- O
RA O
sera O
and O
this O
could O
reduce O
the O
specificity O
of O
the O
test O
. O

The O
use O
of O
synthetic O
citrullinated O
peptides O
gives O
absolute O
control O
over O
the O
exact O
epitopes O
presented O
. O

Furthermore O
, O
it O
is O
difficult O
to O
prepare O
sufficient O
amounts O
of O
high O
- O
quality O
antigenic O
proteins O
with O
a O
well O
- O
defined O
degree O
of O
citrullination O
. O

Synthetic O
citrullinated O
peptides O
, O
in O
contrast O
, O
are O
easily O
obtained O
in O
a O
pure O
form O
with O
a O
well O
- O
defined O
chemical O
structure O
and O
the O
epitopes O
can O
be O
precisely O
oriented O
in O
the O
plate O
by O
covalent O
binding O
of O
the O
peptides O
. O
Chimeric O
peptides O
bearing O
different O
citrullinated O
protein O
domains O
have O
recently O
been O
used O
in O
the O
design O
of O
RA O
diagnosis O
systems O
. O

The O
results O
of O
the O
application O
of O
those O
systems O
indicate O
that O
more O
than O
one O
serological O
test O
is O
required O
to O
classify O
RA O
patients O
based O
on O
the O
presence O
or O
absence O
of O
ACPAs O
. O

Each O
of O
the O
target O
molecules O
reported O
( O
fibrin O
, O
vimentin O
and O
filaggrin O
) O
helps O
to O
identify O
a O
particular O
subset O
of O
RA O
patients O
. O

Benchmark O
quantum O
- O
chemical O
calculations O
on O
a O
complete O
set O
of O
rotameric O
families O
of O
the O
DNA O
sugar B
- O
phosphate B
backbone O
and O
their O
comparison O
with O
modern O
density O
functional O
theory O
. O

The O
DNA O
sugar B
- O
phosphate B
backbone O
has O
a O
substantial O
influence O
on O
the O
DNA O
structural O
dynamics O
. O

Structural O
biology O
and O
bioinformatics O
studies O
revealed O
that O
the O
DNA O
backbone O
in O
experimental O
structures O
samples O
a O
wide O
range O
of O
distinct O
conformational O
substates O
, O
known O
as O
rotameric O
DNA O
backbone O
conformational O
families O
. O

Their O
correct O
description O
is O
essential O
for O
methods O
used O
to O
model O
nucleic O
acids O
and O
is O
known O
to O
be O
the O
Achilles O
heel O
of O
force O
field O
computations O
. O

In O
this O
study O
we O
report O
the O
benchmark O
database O
of O
MP2 O
calculations O
extrapolated O
to O
the O
complete O
basis O
set O
of O
atomic O
orbitals O
with O
aug O
- O
cc O
- O
pVTZ O
and O
aug O
- O
cc O
- O
pVQZ O
basis O
sets O
, O
MP2 O
( O
T O
, O
Q O
) O
, O
augmented O
by O
Delta O
CCSD O
( O
T O
) O
/ O
aug O
- O
cc O
- O
pVDZ O
corrections O
. O

The O
calculations O
are O
performed O
in O
the O
gas O
phase O
as O
well O
as O
using O
a O
COSMO O
solvent O
model O
. O

This O
study O
includes O
a O
complete O
set O
of O
18 O
established O
and O
biochemically O
most O
important O
families O
of O
DNA O
backbone O
conformations O
and O
several O
other O
salient O
conformations O
that O
we O
identified O
in O
experimental O
structures O
. O

We O
utilize O
an O
electronically O
sufficiently O
complete O
DNA O
sugar B
- O
phosphate B
- O
sugar B
( O
) O
backbone O
model O
system O
truncated O
to O
prevent O
undesired O
intramolecular O
interactions O
. O

The O
calculations O
are O
then O
compared O
with O
other O
QM O
methods O
. O

The O
BLYP O
and O
TPSS O
functionals O
supplemented O
with O
Grimme O
' O
s O
D3 O
( O
BJ O
) O
dispersion O
term O
provide O
the O
best O
tradeoff O
between O
computational O
demands O
and O
accuracy O
and O
can O
be O
recommended O
for O
preliminary O
conformational O
searches O
as O
well O
as O
calculations O
on O
large O
model O
systems O
. O

Among O
the O
tested O
methods O
, O
the O
best O
agreement O
with O
the O
benchmark O
database O
has O
been O
obtained O
for O
the O
double O
- O
hybrid O
DSD O
- O
BLYP O
functional O
in O
combination O
with O
a O
quadruple O
- O
zeta O
basis O
set O
, O
which O
is O
, O
however O
, O
computationally O
very O
demanding O
. O

The O
new O
hybrid O
density O
functionals O
PW6B95 O
- O
D3 O
and O
MPW1B95 O
- O
D3 O
yield O
outstanding O
results O
and O
even O
slightly O
outperform O
the O
computationally O
more O
demanding O
PWPB95 O
double O
- O
hybrid O
functional O
. O

B3LYP O
- O
D3 O
is O
somewhat O
less O
accurate O
compared O
to O
the O
other O
hybrids O
. O

Extrapolated O
MP2 O
( O
D O
, O
T O
) O
calculations O
are O
not O
as O
accurate O
as O
the O
less O
demanding O
DFT O
- O
D3 O
methods O
. O

Preliminary O
force O
field O
tests O
using O
several O
charge O
sets O
reveal O
an O
almost O
order O
of O
magnitude O
larger O
deviations O
from O
the O
reference O
QM O
data O
compared O
to O
modern O
DFT O
- O
D3 O
, O
underlining O
the O
challenges O
facing O
force O
field O
simulations O
of O
nucleic O
acids O
. O

As O
expected O
, O
inclusion O
of O
the O
solvent O
environment O
approximated O
by O
a O
continuum O
approach O
has O
a O
large O
impact O
on O
the O
relative O
stabilities O
of O
different O
backbone O
substates O
and O
is O
important O
when O
comparing O
the O
QM O
data O
with O
structural O
bioinformatics O
and O
other O
experimental O
data O
. O

Golimumab O
for O
the O
Treatment O
of O
Rheumatoid O
Arthritis O
After O
the O
Failure O
of O
Previous O
Disease O
- O
Modifying O
Antirheumatic O
Drugs O
: O
A O
NICE O
Single O
Technology O
Appraisal O
. O

As O
part O
of O
the O
National O
Institute O
for O
Health O
and O
Clinical O
Excellence O
( O
NICE O
) O
single O
technology O
appraisal O
( O
STA O
) O
process O
, O
the O
manufacturer O
of O
golimumab O
( O
Simponi O
( O
( O
R O
) O
) O
; O
Merck O
Sharp O
& O
Dohme O
, O
USA O
) O
was O
invited O
to O
submit O
evidence O
for O
its O
clinical O
and O
cost O
effectiveness O
for O
the O
treatment O
of O
rheumatoid O
arthritis O
( O
RA O
) O
after O
the O
failure O
of O
previous O
disease O
- O
modifying O
antirheumatic O
drugs O
( O
DMARDs O
) O
. O

The O
School O
of O
Health O
and O
Related O
Research O
Technology O
Appraisal O
Group O
( O
ScHARR O
- O
TAG O
) O
at O
The O
University O
of O
Sheffield O
was O
commissioned O
to O
act O
as O
the O
independent O
Evidence O
Review O
Group O
( O
ERG O
) O
. O

This O
article O
provides O
details O
of O
the O
manufacturer O
' O
s O
initial O
submission O
, O
the O
ERG O
' O
s O
clarification O
questions O
and O
the O
ERG O
report O
submitted O
to O
NICE O
. O

The O
decision O
made O
by O
NICE O
is O
provided O
alongside O
a O
brief O
comment O
on O
additional O
results O
produced O
from O
an O
additional O
analysis O
requested O
by O
NICE O
on O
behalf O
of O
the O
Committee O
. O

The O
ERG O
produced O
a O
critical O
review O
of O
the O
evidence O
for O
the O
clinical O
and O
cost O
effectiveness O
of O
the O
technology O
based O
on O
upon O
the O
manufacturer O
' O
s O
submission O
to O
NICE O
. O

The O
clinical O
evidence O
was O
derived O
from O
three O
randomized O
controlled O
trials O
of O
golimumab O
in O
the O
treatment O
of O
moderate O
to O
severe O
RA O
: O
GO O
- O
FORWARD O
and O
Kay O
et O
al O
. O

( O
DMARD O
- O
experienced O
population O
) O
and O
GO O
- O
AFTER O
( O
tumour O
necrosis O
factor O
[ O
TNF O
] O
- O
alpha O
inhibitor O
- O
experienced O
population O
) O
. O

The O
ERG O
considered O
that O
the O
trials O
were O
of O
reasonable O
methodological O
quality O
and O
measured O
a O
clinically O
relevant O
range O
of O
outcomes O
. O

The O
trials O
for O
golimumab O
, O
as O
well O
as O
comparator O
treatments O
, O
were O
synthesized O
using O
mixed O
- O
treatment O
comparison O
methods O
for O
the O
DMARD O
- O
experienced O
population O
and O
an O
indirect O
comparison O
using O
the O
Bucher O
method O
for O
the O
TNF O
- O
alpha O
inhibitor O
- O
experienced O
population O
. O

The O
trials O
used O
were O
appropriate O
, O
although O
no O
definitive O
judgement O
regarding O
the O
comparative O
efficacy O
of O
golimumab O
with O
other O
biologics O
was O
possible O
. O

The O
manufacturer O
provided O
a O
DMARD O
- O
experienced O
population O
model O
and O
a O
TNF O
- O
alpha O
inhibitor O
- O
experienced O
population O
model O
. O

The O
models O
allowed O
sequences O
of O
treatments O
to O
be O
evaluated O
for O
each O
population O
, O
although O
a O
fully O
incremental O
analysis O
between O
the O
use O
of O
golimumab O
following O
DMARD O
failure O
and O
the O
use O
of O
golimumab O
following O
TNF O
- O
alpha O
inhibitor O
failure O
was O
not O
possible O
. O

Several O
limitations O
with O
the O
model O
were O
identified O
, O
and O
after O
a O
request O
from O
NICE O
and O
suspension O
of O
the O
appraisal O
, O
the O
manufacturer O
submitted O
sensitivity O
analyses O
with O
an O
additional O
American O
College O
of O
Rheumatology O
70 O
% O
improvement O
criteria O
( O
ACR70 O
) O
health O
state O
included O
, O
using O
SF O
- O
36 O
data O
directly O
from O
the O
GO O
- O
FORWARD O
study O
. O

The O
annual O
rate O
of O
the O
Health O
Assessment O
Questionnaire O
( O
HAQ O
) O
score O
increase O
for O
patients O
receiving O
palliative O
treatment O
was O
also O
changed O
from O
0 O
. O
09 O
to O
0 O
. O
06 O
. O

The O
further O
analyses O
provided O
highlighted O
the O
particular O
sensitivity O
of O
the O
results O
to O
HAQ O
progression O
rates O
and O
the O
re O
- O
administration O
frequency O
for O
rituximab O
in O
the O
TNF O
- O
alpha O
inhibitor O
- O
experienced O
population O
. O

The O
Appraisal O
Committee O
concluded O
that O
golimumab O
should O
be O
recommended O
in O
combination O
with O
methotrexate B
as O
an O
option O
for O
patients O
with O
severe O
active O
RA O
who O
have O
failed O
on O
conventional O
DMARDs O
, O
or O
who O
have O
failed O
on O
a O
TNF O
- O
alpha O
inhibitor O
and O
are O
contraindicated O
to O
or O
withdrawn O
from O
rituximab O
. O

Evolutionary O
concepts O
in O
ecotoxicology O
: O
tracing O
the O
genetic O
background O
of O
differential O
cadmium B
sensitivities O
in O
invertebrate O
lineages O
. O

In O
many O
toxicological O
and O
ecotoxicological O
studies O
and O
experimental O
setups O
, O
the O
investigator O
is O
mainly O
interested O
in O
traditional O
parameters O
such O
as O
toxicity O
data O
and O
effects O
of O
toxicants O
on O
molecular O
, O
cellular O
or O
physiological O
functions O
of O
individuals O
, O
species O
or O
statistical O
populations O
. O

It O
is O
clear O
, O
however O
, O
that O
such O
approaches O
focus O
on O
the O
phenotype O
level O
of O
animal O
species O
, O
whilst O
the O
genetic O
and O
evolutionary O
background O
of O
reactions O
to O
environmental O
toxicants O
may O
remain O
untold O
. O

In O
ecotoxicological O
risk O
assessment O
, O
moreover O
, O
species O
sensitivities O
towards O
pollutants O
are O
often O
regarded O
as O
random O
variables O
in O
a O
statistical O
approach O
. O

Beyond O
statistics O
, O
however O
, O
toxicant O
sensitivity O
of O
every O
species O
assumes O
a O
biological O
significance O
, O
especially O
if O
we O
consider O
that O
sensitivity O
traits O
have O
developed O
in O
lineages O
of O
species O
with O
common O
evolutionary O
roots O
. O

In O
this O
article O
, O
the O
genetic O
and O
evolutionary O
background O
of O
differential O
Cd B
sensitivities O
among O
invertebrate O
populations O
and O
species O
and O
their O
potential O
of O
adaptation O
to O
environmental O
Cd B
exposure O
will O
be O
highlighted O
. O

Important O
evolutionary O
and O
population O
genetic O
concepts O
such O
as O
genome O
structure O
and O
their O
importance O
for O
evolutionary O
adaptation O
, O
population O
structure O
of O
affected O
individuals O
, O
as O
well O
as O
micro O
and O
macroevolutionary O
mechanisms O
of O
Cd B
resistance O
in O
invertebrate O
lineages O
will O
be O
stressed O
by O
discussing O
examples O
of O
work O
from O
our O
own O
laboratory O
along O
with O
a O
review O
of O
relevant O
literature O
data O
and O
a O
brief O
discussion O
of O
open O
questions O
along O
with O
some O
perspectives O
for O
further O
research O
. O

Both O
, O
differences O
and O
similarities O
in O
Cd B
sensitivity O
traits O
of O
related O
invertebrate O
species O
can O
only O
be O
understood O
if O
we O
consider O
the O
underlying O
evolutionary O
processes O
and O
genetic O
( O
or O
epigenetic O
) O
mechanisms O
. O

Keeping O
in O
mind O
this O
perception O
can O
help O
us O
to O
better O
understand O
and O
interpret O
more O
precisely O
why O
the O
sensitivity O
of O
some O
species O
or O
species O
groups O
towards O
a O
certain O
toxicant O
( O
or O
metal O
) O
may O
be O
ranked O
in O
the O
lower O
or O
higher O
range O
of O
species O
sensitivity O
distributions O
. O

Hence O
, O
such O
a O
perspective O
will O
transcend O
a O
purely O
statistical O
view O
of O
the O
sensitivity O
distributions O
concept O
, O
and O
will O
enhance O
ecotoxicology O
in O
many O
respects O
. O

A O
Platform O
for O
Large O
- O
Scale O
Graphene B
Electronics O
- O
CVD O
Growth O
of O
Single O
- O
Layer O
Graphene B
on O
CVD O
- O
Grown O
Hexagonal O
Boron B
Nitride I
. O

Direct O
chemical O
vapor O
deposition O
( O
CVD O
) O
growth O
of O
single O
- O
layer O
graphene B
on O
CVD O
- O
grown O
hexagonal O
boron B
nitride I
( O
h B
- I
BN I
) O
film O
can O
suggest O
a O
large O
- O
scale O
and O
high O
- O
quality O
graphene B
/ O
h B
- I
BN I
film O
hybrid O
structure O
with O
a O
defect O
- O
free O
interface O
. O

This O
sequentially O
grown O
graphene B
/ O
h O
- O
BN O
film O
shows O
better O
electronic O
properties O
than O
that O
of O
graphene B
/ O
SiO2 B
or O
graphene B
transferred O
on O
h O
- O
BN O
film O
, O
and O
suggests O
a O
new O
promising O
template O
for O
graphene B
device O
fabrication O
. O

The O
cation O
- O
pi O
box O
is O
a O
specific O
phosphatidylcholine B
membrane O
targeting O
motif O
. O

PPeripheral O
membrane O
proteins O
can O
be O
targeted O
to O
specific O
organelles O
or O
the O
plasma O
membrane O
by O
differential O
recognition O
of O
phospholipid O
headgroups O
. O

While O
molecular O
determinants O
of O
specificity O
for O
several O
headgroups O
, O
including O
phosphatidylserine B
and O
phosphoinositides B
are O
well O
defined O
, O
specific O
recognition O
of O
the O
headgroup O
of O
the O
zwitterionic O
phosphatidylcholine B
( O
PC O
) O
is O
less O
well O
understood O
. O

In O
cytosolic O
proteins O
the O
cation O
- O
pi O
box O
provides O
a O
suitable O
receptor O
for O
choline B
recognition O
and O
binding O
through O
the O
trimethylammonium B
moiety O
. O

In O
PC O
, O
this O
moiety O
might O
provide O
a O
sufficient O
handle O
to O
bind O
to O
peripheral O
proteins O
via O
a O
cation O
- O
pi O
cage O
, O
where O
the O
pi O
systems O
of O
two O
or O
more O
aromatic O
residues O
are O
within O
4 O
- O
5 O
A O
of O
the O
quaternary B
amine I
. O

We O
prove O
this O
hypothesis O
by O
engineering O
the O
cation O
- O
pi O
box O
into O
secreted O
phosphatidylinositol B
- O
specific O
phospholipase O
C O
from O
Staphylococcus O
aureus O
, O
which O
lacks O
specific O
PC O
recognition O
. O

The O
N254Y O
/ O
H258Y O
variant O
selectively O
binds O
PC O
- O
enriched O
vesicles O
, O
and O
X O
- O
ray O
crystallography O
reveals O
N254Y O
/ O
H258Y O
binds O
choline B
and O
dibutyroylphosphatid B
within O
the O
cation O
- O
pi O
motif O
. O

Such O
simple O
PC O
recognition O
motifs O
could O
be O
engineered O
into O
a O
wide O
variety O
of O
secondary O
structures O
providing O
a O
generally O
applicable O
method O
for O
specific O
recognition O
of O
PC O
. O

Theoretical O
Investigation O
of O
Generator O
- O
Collector O
Microwell O
Arrays O
for O
Improving O
Electroanalytical O
Selectivity O
: O
Application O
to O
Selective O
Dopamine B
Detection O
in O
the O
Presence O
of O
Ascorbic B
Acid I
. O

Recessed O
generator O
- O
collector O
assemblies O
consisting O
of O
an O
array O
of O
recessed O
disks O
( O
generator O
electrodes O
) O
with O
a O
gold O
layer O
( O
collector O
electrode O
) O
deposited O
over O
the O
top O
- O
plane O
insulator O
reportedly O
allow O
increased O
selectivity O
and O
sensitivity O
during O
electrochemical O
detection O
of O
dopamine B
( O
DA O
) O
in O
the O
presence O
of O
ascorbic B
acid I
( O
AA O
) O
, O
a O
situation O
which O
is O
frequently O
encountered O
. O

In O
sensor O
design O
, O
the O
potential O
of O
the O
disk O
electrodes O
is O
set O
to O
the O
wave O
plateau O
of O
DA O
, O
whereas O
the O
plane O
electrode O
is O
biased O
at O
the O
irreversible O
wave O
plateau O
of O
AA O
before O
the O
onset O
of O
the O
DA O
oxidation O
wave O
. O

Thus O
, O
AA O
is O
scavenged O
but O
DA O
is O
allowed O
to O
enter O
the O
nanocavities O
to O
be O
oxidized O
at O
the O
disk O
electrodes O
, O
and O
its O
signal O
is O
further O
amplified O
by O
redox O
cycling O
between O
disk O
and O
plane O
electrodes O
. O

Several O
different O
theoretical O
approaches O
are O
elaborated O
herein O
to O
analyze O
the O
behavior O
of O
the O
system O
, O
and O
their O
conclusions O
are O
successfully O
tested O
by O
experiments O
. O

This O
reveals O
the O
crucial O
role O
of O
the O
plane O
- O
electrode O
area O
which O
screens O
access O
to O
the O
recessed O
disks O
( O
i O
. O
e O
. O
acts O
as O
a O
diffusional O
Faraday O
cage O
) O
and O
simultaneously O
contributes O
to O
amplification O
of O
the O
analyte O
signal O
through O
positive O
feedback O
, O
as O
occurs O
in O
interdigitated O
arrays O
and O
scanning O
electrochemical O
microscopy O
. O

Simulations O
also O
allow O
for O
the O
evaluation O
of O
the O
benefits O
of O
different O
geometries O
inspired O
by O
the O
above O
design O
and O
different O
operating O
modes O
for O
increasing O
the O
sensor O
performance O
. O

Tuning O
the O
Electrical O
and O
Optical O
Properties O
of O
Graphene B
by O
Ozone B
Treatment O
for O
Patterning O
Monolithic O
Transparent O
Electrodes O
. O

Tunable O
electrical O
and O
optical O
properties O
of O
graphene B
are O
vital O
to O
promote O
its O
use O
as O
film O
electrodes O
in O
a O
variety O
of O
devices O
. O

We O
developed O
an O
etching O
- O
free O
ozone B
treatment O
method O
to O
continuously O
tune O
the O
electrical O
resistance O
and O
optical O
transmittance O
of O
graphene B
films O
by O
simply O
varying O
the O
time O
and O
temperature O
of O
graphene B
exposure O
to O
ozone B
. O

Initially O
, O
ozone B
exposure O
dramatically O
decreases O
the O
electrical O
resistance O
of O
graphene B
films O
by O
p O
- O
doping O
, O
but O
this O
is O
followed O
by O
increases O
in O
the O
resistance O
and O
optical O
transmittance O
as O
a O
result O
of O
surface O
oxidation O
. O

The O
rate O
of O
resistance O
increase O
can O
be O
significantly O
increased O
by O
raising O
the O
treatment O
temperature O
. O

The O
ozone B
- O
oxidized O
graphene B
is O
not O
removed O
but O
is O
gradually O
transformed O
to O
graphene B
oxide I
( O
GO O
) O
. O

On O
the O
basis O
of O
such O
effects O
of O
ozone B
treatment O
, O
we O
demonstrate O
a O
well O
- O
defined O
graphene B
pattern O
by O
using O
ozone B
photolithography O
, O
in O
which O
the O
ozone B
- O
treated O
graphene B
electrodes O
are O
monolithic O
but O
separated O
by O
insulating O
GO O
regions O
. O

Such O
a O
monolithic O
graphene B
pattern O
shows O
low O
optical O
contrast O
, O
a O
clean O
and O
more O
hydrophilic O
surface O
, O
indicating O
the O
promising O
use O
of O
ozone B
treatment O
to O
achieve O
high O
- O
performance O
graphene B
- O
based O
optoelectronic O
devices O
. O

Asymmetric O
dimethylarginine B
predicts O
decline O
of O
glucose B
tolerance O
in O
men O
with O
stable O
coronary O
artery O
disease O
: O
a O
4 O
. O
5 O
- O
year O
follow O
- O
up O
study O
. O

BACKGROUND O
: O
Endothelial O
dysfunction O
, O
largely O
dependent O
on O
impaired O
nitric B
oxide I
bioavailability O
, O
has O
been O
reportedly O
associated O
with O
incident O
type O
2 O
diabetes O
. O

Our O
aim O
was O
to O
test O
the O
hypothesis O
that O
asymmetric O
dimethylarginine B
( O
ADMA O
) O
, O
an O
endogenous O
inhibitor O
of O
nitric B
oxide I
formation O
, O
might O
be O
linked O
to O
future O
deterioration O
in O
glucose B
tolerance O
in O
stable O
coronary O
artery O
disease O
( O
CAD O
) O
. O

METHODS O
: O
We O
studied O
80 O
non O
- O
diabetic O
men O
( O
mean O
age O
55 O
+ O
/ O
- O
11 O
years O
) O
with O
stable O
angina O
who O
underwent O
successful O
elective O
complex O
coronary O
angioplasty O
and O
were O
receiving O
a O
standard O
medical O
according O
to O
practice O
guidelines O
. O

Plasma O
ADMA O
and O
its O
structural O
isomer O
symmetric B
dimethylarginine I
( O
SDMA B
) O
were O
measured O
prior O
to O
coronary O
angiography O
. O

An O
estimate O
of O
insulin O
resistance O
by O
homeostasis O
model O
assessment O
( O
HOMA O
- O
IR O
index O
) O
was O
calculated O
from O
fasting O
insulin O
and O
glucose B
. O

Deterioration O
in O
glucose B
tolerance O
was O
defined O
as O
development O
of O
type O
2 O
diabetes O
or O
progression O
from O
a O
normal O
glucose B
tolerance O
to O
impaired O
fasting O
glucose B
. O

RESULTS O
: O
Over O
a O
median O
follow O
- O
up O
of O
55 O
months O
11 O
subjects O
developed O
type O
2 O
diabetes O
and O
13 O
progressed O
to O
impaired O
fasting O
glucose B
. O

Incident O
deterioration O
of O
glucose B
tolerance O
was O
associated O
with O
ADMA O
( O
hazard O
ratio O
[ O
HR O
] O
per O
1 O
- O
SD O
increment O
1 O
. O
64 O
[ O
95 O
% O
CI O
: O
1 O
. O
14 O
- O
- O
2 O
. O
35 O
] O
; O
P O
= O
0 O
. O
007 O
) O
, O
log O
( O
HOMA O
- O
IR O
index O
) O
( O
HR O
= O
1 O
. O
60 O
[ O
1 O
. O
16 O
- O
- O
2 O
. O
20 O
] O
; O
P O
= O
0 O
. O
004 O
) O
and O
body O
- O
mass O
index O
( O
HR O
= O
1 O
. O
44 O
[ O
0 O
. O
95 O
- O
- O
2 O
. O
17 O
] O
; O
P O
= O
0 O
. O
08 O
) O
by O
univariate O
Cox O
regression O

. O

ADMA O
( O
HR O
= O
1 O
. O
65 O
[ O
1 O
. O
14 O
- O
- O
2 O
. O
38 O
] O
; O
p O
= O
0 O
. O
008 O
) O
and O
log O
( O
HOMA O
- O
IR O
index O
) O
( O
HR O
= O
1 O
. O
55 O
[ O
1 O
. O
10 O
- O
- O
2 O
. O
17 O
] O
; O
P O
= O
0 O
. O
01 O
) O
were O
multivariate O
predictors O
of O
a O
decline O
in O
glucose B
tolerance O
. O

ADMA O
and O
SDMA O
were O
unrelated O
to O
body O
- O
mass O
index O
, O
HOMA O
- O
IR O
index O
, O
insulin O
or O
glucose B
. O

CONCLUSIONS O
: O
ADMA O
predicts O
future O
deterioration O
of O
glucose B
tolerance O
independently O
of O
baseline O
insulin O
resistance O
in O
men O
with O
stable O
CAD O
. O

Whether O
this O
association O
reflects O
a O
contribution O
of O
endothelial O
dysfunction O
to O
accelerated O
decline O
of O
insulin O
sensitivity O
, O
or O
represents O
only O
an O
epiphenomenon O
accompanying O
pre O
- O
diabetes O
, O
remains O
to O
be O
elucidated O
. O

The O
observed O
relationship O
might O
contribute O
to O
the O
well O
- O
recognized O
ability O
of O
ADMA O
to O
predict O
cardiovascular O
outcome O
. O

Sodium B
fluoride I
induces O
apoptosis O
in O
odontoblasts O
via O
a O
JNK O
- O
dependent O
mechanism O
. O

Sodium B
fluoride I
( O
NaF B
) O
is O
widely O
used O
for O
the O
treatment O
of O
dental O
caries O
and O
dentin O
hypersensitivity O
. O

However O
, O
its O
pro O
- O
apoptotic O
effect O
on O
odontoblasts O
may O
lead O
to O
harmful O
side O
- O
effects O
. O

The O
purpose O
of O
this O
study O
was O
to O
evaluate O
the O
pro O
- O
apoptotic O
effects O
of O
NaF B
in O
odontoblasts O
and O
elucidate O
the O
possible O
underlying O
molecular O
mechanisms O
. O

NaF B
generated O
cytotoxic O
effects O
in O
odontoblast O
- O
lineage O
cell O
( O
OLC O
) O
in O
a O
dose O
- O
and O
time O
- O
dependent O
manner O
. O

Exposure O
of O
cells O
to O
4mM O
NaF B
for O
24h O
induced O
caspase O
- O
3 O
activation O
, O
ultrastructural O
alterations O
, O
and O
resulted O
in O
the O
translocation O
of O
Bax O
to O
the O
mitochondria O
and O
the O
release O
of O
cytochrome O
c O
from O
the O
mitochondrial O
inter O
- O
membrane O
space O
into O
the O
cytosol O
, O
indicating O
that O
fluoride B
- O
mediated O
apoptosis O
is O
mitochondria O
- O
dependent O
. O

Fluoride B
treatment O
also O
increased O
phosphorylation O
of O
JNK O
and O
ERK O
, O
but O
not O
p38 O
, O
and O
apoptosis O
induced O
by O
fluoride B
was O
notably O
or O
partly O
suppressed O
by O
treatment O
with O
JNK O
or O
ERK O
inhibitors O
, O
respectively O
. O

Taken O
together O
, O
these O
findings O
suggest O
that O
NaF B
induces O
apoptosis O
in O
OLC O
odontoblasts O
through O
a O
JNK O
- O
dependent O
mitochondrial O
pathway O
. O

Perinatal O
exposure O
to O
BDE B
- I
99 I
causes O
learning O
disorders O
and O
decreases O
serum O
thyroid O
hormone O
levels O
and O
BDNF O
gene O
expression O
in O
hippocampus O
in O
rat O
offspring O
. O

Exposure O
of O
pregnant O
women O
to O
polybrominated B
diphenyl I
ethers I
( O
PBDEs B
) O
may O
mean O
serious O
health O
risks O
. O

The O
main O
goal O
of O
the O
present O
study O
was O
to O
examine O
the O
neurobehavioral O
changes O
in O
rat O
offspring O
that O
were O
perinatally O
exposed O
to O
one O
of O
the O
most O
prevalent O
PBDEs B
congeners O
found O
in O
humans O
, O
2 B
, I
2 I
' I
, I
4 I
, I
4 I
' I
, I
5 I
- I
pentaBDE I
( O
BDE B
- I
99 I
) O
. O

Rat O
dams O
were O
exposed O
to O
0 O
, O
1 O
and O
2mg O
/ O
kg O
/ O
day O
of O
BDE B
- I
99 I
from O
gestation O
day O
6 O
to O
post O
- O
natal O
day O
21 O
. O

When O
pups O
were O
weaning O
, O
cortex O
and O
hippocampal O
gene O
expressions O
of O
brain O
- O
derived O
neurotrophic O
factor O
( O
BDNF O
) O
of O
the O
different O
isoforms O
of O
the O
thyroid B
hormone I
( O
TH O
) O
receptors O
( O
TRs O
) O
were O
evaluated O
. O

Serum O
TH O
levels O
were O
also O
determined O
. O

The O
remaining O
pups O
were O
assessed O
by O
neurobehavioral O
testing O
for O
learning O
and O
memory O
function O
. O

The O
results O
showed O
that O
maternal O
transference O
of O
BDE B
- I
99 I
produced O
a O
delay O
in O
the O
spatial O
learning O
task O
in O
the O
water O
maze O
test O
. O

Moreover O
, O
the O
open O
- O
field O
test O
revealed O
a O
significant O
dose O
- O
response O
anxiolytic O
effect O
. O

It O
was O
also O
found O
that O
the O
serum O
levels O
of O
triiodothyronine B
( O
T3 O
) O
, O
tetraiiodothyronine B
( O
T4 O
) O
and O
free O
- O
T4 O
( O
FT4 O
) O
decreased O
. O

Although O
no O
effect O
on O
the O
gene O
expression O
of O
the O
different O
isoforms O
of O
TRs O
was O
observed O
, O
the O
expression O
of O
the O
TH O
- O
mediated O
gene O
BDNF O
was O
down O
- O
regulated O
in O
the O
hippocampus O
. O

These O
results O
indicate O
a O
clear O
signal O
disruption O
of O
TH O
and O
reinforce O
previous O
studies O
in O
which O
neurotoxic O
effects O
of O
PBDEs B
in O
animal O
research O
were O
observed O
at O
levels O
comparable O
to O
those O
found O
in O
humans O
. O

Reward O
and O
aversion O
in O
a O
heterogeneous O
midbrain O
dopamine B
system O
. O

The O
ventral O
tegmental O
area O
( O
VTA O
) O
is O
a O
heterogeneous O
brain O
structure O
that O
serves O
a O
central O
role O
in O
motivation O
and O
reward O
processing O
. O

Abnormalities O
in O
the O
function O
of O
VTA O
dopamine B
( O
DA O
) O
neurons O
and O
the O
targets O
they O
influence O
are O
implicated O
in O
several O
prominent O
neuropsychiatric O
disorders O
including O
addiction O
and O
depression O
. O

Recent O
studies O
suggest O
that O
the O
midbrain O
DA O
system O
is O
composed O
of O
anatomically O
and O
functionally O
heterogeneous O
DA O
subpopulations O
with O
different O
axonal O
projections O
. O

These O
findings O
may O
explain O
a O
number O
of O
previously O
confusing O
observations O
that O
suggested O
a O
role O
for O
DA O
in O
processing O
both O
rewarding O
as O
well O
as O
aversive O
events O
. O

Here O
we O
will O
focus O
on O
recent O
advances O
in O
understanding O
the O
neural O
circuits O
mediating O
reward O
and O
aversion O
in O
the O
VTA O
and O
how O
stress O
as O
well O
as O
drugs O
of O
abuse O
, O
in O
particular O
cocaine B
, O
alter O
circuit O
function O
within O
a O
heterogeneous O
midbrain O
DA O
system O
. O

This O
article O
is O
part O
of O
a O
Special O
Issue O
entitled O
' O
NIDA O
40th O
Anniversary O
Issue O
' O
. O

Phytotoxic O
effects O
of O
the O
cyanobacterial O
neurotoxin O
anatoxin B
- I
a I
: O
Morphological O
, O
physiological O
and O
biochemical O
responses O
in O
aquatic O
macrophyte O
, O
Ceratophyllum O
demersum O
. O

Anatoxin B
- I
a I
is O
one O
of O
the O
common O
and O
major O
cyanobacterial O
neurotoxins O
acting O
as O
a O
powerful O
agonist O
at O
nicotinic O
acetylcholine B
receptors O
( O
nAChR O
) O
. O

In O
recent O
years O
, O
the O
toxin O
has O
become O
the O
focus O
of O
public O
attention O
, O
due O
to O
the O
mass O
development O
of O
cyanobacteria O
( O
cyanobacterial O
blooms O
) O
in O
freshwater O
bodies O
triggered O
by O
eutrophication O
and O
climate O
change O
. O

Anatoxin B
- I
a I
is O
suspected O
to O
have O
a O
distinct O
toxic O
mechanism O
depending O
on O
physiological O
and O
nervous O
systems O
in O
exposed O
organisms O
. O

The O
numerous O
researches O
have O
been O
actively O
conducted O
with O
respect O
to O
the O
toxic O
effects O
of O
anatoxin B
- I
a I
on O
mammals O
; O
however O
, O
little O
research O
has O
aimed O
at O
its O
possible O
effects O
on O
aquatic O
plants O
, O
wherein O
well O
- O
structured O
nervous O
system O
is O
absent O
with O
the O
lack O
of O
various O
components O
of O
the O
acetylcholine B
mechanism O
. O

In O
this O
study O
, O
submerged O
macrophyte O
Ceratophyllum O
demersum O
( O
C O
. O
demersum O
) O
was O
adopted O
to O
examine O
the O
effects O
of O
anatoxin B
- I
a I
on O
morphological O
( O
growth O
) O
, O
physiological O
( O
photosynthetic O
pigment O
contents O
) O
and O
biochemical O
( O
hydrogen B
peroxide I
level O
, O
biotransformation O
and O
antioxidative O
enzymes O
) O
responses O
in O
the O
aquatic O
plant O
at O
environmentally O
relevant O
concentrations O
( O
0 O
. O
005 O
, O
0 O
. O
05 O
, O
0 O
. O
5 O
, O
5 O
and O
50 O
mu O
g O
/ O
L O
) O
. O

The O
significant O
elevation O
of O
antioxidative O
enzymes O
in O
parallel O
with O
increased O
formation O
of O
hydrogen B
peroxide I
appeared O
from O
0 O
. O
5 O
mu O
g O
/ O
L O
of O
anatoxin B
- I
a I
. O

In O
the O
measurement O
of O
photosynthetic O
pigments O
, O
the O
decrease O
in O
chlorophyll B
a I
content O
was O
detected O
at O
5 O
and O
50 O
mu O
g O
/ O
L O
, O
whereas O
the O
increase O
in O
carotenoids O
/ O
total O
chlorophyll B
was O
observed O
from O
0 O
. O
05 O
mu O
g O
/ O
L O
. O

Accordingly O
, O
the O
alteration O
in O
growth O
was O
manifested O
in O
the O
presence O
of O
5 O
and O
50 O
mu O
g O
/ O
L O
of O
anatoxin B
- I
a I
. O

The O
results O
clearly O
indicate O
that O
anatoxin B
- I
a I
can O
disrupt O
homeostasis O
of O
C O
. O
demersum O
through O
induction O
of O
oxidative O
stress O
; O
furthermore O
this O
aquatic O
plant O
possesses O
effective O
defense O
mechanisms O
to O
cope O
with O
low O
concentrations O
of O
anatoxin B
- I
a I
. O

The O
next O
generation O
of O
novel O
low O
- O
density O
lipoprotein O
cholesterol B
- O
lowering O
agents O
: O
Proprotein O
convertase O
subtilisin O
/ O
kexin O
9 O
inhibitors O
. O

Proprotein O
convertase O
subtilisin O
/ O
kexin O
9 O
( O
PCSK9 O
) O
has O
been O
shown O
to O
degrade O
hepatic O
low O
- O
density O
lipoprotein O
receptors O
( O
LDLR O
) O
. O

Gain O
- O
of O
- O
function O
mutations O
promote O
the O
development O
of O
familial O
hypercholesterolemia O
, O
whereas O
loss O
- O
of O
- O
function O
mutations O
are O
associated O
with O
lower O
levels O
of O
circulating O
low O
- O
density O
lipoprotein O
cholesterol B
( O
LDL O
- O
C O
) O
and O
significant O
protection O
against O
coronary O
heart O
disease O
. O

The O
major O
classes O
of O
commonly O
prescribed O
lipid O
- O
lowering O
medications O
, O
such O
as O
statins O
, O
increase O
serum O
PCSK9 O
levels O
, O
thus O
PCSK9 O
inhibition O
would O
increase O
the O
efficacy O
of O
statins O
on O
LDL O
- O
C O
lowering O
. O

Therefore O
, O
PCSK9 O
is O
an O
attractive O
therapeutic O
target O
for O
the O
new O
generation O
of O
cholesterol B
- O
lowering O
drugs O
. O

Here O
, O
we O
present O
a O
brief O
overview O
of O
the O
development O
of O
PCSK9 O
inhibitors O
and O
highlight O
the O
effect O
of O
currently O
prescribed O
LDL O
- O
C O
- O
lowering O
drugs O
on O
PCSK9 O
, O
and O
the O
strategies O
that O
are O
being O
explored O
for O
its O
therapeutic O
inhibition O
. O

Current O
research O
and O
clinical O
trial O
results O
indicate O
that O
a O
PCSK9 O
inhibitor O
may O
be O
an O
exciting O
new O
therapeutic O
drug O
for O
the O
treatment O
of O
dyslipidemia O
and O
relevant O
cardiovascular O
diseases O
. O

Role O
of O
plant O
stanol B
derivatives O
in O
the O
modulation O
of O
cholesterol B
metabolism O
and O
liver O
gene O
expression O
in O
mice O
. O

The O
present O
study O
was O
to O
evaluate O
the O
cholesterol B
- O
lowering O
effect O
of O
two O
novel O
plant O
stanol B
derivatives O
and O
its O
potential O
molecular O
mechanism O
in O
hyper O
- O
cholesterol B
mice O
induced O
by O
a O
high O
- O
cholesterol B
diet O
. O

Results O
showed O
that O
oral O
administration O
of O
plant O
stanyl B
hemisuccinate I
( O
2 O
x O
, O
5 O
x O
) O
and O
plant O
stanyl B
sorbitol I
succinate I
( O
2 O
x O
, O
5 O
x O
) O
effectively O
attenuated O
the O
serum O
total O
cholesterol B
and O
low O
density O
lipoprotein O
cholesterol B
levels O
, O
while O
had O
no O
effect O
on O
the O
serum O
triacylglycerol B
and O
high O
density O
lipoprotein O
cholesterol B
. O

And O
plant O
stanol B
derivatives O
decreased O
liver O
cholesterol B
concentration O
and O
increased O
faecal O
cholesterol B
output O
. O

Meanwhile O
, O
both O
plant O
stanyl B
hemisuccinate I
and O
plant O
stanyl B
sorbitol I
succinate I
could O
remarkably O
promote O
liver O
X O
receptor O
alpha O
( O
LXR O
alpha O
) O
expression O
, O
and O
increased O
cholesterol B
7 O
alpha O
- O
hydroxylase O
( O
CYP7A1 O
) O
expression O
and O
faecal O
total O
bile B
acid I
output O
to O
varying O
degrees O
. O

These O
results O
suggested O
two O
novel O
plant O
stanol B
derivatives O
possessed O
hypocholesterolemic O
effect O
, O
and O
the O
cholesterol B
- O
lowering O
action O
of O
plant O
stanol B
derivatives O
may O
be O
through O
activating O
the O
potential O
LXR O
alpha O
- O
CYP7A1 O
- O
bile B
acid I
excretion O
pathway O
. O

An O
optimised O
method O
for O
the O
accurate O
determination O
of O
zeranol B
and O
diethylstilbestrol B
in O
animal O
tissues O
using O
isotope O
dilution O
- O
liquid O
chromatography O
/ O
mass O
spectrometry O
. O

Isotope O
dilution O
- O
liquid O
chromatography O
/ O
mass O
spectrometry O
( O
ID O
- O
LC O
/ O
MS O
) O
has O
been O
established O
as O
a O
candidate O
reference O
method O
for O
the O
accurate O
determination O
of O
growth O
promoters O
( O
zeranol B
, O
taleranol B
, O
and O
diethylstilbesterol B
) O
in O
raw O
meat O
samples O
. O

Sample O
preparation O
processes O
including O
an O
enzymatic O
hydrolysis O
, O
extraction O
, O
and O
SPE O
clean O
- O
up O
were O
optimised O
. O

The O
sensitivity O
difference O
of O
trans B
- I
and I
cis I
- I
diethylstilbestrol I
( O
isomerizing O
in O
sample O
preparation O
processes O
) O
by O
the O
LC O
/ O
MS O
was O
measured O
by O
running O
a O
trans O
/ O
cis O
mixture O
( O
ratio O
measured O
by O
a O
quantitative O
NMR O
) O
with O
and O
without O
sample O
matrices O
, O
and O
applied O
for O
the O
determination O
of O
total O
diethylstilbestrol B
. O

Validity O
, O
repeatability O
, O
and O
reproducibility O
of O
the O
analytical O
method O
were O
tested O
by O
measuring O
gravimetrically O
fortified O
samples O
( O
chicken O
breast O
, O
bovine O
muscles O
, O
and O
porcine O
muscle O
) O
in O
a O
number O
of O
different O
time O
periods O
. O

Measurement O
results O
agreed O
with O
the O
fortified O
values O
within O
their O
uncertainties O
. O

The O
method O
provided O
accurate O
results O
of O
the O
target O
analytes O
in O
the O
range O
of O
0 O
. O
05 O
- O
15 O
mu O
g O
/ O
kg O
with O
the O
relative O
expanded O
uncertainty O
of O
2 O
- O
15 O
% O
. O

Characterization O
of O
Muscat O
wines O
aroma O
evolution O
using O
comprehensive O
gas O
chromatography O
followed O
by O
a O
post O
- O
analytic O
approach O
to O
2D O
contour O
plots O
comparison O
. O

This O
study O
presents O
the O
application O
of O
a O
headspace O
solid O
- O
phase O
microextraction O
( O
HS O
- O
SPME O
) O
method O
on O
the O
analysis O
of O
Muscat O
- O
based O
wines O
volatiles O
by O
comprehensive O
two O
- O
dimensional O
gas O
chromatography O
( O
GC O
x O
GC O
) O
and O
Time O
- O
Of O
- O
Flight O
mass O
spectrometry O
( O
TOF O
- O
MS O
) O
. O

The O
aroma O
patterns O
were O
established O
for O
different O
samples O
of O
Asti O
Spumante O
and O
Moscato O
d O
' O
Asti O
wines O
, O
stored O
in O
bottles O
for O
6months O
at O
different O
temperatures O
. O

Wines O
stored O
at O
5 O
degrees O
C O
for O
6months O
did O
not O
show O
significant O
changes O
in O
flavor O
; O
otherwise O
, O
the O
samples O
stored O
at O
15 O
and O
25 O
degrees O
C O
, O
showed O
a O
significant O
decrease O
in O
linalool B
, O
beta B
- I
damascenone I
, O
ethyl B
hexanoate I
, O
and O
ethyl B
octanoate I
levels O
. O

In O
these O
last O
samples O
, O
alpha B
- I
terpineol I
, O
hotrienol B
, O
nerol B
oxide I
, O
furanic B
linalool I
oxides I
A I
/ I
B I
and O
rose B
oxide I
concentrations O
significantly O
increased O
. O

A O
mathematical O
approach O
was O
developed O
and O
applied O
to O
raw O
data O
exported O
after O
the O
chromatographic O
course O
, O
in O
order O
( O
i O
) O
to O
normalise O
different O
2D O
chromatograms O
, O
permitting O
their O
direct O
comparison O
and O
( O
ii O
) O
to O
automatically O
identify O
and O
calculate O
from O
pixel O
- O
to O
- O
pixel O
re O
- O
designed O
2D O
chromatograms O
any O
differences O
among O
key O
volatile O
compounds O
. O

Evolution O
of O
quality O
parameters O
during O
red O
wine O
dealcoholization O
by O
osmotic O
distillation O
. O

Osmotic O
distillation O
technique O
was O
used O
for O
the O
total O
dealcoholization O
of O
a O
red O
wine O
( O
Aglianico O
grape O
variety O
) O
up O
to O
0 O
. O
19vol O
. O
% O
. O

The O
dealcoholization O
process O
was O
performed O
in O
subsequent O
cycles O
which O
gave O
rise O
wine O
samples O
at O
different O
alcoholic O
degrees O
. O

The O
effect O
of O
processing O
on O
the O
main O
chemical O
and O
physical O
properties O
of O
Aglianico O
wine O
was O
evaluated O
. O

Among O
wine O
samples O
, O
no O
significant O
differences O
( O
p O
< O
0 O
. O
05 O
) O
of O
oenological O
parameters O
such O
as O
pH O
, O
total O
acidity O
were O
found O
. O

Similarly O
, O
the O
total O
phenolic B
, O
flavonoids B
and O
tartaric B
esters I
content O
and O
the O
composition O
of O
organic O
acids O
did O
not O
show O
significant O
differences O
( O
p O
< O
0 O
. O
05 O
) O
during O
the O
process O
. O

On O
the O
contrary O
, O
colour O
intensity O
and O
tonality O
of O
wine O
samples O
changed O
significantly O
when O
the O
alcohol B
reduction O
was O
over O
the O
6 O
. O
5vol O
. O
% O
. O

Finally O
, O
the O
total O
dealcoholized O
wine O
showed O
properties O
similar O
to O
Aglianico O
wine O
except O
for O
the O
volatile O
compounds O
, O
which O
decreased O
over O
98 O
% O
. O

Hence O
, O
flavour O
enrichment O
may O
be O
required O
to O
produce O
a O
pleasurable O
and O
delicious O
non O
alcoholic O
beverage O
from O
wine O
. O

The O
impact O
of O
catechin B
and O
epicatechin B
, O
total O
phenols B
and O
PPO O
activity O
on O
the O
Mal O
d O
1 O
content O
in O
apple O
fruit O
. O

The O
most O
important O
apple O
allergen O
in O
Central O
Europe O
and O
North O
America O
is O
Mal O
d O
1 O
. O

Apples O
are O
a O
very O
important O
source O
of O
secondary O
plant O
metabolites O
like O
polyphenols B
in O
human O
nutrition O
. O

It O
is O
known O
that O
oxidised O
phenols B
can O
bind O
proteins O
. O

These O
irreversible O
bindings O
can O
lead O
to O
a O
reduced O
allergenicity O
. O

The O
most O
important O
phenols B
in O
apple O
are O
epicatechin B
, O
catechin B
and O
their O
polymeric O
structures O
, O
which O
have O
been O
identified O
as O
substrates O
of O
the O
polyphenoloxidase O
( O
PPO O
) O
. O

The O
aim O
of O
this O
study O
was O
to O
analyse O
the O
influence O
of O
naturally O
occurring O
catechin B
and O
epicatechin B
contents O
in O
apple O
on O
the O
allergenicity O
of O
apple O
fruits O
. O

Fruits O
of O
the O
cultivars O
' O
Elstar O
' O
, O
' O
Diwa O
' O
and O
' O
Boskoop O
' O
were O
harvested O
and O
stored O
for O
8 O
and O
12weeks O
in O
a O
cold O
- O
chamber O
at O
2 O
degrees O
C O
. O

Mal O
d O
1 O
- O
, O
catechin B
- O
, O
epicatechin B
- O
and O
total O
phenol B
content O
as O
well O
as O
the O
activity O
of O
PPO O
were O
determined O
. O

Correlation O
analysis O
showed O
that O
naturally O
occurring O
catechin B
as O
well O
as O
epicatechin B
has O
no O
impact O
on O
the O
Mal O
d O
1 O
content O
of O
the O
tested O
cultivars O
: O
correlation O
coefficient O
ranged O
from O
- O
0 O
. O
203 O
to O
0 O
. O
501 O
for O
the O
correlation O
between O
Mal O
d O
1 O
and O
catechin B
. O

The O
results O
further O
indicated O
that O
the O
activity O
of O
PPO O
is O
more O
important O
than O
the O
content O
of O
total O
phenols B
to O
reduce O
the O
Mal O
d O
1 O
level O
. O

If O
there O
is O
a O
high O
PPO O
activity O
, O
Mal O
d O
1 O
could O
be O
reduced O
even O
if O
the O
total O
phenol B
concentration O
is O
low O
. O

Modeling O
and O
prediction O
of O
extraction O
profile O
for O
microwave O
- O
assisted O
extraction O
based O
on O
absorbed O
microwave O
energy O
. O

A O
modeling O
technique O
based O
on O
absorbed O
microwave O
energy O
was O
proposed O
to O
model O
microwave O
- O
assisted O
extraction O
( O
MAE O
) O
of O
antioxidant O
compounds O
from O
cocoa O
( O
Theobroma O
cacao O
L O
. O
) O
leaves O
. O

By O
adapting O
suitable O
extraction O
model O
at O
the O
basis O
of O
microwave O
energy O
absorbed O
during O
extraction O
, O
the O
model O
can O
be O
developed O
to O
predict O
extraction O
profile O
of O
MAE O
at O
various O
microwave O
irradiation O
power O
( O
100 O
- O
600W O
) O
and O
solvent O
loading O
( O
100 O
- O
300ml O
) O
. O

Verification O
with O
experimental O
data O
confirmed O
that O
the O
prediction O
was O
accurate O
in O
capturing O
the O
extraction O
profile O
of O
MAE O
( O
R O
- O
square O
value O
greater O
than O
0 O
. O
87 O
) O
. O

Besides O
, O
the O
predicted O
yields O
from O
the O
model O
showed O
good O
agreement O
with O
the O
experimental O
results O
with O
less O
than O
10 O
% O
deviation O
observed O
. O

Furthermore O
, O
suitable O
extraction O
times O
to O
ensure O
high O
extraction O
yield O
at O
various O
MAE O
conditions O
can O
be O
estimated O
based O
on O
absorbed O
microwave O
energy O
. O

The O
estimation O
is O
feasible O
as O
more O
than O
85 O
% O
of O
active O
compounds O
can O
be O
extracted O
when O
compared O
with O
the O
conventional O
extraction O
technique O
. O

A O
new O
method O
for O
detection O
of O
five O
alternaria O
toxins O
in O
food O
matrices O
based O
on O
LC O
- O
APCI O
- O
MS O
. O

A O
new O
method O
for O
the O
detection O
of O
alternariol B
( O
AOH B
) O
, O
alternariol B
monomethyl I
ether I
( O
AME B
) O
, O
altenuene B
( O
ALT B
) O
, O
tentoxin B
( O
TEN B
) O
, O
and O
tenuazonic B
acid I
( O
TeA B
) O
, O
five O
alternaria O
toxins O
( O
ATs O
) O
was O
developed O
by O
liquid O
chromatography O
- O
triple O
quadrupole O
mass O
spectrometry O
equipped O
with O
atmospheric O
pressure O
chemical O
ionisation O
( O
APCI O
) O
. O

A O
single O
extraction O
was O
used O
to O
recover O
the O
five O
ATs O
by O
apple O
juices O
, O
beers O
, O
tomato O
sauces O
, O
olives O
and O
dried O
basil O
. O

Different O
Solid O
Phase O
Extractions O
( O
SPE O
) O
and O
clean O
- O
up O
were O
selected O
to O
optimise O
the O
purification O
step O
for O
each O
food O
matrix O
. O

Limits O
of O
detection O
and O
quantification O
were O
, O
respectively O
, O
in O
the O
range O
0 O
. O
16 O
- O
12 O
. O
31 O
and O
0 O
. O
54 O
- O
41 O
. O
04ngg O
( O
- O
1 O
) O
. O

Recovery O
rates O
were O
generally O
above O
70 O
% O
, O
except O
for O
dried O
basil O
and O
olives O
. O

Thirty O
out O
of O
70 O
samples O
analysed O
( O
7 O
apple O
juices O
, O
14 O
beers O
and O
9 O
tomato O
sauces O
) O
resulted O
positive O
to O
at O
least O
one O
alternaria O
toxin O
investigated O
. O

AOH O
was O
the O
most O
common O
AT O
( O
14 O
samples O
) O
, O
followed O
by O
ALT O
( O
10 O
samples O
) O
. O

The O
highest O
concentration O
of O
ATs O
was O
found O
in O
commercial O
apple O
juices O
( O
35 O
. O
33ngg O
( O
- O
1 O
) O
) O
. O

Extraction O
of O
oak O
volatiles O
and O
ellagitannins O
compounds O
and O
sensory O
profile O
of O
wine O
aged O
with O
French O
winewoods O
subjected O
to O
different O
toasting O
methods O
: O
Behaviour O
during O
storage O
. O

In O
Merlot O
wines O
the O
evolution O
of O
volatile O
and O
non O
- O
volatile O
( O
ellagitannins O
) O
compounds O
extracted O
from O
winewoods O
while O
being O
macerated O
for O
12months O
was O
studied O
. O

Seven O
types O
of O
winewoods O
subjected O
to O
different O
toasting O
methods O
were O
used O
. O

Different O
rates O
of O
extraction O
, O
depending O
mainly O
on O
wood O
compounds O
origin O
( O
toasting O
or O
naturally O
present O
in O
wood O
) O
and O
on O
the O
watering O
process O
during O
toasting O
, O
were O
observed O
, O
which O
were O
reflected O
in O
sensory O
differences O
. O

Globally O
, O
volatile O
phenols B
together O
with O
aldehydes B
, O
phenols B
and O
lactones B
showed O
an O
increase O
with O
increasing O
maceration O
time O
. O

Ellagitannins O
were O
extracted O
faster O
during O
the O
first O
3months O
; O
after O
6months O
an O
important O
decrease O
was O
observed O
. O

Wines O
with O
winewoods O
subjected O
to O
watering O
during O
toasting O
were O
lower O
in O
ellagitannins O
concentrations O
and O
demonstrated O
the O
greatest O
decrease O
of O
these O
compounds O
during O
maceration O
. O

Astringency O
and O
bitterness O
intensified O
with O
increasing O
ellagitannins O
. O

Lactones B
induced O
positive O
sweetness O
sensations O
, O
whereas O
furanic B
and I
guaiacol I
compounds O
influenced O
bitterness O
and O
astringency O
. O

Spicy O
and O
vanilla O
descriptors O
were O
related O
to O
eugenol B
, O
vanillin B
and O
other O
odorous O
chemicals O
. O

Selenium B
bioaccessibility O
and O
speciation O
in O
biofortified O
Pleurotus O
mushrooms O
grown O
on O
selenium B
- O
rich O
agricultural O
residues O
. O

Cultivation O
of O
saprophytic O
fungi O
on O
selenium B
- O
rich O
substrates O
can O
be O
an O
effective O
means O
to O
produce O
selenium B
- O
fortified O
food O
. O

Pleurotus O
florida O
, O
an O
edible O
species O
of O
oyster O
mushrooms O
, O
was O
grown O
on O
wheat O
straw O
from O
the O
seleniferous O
belt O
of O
Punjab O
( O
India O
) O
and O
its O
potential O
to O
mobilize O
and O
accumulate O
selenium B
from O
the O
growth O
substrate O
was O
studied O
. O

Selenium B
concentration O
in O
biofortified O
mushrooms O
was O
800 O
times O
higher O
compared O
with O
control O
samples O
grown O
on O
wheat O
straw O
from O
non O
selenium B
- O
rich O
areas O
( O
141 O
vs O
0 O
. O
17 O
mu O
gSeg O
( O
- O
1 O
) O
dry O
weight O
) O
. O

Seventy O
- O
five O
percent O
of O
the O
selenium B
was O
extracted O
after O
in O
vitro O
simulated O
gastrointestinal O
digestion O
and O
investigation O
of O
the O
selenium B
molecular O
fractions O
by O
size O
exclusion O
HPLC O
- O
ICP O
- O
MS O
revealed O
that O
proteins O
and O
any O
other O
high O
molecular O
weight O
selenium B
- O
containing O
molecule O
were O
hydrolyzed O
to O
peptides O
and O
low O
molecular O
weight O
selenocompounds O
. O

Analysis O
of O
the O
gastrointestinal O
hydrolysates O
by O
anion O
exchange O
HPLC O
- O
ICP O
- O
MS O
showed O
that O
the O
bioaccessible O
selenium B
was O
mainly O
present O
as O
selenomethionine B
, O
a O
good O
bioavailable O
source O
of O
selenium B
, O
which O
accounted O
for O
73 O
% O
of O
the O
sum O
of O
the O
detected O
species O
. O

This O
study O
demonstrates O
the O
feasibility O
of O
producing O
selenium B
- O
biofortified O
edible O
mushrooms O
using O
selenium B
- O
rich O
agricultural O
by O
- O
products O
as O
growth O
substrates O
. O

The O
proposed O
approach O
can O
be O
used O
to O
evaluate O
whether O
selenium B
- O
contaminated O
plant O
waste O
materials O
harvested O
from O
high O
- O
selenium B
areas O
may O
be O
used O
to O
produce O
selenium B
- O
biofortified O
edible O
mushrooms O
based O
on O
the O
concentration O
, O
bioaccessibility O
and O
speciation O
of O
selenium B
in O
the O
mushrooms O
. O

Characterization O
of O
Hatay O
honeys O
according O
to O
their O
multi O
- O
element O
analysis O
using O
ICP O
- O
OES O
combined O
with O
chemometrics O
. O

Chemical O
characterisation O
has O
been O
carried O
out O
on O
45 O
honey O
samples O
collected O
from O
Hatay O
region O
of O
Turkey O
. O

The O
concentrations O
of O
17 O
elements O
were O
determined O
by O
inductively O
coupled O
plasma O
optical O
emission O
spectrometry O
( O
ICP O
- O
OES O
) O
. O

Ca B
, O
K B
, O
Mg B
and O
Na B
were O
the O
most O
abundant O
elements O
, O
with O
mean O
contents O
of O
219 O
. O
38 O
, O
446 O
. O
93 O
, O
49 O
. O
06 O
and O
95 O
. O
91mgkg O
( O
- O
1 O
) O
respectively O
. O

The O
trace O
element O
mean O
contents O
ranged O
between O
0 O
. O
03 O
and O
15 O
. O
07mgkg O
( O
- O
1 O
) O
. O

Chemometric O
methods O
such O
as O
principal O
component O
analysis O
( O
PCA O
) O
and O
cluster O
analysis O
( O
CA O
) O
techniques O
were O
applied O
to O
classify O
honey O
according O
to O
mineral O
content O
. O

The O
first O
most O
important O
principal O
component O
( O
PC O
) O
was O
strongly O
associated O
with O
the O
value O
of O
Al B
, O
B B
, O
Cd B
and O
Co B
. O

CA O
showed O
eight O
clusters O
corresponding O
to O
the O
eight O
botanical O
origins O
of O
honey O
. O

PCA O
explained O
75 O
. O
69 O
% O
of O
the O
variance O
with O
the O
first O
six O
PC O
variables O
. O

Chemometric O
analysis O
of O
the O
analytical O
data O
allowed O
the O
accurate O
classification O
of O
the O
honey O
samples O
according O
to O
origin O
. O

Proteolytic O
activities O
in O
fillets O
of O
selected O
underutilized O
Australian O
fish O
species O
. O

The O
hydrolytic O
activity O
of O
major O
endogenous O
proteases O
, O
responsible O
for O
proteolysis O
of O
myofibrillar O
proteins O
during O
post O
- O
mortem O
storage O
, O
may O
be O
an O
indicator O
of O
the O
textural O
quality O
of O
fish O
which O
influences O
consumer O
purchasing O
behaviour O
and O
thus O
market O
value O
of O
the O
final O
product O
. O

Furthermore O
, O
it O
may O
also O
influence O
the O
type O
and O
bioactive O
properties O
of O
the O
peptides O
released O
during O
post O
- O
mortem O
proteolysis O
of O
myofibrillar O
proteins O
. O

This O
study O
compared O
the O
activities O
of O
cathepsins O
B O
, O
B O
+ O
L O
, O
D O
, O
H O
and O
calpain O
- O
like O
enzymes O
in O
crude O
muscle O
extracted O
from O
16 O
Australian O
underutilized O
fish O
species O
. O

Fish O
species O
had O
a O
significant O
effect O
on O
the O
activity O
of O
these O
enzymes O
with O
barracouta O
showing O
the O
highest O
cathepsins O
B O
, O
B O
+ O
L O
, O
D O
and O
H O
activities O
. O

Activities O
of O
cathepsins O
B O
and O
B O
+ O
L O
were O
higher O
than O
cathepsin O
H O
for O
all O
studied O
species O
. O

The O
more O
commercially O
important O
rock O
ling O
and O
tiger O
flathead O
demonstrated O
higher O
cathepsin O
B O
+ O
L O
activity O
, O
whereas O
gemfish O
and O
eastern O
school O
whiting O
showed O
higher O
activity O
towards O
cathepsin O
B O
. O

Underutilized O
fish O
species O
showing O
higher O
endogenous O
protease O
activities O
may O
be O
suitable O
for O
fish O
sauce O
production O
, O
whereas O
those O
with O
lower O
protease O
activities O
for O
surimi O
processing O
. O

Flavonol B
glycosides I
with O
lipid O
accumulation O
inhibitory O
activity O
and O
simultaneous O
quantitative O
analysis O
of O
15 O
polyphenols B
and O
caffeine B
in O
the O
flower O
buds O
of O
Camellia O
sinensis O
from O
different O
regions O
by O
LCMS O
. O

A O
simultaneous O
quantitative O
analytical O
method O
for O
15 O
major O
polyphenols B
, O
e O
. O
g O
. O
five O
catechins B
( O
1 O
- O
5 O
) O
and O
10 O
flavonols B
( O
6 O
- O
15 O
) O
, O
as O
functional O
constituents O
in O
the O
extracts O
of O
" O
tea O
flowers O
" O
, O
the O
flower O
buds O
of O
Camellia O
sinensis O
( O
Theaceae O
) O
, O
has O
been O
developed O
. O

The O
content O
of O
caffeine B
( O
16 O
) O
, O
which O
showed O
similar O
chromatographic O
behaviour O
under O
the O
analytical O
conditions O
, O
was O
also O
determined O
. O

To O
approve O
the O
validity O
of O
the O
newly O
developed O
protocol O
, O
thirteen O
extracts O
of O
the O
plant O
' O
s O
flower O
buds O
collected O
from O
different O
regions O
, O
i O
. O
e O
. O
China O
, O
Taiwan O
, O
Japan O
and O
India O
, O
were O
evaluated O
. O

The O
results O
indicated O
that O
the O
assay O
was O
reproducible O
and O
precise O
, O
and O
could O
be O
readily O
underutilised O
for O
the O
quality O
evaluation O
of O
tea O
flowers O
on O
the O
basis O
of O
polyphenols B
' O
contents O
. O

It O
was O
noteworthy O
that O
the O
contents O
of O
two O
major O
constituents O
, O
kaempferol B
3 I
- I
O I
- I
beta I
- I
d I
- I
glucopyranosyl I
- I
( I
1 I
- I
- I
> I
3 I
) I
- I
alpha I
- I
l I
- I
rhamnopyranosyl I
- I
( I
1 I
- I
- I
> I
6 I
) I
- I
beta I
- I
d I
- I
glucopyranoside I
( O
10 O
) O
and O
kaempferol B
3 I
- I
O I
- I
beta I
- I
d I
- I
glucopyranosyl I
- I
( I
1 I
- I
- I
> I
3 I
) I
- I
alpha I
- I
l I
- I
rhamnopyranosyl I
- I
( I
1 I
- I
- I
> I
6 I
) I
- I
beta I
- I
d I
- I

galactopyranoside I
( O
11 O
) O
, O
varied O
by O
region O
where O
the O
flower O
buds O
were O
produced O
. O

A O
new O
flavonol B
glycoside I
, O
chakaflavonoside B
B I
( O
17 O
) O
, O
which O
was O
isolated O
in O
the O
course O
of O
this O
analytical O
study O
, O
was O
found O
to O
show O
oleic B
acid I
- O
albumin O
- O
induced O
lipid O
accumulation O
inhibitory O
activity O
. O

Hemocyanin O
- O
derived O
phenoloxidase O
activity O
: O
A O
contributing O
factor O
to O
hyperpigmentation O
in O
Nephrops O
norvegicus O
. O

The O
phenomenon O
of O
hyperpigmentation O
( O
melanosis O
) O
in O
shellfish O
has O
long O
been O
attributed O
to O
phenoloxidase O
enzymes O
. O

Over O
the O
last O
number O
of O
years O
, O
the O
oxygen B
carrier O
hemocyanin O
, O
has O
demonstrated O
several O
immune O
- O
and O
physiological O
functionalities O
, O
most O
notably O
, O
inducible O
phenoloxidase O
activity O
. O

In O
this O
study O
, O
hemocyanin O
purified O
from O
the O
hemolymph O
of O
Nephrops O
norvegicus O
displays O
diphenoloxidase O
activity O
in O
the O
presence O
of O
a O
number O
of O
elicitors O
and O
retains O
structural O
and O
functional O
integrity O
throughout O
the O
process O
of O
freeze O
- O
thawing O
( O
at O
- O
25 O
degrees O
C O
) O
. O

Conversely O
, O
cellular O
phenoloxidase O
activity O
( O
present O
in O
cell O
- O
lysates O
) O
, O
demonstrates O
> O
98 O
% O
reduction O
in O
activity O
after O
freeze O
- O
thawing O
. O

We O
present O
evidence O
that O
hemocyanin O
may O
act O
as O
a O
causative O
agent O
of O
hyperpigmentation O
in O
N O
. O
norvegicus O
. O

The O
inhibition O
of O
hemocyanin O
- O
derived O
phenoloxidase O
activity O
is O
discussed O
, O
and O
for O
the O
first O
time O
, O
the O
biophysical O
interactions O
of O
shellfish O
hemocyanin O
with O
known O
phenoloxidase O
inhibitors O
are O
presented O
. O

Residues O
and O
dissipation O
of O
kresoxim B
methyl I
in O
apple O
under O
field O
condition O
. O

The O
dissipation O
and O
residual O
levels O
of O
kresoxim B
methyl I
in O
apple O
under O
field O
condition O
were O
determined O
by O
using O
HPLC O
- O
DAD O
with O
QuEChERS O
method O
. O

At O
fortification O
levels O
of O
0 O
. O
05 O
, O
0 O
. O
1 O
, O
0 O
. O
5 O
and O
1 O
. O
0mgkg O
( O
- O
1 O
) O
in O
apple O
, O
it O
was O
shown O
that O
recoveries O
were O
ranged O
from O
91 O
. O
1 O
% O
to O
96 O
. O
9 O
% O
with O
coefficient O
variation O
of O
the O
method O
( O
CV O
% O
) O
for O
repeatability O
ranged O
from O
1 O
. O
27 O
% O
to O
4 O
. O
77 O
% O
. O

The O
limit O
of O
quantification O
( O
LOQ O
) O
of O
the O
method O
was O
0 O
. O
05mgkg O
( O
- O
1 O
) O
. O

The O
dissipation O
rates O
of O
kresoxim B
methyl I
were O
described O
by O
using O
first O
- O
order O
kinetics O
and O
its O
half O
- O
life O
, O
as O
they O
are O
ranged O
from O
4 O
. O
58 O
to O
4 O
. O
77days O
in O
apple O
. O

The O
terminal O
residues O
of O
kresoxim B
methyl I
were O
below O
the O
FAO O
/ O
WHO O
maximum O
residue O
limit O
( O
MRL O
, O
0 O
. O
2mgkg O
( O
- O
1 O
) O
) O
in O
apple O
when O
measured O
14days O
after O
the O
final O
application O
, O
which O
suggested O
that O
the O
use O
of O
this O
fungicide O
was O
safe O
for O
humans O
. O

This O
study O
would O
help O
in O
providing O
the O
basic O
information O
for O
developing O
regulation O
to O
guard O
a O
safe O
use O
of O
kresoxim B
methyl I
in O
apple O
orchard O
and O
to O
prevent O
health O
problem O
from O
consumers O
. O

Impact O
of O
the O
Mediterranean O
fruit O
fly O
( O
Medfly O
) O
Ceratitis O
capitata O
on O
different O
peach O
cultivars O
: O
The O
possible O
role O
of O
peach O
volatile O
compounds O
. O

The O
relationship O
between O
susceptibility O
of O
different O
peach O
cultivars O
( O
cvs O
) O
to O
the O
Mediterranean O
fruit O
fly O
( O
medfly O
) O
, O
Ceratitis O
capitata O
, O
and O
the O
volatile O
composition O
of O
ripe O
fruit O
of O
each O
cv O
has O
been O
investigated O
, O
since O
understanding O
the O
fruit O
- O
insect O
interaction O
mechanism O
is O
crucial O
for O
developing O
control O
strategies O
for O
such O
a O
pest O
. O

Volatile O
compounds O
were O
analyzed O
by O
SPME O
- O
GC O
- O
MS O
in O
three O
cvs O
highly O
susceptible O
to O
medfly O
attack O
( O
Fair O
Time O
, O
Flaminia O
, O
Sicilia O
Piatta O
) O
, O
and O
in O
two O
less O
susceptible O
cvs O
( O
Percoca O
Romagnola O
7 O
and O
Doctor O
Davis O
) O
. O

Among O
the O
volatile O
compounds O
detected O
, O
88 O
could O
be O
identified O
. O

The O
main O
differences O
found O
in O
the O
volatile O
composition O
of O
the O
cvs O
, O
concerned O
the O
relative O
abundance O
of O
esters B
. O

The O
least O
susceptible O
cvs O
, O
above O
all O
Percoca O
Romagnola O
7 O
, O
contained O
the O
higher O
amounts O
of O
hexenyl B
, I
hexyl I
, I
3 I
- I
methylbutyl I
, I
butyl I
and I
2 I
- I
methylpropyl I
esters I
; O
among O
these O
, O
some O
C6 O
derivatives O
detected O
, O
such O
as O
( B
Z I
) I
- I
3 I
- I
hexenyl I
acetate I
, O
are O
known O
to O
act O
as O
priming O
agents O
, O
enhancing O
plant O
defence O
response O
to O
insects O
. O

Instead O
, O
a O
lower O
relative O
content O
of O
methyl B
esters I
, O
such O
as O
methyl B
hexanoate I
and O
methyl B
octanoate I
, O
known O
to O
act O
as O
medfly O
pheromone O
and O
attractant O
respectively O
, O
was O
found O
in O
the O
least O
susceptible O
cvs O
. O

Comparison O
of O
spectrophotometric O
and O
HPLC O
methods O
for O
determination O
of O
carotenoids O
in O
foods O
. O

This O
report O
is O
aimed O
at O
intra O
- O
laboratory O
and O
inter O
- O
laboratory O
comparison O
of O
the O
results O
obtained O
during O
spectrophotometric O
and O
HPLC O
analyses O
of O
lycopene B
, O
beta B
- I
carotene I
and O
total O
carotenoids O
in O
tomato O
products O
and O
yellow O
maize O
flours O
/ O
grits O
. O

Extensive O
statistical O
analyses O
are O
performed O
in O
order O
to O
identify O
the O
main O
sources O
of O
uncertainties O
which O
may O
occur O
when O
using O
: O
( O
i O
) O
different O
techniques O
/ O
methods O
/ O
approaches O
in O
the O
same O
/ O
different O
laboratories O
, O
in O
various O
food O
samples O
, O
and O
( O
ii O
) O
to O
indicate O
the O
facts O
/ O
conditions O
under O
which O
the O
biases O
between O
results O
may O
remain O
unidentified O
after O
applying O
statistical O
testing O
. O

Our O
data O
points O
to O
the O
inertness O
of O
t O
- O
test O
to O
detect O
significance O
of O
differences O
, O
particularly O
at O
low O
R O
values O
: O
in O
general O
, O
the O
higher O
correlation O
coefficient O
, O
the O
higher O
is O
sensitivity O
of O
statistical O
testing O
, O
especially O
of O
the O
paired O
t O
- O
test O
. O

Therefore O
, O
simple O
deviation O
of O
relationship O
line O
slope O
from O
unity O
could O
be O
used O
as O
additional O
evaluation O
parameter O
. O

This O
adds O
to O
reliable O
and O
objective O
quality O
assurance O
of O
foods O
in O
regard O
to O
carotenoids O
. O

Animal O
communication O
: O
sniffing O
is O
about O
more O
than O
just O
smell O
. O

A O
recent O
study O
shows O
that O
subordinate O
rats O
reduce O
their O
rate O
of O
sniffing O
while O
dominants O
explore O
their O
faces O
thus O
delaying O
dominants O
' O
subsequent O
aggression O
. O

Sniffing O
not O
only O
facilitates O
acquisition O
of O
olfactory O
information O
, O
but O
unexpectedly O
, O
also O
serves O
as O
a O
medium O
for O
communication O
. O

Irisin O
levels O
correlate O
with O
energy O
expenditure O
in O
a O
subgroup O
of O
humans O
with O
energy O
expenditure O
greater O
than O
predicted O
by O
fat O
free O
mass O
. O

OBJECTIVE O
: O
Obesity O
is O
a O
result O
of O
chronic O
overconsumption O
of O
calories O
relative O
to O
the O
amount O
of O
energy O
expended O
. O

While O
fat O
free O
mass O
can O
account O
for O
~ O
80 O
% O
of O
the O
variance O
in O
energy O
expenditure O
, O
there O
is O
still O
considerable O
variability O
in O
energy O
requirements O
between O
individuals O
that O
cannot O
be O
explained O
. O

We O
hypothesized O
that O
responsiveness O
to O
the O
recently O
discovered O
myokine O
, O
irisin O
, O
which O
has O
been O
touted O
to O
increase O
energy O
expenditure O
via O
activation O
of O
brown O
adipocytes O
in O
rodents O
and O
possibly O
humans O
, O
may O
explain O
some O
of O
the O
variability O
in O
energy O
expenditure O
. O

MATERIALS O
/ O
METHODS O
: O
Post O
- O
menopausal O
women O
( O
n O
= O
17 O
) O
spent O
24 O
- O
h O
in O
a O
whole O
room O
indirect O
calorimeter O
. O

During O
the O
study O
day O
, O
subjects O
remained O
sedentary O
and O
consumed O
meals O
tailored O
to O
their O
energy O
requirements O
. O

Plasma O
irisin O
, O
leptin O
and O
adiponectin O
were O
measured O
in O
samples O
taken O
from O
each O
subject O
. O

RESULTS O
: O
Our O
results O
suggest O
that O
in O
general O
, O
irisin B
levels O
do O
not O
correlate O
with O
24 O
- O
h O
energy O
expenditure O
, O
however O
, O
for O
a O
subpopulation O
irisin B
levels O
and O
energy O
expenditure O
are O
highly O
correlative O
. O

CONCLUSION O
: O
Irisin O
may O
help O
explain O
some O
of O
the O
observed O
variability O
in O
individual O
energy O
requirements O
that O
cannot O
be O
accounted O
for O
by O
fat O
free O
mass O
. O

Therefore O
, O
interventions O
designed O
to O
increase O
irisin O
action O
may O
prove O
to O
be O
promising O
avenues O
for O
the O
treatment O
of O
obesity O
. O

In O
vitro O
toxicological O
assessment O
of O
clays O
for O
their O
use O
in O
food O
packaging O
applications O
. O

Montmorillonite B
based O
clays O
have O
a O
wide O
range O
of O
applications O
that O
are O
going O
to O
contribute O
to O
increase O
human O
exposure O
to O
these O
materials O
. O

One O
of O
the O
most O
promising O
uses O
of O
clays O
is O
the O
development O
of O
reinforced O
food O
contact O
materials O
that O
results O
in O
nanocomposites O
with O
improved O
barrier O
properties O
. O

Different O
organoclays O
have O
been O
developed O
introducing O
modifiers O
in O
the O
natural O
clay O
which O
is O
commercially O
available O
. O

However O
, O
the O
toxicological O
aspects O
of O
these O
materials O
have O
been O
scarcely O
studied O
so O
far O
. O

In O
the O
present O
study O
, O
the O
cytotoxic O
effects O
of O
a O
non O
- O
modified O
clay O
( O
Cloisite B
( O
R O
) O
Na B
+ I
) O
and O
an O
organoclay O
( O
Cloisite B
( O
R O
) O
30B O
) O
have O
been O
investigated O
in O
the O
hepatic O
cell O
line O
HepG2 O
. O

Only O
Cloisite B
( O
R O
) O
30B O
showed O
cytotoxicity O
. O

In O
order O
to O
elucidate O
the O
toxic O
mechanisms O
underlying O
these O
effects O
, O
apoptosis O
, O
inflammation O
, O
oxidative O
stress O
and O
genotoxicity O
biomarkers O
were O
assayed O
. O

Moreover O
, O
a O
morphology O
study O
with O
light O
and O
electron O
microscopy O
was O
performed O
. O

Results O
showed O
genotoxic O
effects O
and O
glutathione B
decrease O
. O

The O
most O
relevant O
ultraestructural O
alterations O
observed O
were O
mitochondrial O
degeneration O
, O
dilated O
endomembrane O
systems O
, O
heterophagosomes O
formation O
, O
fat O
droplets O
appearance O
and O
presence O
of O
nuclear O
lipid O
inclusions O
. O

Cloisite B
( O
R O
) O
30B O
, O
therefore O
, O
induces O
toxic O
effects O
in O
HepG2 O
cells O
. O

Further O
research O
is O
needed O
to O
assess O
the O
risk O
of O
this O
clay O
on O
the O
human O
health O
. O

Sclerostin O
: O
how O
human O
mutations O
have O
helped O
reveal O
a O
new O
target O
for O
the O
treatment O
of O
osteoporosis O
. O

In O
the O
1990s O
there O
was O
a O
tremendous O
mood O
of O
optimism O
among O
pharmaceutical O
scientists O
that O
identification O
of O
disease O
- O
associated O
variations O
in O
the O
human O
genome O
would O
result O
in O
a O
surge O
of O
new O
drug O
targets O
( O
the O
' O
gene O
- O
to O
- O
drug O
' O
mantra O
) O
. O

To O
date O
the O
expected O
deluge O
of O
new O
drugs O
has O
not O
arrived O
. O

However O
, O
a O
small O
number O
of O
drugs O
arising O
directly O
from O
the O
study O
of O
rare O
human O
disorders O
showing O
Mendelian O
inheritance O
are O
now O
entering O
late O
stage O
clinical O
trials O
. O

Here O
we O
describe O
the O
advantages O
of O
this O
approach O
and O
discuss O
the O
background O
and O
early O
clinical O
trial O
findings O
with O
antibodies O
directed O
at O
a O
target O
identified O
in O
this O
way O
. O

Mechanisms O
of O
Glucose B
Lowering O
of O
Dipeptidyl O
Peptidase O
- O
4 O
Inhibitor O
Sitagliptin B
When O
Used O
Alone O
or O
With O
Metformin B
in O
Type O
2 O
Diabetes O
: O
A O
double O
- O
tracer O
study O
. O

OBJECTIVETo O
assess O
glucose B
- O
lowering O
mechanisms O
of O
sitagliptin B
( O
S O
) O
, O
metformin B
( O
M O
) O
, O
and O
the O
two O
combined O
( O
M O
+ O
S O
) O
. O
RESEARCH O
DESIGN O
AND O
METHODSWe O
randomized O
16 O
patients O
with O
type O
2 O
diabetes O
mellitus O
( O
T2DM O
) O
to O
four O
6 O
- O
week O
treatments O
with O
placebo O
( O
P O
) O
, O
M O
, O
S O
, O
and O
M O
+ O
S O
. O

After O
each O
period O
, O
subjects O
received O
a O
6 O
- O
h O
meal O
tolerance O
test O
( O
MTT O
) O
with O
[ B
( I
14 I
) I
C I
] I
glucose I
to O
calculate O
glucose B
kinetics O
. O

Fasting O
plasma O
glucose B
( O
FPG O
) O
, O
fasting O
plasma O
insulin O
, O
C O
- O
peptide O
( O
insulin O
secretory O
rate O
[ O
ISR O
] O
) O
, O
fasting O
plasma O
glucagon O
, O
and O
bioactive O
glucagon O
- O
like O
peptide O
( O
GLP O
- O
1 O
) O
and O
gastrointestinal O
insulinotropic O
peptide O
( O
GIP O
) O
was O
measured O
. O
RESULTSFPG O
decreased O
from O
P O
, O
160 O
+ O
/ O
- O
4 O
to O
M O
, O
150 O
+ O
/ O
- O
4 O
; O
S O
, O
154 O
+ O
/ O
- O
4 O
; O
and O
M O
+ O
S O
, O
125 O
+ O
/ O
- O
3 O
mg O
/ O
dL O
. O

Mean O
post O
- O
MTT B
PG O
decreased O
from O
P O
, O
207 O
+ O
/ O
- O
5 O
to O
M O
, O
191 O
+ O
/ O
- O
4 O
; O
S O
, O
195 O
+ O
/ O
- O
4 O
; O
and O
M O
+ O
S O
, O
161 O
+ O
/ O
- O
3 O
mg O
/ O
dL O
( O
P O
< O
0 O
. O
01 O
] O
. O

The O
increase O
in O
mean O
post O
- O
MTT O
plasma O
insulin O
and O
in O
ISR O
was O
similar O
in O
P O
, O
M O
, O
and O
S O
and O
slightly O
greater O
in O
M O
+ O
S O
. O

Fasting O
plasma O
glucagon O
was O
equal O
( O
~ O
65 O
- O
75 O
pg O
/ O
mL O
) O
with O
all O
treatments O
, O
but O
there O
was O
a O
significant O
drop O
during O
the O
initial O
120 O
min O
with O
S O
24 O
% O
and O
M O
+ O
S O
34 O
% O
( O
both O
P O
< O
0 O
. O
05 O
) O
vs O
. O
P O
17 O
% O
and O
M O
16 O
% O
. O

Fasting O
and O
mean O
post O
- O
MTT B
plasma O
bioactive O
GLP O
- O
1 O
were O
higher O
( O
P O
< O
0 O
. O
01 O
) O
after O
S O
and O
M O
+ O
S O
vs O
. O
M O
and O
P O
. O

Basal O
endogenous O
glucose B
production O
( O
EGP O
) O
fell O
from O
P O
2 O
. O
0 O
+ O
/ O
- O
0 O
. O
1 O
to O
S O
1 O
. O
8 O
+ O
/ O
- O
0 O
. O
1 O
mg O
/ O
kg O
. O
min O
, O
M O
1 O
. O
8 O
+ O
/ O
- O
0 O
. O
2 O
mg O
/ O
kg O
. O
min O
[ O
both O
P O
< O
0 O
. O
05 O
vs O
. O
P O
) O
, O
and O
M O
+ O
S O
1 O
. O
5 O
+ O
/ O
- O
0 O
. O
1 O
mg O
/ O
kg O
. O
min O
( O
P O
< O
0 O
. O
01 O
vs O
. O
P O
) O
. O

Although O
the O
EGP O
slope O
of O
decline O
was O
faster O
in O
M O
and O
M O
+ O
S O
vs O
. O
S O
, O
all O
had O
comparable O
greater O
post O
- O
MTT O
EGP O
inhibition O
vs O
. O
P O
( O
P O
< O
0 O
. O
05 O
) O
. O
CONCLUSIONSM O
+ O
S O
combined O
produce O
additive O
effects O
to O
1 O
) O
reduce O
FPG O
and O
postmeal O
PG O
, O
2 O
) O
augment O
GLP O
- O
1 O
secretion O
and O
beta O
- O
cell O
function O
, O
3 O
) O
decrease O
plasma O
glucagon O
, O
and O
4 O
) O
inhibit O
fasting O
and O
postmeal O
EGP O
compared O
with O
M O
or O
S O
monotherapy O
. O

Involvement O
of O
nNOS O
/ O
NO B
/ O
sGC O
/ O
cGMP B
signaling O
pathway O
in O
cocaine B
sensitization O
and O
in O
the O
associated O
hippocampal O
alterations O
: O
does O
phosphodiesterase O
5 O
inhibition O
help O
to O
drug O
vulnerability O
? O

RATIONALE O
: O
Repeated O
cocaine B
administration O
induces O
behavioral O
sensitization O
in O
about O
50 O
% O
of O
treated O
animals O
. O

Nitric B
oxide I
could O
be O
involved O
in O
the O
acquisition O
and O
maintenance O
of O
behavioral O
cocaine B
effects O
, O
probably O
by O
activation O
of O
neuronal O
nitric B
oxide I
synthase O
( O
nNOS O
) O
/ O
NO B
/ O
soluble O
guanylyl B
cyclase O
( O
sGC O
) O
/ O
cyclic B
guanosine I
monophosphate I
( O
cGMP B
) O
signaling O
pathway O
, O
since O
inhibition O
of O
the O
nNOS O
enzyme O
attenuates O
development O
of O
sensitization O
in O
rats O
. O

On O
the O
other O
hand O
, O
increased O
cGMP B
availability O
by O
phosphodiesterase O
5 O
inhibitors O
has O
been O
correlated O
to O
the O
misuse O
and O
recreational O
use O
of O
these O
agents O
and O
also O
to O
the O
concomitant O
use O
with O
illicit O
drugs O
in O
humans O
. O

Hippocampus O
is O
an O
important O
brain O
region O
for O
conditioning O
to O
general O
context O
previously O
associated O
to O
drug O
availability O
, O
influencing O
drug O
- O
seeking O
behavior O
and O
sensitization O
. O

Moreover O
, O
cocaine B
and O
other O
drugs O
of O
abuse O
can O
affect O
the O
strength O
of O
glutamate B
synapses O
in O
this O
structure O
, O
lastly O
modifying O
neuronal O
activity O
in O
main O
regions O
of O
the O
reward O
circuitry O
. O

OBJECTIVE O
: O
The O
objective O
of O
this O
study O
is O
to O
determine O
whether O
the O
pharmacological O
manipulation O
of O
nNOS O
/ O
NO B
/ O
sGC O
/ O
cGMP B
signaling O
pathway O
altered O
changes O
induced O
by O
repeated O
cocaine B
exposure O
. O

RESULTS O
: O
The O
present O
investigation O
showed O
a O
relationship O
between O
behavioral O
cocaine B
sensitization O
, O
reduced O
threshold O
to O
generate O
long O
- O
term O
potentiation O
( O
LTP O
) O
in O
hippocampal O
dentate O
gyrus O
, O
and O
increased O
nNOS O
activity O
in O
this O
structure O
. O

However O
, O
when O
nNOS O
or O
sGC O
were O
inhibited O
, O
the O
number O
of O
sensitized O
animals O
was O
reduced O
, O
and O
the O
threshold O
to O
generate O
LTP O
was O
increased O
. O

The O
opposite O
occurred O
when O
cGMP B
availability O
was O
increased O
. O

CONCLUSION O
: O
We O
demonstrate O
a O
key O
role O
of O
the O
nNOS O
activity O
and O
NO B
/ O
sGC O
/ O
cGMP B
signaling O
pathway O
in O
the O
development O
of O
cocaine B
sensitization O
and O
in O
the O
associated O
enhancement O
of O
hippocampal O
synaptic O
transmission O
. O

Plasmonic O
fluorescence O
enhancement O
by O
metal O
nanostructures O
: O
shaping O
the O
future O
of O
bionanotechnology O
. O

This O
review O
focuses O
on O
metal O
enhanced O
fluorescence O
( O
MEF O
) O
and O
its O
current O
and O
future O
applications O
in O
biotechnology O
. O

The O
mechanisms O
of O
MEF B
are O
discussed O
in O
terms O
of O
the O
additional O
radiative O
and O
nonradiative O
decay O
rates O
caused O
by O
the O
close O
proximity O
of O
the O
metal O
. O

We O
then O
review O
the O
current O
MEF O
materials O
and O
structures O
that O
show O
promise O
in O
bioapplications O
. O

The O
use O
of O
electromagnetic O
modelling O
to O
predict O
fluorescent O
rate O
enhancement O
is O
then O
considered O
. O

We O
then O
give O
particular O
focus O
to O
the O
recent O
work O
carried O
out O
in O
the O
homogeneous O
fabrication O
of O
metal O
nanoparticles O
using O
colloidal O
lithography O
. O

It O
is O
concluded O
that O
the O
use O
of O
computational O
electromagnetic O
modelling O
alongside O
homogeneous O
fabrication O
techniques O
will O
lead O
to O
predictable O
and O
controllable O
MEF O
, O
paving O
the O
way O
for O
increased O
applications O
in O
biotechnology O
. O

A O
statistical O
approach O
for O
analyzing O
the O
development O
of O
( B
1 I
) I
H I
multiple O
- O
quantum O
coherence O
in O
solids O
. O

A O
novel O
statistical O
approach O
for O
analyzing O
( B
1 I
) I
H I
multiple O
- O
quantum O
( O
MQ O
) O
spin O
dynamics O
in O
so O
- O
called O
spin O
- O
counting O
solid O
- O
state O
NMR O
experiments O
is O
presented O
. O

The O
statistical O
approach O
is O
based O
on O
the O
percolation O
theory O
with O
Monte O
Carlo O
methods O
and O
is O
examined O
by O
applying O
it O
to O
the O
experimental O
results O
of O
three O
solid O
samples O
having O
unique O
hydrogen B
arrangement O
for O
1 O
- O
3 O
dimensions O
: O
the O
n B
- I
alkane I
/ O
d B
- I
urea I
inclusion O
complex O
as O
a O
one O
- O
dimensional O
( O
1D O
) O
system O
, O
whose O
( B
1 I
) I
H I
nuclei O
align O
approximately O
in O
1D O
, O
and O
magnesium B
hydroxide I
and O
adamantane B
as O
a O
two O
- O
dimensional O
( O
2D O
) O
and O
a O
three O
- O
dimensional O
( O
3D O
) O
system O
, O
respectively O
. O

Four O
lattice O
models O
, O
linear O
, O
honeycomb O
, O
square O
and O
cubic O
, O
are O
used O
to O
represent O
the O
( B
1 I
) I
H I
arrangement O
of O
the O
three O
samples O
. O

It O
is O
shown O
that O
the O
MQ O
dynamics O
in O
adamantane B
is O
consistent O
with O
that O
calculated O
using O
the O
cubic O
lattice O
and O
that O
in O
Mg B
( I
OH I
) I
2 I
with O
that O
calculated O
using O
the O
honeycomb O
and O
the O
square O
lattices O
. O

For O
n B
- I
C20H42 I
/ I
d I
- I
urea I
, O
these O
4 O
lattice O
models O
fail O
to O
express O
its O
result O
. O

It O
is O
shown O
that O
a O
more O
realistic O
model O
representing O
the O
( B
1 I
) I
H I
arrangement O
of O
n B
- I
C20H42 I
/ O
d I
- I
urea I
can O
describe O
the O
result O
. O

The O
present O
approach O
can O
thus O
be O
used O
to O
determine O
( B
1 I
) I
H I
arrangement O
in O
solids O
. O

Graphene B
sheets O
: O
gram O
- O
scale O
synthesis O
of O
graphene B
sheets O
by O
a O
catalytic O
arc O
- O
discharge O
method O
( O
small O
8 O
/ O
2013 O
) O
. O

Gram O
- O
scale O
amounts O
of O
high O
- O
quality O
graphene B
sheets O
are O
synthesized O
on O
page O
1330 O
through O
an O
arc O
- O
discharge O
method O
. O

An O
arc O
, O
which O
is O
generated O
between O
two O
graphite B
rods O
when O
a O
high O
voltage O
is O
applied O
by O
Y O
. O

Liu O
and O
co O
- O
workers O
, O
can O
cause O
the O
graphite B
layers O
to O
separate O
into O
graphene B
sheets O
via O
a O
high O
- O
temperature O
exfoliation O
, O
or O
even O
broken O
into O
small O
clusters O
/ O
atoms O
, O
which O
then O
form O
graphene B
sheets O
by O
catalytic O
growth O
, O
demonstrating O
that O
two O
mechanisms O
exist O
in O
an O
arc O
discharge O
process O
simultaneously O
. O

Free O
radicals O
: O
free O
radical O
reactions O
in O
two O
dimensions O
: O
a O
case O
study O
on O
photochlorination O
of O
graphene B
( O
small O
8 O
/ O
2013 O
) O
. O

Graphene B
is O
a O
2D O
giant O
polycyclic O
aromatic O
molecule O
that O
provides O
opportunities O
for O
studying O
chemical O
reactions O
in O
two O
dimensions O
. O

H O
. O

Peng O
, O
Z O
. O

Liu O
, O
and O
co O
- O
workers O
have O
systematically O
investigated O
the O
influence O
of O
specific O
features O
of O
2D O
molecules O
, O
such O
as O
their O
thickness O
, O
stacking O
order O
, O
single O
- O
and O
double O
- O
side O
upon O
graphene B
' O
s O
radical O
reactivity O
by O
utilizing O
a O
free O
radical O
photochlorination O
as O
a O
probe O
. O

The O
result O
, O
described O
on O
page O
1388 O
, O
can O
contribute O
to O
a O
deeper O
understanding O
of O
dimensionality O
effects O
for O
the O
chemistry O
of O
2D O
graphene B
. O

Optoelectronic O
Processes O
in O
Squaraine B
Dye O
- O
Doped O
OLEDs O
for O
Emission O
in O
the O
Near O
- O
Infrared O
. O

A O
novel O
all O
- O
organic O
host O
- O
guest O
system O
for O
emission O
in O
the O
NIR O
is O
introduced O
and O
investigated O
with O
respect O
to O
its O
opto O
- O
electronic O
processes O
. O

The O
good O
agreement O
between O
theoretical O
and O
experimental O
results O
highlights O
the O
model O
character O
of O
this O
system O
and O
its O
potential O
for O
electroluminescent O
application O
. O

Comparative O
measurements O
provide O
access O
to O
the O
recombination O
mechanisms O
on O
molecular O
length O
scale O
and O
show O
that O
the O
emission O
behavior O
of O
the O
device O
under O
operation O
is O
controlled O
by O
charge O
carrier O
dynamics O
. O

Small O
Molecule O
Inhibitors O
of O
ERCC1 O
- O
XPF O
Protein O
- O
Protein O
Interaction O
Synergize O
Alkylating O
Agents O
in O
Cancer O
Cells O
. O

The O
benefit O
of O
cancer O
chemotherapy O
based O
on O
alkylating O
agents O
is O
limited O
due O
to O
the O
action O
of O
DNA O
repair O
enzymes O
which O
mitigate O
the O
damage O
induced O
by O
these O
agents O
. O

The O
interaction O
between O
the O
proteins O
ERCC1 O
and O
XPF O
, O
involves O
two O
major O
components O
of O
the O
nucleotide B
excision O
repair O
pathway O
. O

Here O
, O
novel O
inhibitors O
of O
this O
interaction O
were O
identified O
by O
virtual O
screening O
based O
on O
available O
structures O
using O
the O
National O
Cancer O
Institute O
( O
NCI O
) O
diversity O
set O
and O
a O
panel O
of O
DrugBank O
- O
small O
- O
molecules O
. O

Subsequently O
, O
experimental O
validation O
of O
the O
in O
silico O
screening O
was O
undertaken O
. O

Top O
hits O
were O
evaluated O
on O
A549 O
and O
HCT116 O
cancer O
cells O
. O

In O
particular O
, O
the O
compound O
labeled O
NSC130813 B
was O
shown O
to O
act O
synergistically O
with O
cisplatin B
and O
mitomycin B
C I
, O
to O
increase O
UVC O
mediated O
cytotoxicity O
, O
to O
modify O
DNA O
repair O
as O
indicated O
by O
the O
staining O
of O
phosphorylated O
H2AX O
and O
to O
disrupt O
interaction O
between O
ERCC1 O
and O
XPF O
in O
cells O
. O

In O
addition O
, O
using O
the O
Biacore O
technique O
, O
we O
showed O
that O
this O
compound O
interacts O
with O
the O
domain O
of O
XPF O
responsible O
for O
interaction O
with O
ERCC1 O
. O

This O
study O
shows O
that O
small O
molecules O
targeting O
the O
protein O
- O
protein O
interaction O
of O
ERCC1 O
and O
XPF O
can O
be O
developed O
in O
order O
to O
enhance O
the O
effects O
of O
alkylating O
agents O
on O
cancer O
cells O
. O

Magnetic O
Cooling O
at O
a O
Single O
Molecule O
Level O
: O
a O
Spectroscopic O
Investigation O
of O
Isolated O
Molecules O
on O
a O
Surface O
. O

A O
sub O
- O
monolayer O
distribution O
of O
isolated O
molecular O
Fe14 B
( I
bta I
) I
6 I
nanomagnets O
is O
deposited O
intact O
on O
a O
Au B
( I
111 I
) I
surface O
and O
investigated O
by O
X O
- O
ray O
magnetic O
circular O
dichroism O
spectroscopy O
. O

The O
entropy O
variation O
with O
respect O
to O
the O
applied O
magnetic O
field O
is O
extracted O
from O
the O
magnetization O
curves O
and O
evidences O
high O
magnetocaloric O
values O
at O
the O
single O
molecule O
level O
. O

Transgenic O
Mouse O
alpha O
- O
and O
beta O
- O
Cardiac O
Myosins O
Containing O
the O
R403Q O
Mutation O
Show O
Isoform O
Dependent O
Transient O
Kinetic O
Differences O
. O

Familial O
hypertrophic O
cardiomyopathy O
( O
FHC O
) O
is O
a O
major O
cause O
of O
sudden O
cardiac O
death O
in O
young O
athletes O
. O

The O
discovery O
in O
1990 O
that O
a O
point O
mutation O
at O
residue O
403 O
( O
R403Q O
) O
in O
the O
beta O
- O
myosin O
heavy O
chain O
( O
MHC O
) O
caused O
a O
severe O
form O
of O
FHC O
was O
the O
first O
of O
many O
demonstrations O
linking O
FHC O
to O
mutations O
in O
muscle O
proteins O
. O

A O
mouse O
model O
for O
FHC O
has O
been O
widely O
used O
to O
study O
the O
mechanochemical O
properties O
of O
mutated O
cardiac O
myosin O
, O
but O
mouse O
hearts O
express O
alpha O
- O
MHC O
, O
whereas O
the O
ventricles O
of O
larger O
mammals O
express O
predominantly O
beta O
- O
MHC O
. O

To O
address O
the O
role O
of O
the O
isoform O
backbone O
on O
function O
, O
we O
generated O
a O
transgenic O
mouse O
in O
which O
the O
endogenous O
alpha O
- O
MHC O
was O
partially O
replaced O
with O
transgenically O
encoded O
beta O
- O
MHC O
or O
alpha O
- O
MHC O
. O

A O
His O
- O
tag O
was O
cloned O
at O
the O
N B
- O
terminus O
, O
along O
with O
R403Q O
, O
to O
facilitate O
isolation O
of O
myosin O
subfragment O
- O
1 O
( O
S1 O
) O
. O

Stopped O
- O
flow O
kinetics O
were O
used O
to O
measure O
the O
equilibrium O
constants O
and O
rates O
of O
nucleotide B
binding O
and O
release O
for O
the O
mouse O
S1 O
isoforms O
bound O
to O
actin O
. O

For O
the O
wildtype O
isoforms O
, O
we O
found O
that O
the O
affinity O
of O
MgADP B
for O
alpha O
- O
S1 O
( O
100 O
mu O
M O
) O
is O
~ O
4 O
- O
fold O
weaker O
than O
for O
beta O
- O
S1 O
( O
25 O
mu O
M O
) O
. O

Correspondingly O
, O
the O
MgADP B
release O
rate O
for O
alpha O
- O
S1 O
( O
350 O
s O
- O
1 O
) O
is O
~ O
3 O
- O
fold O
greater O
than O
for O
beta O
- O
S1 O
( O
120 O
s O
- O
1 O
) O
. O

Introducing O
the O
R403Q O
mutation O
caused O
only O
a O
minor O
reduction O
in O
kinetics O
for O
beta O
- O
S1 O
, O
but O
R403Q O
in O
alpha O
- O
S1 O
caused O
the O
ADP B
release O
rate O
to O
increase O
by O
20 O
% O
( O
430 O
s O
- O
1 O
) O
. O

These O
transient O
kinetic O
studies O
on O
mouse O
cardiac O
myosins O
provide O
strong O
evidence O
that O
the O
functional O
impact O
of O
an O
FHC O
mutation O
on O
myosin O
depends O
on O
the O
isoform O
backbone O
. O

A O
new O
isobenzofuranone B
from O
the O
mangrove O
endophytic O
fungus O
Penicillium O
sp O
. O

( O
ZH58 O
) O
. O

A O
new O
isobenzofuranone B
, O
4 B
- I
( I
methoxymethyl I
) I
- I
7 I
- I
methoxy I
- I
6 I
- I
methyl I
- I
1 I
( I
3H I
) I
- I
isobenzofuranone I
( O
1 O
) O
, O
together O
with O
seven O
known O
compounds O
, O
dilation O
( O
2 O
) O
, O
lumichrome B
( O
3 O
) O
, O
curvulari O
( O
4 O
) O
, O
5 B
, I
5 I
' I
- I
oxy I
- I
dimethylene I
- I
bis I
( I
2 I
- I
furaldehyde I
) I
( O
5 O
) O
, O
chromone B
( O
6 O
) O
, O
harman B
( O
1 B
- I
methyl I
- I
beta I
- I
carboline I
) O

( O
7 O
) O
, O
N9 B
- I
methyl I
- I
1methyl I
- I
beta I
- I
carboline I
( O
8 O
) O
, O
was O
isolated O
from O
the O
mangrove O
endophytic O
fungus O
, O
Penicillium O
sp O
. O

ZH58 O
obtained O
from O
the O
South O
China O
Sea O
coast O
. O

Their O
structures O
were O
determined O
by O
analysis O
of O
spectroscopic O
data O
. O

Compound O
1 O
exhibited O
cytotoxicity O
against O
KB O
and O
KBV200 O
cells O
with O
IC50 O
values O
of O
6 O
and O
10 O
mu O
g O
/ O
mL O
, O
respectively O
. O

Design O
, O
Synthesis O
, O
and O
Structure O
- O
Activity O
Relationship O
Studies O
of O
Novel O
3 B
- I
Alkylindole I
Derivatives O
as O
Selective O
and O
Highly O
Potent O
Myeloperoxidase O
Inhibitors O
. O

Due O
to O
its O
production O
of O
potent O
antimicrobial O
oxidants O
including O
hypochlorous B
acid I
, O
human O
myeloperoxidase O
( O
MPO O
) O
plays O
a O
critical O
role O
in O
innate O
immunity O
and O
inflammatory O
diseases O
. O

Thus O
MPO O
is O
an O
attractive O
target O
in O
drug O
design O
. O

( B
Aminoalkyl I
) I
fluoroindole I
derivatives O
were O
detected O
to O
be O
very O
potent O
MPO O
inhibitors O
; O
however O
, O
they O
also O
promote O
inhibition O
of O
the O
serotonin B
reuptake O
transporter O
( O
SERT O
) O
at O
the O
same O
concentration O
range O
. O

Via O
structure O
- O
based O
drug O
design O
, O
a O
new O
series O
of O
MPO O
inhibitors O
derived O
from O
3 B
- I
alkylindole I
were O
synthesized O
and O
their O
effects O
were O
assessed O
on O
MPO O
- O
mediated O
taurine B
chlorination O
and O
low O
- O
density O
lipoprotein O
oxidation O
as O
well O
as O
on O
inhibition O
of O
SERT O
. O

The O
fluoroindole B
compound O
with O
three O
carbons B
in O
the O
side O
chain O
and O
one O
amide B
group O
exhibited O
a O
selectivity O
index O
of O
35 O
( O
Ki O
/ O
IC50 O
) O
with O
high O
inhibition O
of O
MPO O
activity O
( O
IC50 O
= O
18 O
nM O
) O
, O
whereas O
its O
effect O
on O
SERT O
was O
in O
the O
micromolar O
range O
. O

Structure O
- O
function O
relationships O
, O
mechanism O
of O
action O
, O
and O
safety O
of O
the O
molecule O
are O
discussed O
. O

Sacchathridine B
A I
, O
a O
Prostaglandin B
Release O
Inhibitor O
from O
Saccharothrix O
sp O
. O

Sacchathridine B
A I
( O
1 O
) O
was O
isolated O
from O
the O
fermentation O
broth O
of O
strain O
Saccharothrix O
sp O
. O

MI559 O
- O
46F5 O
. O

The O
structure O
was O
determined O
as O
a O
new O
naphthoquinone B
derivative O
with O
an O
acetylhydrazino B
moiety O
by O
a O
combination O
of O
NMR O
, O
MS O
spectral O
analyses O
, O
and O
chemical O
degradation O
. O

Compound O
1 O
showed O
inhibitory O
activity O
of O
prostaglandin B
E2 I
release O
in O
a O
concentration O
- O
dependent O
manner O
from O
human O
synovial O
sarcoma O
cells O
, O
SW982 O
, O
with O
an O
IC50 O
value O
of O
1 O
. O
0 O
mu O
M O
, O
but O
had O
no O
effect O
on O
cell O
growth O
up O
to O
30 O
mu O
M O
. O

Design O
and O
synthesis O
of O
a O
tetrahydroisoquinoli B
- O
based O
hydroxamate B
derivative O
( O
ZYJ B
- I
34v I
) O
, O
an O
oral O
active O
histone O
deacetylase O
inhibitor O
with O
potent O
antitumor O
activity O
. O

In O
our O
previous O
study O
we O
developed O
a O
novel O
series O
of O
tetrahydroisoquinoli B
- O
based O
hydroxamic B
acid I
derivatives O
as O
histone O
deacetylase O
( O
HDAC O
) O
inhibitors O
( O
Bioorg O
. O
Med O
. O
Chem O
. O
, O
2010 O
, O
18 O
, O
1761 O
- O
1772 O
. O
, O
J O
. O
Med O
. O
Chem O
. O
, O
2011 O
, O
54 O
, O
2823 O
- O
2838 O
. O
) O
, O
among O
which O
compound O
ZYJ B
- I
34c I
( O
1 O
) O
was O
identified O
and O
validated O
as O
the O
most O
potent O
one O
with O
marked O
in O
vitro O
and O
in O
vivo O
antitumor O
potency O
( O
J O
. O
Med O
. O

Chem O
. O
, O
2011 O
, O
54 O
, O
5532 O
- O
5539 O
. O
) O
. O

Herein O
further O
modification O
of O
1 O
afforded O
another O
oral O
active O
analogue O
ZYJ B
- I
34v I
( O
2 O
) O
with O
simplified O
structure O
and O
lower O
molecular O
weight O
. O

Biological O
evaluation O
of O
compound O
2 O
showed O
efficacious O
inhibition O
against O
HDAC1 O
, O
2 O
, O
3 O
and O
6 O
, O
which O
was O
confirmed O
by O
western O
blot O
analysis O
results O
. O

Most O
importantly O
, O
compound O
2 O
exhibited O
similar O
even O
more O
potent O
in O
vitro O
and O
in O
vivo O
antitumor O
activities O
relative O
to O
the O
approved O
HDAC O
inhibitor O
SAHA B
This O
article O
is O
protected O
by O
copyright O
. O

All O
rights O
reserved O
. O

Metabolism O
of O
2 B
, I
2 I
' I
, I
3 I
, I
3 I
' I
, I
6 I
, I
6 I
' I
- I
hexachlorobiphenyl I
( O
PCB B
136 I
) O
atropisomers O
in O
tissue O
slices O
from O
phenobarbital B
or O
dexamethasone B
- O
induced O
rats O
is O
sex O
- O
dependent O
. O

Abstract O
1 O
. O

Chiral O
polychlorinated B
biphenyls I
( O
PCBs B
) O
such O
as O
PCB B
136 I
enantioselectively O
sensitize O
the O
ryanodine B
receptor O
( O
RyR O
) O
. O

In O
light O
of O
recent O
evidence O
that O
PCBs B
cause O
developmental O
neurotoxicity O
via O
RyR O
- O
dependent O
mechanisms O
, O
this O
suggests O
that O
enantioselective O
PCB B
metabolism O
may O
influence O
the O
developmental O
neurotoxicity O
of O
chiral O
PCBs B
. O

However O
, O
enantioselective O
disposition O
of O
PCBs B
has O
not O
been O
fully O
characterized O
. O

2 O
. O

The O
effect O
of O
sex O
and O
cytochrome O
P450 O
( O
P450 O
) O
enzyme O
induction O
on O
the O
enantioselective O
metabolism O
of O
PCB B
136 I
was O
studied O
using O
liver O
tissue O
slices O
prepared O
from O
na O
i O
ve O
control O
( O
CTL O
) O
, O
phenobarbital B
( O
PB O
; O
CYP2B O
inducer O
) O
or O
dexamethasone B
( O
DEX B
; O
CYP3A O
inducer O
) O
pretreated O
adult O
Sprague O
- O
Dawley O
rats O
. O

PCB B
136 I
metabolism O
was O
also O
examined O
in O
hippocampal O
slices O
derived O
from O
untreated O
rat O
pups O
. O

3 O
. O

In O
liver O
tissue O
slices O
, O
hydroxylated B
PCB I
( O
OH B
- I
PCB I
) O
profiles O
depended O
on O
sex O
and O
inducer O
pretreatment O
, O
and O
OH B
- I
PCB I
levels O
followed O
the O
rank O
orders O
male O
> O
female O
and O
PB B
> O
DEX B
> O
CTL O
. O

In O
contrast O
, O
the O
enantiomeric O
enrichment O
of O
PCB B
136 I
and O
its O
metabolites O
was O
independent O
of O
sex O
and O
inducer O
pretreatment O
. O

Only O
small O
amounts O
of O
PCB B
136 I
partitioned O
into O
hippocampal O
tissue O
slices O
and O
no O
OH B
- I
PCB I
metabolites O
were O
detected O
. O

4 O
. O

Our O
results O
suggest O
that O
enantioselective O
metabolism O
, O
sex O
and O
induction O
status O
of O
P450 O
enzymes O
in O
the O
liver O
may O
modulate O
the O
neurotoxic O
outcomes O
of O
developmental O
exposure O
to O
chiral O
PCBs B
. O

Self O
- O
Sorting O
Click O
Reactions O
That O
Generate O
Spatially O
Controlled O
Chemical O
Functionality O
on O
Surfaces O
. O

This O
Article O
describes O
the O
generation O
of O
a O
patterned O
surface O
that O
can O
be O
postpolymerization O
modified O
to O
incorporate O
fragile O
macromolecules O
or O
delicate O
biomolecules O
without O
the O
need O
for O
special O
equipment O
. O

Two O
monomers O
that O
undergo O
different O
click O
reactions O
, O
pentafluorophenyl B
acrylate I
( O
PFPA B
) O
and O
4 B
- I
( I
trimethylsilyl I
) I
ethynylstyrene I
( O
TMSES B
) O
, O
were O
sequentially O
polymerized O
from O
a O
silicon B
surface O
in O
the O
presence O
of O
a O
shadowmask O
with O
UV O
light O
, O
generating O
12 O
. O
5 O
and O
62 O
mu O
m O
pitch O
patterns O
. O

Two O
different O
dyes O
, O
1 B
- I
aminomethylpyrene I
( O
AMP B
) O
and O
5 B
- I
azidofluorescein I
( O
AF O
) O
, O
were O
covalently O
attached O
to O
the O
polymer O
brushes O
through O
aminolysis O
and O
dual O
desilylation O
/ O
copper B
( I
I I
) I
- O
catalyzed O
alkyne B
/ O
azide B
cycloaddition O
( O
CuAAC O
) O
in O
one O
pot O
. O

Unlike O
most O
CuAAC O
reactions O
, O
the O
terminal O
alkyne B
of O
TMSES O
was O
not O
deprotected O
prior O
to O
functionalization O
. O

Although O
a O
2 O
nm O
thickness O
increase O
was O
observed O
for O
poly O
( O
PFPA B
) O
brushes O
after O
polymerization O
of O
TMSES O
, O
cross O
- O
contamination O
was O
not O
visible O
through O
fluorescence O
microscopy O
after O
functionalization O
. O

Agonism O
of O
human O
pregnane B
X O
receptor O
by O
rilpivirine B
and O
etravirine B
: O
Comparison O
with O
first O
generation O
non O
- O
nucleoside B
reverse O
transcriptase O
inhibitors O
. O

Rilpivirine B
and O
etravirine B
are O
second O
generation O
non O
- O
nucleoside B
reverse O
transcriptase O
inhibitors O
approved O
recently O
by O
the O
United O
States O
Food O
and O
Drug O
Administration O
for O
the O
treatment O
of O
human O
immunodeficiency O
virus O
- O
1 O
infection O
. O

Pregnane B
X O
receptor O
( O
PXR O
) O
is O
a O
member O
of O
the O
superfamily O
of O
nuclear O
receptors O
that O
regulate O
the O
expression O
of O
various O
genes O
controlling O
diverse O
biological O
functions O
. O

The O
present O
study O
investigated O
the O
effects O
of O
rilpivirine B
and O
etravirine B
on O
the O
activity O
of O
human O
PXR O
( O
hPXR O
) O
, O
including O
the O
mode O
of O
activation O
, O
and O
compared O
them O
to O
those O
of O
efavirenz B
, O
nevirapine B
, O
and O
delavirdine B
, O
which O
are O
first O
generation O
non O
- O
nucleoside O
reverse O
transcriptase O
inhibitors O
. O

In O
transiently O
transfected O
HepG2 O
cells O
, O
rilpivirine B
, O
etravirine B
, O
and O
efavirenz B
, O
but O
not O
nevirapine B
or O
delavirdine B
, O
activated O
human O
, O
mouse O
, O
and O
rat O
PXR O
. O

Results O
from O
mechanistic O
studies O
indicated O
that O
rilpivirine B
, O
etravirine B
, O
and O
efavirenz B
, O
but O
not O
nevirapine B
or O
delavirdine B
, O
bound O
to O
the O
ligand O
- O
binding O
domain O
of O
hPXR O
, O
as O
assessed O
by O
a O
transactivation O
assay O
and O
by O
a O
competitive O
ligand O
- O
binding O
assay O
using O
time O
- O
resolved O
fluorescence O
resonance O
energy O
transfer O
; O
triggered O
nuclear O
translocation O
of O
a O
green O
fluorescence O
protein O
- O
tagged O
hPXR O
, O
as O
visualized O
by O
confocal O
imaging O
; O
and O
recruited O
steroid B
receptor O
coactivator O
- O
1 O
( O

SRC O
- O
1 O
) O
, O
SRC O
- O
2 O
, O
and O
SRC O
- O
3 O
to O
hPXR O
, O
as O
demonstrated O
by O
mammalian O
two O
- O
hybrid O
assays O
. O

Rilpivirine B
, O
etravirine B
, O
and O
efavirenz B
, O
but O
not O
nevirapine B
or O
delavirdine B
, O
increased O
hPXR O
target O
gene O
( O
CYP3A4 O
) O
expression O
in O
primary O
cultures O
of O
human O
hepatocytes O
. O

In O
summary O
, O
select O
non O
- O
nucleoside B
reverse O
transcriptase O
inhibitors O
activated O
human O
and O
rodent O
PXR O
. O

Rilpivirine B
, O
etravirine B
, O
and O
efavirenz B
, O
but O
not O
nevirapine B
or O
delavirdine B
, O
were O
identified O
as O
agonists O
of O
hPXR O
, O
as O
assessed O
in O
mechanistic O
experiments O
, O
and O
inducers O
of O
CYP3A4 O
, O
as O
determined O
in O
primary O
cultures O
of O
human O
hepatocytes O
. O

Inhibitory O
effects O
of O
gypenosides B
on O
seven O
human O
cytochrome O
P450 O
enzymes O
in O
vitro O
. O

Among O
the O
various O
possible O
causes O
for O
drug O
interactions O
, O
pharmacokinetic O
factors O
such O
as O
inhibition O
of O
drug O
- O
metabolizing O
enzymes O
, O
especially O
cytochrome O
P450 O
( O
CYP O
) O
enzymes O
, O
are O
regarded O
as O
the O
most O
frequent O
and O
clinically O
important O
. O

Gypenosides B
is O
widely O
used O
as O
functional O
food O
and O
over O
- O
the O
- O
counter O
drug O
in O
East O
Asia O
. O

In O
this O
study O
, O
the O
in O
vitro O
inhibitory O
effects O
of O
gypenosides B
on O
the O
major O
human O
CYP O
enzymes O
( O
CYP1A2 O
, O
CYP2B6 O
, O
CYP2C8 O
, O
CYP2C9 O
, O
CYP2C19 O
, O
CYP2D6 O
, O
and O
CYP3A4 O
) O
activities O
in O
human O
liver O
microsomes O
were O
examined O
using O
liquid O
chromatography O
- O
tandem O
mass O
spectrometry O
. O

Gypenosides B
showed O
the O
strongest O
inhibition O
of O
CYP2D6 O
, O
followed O
by O
CYP2C8 O
, O
CYP3A4 O
and O
CYP2C9 O
. O

The O
IC50 O
values O
were O
1 O
. O
61 O
mu O
g O
/ O
mL O
, O
20 O
. O
06 O
mu O
g O
/ O
mL O
, O
34 O
. O
76 O
mu O
g O
/ O
mL O
( O
CYP3A4 O
/ O
midazolam B
) O
, O
46 O
. O
73 O
mu O
g O
/ O
mL O
( O
CYP3A4 O
/ O
testosterone B
) O
, O
and O
54 O
. O
52 O
mu O
g O
/ O
mL O
, O
respectively O
. O

Gypenosides B
exhibited O
competitive O
inhibition O
of O
CYP2D6 O
( O
Ki O
= O
1 O
. O
18 O
) O
. O

In O
conclusion O
, O
Gypenosides B
might O
cause O
herb O
- O
drug O
interactions O
via O
inhibition O
of O
CYP2D6 O
. O

An O
in O
vivo O
study O
is O
needed O
to O
examine O
this O
further O
. O

Novel O
racemic O
tetrahydrocurcuminoi B
dihydropyrimidinone I
analogues O
as O
potent O
acetylcholinesterase O
inhibitors O
. O

The O
synthesis O
of O
racemic O
tetrahydrocurcumin B
- O
( O
THC B
- O
) O
, O
tetrahydrodemethoxyc B
- O
( O
THDC B
- O
) O
and O
tetrahydrobisdemetho B
- O
( O
THBDC B
- O
) O
dihydropyrimidinone B
( O
DHPM B
) O
analogues O
was O
achieved O
by O
utilizing O
the O
multi O
- O
component O
Biginelli O
reaction O
in O
the O
presence O
of O
copper B
sulphate I
as O
a O
catalyst O
. O

The O
evaluation O
of O
acetylcholinesterase O
inhibitors O
for O
Alzheimer O
' O
s O
disease O
of O
these O
compounds O
showed O
that O
they O
exhibited O
higher O
inhibitory O
activity O
than O
their O
parent O
analogues O
. O

THBDC B
- I
DHPM I
demonstrated O
the O
most O
potent O
inhibitory O
activity O
with O
an O
IC50 O
value O
of O
1 O
. O
34 O
+ O
/ O
- O
0 O
. O
03 O
mu O
M O
which O
was O
more O
active O
than O
the O
approved O
drug O
galanthamine B
( O
IC50 O
= O
1 O
. O
45 O
+ O
/ O
- O
0 O
. O
04 O
mu O
M O
) O
. O

Design O
considerations O
for O
PAMAM B
dendrimer O
therapeutics O
. O

We O
have O
previously O
shown O
that O
methotrexate B
( O
MTX B
) O
conjugated O
to O
a O
cancer O
- O
specific O
poly B
amido I
amine I
( O
PAMAM B
) O
dendrimer O
has O
a O
higher O
therapeutic O
index O
than O
MTX B
alone O
. O

Unfortunately O
, O
these O
therapeutics O
have O
been O
difficult O
to O
advance O
because O
of O
the O
complicated O
syntheses O
and O
an O
incomplete O
understanding O
of O
the O
dendrimer O
properties O
. O

We O
wished O
to O
address O
these O
obstacles O
by O
using O
copper B
- O
free O
click O
chemistry O
to O
functionalize O
the O
dendrimer O
scaffolds O
and O
to O
exploring O
the O
effects O
of O
two O
dendrimer O
properties O
( O
the O
targeting O
ligand O
and O
drug O
linkage O
) O
on O
cytotoxicity O
. O

We O
conjugated O
either O
ester B
or O
amide B
- O
linker O
modified O
MTX B
to O
dendrimer O
scaffolds O
with O
or O
without O
folic B
acid I
( O
FA O
) O
. O

Because O
of O
multivalency O
, O
the O
FA O
and O
MTX B
functionalized O
dendrimers O
had O
similar O
capacities O
to O
target O
the O
folate B
receptor O
on O
cancer O
cells O
. O

Additionally O
, O
we O
found O
that O
the O
ester B
- O
and O
amide B
- O
linker O
modified O
MTX B
compounds O
had O
similar O
cytotoxicity O
but O
the O
dendrimer O
- O
ester B
MTX B
conjugates O
were O
much O
more O
cytotoxic O
than O
the O
dendrimer O
- O
amide B
MTX B
conjugates O
. O

These O
results O
clarify O
the O
impact O
of O
these O
properties O
on O
therapeutic O
efficacy O
and O
will O
allow O
us O
to O
design O
more O
effective O
polymer O
therapeutics O
. O

A O
urinary O
metabonomics O
study O
on O
biochemical O
changes O
in O
yeast O
- O
induced O
pyrexia O
rats O
: O
a O
new O
approach O
to O
elucidating O
the O
biochemical O
basis O
of O
the O
febrile O
response O
. O

Fever O
is O
a O
prominent O
feature O
of O
many O
diseases O
, O
such O
as O
infection O
, O
inflammation O
and O
trauma O
. O

In O
the O
clinic O
, O
fever O
can O
be O
easily O
judged O
by O
measuring O
the O
body O
temperature O
; O
however O
, O
the O
pathogenesis O
of O
fever O
is O
still O
not O
fully O
understood O
. O

A O
febrile O
response O
is O
a O
systemic O
pathological O
process O
that O
can O
cause O
metabolic O
disorders O
. O

Metabonomics O
can O
provide O
powerful O
tools O
to O
reveal O
the O
pathological O
mechanisms O
for O
such O
a O
systemic O
disease O
. O

Thus O
, O
to O
reveal O
subtle O
metabolic O
changes O
under O
the O
condition O
of O
fever O
and O
to O
explore O
its O
mechanism O
, O
an O
ultra O
performance O
liquid O
chromatography O
coupled O
with O
a O
quadrupole O
time O
- O
of O
- O
flight O
mass O
spectrometry O
metabonomics O
approach O
was O
employed O
to O
investigate O
the O
urine O
biochemical O
characteristics O
of O
yeast O
- O
induced O
pyrexia O
rats O
. O

The O
acquired O
data O
were O
subjected O
to O
principal O
component O
analysis O
for O
differentiating O
the O
pyrexia O
rats O
from O
the O
control O
rats O
. O

Potential O
biomarkers O
were O
screened O
by O
using O
orthogonal O
partial O
least O
- O
squares O
- O
discriminant O
analysis O
and O
were O
identified O
by O
accurate O
mass O
, O
database O
, O
and O
MS O
/ O
MS O
fragment O
information O
obtained O
from O
the O
MS O
( O
E O
) O
technique O
. O

Sixteen O
metabolites O
in O
rat O
urine O
were O
identified O
as O
potential O
biomarkers O
. O

The O
relative O
intensities O
of O
the O
15 O
potential O
biomarkers O
were O
calculated O
. O

The O
thermoregulatory O
circuitry O
of O
" O
endogenous O
pyrogen O
( O
EP O
) O
^ O
- O
hypothalamus O
Na B
( I
+ I
) I
/ O
Ca B
( I
2 I
+ I
) I
- O
cAMP B
^ O
" O
was O
partially O
confirmed O
in O
this O
study O
. O

The O
results O
suggested O
that O
UPLC O
/ O
MS O
- O
based O
metabolic O
profiling O
of O
rat O
urine O
identifies O
impaired O
tryptophan B
metabolism O
as O
the O
mechanism O
of O
yeast O
- O
induced O
fever O
. O

This O
research O
provided O
informative O
data O
that O
the O
impaired O
tryptophan B
metabolism O
might O
be O
one O
of O
the O
important O
reasons O
in O
elucidating O
the O
biochemical O
basis O
of O
the O
febrile O
response O
. O

Xiaoxuming O
decoction O
for O
acute O
ischemic O
stroke O
: O
A O
systematic O
review O
and O
meta O
- O
analysis O
. O

ETHNOPHARMACOLOGICAL O
RELEVANCE O
: O
Xiaoxuming O
decoction O
( O
XXMD O
) O
is O
a O
well O
- O
known O
traditional O
Chinese O
herbal O
prescription O
in O
treatment O
of O
patients O
with O
stroke O
. O

The O
objective O
of O
this O
study O
is O
to O
assess O
the O
efficacy O
and O
safety O
of O
XXMD O
for O
acute O
ischemic O
stroke O
. O

MATERIALS O
AND O
METHODS O
: O
A O
systematic O
literature O
search O
was O
conducted O
in O
6 O
databases O
until O
June O
2012 O
to O
identify O
randomized O
controlled O
trials O
( O
RCTs O
) O
of O
XXMD O
for O
acute O
ischemic O
stroke O
compared O
with O
western O
conventional O
medicine O
( O
WCM O
) O
. O

The O
primary O
outcome O
measures O
were O
National O
Institutes O
of O
Health O
Stroke O
Scale O
( O
NIHSS O
) O
scores O
and O
modified O
Rankin O
Scale O
( O
mRS O
) O
scores O
. O

The O
secondary O
outcome O
measures O
were O
the O
clinical O
effective O
rate O
and O
adverse O
events O
at O
the O
end O
of O
treatment O
course O
. O

The O
methodological O
quality O
of O
RCTs O
was O
assessed O
independently O
using O
12 O
- O
item O
criteria O
according O
to O
the O
Cochrane O
Back O
Review O
Group O
. O

All O
data O
were O
analyzed O
using O
Review O
Manager O
5 O
. O
0 O
software O
. O

RESULTS O
: O
Eight O
RCTs O
with O
601 O
individuals O
published O
from O
1992 O
to O
2012 O
were O
identified O
. O

The O
studies O
were O
deemed O
to O
have O
a O
high O
risk O
of O
bias O
. O

Compared O
with O
WCM O
, O
1 O
RCT O
showed O
significant O
effects O
of O
XXMD O
for O
improving O
mRS O
after O
stroke O
( O
p O
< O
0 O
. O
05 O
) O
; O
3 O
RCTs O
for O
improving O
NIHSS O
scores O
[ O
n O
= O
186 O
, O
weighted O
mean O
difference O
( O
WMD O
) O
: O
- O
1 O
. O
86 O
, O
95 O
% O
CI O
: O
- O
3 O
. O
25 O
to O
- O
0 O
. O
48 O
, O
z O
= O
2 O
. O
63 O
, O
p O
< O
0 O
. O
01 O
] O
; O
7 O
RCTs O
for O
improving O
the O
clinical O
effective O
rate O
[ O
n O
= O
531 O
, O
risk O
ratio O
( O
RR O
) O
= O
1 O
. O
17 O
, O
95 O
% O
CI O
, O
1 O
. O
09 O
to O
1 O
. O
26 O
, O

z O
= O
4 O
. O
38 O
, O
p O
< O
0 O
. O
01 O
] O
. O

Five O
trials O
contained O
safety O
assessments O
and O
stated O
that O
no O
adverse O
event O
was O
found O
, O
whereas O
the O
other O
3 O
trials O
did O
not O
provide O
the O
information O
about O
adverse O
events O
. O

CONCLUSIONS O
: O
This O
systematic O
review O
showed O
positive O
but O
weak O
evidence O
of O
XXMD O
for O
acute O
ischemic O
stroke O
because O
of O
the O
poor O
methodological O
quality O
and O
the O
small O
quantity O
of O
the O
included O
trials O
. O

The O
difficulties O
of O
fitting O
Chinese O
herbal O
medicine O
( O
CHM O
) O
into O
the O
double O
blinded O
RCTs O
have O
raised O
as O
follows O
: O
( O
A O
) O
traditional O
Chinese O
medicine O
( O
TCM O
) O
as O
whole O
systems O
of O
healthcare O
offers O
unique O
methodological O
and O
theoretical O
challenges O
for O
RCTs O
; O
( O
B O
) O
suspicions O
against O
the O
placebo O
and O
unwillingness O
to O
stop O
taking O
other O
CHMs O
make O
recruitment O
more O
difficulty O
, O
time O
- O
consumption O
, O
and O
cost O
; O
( O
C O
) O
the O
shortcomings O
of O
the O
TCM O
diagnostic O
process O
includes O
the O
lack O
of O
standardization O
in O
terminology O
, O
disagreement O
of O
pattern O
differentiation O
( O
Bianzheng O
) O
, O
and O
neglect O
of O
formula O
corresponding O
to O
syndrome O
( O
TCM O
Zheng O
) O
; O

( O
D O
) O
It O
is O
difficult O
to O
design O
credible O
herbal O
placebos O
with O
similar O
appearance O
, O
smells O
and O
tastes O
to O
the O
experimental O
CHM O
and O
at O
the O
same O
time O
is O
absent O
of O
any O
pharmacological O
activity O
; O
( O
E O
) O
the O
achieving O
efficacy O
of O
CHM O
complex O
interventions O
is O
often O
nonspecific O
and O
the O
outcome O
measures O
is O
subjective O
using O
Chinese O
quantitative O
instrument O
. O

Insights O
into O
mast O
cell O
functions O
in O
asthma O
using O
mouse O
models O
. O

Therapeutics O
targeting O
specific O
mechanisms O
of O
asthma O
have O
shown O
promising O
results O
in O
mouse O
models O
of O
asthma O
. O

However O
, O
these O
successes O
have O
not O
transferred O
well O
to O
the O
clinic O
or O
to O
the O
treatment O
of O
asthma O
sufferers O
. O

We O
suggest O
a O
reason O
for O
this O
incongruity O
is O
that O
mast O
cell O
- O
dependent O
responses O
, O
which O
may O
play O
an O
important O
role O
in O
the O
pathogenesis O
of O
both O
atopic O
and O
non O
- O
atopic O
asthma O
, O
are O
not O
a O
key O
component O
in O
most O
of O
the O
current O
asthma O
mouse O
models O
. O

Two O
reasons O
for O
this O
are O
that O
wild O
type O
mice O
have O
, O
in O
contrast O
to O
humans O
, O
a O
negligible O
number O
of O
mast O
cells O
localized O
in O
the O
smaller O
airways O
and O
in O
the O
parenchyma O
, O
and O
that O
only O
specific O
protocols O
show O
mast O
cell O
- O
dependent O
reactions O
. O

The O
development O
of O
mast O
cell O
- O
deficient O
mice O
and O
the O
reconstitution O
of O
mast O
cells O
within O
these O
mice O
have O
opened O
up O
the O
possibility O
to O
generate O
mouse O
models O
of O
asthma O
with O
a O
marked O
role O
of O
mast O
cells O
. O

In O
addition O
, O
mast O
cell O
- O
deficient O
mice O
engrafted O
with O
mast O
cells O
have O
a O
distribution O
of O
mast O
cells O
more O
similar O
to O
humans O
. O

In O
this O
article O
we O
review O
and O
highlight O
the O
mast O
cell O
- O
dependent O
and O
- O
independent O
responses O
with O
respect O
to O
airway O
hyperresponsiveness O
and O
inflammation O
in O
asthma O
models O
using O
mast O
cell O
- O
deficient O
and O
mast O
cell O
- O
engrafted O
mice O
. O

Melanoidins B
isolated O
from O
heated O
potato O
fiber O
( O
Potex O
) O
affect O
human O
colon O
cancer O
cells O
growth O
via O
modulation O
of O
cell O
cycle O
and O
proliferation O
regulatory O
proteins O
. O

Melanoidins B
are O
brown O
, O
nitrogen B
containing O
, O
high O
molecular O
weight O
end O
products O
of O
Maillard O
reaction O
with O
poorly O
established O
activity O
towards O
tumor O
cells O
. O

The O
goal O
of O
present O
study O
was O
to O
verify O
whether O
both O
heated O
potato O
fiber O
Potex O
extract O
( O
180 O
degrees O
C O
for O
2h O
) O
and O
melanoidins B
isolated O
from O
the O
extract O
exerts O
growth O
- O
inhibiting O
activity O
in O
human O
colon O
cancer O
cells O
in O
vitro O
. O

The O
cells O
of O
LS180 O
colon O
cancer O
cell O
line O
were O
tested O
upon O
treatment O
with O
roasted O
potato O
fiber O
extract O
( O
AM4 O
) O
as O
well O
as O
with O
high O
( O
HMW O
) O
and O
low O
( O
LMW O
) O
molecular O
weight O
fractions O
isolated O
from O
the O
extract O
, O
since O
both O
may O
be O
regarded O
as O
/ O
or O
contain O
melanoidins O
. O

The O
tested O
compounds O
at O
concentration O
of O
1000 O
mu O
g O
/ O
ml O
reduced O
cell O
growth O
down O
to O
45 O
% O
, O
69 O
% O
and O
54 O
% O
, O
respectively O
. O

Furthermore O
, O
deregulated O
ERK1 O
/ O
2 O
signaling O
was O
revealed O
upon O
treatment O
. O

Moreover O
, O
multiple O
alternations O
in O
cell O
cycle O
regulators O
activity O
were O
found O
( O
i O
. O
e O
. O
cyclinD1 O
, O
cyclin O
- O
dependent O
kinase O
4 O
and O
6 O
, O
p21 O
, O
p27 O
, O
p53 O
, O
pRb O
) O
leading O
to O
cell O
cycle O
cessation O
in O
G0 O
phase O
. O

Importantly O
, O
LMW O
compounds O
revealed O
markedly O
stronger O
potential O
to O
alter O
specific O
molecular O
targets O
comparing O
to O
HMW O
compounds O
. O

Summarizing O
, O
the O
results O
emphasize O
that O
both O
high O
and O
low O
molecular O
weight O
melanoidins B
contribute O
to O
antiproliferative O
activity O
of O
heated O
potato O
fiber O
in O
LS180 O
colon O
cancer O
cells O
in O
vitro O
. O

Short O
- O
term O
heating O
reduces O
the O
anti O
- O
inflammatory O
effects O
of O
fresh O
raw O
garlic O
extracts O
on O
the O
LPS O
- O
induced O
production O
of O
NO B
and O
pro O
- O
inflammatory O
cytokines O
by O
downregulating O
allicin B
activity O
in O
RAW O
264 O
. O
7 O
macrophages O
. O

Garlic O
has O
a O
variety O
of O
biologic O
activities O
, O
including O
anti O
- O
inflammatory O
properties O
. O

Although O
garlic O
has O
several O
biologic O
activities O
, O
some O
people O
dislike O
eating O
fresh O
raw O
garlic O
because O
of O
its O
strong O
taste O
and O
smell O
. O

Therefore O
, O
garlic O
formulations O
involving O
heating O
procedures O
have O
been O
developed O
. O

In O
this O
study O
, O
we O
investigated O
whether O
short O
- O
term O
heating O
affects O
the O
anti O
- O
inflammatory O
properties O
of O
garlic O
. O

Fresh O
and O
heated O
raw O
garlic O
extracts O
( O
FRGE O
and O
HRGE O
) O
were O
prepared O
with O
incubation O
at O
25 O
degrees O
C O
and O
95 O
degrees O
C O
, O
respectively O
, O
for O
2h O
. O

Treatment O
with O
FRGE O
and O
HRGE O
significantly O
reduced O
the O
LPS O
- O
induced O
increase O
in O
the O
pro O
- O
inflammatory O
cytokine O
concentration O
( O
TNF O
- O
alpha O
, O
IL O
- O
1 O
beta O
, O
and O
IL O
- O
6 O
) O
and O
NO B
through O
HO O
- O
1 O
upregulation O
in O
RAW O
264 O
. O
7 O
macrophages O
. O

The O
anti O
- O
inflammatory O
effect O
was O
greater O
in O
FRGE O
than O
in O
HRGE O
. O

The O
allicin B
concentration O
was O
higher O
in O
FRGE O
than O
in O
HRGE O
. O

Allicin B
treatment O
showed O
reduced O
production O
of O
pro O
- O
inflammatory O
cytokines O
and O
NO B
and O
increased O
HO O
- O
1 O
activity O
. O

The O
results O
show O
that O
the O
decrease O
in O
LPS O
- O
induced O
NO B
and O
pro O
- O
inflammatory O
cytokines O
in O
RAW O
264 O
. O
7 O
macrophages O
through O
HO O
- O
1 O
induction O
was O
greater O
for O
FRGE O
compared O
with O
HRGE O
. O

Additionally O
, O
the O
results O
indicate O
that O
allicin B
is O
responsible O
for O
the O
anti O
- O
inflammatory O
effect O
of O
FRGE O
. O

Our O
results O
suggest O
a O
potential O
therapeutic O
use O
of O
allicin B
in O
the O
treatment O
of O
chronic O
inflammatory O
disease O
. O

Motor O
neuron O
dysfunction O
in O
a O
mouse O
model O
of O
ALS O
: O
Gender O
- O
dependent O
effect O
of O
P2X7 O
antagonism O
. O

Amyotrophic O
lateral O
sclerosis O
( O
ALS O
) O
is O
a O
neurodegenerative O
progressive O
currently O
untreatable O
disease O
, O
characterized O
by O
selective O
motor O
neuron O
degeneration O
; O
the O
incidence O
and O
prevalence O
of O
ALS O
are O
greater O
in O
men O
than O
in O
women O
. O

Although O
some O
important O
mechanisms O
that O
might O
contribute O
to O
the O
death O
of O
motor O
neurons O
have O
been O
identified O
, O
the O
mechanisms O
underlying O
disease O
pathophysiology O
are O
still O
uncertain O
. O

In O
particular O
, O
the O
mechanisms O
underlying O
the O
role O
of O
gender O
in O
ALS O
and O
whether O
treatments O
should O
take O
into O
account O
sexual O
dimorphism O
remain O
only O
partially O
understood O
. O

Recently O
, O
the O
P2X7 O
receptor O
for O
ATP B
was O
reported O
to O
display O
neurotoxic O
potential O
in O
motor O
neuron O
disorders O
, O
and O
antagonism O
of O
the O
receptor O
has O
been O
suggested O
to O
be O
helpful O
in O
these O
disorders O
. O

Studying O
transgenic O
mice O
with O
superoxide B
dismutase O
1 O
gene O
mutations O
, O
widely O
used O
as O
model O
for O
ALS O
, O
may O
provide O
a O
better O
understanding O
of O
pathogenic O
mechanisms O
and O
of O
toxicity O
towards O
motor O
neurons O
, O
also O
possibly O
helping O
to O
understand O
whether O
treatments O
for O
ALS O
should O
take O
into O
account O
sexual O
dimorphism O
. O

The O
aim O
of O
the O
work O
was O
( O
1 O
) O
investigating O
on O
gender O
- O
dependence O
of O
disease O
progression O
in O
the O
standard O
model O
for O
ALS O
- O
the O
transgenic O
mouse O
bearing O
superoxide B
dismutase O
1 O
gene O
mutations O
- O
and O
( O
2 O
) O
assessing O
if O
a O
P2X7 O
receptor O
antagonist O
treatment O
should O
take O
into O
account O
sexual O
dimorphism O
. O

We O
evaluated O
if O
gender O
affect O
the O
disease O
course O
, O
the O
motor O
performance O
, O
the O
weight O
loss O
and O
the O
lifespan O
in O
mice O
overexpressing O
mutant O
superoxide B
dismutase O
1 O
. O

We O
measured O
motor O
impairment O
, O
motor O
strength O
and O
coordination O
by O
rotarod O
and O
grip O
strength O
testing O
. O

Further O
, O
we O
assessed O
if O
a O
treatment O
with O
the O
P2X7 O
receptor O
antagonist O
Brilliant B
Blue I
G I
- O
a O
dye O
that O
can O
cross O
the O
blood O
- O
brain O
barrier O
, O
has O
low O
toxicity O
, O
and O
has O
exhibited O
therapeutic O
effects O
in O
animal O
models O
of O
neurodegenerative O
diseases O
- O
impact O
on O
the O
disease O
progression O
, O
in O
male O
and O
female O
ALS O
mice O
. O

We O
found O
that O
( O
1 O
) O
the O
onset O
and O
the O
disease O
progression O
, O
and O
the O
survival O
were O
dependent O
on O
gender O
: O
male O
performed O
worst O
than O
female O
, O
lost O
body O
weight O
and O
died O
before O
; O
( O
2 O
) O
treatment O
with O
the O
P2X7 O
receptor O
antagonist O
Brilliant B
Blue I
G I
ameliorated O
the O
disease O
progression O
. O

The O
treatment O
effect O
was O
gender O
- O
dependent O
: O
amelioration O
was O
greater O
in O
male O
than O
in O
female O
. O

In O
conclusions O
, O
we O
suggest O
that O
not O
only O
pathogenetic O
mechanism O
of O
motor O
neuron O
toxicity O
but O
also O
the O
drug O
treatment O
effectiveness O
may O
depend O
on O
gender O
; O
sexual O
dimorphism O
should O
be O
considered O
when O
investigating O
on O
ALS O
treatment O
efficacy O
in O
the O
ALS O
animal O
model O
. O

Our O
findings O
also O
point O
on O
the O
potential O
relevance O
of O
P2X7 O
receptor O
antagonism O
for O
ALS O
treatment O
, O
and O
highlight O
the O
importance O
of O
adopting O
a O
sex O
- O
specific O
approach O
to O
searching O
for O
treatment O
of O
ALS O
. O

2 B
, I
3 I
, I
7 I
, I
8 I
- I
Tetrachlorodibenzo I
- I
p I
- I
dioxin I
- O
induced O
inflammatory O
activation O
is O
mediated O
by O
intracellular O
free O
calcium B
in O
microglial O
cells O
. O

2 B
, I
3 I
, I
7 I
, I
8 I
- I
Tetrachlorodibenzo I
- I
p I
- I
dioxin I
( O
TCDD B
) O
has O
been O
known O
to O
induce O
inflammatory O
signaling O
in O
a O
number O
of O
cell O
types O
and O
tissues O
. O

However O
, O
the O
adverse O
effects O
of O
TCDD B
on O
the O
central O
nervous O
system O
( O
CNS O
) O
have O
not O
been O
entirely O
elucidated O
. O

In O
this O
study O
, O
using O
reverse O
transcriptase O
PCR O
( O
RT O
- O
PCR O
) O
and O
ELISA O
, O
we O
showed O
that O
TCDD B
up O
- O
regulated O
the O
expression O
and O
secretion O
of O
tumor O
necrosis O
factor O
- O
alpha O
( O
TNF O
- O
alpha O
) O
in O
a O
time O
- O
dependent O
manner O
in O
cultured O
HAPI O
microglial O
cells O
. O

TCDD B
also O
caused O
a O
fast O
( O
within O
30min O
as O
judged O
by O
the O
increase O
in O
its O
mRNA O
level O
) O
activation O
of O
cytosolic O
phospholipase O
A2 O
( O
cPLA2 O
) O
. O

This O
initial O
action O
was O
accompanied O
by O
up O
- O
regulation O
of O
cyclooxygenase O
- O
2 O
( O
COX O
- O
2 O
) O
, O
an O
important O
inflammation O
marker O
within O
1h O
after O
TCDD B
treatment O
. O

These O
pro O
- O
inflammatory O
responses O
were O
inhibited O
by O
two O
types O
of O
Ca B
( I
2 I
+ I
) I
blockers O
, O
bis B
- I
( I
o I
- I
aminophenoxy I
) I
ethane I
- I
N I
, I
N I
, I
N I
' I
, I
N I
' I
- I
tetra I
- I
acetic I
acid I
acetoxymethyl I
ester I
( O
BAPTA B
- I
AM I
) O
and O
nifedipine B
, O
thus O
, O
indicating O
that O
the O
effects O
are O
triggered O
by O
initial O
increase O
in O
the O
intracellular O
concentration O
of O
free O
Ca B
( I
2 I
+ I
) I
( O
[ O
Ca B
( I
2 I
+ I
) I
] O
i O
) O
. O

Further O
, O
TCDD B
exposure O
could O
induce O
phosphorylation O
- O
and O
ubiquitination O
- O
dependent O
degradation O
of O
I O
k O
B O
alpha O
, O
and O
the O
translocation O
of O
NF O
- O
kappa O
B O
p65 O
from O
the O
cytosol O
to O
the O
nucleus O
in O
this O
microglial O
cell O
line O
. O

Thus O
, O
the O
NF O
- O
kappa O
B O
signaling O
pathway O
can O
be O
activated O
after O
TCDD B
treatment O
. O

However O
, O
Ca B
( I
2 I
+ I
) I
blockers O
also O
obviously O
attenuated O
NF O
- O
kappa O
B O
activation O
and O
transnuclear O
transport O
induced O
by O
TCDD B
. O

In O
concert O
with O
these O
results O
, O
we O
highlighted O
that O
the O
secretion O
of O
pro O
- O
inflammatory O
cytokine O
and O
NF O
- O
kappa O
B O
activation O
induced O
by O
TCDD B
can O
be O
mediated O
by O
elevation O
of O
[ O
Ca B
( I
2 I
+ I
) I
] O
i O
in O
HAPI O
microglial O
cells O
. O

Extract O
from O
Mimosa O
pigra O
attenuates O
chronic O
experimental O
pulmonary O
hypertension O
. O

ETHNOPHARMACOLOGICAL O
RELEVANCE O
: O
Different O
parts O
of O
Mimosa O
pigra O
( O
MPG O
) O
are O
used O
in O
traditional O
medicine O
in O
Madagascar O
, O
tropical O
Africa O
, O
South O
America O
and O
Indonesia O
for O
various O
troubles O
including O
cardiovascular O
disorders O
. O

AIM O
OF O
THE O
STUDY O
: O
To O
investigate O
the O
mechanisms O
underlying O
the O
vascular O
effects O
of O
MPG B
by O
assessing O
in O
vitro O
its O
antioxidant O
and O
anti O
- O
inflammatory O
properties O
, O
and O
its O
vascular O
relaxing O
effects O
, O
and O
in O
vivo O
, O
its O
action O
on O
hypoxic O
pulmonary O
hypertension O
( O
PAH O
) O
in O
rats O
. O

MATERIAL O
AND O
METHODS O
: O
The O
antioxidant O
activity O
of O
MPG O
leaf O
hydromethanolic O
extract O
was O
determined O
by O
using O
both O
the O
1 B
, I
1 I
- I
diphenyl I
- I
2 I
- I
picrylhydrazyl I
radical O
scavenging O
and O
the O
oxygen O
radical O
absorbance O
capacity O
in O
vitro O
assays O
. O

Anti O
- O
inflammatory O
properties O
were O
assayed O
on O
TNF O
alpha O
- O
induced O
VCAM O
- O
1 O
expression O
in O
endothelial O
cells O
. O

The O
vasorelaxant O
effect O
of O
MPG O
extract O
was O
studied O
on O
rat O
arterial O
rings O
pre O
- O
contracted O
with O
phenylephrine B
( O
1 O
mu O
M O
) O
in O
the O
presence O
or O
absence O
of O
the O
endothelium O
. O

In O
vivo O
MPG O
extract O
effects O
were O
analyzed O
in O
chronic O
hypoxic O
PAH O
, O
obtained O
by O
housing O
male O
Wistar O
rats O
, O
orally O
treated O
or O
not O
with O
MPG O
extract O
( O
400mg O
/ O
kg O
/ O
d O
) O
, O
in O
a O
hypobaric O
chamber O
for O
21 O
days O
. O

RESULTS O
: O
MPG O
leaf O
extract O
had O
antioxidant O
and O
anti O
- O
inflammatory O
properties O
. O

It O
induced O
endothelium O
- O
dependent O
, O
NO B
- O
mediated O
relaxation O
of O
rat O
aorta O
and O
pulmonary O
artery O
. O

In O
vivo O
, O
chronic O
MPG B
treatment O
reduced O
hypoxic O
PAH O
in O
rat O
by O
decreasing O
by O
22 O
. O
3 O
% O
the O
pulmonary O
arterial O
pressure O
and O
by O
20 O
. O
0 O
% O
and O
23 O
. O
9 O
% O
the O
pulmonary O
artery O
and O
cardiac O
remodelling O
, O
respectively O
. O

This O
effect O
was O
associated O
with O
a O
restoration O
of O
endothelium O
function O
and O
a O
2 O
. O
3 O
- O
fold O
increase O
in O
endothelial O
NO B
synthase O
phosphorylation O
. O

MPG O
leaf O
hydromethanolic O
extract O
contained O
tryptophan B
and O
flavonoids B
, O
including O
quercetin B
glycosides I
. O

Both O
compounds O
also O
efficiently O
limit O
hypoxia O
- O
induced O
PAH O
. O

CONCLUSIONS O
: O
Our O
results O
show O
endothelial O
protective O
action O
of O
MPG O
leaf O
hydromethanolic O
extract O
which O
is O
likely O
to O
be O
due O
to O
its O
antioxidant O
action O
. O

MPG B
successfully O
attenuated O
the O
development O
of O
PAH O
, O
thus O
demonstrating O
the O
protective O
effect O
of O
MPG B
on O
cardiovascular O
diseases O
. O

The O
ATP B
required O
for O
potentiation O
of O
skeletal O
muscle O
contraction O
is O
released O
via O
pannexin O
hemichannels O
. O

During O
repetitive O
stimulation O
of O
skeletal O
muscle O
, O
extracellular O
ATP B
levels O
raise O
, O
activating O
purinergic O
receptors O
, O
increasing O
Ca B
( I
2 I
+ I
) I
influx O
, O
and O
enhancing O
contractile O
force O
, O
a O
response O
called O
potentiation O
. O

We O
found O
that O
ATP B
appears O
to O
be O
released O
through O
pannexin1 O
hemichannels O
( O
Panx1 O
HCs O
) O
. O

Immunocytochemical O
analyses O
and O
function O
were O
consistent O
with O
pannexin1 O
localization O
to O
T O
- O
tubules O
intercalated O
with O
dihydropyridine B
and O
ryanodine B
receptors O
in O
slow O
( O
soleus O
) O
and O
fast O
( O
extensor O
digitorum O
longus O
, O
EDL O
) O
muscles O
. O

Isolated O
myofibers O
took O
up O
ethidium B
( O
Etd B
( I
+ I
) I
) O
and O
released O
small O
molecules O
( O
as O
ATP B
) O
during O
electrical O
stimulation O
. O

Consistent O
with O
two O
glucose B
uptake O
pathways O
, O
induced O
uptake O
of O
2 B
- I
NBDG I
, O
a O
fluorescent O
glucose B
derivative O
, O
was O
decreased O
by O
inhibition O
of O
HCs O
or O
glucose B
transporter O
( O
GLUT4 O
) O
, O
and O
blocked O
by O
dual O
blockade O
. O

Adult O
skeletal O
muscles O
apparently O
do O
not O
express O
connexins O
, O
making O
it O
unlikely O
that O
connexin O
hemichannels O
contribute O
to O
the O
uptake O
and O
release O
of O
small O
molecules O
. O

ATP B
release O
, O
Etd B
( I
+ I
) I
uptake O
, O
and O
potentiation O
induced O
by O
repetitive O
electrical O
stimulation O
were O
blocked O
by O
HC O
blockers O
and O
did O
not O
occur O
in O
muscles O
of O
pannexin1 O
knockout O
mice O
. O

MRS2179 B
, O
a O
P2Y1R O
blocker O
, O
prevented O
potentiation O
in O
EDL O
, O
but O
not O
soleus O
muscles O
, O
suggesting O
that O
in O
fast O
muscles O
ATP B
activates O
P2Y1 O
but O
not O
P2X O
receptors O
. O

Phosphorylation O
on O
Ser B
and O
Thr B
residues O
of O
pannexin1 O
was O
increased O
during O
potentiation O
, O
possibly O
mediating O
HC O
opening O
. O

Opening O
of O
Panx1 O
HCs O
during O
repetitive O
activation O
allows O
efflux O
of O
ATP B
, O
influx O
of O
glucose B
and O
possibly O
Ca B
( I
2 I
+ I
) I
too O
, O
which O
are O
required O
for O
potentiation O
of O
contraction O
. O

This O
article O
is O
part O
of O
a O
Special O
Issue O
entitled O
' O
Connexin O
based O
channels O
' O
. O

Genetic O
deletion O
of O
the O
adenosine B
A2A O
receptor O
prevents O
nicotine B
- O
induced O
upregulation O
of O
alpha O
7 O
, O
but O
not O
alpha O
4 O
beta O
2 O
* O
nicotinic O
acetylcholine B
receptor O
binding O
in O
the O
brain O
. O

Considerable O
evidence O
indicates O
that O
adenosine B
A2A O
receptors O
( O
A2ARs O
) O
modulate O
cholinergic O
neurotransmission O
, O
nicotinic O
acetylcholine B
receptor O
( O
nAChR O
) O
function O
, O
and O
nicotine B
- O
induced O
behavioural O
effects O
. O

To O
explore O
the O
interaction O
between O
A2A O
and O
nAChRs O
, O
we O
examined O
if O
the O
complete O
genetic O
deletion O
of O
adenosine B
A2ARs O
in O
mice O
induces O
compensatory O
alterations O
in O
the O
binding O
of O
different O
nAChR O
subtypes O
, O
and O
whether O
the O
long O
- O
term O
effects O
of O
nicotine B
on O
nAChR O
regulation O
are O
altered O
in O
the O
absence O
of O
the O
A2AR O
gene O
. O

Quantitative O
autoradiography O
was O
used O
to O
measure O
cytisine B
- O
sensitive O
[ B
( I
125 I
) I
I I
] I
epibatidine I
and O
[ O
( B
125 I
) I
I I
] O
alpha O
- O
bungarotoxin O
binding O
to O
alpha O
4 O
beta O
2 O
* O
and O
alpha O
7 O
nAChRs O
, O
respectively O
, O
in O
brain O
sections O
of O
drug O
- O
na O
i O
ve O
( O
n O
= O
6 O
) O
or O
nicotine B
treated O
( O
n O
= O
5 O
- O
7 O
) O
, O
wild O
- O
type O
and O
adenosine B
A2AR O
knockout O
mice O
. O

Saline O
or O
nicotine B
( O
7 O
. O
8 O
mg O
/ O
kg O
/ O
day O
; O
free O
- O
base O
weight O
) O
were O
administered O
to O
male O
CD1 O
mice O
via O
subcutaneous O
osmotic O
minipumps O
for O
a O
period O
of O
14 O
days O
. O

Blood O
plasma O
levels O
of O
nicotine B
and O
cotinine B
were O
measured O
at O
the O
end O
of O
treatment O
. O

There O
were O
no O
compensatory O
developmental O
alterations O
in O
nAChR O
subtype O
distribution O
or O
density O
in O
drug O
- O
na O
i O
ve O
A2AR O
knockout O
mice O
. O

In O
nicotine B
treated O
wild O
- O
type O
mice O
, O
both O
alpha O
4 O
beta O
2 O
* O
and O
alpha O
7 O
nAChR O
binding O
sites O
were O
increased O
compared O
with O
saline O
treated O
controls O
. O

The O
genetic O
ablation O
of O
adenosine B
A2ARs O
prevented O
nicotine B
- O
induced O
upregulation O
of O
alpha O
7 O
nAChRs O
, O
without O
affecting O
alpha O
4 O
beta O
2 O
* O
receptor O
upregulation O
. O

This O
selective O
effect O
was O
observed O
at O
plasma O
levels O
of O
nicotine B
that O
were O
within O
the O
range O
reported O
for O
smokers O
( O
10 O
- O
50 O
ng O
ml O
( O
- O
1 O
) O
) O
. O

Our O
data O
highlight O
the O
involvement O
of O
adenosine B
A2ARs O
in O
the O
mechanisms O
of O
nicotine B
- O
induced O
alpha O
7 O
nAChR O
upregulation O
, O
and O
identify O
A2ARs O
as O
novel O
pharmacological O
targets O
for O
modulating O
the O
long O
- O
term O
effects O
of O
nicotine B
on O
alpha O
7 O
receptors O
. O

Profiling O
the O
venom O
gland O
transcriptome O
of O
Tetramorium O
bicarinatum O
( O
Hymenoptera O
: O
Formicidae O
) O
: O
The O
first O
transcriptome O
analysis O
of O
an O
ant O
species O
. O

Animal O
venoms O
are O
complex O
mixtures O
containing O
a O
range O
of O
bioactive O
elements O
with O
potential O
pharmacological O
and O
therapeutic O
use O
. O

Even O
though O
ants O
account O
among O
the O
most O
diverse O
zoological O
group O
, O
little O
information O
is O
available O
regarding O
their O
venom O
composition O
. O

To O
initiate O
the O
characterization O
of O
the O
transcriptomic O
venom O
gland O
expression O
of O
the O
ant O
species O
Tetramorium O
bicarinatum O
, O
400 O
randomly O
selected O
clones O
from O
cDNA O
library O
were O
sequenced O
and O
a O
total O
of O
364 O
high O
quality O
expressed O
sequence O
tags O
( O
ESTs O
) O
were O
generated O
. O

Based O
on O
the O
results O
of O
BLAST O
searches O
, O
these O
sequences O
were O
clustered O
and O
assembled O
into O
83 O
contigs O
( O
22 O
multiple O
sequences O
) O
and O
61 O
singletons O
. O

About O
74 O
% O
( O
267 O
) O
of O
the O
contigs O
matched O
BLASTx O
hits O
with O
an O
interesting O
diversity O
together O
with O
an O
unusual O
abundance O
of O
cellular O
transcripts O
related O
to O
gene O
expression O
regulation O
( O
29 O
% O
of O
the O
total O
library O
) O
reflecting O
the O
specialization O
of O
this O
tissue O
. O

About O
eighteen O
per O
cent O
of O
the O
ESTs O
were O
categorized O
as O
Hymenoptera O
venom O
compounds O
, O
the O
major O
part O
represented O
by O
allergens O
( O
62 O
% O
of O
the O
total O
venom O
compounds O
) O
. O

In O
addition O
, O
a O
high O
number O
of O
sequences O
( O
26 O
% O
) O
had O
no O
similarity O
to O
any O
known O
sequences O
. O

This O
study O
provides O
a O
first O
insight O
of O
the O
gene O
expression O
scenario O
of O
the O
venom O
gland O
of O
T O
. O
bicarinatum O
which O
might O
contribute O
to O
acquiring O
a O
more O
comprehensive O
view O
on O
the O
origin O
and O
functional O
diversity O
of O
venom O
proteins O
among O
ants O
and O
more O
broadly O
among O
Hymenopteran O
insects O
. O

Simultaneous O
determination O
of O
methanol B
, O
acetaldehyde B
, O
acetone B
, O
and O
ethanol B
in O
human O
blood O
by O
gas O
chromatography O
with O
flame O
ionization O
detection O
. O

Background O
: O
Methanol B
, O
acetaldehyde B
, O
acetone B
, O
and O
ethanol B
, O
which O
are O
commonly O
used O
as O
biomarkers O
of O
several O
diseases O
, O
in O
acute O
intoxications O
, O
and O
forensic O
settings O
, O
can O
be O
detected O
and O
quantified O
in O
biological O
fluids O
. O

Gas O
chromatography O
( O
GC O
) O
- O
mass O
spectrometry O
techniques O
are O
complex O
, O
require O
highly O
trained O
personnel O
and O
expensive O
materials O
. O

Gas O
chromatographic O
determinations O
of O
ethanol B
, O
methanol B
, O
and O
acetone B
have O
been O
reported O
in O
one O
study O
with O
suboptimal O
accuracy O
. O

Our O
objective O
was O
to O
improve O
the O
assessment O
of O
these O
compounds O
in O
human O
blood O
using O
GC O
with O
flame O
ionization O
detection O
. O
Methods O
: O
An O
amount O
of O
50 O
micro O
l O
of O
blood O
was O
diluted O
with O
300 O
micro O
l O
of O
sterile O
water O
, O
40 O
micro O
l O
of O
10 O
% O
sodium B
tungstate I
, O
and O
20 O
micro O
l O
of O
1 O
% O
sulphuric B
acid I
. O

After O
centrifugation O
, O
1 O
micro O
l O
of O
the O
supernatant O
was O
inje O
- O
cted O
into O
the O
gas O
chromatograph O
. O

We O
used O
a O
dimethylpolysiloxane B
capillary O
column O
of O
30 O
m O
0 O
. O
25 O
mm O
0 O
. O
25 O
micro O
m O
. O
Results O
: O
We O
observed O
linear O
correlations O
from O
7 O
. O
5 O
to O
240 O
mg O
/ O
l O
for O
methanol B
, O
acetaldehyde B
, O
and O
acetone B
and O
from O
75 O
to O
2400 O
mg O
/ O
l O
for O
ethanol B
. O

Precision O
at O
concentrations O
15 O
, O
60 O
, O
and O
120 O
mg O
/ O
l O
for O
methanol B
, O
acetaldehyde B
, O
and O
acetone B
and O
150 O
, O
600 O
, O
and O
1200 O
mg O
/ O
ml O
for O
ethanol B
were O
0 O
. O
8 O
- O
6 O
. O
9 O
% O
. O

Ranges O
of O
accuracy O
were O
94 O
. O
7 O
- O
98 O
. O
9 O
% O
for O
methanol B
, O
91 O
. O
2 O
- O
97 O
. O
4 O
% O
for O
acetaldehyde B
, O
96 O
. O
1 O
- O
98 O
. O
7 O
% O
for O
acetone B
, O
and O
105 O
. O
5 O
- O
111 O
. O
6 O
% O
for O
ethanol B
. O

Limits O
of O
detection O
were O
0 O
. O
80 O
mg O
/ O
l O
for O
methanol B
, O
0 O
. O
61 O
mg O
/ O
l O
for O
acetaldehyde B
, O
0 O
. O
58 O
mg O
/ O
l O
for O
acetone B
, O
and O
0 O
. O
53 O
mg O
/ O
l O
for O
ethanol B
. O
Conclusion O
: O
This O
method O
is O
suitable O
for O
routine O
clinical O
and O
forensic O
practices O
. O

Progression O
rates O
from O
HbA1c O
6 O
. O
0 O
- O
6 O
. O
4 O
% O
and O
other O
prediabetes O
definitions O
to O
type O
2 O
diabetes O
: O
a O
meta O
- O
analysis O
. O

AIMS O
/ O
HYPOTHESIS O
: O
Precise O
estimates O
of O
progression O
rates O
from O
' O
prediabetes O
' O
to O
type O
2 O
diabetes O
are O
needed O
to O
optimise O
prevention O
strategies O
for O
high O
- O
risk O
individuals O
. O

There O
is O
acceptance O
of O
prediabetes O
defined O
by O
impaired O
fasting O
glucose B
( O
IFG O
) O
and O
impaired O
glucose B
tolerance O
( O
IGT O
) O
, O
but O
there O
is O
some O
controversy O
surrounding O
HbA1c O
- O
defined O
prediabetes O
ranges O
, O
with O
some O
favouring O
6 O
. O
0 O
- O
6 O
. O
4 O
% O
( O
42 O
- O
46 O
mmol O
/ O
mol O
) O
. O

Comparing O
progression O
rates O
between O
groups O
might O
aid O
this O
issue O
, O
thus O
we O
aimed O
to O
accurately O
estimate O
progression O
rates O
to O
diabetes O
from O
different O
prediabetes O
categories O
. O

METHODS O
: O
Meta O
- O
analysis O
of O
prospective O
observational O
studies O
in O
which O
participants O
had O
prediabetes O
at O
baseline O
( O
ADA O
- O
defined O
IFG O
[ O
5 O
. O
6 O
- O
6 O
. O
9 O
mmol O
/ O
l O
] O
, O
WHO O
- O
defined O
IFG O
[ O
6 O
. O
1 O
- O
6 O
. O
9 O
mmol O
/ O
l O
] O
, O
IGT O
( O
7 O
. O
8 O
- O
11 O
. O
0 O
mmol O
/ O
l O
) O
or O
raised O
HbA1c O
[ O
6 O
. O
0 O
- O
6 O
. O
4 O
% O
/ O
42 O
- O
46 O
mmol O
/ O
mol O
] O
) O
and O
were O
followed O
up O
for O
incident O
diabetes O
. O

Incidence O
rates O
were O
combined O
using O
Bayesian O
random O
effects O
models O
. O

RESULTS O
: O
Overall O
, O
70 O
studies O
met O
the O
inclusion O
criteria O
. O

In O
the O
six O
studies O
that O
used O
raised O
HbA1c O
, O
the O
pooled O
incidence O
rate O
( O
95 O
% O
credible O
interval O
) O
of O
diabetes O
was O
35 O
. O
6 O
( O
15 O
. O
1 O
, O
83 O
. O
0 O
) O
per O
1 O
, O
000 O
person O
- O
years O
. O

This O
rate O
was O
most O
similar O
to O
that O
for O
ADA O
- O
defined O
IFG O
( O
11 O
studies O
; O
35 O
. O
5 O
[ O
26 O
. O
6 O
, O
48 O
. O
0 O
] O
) O
and O
was O
non O
- O
significantly O
lower O
than O
WHO O
- O
defined O
IFG O
( O
34 O
studies O
; O
47 O
. O
4 O
[ O
37 O
. O
4 O
, O
59 O
. O
8 O
] O
) O
, O
IGT O
( O
46 O
studies O
, O
45 O
. O
5 O
[ O
37 O
. O
8 O
, O
54 O
. O
5 O
] O
) O
and O
IFG O
plus O
IGT O
( O
15 O
studies O
, O
70 O
. O
4 O
[ O
53 O
. O
8 O
, O
89 O
. O
7 O
] O
) O
. O

Similar O
results O
were O
seen O
when O
the O
data O
were O
analysed O
by O
the O
criteria O
used O
to O
diagnose O
diabetes O
. O

CONCLUSIONS O
/ O
INTERPRETATION O
: O
This O
study O
provides O
evidence O
that O
progression O
rates O
differ O
by O
prediabetes O
definition O
, O
which O
has O
implications O
for O
the O
planning O
and O
implementation O
of O
diabetes O
prevention O
programmes O
. O

HbA1c O
6 O
. O
0 O
- O
6 O
. O
4 O
% O
might O
identify O
people O
at O
a O
lower O
diabetes O
risk O
than O
other O
prediabetes O
definitions O
, O
but O
further O
research O
is O
needed O
. O

Antibacterial O
oxazolidinone B
analogues O
having O
a O
N B
- I
hydroxyacetyl I
- O
substituted O
seven O
- O
membered O
[ B
1 I
, I
2 I
, I
5 I
] I
triazepane I
or O
[ B
1 I
, I
2 I
, I
5 I
] I
oxadiazepane I
C O
- O
ring O
unit O
. O

We O
synthesized O
a O
series O
of O
oxazolidinone B
analogues O
bearing O
a O
N B
- I
hydroxyacetyl I
- I
substituted I
[ I
1 I
, I
2 I
, I
5 I
] I
triazepane I
or O
[ B
1 I
, I
2 I
, I
5 I
] I
oxadiazepane I
C O
- O
ring O
unit O
as O
homologues O
of O
an O
earlier O
drug O
candidate O
, O
eperezolid B
. O

Several O
of O
these O
compounds O
exhibited O
potent O
in O
vitro O
antibacterial O
activities O
towards O
not O
only O
Gram O
- O
positive O
, O
but O
also O
Gram O
- O
negative O
and O
linezolid B
- O
resistant O
pathogens O
. O

Compounds O
21a O
and O
21b O
, O
bearing O
a O
thiocarbamate B
side O
chain O
, O
showed O
high O
in O
vivo O
activity O
against O
methicillin B
- O
resistant O
Staphylococcus O
aureus O
SR3637 O
, O
together O
with O
a O
promising O
safety O
profile O
in O
terms O
of O
weak O
inhibition O
of O
monoamine B
oxidase O
and O
cytochrome O
P450 O
isozymes O
. O

Proteasomal O
cleavage O
site O
prediction O
of O
protein O
antigen O
using O
BP O
neural O
network O
based O
on O
a O
new O
set O
of O
amino B
acid I
descriptor O
. O

The O
accurate O
identification O
of O
cytotoxic O
T O
lymphocyte O
epitopes O
is O
becoming O
increasingly O
important O
in O
peptide O
vaccine O
design O
. O

The O
ubiquitin O
- O
proteasome O
system O
plays O
a O
key O
role O
in O
processing O
and O
presenting O
major O
histocompatibility O
complex O
class O
I O
restricted O
epitopes O
by O
degrading O
the O
antigenic O
protein O
. O

To O
enhance O
the O
specificity O
and O
efficiency O
of O
epitope O
prediction O
and O
identification O
, O
the O
recognition O
mode O
between O
the O
ubiquitin O
- O
proteasome O
complex O
and O
the O
protein O
antigen O
must O
be O
considered O
. O

Hence O
, O
a O
model O
that O
accurately O
predicts O
proteasomal O
cleavage O
must O
be O
established O
. O

This O
study O
proposes O
a O
new O
set O
of O
parameters O
to O
characterize O
the O
cleavage O
window O
and O
uses O
a O
backpropagation O
neural O
network O
algorithm O
to O
build O
a O
model O
that O
accurately O
predicts O
proteasomal O
cleavage O
. O

The O
accuracy O
of O
the O
prediction O
model O
, O
which O
depends O
on O
the O
window O
sizes O
of O
the O
cleavage O
, O
reaches O
95 O
. O
454 O
% O
for O
the O
N O
- O
terminus O
and O
95 O
. O
011 O
% O
for O
the O
C O
- O
terminus O
. O

The O
results O
show O
that O
the O
identification O
of O
proteasomal O
cleavage O
sites O
depends O
on O
the O
sequence O
next O
to O
it O
and O
that O
the O
prediction O
performance O
of O
the O
C B
- O
terminus O
is O
better O
than O
that O
of O
the O
N B
- O
terminus O
on O
average O
. O

Thus O
, O
models O
based O
on O
the O
properties O
of O
amino B
acids I
can O
be O
highly O
reliable O
and O
reflect O
the O
structural O
features O
of O
interactions O
between O
proteasomes O
and O
peptide O
sequences O
. O

Effects O
of O
Dietary O
Factors O
on O
the O
Pharmacokinetics O
of O
( B
58 I
) I
Fe I
- O
labeled O
Hemin O
After O
Oral O
Administration O
in O
Normal O
Rats O
and O
the O
Iron B
- O
deficient O
Rats O
. O

Hemin B
, O
iron B
( I
III I
) I
protoporphyrin I
chloride I
( I
IX I
) I
, O
as O
a O
stable O
form O
of O
heme B
iron B
, O
has O
been O
used O
in O
iron B
absorption O
studies O
. O

The O
aim O
of O
the O
present O
study O
was O
to O
elucidate O
the O
influences O
of O
body O
iron B
status O
and O
three O
dietary O
factors O
( O
green O
tea O
extract O
, O
ascorbic B
acid I
, O
and O
calcium B
) O
on O
the O
pharmacokinetics O
of O
hemin B
using O
stable O
isotope O
labeling O
methods O
followed O
by O
ICP O
- O
MS O
measurement O
. O

In O
this O
study O
, O
a O
rapid O
, O
sensitive O
, O
and O
specific O
ICP O
- O
MS O
method O
for O
the O
determination O
of O
( B
58 I
) I
Fe I
originating O
from O
hemin B
in O
rat O
plasma O
was O
developed O
and O
a O
rat O
model O
of O
iron B
deficiency O
anemia O
was O
established O
. O

It O
was O
found O
that O
hemin B
iron B
absorption O
increased O
significantly O
under O
iron B
deficiency O
anemia O
status O
, O
with O
AUC0 O
- O
t O
and O
AUC0 O
- O
infinity O
showing O
significant O
increase O
in O
anemic O
rats O
compared O
to O
normal O
ones O
. O

Green O
tea O
extract O
strongly O
inhibited O
hemin O
iron B
absorption O
in O
both O
normal O
rats O
and O
iron B
- O
deficient O
rats O
. O

In O
normal O
rats O
administered O
with O
green O
tea O
extract O
, O
C O
max O
resulted O
significantly O
reduced O
, O
whereas O
in O
anemic O
rats O
administered O
with O
green O
tea O
extract O
both O
AUC0 O
- O
t O
and O
AUC0 O
- O
infinity O
were O
reduced O
. O

On O
the O
other O
hand O
, O
ascorbic B
acid I
significantly O
affected O
hemin O
iron B
absorption O
only O
in O
iron B
- O
deficient O
rats O
, O
in O
which O
C O
max O
showed O
a O
significant O
increase O
. O

Interestingly O
, O
calcium B
slowed O
down O
the O
hemin O
iron B
absorption O
rate O
in O
normal O
rats O
, O
MRT0 O
- O
t O
being O
significantly O
different O
in O
calcium B
- O
treated O
animals O
compared O
to O
untreated O
ones O
. O

This O
trend O
also O
appeared O
in O
the O
iron B
- O
deficient O
group O
but O
it O
did O
not O
reach O
statistical O
significance O
. O

Our O
data O
suggest O
that O
the O
mechanism O
of O
hemin B
iron B
absorption O
is O
regulated O
by O
body O
iron B
status O
and O
dietary O
factors O
can O
influence O
hemin B
iron B
absorption O
to O
varying O
degrees O
. O

Moreover O
, O
these O
results O
may O
also O
have O
general O
implication O
in O
the O
iron B
deficiency O
treatment O
with O
iron B
supplements O
and O
fortification O
of O
foods O
. O

Biocatalytic O
and O
structural O
properties O
of O
a O
highly O
engineered O
halohydrin B
dehalogenase O
. O

Two O
highly O
engineered O
halohydrin B
dehalogenase O
variants O
were O
characterized O
in O
terms O
of O
their O
performance O
in O
dehalogenation O
and O
epoxide B
cyanolysis O
reactions O
. O

Both O
enzyme O
variants O
outperformed O
the O
wild O
- O
type O
enzyme O
in O
the O
cyanolysis O
of O
ethyl B
( I
S I
) I
- I
3 I
, I
4 I
- I
epoxybutyrate I
, O
a O
conversion O
yielding O
ethyl B
( I
R I
) I
- I
4 I
- I
cyano I
- I
3 I
- I
hydroxybutyrate I
, O
an O
important O
chiral O
building O
block O
for O
statin O
synthesis O
. O

One O
of O
the O
enzyme O
variants O
, O
HheC2360 O
, O
displayed O
catalytic O
rates O
for O
this O
cyanolysis O
reaction O
enhanced O
up O
to O
tenfold O
. O

Furthermore O
, O
the O
enantioselectivity O
of O
this O
variant O
was O
the O
opposite O
of O
that O
of O
the O
wild O
- O
type O
enzyme O
, O
both O
for O
dehalogenation O
and O
for O
cyanolysis O
reactions O
. O

The O
37 O
- O
fold O
mutant O
HheC2360 O
showed O
an O
increase O
in O
thermal O
stability O
of O
8 O
degrees O
C O
relative O
to O
the O
wild O
- O
type O
enzyme O
. O

Crystal O
structures O
of O
this O
enzyme O
were O
elucidated O
with O
chloride B
and O
ethyl B
( I
S I
) I
- I
3 I
, I
4 I
- I
epoxybutyrate I
or O
with O
ethyl B
( I
R I
) I
- I
4 I
- I
cyano I
- I
3 I
- I
hydroxybutyrate I
bound O
in O
the O
active O
site O
. O

The O
observed O
increase O
in O
temperature O
stability O
was O
explained O
in O
terms O
of O
a O
substantial O
increase O
in O
buried O
surface O
area O
relative O
to O
the O
wild O
- O
type O
HheC O
, O
together O
with O
enhanced O
interfacial O
interactions O
between O
the O
subunits O
that O
form O
the O
tetramer O
. O

The O
structures O
also O
revealed O
that O
the O
substrate O
binding O
pocket O
was O
modified O
both O
by O
substitutions O
and O
by O
backbone O
movements O
in O
loops O
surrounding O
the O
active O
site O
. O

The O
observed O
changes O
in O
the O
mutant O
structures O
are O
partly O
governed O
by O
coupled O
mutations O
, O
some O
of O
which O
are O
necessary O
to O
remove O
steric O
clashes O
or O
to O
allow O
backbone O
movements O
to O
occur O
. O

The O
importance O
of O
interactions O
between O
substitutions O
suggests O
that O
efficient O
directed O
evolution O
strategies O
should O
allow O
for O
compensating O
and O
synergistic O
mutations O
during O
library O
design O
. O

RNA O
global O
alignment O
in O
the O
joint O
sequence O
- O
structure O
space O
using O
elastic O
shape O
analysis O
. O

The O
functions O
of O
RNAs O
, O
like O
proteins O
, O
are O
determined O
by O
their O
structures O
, O
which O
, O
in O
turn O
, O
are O
determined O
by O
their O
sequences O
. O

Comparison O
/ O
alignment O
of O
RNA O
molecules O
provides O
an O
effective O
means O
to O
predict O
their O
functions O
and O
understand O
their O
evolutionary O
relationships O
. O

For O
RNA O
sequence O
alignment O
, O
most O
methods O
developed O
for O
protein O
and O
DNA O
sequence O
alignment O
can O
be O
directly O
applied O
. O

RNA O
3 O
- O
dimensional O
structure O
alignment O
, O
on O
the O
other O
hand O
, O
tends O
to O
be O
more O
difficult O
than O
protein O
structure O
alignment O
due O
to O
the O
lack O
of O
regular O
secondary O
structures O
as O
observed O
in O
proteins O
. O

Most O
of O
the O
existing O
RNA O
3D O
structure O
alignment O
methods O
use O
only O
the O
backbone O
geometry O
and O
ignore O
the O
sequence O
information O
. O

Using O
both O
the O
sequence O
and O
backbone O
geometry O
information O
in O
RNA O
alignment O
may O
not O
only O
produce O
more O
accurate O
classification O
, O
but O
also O
deepen O
our O
understanding O
of O
the O
sequence O
- O
structure O
- O
function O
relationship O
of O
RNA O
molecules O
. O

In O
this O
study O
, O
we O
developed O
a O
new O
RNA O
alignment O
method O
based O
on O
elastic O
shape O
analysis O
( O
ESA O
) O
. O

ESA O
treats O
RNA O
structures O
as O
three O
dimensional O
curves O
with O
sequence O
information O
encoded O
on O
additional O
dimensions O
so O
that O
the O
alignment O
can O
be O
performed O
in O
the O
joint O
sequence O
- O
structure O
space O
. O

The O
similarity O
between O
two O
RNA O
molecules O
is O
quantified O
by O
a O
formal O
distance O
, O
geodesic O
distance O
. O

Based O
on O
ESA O
, O
a O
rigorous O
mathematical O
framework O
can O
be O
built O
for O
RNA O
structure O
comparison O
. O

Means O
and O
covariances O
of O
full O
structures O
can O
be O
defined O
and O
computed O
, O
and O
probability O
distributions O
on O
spaces O
of O
such O
structures O
can O
be O
constructed O
for O
a O
group O
of O
RNAs O
. O

Our O
method O
was O
further O
applied O
to O
predict O
functions O
of O
RNA O
molecules O
and O
showed O
superior O
performance O
compared O
with O
previous O
methods O
when O
tested O
on O
benchmark O
datasets O
. O

The O
programs O
are O
available O
at O
http O
: O
/ O
/ O
stat O
. O
fsu O
. O
edu O
/ O
~ O
jinfeng O
/ O
ESA O
. O
html O
. O

Fine O
Tuning O
of O
the O
Structure O
of O
Pt B
- O
Cu I
Alloy O
Nanocrystals O
by O
Glycine B
- O
Mediated O
Sequential O
Reduction O
Kinetics O
. O

Uniform O
Pt B
- O
Cu I
alloy O
nanocrystals O
in O
the O
shape O
of O
dendrite O
, O
, O
yolk O
- O
cage O
, O
and O
box O
structures O
are O
prepared O
via O
a O
facile O
wet O
- O
chemical O
reduction O
route O
in O
which O
glycine B
is O
demonstrated O
to O
alter O
the O
reduction O
kinetics O
of O
metal O
cations O
, O
critical O
to O
the O
morphology O
of O
the O
obtained O
product O
. O

These O
alloy O
nanocrystals O
exhibit O
superior O
specific O
activity O
and O
stability O
in O
the O
electro O
- O
oxidation O
of O
methanol B
. O

Relationship O
between O
serum O
thyrotropin B
levels O
and O
intrarenal O
hemodynamic O
parameters O
in O
euthyroid O
subjects O
. O

OBJECTIVE O
: O
Low O
thyroid O
function O
may O
be O
associated O
with O
a O
reduced O
glomerular O
filtration O
rate O
( O
GFR O
) O
calculated O
on O
the O
basis O
of O
creatinine B
metabolism O
. O

Thyroid B
hormone I
directly O
affects O
serum O
creatinine B
in O
muscle O
and O
low O
thyroid O
function O
might O
exert O
a O
similar O
direct O
effect O
in O
the O
kidney O
. O

The O
goal O
of O
the O
study O
was O
to O
evaluate O
this O
possibility O
by O
assessment O
of O
the O
inulin O
- O
based O
GFR O
and O
to O
examine O
the O
mechanism O
underlying O
the O
reduction O
of O
GFR O
. O

PATIENTS O
AND O
METHODS O
: O
Renal O
and O
glomerular O
hemodynamics O
were O
assessed O
by O
simultaneous O
measurements O
of O
plasma O
clearance O
of O
para B
- I
aminohippurate I
( O
CPAH O
) O
and O
inulin O
( O
Cin O
) O
in O
26 O
patients O
with O
serum O
creatinine B
< O
1 O
. O
00 O
mg O
/ O
dl O
and O
without O
thyroid O
disease O
. O

All O
subjects O
were O
normotensive O
with O
or O
without O
antihypertensive O
treatment O
and O
were O
kept O
in O
a O
sodium B
- O
replete O
state O
. O

Renal O
and O
glomerular O
hemodynamics O
were O
calculated O
using O
Gomez O
` O
s O
formulae O
. O

RESULTS O
: O
Serum O
thyroid O
stimulating O
hormone O
( O
TSH O
) O
, O
including O
within O
the O
normal O
range O
( O
0 O
. O
69 O
- O
4 O
. O
30 O
mu O
IU O
/ O
ml O
) O
, O
was O
positively O
correlated O
with O
vascular O
resistance O
at O
the O
afferent O
arteriole O
( O
Ra O
) O
( O
r O
= O
0 O
. O
609 O
, O
p O
= O
0 O
. O
0010 O
) O
, O
but O
not O
at O
the O
efferent O
arteriole O
( O
Re O
) O
. O

Serum O
TSH O
was O
significantly O
and O
negatively O
correlated O
with O
renal O
plasma O
flow O
( O
RPF O
) O
, O
renal O
blood O
flow O
( O
RBF O
) O
, O
and O
glomerular O
filtration O
rate O
( O
GFR O
) O
( O
r O
= O
- O
0 O
. O
456 O
, O
p O
= O
0 O
. O
0192 O
; O
r O
= O
- O
0 O
. O
438 O
, O
p O
= O
0 O
. O
0252 O
; O
r O
= O
- O
0 O
. O
505 O
, O
p O
= O
0 O
. O
0086 O
, O
respectively O
) O
. O

In O
multiple O
regression O
analysis O
, O
serum O
TSH O
was O
significantly O
positively O
associated O
with O
Ra O
after O
adjustment O
for O
age O
and O
mean O
blood O
pressure O
. O

CONCLUSIONS O
: O
These O
findings O
suggest O
that O
low O
thyroid O
function O
, O
even O
within O
the O
normal O
range O
, O
is O
associated O
with O
reduced O
RPF O
, O
RBF O
and O
GFR O
, O
which O
might O
be O
caused O
by O
a O
preferential O
increase O
of O
Ra O
. O

Deformation O
of O
an O
elastic O
capsule O
in O
a O
rectangular O
microfluidic O
channel O
. O

In O
the O
present O
study O
we O
investigate O
computationally O
the O
deformation O
of O
an O
elastic O
capsule O
in O
a O
rectangular O
microfluidic O
channel O
and O
compare O
it O
with O
that O
of O
a O
droplet O
. O

In O
contrast O
to O
the O
bullet O
or O
parachute O
shape O
in O
a O
square O
or O
cylindrical O
channel O
where O
the O
capsule O
extends O
along O
the O
flow O
direction O
, O
in O
a O
rectangular O
channel O
the O
capsule O
extends O
mainly O
along O
the O
less O
- O
confined O
lateral O
direction O
of O
the O
channel O
cross O
- O
section O
( O
i O
. O
e O
. O
the O
channel O
width O
) O
, O
obtaining O
a O
pebble O
- O
like O
shape O
. O

The O
different O
shape O
evolution O
in O
these O
two O
types O
of O
solid O
channels O
results O
from O
the O
different O
tension O
development O
on O
the O
capsule O
membrane O
required O
for O
interfacial O
stability O
. O

Furthermore O
, O
in O
asymmetric O
channel O
flows O
, O
capsules O
show O
a O
different O
deformation O
compared O
to O
droplets O
with O
constant O
surface O
tension O
( O
which O
extend O
mainly O
along O
the O
flow O
direction O
) O
and O
to O
vesicles O
which O
extend O
along O
the O
more O
- O
confined O
channel O
height O
. O

Therefore O
, O
our O
study O
highlights O
the O
different O
stability O
dynamics O
associated O
with O
these O
three O
types O
of O
interfaces O
. O

Our O
findings O
suggest O
that O
the O
erythrocyte O
deformation O
in O
asymmetric O
vessels O
( O
which O
is O
similar O
to O
that O
of O
capsules O
) O
results O
from O
the O
erythrocyte O
' O
s O
inner O
spectrin O
skeleton O
rather O
than O
from O
its O
outer O
lipid O
bilayer O
. O

Molecular O
- O
Beam O
Optical O
Stark O
and O
Zeeman O
Study O
of O
the O
[ O
17 O
. O
8 O
] O
0 O
( O
+ O
) O
- O
X O
( O
1 O
) O
Sigma O
( O
+ O
) O
( O
0 O
, O
0 O
) O
Band O
System O
of O
AuF B
. O

The O
[ O
17 O
. O
8 O
] O
0 O
( O
+ O
) O
- O
X O
( O
1 O
) O
Sigma O
( O
+ O
) O
( O
0 O
, O
0 O
) O
band O
of O
gold B
monofluoride I
, O
AuF B
, O
has O
been O
recorded O
at O
a O
resolution O
of O
40 O
MHz O
both O
field O
free O
and O
in O
the O
presence O
of O
a O
static O
electric O
and O
magnetic O
field O
. O

The O
observed O
Stark O
shifts O
were O
analyzed O
to O
determine O
the O
permanent O
electric O
dipole O
moment O
, O
mu O
el O
, O
of O
2 O
. O
03 O
+ O
/ O
- O
0 O
. O
05 O
D O
and O
4 O
. O
13 O
+ O
/ O
- O
0 O
. O
02 O
D O
, O
for O
the O
[ O
17 O
. O
8 O
] O
0 O
( O
+ O
) O
( O
v O
= O
0 O
) O
and O
X O
( O
1 O
) O
Sigma O
( O
+ O
) O
( O
v O
= O
0 O
) O
states O
, O
respectively O
. O

The O
small O
magnetic O
tuning O
observed O
for O
the O
[ O
17 O
. O
8 O
] O
0 O
( O
+ O
) O
( O
v O
= O
0 O
) O
state O
is O
attributed O
to O
rotational O
and O
magnetic O
field O
mixing O
with O
the O
[ O
17 O
. O
7 O
] O
1 O
state O
and O
has O
been O
successfully O
modeled O
using O
an O
effective O
Hamiltonian O
for O
the O
( O
3 O
) O
Pi O
state O
. O

A O
comparison O
with O
the O
numerous O
published O
theoretical O
predictions O
is O
made O
. O

Dynamic O
and O
Electronic O
Transport O
Properties O
of O
DNA O
Translocation O
through O
Graphene B
Nanopores O
. O

Graphene B
layers O
have O
been O
targeted O
in O
the O
last O
years O
as O
excellent O
host O
materials O
for O
sensing O
a O
remarkable O
variety O
of O
gases O
and O
molecules O
. O

Such O
sensing O
abilities O
can O
also O
benefit O
other O
important O
scientific O
fields O
such O
as O
medicine O
and O
biology O
. O

This O
has O
automatically O
led O
scientists O
to O
probe O
graphene B
as O
a O
potential O
platform O
for O
sequencing O
DNA O
strands O
. O

In O
this O
work O
, O
we O
use O
robust O
numerical O
tools O
to O
model O
the O
dynamic O
and O
electronic O
properties O
of O
molecular O
sensor O
devices O
composed O
of O
a O
graphene B
nanopore O
through O
which O
DNA O
molecules O
are O
driven O
by O
external O
electric O
fields O
. O

We O
performed O
molecular O
dynamic O
simulations O
to O
determine O
the O
relation O
between O
the O
intensity O
of O
the O
electric O
field O
and O
the O
translocation O
time O
spent O
by O
the O
DNA O
to O
pass O
through O
the O
pore O
. O

Our O
results O
reveal O
that O
one O
can O
have O
extra O
control O
on O
the O
DNA O
passage O
when O
four O
additional O
graphene B
layers O
are O
deposited O
on O
the O
top O
of O
the O
main O
graphene B
platform O
containing O
the O
pore O
in O
a O
2 O
x O
2 O
grid O
arrangement O
. O

In O
addition O
to O
the O
dynamic O
analysis O
, O
we O
carried O
electronic O
transport O
calculations O
on O
realistic O
pore O
structures O
with O
diameters O
reaching O
nanometer O
scales O
. O

The O
transmission O
obtained O
along O
the O
graphene B
sensor O
at O
the O
Fermi O
level O
is O
affected O
by O
the O
presence O
of O
the O
DNA O
. O

However O
, O
it O
is O
rather O
hard O
to O
distinguish O
the O
respective O
nucleobases B
. O

This O
scenario O
can O
be O
significantly O
altered O
when O
the O
transport O
is O
conducted O
away O
from O
the O
Fermi O
level O
of O
the O
graphene B
platform O
. O

Under O
an O
energy O
shift O
, O
we O
observed O
that O
the O
graphene B
pore O
manifests O
selectiveness O
toward O
DNA O
nucleobases O
. O

The O
tail O
wagging O
the O
dog O
- O
regulation O
of O
lipid O
metabolism O
by O
protein O
kinase O
C O
. O

Upon O
their O
discovery O
almost O
40 O
years O
ago O
, O
isoforms O
of O
the O
lipid O
- O
activated O
protein O
kinase O
C O
( O
PKC O
) O
family O
were O
initially O
regarded O
only O
as O
downstream O
effectors O
of O
the O
second O
messengers O
calcium B
and O
diacylglycerol B
, O
undergoing O
activation O
upon O
phospholipid O
hydrolysis O
in O
response O
to O
acute O
stimuli O
. O

Subsequently O
, O
several O
isoforms O
were O
found O
to O
be O
associated O
with O
the O
inhibitory O
effects O
of O
lipid O
over O
- O
supply O
on O
glucose B
homeostasis O
, O
especially O
the O
negative O
cross O
- O
talk O
with O
insulin O
signal O
transduction O
, O
observed O
upon O
accumulation O
of O
diacylglycerol B
in O
insulin O
target O
tissues O
. O

The O
PKC O
family O
has O
therefore O
attracted O
much O
attention O
in O
diabetes O
and O
obesity O
research O
, O
because O
intracellular O
lipid O
accumulation O
is O
strongly O
correlated O
with O
defective O
insulin O
action O
and O
the O
development O
of O
type O
2 O
diabetes O
. O

Causal O
roles O
for O
various O
isoforms O
in O
the O
generation O
of O
insulin O
resistance O
have O
more O
recently O
been O
confirmed O
using O
PKC O
- O
deficient O
mice O
. O

However O
, O
during O
characterization O
of O
these O
animals O
, O
it O
became O
increasingly O
evident O
that O
the O
enzymes O
play O
key O
roles O
in O
the O
modulation O
of O
lipid O
metabolism O
itself O
, O
and O
may O
control O
the O
supply O
of O
lipids O
between O
tissues O
such O
as O
adipose O
and O
liver O
. O

Molecular O
studies O
have O
also O
demonstrated O
roles O
for O
PKC O
isoforms O
in O
several O
aspects O
of O
lipid O
metabolism O
, O
such O
as O
adipocyte O
differentiation O
and O
hepatic O
lipogenesis O
. O

While O
the O
precise O
mechanisms O
involved O
, O
especially O
the O
identities O
of O
protein O
substrates O
, O
are O
still O
unclear O
, O
the O
emerging O
picture O
suggests O
that O
the O
currently O
held O
view O
of O
the O
contribution O
of O
PKC O
isoforms O
to O
metabolism O
is O
an O
over O
- O
simplification O
. O

Although O
PKCs O
may O
inhibit O
insulin O
signal O
transduction O
, O
these O
enzymes O
are O
not O
merely O
downstream O
effectors O
of O
lipid O
accumulation O
, O
but O
in O
fact O
control O
the O
fate O
of O
fatty B
acids I
, O
thus O
the O
tail O
wags O
the O
dog O
. O

Kappa O
- O
opioid O
receptor O
- O
selective O
dicarboxylic B
ester I
- O
derived O
salvinorin B
A I
ligands O
. O

Salvinorin B
A I
, O
the O
active O
ingredient O
of O
the O
hallucinogenic O
plant O
Salvia O
divinorum O
is O
the O
most O
potent O
known O
naturally O
occurring O
hallucinogen O
and O
is O
a O
selective O
kappa O
- O
opioid O
receptor O
agonist O
. O

To O
better O
understand O
the O
ligand O
- O
receptor O
interactions O
, O
a O
series O
of O
dicarboxylic B
ester I
- O
type O
of O
salvinorin B
A I
derivatives O
were O
synthesized O
and O
evaluated O
for O
their O
binding O
affinity O
at O
kappa O
- O
, O
delta O
- O
and O
mu O
- O
opioid O
receptors O
. O

Most O
of O
the O
analogues O
show O
high O
affinity O
to O
the O
kappa O
- O
opioid O
receptor O
. O

Methyl B
malonyl I
derivative O
4 O
shows O
the O
highest O
binding O
affinity O
( O
Ki O
= O
2nM O
) O
, O
analogues O
5 O
, O
7 O
, O
and O
14 O
exhibit O
significant O
affinity O
for O
the O
kappa O
- O
receptor O
( O
Ki O
= O
21 O
, O
36 O
and O
39nM O
) O
. O

Acute O
and O
chronic O
interference O
with O
BDNF O
/ O
TrkB O
- O
signaling O
impair O
LTP O
selectively O
at O
mossy O
fiber O
synapses O
in O
the O
CA3 O
region O
of O
mouse O
hippocampus O
. O

Brain O
- O
derived O
neurotrophic O
factor O
( O
BDNF O
) O
signaling O
via O
TrkB O
crucially O
regulates O
synaptic O
plasticity O
in O
the O
brain O
. O

Although O
BDNF O
is O
abundant O
at O
hippocampal O
mossy O
fiber O
( O
MF O
) O
synapses O
, O
which O
critically O
contribute O
to O
hippocampus O
dependent O
memory O
, O
its O
role O
in O
MF O
synaptic O
plasticity O
( O
long O
- O
term O
potentiation O
, O
LTP O
) O
remained O
largely O
unclear O
. O

Using O
field O
potential O
recordings O
in O
CA3 O
of O
adult O
heterozygous O
BDNF O
knockout O
( O
ko O
, O
BDNF O
+ O
/ O
- O
) O
mice O
we O
observed O
impaired O
( O
~ O
50 O
% O
) O
NMDAR O
- O
independent O
MF O
- O
LTP O
. O

In O
contrast O
to O
MF O
synapses O
, O
LTP O
at O
neighboring O
associative O
/ O
commissural O
( O
A O
/ O
C O
) O
fiber O
synapses O
remained O
unaffected O
. O

To O
exclude O
that O
impaired O
MF O
- O
LTP O
in O
BDNF O
+ O
/ O
- O
mice O
was O
due O
to O
developmental O
changes O
in O
response O
to O
chronically O
reduced O
BDNF O
levels O
, O
and O
to O
prove O
the O
importance O
of O
acute O
availability O
of O
BDNF O
in O
MF O
- O
LTP O
, O
we O
also O
tested O
effects O
of O
acute O
interference O
with O
BDNF O
/ O
TrkB O
signaling O
. O

Inhibition O
of O
TrkB O
tyrosine B
kinase O
signaling O
with O
k252a O
, O
or O
with O
the O
selective O
BDNF O
scavenger O
TrkB O
- O
Fc O
, O
both O
inhibited O
MF O
- O
LTP O
to O
the O
same O
extent O
as O
observed O
in O
BDNF O
+ O
/ O
- O
mice O
. O

Basal O
synaptic O
transmission O
, O
short O
- O
term O
plasticity O
, O
and O
synaptic O
fatigue O
during O
LTP O
induction O
were O
not O
significantly O
altered O
by O
treatment O
with O
k252a O
or O
TrkB O
- O
Fc O
, O
or O
by O
chronic O
BDNF O
reduction O
in O
BDNF O
+ O
/ O
- O
mice O
. O

Since O
the O
acute O
interference O
with O
BDNF O
- O
signaling O
did O
not O
completely O
block O
MF O
- O
LTP O
, O
our O
results O
provide O
evidence O
that O
an O
additional O
mechanism O
besides O
BDNF O
induced O
TrkB O
signaling O
contributes O
to O
this O
type O
of O
LTP O
. O

Our O
results O
prove O
for O
the O
first O
time O
a O
mechanistic O
action O
of O
acute O
BDNF O
/ O
TrkB O
signaling O
in O
presynaptic O
expression O
of O
MF O
- O
LTP O
in O
adult O
hippocampus O
. O

Genetics O
of O
diabetes O
- O
Are O
we O
missing O
the O
genes O
or O
the O
disease O
? O

Diabetes O
is O
a O
group O
of O
metabolic O
diseases O
characterized O
by O
hyperglycemia O
resulting O
from O
defects O
in O
insulin O
secretion O
, O
insulin O
action O
, O
or O
both O
. O

The O
chronic O
hyperglycemia O
of O
diabetes O
is O
associated O
with O
long O
- O
term O
damage O
, O
dysfunction O
, O
and O
failure O
of O
different O
organs O
, O
especially O
the O
eyes O
, O
kidneys O
, O
nerves O
, O
heart O
, O
and O
blood O
vessels O
. O

Several O
pathogenic O
processes O
are O
involved O
in O
the O
development O
of O
diabetes O
. O

These O
range O
from O
autoimmune O
destruction O
of O
the O
beta O
- O
cells O
of O
the O
pancreas O
with O
consequent O
insulin O
deficiency O
to O
abnormalities O
that O
result O
in O
resistance O
to O
insulin O
action O
( O
American O
Diabetes O
Association O
, O
2011 O
) O
. O

The O
vast O
majority O
of O
cases O
of O
diabetes O
fall O
into O
two O
broad O
categories O
. O

In O
type O
1 O
diabetes O
( O
T1D O
) O
, O
the O
cause O
is O
an O
absolute O
deficiency O
of O
insulin O
secretion O
, O
whereas O
in O
type O
2 O
diabetes O
( O
T2D O
) O
, O
the O
cause O
is O
a O
combination O
of O
resistance O
to O
insulin O
action O
and O
an O
inadequate O
compensatory O
insulin O
secretory O
response O
. O

However O
, O
the O
subdivision O
into O
two O
main O
categories O
represents O
a O
simplification O
of O
the O
real O
situation O
, O
and O
research O
during O
the O
recent O
years O
has O
shown O
that O
the O
disease O
is O
much O
more O
heterogeneous O
than O
a O
simple O
subdivision O
into O
two O
major O
subtypes O
assumes O
. O

Worldwide O
prevalence O
figures O
estimate O
that O
there O
are O
280 O
million O
diabetic O
patients O
in O
2011 O
and O
more O
than O
500 O
million O
in O
2030 O
( O
http O
: O
/ O
/ O
www O
. O
diabetesatlas O
. O
org O
/ O
) O
. O

In O
Europe O
, O
about O
6 O
- O
8 O
% O
of O
the O
population O
suffer O
from O
diabetes O
, O
of O
them O
about O
90 O
% O
has O
T2D O
and O
10 O
% O
T1D O
, O
thereby O
making O
T2D O
to O
the O
fastest O
increasing O
disease O
in O
Europe O
and O
worldwide O
. O

This O
epidemic O
has O
been O
ascribed O
to O
a O
collision O
between O
the O
genes O
and O
the O
environment O
. O

While O
our O
knowledge O
about O
the O
genes O
is O
clearly O
better O
for O
T1D O
than O
for O
T2D O
given O
the O
strong O
contribution O
of O
variation O
in O
the O
HLA O
region O
to O
the O
risk O
of O
T1D O
, O
the O
opposite O
is O
the O
case O
for O
T2D O
, O
where O
our O
knowledge O
about O
the O
environmental O
triggers O
( O
obesity O
, O
lack O
of O
exercise O
) O
is O
much O
better O
than O
the O
understanding O
of O
the O
underlying O
genetic O
causes O
. O

This O
lack O
of O
knowledge O
about O
the O
underlying O
genetic O
causes O
of O
diabetes O
is O
often O
referred O
to O
as O
missing O
heritability O
( O
Manolio O
et O
al O
. O
, O
2009 O
) O
which O
exceeds O
80 O
% O
for O
T2D O
but O
less O
than O
25 O
% O
for O
T1D O
. O

In O
the O
following O
review O
, O
we O
will O
discuss O
potential O
sources O
of O
this O
missing O
heritability O
which O
also O
includes O
the O
possibility O
that O
our O
definition O
of O
diabetes O
and O
its O
subgroups O
is O
imprecise O
and O
thereby O
making O
the O
identification O
of O
genetic O
causes O
difficult O
. O

Structure O
- O
activity O
relationships O
of O
hybrid O
annonaceous B
acetogenins I
: O
Powerful O
growth O
inhibitory O
effects O
of O
their O
connecting O
groups O
between O
heterocycle O
and O
hydrophobic O
carbon B
chain O
bearing O
THF B
ring O
on O
human O
cancer O
cell O
lines O
. O

Five O
novel O
hybrid O
molecules O
of O
annonaceous O
acetogenins B
and O
insecticides O
targeting O
mitochondrial O
complex O
I O
were O
synthesized O
and O
their O
growth O
inhibitory O
activities O
against O
39 O
human O
cancer O
cell O
lines O
were O
investigated O
. O

It O
was O
revealed O
that O
the O
connecting O
group O
between O
the O
N B
- I
methylpyrazole I
part O
and O
the O
hydrophobic O
alkyl O
chain O
bearing O
the O
THF B
ring O
influenced O
their O
biological O
activities O
significantly O
. O

Amide B
- O
connected O
analog O
2 O
, O
in O
particular O
, O
showed O
selective O
and O
very O
potent O
activity O
( O
< O
10 O
nM O
) O
against O
some O
cancer O
cell O
lines O
. O

Prevalence O
and O
natural O
history O
of O
Graves O
' O
orbitopathy O
in O
the O
XXI O
century O
. O

Graves O
' O
orbitopathy O
( O
GO O
) O
is O
an O
autoimmune O
disorder O
and O
the O
main O
extrathyroidal O
expression O
of O
Graves O
' O
disease O
. O

There O
is O
a O
spectrum O
of O
ocular O
involvement O
in O
Graves O
' O
disease O
, O
from O
complete O
absence O
of O
symptoms O
and O
signs O
to O
sight O
- O
threatening O
conditions O
. O

The O
prevalence O
of O
GO O
varies O
in O
different O
published O
series O
of O
Graves O
' O
patients O
, O
due O
to O
confounding O
factors O
( O
new O
diagnosis O
vs O
. O
long O
- O
lasting O
disease O
, O
way O
of O
defining O
and O
assessing O
ocular O
involvement O
, O
treatment O
of O
hyperthyroidism O
with O
potentially O
GO O
- O
modifying O
treatments O
, O
such O
as O
radioiodine B
) O
. O

Recent O
studies O
, O
however O
, O
suggest O
that O
most O
Graves O
' O
patients O
have O
mild O
or O
no O
GO O
at O
presentation O
, O
while O
moderate O
- O
to O
- O
severe O
GO O
is O
rare O
, O
and O
sight O
- O
threatening O
GO O
( O
mostly O
due O
to O
dysthyroid O
optic O
neuropathy O
) O
is O
exceptional O
in O
non O
- O
tertiary O
referral O
centers O
. O

The O
natural O
course O
of O
GO O
is O
incompletely O
defined O
, O
particularly O
in O
patients O
with O
moderate O
- O
to12 O
severe O
GO O
, O
because O
these O
patients O
require O
prompt O
and O
disease O
- O
modifying O
therapies O
for O
orbital O
disease O
. O

In O
patients O
with O
mild O
GO O
at O
presentation O
, O
progression O
to O
severe O
forms O
is O
rare O
, O
while O
partial O
or O
complete O
remission O
is O
frequent O
. O

Progression O
of O
preexisting O
GO O
or O
de O
novo O
occurrence O
of O
GO O
is O
more O
likely O
in O
smokers O
. O

There O
seems O
to O
be O
a O
trend O
towards O
a O
decline O
in O
progression O
of O
GO O
, O
possibly O
due O
to O
a O
better O
control O
of O
risk O
factors O
( O
cigarette O
smoking O
, O
thyroid O
dysfunction O
, O
etc O
. O
) O
and O
a O
closer O
interaction O
between O
endocrinologists O
and O
ophthalmologists O
allowing O
an O
improved O
integrated O
management O
of O
thyroid O
and O
orbital O
disease O
. O

Antiulcer O
and O
gastric O
antisecretory O
effects O
of O
dichloromethane B
fraction O
and O
piplartine B
obtained O
from O
fruits O
of O
Piper O
tuberculatum O
Jacq O
. O
in O
rats O
. O

ETHNOPHARMACOLOGICAL O
RELEVANCE O
: O
Piper O
tuberculatum O
Jacq O
. O

( O
Piperaceae O
) O
is O
medicinally O
used O
as O
an O
analgesic O
and O
as O
a O
treatment O
for O
gastric O
complaints O
. O

Thus O
, O
the O
current O
study O
aimed O
to O
investigate O
the O
gastroprotective O
and O
antisecretory O
properties O
of O
the O
dichloromethane B
fraction O
of O
the O
fruit O
of O
Piper O
tuberculatum O
( O
DFPT O
) O
and O
piplartine B
, O
a O
compound O
isolated O
from O
the O
DFPT O
, O
in O
rats O
. O

MATERIALS O
AND O
METHODS O
: O
Gastric O
ulcers O
were O
induced O
in O
fasted O
rats O
by O
oral O
administration O
of O
absolute O
ethanol B
and O
then O
mucus O
content O
and O
glutathione B
( O
GSH B
) O
levels O
were O
measured O
. O

Mechanisms O
underlying O
the O
antisecretory O
action O
were O
studied O
through O
gastric O
H B
( I
+ I
) I
, O
K B
( I
+ I
) I
- O
ATPase O
activity O
of O
highly O
purified O
rabbit O
gastric O
microsomes O
and O
pylorus O
ligature O
method O
in O
rats O
. O

RESULTS O
: O
In O
the O
acute O
toxicity O
test O
the O
values O
of O
estimated O
LD50 O
for O
oral O
and O
intraperitoneal O
administration O
of O
DFPT B
were O
1 O
. O
6266 O
and O
0 O
. O
2684g O
/ O
kg O
, O
respectively O
. O

The O
DFPT O
( O
ED50 O
= O
29mg O
/ O
kg O
, O
p O
. O
o O
. O
) O
and O
piplartine B
( O
4 O
. O
5mg O
/ O
kg O
, O
p O
. O
o O
. O
) O
promoted O
gastroprotection O
against O
acute O
lesions O
induced O
by O
ethanol B
, O
effect O
that O
could O
be O
related O
with O
the O
maintenance O
of O
GSH B
levels O
in O
the O
gastric O
mucosa O
. O

However O
, O
only O
DFPT B
stimulated O
gastric O
mucus O
secretion O
. O

In O
vitro O
, O
the O
DFPT O
and O
piplartine B
inhibited O
the O
H B
( I
+ I
) I
, O
K B
( I
+ I
) I
- O
ATPase O
activity O
and O
, O
in O
vivo O
DFPT O
and O
piplartine B
also O
reduced O
basal O
gastric O
acid O
secretion O
, O
as O
well O
as O
that O
stimulated O
by O
pentagastrin B
. O

CONCLUSIONS O
: O
These O
results O
demonstrate O
that O
DFPT B
and O
piplatine B
cause O
marked O
gastroprotective O
effects O
accompanied O
by O
the O
increase O
and O
maintenance O
of O
gastric O
mucus O
and O
GSH B
levels O
, O
as O
well O
as O
a O
reduction O
in O
gastric O
acid O
secretion O
through O
the O
gastrinergic O
pathway O
. O

Emerging O
Transporters O
of O
Clinical O
Importance O
: O
An O
Update O
from O
the O
International O
Transporter O
Consortium O
. O

The O
International O
Transporter O
Consortium O
( O
ITC O
) O
has O
described O
recently O
seven O
transporters O
of O
particular O
relevance O
for O
drug O
development O
( O
Giacomini O
et O
al O
. O
, O
Nat O
. O
Rev O
. O
Drug O
Discov O
. O
9 O
: O
215 O
- O
236 O
, O
2010 O
) O
. O

Based O
on O
the O
second O
ITC O
transporter O
workshop O
in O
2012 O
, O
we O
have O
identified O
additional O
transporters O
of O
emerging O
importance O
in O
pharmacokinetics O
, O
interference O
of O
drugs O
with O
transport O
of O
endogenous O
compounds O
and O
drug O
- O
drug O
interactions O
in O
humans O
. O

The O
multidrug O
and O
toxin O
extrusion O
proteins O
( O
MATEs O
, O
gene O
symbol O
SLC47A O
) O
mediate O
excretion O
of O
organic O
cations O
into O
bile O
and O
urine O
. O

MATEs O
are O
important O
in O
renal O
drug O
- O
drug O
interactions O
. O

Multidrug O
resistance O
proteins O
( O
MRPs O
or O
ABCCs O
) O
are O
drug O
and O
conjugate O
efflux O
pumps O
, O
and O
impaired O
activity O
of O
MRP2 O
results O
in O
conjugated O
hyperbilirubinemia O
. O

The O
bile B
salt I
export O
pump O
( O
BSEP O
or O
ABCB11 O
) O
prevents O
accumulation O
of O
toxic O
bile B
salt I
concentrations O
in O
hepatocytes O
, O
and O
BSEP O
inhibition O
or O
deficiency O
may O
cause O
cholestasis O
and O
liver O
injury O
. O

Additionally O
, O
examples O
are O
presented O
on O
the O
roles O
of O
nucleoside B
and O
peptide O
transporters O
in O
drug O
targeting O
and O
disposition O
. O
Clinical O
Pharmacology O
& O
Therapeutics O
( O
2013 O
) O
; O
accepted O
article O
preview O
online O
8 O
April O
2013 O
doi O
: O
10 O
. O
1038 O
/ O
clpt O
. O
2013 O
. O
74 O
. O

Biomarkers O
for O
Smoking O
Cessation O
. O

One O
way O
to O
enhance O
therapeutic O
development O
is O
through O
the O
identification O
and O
development O
of O
evaluative O
tools O
such O
as O
biomarkers O
. O

This O
review O
focuses O
on O
putative O
diagnostic O
, O
pharmacodynamic O
, O
and O
predictive O
biomarkers O
for O
smoking O
cessation O
. O

These O
types O
of O
biomarkers O
may O
be O
used O
to O
more O
accurately O
diagnose O
a O
disease O
, O
personalize O
treatment O
, O
identify O
novel O
targets O
for O
drug O
discovery O
, O
and O
enhance O
the O
efficiency O
of O
drug O
development O
. O

Promising O
biomarkers O
are O
presented O
across O
a O
range O
of O
approaches O
including O
metabolism O
, O
genetics O
, O
and O
neuroimaging O
. O

A O
preclinical O
viewpoint O
is O
also O
offered O
, O
as O
are O
analytical O
considerations O
and O
a O
regulatory O
perspective O
summarizing O
a O
pathway O
toward O
biomarker O
qualification O
. O
Clinical O
Pharmacology O
& O
Therapeutics O
( O
2013 O
) O
; O
advance O
online O
publication O
8 O
May O
2013 O
. O
doi O
: O
10 O
. O
1038 O
/ O
clpt O
. O
2013 O
. O
57 O
. O

The O
effects O
of O
water O
molecules O
on O
the O
electronic O
and O
structural O
properties O
of O
peptide O
nanotubes O
. O

The O
self O
- O
assembly O
of O
short O
amino B
acid I
chains O
appears O
to O
be O
one O
of O
the O
most O
promising O
strategies O
for O
the O
fabrication O
of O
nanostructures O
. O

Their O
solubility O
in O
water O
and O
the O
possibility O
of O
chemical O
modification O
by O
targeting O
the O
amino B
or O
carboxyl B
terminus O
give O
peptide O
- O
based O
nanostructures O
several O
advantages O
over O
carbon B
nanotube O
nanostructures O
. O

However O
, O
because O
these O
systems O
are O
synthesized O
in O
aqueous O
solution O
, O
a O
deeper O
understanding O
is O
needed O
on O
the O
effects O
of O
water O
especially O
with O
respect O
to O
the O
electronic O
, O
structural O
and O
transport O
properties O
. O

In O
this O
work O
, O
the O
electronic O
properties O
of O
l B
- I
diphenylalanine I
nanotubes O
( O
FF O
- O
NTs O
) O
have O
been O
studied O
using O
the O
Self O
- O
Consistent O
Charge O
Density O
- O
Functional O
- O
based O
Tight O
- O
Binding O
method O
augmented O
with O
dispersion O
interaction O
. O

The O
presence O
of O
water O
molecules O
in O
the O
central O
hydrophilic O
channel O
and O
their O
interaction O
with O
the O
nanostructures O
are O
addressed O
. O

We O
demonstrate O
that O
the O
presence O
of O
water O
leads O
to O
significant O
changes O
in O
the O
electronic O
properties O
of O
these O
systems O
decreasing O
the O
band O
gap O
which O
can O
lead O
to O
an O
increase O
in O
the O
hopping O
probability O
and O
the O
conductivity O
. O

Low O
allopurinol B
doses O
are O
sufficient O
to O
optimize O
azathioprine B
therapy O
in O
inflammatory O
bowel O
disease O
patients O
with O
inadequate O
thiopurine B
metabolite O
concentrations O
. O

PURPOSE O
: O
Recent O
studies O
in O
patients O
with O
inflammatory O
bowel O
diseases O
( O
IBD O
) O
on O
thiopurine B
therapy O
suggest O
that O
too O
low O
6 B
- I
thioguanine I
nucleotide I
concentrations O
( O
6 B
- I
TGN I
) O
and O
too O
high O
methylmercaptopurine B
nucleotide I
concentrations O
( O
MMPN O
) O
can O
be O
reversed O
by O
a O
combination O
therapy O
of O
allopurinol B
and O
low O
- O
dose O
thiopurines B
. O

To O
date O
, O
however O
, O
optimal O
dosing O
has O
not O
been O
established O
. O

The O
aim O
of O
this O
study O
was O
to O
evaluate O
the O
minimal O
allopurinol B
doses O
necessary O
to O
achieve O
adequate O
6 B
- I
TGN I
concentrations O
in O
combination O
with O
low O
- O
dose O
azathioprine B
. O

METHODS O
: O
A O
stepwise O
dose O
- O
escalation O
of O
allopurinol B
was O
performed O
in O
11 O
azathioprine B
- O
pretreated O
IBD O
patients O
with O
inadequately O
low O
6 B
- I
TGN I
concentrations O
( O
< O
235 O
pmol O
/ O
8 O
x O
10 O
( O
8 O
) O
erythrocytes O
) O
and O
/ O
or O
elevated O
MMPN B
concentrations O
( O
> O
5 O
, O
000 O
pmol O
/ O
8 O
x O
10 O
( O
8 O
) O
erythrocytes O
) O
and O
/ O
or O
elevated O
liver O
enzymes O
( O
alanine B
aminotransferase O
and O
/ O
or O
aspartate B
aminotransferase O
levels O
one O
- O
to O
threefold O
the O
upper O
limit O
of O

normal O
) O
. O

Six O
patients O
were O
recruited O
into O
an O
open O
study O
, O
and O
five O
were O
treated O
in O
the O
context O
of O
an O
individualized O
therapeutic O
approach O
. O

Adverse O
effects O
, O
azathioprine B
metabolites O
, O
liver O
enzymes O
and O
whole O
blood O
counts O
were O
monitored O
two O
to O
three O
times O
per O
month O
. O

RESULTS O
: O
Adequate O
6 B
- I
TGN I
concentrations O
were O
achieved O
with O
a O
combination O
of O
25 O
mg O
allopurinol B
and O
50 O
mg O
azathioprine B
in O
one O
patient O
and O
with O
50 O
mg O
allopurinol B
and O
50 O
mg O
azathioprine B
in O
nine O
patients O
. O

Median O
6 B
- I
TGN I
concentrations O
( O
range O
) O
were O
336 O
( O
290 O
- O
488 O
) O
pmol O
/ O
8 O
x O
10 O
( O
8 O
) O
erythrocytes O
after O
an O
8 O
- O
week O
- O
long O
intake O
of O
the O
final O
dose O
combination O
. O

One O
patient O
dropped O
out O
due O
to O
nausea O
after O
the O
first O
intake O
. O

MMPN B
concentrations O
and O
liver O
enzymes O
normalized O
immediately O
in O
all O
affected O
patients O
. O

All O
patients O
finishing O
the O
dose O
- O
escalation O
regimen O
tolerated O
the O
treatment O
without O
toxicity O
. O

CONCLUSIONS O
: O
Combination O
therapy O
with O
only O
50 O
mg O
allopurinol B
and O
50 O
mg O
azathioprine B
daily O
is O
sufficient O
, O
efficacious O
and O
safe O
in O
most O
IBD O
patients O
with O
inadequate O
thiopurine B
metabolite O
concentrations O
to O
optimize O
azathioprine B
- O
based O
IBD O
therapy O
. O

Population O
pharmacokinetics O
analysis O
of O
cyclophosphamide B
with O
genetic O
effects O
in O
patients O
undergoing O
hematopoietic O
stem O
cell O
transplantation O
. O

PURPOSE O
: O
To O
build O
a O
population O
pharmacokinetic O
( O
PK O
) O
model O
of O
cyclophosphamide B
( O
CY O
) O
and O
its O
metabolite O
, O
4 B
- I
hydroxycyclophospham I
( O
HCY B
) O
, O
in O
patients O
undergoing O
allogeneic O
haematopoietic O
stem O
cell O
transplantation O
( O
HSCT O
) O
and O
to O
identify O
covariates O
, O
including O
genetic O
polymorphisms O
, O
which O
affect O
CY O
and O
HCY B
PK O
parameters O
. O

METHOD O
: O
The O
study O
cohort O
comprised O
21 O
patients O
undergoing O
HSCT O
who O
received O
CY O
intravenously O
between O
2009 O
and O
2011 O
. O

Clinical O
characteristics O
and O
CY O
and O
HCY B
concentration O
data O
were O
collected O
for O
all O
patients O
, O
and O
ABCB1 O
, O
ABCC2 O
, O
GSTA1 O
, O
GSTM1 O
, O
GSTP1 O
, O
GSTT1 O
, O
CYP2B6 O
, O
CYP2C19 O
, O
and O
CYP3A5 O
genotyping O
was O
performed O
. O

A O
hypothetical O
enzyme O
compartment O
was O
conducted O
using O
the O
NONMEM O
program O
. O

RESULTS O
: O
A O
population O
PK O
analysis O
showed O
that O
the O
ABCC2 O
1249 O
genotype O
and O
aspartate B
aminotransferase O
levels O
significantly O
affected O
non O
- O
induced O
clearance O
( O
CL O
UI O
) O
and O
induced O
clearance O
( O
CL O
I O
) O
of O
CY O
, O
respectively O
. O

The O
final O
estimate O
of O
the O
mean O
CL O
UI O
and O
CL O
I O
of O
CY O
was O
15 O
. O
5 O
and O
0 O
. O
683 O
L O
/ O
h O
, O
respectively O
, O
and O
the O
mean O
volume O
of O
distribution O
( O
V O
1 O
) O
of O
CY O
was O
88 O
. O
0 O
L O
. O

The O
inter O
- O
individual O
variability O
for O
CL O
UI O
, O
CL O
I O
, O
and O
V O
1 O
of O
CY O
was O
52 O
. O
8 O
, O
200 O
, O
and O
18 O
. O
0 O
% O
, O
respectively O
. O

Additionally O
, O
the O
CL O
UI O
of O
CY O
was O
significantly O
decreased O
to O
approximately O
51 O
% O
in O
patients O
with O
the O
1249 O
GA O
heterozygous O
genotype O
compared O
to O
those O
with O
the O
1249 O
GG O
wild O
- O
type O
genotype O
( O
p O
< O
0 O
. O
05 O
) O
. O

There O
were O
only O
three O
heterozygous O
GA O
variants O
of O
ABCC2 O
1249 O
in O
the O
study O
patients O
. O

CONCLUSIONS O
: O
The O
population O
PK O
model O
developed O
in O
this O
study O
implies O
an O
influence O
of O
genetic O
factors O
on O
the O
clearance O
of O
CY O
. O

Clearance O
was O
moderately O
reduced O
in O
patients O
with O
the O
ABCC2 O
1249GA O
heterozygous O
genotype O
. O

Synthesis O
, O
characterization O
and O
organic O
field O
effect O
transistor O
performance O
of O
a O
diketopyrrolopyrrole B
- O
fluorenone B
copolymer O
. O

A O
diketopyrrolopyrrole B
( O
DPP B
) O
with O
fluorenone B
( O
FN O
) O
based O
low O
band O
gap O
alternating O
copolymer O
( O
PDPPT B
- I
alt I
- I
FN I
) O
has O
been O
synthesized O
via O
Suzuki O
coupling O
. O

PDPPT B
- I
alt I
- I
FN I
exhibits O
a O
deep O
HOMO O
level O
with O
a O
lower O
band O
gap O
. O

Fabricated O
organic O
thin O
film O
transistors O
using O
PDPPT B
- I
alt I
- I
FN I
as O
a O
channel O
semiconductor O
show O
p O
- O
channel O
behaviour O
with O
the O
highest O
hole O
mobility O
of O
0 O
. O
083 O
cm O
( O
2 O
) O
V O
( O
- O
1 O
) O
s O
( O
- O
1 O
) O
measured O
in O
air O
. O

Dermatoprotective O
effects O
of O
some O
plant O
extracts O
( O
genus O
Ficus O
) O
against O
experimentally O
induced O
toxicological O
insults O
in O
rabbits O
. O

Aim O
: O
Present O
study O
was O
conducted O
to O
evaluate O
the O
dermatoprotective O
effects O
of O
plant O
extracts O
( O
Ficus O
religiosa O
, O
Ficus O
benghalensis O
, O
and O
Ficus O
racemosa O
) O
against O
known O
irritants O
such O
as O
sodium B
dodecyl I
sulfate I
( O
SDS B
) O
, O
atrazine B
, O
and O
petrol B
. O

METHODS O
: O
The O
study O
was O
conducted O
in O
adult O
male O
rabbits O
. O

Ethanol B
extracts O
of O
plants O
were O
obtained O
through O
Soxhlet O
. O

All O
irritants O
and O
Ficus O
extracts O
were O
topically O
applied O
to O
the O
backs O
of O
rabbits O
daily O
for O
4 O
days O
, O
while O
pure O
ethanol B
served O
as O
control O
. O

Skin O
was O
examined O
after O
24 O
, O
48 O
, O
and O
96 O
h O
for O
erythema O
. O

Skin O
biopsies O
were O
taken O
on O
5th O
day O
for O
microscopic O
examination O
. O

RESULTS O
: O
Erythema O
produced O
by O
irritants O
reduced O
significantly O
with O
the O
simultaneous O
application O
of O
Ficus O
extracts O
. O

The O
mean O
+ O
/ O
- O
SEM O
epidermal O
thickness O
( O
micrometer O
) O
with O
SDS B
was O
45 O
. O
40 O
+ O
/ O
- O
1 O
. O
89 O
, O
F O
. O
religiosa O
+ O
SDS B
was O
18 O
. O
60 O
+ O
/ O
- O
0 O
. O
51 O
, O
F O
. O
benghalensis O
+ O
SDS B
was O
18 O
. O
40 O
+ O
/ O
- O
0 O
. O
25 O
, O
F O
. O
racemosa O
+ O
SDS B
was O
18 O
. O
80 O
+ O
/ O
- O
0 O
. O
37 O
, O
and O
mixture O
of O
three O
Ficus O
species O
+ O
SDS B
was O
16 O
. O
80 O
+ O
/ O
- O
0 O
. O
37 O
. O

Similar O
findings O
were O
revealed O
after O
using O
plant O
extracts O
with O
atrazine B
and O
petrol B
. O

The O
mean O
+ O
/ O
- O
SEM O
epidermal O
layer O
count O
for O
SDS B
was O
3 O
. O
60 O
+ O
/ O
- O
0 O
. O
25 O
, O
atrazine B
was O
3 O
. O
40 O
+ O
/ O
- O
0 O
. O
25 O
, O
petrol B
was O
3 O
. O
40 O
+ O
/ O
- O
0 O
. O
25 O
, O
and O
ethanol B
( O
control O
) O
was O
1 O
. O
00 O
+ O
/ O
- O
0 O
. O
20 O
. O

This O
count O
reduced O
to O
1 O
. O
20 O
+ O
/ O
- O
0 O
. O
20 O
for O
three O
Ficus O
species O
+ O
SDS B
, O
1 O
. O
40 O
+ O
/ O
- O
0 O
. O
25 O
for O
Ficus O
species O
+ O
atrazine B
, O
and O
1 O
. O
40 O
+ O
/ O
- O
0 O
. O
25 O
for O
Ficus O
species O
+ O
petrol O
. O

CONCLUSION O
: O
Ficus O
species O
demonstrated O
the O
potential O
to O
block O
the O
dermatotoxic O
effects O
of O
topical O
irritants O
and O
could O
be O
used O
successfully O
to O
prevent O
skin O
toxicity O
. O

Protective O
effects O
of O
caffeic B
acid I
phenethyl I
ester I
on O
dose O
- O
dependent O
intoxication O
of O
rats O
with O
paraquat B
. O

PURPOSE O
: O
Paraquat B
( O
PQ O
; O
1 B
, I
1 I
' I
dimethyl I
- I
bipyridilium I
4 I
, I
4 I
' I
- I
dichloride I
) O
, O
which O
is O
used O
extensively O
throughout O
the O
world O
, O
is O
highly O
toxic O
to O
humans O
. O

We O
aimed O
to O
investigate O
the O
protective O
effects O
of O
different O
doses O
of O
caffeic B
acid I
phenethyl I
ester I
( O
CAPE B
) O
on O
PQ O
- O
intoxicated O
rats O
. O
Materials O
and O
methods O
: O
A O
total O
of O
80 O
rats O
were O
divided O
into O
the O
following O
eight O
groups O
, O
comprising O
10 O
rats O
in O
each O
group O
: O
group O
1 O
: O
control O
; O
group O
2 O
: O
administered O
with O
CAPE B
( O
10 O
micro O
mol O
/ O
kg O
) O
; O
group O
3 O
: O
administered O
with O
15 O
mg O
/ O
kg O
PQ O
( O
PQ15 O
group O
) O
; O
group O
4 O
: O
administered O
with O
30 O
mg O
/ O
kg O
PQ O
( O
PQ30 O
group O
) O
; O
group O
5 O
: O
administered O
with O
45 O
mg O
/ O
kg O

PQ O
( O
PQ45 O
group O
) O
; O
group O
6 O
: O
administered O
with O
15 O
mg O
/ O
kg O
PQ O
+ O
CAPE B
; O
group O
7 O
: O
administered O
with O
30 O
mg O
/ O
kg O
PQ O
+ O
CAPE B
and O
group O
8 O
: O
administered O
with O
45 O
mg O
/ O
kg O
PQ O
+ O
CAPE B
. O

Both O
PQ O
and O
CAPE B
were O
injected O
intraperitoneally O
. O

Pancreatic O
tissue O
was O
examined O
with O
both O
haematoxylin B
and O
eosin B
and O
immunochemical O
staining O
. O

RESULTS O
: O
The O
ratio O
of O
the O
immunohistochemical O
staining O
area O
to O
the O
total O
pancreatic O
area O
of O
the O
beta O
cells O
revealed O
that O
statistically O
significant O
differences O
were O
observed O
only O
between O
the O
PQ O
and O
PQ O
+ O
CAPE B
groups O
( O
p O
< O
0 O
. O
05 O
) O
. O

Discussion O
: O
The O
evaluation O
of O
the O
data O
suggests O
that O
CAPE B
can O
be O
used O
to O
prevent O
acute O
effects O
of O
PQ O
intoxication O
. O

Modulation O
of O
carbon B
tetrachloride I
- O
induced O
nephrotoxicity O
in O
rats O
by O
n B
- I
hexane I
extract O
of O
Sonchus O
asper O
. O

Sonchus O
asper O
is O
traditionally O
used O
in O
the O
treatment O
of O
renal O
dysfunction O
. O

In O
the O
present O
study O
, O
protective O
effects O
of O
S O
. O
asper O
against O
carbon B
tetrachloride I
( O
CCl4 B
) O
- O
induced O
nephrotoxicity O
of O
rats O
were O
determined O
. O

In O
this O
study O
, O
24 O
male O
albino O
rats O
( O
190 O
- O
200 O
g O
) O
were O
equally O
divided O
into O
four O
groups O
. O

Group O
I O
( O
control O
group O
) O
was O
given O
saline O
( O
1 O
ml O
/ O
kg O
body O
weight O
( O
b O
. O
w O
. O
) O
, O
0 O
. O
85 O
% O
NaCl B
) O
and O
dimethyl B
sulfoxide I
( O
1 O
ml O
/ O
kg O
b O
. O
w O
. O
) O
; O
group O
II O
was O
treated O
with O
CCl4 B
( O
1 O
ml O
/ O
kg O
b O
. O
w O
. O
intraperitoneally O
) O
; O
groups O
III O
and O
IV O
were O
administered O
with O
CCl4 B
and O
after O
48 O
h O
with O
S O
. O
asper O
n B
- I
hexane I
extract O
( O
SHE O
; O
100 O
and O
200 O
mg O
/ O
kg O
b O
. O
w O
. O
) O
. O

All O
the O
treatments O
were O
given O
twice O
a O
week O
for O
4 O
weeks O
. O

The O
results O
revealed O
that O
CCl4 B
- O
induced O
oxidative O
stress O
as O
evidenced O
by O
the O
significant O
depletion O
of O
antioxidant O
enzymes O
, O
namely O
, O
superoxide B
dismutase O
, O
catalase O
, O
peroxidase O
, O
glutathione B
- O
S B
- O
transferase O
, O
glutathione B
peroxidase O
, O
glutathione B
reductase O
, O
and O
glutathione B
contents O
, O
while O
increased O
lipid O
peroxidation O
( O
thiobarbituric B
acid I
- O
reactive O
substances O
contents O
) O
. O

Administration O
of O
SHE O
significantly O
ameliorated O
( O
p O
< O
0 O
. O
01 O
) O
the O
activity O
of O
antioxidant O
enzymes O
and O
reduced O
lipid O
peroxides B
. O

Coadministration O
revealed O
that O
S O
. O
asper O
extract O
can O
protect O
the O
kidney O
against O
CCl4 B
- O
mediated O
oxidative O
damage O
by O
restoring O
the O
activity O
of O
antioxidant O
enzyme O
, O
due O
to O
the O
presence O
of O
plant O
bioactive O
constituents O
. O

Ecosystem O
services O
and O
the O
protection O
, O
restoration O
, O
and O
management O
of O
ecosystems O
exposed O
to O
chemical O
stressors O
. O

Ecosystem O
services O
- O
the O
benefits O
people O
obtain O
from O
ecosystem O
structures O
and O
processes O
- O
are O
essential O
for O
human O
survival O
and O
well O
- O
being O
. O

Chemicals O
are O
also O
an O
essential O
component O
of O
modern O
life O
; O
however O
, O
they O
may O
cause O
adverse O
ecological O
effects O
and O
reduce O
ecosystem O
service O
provision O
. O

Environmental O
policy O
makers O
are O
increasingly O
adopting O
the O
ecosystem O
services O
concept O
, O
but O
applying O
this O
approach O
to O
the O
protection O
, O
restoration O
, O
and O
management O
of O
ecosystems O
requires O
the O
development O
of O
new O
understanding O
, O
tools O
, O
and O
frameworks O
. O

There O
is O
an O
urgent O
need O
to O
understand O
and O
predict O
the O
effect O
of O
single O
and O
multiple O
stressors O
on O
ecosystem O
service O
delivery O
across O
different O
spatial O
scales O
( O
local O
to O
global O
) O
, O
to O
develop O
indicators O
that O
can O
be O
used O
to O
quantify O
and O
map O
services O
and O
identify O
synergies O
and O
trade O
- O
offs O
between O
them O
, O
to O
establish O
protection O
goals O
and O
restoration O
targets O
defined O
in O
terms O
of O
the O
types O
and O
levels O
of O
service O
delivery O
required O
, O
and O
to O
develop O
approaches O
for O
the O
assessment O
and O
management O
of O
chemical O
risk O
to O
ecosystem O
services O
that O
consider O
the O
whole O
life O
cycle O
of O
products O
and O
processes O
. O

These O
are O
major O
research O
challenges O
for O
the O
environmental O
science O
community O
in O
general O
and O
for O
ecotoxicologists O
and O
risk O
assessors O
in O
particular O
. O

Environ O
. O

Toxicol O
. O

Chem O
. O

2013 O
; O
32 O
: O
974 O
- O
983 O
. O

( O
c O
) O
2013 O
SETAC O
. O

Hypoglycemia O
and O
diabetes O
: O
a O
report O
of O
a O
workgroup O
of O
the O
american O
diabetes O
association O
and O
the O
endocrine O
society O
. O

OBJECTIVE O
To O
review O
the O
evidence O
about O
the O
impact O
of O
hypoglycemia O
on O
patients O
with O
diabetes O
that O
has O
become O
available O
since O
the O
past O
reviews O
of O
this O
subject O
by O
the O
American O
Diabetes O
Association O
and O
The O
Endocrine O
Society O
and O
to O
provide O
guidance O
about O
how O
this O
new O
information O
should O
be O
incorporated O
into O
clinical O
practice O
. O

PARTICIPANTS O
Five O
members O
of O
the O
American O
Diabetes O
Association O
and O
five O
members O
of O
The O
Endocrine O
Society O
with O
expertise O
in O
different O
aspects O
of O
hypoglycemia O
were O
invited O
by O
the O
Chair O
, O
who O
is O
a O
member O
of O
both O
, O
to O
participate O
in O
a O
planning O
conference O
call O
and O
a O
2 O
- O
day O
meeting O
that O
was O
also O
attended O
by O
staff O
from O
both O
organizations O
. O

Subsequent O
communications O
took O
place O
via O
e O
- O
mail O
and O
phone O
calls O
. O

The O
writing O
group O
consisted O
of O
those O
invitees O
who O
participated O
in O
the O
writing O
of O
the O
manuscript O
. O

The O
workgroup O
meeting O
was O
supported O
by O
educational O
grants O
to O
the O
American O
Diabetes O
Association O
from O
Lilly O
USA O
, O
LLC O
and O
Novo O
Nordisk O
and O
sponsorship O
to O
the O
American O
Diabetes O
Association O
from O
Sanofi O
. O

The O
sponsors O
had O
no O
input O
into O
the O
development O
of O
or O
content O
of O
the O
report O
. O

EVIDENCE O
The O
writing O
group O
considered O
data O
from O
recent O
clinical O
trials O
and O
other O
studies O
to O
update O
the O
prior O
workgroup O
report O
. O

Unpublished O
data O
were O
not O
used O
. O

Expert O
opinion O
was O
used O
to O
develop O
some O
conclusions O
. O

CONSENSUS O
PROCESS O
Consensus O
was O
achieved O
by O
group O
discussion O
during O
conference O
calls O
and O
face O
- O
to O
- O
face O
meetings O
, O
as O
well O
as O
by O
iterative O
revisions O
of O
the O
written O
document O
. O

The O
document O
was O
reviewed O
and O
approved O
by O
the O
American O
Diabetes O
Association O
' O
s O
Professional O
Practice O
Committee O
in O
October O
2012 O
and O
approved O
by O
the O
Executive O
Committee O
of O
the O
Board O
of O
Directors O
in O
November O
2012 O
and O
was O
reviewed O
and O
approved O
by O
The O
Endocrine O
Society O
' O
s O
Clinical O
Affairs O
Core O
Committee O
in O
October O
2012 O
and O
by O
Council O
in O
November O
2012 O
. O

CONCLUSIONS O
The O
workgroup O
reconfirmed O
the O
previous O
definitions O
of O
hypoglycemia O
in O
diabetes O
, O
reviewed O
the O
implications O
of O
hypoglycemia O
on O
both O
short O
- O
and O
long O
- O
term O
outcomes O
, O
considered O
the O
implications O
of O
hypoglycemia O
on O
treatment O
outcomes O
, O
presented O
strategies O
to O
prevent O
hypoglycemia O
, O
and O
identified O
knowledge O
gaps O
that O
should O
be O
addressed O
by O
future O
research O
. O

In O
addition O
, O
tools O
for O
patients O
to O
report O
hypoglycemia O
at O
each O
visit O
and O
for O
clinicians O
to O
document O
counseling O
are O
provided O
. O

Free O
- O
Standing O
Polyelectrolyte O
Membranes O
Made O
of O
Chitosan O
and O
Alginate O
. O

Free O
- O
standing O
films O
have O
increasing O
applications O
in O
the O
biomedical O
field O
as O
drug O
delivery O
systems O
for O
wound O
healing O
and O
tissue O
engineering O
. O

Here O
, O
we O
prepared O
free O
- O
standing O
membranes O
by O
the O
layer O
- O
by O
- O
layer O
assembly O
of O
chitosan O
and O
alginate O
, O
two O
widely O
used O
biomaterials O
. O

Our O
aim O
was O
to O
produce O
a O
thick O
membrane O
and O
to O
study O
the O
permeation O
of O
model O
drugs O
and O
the O
adhesion O
of O
muscle O
cells O
. O

We O
first O
defined O
the O
optimal O
growth O
conditions O
in O
terms O
of O
pH O
and O
alginate O
concentration O
. O

The O
membranes O
could O
be O
easily O
detached O
from O
polystyrene B
or O
polypropylene B
substrate O
without O
any O
postprocessing O
step O
. O

The O
dry O
thickness O
was O
varied O
over O
a O
large O
range O
from O
4 O
to O
35 O
mu O
m O
. O

A O
2 O
- O
fold O
swelling O
was O
observed O
by O
confocal O
microscopy O
when O
they O
were O
immersed O
in O
PBS O
. O

In O
addition O
, O
we O
quantified O
the O
permeation O
of O
model O
drugs O
( O
fluorescent O
dextrans O
) O
through O
the O
free O
- O
standing O
membrane O
, O
which O
depended O
on O
the O
dextran O
molecular O
weight O
. O

Finally O
, O
we O
showed O
that O
myoblast O
cells O
exhibited O
a O
preferential O
adhesion O
on O
the O
alginate O
- O
ending O
membrane O
as O
compared O
to O
the O
chitosan O
- O
ending O
membrane O
or O
to O
the O
substrate O
side O
. O

Concentration O
- O
Dependent O
Supramolecular O
Engineering O
of O
Hydrogen B
- O
Bonded O
Nanostructures O
at O
Surfaces O
: O
Predicting O
Self O
- O
Assembly O
in O
2D O
. O

We O
report O
a O
joint O
computational O
and O
experimental O
study O
on O
the O
concentration O
- O
dependent O
self O
- O
assembly O
of O
a O
flat O
C3 O
- O
symmetric O
molecule O
at O
surfaces O
. O

As O
a O
model O
system O
we O
have O
chosen O
a O
rigid O
molecular O
module O
, O
1 B
, I
3 I
, I
5 I
- I
tris I
( I
pyridine I
- I
4 I
- I
ylethynyl I
) I
benzene I
, O
which O
can O
undergo O
self O
- O
association O
via O
hydrogen B
bonding O
( O
H B
- O
bonding O
) O
to O
form O
ordered O
2D O
nanostructures O
. O

In O
particular O
, O
the O
lattice O
Monte O
Carlo O
method O
, O
combined O
with O
density O
functional O
calculations O
, O
was O
employed O
to O
explore O
the O
spontaneous O
supramolecular O
organization O
of O
this O
tripod O
- O
shaped O
molecule O
under O
surface O
confinement O
. O

We O
analyzed O
the O
stability O
of O
different O
weak O
H B
- O
bonded O
patterns O
and O
the O
influence O
of O
the O
concentration O
of O
the O
starting O
molecule O
on O
the O
2D O
supramolecular O
packing O
. O

We O
found O
that O
ordered O
, O
densely O
packed O
monolayers O
and O
2D O
porous O
networks O
are O
obtained O
at O
high O
and O
low O
concentrations O
, O
respectively O
. O

A O
concentration O
- O
dependent O
scanning O
tunneling O
microscopy O
investigation O
of O
the O
molecular O
self O
- O
assembly O
at O
a O
graphite B
- O
solution O
interface O
revealed O
supramolecular O
motifs O
, O
which O
are O
in O
perfect O
agreement O
with O
those O
obtained O
by O
simulations O
. O

Therefore O
, O
our O
computational O
approach O
represents O
a O
step O
forward O
toward O
the O
deterministic O
prediction O
of O
molecular O
self O
- O
assembly O
at O
surfaces O
and O
interfaces O
. O

Emergence O
of O
whole O
- O
cell O
MALDI O
- O
MS O
biotyping O
for O
high O
- O
throughput O
bioanalysis O
of O
mammalian O
cells O
? O

Since O
their O
inception O
in O
the O
1970s O
, O
methods O
for O
classification O
of O
microorganisms O
based O
on O
mass O
spectral O
fingerprints O
obtained O
by O
MALDI O
- O
TOF O
MS O
have O
become O
a O
mainstay O
in O
environmental O
as O
well O
as O
in O
clinical O
microbiology O
. O

Recently O
, O
related O
whole O
- O
cell O
MALDI O
- O
TOF O
fingerprinting O
workflows O
have O
been O
adopted O
for O
the O
classification O
of O
mammalian O
cells O
. O

In O
this O
report O
we O
summarize O
this O
work O
and O
discuss O
the O
challenges O
of O
adapting O
whole O
- O
cell O
MS O
fingerprinting O
methods O
for O
the O
successful O
classification O
of O
mammalian O
cells O
. O

We O
highlight O
current O
limitations O
as O
well O
as O
opportunities O
and O
emerging O
applications O
of O
this O
technology O
in O
industrial O
and O
clinical O
settings O
, O
such O
as O
cell O
- O
line O
authentication O
, O
clinical O
diagnostics O
, O
and O
quality O
and O
productivity O
control O
in O
bioprocesses O
. O

Theoretical O
and O
Kinetic O
Study O
of O
the O
Reaction O
of O
Ethyl B
Methyl I
Ketone I
with O
HO2 B
for O
T O
= O
600 O
- O
1 O
, O
600 O
K O
. O

Part O
II O
: O
Addition O
Reaction O
Channels O
. O

The O
temperature O
and O
pressure O
dependence O
of O
the O
addition O
reaction O
of O
ethyl B
methyl I
ketone I
( O
EMK B
) O
with O
HO2 B
radical O
has O
been O
calculated O
with O
the O
master O
equation O
method O
employing O
conventional O
transition O
state O
theory O
estimates O
for O
the O
microcanonical O
rate O
coefficients O
in O
the O
temperature O
range O
of O
600 O
- O
1600 O
K O
. O

Geometries O
, O
frequencies O
, O
and O
hindrance O
potentials O
were O
obtained O
at O
the O
B3LYP O
/ O
6 O
- O
311G O
( O
d O
, O
p O
) O
level O
of O
theory O
. O

A O
modified O
G3 O
( O
MP2 O
, O
CC O
) O
method O
has O
been O
used O
to O
calculate O
accurate O
electronic O
energies O
for O
all O
of O
the O
species O
involved O
in O
the O
reactions O
. O

The O
rigid O
- O
rotor O
harmonic O
oscillator O
approximation O
has O
been O
used O
for O
all O
of O
the O
vibrations O
except O
for O
the O
torsional O
degrees O
of O
freedom O
which O
are O
being O
treated O
as O
1D O
hindered O
rotor O
. O

Asymmetric O
Eckart O
barriers O
were O
used O
to O
model O
tunneling O
effect O
in O
a O
one O
- O
dimensional O
reaction O
coordinate O
through O
saddle O
points O
. O

Our O
calculated O
results O
show O
that O
the O
four O
reaction O
channels O
forming O
1 B
- I
buten I
- I
2 I
- I
ol I
+ O
H B
y O
O2 B
radical O
( O
R5 O
) O
, O
2 B
- I
buten I
- I
2 I
- I
ol I
+ O
H B
y O
O2 B
radical O
( O
R10 O
) O
, O
acetic B
acid I
+ O
ethylene B
+ O
y O
O B
H I
radical O
( O
R13 O
) O
, O
2 B
- I
methyl I
- I
2 I
- I
oxetanol I
+ O
y O
OH B
radical O
( O
R15 O
) O
are O
the O
dominant O
channels O
. O

When O
the O
temperature O
is O
below O
1000 O
K O
, O
the O
reaction O
R15 O
forming O
the O
cyclic B
ether I
, O
2 B
- I
methyl I
- I
2 I
- I
oxetanol I
, O
is O
dominant O
; O
while O
the O
reaction O
R13 O
forming O
acetic B
acid I
+ O
ethylene B
+ O
y O
OH B
radical O
becomes O
increasingly O
dominant O
at O
temperatures O
above O
1000 O
K O
. O

The O
other O
two O
channels O
forming O
1 B
- I
buten I
- I
2 I
- I
ol I
, O
2 B
- I
buten I
- I
2 I
- I
ol I
and O
HO2 B
radical O
are O
not O
dominant O
but O
are O
still O
important O
product O
channels O
over O
the O
whole O
temperature O
range O
investigated O
here O
. O

No O
pressure O
dependence O
has O
been O
found O
for O
the O
reaction O
channels O
forming O
2 B
- I
methyl I
- I
2 I
- I
oxetanol I
+ O
OH B
radical O
and O
acetic B
acid I
+ O
ethylene B
+ O
OH B
radical O
. O

A O
slightly O
negative O
pressure O
dependence O
has O
been O
found O
for O
the O
reaction O
channels O
producing O
the O
two O
butenols B
. O

Rate O
constants O
for O
the O
four O
important O
reaction O
channels O
at O
1 O
atm O
( O
in O
cm3mol O
- O
1s O
- O
1 O
) O
are O
: O
kR5 O
= O
2 O
. O
67 O
x O
1015 O
x O
T O
- O
1 O
. O
32 O
exp O
( O
- O
16637 O
/ O
T O
) O
kR10 O
= O
1 O
. O
62 O
x O
108 O
x O
T O
0 O
. O
57 O
exp O
( O
- O
13142 O
/ O
T O
) O
kR13 O
= O
2 O
. O
29 O
x O
1017 O
x O
T O
- O
1 O
. O
66 O
exp O
( O
- O
18169 O
/ O
T O
) O
kR15 O
= O
6 O
. O
17 O
x O
10 O
- O
2 O
x O
T O
3 O
. O
35 O
exp O
( O
- O
10136 O
/ O
T O
) O
A O

comparison O
of O
the O
total O
rate O
constants O
for O
the O
addition O
of O
HO2 B
radical O
to O
EMK O
and O
that O
for O
H B
- O
atom O
abstraction O
by O
HO2 B
radical O
from O
EMK O
has O
also O
been O
carried O
out O
. O

We O
find O
that O
the O
abstraction O
reaction O
channels O
are O
dominant O
over O
the O
entire O
temperature O
range O
of O
600 O
- O
1600 O
K O
. O

Phase O
- O
selective O
sorbent O
xerogels O
as O
reclamation O
agents O
for O
oil O
spills O
. O

12 B
- I
Hydroxystearic I
acid I
( O
12 O
- O
HSA O
) O
xerogels O
derived O
from O
12 O
- O
HSA O
- O
acetronitrile B
organogels O
are O
highly O
effective O
sorbent O
materials O
capable O
of O
adsorbing O
apolar O
, O
spilled O
materials O
in O
aqueous O
environments O
. O

12 O
- O
HSA O
xerogels O
made O
from O
12 O
- O
HSA O
- O
acetronitrile B
organogels O
are O
more O
effective O
than O
12 O
- O
HSA O
xerogels O
made O
from O
12 O
- O
HSA O
- O
pentane B
organogels O
because O
of O
the O
highly O
branched O
fibrillar O
networks O
established O
in O
acetonitrile B
molecular O
gels O
. O

This O
difference O
arises O
because O
of O
dissimilarities O
in O
the O
network O
structure O
between O
12 O
- O
HSA O
in O
various O
solvents O
. O

These O
xerogels O
, O
being O
thermoreversible O
, O
allow O
for O
both O
the O
spilled O
oil O
to O
be O
reclaimed O
but O
also O
the O
gelator O
may O
be O
reused O
to O
engineer O
new O
xerogels O
for O
oil O
spill O
containment O
and O
cleanup O
. O

Pregnancy O
outcome O
in O
women O
exposed O
to O
antiepileptic O
drugs O
: O
teratogenic O
role O
of O
maternal O
epilepsy O
and O
its O
pharmacologic O
treatment O
. O

Infants O
born O
to O
epileptic O
women O
treated O
with O
Antiepileptic O
Drugs O
( O
AEDs O
) O
have O
an O
increased O
risk O
of O
major O
congenital O
malformations O
( O
MCMs O
) O
. O

In O
order O
to O
determine O
the O
role O
of O
maternal O
epilepsy O
we O
conducted O
a O
prospective O
cohort O
study O
on O
three O
cohorts O
of O
pregnant O
women O
: O
i O
) O
385 O
epileptic O
women O
treated O
with O
AEDs O
, O
ii O
) O
310 O
non O
- O
epileptic O
women O
treated O
with O
AEDs O
, O
iii O
) O
867 O
healthy O
women O
not O
exposed O
to O
AEDs O
( O
control O
group O
) O
. O

The O
rate O
of O
MCMs O
in O
the O
epileptic O
group O
( O
7 O
. O
7 O
% O
) O
was O
not O
statistically O
higher O
than O
in O
the O
non O
- O
epileptic O
one O
( O
3 O
. O
9 O
% O
) O
( O
p O
= O
0 O
. O
068 O
) O
. O

The O
rate O
in O
the O
first O
group O
was O
higher O
compared O
to O
the O
control O
group O
( O
p O
= O
0 O
. O
001 O
) O
, O
while O
the O
rate O
in O
the O
second O
one O
was O
not O
( O
p O
= O
0 O
. O
534 O
) O
. O

Our O
data O
confirm O
that O
AEDs O
therapy O
is O
the O
main O
cause O
of O
the O
increased O
risk O
of O
malformations O
in O
the O
offspring O
of O
epileptic O
women O
; O
however O
a O
teratogenic O
role O
of O
the O
maternal O
epilepsy O
itself O
cannot O
be O
excluded O
. O

Electrophysiological O
evidence O
for O
4 B
- I
isobutyl I
- I
3 I
- I
isopropylbicyclophos I
as O
a O
selective O
blocker O
of O
insect O
GABA B
- O
gated O
chloride B
channels O
. O

Invertebrate O
gamma B
- I
aminobutyric I
acid I
( O
GABA B
) O
- O
gated O
chloride B
channels O
( O
GABACls O
) O
and O
glutamate B
- O
gated O
chloride B
channels O
( O
GluCls O
) O
, O
which O
function O
as O
inhibitory O
neurotransmitter O
receptors O
, O
are O
important O
targets O
of O
insecticides O
and O
antiparasitic O
agents O
. O

The O
antagonism O
of O
GABACls O
and O
GluCls O
by O
4 B
- I
isobutyl I
- I
3 I
- I
isopropylbicyclophos I
( O
PS B
- I
14 I
) O
was O
examined O
in O
cultured O
cockroach O
and O
rat O
neurons O
using O
a O
whole O
- O
cell O
patch O
- O
clamp O
method O
. O

The O
results O
indicated O
that O
PS O
- O
14 O
selectively O
blocks O
cockroach O
GABACls O
relative O
to O
cockroach O
GluCls O
and O
rat O
GABACls O
. O

PS O
- O
14 O
represents O
a O
useful O
probe O
for O
the O
study O
of O
insect O
GABA B
receptors O
. O

Synthesis O
and O
antibacterial O
evaluation O
of O
a O
novel O
series O
of O
10 B
- I
hydroxyl I
ketolide I
derivatives O
. O

A O
novel O
series O
of O
10 B
- I
hydroxyl I
ketolide I
derivatives O
were O
synthesized O
, O
during O
which O
a O
distinctive O
intermediate O
, O
3 B
- I
O I
- I
descladinosyl I
- I
3 I
- I
oxo I
- I
11 I
- I
deoxy I
- I
10 I
, I
11 I
- I
epoxy I
- I
6 I
- I
O I
- I
methylerythromycin I
A I
, O
was O
obtained O
from O
6 B
- I
O I
- I
methylerythromycin I
A I
. O

The O
structure O
and O
stereochemistry O
of O
this O
novel O
structure O
were O
confirmed O
via O
NMR O
and O
X O
- O
ray O
crystallography O
. O

Moreover O
, O
antibacterial O
evaluations O
were O
established O
in O
order O
to O
assess O
our O
modifications O
and O
acquire O
a O
deep O
understanding O
of O
the O
ketolides B
' O
structure O
- O
activity O
relationship O
( O
SAR O
) O
. O

Synthesis O
and O
cytotoxic O
evaluation O
of O
novel O
pyrimidine B
deoxyapiothionucleos O
. O

The O
synthesis O
of O
novel O
pyrimidine B
deoxyapiothionucleos O
of O
d O
- O
and O
l O
- O
series O
was O
realized O
following O
application O
of O
a O
versatile O
and O
high O
- O
yielding O
scheme O
, O
which O
utilized O
inexpensive O
l B
- I
and I
d I
- I
arabinose I
as O
starting O
materials O
, O
respectively O
, O
and O
which O
makes O
use O
of O
a O
regio O
- O
and O
stereo O
- O
selective O
Pummerer O
rearrangement O
reaction O
for O
the O
coupling O
of O
the O
nucleobase B
with O
the O
thiosugar B
moiety O
. O

Some O
of O
the O
targeted O
compounds O
have O
shown O
selective O
cytotoxic O
effects O
( O
with O
IC50 O
< O
10 O
mu O
M O
) O
against O
specific O
cancer O
cell O
lines O
. O

All O
of O
the O
tested O
compounds O
had O
no O
cytotoxic O
effect O
on O
the O
normal O
cell O
line O
tested O
. O

Oxidative O
stress O
and O
MAPK O
involved O
into O
ATF2 O
expression O
in O
immortalized O
human O
urothelial O
cells O
treated O
by O
arsenic B
. O

ATF2 O
is O
a O
subfamily O
member O
of O
AP O
- O
1 O
and O
has O
an O
important O
role O
in O
cellular O
stress O
responses O
. O

ATF2 O
has O
been O
implicated O
in O
a O
transcriptional O
response O
leading O
to O
cell O
migration O
and O
malignant O
tumor O
progression O
. O

However O
, O
little O
is O
known O
about O
the O
effect O
of O
arsenic B
on O
expression O
of O
ATF2 O
and O
regulatory O
pathways O
in O
human O
urothelial O
cells O
. O

In O
this O
study O
, O
ATF2 O
expression O
was O
measured O
in O
NaAsO2 B
- O
treated O
human O
uroepithelial O
cell O
line O
( O
SV O
- O
HUC O
- O
1 O
) O
with O
1 O
, O
2 O
, O
4 O
, O
8 O
and O
10 O
mu O
M O
concentrations O
in O
order O
to O
provide O
some O
basis O
data O
for O
the O
study O
on O
mechanism O
of O
bladder O
cancer O
induced O
by O
arsenic B
. O

We O
found O
that O
ATF2 O
expression O
levels O
at O
2 O
, O
4 O
, O
8 O
and O
10 O
mu O
M O
arsenic B
- O
treated O
cells O
were O
significantly O
higher O
than O
those O
of O
control O
cells O
, O
and O
the O
strongest O
expression O
occurred O
in O
4 O
mu O
M O
NaAsO2 B
- O
treated O
cells O
. O

Antioxidants O
( O
melatonin B
) O
and O
JNK O
or O
p38 O
inhibitors O
decreased O
significantly O
arsenic B
- O
induced O
ATF2 O
expression O
. O

Taken O
together O
, O
these O
data O
indicated O
that O
the O
increasing O
of O
ATF2 O
expression O
is O
mediated O
via O
oxidative O
stress O
induced O
by O
arsenic B
in O
SV O
- O
HUC O
- O
1 O
cells O
, O
and O
JNK O
or O
p38 O
rather O
than O
ERK O
is O
responsible O
for O
arsenic B
- O
induced O
ATF2 O
expression O
. O

ROS O
were O
also O
involved O
in O
arsenic B
induced O
the O
activation O
of O
JNK O
and O
p38 O
MAPK O
signaling O
pathway O
. O

Two O
Common O
Bean O
Genotypes O
with O
Contrasting O
Response O
to O
Phosphorus B
Deficiency O
Show O
Variations O
in O
the O
microRNA O
399 O
- O
Mediated O
PvPHO2 O
Regulation O
within O
the O
PvPHR1 O
Signaling O
Pathway O
. O

Crop O
production O
of O
the O
important O
legume O
, O
the O
common O
bean O
( O
Phaseolus O
vulgaris O
) O
, O
is O
often O
limited O
by O
low O
phosphorus B
( O
P B
) O
in O
the O
soil O
. O

The O
genotypes O
, O
BAT477 O
and O
DOR364 O
, O
of O
the O
common O
bean O
have O
contrasting O
responses O
to O
P B
starvation O
. O

Plants O
from O
the O
BAT477 O
P B
deficiency O
tolerant O
genotype O
showed O
higher O
phosphate B
content O
and O
root O
biomass O
as O
compared O
to O
the O
DOR364 O
plants O
under O
P B
starvation O
. O

The O
PvPHR1 O
transcription O
factor O
- O
signaling O
pathway O
plays O
an O
essential O
role O
in O
the O
response O
to O
P B
starvation O
. O

PvPHO2 O
, O
a O
negative O
regulator O
of O
this O
pathway O
, O
encodes O
an O
ubiquitin O
E2 O
conjugase O
that O
promotes O
degradation O
of O
P O
- O
responsive O
proteins O
and O
is O
the O
target O
gene O
of O
PvmiR399 O
. O

PvPHO2 O
is O
downregulated O
in O
BAT477 O
plants O
under O
P B
deficiency O
, O
while O
such O
a O
response O
is O
not O
observed O
in O
P B
- O
starved O
DOR364 O
plants O
. O

Five O
putative O
PvmiR399 O
binding O
sites O
were O
identified O
in O
the O
5 O
' O
UTR O
region O
in O
both O
genotypes O
. O

While O
four O
sites O
showed O
an O
identical O
DNA O
sequence O
, O
the O
fifth O
( O
binding O
site O
of O
PvPHO2 O
one O
) O
showed O
three O
base O
changes O
and O
higher O
complementarity O
scores O
in O
DOR364 O
as O
compared O
to O
BAT477 O
. O

Modified O
5 O
' O
RACE O
experiments O
indicated O
that O
PvmiR399 O
binding O
and O
/ O
or O
processing O
was O
affected O
in O
DOR364 O
P B
- O
starved O
plants O
. O

We O
propose O
that O
a O
less O
efficient O
cleavage O
of O
the O
PvPHO2 O
mRNA O
directed O
by O
PvmiR399 O
would O
result O
in O
a O
higher O
PvPHO2 O
- O
mediated O
degradation O
of O
P O
- O
responsive O
proteins O
in O
the O
DOR364 O
genotype O
with O
decreased O
P B
deficiency O
tolerance O
. O

Widening O
the O
pH O
Activity O
Profile O
of O
a O
Fungal O
Laccase O
by O
Directed O
Evolution O
. O

Unnatural O
selection O
: O
A O
fungal O
laccase O
was O
tailored O
by O
directed O
evolution O
to O
be O
active O
at O
neutral O
/ O
alkaline O
pH O
. O

After O
five O
generations O
, O
the O
final O
mutant O
showed O
a O
broader O
pH O
profile O
while O
retaining O
50 O
to O
80 O
% O
of O
its O
activity O
at O
neutral O
pH O
. O

An O
in O
Vivo O
Tagging O
Method O
Reveals O
that O
Ras O
Undergoes O
Sustained O
Activation O
upon O
Transglutaminase O
- O
Mediated O
Protein O
Serotonylation O
. O

Don O
' O
t O
interrupt O
! O

Protein O
serotonylation O
has O
been O
implicated O
in O
living O
cells O
, O
yet O
its O
role O
remains O
poorly O
defined O
because O
of O
the O
lack O
of O
characterization O
tools O
. O

We O
synthesized O
a O
serotonin B
derivative O
to O
enable O
selective O
tagging O
of O
serotonylation O
and O
to O
investigate O
its O
effect O
on O
Ras O
; O
the O
latter O
displayed O
undisrupted O
interaction O
with O
Raf O
- O
1 O
at O
the O
Ras O
binding O
domain O
. O

A O
Surgical O
Model O
in O
Male O
Obese O
Rats O
Uncovers O
Protective O
Effects O
of O
Bile B
Acids I
Post O
- O
Bariatric O
Surgery O
. O

Bariatric O
surgery O
elevates O
serum O
bile B
acids I
. O

Conjugated O
bile B
acid I
administration O
, O
such O
as O
tauroursodeoxycholic B
acid I
( O
TUDCA B
) O
, O
improves O
insulin O
sensitivity O
, O
while O
short O
- O
circuiting O
bile B
acid I
circulation O
through O
ileal O
interposition O
surgery O
in O
rats O
raises O
TUDCA B
levels O
. O

We O
hypothesized O
that O
bariatric O
surgery O
outcomes O
could O
be O
recapitulated O
by O
short O
- O
circuiting O
the O
normal O
entero O
- O
hepatic O
bile O
circulation O
. O

We O
established O
a O
model O
wherein O
male O
obese O
rats O
underwent O
either O
bile O
diversion O
( O
BD O
) O
or O
Sham O
( O
SH O
) O
surgery O
. O

The O
BD O
group O
had O
a O
catheter O
inserted O
into O
the O
common O
bile O
duct O
and O
its O
distal O
end O
anchored O
into O
the O
mid O
- O
distal O
jejunum O
for O
4 O
- O
5 O
weeks O
. O

Glucose B
tolerance O
, O
insulin O
and O
glucagon O
- O
like O
peptide O
- O
1 O
( O
GLP O
- O
1 O
) O
response O
, O
hepatic O
steatosis O
and O
endoplasmic O
reticulum O
( O
ER O
) O
stress O
were O
measured O
. O

Rats O
' O
post O
- O
BD O
lost O
significantly O
more O
weight O
than O
the O
SH O
- O
rats O
. O

BD O
rats O
gained O
less O
fat O
mass O
post O
- O
surgery O
. O

BD O
rats O
had O
improved O
glucose B
tolerance O
, O
increased O
higher O
post O
- O
prandial O
GLP O
- O
1 O
response O
and O
serum O
bile B
acids I
but O
less O
liver O
steatosis O
. O

Serum O
bile B
acid I
levels O
including O
TUDCA B
concentrations O
were O
higher O
in O
BD O
compared O
to O
SH O
pair O
- O
fed O
rats O
. O

Fecal O
bile B
acid I
levels O
were O
not O
different O
. O

Liver O
ER O
stress O
( O
CHOP O
mRNA O
and O
pJNK O
protein O
) O
was O
decreased O
in O
BD O
rats O
. O

Bile B
acid I
gavage O
( O
TUDCA B
/ O
UDCA B
) O
in O
diet O
- O
induced O
obese O
rats O
, O
elevated O
serum O
TUDCA B
and O
concomitantly O
reduced O
hepatic O
steatosis O
and O
ER O
stress O
( O
CHOP O
mRNA O
) O
. O

These O
data O
demonstrate O
the O
ability O
of O
alterations O
in O
bile B
acids I
to O
recapitulate O
important O
metabolic O
improvements O
seen O
after O
bariatric O
surgery O
. O

Further O
, O
our O
work O
establishes O
a O
model O
for O
focused O
study O
of O
bile B
acids I
in O
the O
context O
of O
bariatric O
surgery O
that O
may O
lead O
to O
the O
identification O
of O
therapeutics O
for O
metabolic O
disease O
. O

Silver B
nanoparticles O
enhance O
Pseudomonas O
aeruginosa O
PAO1 O
biofilm O
detachment O
. O

Abstract O
Objectives O
: O
Silver B
nanoparticles O
( O
AgNPs O
) O
with O
a O
size O
ranging O
from O
7 O
to O
70 O
nm O
were O
synthesized O
using O
the O
ascorbic B
acid I
- O
citrate B
seed O
- O
mediated O
growth O
approach O
at O
room O
temperature O
. O

Methods O
: O
The O
8 O
nm O
silver B
particles O
were O
prepared O
using O
gallic B
acid I
in O
alkaline O
conditions O
and O
used O
as O
seed O
to O
prepare O
AgNPs O
. O

Results O
: O
The O
presence O
of O
ascorbic B
acid I
and O
citrate B
allows O
the O
regulation O
of O
size O
and O
size O
distribution O
of O
the O
nanoparticles O
. O

The O
increase O
in O
free O
silver B
ion O
- O
to O
- O
seed O
ratio O
( O
Ag B
( I
+ I
) I
/ O
Ag B
( I
0 I
) I
) O
resulted O
in O
changes O
of O
particle O
shape O
from O
spherical O
to O
pseudo O
- O
spherical O
and O
minor O
cylindrical O
shape O
. O

Further O
, O
a O
repetitive O
seeding O
approach O
resulted O
in O
the O
formation O
of O
pseudo O
- O
spherical O
particles O
with O
higher O
polydispersity O
index O
and O
minor O
distributions O
of O
tetrahedral O
particles O
. O

Citrate B
- O
capped O
AgNPs O
were O
stable O
and O
did O
not O
agglomerate O
upon O
centrifugation O
. O

The O
effect O
of O
AgNPs O
on O
biofilm O
reduction O
was O
evaluated O
using O
static O
culture O
on O
96 O
- O
well O
microtiter O
plates O
. O

Results O
showed O
that O
AgNPs O
with O
the O
smallest O
average O
diameter O
were O
most O
effective O
in O
the O
reduction O
of O
Pseudomonas O
aeruginosa O
biofilm O
colonies O
, O
which O
accounted O
for O
90 O
% O
of O
removal O
. O

Conclusion O
: O
The O
biofilm O
removal O
activities O
of O
the O
nanoparticles O
were O
found O
to O
be O
concentration O
- O
independent O
particularly O
for O
the O
concentration O
within O
the O
range O
of O
80 O
- O
200 O
micro O
g O
/ O
mL O
. O

Bacteriolysis O
by O
vancomycin B
- O
conjugated O
acryl B
nanoparticles O
and O
morphological O
component O
analysis O
. O

Abstract O
Nanoparticles O
are O
currently O
attracting O
considerable O
attention O
because O
of O
their O
ability O
to O
conjugate O
to O
various O
substances O
. O

As O
such O
, O
these O
nanoparticles O
can O
assist O
the O
transfer O
of O
the O
conjugated O
substance O
to O
target O
tissues O
where O
they O
are O
gradually O
released O
. O

In O
this O
study O
, O
vancomycin B
- O
conjugated O
nanoparticles O
( O
VCM B
NPs O
) O
were O
prepared O
. O

The O
antibacterial O
activity O
of O
VCM B
NPs O
was O
compared O
with O
that O
of O
VCM B
alone O
by O
exposure O
to O
vancomycin B
- O
resistant O
enterococci O
( O
VRE O
) O
. O

The O
morphology O
of O
the O
cells O
was O
then O
analyzed O
by O
electron O
microscopy O
. O

VCM B
NPs O
were O
found O
to O
have O
more O
potent O
antibacterial O
activity O
against O
VRE O
compared O
to O
VCM B
alone O
, O
but O
the O
activity O
against O
vancomycin B
- O
sensitive O
enterococci O
( O
VSE O
) O
remained O
the O
same O
. O

The O
antibacterial O
activity O
of O
nanoparticles O
alone O
was O
the O
same O
against O
VSE O
and O
VRE O
. O

The O
nanoparticles O
were O
found O
to O
induce O
characteristic O
morphological O
changes O
in O
the O
bacteria O
based O
on O
scanning O
and O
transmission O
electron O
microscopy O
. O

The O
results O
suggest O
that O
the O
strong O
antibacterial O
activity O
of O
VCM B
NPs O
against O
VRE O
may O
be O
attributable O
not O
only O
to O
the O
well O
- O
known O
control O
release O
carrier O
property O
of O
the O
nanoparticles O
but O
to O
an O
additional O
mechanism O
that O
involves O
VCM B
NPs O
avoiding O
the O
drug O
resistant O
mechanism O
of O
VRE O
. O

Ingestion O
toxicity O
of O
three O
Lamiaceae O
essential O
oils O
incorporated O
in O
protein O
baits O
against O
the O
olive O
fruit O
fly O
, O
Bactrocera O
oleae O
( O
Rossi O
) O
( O
Diptera O
Tephritidae O
) O
. O

The O
ingestion O
toxicity O
of O
three O
Lamiaceae O
essential O
oils O
( O
EOs O
) O
- O
Hyptis O
suaveolens O
, O
Rosmarinus O
officinalis O
and O
Lavandula O
angustifolia O
- O
incorporated O
in O
protein O
baits O
was O
evaluated O
against O
Bactrocera O
oleae O
, O
a O
worldwide O
pest O
of O
olive O
fruits O
. O

In O
laboratory O
conditions O
, O
all O
the O
tested O
EOs O
showed O
dose O
- O
dependent O
toxicity O
on O
B O
. O
oleae O
, O
with O
mortality O
rates O
ranging O
from O
12 O
% O
( O
EO O
concentration O
: O
0 O
. O
01 O
% O
w O
: O
v O
) O
to O
100 O
% O
( O
EO O
concentration O
: O
1 O
. O
75 O
% O
w O
: O
v O
) O
. O

Semi O
- O
field O
results O
highlighted O
the O
toxicity O
of O
L O
. O
angustifolia O
and O
H O
. O
suaveolens O
EOs O
, O
which O
exerted O
more O
than O
60 O
% O
of O
flies O
mortality O
at O
a O
concentration O
of O
1 O
. O
75 O
% O
( O
w O
: O
v O
) O
. O

Gas O
Chromatography O
- O
Electron O
Impact O
Mass O
Spectrometry O
analyses O
of O
the O
three O
EOs O
showed O
that O
H O
. O
suaveolens O
EO O
was O
dominated O
by O
monoterpene B
and O
sesquiterpene I
hydrocarbons I
. O

Oxygenated O
monoterpenes B
were O
the O
main O
chemical O
class O
in O
R O
. O
officinalis O
and O
L O
. O
angustifolia O
EOs O
. O

Further O
research O
is O
needed O
to O
evaluate O
the O
efficacy O
of O
these O
EOs O
plus O
food O
bait O
against O
the O
olive O
fruit O
fly O
in O
the O
open O
field O
. O

Aberrant O
free O
radical O
biology O
is O
a O
unifying O
theme O
in O
the O
etiology O
and O
pathogenesis O
of O
major O
human O
diseases O
. O

The O
seemingly O
disparate O
areas O
of O
oxygen B
toxicity O
, O
radiation O
exposure O
, O
and O
aging O
are O
now O
recognized O
to O
share O
a O
common O
feature O
- O
the O
aberrant O
production O
and O
/ O
or O
removal O
of O
biologically O
derived O
free O
radicals O
and O
other O
reactive O
oxygen B
and O
nitrogen B
species O
( O
ROS O
/ O
RNS O
) O
. O

Advances O
in O
our O
understanding O
of O
the O
effects O
of O
free O
radicals O
in O
biology O
and O
medicine O
have O
been O
, O
and O
continue O
to O
be O
, O
actively O
translated O
into O
clinically O
tractable O
diagnostic O
and O
therapeutic O
applications O
. O

This O
issue O
is O
dedicated O
to O
recent O
advances O
, O
both O
basic O
discoveries O
and O
clinical O
applications O
, O
in O
the O
field O
of O
free O
radicals O
in O
biology O
and O
medicine O
. O

As O
more O
is O
understood O
about O
the O
proximal O
biological O
targets O
of O
aberrantly O
produced O
or O
removed O
reactive O
species O
, O
their O
sensors O
, O
and O
effectors O
of O
compensatory O
response O
, O
a O
great O
deal O
more O
will O
be O
learned O
about O
the O
commonalities O
in O
mechanisms O
underlying O
seemingly O
disparate O
disease O
states O
. O

Together O
with O
this O
deeper O
understanding O
, O
opportunities O
will O
arise O
to O
devise O
rational O
therapeutic O
interventions O
to O
decrease O
the O
incidence O
and O
severity O
of O
these O
diseases O
and O
positively O
impact O
the O
human O
healthspan O
. O

Structural O
and O
Immunochemical O
Studies O
of O
the O
Lipopolysaccharide O
from O
the O
Fish O
Pathogen O
, O
Aeromonas O
bestiarum O
Strain O
K296 O
, O
Serotype O
O18 O
. O

Chemical O
analyses O
and O
mass O
spectrometry O
were O
used O
to O
study O
the O
structure O
of O
the O
lipopolysaccharide O
( O
LPS O
) O
isolated O
from O
Aeromonas O
bestiarum O
strain O
K296 O
, O
serotype O
O18 O
. O

ESI O
- O
MS O
revealed O
that O
the O
most O
abundant O
A O
. O
bestiarum O
LPS O
glycoforms O
have O
a O
hexa B
- I
acylated I
or I
tetra I
- I
acylated I
lipid I
A I
with O
conserved O
architecture O
of O
the O
backbone O
, O
consisting O
of O
a O
1 B
, I
4 I
' I
- I
bisphosphorylated I
beta I
- I
( I
1 I
- I
- I
> I
6 I
) I
- I
linked I
d I
- I
GlcN I
disaccharide I
with O
an O
AraN B
residue O
as O
a O
non O
- O
stoichiometric O
substituent O
and O
a O
core O
oligosaccharide O
composed O
of O
Kdo1Hep6Hex1HexN1P1 B

. O

1D O
and O
2D O
NMR O
spectroscopy O
revealed O
that O
the O
O O
- O
specific O
polysaccharide O
( O
OPS O
) O
of O
A O
. O
bestiarum O
K296 O
consists O
of O
a O
branched O
tetrasaccharide B
repeating O
unit O
containing O
two O
6 B
- I
deoxy I
- I
l I
- I
talose I
( O
6dTalp B
) O
, O
one O
Manp B
and O
one O
GalpNAc B
residues O
; O
thus O
, O
it O
is O
similar O
to O
that O
of O
the O
OPS O
of O
A O
. O
hydrophila O
AH O
- O
3 O
( O
serotype O
O34 O
) O
in O
both O
the O
sugar O
composition O
and O
the O
glycosylation O
pattern O
. O

Moreover O
, O
3 B
- I
substituted I
6dTalp I
was O
2 B
- O
O B
- O
acetylated O
and O
additional O
O B
- I
acetyl I
groups O
were O
identified O
at O
O O
- O
2 O
and O
O O
- O
4 O
( O
or O
O B
- O
3 O
) O
positions O
of O
the O
terminal O
6dTalp B
. O

Western O
blots O
with O
polyclonal O
rabbit O
sera O
showed O
that O
serotypes O
O18 O
and O
O34 O
share O
some O
epitopes O
in O
the O
LPS O
. O

The O
very O
weak O
reaction O
of O
the O
anti O
- O
O34 O
serum O
with O
the O
O B
- O
deacylated O
LPS O
of O
A O
. O
bestiarum O
K296 O
might O
have O
been O
due O
to O
the O
different O
O B
- O
acetylation O
pattern O
of O
the O
terminal O
6dTalp B
. O

The O
latter O
suggestion O
was O
further O
confirmed O
by O
NMR O
. O

Protective O
Effects O
of O
HemoHIM O
on O
Immune O
and O
Hematopoietic O
Systems O
Against O
gamma O
- O
Irradiation O
. O

We O
examined O
the O
effect O
of O
HemoHIM O
on O
the O
protective O
efficacy O
of O
hematopoietic O
stem O
cells O
and O
on O
the O
recovery O
of O
immune O
cells O
against O
sublethal O
doses O
of O
ionizing O
radiation O
. O

Two O
- O
month O
- O
old O
mice O
were O
exposed O
to O
gamma O
- O
rays O
at O
a O
dose O
of O
8 O
, O
6 O
. O
5 O
, O
or O
5 O
Gy O
for O
a30 O
- O
day O
survival O
study O
, O
endogenous O
spleen O
colony O
formation O
, O
or O
other O
experiments O
, O
respectively O
. O

HemoHIM O
was O
injected O
intraperitoneally O
before O
and O
after O
irradiation O
. O

Our O
results O
showed O
that O
HemoHIM O
significantly O
decreased O
the O
mortality O
of O
sublethally O
irradiated O
mice O
. O

The O
HemoHIM O
administration O
decreased O
the O
apoptosis O
of O
bone O
marrow O
cells O
in O
irradiated O
mice O
. O

On O
the O
other O
hand O
, O
HemoHIM O
increased O
the O
formation O
of O
endogenous O
spleen O
colony O
in O
irradiated O
mice O
. O

In O
irradiated O
mice O
, O
the O
recovery O
of O
total O
leukocytes O
in O
the O
peripheral O
blood O
and O
lymphocytes O
in O
the O
spleen O
were O
enhanced O
significantly O
by O
HemoHIM O
. O

Moreover O
, O
the O
function O
of O
B O
cells O
, O
T O
cells O
, O
and O
NK O
cells O
regenerated O
in O
irradiated O
mice O
were O
significantly O
improved O
by O
the O
administration O
of O
HemoHIM O
. O

HemoHIM O
showed O
an O
ideal O
radioprotector O
for O
protecting O
hematopoietic O
stem O
cells O
and O
for O
accelerating O
the O
recovery O
of O
immune O
cells O
. O

We O
propose O
HemoHIM O
as O
a O
beneficial O
supplement O
drug O
during O
radiotherapy O
to O
alleviate O
adverse O
radiation O
- O
induced O
effects O
for O
cancer O
patients O
. O

Copyright O
( O
c O
) O
2013 O
John O
Wiley O
& O
Sons O
, O
Ltd O
. O

Palbinone B
from O
Paeonia O
suffruticosa O
Protects O
Hepatic O
Cells O
via O
Up O
- O
regulation O
of O
Heme O
Oxygenase O
- O
1 O
. O

Paeonia O
suffruticosa O
has O
been O
traditionally O
employed O
for O
vitalizing O
blood O
circulation O
and O
alleviating O
liver O
and O
inflammatory O
diseases O
. O

The O
pathways O
by O
which O
palbinone B
( O
PB B
) O
isolated O
from O
P O
. O
suffruticosa O
mediates O
heme O
oxygenase O
- O
1 O
( O
HO O
- O
1 O
) O
induction O
were O
investigated O
using O
the O
specific O
inhibitors O
for O
PI3K O
and O
mitogen O
activated O
protein O
kinases O
pathways O
. O

The O
effect O
of O
PB B
- O
treatment O
on O
Nrf2 O
translocalization O
and O
HO O
- O
1 O
- O
antioxidant O
response O
element O
( O
ARE O
) O
regulation O
was O
examined O
employing O
Western O
blot O
and O
luciferase O
assays O
. O

PB B
induced O
HO O
- O
1 O
expression O
via O
the O
activation O
of O
Nrf2 O
in O
the O
hepatic O
cells O
, O
and O
ARE O
- O
dependent O
genes O
were O
stimulated O
via O
the O
PB B
- O
mediated O
Nrf2 O
activation O
. O

PB B
- O
mediated O
HO O
- O
1 O
expression O
could O
be O
involved O
with O
PI3K O
/ O
Akt O
and O
ERK1 O
/ O
2 O
pathways O
. O

Our O
study O
suggests O
the O
mechanism O
by O
which O
PB B
induces O
HO O
- O
1 O
expression O
in O
the O
hepatic O
cells O
. O

This O
might O
substantiate O
the O
traditional O
applications O
of O
P O
. O
suffruticosa O
for O
the O
treatment O
of O
oxidative O
stress O
- O
related O
diseases O
including O
oxidant O
and O
inflammatory O
- O
mediated O
vascular O
and O
liver O
diseases O
. O

Copyright O
( O
c O
) O
2013 O
John O
Wiley O
& O
Sons O
, O
Ltd O
. O

Identification O
of O
candidate O
genes O
encoding O
an O
LDL O
- O
C O
QTL O
in O
baboons O
. O

Cardiovascular O
disease O
( O
CVD O
) O
, O
the O
leading O
cause O
of O
death O
in O
developed O
countries O
and O
dyslipidemia O
, O
is O
a O
major O
risk O
factor O
for O
CVD O
. O

We O
previously O
identified O
a O
cluster O
of O
quantitative O
trait O
loci O
( O
QTL O
) O
on O
baboon O
chromosome O
11 O
for O
multiple O
related O
quantitative O
traits O
for O
serum O
low O
- O
density O
lipoprotein O
cholesterol B
( O
LDL O
- O
C O
) O
. O

Here O
we O
report O
differentially O
regulated O
hepatic O
genes O
that O
appear O
to O
encode O
an O
LDL O
- O
C O
QTL O
that O
influences O
LDL O
- O
C O
levels O
in O
baboons O
. O

We O
performed O
hepatic O
whole O
genome O
expression O
profiling O
for O
LDL O
- O
C O
discordant O
baboons O
fed O
a O
high O
- O
cholesterol B
, O
high O
- O
fat O
( O
HCHF O
) O
diet O
for O
7 O
weeks O
. O

We O
detected O
expression O
of O
117 O
genes O
within O
the O
QTL O
2 O
- O
LOD O
- O
support O
interval O
. O

Three O
genes O
were O
differentially O
expressed O
in O
low O
LDL O
- O
C O
responders O
and O
8 O
in O
high O
LDL O
- O
C O
responders O
in O
response O
to O
a O
HCHF O
diet O
. O

Seven O
genes O
( O
ACVR1B O
, O
CALCOCO1 O
, O
DGKA O
, O
ERBB3 O
, O
KRT73 O
, O
MYL6B O
, O
TENC1 O
) O
showed O
discordant O
expression O
between O
low O
and O
high O
LDL O
- O
C O
responders O
. O

To O
prioritize O
candidate O
genes O
, O
we O
integrated O
miRNA O
and O
mRNA O
expression O
profiles O
using O
network O
tools O
and O
found O
that O
four O
candidates O
( O
ACVR1B O
, O
DGKA O
, O
ERBB3 O
, O
TENC1 O
) O
were O
miRNA O
targets O
and O
the O
miRNAs O
were O
inversely O
expressed O
to O
the O
target O
genes O
. O

Candidate O
gene O
expression O
was O
validated O
using O
QRT O
- O
PCR O
and O
Westerns O
. O

This O
study O
reveals O
candidate O
genes O
that O
influence O
variation O
in O
LDL O
- O
C O
in O
baboons O
and O
potential O
genetic O
mechanisms O
for O
further O
investigation O
. O

Macromolecular O
amplification O
of O
binding O
response O
in O
superaptamer O
hydrogels O
. O

It O
is O
becoming O
more O
important O
to O
detect O
ultralow O
concentrations O
of O
analytes O
for O
biomedical O
, O
environmental O
, O
and O
national O
security O
applications O
. O

Equally O
important O
is O
that O
new O
methods O
should O
be O
easy O
to O
use O
, O
inexpensive O
, O
portable O
, O
and O
if O
possible O
allow O
detection O
by O
the O
naked O
eye O
. O

By O
and O
large O
, O
detection O
of O
low O
concentrations O
of O
analytes O
cannot O
be O
achieved O
directly O
but O
requires O
signal O
amplification O
by O
catalysts O
, O
macromolecules O
, O
metal O
surfaces O
, O
or O
supramolecular O
aggregates O
. O

The O
rapidly O
progressing O
field O
of O
macromolecular O
signal O
amplification O
has O
been O
advanced O
using O
conjugated O
polymers O
, O
chirality O
in O
polymers O
, O
solvating O
polymers O
, O
and O
polymerization O
/ O
depolymerization O
strategies O
. O

A O
new O
type O
of O
aptamer O
- O
based O
hydrogel O
with O
specific O
response O
to O
target O
proteins O
presented O
in O
this O
report O
demonstrates O
an O
additional O
category O
of O
macromolecular O
signal O
amplification O
. O

This O
superaptamer O
assembly O
provides O
the O
first O
example O
of O
using O
protein O
- O
specific O
aptamers O
to O
create O
volume O
- O
changing O
hydrogels O
with O
amplified O
response O
to O
the O
target O
protein O
. O

A O
remarkable O
aspect O
of O
these O
superaptamer O
hydrogels O
is O
that O
volume O
shrinking O
is O
visible O
to O
the O
naked O
eye O
down O
to O
femtomolar O
concentrations O
of O
protein O
. O

This O
extraordinary O
macromolecular O
amplification O
is O
attributed O
to O
a O
complex O
interplay O
between O
protein O
- O
aptamer O
supramolecular O
cross O
- O
links O
and O
the O
consequential O
reduction O
of O
excluded O
volume O
in O
the O
hydrogel O
. O

Specific O
recognition O
is O
even O
maintained O
in O
biological O
matrices O
such O
as O
urine O
and O
tears O
. O

Furthermore O
, O
the O
gels O
can O
be O
dried O
for O
long O
- O
term O
storage O
and O
regenerated O
for O
use O
without O
loss O
of O
activity O
. O

In O
practice O
, O
the O
ease O
of O
this O
biomarker O
detection O
method O
offers O
an O
alternative O
to O
traditional O
analytical O
techniques O
that O
require O
sophisticated O
instrumentation O
and O
highly O
trained O
personnel O
. O

Polyelectrolyte O
Multilayers O
Promote O
Stent O
- O
Mediated O
Delivery O
of O
DNA O
to O
Vascular O
Tissue O
. O

We O
report O
an O
approach O
to O
deliver O
DNA O
to O
vascular O
tissue O
in O
vivo O
using O
intravascular O
stents O
coated O
with O
degradable O
, O
DNA O
- O
containing O
polyelectrolyte O
multilayers O
( O
PEMs O
) O
. O

Ionically O
cross O
- O
linked O
multilayers O
~ O
120 O
nm O
thick O
were O
fabricated O
layer O
- O
by O
- O
layer O
on O
the O
surfaces O
of O
balloon O
- O
mounted O
stainless O
steel O
stents O
using O
plasmid O
DNA O
and O
a O
hydrolytically O
degradable O
poly B
( I
beta I
- I
amino I
ester I
) I
( O
polymer O
1 O
) O
. O

Characterization O
of O
stents O
coated O
using O
a O
fluorescently O
end O
- O
labeled O
analog O
of O
polymer O
1 O
revealed O
film O
erosion O
to O
be O
uniform O
across O
the O
surfaces O
of O
the O
stents O
; O
differential O
stresses O
experienced O
upon O
balloon O
expansion O
did O
not O
lead O
to O
faster O
film O
erosion O
or O
dose O
dumping O
of O
DNA O
in O
areas O
near O
stent O
joints O
when O
stents O
were O
incubated O
in O
physiologically O
relevant O
media O
. O

The O
ability O
of O
film O
- O
coated O
stents O
to O
transfer O
DNA O
and O
transfect O
arterial O
tissue O
in O
vivo O
was O
then O
investigated O
in O
pigs O
and O
rabbits O
. O

Stents O
coated O
with O
films O
fabricated O
using O
fluorescently O
labeled O
DNA O
resulted O
in O
uniform O
transfer O
of O
DNA O
to O
sub O
- O
endothelial O
tissue O
in O
the O
arteries O
of O
pigs O
in O
patterns O
corresponding O
to O
the O
locations O
and O
geometries O
of O
stent O
struts O
. O

Stents O
coated O
with O
films O
fabricated O
using O
polymer O
1 O
and O
plasmid O
DNA O
encoding O
EGFP O
resulted O
in O
expression O
of O
EGFP O
in O
the O
medial O
layers O
of O
stented O
tissue O
in O
both O
pigs O
and O
rabbits O
two O
days O
after O
implantation O
. O

The O
results O
of O
this O
study O
, O
combined O
with O
the O
modular O
and O
versatile O
nature O
of O
layer O
- O
by O
- O
layer O
assembly O
, O
provide O
a O
polymer O
- O
based O
platform O
that O
is O
well O
suited O
for O
fundamental O
studies O
of O
stent O
- O
mediated O
gene O
transfer O
. O

With O
further O
development O
, O
this O
approach O
could O
also O
prove O
useful O
for O
the O
design O
of O
nonviral O
, O
gene O
- O
based O
approaches O
for O
prevention O
of O
complications O
that O
arise O
from O
the O
implantation O
of O
stents O
and O
other O
implantable O
interventional O
devices O
. O

Kinase O
Scaffold O
Repurposing O
for O
Neglected O
Disease O
Drug O
Discovery O
: O
Discovery O
of O
an O
Efficacious O
, O
Lapatanib B
- O
Derived O
Lead O
Compound O
for O
Trypanosomiasis O
. O

Human O
African O
trypanosomiasis O
( O
HAT O
) O
is O
a O
neglected O
tropical O
disease O
caused O
by O
the O
protozoan O
parasite O
Trypanosoma O
brucei O
. O

Because O
drugs O
in O
use O
against O
HAT O
are O
toxic O
and O
require O
intravenous O
dosing O
, O
new O
drugs O
are O
needed O
. O

Initiating O
lead O
discovery O
campaigns O
by O
using O
chemical O
scaffolds O
from O
drugs O
approved O
for O
other O
indications O
can O
speed O
up O
drug O
discovery O
for O
neglected O
diseases O
. O

We O
demonstrated O
recently O
that O
the O
4 B
- I
anilinoquinazolines I
lapatinib B
( O
GW572016 B
, O
1 O
) O
and O
canertinib B
( O
CI B
- I
1033 I
) O
kill O
T O
. O
brucei O
with O
low O
micromolar O
EC50 O
values O
. O

We O
now O
report O
promising O
activity O
of O
analogues O
of O
1 O
, O
which O
provided O
an O
excellent O
starting O
point O
for O
optimization O
of O
the O
chemotype O
. O

Our O
compound O
optimization O
that O
has O
led O
to O
synthesis O
of O
several O
potent O
4 B
- I
anilinoquinazolines I
, O
including O
NEU617 B
, O
23a O
, O
a O
highly O
potent O
, O
orally O
bioavailable O
inhibitor O
of O
trypanosome O
replication O
. O

At O
the O
cellular O
level O
, O
23a O
blocks O
duplication O
of O
the O
kinetoplast O
and O
arrests O
cytokinesis O
, O
making O
it O
a O
new O
chemical O
tool O
for O
studying O
regulation O
of O
the O
trypanosome O
cell O
cycle O
. O

Molecular O
Mechanisms O
in O
the O
Pyrolysis O
of O
Unsaturated B
Chlorinated I
Hydrocarbons I
: O
Formation O
of O
Benzene B
Rings O
Part O
II O
- O
Experimental O
and O
Kinetic O
Modeling O
Studies O
. O

The O
mechanism O
of O
formation O
of O
benzene B
rings O
during O
the O
pyrolysis O
of O
dichloro B
- I
and I
trichloroethylene I
has O
been O
investigated O
by O
the O
method O
of O
Laser O
Powered O
Homogeneous O
Pyrolysis O
coupled O
with O
product O
analysis O
by O
gas O
chromatography O
. O

Additionally O
, O
selected O
( O
co O
) O
- O
pyrolyses O
between O
the O
chlorinated B
ethylenes I
, O
CH2Cl2 B
, O
C4Cl4 B
, O
C4Cl6 B
, O
and O
C2H2 B
have O
been O
performed O
to O
explicitly O
probe O
the O
roles O
of O
2C3 B
and O
C4 B
/ O
C2 B
reaction O
pairs O
in O
aromatic O
growth O
. O

The O
presence O
of O
odd O
- O
carbon B
products O
in O
neat O
C4Cl6 B
pyrolyses O
indicates O
2C3 O
processes O
are O
operative O
in O
these O
systems O
; O
however O
, O
comparison O
with O
product O
yields O
from O
C2HCl3 B
suggests O
C4 O
/ O
C2 O
processes O
dominate O
most O
other O
systems O
. O

This O
is O
further O
evidenced O
by O
an O
absence O
of O
C3 O
and O
other O
odd O
- O
carbon B
species O
in O
( O
co O
) O
- O
pyrolyses O
with O
dichloromethane B
which O
should O
seed O
C3 O
- O
based O
growth O
. O

The O
reactions O
of O
perchlorinated O
C4 B
species O
C4Cl5 B
, O
C4Cl3 B
, O
and O
C4Cl4 B
with O
C2Cl2 B
were O
subsequently O
explored O
through O
extensive O
kinetic O
simulations O
of O
the O
possible O
reaction O
pathways O
based O
on O
previous O
kinetic O
models O
and O
the O
exhaustive O
quantum O
chemical O
investigations O
of O
our O
preceding O
work O
. O

The O
experimental O
and O
theoretical O
results O
strongly O
suggest O
that O
, O
at O
moderate O
temperatures O
, O
aromatic O
ring O
formation O
from O
chlorinated B
ethylenes I
normally O
follows O
a O
Diels O
- O
Alder O
coupling O
of O
C4 B
and O
C2 B
molecular O
units O
followed O
by O
internal O
shifts O
; O
the O
one O
exception O
is O
the O
C4Cl4 B
+ O
C2Cl2 B
system O
, O
where O
steric O
factors O
lead O
to O
the O
formation O
of O
non O
- O
aromatic O
products O
. O

There O
is O
little O
evidence O
for O
radical O
- O
based O
routes O
in O
these O
systems O
. O

CH O
- O
01 O
is O
a O
hypoxia O
- O
activated O
prodrug O
that O
sensitizes O
cells O
to O
hypoxia O
/ O
reoxygenation O
through O
inhibition O
of O
Chk1 O
and O
Aurora O
A O
. O

The O
increased O
resistance O
of O
hypoxic O
cells O
to O
all O
forms O
of O
cancer O
therapy O
presents O
a O
major O
barrier O
to O
the O
successful O
treatment O
of O
most O
solid O
tumors O
. O

Inhibition O
of O
the O
essential O
kinase O
, O
Checkpoint O
kinase O
1 O
( O
Chk1 O
) O
has O
been O
described O
as O
a O
promising O
cancer O
therapy O
for O
tumors O
with O
high O
levels O
of O
hypoxia O
- O
induced O
replication O
stress O
. O

However O
, O
as O
inhibition O
of O
Chk1 O
affects O
normal O
replication O
and O
induces O
DNA O
damage O
, O
these O
agents O
also O
have O
the O
potential O
to O
induce O
genomic O
instability O
and O
contribute O
to O
tumorigenesis O
. O

To O
overcome O
this O
problem O
, O
we O
have O
developed O
a O
bioreductive O
prodrug O
, O
which O
functions O
as O
a O
Chk1 O
/ O
Aurora O
A O
inhibitor O
specifically O
in O
hypoxic O
conditions O
. O

To O
achieve O
this O
activity O
, O
a O
key O
functionality O
on O
the O
Chk1 O
inhibitor O
( O
CH O
- O
01 O
) O
is O
masked O
by O
a O
bioreductive O
group O
, O
rendering O
the O
compound O
inactive O
as O
a O
Chk1 O
/ O
Aurora O
A O
inhibitor O
. O

Reduction O
of O
the O
bioreductive O
group O
nitro B
moiety O
, O
under O
hypoxic O
conditions O
, O
reveals O
an O
electron O
- O
donating O
substituent O
that O
leads O
to O
fragmentation O
of O
the O
molecule O
, O
affording O
the O
active O
inhibitor O
. O

Most O
importantly O
, O
we O
show O
a O
significant O
loss O
of O
viability O
in O
cancer O
cell O
lines O
exposed O
to O
hypoxia O
in O
the O
presence O
of O
CH O
- O
01 O
. O

This O
novel O
approach O
targets O
the O
most O
aggressive O
and O
therapy O
- O
resistant O
tumor O
fraction O
while O
protecting O
normal O
tissue O
from O
therapy O
- O
induced O
genomic O
instability O
. O

Toxicity O
study O
of O
isolated O
polypeptide O
from O
wool O
hydrolysate O
. O

The O
cytotoxicity O
of O
wool O
polypeptide O
has O
been O
evaluated O
by O
both O
cell O
and O
animal O
models O
. O

Wool O
was O
dissolved O
in O
sodium B
hydroxide I
solution O
, O
the O
pH O
value O
of O
the O
solution O
was O
adjusted O
to O
5 O
. O
55 O
and O
the O
precipitate O
was O
harvested O
as O
wool O
polypeptide O
. O

The O
spray O
- O
dried O
polypeptide O
was O
collected O
as O
powders O
and O
characterized O
by O
SEM O
, O
FTIR O
and O
TG O
- O
DSC O
. O

The O
cell O
culturing O
results O
showed O
that O
wool O
polypeptide O
had O
no O
obvious O
negative O
effect O
on O
cell O
viability O
in O
vitro O
. O

Both O
acute O
oral O
toxicity O
and O
subacute O
30 O
- O
day O
oral O
toxicology O
studies O
showed O
that O
wool O
polypeptide O
had O
no O
influence O
on O
body O
weight O
, O
feed O
consumption O
, O
blood O
chemistry O
, O
and O
hematology O
at O
any O
dose O
levels O
. O

There O
were O
no O
treatment O
related O
findings O
on O
gross O
or O
detailed O
necroscopy O
, O
organ O
weights O
, O
organ O
/ O
body O
weight O
ratios O
and O
histology O
. O

Our O
study O
indicated O
the O
absence O
of O
toxicity O
in O
wool O
polypeptide O
and O
supported O
its O
safe O
use O
as O
a O
food O
ingredient O
or O
drug O
carrier O
. O

A O
c O
ai O
( O
Euterpe O
oleracea O
Mart O
. O
) O
feeding O
attenuates O
dimethylhydrazine B
- O
induced O
rat O
colon O
carcinogenesis O
. O

This O
study O
investigated O
the O
protective O
effect O
of O
spray O
- O
dried O
a O
c O
a O
i O
powder O
( O
AP O
) O
intake O
on O
colon O
carcinogenesis O
induced O
by O
1 B
, I
2 I
- I
dimethylhydrazine I
( O
DMH B
) O
in O
male O
Wistar O
rats O
. O

After O
4weeks O
of O
DMH B
administrations O
, O
the O
groups O
were O
fed O
with O
standard O
diet O
, O
a O
diet O
containing O
2 O
. O
5 O
% O
or O
5 O
. O
0 O
% O
AP O
or O
a O
diet O
containing O
0 O
. O
2 O
% O
N B
- I
acetylcysteine I
( O
NAC B
) O
for O
10weeks O
, O
using O
aberrant O
crypt O
foci O
( O
ACF O
) O
as O
the O
endpoint O
. O

Additionally O
, O
two O
groups O
were O
fed O
with O
standard O
diet O
or O
a O
diet O
containing O
5 O
. O
0 O
% O
AP O
for O
20weeks O
, O
using O
colon O
tumors O
as O
the O
endpoint O
. O

In O
ACF O
assay O
, O
a O
reduction O
in O
the O
number O
of O
aberrant O
crypts O
( O
ACs O
) O
and O
ACF O
( O
1 O
- O
3 O
AC O
) O
were O
observed O
in O
the O
groups O
fed O
with O
5 O
. O
0 O
% O
AP O
( O
37 O
% O
AC O
and O
47 O
% O
ACF O
inhibition O
, O
p O
= O
0 O
. O
036 O
) O
and O
0 O
. O
2 O
% O
NAC B
( O
39 O
% O
AC O
and O
41 O
% O
ACF O
inhibition O
, O
p O
= O
0 O
. O
042 O
) O
. O

In O
tumor O
assay O
, O
a O
reduction O
in O
the O
number O
of O
invasive O
tumors O
( O
p O
< O
0 O
. O
005 O
) O
and O
tumor O
multiplicity O
( O
p O
= O
0 O
. O
001 O
) O
was O
observed O
in O
the O
group O
fed O
with O
5 O
. O
0 O
% O
AP O
. O

Also O
, O
a O
reduction O
in O
tumor O
Ki O
- O
67 O
cell O
proliferation O
( O
p O
= O
0 O
. O
003 O
) O
and O
net O
growth O
index O
( O
p O
= O
0 O
. O
001 O
) O
was O
observed O
in O
the O
group O
fed O
with O
5 O
. O
0 O
% O
AP O
. O

Therefore O
the O
findings O
of O
this O
study O
indicate O
that O
AP O
feeding O
may O
reduce O
the O
development O
of O
chemically O
- O
induced O
rat O
colon O
carcinogenesis O
. O

Connexin O
channel O
modulators O
and O
their O
mechanisms O
of O
action O
. O

Gap O
junction O
channels O
and O
hemichannels O
formed O
by O
the O
connexin O
family O
of O
proteins O
play O
important O
roles O
in O
many O
aspects O
of O
tissue O
homeostasis O
in O
the O
brain O
and O
in O
other O
organs O
. O

In O
addition O
, O
connexin O
channels O
have O
been O
proposed O
as O
pharmacological O
targets O
in O
the O
treatment O
of O
a O
number O
of O
human O
disorders O
. O

In O
this O
review O
, O
we O
describe O
the O
connexin O
- O
subtype O
selectivity O
and O
specificity O
of O
pharmacological O
agents O
that O
are O
commonly O
used O
to O
modulate O
connexin O
channels O
. O

We O
also O
highlight O
recent O
progress O
made O
towardtoward O
identifying O
new O
agents O
for O
connexin O
channels O
that O
act O
in O
a O
selective O
and O
specific O
manner O
. O

Finally O
, O
we O
discuss O
developing O
insights O
into O
possible O
mechanisms O
by O
which O
these O
agents O
modulate O
connexin O
channel O
function O
. O

This O
article O
is O
part O
of O
a O
Special O
Issue O
entitled O
' O
Connexin O
based O
channels O
' O
. O

1 B
, I
1 I
- I
Difluoroethyl I
- I
substituted I
triazolothienopyrimi I
as O
inhibitors O
of O
a O
human O
urea B
transport O
protein O
( O
UT O
- O
B O
) O
: O
New O
analogs O
and O
binding O
model O
. O

The O
kidney O
urea B
transport O
protein O
UT O
- O
B O
is O
an O
attractive O
target O
for O
the O
development O
of O
small O
- O
molecule O
inhibitors O
with O
a O
novel O
diuretic O
( O
' O
urearetic O
' O
) O
action O
. O

Previously O
, O
two O
compounds O
in O
the O
triazolothienopyrimi B
scaffold O
( O
1a O
and O
1c O
) O
were O
reported O
as O
UT O
- O
B O
inhibitors O
. O

Compound O
1c O
incorporates O
a O
1 B
, I
1 I
- I
difluoroethyl I
group O
, O
which O
affords O
improved O
microsomal O
stability O
when O
compared O
to O
the O
corresponding O
ethyl B
- O
substituted O
compound O
1a O
. O

Here O
, O
a O
small O
focused O
library O
( O
4a O
- O
4f O
) O
was O
developed O
around O
lead O
inhibitor O
1c O
to O
investigate O
the O
requirement O
of O
an O
amidine B
- O
linked O
thiophene B
in O
the O
inhibitor O
scaffold O
. O

Two O
compounds O
( O
4a O
and O
4b O
) O
with O
nanomolar O
inhibitory O
potency O
( O
IC50 O
= O
~ O
40nM O
) O
were O
synthesized O
. O

Computational O
docking O
of O
lead O
structure O
1c O
and O
4a O
- O
4f O
into O
a O
homology O
model O
of O
the O
UT O
- O
B O
cytoplasmic O
surface O
suggested O
binding O
with O
the O
core O
heterocycle O
buried O
deep O
into O
the O
hydrophobic O
pore O
region O
of O
the O
protein O
. O

Greater O
impairment O
of O
postprandial O
triacylglycerol B
than O
glucose B
response O
in O
metabolic O
syndrome O
subjects O
with O
fasting O
hyperglycaemia O
. O

OBJECTIVE O
: O
Studies O
have O
started O
to O
question O
whether O
a O
specific O
component O
or O
combinations O
of O
metabolic O
syndrome O
( O
MetS O
) O
components O
may O
be O
more O
important O
in O
relation O
to O
cardiovascular O
disease O
risk O
. O

Our O
aim O
was O
to O
examine O
the O
impact O
of O
the O
presence O
of O
raised O
fasting O
glucose B
as O
a O
MetS O
component O
on O
postprandial O
lipaemia O
. O

METHODS O
: O
Men O
classified O
with O
the O
MetS O
underwent O
a O
sequential O
test O
meal O
investigation O
, O
in O
which O
blood O
samples O
were O
taken O
at O
regular O
intervals O
after O
a O
test O
breakfast O
( O
t O
= O
0 O
min O
) O
and O
lunch O
( O
t O
= O
330 O
min O
) O
. O

Lipids O
, O
glucose B
and O
insulin O
were O
measured O
in O
the O
fasting O
and O
postprandial O
samples O
. O

RESULTS O
: O
MetS O
subjects O
with O
3 O
or O
4 O
components O
were O
subdivided O
into O
those O
without O
( O
n O
= O
34 O
) O
and O
with O
( O
n O
= O
23 O
) O
fasting O
hyperglycaemia O
( O
> O
= O
5 O
. O
6mmol O
/ O
l O
) O
, O
irrespective O
of O
the O
combination O
of O
components O
. O

Fasting O
lipids O
and O
insulin O
were O
similar O
in O
the O
two O
groups O
, O
with O
glucose B
significantly O
higher O
in O
the O
men O
with O
glucose B
as O
a O
MetS O
component O
( O
P O
< O
0 O
. O
001 O
) O
. O

Following O
the O
test O
meals O
, O
there O
were O
higher O
maximum O
concentration O
( O
maxC O
) O
, O
area O
under O
the O
curve O
( O
AUC O
) O
and O
incremental O
AUC O
( O
P O
< O
= O
0 O
. O
016 O
) O
for O
the O
postprandial O
triacylglycerol B
( O
TAG B
) O
response O
in O
men O
with O
fasting O
hyperglycaemia O
. O

Greater O
glucose B
AUC O
( O
P O
< O
0 O
. O
001 O
) O
and O
insulin O
maxC O
( O
P O
= O
0 O
. O
010 O
) O
were O
also O
observed O
in O
these O
individuals O
after O
the O
test O
meals O
. O

Multiple O
regression O
analysis O
revealed O
fasting O
glucose B
to O
be O
an O
important O
predictor O
of O
the O
postprandial O
TAG B
and O
glucose B
response O
. O

CONCLUSION O
: O
Our O
data O
analysis O
has O
revealed O
a O
greater O
impairment O
of O
postprandial O
TAG B
than O
glucose B
response O
in O
MetS O
subjects O
with O
raised O
fasting O
glucose B
. O

The O
worsening O
of O
postprandial O
lipaemic O
control O
may O
contribute O
to O
the O
greater O
CVD O
risk O
reported O
in O
individuals O
with O
MetS O
component O
combinations O
which O
include O
hyperglycaemia O
. O

HIV O
Cure O
: O
Knocking O
on O
the O
Door O
. O

Although O
major O
advances O
in O
drug O
development O
and O
public O
health O
are O
helping O
to O
control O
the O
HIV O
/ O
AIDS O
epidemic O
, O
there O
is O
a O
strong O
rationale O
for O
pursuing O
a O
more O
definitive O
cure O
. O

Several O
bold O
but O
unproven O
strategies O
for O
HIV O
eradication O
are O
reviewed O
in O
this O
issue O
of O
CPT O
, O
including O
novel O
drugs O
, O
gene O
therapy O
, O
and O
bone O
marrow O
transplantation O
( O
BMT O
) O
. O

Early O
results O
, O
including O
one O
probable O
case O
of O
HIV O
eradication O
in O
a O
leukemia O
patient O
, O
are O
intriguing O
but O
raise O
many O
questions O
. O

New O
Diterpenes B
from O
a O
Godavari O
Mangrove O
, O
Ceriops O
decandra O
. O

Eleven O
new O
diterpenes B
, O
named O
decandrins B
A I
- I
K I
( O
1 O
- O
11 O
) O
, O
including O
nine O
abietanes B
( O
1 O
- O
9 O
) O
and O
two O
podocarpanes B
( O
10 O
- O
11 O
) O
, O
were O
isolated O
from O
the O
barks O
of O
an O
Indian O
mangrove O
, O
Ceriops O
decandra O
, O
collected O
in O
the O
mangrove O
swamp O
of O
Godavari O
estuary O
, O
Andhra O
Pradesh O
, O
together O
with O
four O
known O
abietanes B
. O

The O
structures O
of O
these O
compounds O
were O
established O
on O
the O
basis O
of O
spectroscopic O
data O
( O
new O
compounds O
) O
or O
comparison O
with O
data O
in O
the O
literature O
( O
known O
compounds O
) O
. O

This O
is O
the O
first O
report O
of O
abietane B
and O
podocarpane B
diterpenoids B
from O
C O
. O
decandra O
. O

Spin O
- O
polarized O
transport O
through O
single O
- O
molecule O
magnet O
Mn6 B
complexes O
. O

The O
coherent O
transport O
properties O
of O
a O
device O
, O
constructed O
by O
sandwiching O
a O
Mn6 B
single O
- O
molecule O
magnet O
between O
two O
gold O
surfaces O
, O
are O
studied O
theoretically O
by O
using O
the O
non O
- O
equilibrium O
Green O
' O
s O
function O
approach O
combined O
with O
density O
functional O
theory O
. O

Two O
spin O
states O
of O
such O
Mn6 B
complexes O
are O
explored O
, O
namely O
the O
ferromagnetically O
coupled O
configuration O
of O
the O
six O
Mn B
( I
III I
) I
cations O
, O
leading O
to O
the O
S O
= O
12 O
ground O
state O
, O
and O
the O
low O
S O
= O
4 O
spin O
state O
. O

For O
voltages O
up O
to O
1 O
volt O
the O
S O
= O
12 O
ground O
state O
shows O
a O
current O
one O
order O
of O
magnitude O
larger O
than O
that O
of O
the O
S O
= O
4 O
state O
. O

Furthermore O
this O
is O
almost O
completely O
spin O
- O
polarized O
, O
since O
the O
Mn6 B
frontier O
molecular O
orbitals O
for O
S O
= O
12 O
belong O
to O
the O
same O
spin O
manifold O
. O

As O
such O
the O
high O
- O
anisotropy O
Mn6 B
molecule O
appears O
as O
a O
promising O
candidate O
for O
implementing O
, O
at O
the O
single O
molecular O
level O
, O
both O
spin O
- O
switches O
and O
low O
- O
temperature O
spin O
- O
valves O
. O

Concentration O
and O
Strain O
Fields O
inside O
a O
Ag B
/ O
Au B
Core O
- O
Shell O
Nanowire O
Studied O
by O
Coherent O
X O
- O
ray O
Diffraction O
. O

Three O
- O
dimensional O
coherent O
diffraction O
patterns O
of O
an O
isolated O
, O
single O
- O
crystalline O
Ag B
/ O
Au B
core O
- O
shell O
nanowire O
were O
recorded O
at O
different O
X O
- O
ray O
beam O
energies O
close O
to O
the O
Au B
LIII O
absorption O
edge O
. O

Two O
- O
dimensional O
slices O
of O
the O
three O
- O
dimensional O
diffraction O
pattern O
, O
with O
the O
diffraction O
vector O
oriented O
perpendicular O
to O
the O
wire O
axis O
, O
were O
investigated O
in O
detail O
. O

In O
reciprocal O
space O
, O
facet O
streaks O
with O
thickness O
fringes O
were O
clearly O
observed O
in O
the O
two O
- O
dimensional O
diffraction O
patterns O
, O
from O
which O
the O
shape O
and O
size O
of O
the O
corresponding O
cross O
sections O
of O
the O
nanowire O
could O
be O
revealed O
. O

Comparison O
with O
simulated O
diffraction O
patterns O
exhibited O
the O
coherency O
strain O
field O
in O
the O
nanowire O
. O

During O
in O
situ O
annealing O
at O
temperatures O
which O
would O
lead O
to O
significant O
intermixing O
by O
volume O
diffusion O
in O
bulk O
material O
, O
according O
to O
literature O
data O
, O
a O
core O
- O
shell O
morphology O
was O
preserved O
; O
that O
is O
, O
intermixing O
in O
the O
nanowire O
was O
pronouncedly O
decelerated O
compared O
to O
bulk O
diffusion O
. O

Assessing O
the O
Accuracy O
and O
Performance O
of O
Implicit O
Solvent O
Models O
for O
Drug O
Molecules O
: O
Conformational O
Ensemble O
Approaches O
. O

The O
accuracy O
and O
performance O
of O
implicit O
solvent O
methods O
for O
solvation O
free O
energy O
calculations O
were O
assessed O
on O
a O
set O
of O
20 O
neutral O
drug O
molecules O
. O

Molecular O
dynamics O
( O
MD O
) O
provided O
ensembles O
of O
conformations O
in O
water O
and O
water O
- O
saturated B
octanol I
. O

The O
solvation O
free O
energies O
were O
calculated O
by O
popular O
implicit O
solvent O
models O
based O
on O
quantum O
mechanical O
( O
QM O
) O
electronic O
densities O
( O
COSMO O
- O
RS O
, O
MST O
, O
SMD O
) O
as O
well O
as O
on O
molecular O
mechanical O
( O
MM O
) O
point O
- O
charge O
models O
( O
GB O
, O
PB O
) O
. O

The O
performance O
of O
the O
implicit O
models O
was O
tested O
by O
a O
comparison O
with O
experimental O
water O
- O
octanol B
transfer O
free O
energies O
( O
Delta O
Gow O
) O
by O
using O
single O
- O
and O
multiconformation O
approaches O
. O

MD O
simulations O
revealed O
difficulties O
in O
a O
priori O
estimation O
of O
the O
flexibility O
features O
of O
the O
solutes O
from O
simple O
structural O
descriptors O
, O
such O
as O
the O
number O
of O
rotatable O
bonds O
. O

An O
increasing O
accuracy O
of O
the O
calculated O
Delta O
Gow O
was O
observed O
in O
the O
following O
order O
: O
GB1 O
~ O
PB O
< O
GB7 O
< O
< O
MST O
< O
SMD O
~ O
COSMO O
- O
RS O
with O
a O
clear O
distinction O
identified O
between O
MM O
- O
and O
QM O
- O
based O
models O
, O
although O
for O
the O
set O
excluding O
three O
largest O
molecules O
, O
the O
differences O
among O
COSMO O
- O
RS O
, O
MST O
, O
and O
SMD O
were O
negligible O
. O

It O
was O
shown O
that O
the O
single O
- O
conformation O
approach O
applied O
to O
crystal O
geometries O
provides O
a O
rather O
accurate O
estimate O
of O
Delta O
Gow O
for O
rigid O
molecules O
yet O
fails O
completely O
for O
the O
flexible O
ones O
. O

The O
multiconformation O
approaches O
improved O
the O
performance O
, O
but O
only O
when O
the O
deformation O
contribution O
was O
ignored O
. O

It O
was O
revealed O
that O
for O
large O
- O
scale O
calculations O
on O
small O
molecules O
a O
recent O
GB O
model O
, O
GB7 O
, O
provided O
a O
reasonable O
accuracy O
/ O
speed O
ratio O
. O

In O
conclusion O
, O
the O
study O
contributes O
to O
the O
understanding O
of O
solvation O
free O
energy O
calculations O
for O
physical O
and O
medicinal O
chemistry O
applications O
. O

Three O
- O
dimensional O
plasmonic O
chiral O
tetramers O
assembled O
by O
DNA O
origami O
. O

Molecular O
chemistry O
offers O
a O
unique O
toolkit O
to O
draw O
inspiration O
for O
the O
design O
of O
artificial O
metamolecules O
. O

For O
a O
long O
time O
, O
optical O
circular O
dichroism O
has O
been O
exclusively O
the O
terrain O
of O
natural O
chiral O
molecules O
, O
which O
exhibit O
optical O
activity O
mainly O
in O
the O
UV O
spectral O
range O
, O
thus O
greatly O
hindering O
their O
significance O
for O
a O
broad O
range O
of O
applications O
. O

Here O
we O
demonstrate O
that O
circular O
dichroism O
can O
be O
generated O
with O
artificial O
plasmonic O
chiral O
nanostructures O
composed O
of O
the O
minimum O
number O
of O
spherical O
gold O
nanoparticles O
required O
for O
three O
- O
dimensional O
( O
3D O
) O
chirality O
. O

We O
utilize O
a O
rigid O
addressable O
DNA O
origami O
template O
to O
precisely O
organize O
four O
nominally O
identical O
gold O
nanoparticles O
into O
a O
three O
- O
dimensional O
asymmetric O
tetramer O
. O

Because O
of O
the O
chiral O
structural O
symmetry O
and O
the O
strong O
plasmonic O
resonant O
coupling O
between O
the O
gold O
nanoparticles O
, O
the O
3D O
plasmonic O
assemblies O
undergo O
different O
interactions O
with O
left O
and O
right O
circularly O
polarized O
light O
, O
leading O
to O
pronounced O
circular O
dichroism O
. O

Our O
experimental O
results O
agree O
well O
with O
theoretical O
predictions O
. O

The O
simplicity O
of O
our O
structure O
geometry O
and O
, O
most O
importantly O
, O
the O
concept O
of O
resorting O
on O
biology O
to O
produce O
artificial O
photonic O
functionalities O
open O
a O
new O
pathway O
to O
designing O
smart O
artificial O
plasmonic O
nanostructures O
for O
large O
- O
scale O
production O
of O
optically O
active O
metamaterials O
. O

Demonstration O
of O
Efficient O
On O
- O
Chip O
Photon O
Transfer O
in O
Self O
- O
Assembled O
Optoplasmonic O
Networks O
. O

Plasmonic O
nanoantennas O
facilitate O
the O
manipulation O
of O
light O
fields O
on O
deeply O
sub O
- O
diffraction O
- O
limited O
length O
scales O
, O
but O
high O
dissipative O
losses O
in O
metals O
make O
new O
approaches O
for O
an O
efficient O
energy O
transfer O
in O
extended O
on O
- O
chip O
integrated O
plasmonic O
circuits O
mandatory O
. O

We O
demonstrate O
in O
this O
article O
efficient O
photon O
transfer O
in O
discrete O
optoplasmonic O
molecules O
comprising O
gold O
nanoparticle O
( O
NP O
) O
dimer O
antennas O
located O
in O
the O
evanescent O
field O
of O
a O
2 O
mu O
m O
diameter O
polystyrene B
bead O
, O
which O
served O
as O
an O
optical O
microcavity O
( O
OM O
) O
. O

The O
optoplasmonic O
molecules O
were O
generated O
through O
a O
guided O
self O
- O
assembly O
strategy O
in O
which O
the O
OMs O
were O
immobilized O
in O
binding O
sites O
generated O
by O
quartz B
( O
SiO2 B
) O
or O
silicon B
posts O
that O
contained O
plasmonic O
nanoantennas O
on O
their O
tips O
. O

Control O
of O
the O
post O
height O
facilitated O
an O
accurate O
positioning O
of O
the O
plasmonic O
antennas O
into O
the O
evanescent O
field O
of O
the O
whispering O
gallery O
modes O
located O
in O
the O
equatorial O
plane O
of O
the O
OM O
. O

Cy3 O
and O
Cy5 O
. O
5 O
dyes O
were O
tethered O
to O
the O
plasmonic O
antennas O
through O
oligonucleotide O
spacers O
to O
act O
as O
on O
- O
chip O
light O
sources O
. O

The O
intensity O
of O
Cy3 O
was O
found O
to O
be O
increased O
relative O
to O
that O
of O
Cy5 O
. O
5 O
in O
the O
vicinity O
of O
the O
plasmonic O
antennas O
where O
strongly O
enhanced O
electric O
field O
intensity O
and O
optical O
density O
of O
states O
selectively O
increase O
the O
excitation O
and O
emission O
rates O
of O
Cy3 O
due O
to O
spectral O
overlap O
with O
the O
plasmon O
. O

The O
fluorescent O
dyes O
preferentially O
emitted O
into O
the O
OM O
, O
which O
efficiently O
trapped O
and O
recirculated O
the O
photons O
. O

We O
experimentally O
determined O
a O
relative O
photon O
transfer O
efficiency O
of O
44 O
% O
in O
non O
- O
optimized O
self O
- O
assembled O
optoplasmonic O
molecules O
in O
this O
proof O
- O
of O
- O
principle O
study O
. O

The O
effect O
of O
inorganic O
salt O
type O
and O
concentration O
on O
hydrophilic O
drug O
loading O
into O
microspheres O
using O
the O
emulsion O
/ O
solvent O
diffusion O
method O
. O

Abstract O
Aim O
: O
In O
order O
to O
avoid O
gastric O
irritation O
caused O
by O
tolmetin B
sodium I
( O
TS O
) O
, O
gastro O
resistant O
Eudragit B
( O
R O
) O
S O
100 O
microsphere O
formulations O
were O
prepared O
with O
the O
emulsion O
/ O
solvent O
diffusion O
method O
. O

Materials O
: O
Considering O
the O
high O
water O
solubility O
of O
the O
TS O
molecule O
, O
the O
effects O
of O
the O
presence O
of O
inorganic O
salt O
( O
NaCl B
, O
NaBr B
and O
KH2PO4 B
; O
0 O
. O
1 O
M O
and O
1 O
. O
0 O
M O
) O
in O
external O
phase O
and O
external O
phase O
pH O
on O
the O
encapsulation O
efficiency O
were O
evaluated O
. O

Results O
: O
Percentage O
yield O
value O
was O
found O
to O
vary O
between O
55 O
. O
8 O
% O
and O
72 O
. O
1 O
% O
. O

Improvement O
in O
encapsulation O
efficiency O
was O
determined O
by O
increasing O
concentrations O
of O
NaCl B
, O
NaBr B
and O
KH2PO4 B
. O

The O
microspheres O
were O
observed O
to O
have O
a O
spherical O
shape O
and O
the O
measured O
particle O
size O
values O
varied O
between O
52 O
. O
1 O
and O
81 O
. O
5 O
micro O
m O
. O

The O
released O
amounts O
of O
the O
drug O
were O
found O
to O
be O
low O
as O
the O
inorganic O
salt O
concentrations O
increased O
. O

Conclusion O
: O
Conclusively O
, O
drug O
release O
in O
stomach O
pH O
was O
significantly O
prevented O
by O
the O
microspheres O
prepared O
using O
Eudragit B
( O
R O
) O
S O
100 O
polymer O
, O
and O
these O
formulations O
are O
considered O
to O
be O
a O
model O
for O
other O
orally O
administered O
drugs O
with O
similar O
problems O
. O

Development O
and O
in O
vitro O
evaluation O
of O
a O
nanoemulsion O
for O
transcutaneous O
delivery O
. O

Abstract O
Objective O
: O
The O
purpose O
of O
this O
study O
is O
to O
develop O
a O
nanoemulsion O
formulation O
for O
its O
use O
as O
a O
transcutaneous O
vaccine O
delivery O
system O
. O

Materials O
and O
methods O
: O
With O
bovine O
albumin O
- O
fluorescein B
isothiocyanate I
conjugate O
( O
FITC B
- O
BSA O
) O
as O
a O
vaccine O
model O
, O
formulations O
were O
selected O
with O
the O
construction O
of O
pseudo O
- O
ternary O
phase O
diagrams O
and O
a O
short O
- O
term O
stability O
study O
. O

The O
size O
of O
the O
emulsion O
droplets O
was O
furthered O
optimized O
with O
high O
- O
pressure O
homogenization O
. O

The O
optimized O
formulation O
was O
evaluated O
for O
its O
skin O
permeation O
efficiency O
. O

In O
vitro O
skin O
permeation O
studies O
were O
conducted O
with O
shaved O
BALB O
/ O
c O
mice O
skin O
samples O
with O
a O
Franz O
diffusion O
cell O
system O
. O

Different O
drug O
concentrations O
were O
compared O
, O
and O
the O
effect O
of O
the O
nanoemulsion O
excipients O
on O
the O
permeation O
of O
the O
FITC B
- O
BSA O
was O
also O
studied O
. O

Results O
: O
The O
optimum O
homogenization O
regime O
was O
determined O
to O
be O
five O
passes O
at O
20 O
000 O
psi O
, O
with O
no O
evidence O
of O
protein O
degradation O
during O
processing O
. O

With O
these O
conditions O
, O
the O
particle O
diameter O
was O
85 O
. O
2 O
nm O
+ O
/ O
- O
15 O
. O
5 O
nm O
with O
a O
polydispersity O
index O
of O
0 O
. O
186 O
+ O
/ O
- O
0 O
. O
026 O
and O
viscosity O
of O
14 O
. O
6 O
cP O
+ O
/ O
- O
1 O
. O
2 O
cP O
. O

The O
optimized O
formulation O
proved O
stable O
for O
1 O
year O
at O
4 O
degrees O
C O
. O

In O
vitro O
skin O
diffusion O
studies O
show O
that O
the O
optimized O
formulation O
improves O
the O
permeation O
of O
FITC B
- O
BSA O
through O
skin O
with O
an O
enhancement O
ratio O
of O
4 O
. O
2 O
compared O
to O
a O
neat O
control O
solution O
. O

Finally O
, O
a O
comparison O
of O
the O
skin O
permeation O
of O
the O
nanoemulsion O
versus O
only O
the O
surfactant O
excipients O
resulted O
in O
a O
steady O
state O
flux O
of O
23 O
. O
44 O
mu O
g O
/ O
cm O
( O
2 O
) O
/ O
h O
for O
the O
nanoemulsion O
as O
opposed O
to O
6 O
. O
10 O
mu O
g O
/ O
cm O
( O
2 O
) O
/ O
h O
for O
the O
emulsifiers O
. O

Conclusion O
: O
A O
novel O
nanoemulsion O
with O
optimized O
physical O
characteristics O
and O
superior O
skin O
permeation O
compared O
to O
control O
solution O
was O
manufactured O
. O

The O
formulation O
proposed O
in O
this O
study O
has O
the O
flexibility O
for O
the O
incorporation O
of O
a O
variety O
of O
active O
ingredients O
and O
warrants O
further O
development O
as O
a O
transcutaneous O
vaccine O
delivery O
vehicle O
. O

Polymer O
- O
based O
protein O
engineering O
can O
rationally O
tune O
enzyme O
activity O
, O
pH O
- O
dependence O
, O
and O
stability O
. O

The O
attachment O
of O
inert O
polymers O
, O
such O
as O
polyethyleneglycol B
, O
to O
proteins O
has O
driven O
the O
emergence O
of O
a O
multibillion O
dollar O
biotechnology O
industry O
. O

In O
all O
cases O
, O
proteins O
have O
been O
stabilized O
or O
altered O
by O
covalently O
coupling O
the O
pre O
- O
existing O
polymer O
to O
the O
surface O
of O
the O
protein O
. O

This O
approach O
is O
inherently O
limited O
by O
a O
lack O
of O
exquisite O
control O
of O
polymer O
architecture O
, O
chain O
length O
, O
site O
and O
density O
of O
attachment O
. O

Using O
a O
novel O
water O
- O
soluble O
atom O
transfer O
radical O
polymerization O
initiator O
, O
we O
have O
grown O
temperature O
- O
and O
pH O
- O
responsive O
polymers O
from O
the O
surface O
of O
a O
model O
protein O
, O
the O
enzyme O
chymotrypsin O
. O

Poly B
( I
2 I
- I
( I
dimethylamino I
) I
ethyl I
methacrylate I
) I
changes O
in O
conformation O
with O
altered O
temperature O
and O
pH O
. O

Growing O
the O
polymer O
from O
the O
surface O
of O
chymotrypsin O
we O
were O
able O
to O
demonstrate O
that O
changes O
in O
temperature O
or O
pH O
can O
change O
predictably O
the O
conformation O
of O
the O
polymer O
surrounding O
the O
enzyme O
, O
which O
in O
turn O
enabled O
the O
rational O
tailoring O
of O
enzyme O
activity O
and O
stability O
. O

Using O
what O
we O
now O
term O
" O
Polymer O
- O
Based O
Protein O
Engineering O
" O
we O
have O
increased O
the O
activity O
and O
stability O
of O
chymotrypsin O
by O
an O
order O
of O
magnitude O
at O
pH O
' O
s O
where O
the O
enzyme O
is O
usually O
inactive O
or O
unstable O
. O

The O
Chemical O
constituents O
of O
the O
twigs O
of O
Ammopiptanthus O
nanus O
. O

Two O
new O
isoflavone B
glycosides I
, O
ammopiptanosides B
A I
and I
B I
, O
have O
been O
isolated O
from O
the O
95 O
% O
EtOH B
extract O
of O
the O
twigs O
of O
Ammopiptanthus O
nanus O
( O
M O
. O
Pop O
. O
) O
Cheng O
f O
. O
, O
together O
with O
six O
known O
compounds O
, O
and O
their O
structures O
were O
characterized O
by O
spectroscopic O
methods O
and O
compared O
with O
the O
data O
in O
the O
literature O
. O

Sulfonated B
Polyaniline I
- O
Based O
Organic O
Electrodes O
for O
Controlled O
Electrical O
Stimulation O
of O
Human O
Osteosarcoma O
Cells O
. O

Electrically O
conducting O
polymers O
( O
CPs O
) O
were O
found O
to O
stimulate O
various O
cell O
types O
such O
as O
neurons O
, O
osteoblasts O
, O
and O
fibroblasts O
in O
both O
in O
vitro O
and O
in O
vivo O
studies O
. O

However O
, O
to O
our O
knowledge O
, O
no O
studies O
have O
been O
reported O
on O
the O
utility O
of O
CPs O
in O
stimulation O
of O
cancer O
or O
tumor O
cells O
in O
the O
literature O
. O

Here O
we O
report O
a O
facile O
fabrication O
method O
of O
self B
- I
doped I
sulfonated I
polyaniline I
( O
SPAN B
) O
- O
based O
interdigitated O
electrodes O
( O
IDEs O
) O
for O
controlled O
electrical O
stimulation O
of O
human O
osteosarcoma O
( O
HOS O
) O
cells O
. O

Increased O
degree O
of O
sulfonation O
was O
found O
to O
increase O
the O
SPAN O
conductivity O
, O
which O
in O
turn O
improved O
the O
cell O
attachment O
and O
cell O
growth O
without O
electrical O
stimulation O
. O

However O
, O
an O
enhanced O
cell O
growth O
was O
observed O
under O
controlled O
electrical O
( O
AC O
) O
stimulation O
at O
low O
applied O
voltage O
and O
frequency O
( O
< O
= O
800 O
mV O
and O
< O
= O
1 O
kHz O
) O
. O

The O
cell O
growth O
reached O
a O
maximum O
threshold O
at O
an O
applied O
voltage O
or O
frequency O
and O
beyond O
which O
pronounced O
cell O
death O
was O
observed O
. O

We O
believe O
that O
these O
organic O
electrodes O
may O
find O
utility O
in O
electrical O
stimulation O
of O
cancer O
or O
tumor O
cells O
for O
therapy O
and O
research O
and O
may O
also O
provide O
an O
alternative O
to O
the O
conventional O
metal O
- O
based O
electrodes O
. O

Three O
new O
triterpene B
glycosides I
from O
Ilex O
asprella O
. O

Three O
new O
sulfated B
triterpene I
glycosides I
, O
asprellanosides B
C I
- I
E I
( O
1 O
- O
3 O
) O
, O
were O
isolated O
from O
the O
roots O
of O
Ilex O
asprella O
. O

Their O
structures O
were O
elucidated O
as O
3 B
beta I
- I
[ I
( I
2 I
- I
O I
- I
sulfo I
- I
beta I
- I
d I
- I
xylopyranosyl I
) I
oxy I
] I
urs I
- I
12 I
, I
19 I
( I
29 I
) I
- I
diene I
- I
28 I
- I
oic I
acid I
28 I
- I
beta I
- I
d I
- I
glucopyranoside I
( O
1 O
) O
, O
3 B
beta I
- I
[ I
( I
2 I
- I
O I
- I
sulfo I
- I
beta I
- I
d I
- I
xylopyranosyl I
) I
oxy I
] I
urs I
- I
12 I
, I
19 I
- I
diene I
- I
28 I
- I
oic I
acid I
28 I
- I
beta I
- I
d I
- I
glucopyranoside I
( O
2 O
) O
, O
and O
3 B

beta I
- I
[ I
( I
2 I
- I
O I
- I
sulfo I
- I
beta I
- I
d I
- I
xylopyranosyl I
) I
oxy I
] I
urs I
- I
12 I
, I
19 I
- I
diene I
- I
28 I
- I
oic I
acid I
( O
3 O
) O
on O
the O
basis O
of O
the O
spectral O
and O
chemical O
methods O
. O

The O
potential O
of O
sarcospan O
in O
adhesion O
complex O
replacement O
therapeutics O
for O
the O
treatment O
of O
muscular O
dystrophy O
. O

Three O
adhesion O
complexes O
span O
the O
sarcolemma O
and O
facilitate O
critical O
connections O
between O
the O
extracellular O
matrix O
and O
the O
actin O
cytoskeleton O
: O
the O
dystrophin O
- O
and O
utrophin O
- O
glycoprotein O
complexes O
and O
alpha O
7 O
beta O
1 O
integrin O
. O

Loss O
of O
individual O
protein O
components O
results O
in O
a O
loss O
of O
the O
entire O
protein O
complex O
and O
muscular O
dystrophy O
. O

Muscular O
dystrophy O
is O
a O
progressive O
, O
lethal O
wasting O
disease O
characterized O
by O
repetitive O
cycles O
of O
myofiber O
degeneration O
and O
regeneration O
. O

Protein O
replacement O
therapy O
offers O
a O
promising O
approach O
for O
the O
treatment O
of O
muscular O
dystrophy O
. O

Recently O
, O
we O
demonstrated O
that O
sarcospan O
facilitates O
protein O
- O
protein O
interactions O
amongst O
the O
adhesion O
complexes O
and O
is O
an O
important O
therapeutic O
target O
. O

Here O
, O
we O
review O
current O
protein O
replacement O
strategies O
, O
discuss O
the O
potential O
benefits O
of O
sarcospan O
expression O
, O
and O
identify O
important O
experiments O
that O
must O
be O
addressed O
for O
sarcospan O
to O
move O
to O
the O
clinic O
. O

This O
article O
is O
protected O
by O
copyright O
. O

All O
rights O
reserved O
. O

Design O
, O
Synthesis O
and O
biological O
evaluation O
of O
catecholamine B
vehicle O
for O
studying O
dopaminergic O
system O
. O

Catecholamine B
mimetic O
EDTA B
- I
bis I
( I
tyramide I
) I
was O
synthesized O
and O
characterized O
by O
various O
spectroscopic O
techniques O
( O
NMR O
, O
Mass O
spectroscopy O
) O
and O
lambda O
em O
310 O
nm O
for O
the O
excitation O
at O
270 O
nm O
. O

Molecular O
docking O
studies O
were O
performed O
with O
Human O
Serum O
Albumin O
( O
HSA O
: O
PDB O
1E78 O
) O
, O
showing O
binding O
pattern O
with O
amino B
acid I
residues O
Arg218 B
, O
Arg222 B
and O
Lys444 B
, O
identifies O
the O
ligand O
- O
HSA O
interaction O
for O
the O
transportation O
affinity O
of O
the O
ligand O
at O
the O
specific O
site O
of O
the O
target O
. O

Subsequently O
binding O
study O
with O
HSA O
at O
lambda O
ex O
= O
350 O
nm O
found O
to O
be O
5 O
. O
847x10 O
( O
4 O
) O
M O
( O
- O
1 O
) O
shows O
effective O
quenching O
effect O
. O

Additionally O
to O
go O
more O
insight O
AChE O
binding O
affinity O
was O
investigated O
, O
which O
shows O
90 O
% O
binding O
affinity O
for O
the O
10 O
mM O
concentration O
. O

IC50 O
value O
was O
was O
found O
18 O
. O
60 O
mu O
M O
for O
MAO O
- O
B O
inhibition O
. O

Finally O
, O
EDTA B
- O
bis B
( I
tyramide I
) I
labeled O
with O
( B
99m I
) I
Tc I
to O
investigate O
its O
in O
- O
vivo O
radiopharmaceutical O
efficiency O
, O
having O
97 O
% O
binding O
affinity O
with O
98 O
% O
radiochemical O
purity O
. O

In O
- O
vivo O
studies O
were O
carried O
out O
for O
( B
99m I
) I
Tc I
- I
EDTA I
- I
bis I
( I
tyramide I
) I
included O
blood O
kinetics O
showed O
a O
quick O
wash O
out O
from O
the O
circulation O
via O
renal O
route O
and O
biodistribution O
revealed O
that O
maximum O
% O
ID O
/ O
g O
was O
found O
in O
kidney O
at O
1h O
and O
its O
scintigraphy O
image O
shows O
3 O
. O
96 O
% O
brain O
uptake O
with O
respect O
to O
whole O
body O
. O

This O
article O
is O
protected O
by O
copyright O
. O

All O
rights O
reserved O
. O

Discovery O
of O
a O
new O
bioactive O
molecule O
for O
neuroblastoma O
. O

Neuroblastoma O
, O
a O
common O
pediatric O
malignancy O
of O
neural O
crest O
origin O
, O
is O
unique O
in O
its O
wide O
spectrum O
of O
clinical O
and O
biological O
behavior O
, O
ranging O
from O
spontaneous O
regression O
or O
differentiation O
to O
rapid O
progression O
and O
metastasis O
. O

Overexpression O
of O
neurotrophin O
receptors O
of O
the O
tyrosine B
kinase O
( O
Trk O
) O
family O
has O
been O
identified O
as O
a O
major O
prognostic O
and O
biological O
factor O
for O
this O
disease O
. O

Novel O
molecules O
were O
selected O
using O
cheminformatics O
tools O
( O
SBVS O
& O
LBVS O
) O
and O
screened O
in O
cell O
- O
based O
assays O
to O
modulate O
Trk O
receptor O
activity O
. O

One O
compound O
( O
C390 B
- I
0031 I
) O
had O
a O
potent O
anti O
- O
proliferative O
activity O
in O
dose O
- O
response O
studies O
using O
neuroblastoma O
cell O
lines O
. O

The O
molecular O
effects O
of O
this O
molecule O
were O
further O
characterized O
by O
using O
cell O
- O
cycle O
and O
western O
blot O
analysis O
. O

Interestingly O
, O
despite O
the O
presence O
of O
the O
anchoring O
fragment O
to O
the O
Trk O
kinase O
domain O
composing O
its O
structure O
, O
this O
molecule O
does O
not O
inhibit O
TrkA O
like O
lestaurtinib B
, O
constituting O
a O
new O
chemical O
with O
a O
yet O
unknown O
mechanism O
of O
action O
. O

This O
article O
is O
protected O
by O
copyright O
. O

All O
rights O
reserved O
. O

Health O
benefits O
of O
seafood O
; O
Is O
it O
just O
the O
fatty B
acids I
? O

There O
is O
a O
considerable O
body O
of O
literature O
suggesting O
a O
wide O
range O
of O
health O
benefits O
associated O
with O
diets O
high O
in O
seafood O
. O

However O
, O
the O
demand O
for O
seafood O
across O
the O
world O
now O
exceeds O
that O
available O
from O
capture O
fisheries O
. O

This O
has O
created O
a O
rapidly O
increasing O
market O
for O
aquaculture O
products O
, O
the O
nutrient O
composition O
of O
which O
is O
dependent O
on O
feed O
composition O
. O

The O
use O
of O
fishmeal O
in O
this O
food O
chain O
does O
little O
to O
counteract O
the O
environmental O
impact O
of O
fisheries O
and O
so O
the O
on O
- O
going O
development O
of O
alternative O
sources O
is O
to O
be O
welcomed O
. O

Nevertheless O
, O
an O
in O
- O
depth O
understanding O
as O
to O
which O
nutrients O
in O
seafood O
provide O
benefit O
is O
required O
to O
permit O
the O
production O
of O
foods O
of O
maximal O
health O
benefit O
to O
humans O
. O

This O
paper O
reviews O
our O
current O
knowledge O
of O
the O
beneficial O
nutrient O
composition O
of O
seafood O
, O
in O
particular O
omega B
- I
3 I
fatty I
acids I
, O
selenium B
, O
taurine B
, O
vitamins B
D I
and I
B12 I
, O
in O
the O
context O
of O
the O
development O
of O
environmentally O
sustainable O
aquaculture O
. O

Assessing O
caffeine B
intake O
in O
the O
United O
Kingdom O
diet O
. O

Caffeine B
occurs O
naturally O
in O
the O
leaves O
and O
seeds O
of O
many O
plants O
and O
is O
artificially O
added O
to O
some O
beverages O
. O

Consumption O
of O
caffeine B
has O
been O
linked O
to O
both O
positive O
and O
adverse O
health O
outcomes O
. O

We O
incorporated O
estimates O
of O
caffeine B
content O
( O
mg O
/ O
100g O
or O
ml O
) O
of O
foods O
and O
drinks O
, O
taken O
from O
the O
published O
literature O
, O
to O
provide O
a O
preliminary O
estimate O
of O
caffeine B
intake O
for O
the O
UK O
population O
, O
based O
on O
data O
collected O
in O
the O
National O
Diet O
and O
Nutrition O
Survey O
2008 O
- O
10 O
. O

Among O
consumers O
mean O
total O
caffeine B
intakes O
of O
adult O
men O
19 O
+ O
y O
were O
significantly O
greater O
than O
intakes O
by O
boys O
4 O
- O
10y O
and O
11 O
- O
18y O
( O
p O
< O
0 O
. O
05 O
) O
, O
with O
the O
same O
age O
- O
related O
differences O
seen O
for O
females O
. O

4 O
. O
1 O
% O
of O
men O
19 O
+ O
y O
and O
3 O
. O
8 O
% O
of O
women O
19 O
+ O
y O
had O
caffeine B
intakes O
in O
excess O
of O
300mg O
/ O
d O
. O

The O
addition O
of O
caffeine B
to O
UK O
food O
composition O
databases O
will O
allow O
more O
detailed O
study O
of O
the O
health O
effects O
of O
caffeine B
consumption O
. O

Nutrients O
and O
bioactive O
compounds O
of O
Thai O
indigenous O
fruits O
. O

This O
study O
determined O
the O
nutritional O
potential O
of O
Thai O
indigenous O
fruits O
in O
terms O
of O
nutrients O
, O
bioactive O
compounds O
, O
and O
antioxidant O
activities O
. O

Three O
indigenous O
fruits O
were O
collected O
at O
two O
conservation O
areas O
in O
Kanchanaburi O
province O
, O
Thailand O
. O

The O
results O
showed O
that O
Phyllanthus O
emblica O
L O
. O
exhibited O
the O
highest O
levels O
of O
vitamin B
C I
( O
575 O
+ O
/ O
- O
452mg O
/ O
100g O
) O
, O
total O
phenolics B
( O
TP O
) O
( O
3703 O
+ O
/ O
- O
1244mGAE O
/ O
100g O
) O
, O
and O
antioxidant O
activities O
, O
as O
measured O
by O
DPPH B
, O
FRAP O
and O
ORAC O
assays O
. O

Compared O
to O
the O
other O
two O
fruits O
, O
Antidesma O
velutinosum O
Blume O
contained O
higher O
levels O
of O
most O
nutrients O
and O
dietary O
fibre O
( O
15 O
. O
6 O
+ O
/ O
- O
5 O
. O
9g O
/ O
100g O
) O
, O
as O
well O
as O
carotenoids O
( O
335 O
+ O
/ O
- O
98 O
mu O
g O
/ O
100g O
) O
and O
phytosterols B
( O
22 O
. O
1 O
+ O
/ O
- O
3 O
. O
9mg O
/ O
100g O
) O
. O

Spondias O
pinnata O
( O
L O
. O
f O
. O
) O
Kurz O
was O
high O
in O
total O
phenolics B
( O
3178 O
+ O
/ O
- O
887mGAE O
/ O
100g O
) O
and O
antioxidant O
activity O
. O

Moreover O
, O
high O
correlations O
were O
found O
between O
TP O
and O
antioxidant O
activities O
( O
r O
> O
0 O
. O
9 O
) O
. O

These O
Thai O
indigenous O
fruits O
are O
potentially O
good O
sources O
of O
nutrients O
, O
bioactive O
compounds O
, O
and O
antioxidant O
activities O
. O

Conservation O
and O
utilisation O
should O
be O
promoted O
for O
food O
security O
and O
consumption O
as O
part O
of O
a O
healthy O
diet O
. O

Effect O
of O
different O
maize O
meal O
diets O
on O
growth O
and O
vitamin B
A I
: O
Case O
- O
study O
on O
chickens O
. O

South O
Africa O
embarked O
on O
mandatory O
vitamin O
and O
mineral O
fortification O
of O
wheat O
flour O
and O
maize O
meal O
in O
2003 O
as O
part O
of O
a O
multi O
- O
faceted O
approach O
to O
alleviate O
malnutrition O
. O

However O
, O
it O
was O
reported O
, O
in O
2008 O
, O
that O
vitamin B
A I
deficiency O
increased O
despite O
the O
mandatory O
fortification O
programme O
. O

This O
motivates O
an O
investigation O
into O
the O
absorption O
of O
vitamin B
A I
as O
fortificant O
in O
the O
maize O
meal O
. O

Relative O
absorption O
, O
in O
chickens O
as O
the O
biological O
model O
, O
was O
determined O
by O
evaluating O
growth O
and O
vitamin B
A I
status O
. O

The O
weight O
, O
cumulative O
feed O
intake O
and O
liver O
retinol B
stores O
of O
chickens O
on O
different O
diets O
were O
measured O
over O
a O
6week O
period O
. O

The O
fortified O
white O
maize O
meal O
diet O
was O
able O
to O
maintain O
the O
vitamin B
A I
status O
of O
the O
chickens O
. O

Poor O
absorption O
of O
the O
fortificant O
vitamin B
A I
is O
therefore O
not O
a O
constraint O
in O
combating O
vitamin B
A I
deficiency O
. O

It O
is O
in O
therefore O
also O
important O
to O
focus O
on O
the O
level O
of O
fortification O
delivered O
when O
consumed O
as O
a O
traditional O
prepared O
dish O
. O

In O
the O
traditional O
diet O
, O
maize O
porridge O
is O
often O
consumed O
with O
only O
a O
relish O
. O

The O
total O
fat O
content O
of O
the O
traditional O
meal O
is O
very O
low O
, O
lacking O
absorption O
enhancers O
. O

Voluntary O
food O
fortification O
with O
folic B
acid I
in O
Spain O
: O
Predicted O
contribution O
to O
children O
' O
s O
dietary O
intakes O
as O
assessed O
with O
new O
food O
folate B
composition O
data O
. O

The O
Spanish O
market O
offers O
a O
significant O
number O
of O
folic B
acid I
( O
FA O
) O
voluntarily O
fortified O
foods O
. O

We O
analysed O
FA O
and O
( B
6S I
) I
- I
5 I
- I
methyltetrahydrofoli I
acid I
( O
( B
6S I
) I
- I
5 I
- I
CH3 I
- I
H4PteGlu I
) O
content O
in O
ready O
- O
to O
- O
eat O
cereals O
( O
RTEC O
) O
( O
n O
= O
68 O
) O
and O
cow O
' O
s O
milk O
( O
n O
= O
25 O
) O
by O
a O
previously O
validated O
affinity O
chromatography O
- O
HPLC O
method O
. O

Contribution O
to O
potential O
FA O
intakes O
for O
children O
aged O
2 O
- O
13years O
, O
was O
assessed O
using O
food O
consumption O
data O
from O
a O
representative O
nationwide O
study O
, O
folate B
Recommended O
Dietary O
Intakes O
( O
RDI O
) O
, O
and O
Upper O
Levels O
( O
UL O
) O
. O

Results O
showed O
that O
at O
all O
food O
fortification O
levels O
obtained O
, O
fortified O
products O
provided O
more O
than O
tenfold O
FA O
than O
( B
6S I
) I
- I
5 I
- I
CH3 I
- I
H4PteGlu I
. O

For O
RTEC O
, O
the O
high O
fortification O
level O
provided O
6 O
- O
21 O
% O
, O
per O
serving O
, O
of O
RDI O
and O
> O
= O
32 O
% O
of O
ULs O
at O
90th O
percentile O
of O
RTEC O
consumption O
( O
P90 O
) O
. O

Milk O
products O
fortified O
at O
the O
higher O
level O
reached O
on O
average O
54 O
- O
136 O
% O
of O
RDI O
per O
serving O
and O
only O
exceeded O
UL O
at O
P90 O
of O
milk O
consumption O
in O
children O
aged O
2 O
- O
5years O
. O

Data O
collection O
and O
assessment O
of O
commonly O
consumed O
foods O
and O
recipes O
in O
six O
geo O
- O
political O
zones O
in O
Nigeria O
: O
Important O
for O
the O
development O
of O
a O
National O
Food O
Composition O
Database O
and O
Dietary O
Assessment O
. O

A O
cross O
- O
sectional O
study O
was O
undertaken O
to O
collect O
and O
assess O
commonly O
consumed O
foods O
/ O
recipes O
from O
the O
six O
geopolitical O
zones O
in O
Nigeria O
for O
the O
production O
of O
food O
composition O
database O
( O
FCDB O
) O
for O
dietary O
assessment O
. O

Communities O
used O
were O
selected O
using O
a O
multi O
- O
stage O
sampling O
plan O
. O

Focus O
group O
discussions O
, O
interviews O
, O
recipe O
documentation O
, O
food O
preparations O
and O
literature O
reviews O
were O
employed O
. O

Qualitative O
methods O
were O
used O
to O
analyse O
and O
present O
data O
. O

SWOT O
( O
strengths O
, O
weaknesses O
, O
opportunities O
, O
and O
threats O
) O
analysis O
was O
used O
to O
evaluate O
the O
project O
. O

A O
total O
of O
322 O
recipes O
were O
collected O
out O
of O
which O
110 O
were O
soups O
. O

Food O
consumption O
patterns O
across O
the O
geographical O
zones O
were O
found O
to O
be O
changing O
. O

Variations O
in O
recipes O
and O
methods O
of O
preparation O
of O
similar O
foods O
were O
observed O
. O

Factors O
to O
be O
considered O
in O
the O
development O
of O
a O
country O
- O
specific O
FCDB O
were O
identified O
. O

There O
were O
challenges O
with O
the O
use O
of O
values O
reported O
in O
literature O
for O
Nigerian O
foods O
. O

The O
study O
justifies O
the O
need O
for O
a O
country O
- O
specific O
FCDB O
that O
will O
include O
traditional O
recipes O
. O

Dietary O
fibre O
fractions O
in O
cereal O
foods O
measured O
by O
a O
new O
integrated O
AOAC O
method O
. O

The O
reliable O
determination O
of O
soluble O
, O
insoluble O
and O
total O
dietary O
fibre O
in O
baked O
goods O
and O
cereal O
flours O
is O
an O
important O
issue O
for O
research O
, O
nutritional O
labelling O
and O
marketing O
. O

We O
compared O
total O
dietary O
fibre O
( O
TDF O
) O
contents O
of O
selected O
cereal O
based O
foods O
determined O
by O
AOAC O
Method O
991 O
. O
43 O
and O
the O
new O
AOAC O
Method O
2009 O
. O
01 O
. O

Fifteen O
bread O
and O
bakery O
products O
were O
included O
in O
the O
study O
. O

Our O
results O
showed O
that O
TDF O
values O
of O
cereal O
products O
determined O
by O
AOAC O
Method O
2009 O
. O
01 O
were O
always O
significantly O
higher O
than O
those O
determined O
by O
AOAC O
Method O
991 O
. O
43 O
. O

This O
was O
explained O
by O
the O
inclusion O
of O
low O
molecular O
weight O
soluble O
fibre O
fractions O
and O
resistant O
starch O
fractions O
in O
the O
TDF O
measurement O
by O
AOAC O
2009 O
. O
01 O
. O

This O
documents O
that O
nutritional O
labelling O
of O
cereal O
products O
poses O
the O
challenge O
how O
to O
update O
TDF O
data O
in O
nutrient O
databases O
in O
a O
reasonable O
time O
with O
an O
acceptable O
expenditure O
. O

Total O
nitrogen B
vs O
. O
amino B
- I
acid I
profile O
as O
indicator O
of O
protein O
content O
of O
beef O
. O

In O
most O
cited O
food O
composition O
studies O
and O
tables O
, O
the O
proximate O
system O
measures O
protein O
as O
total O
nitrogen B
( O
N B
) O
( O
determined O
by O
Kjeldahl O
or O
Dumas O
method O
) O
multiplied O
by O
a O
specific O
factor O
. O

A O
factor O
of O
6 O
. O
25 O
is O
used O
for O
determining O
total O
protein O
from O
total O
N O
( O
Jones O
, O
Munsey O
, O
& O
Walker O
, O
1942 O
) O
. O

Although O
more O
expensive O
, O
it O
is O
considered O
more O
accurate O
to O
base O
protein O
content O
of O
foods O
on O
amino B
acid I
data O
( O
Greenfield O
& O
Southgate O
, O
2003 O
) O
. O

A O
study O
on O
the O
nutrient O
composition O
of O
beef O
analysed O
the O
full O
amino B
- I
acid I
profile O
of O
fifteen O
retail O
cuts O
from O
three O
age O
groups O
and O
six O
fat O
codes O
, O
as O
well O
as O
determined O
total O
nitrogen B
content O
to O
determine O
proximate O
protein O
composition O
. O

For O
all O
cuts O
, O
the O
correlation O
coefficient O
of O
total O
amino B
acids I
to O
protein O
( O
N O
x O
6 O
. O
25 O
) O
was O
0 O
. O
635 O
. O

This O
indicates O
a O
poor O
correlation O
for O
predicting O
actual O
protein O
content O
( O
as O
determined O
by O
total O
amino B
acid I
count O
) O
, O
based O
on O
the O
nitrogen B
factor O
of O
6 O
. O
25 O
. O

On O
average O
, O
the O
sum O
of O
amino B
acids I
per O
cut O
amounted O
to O
91 O
% O
of O
total O
determined O
protein O
( O
N O
x O
6 O
. O
25 O
) O
for O
the O
same O
cut O
. O

Biosynthetic O
conclusions O
from O
the O
functional O
dissection O
of O
oxygenases O
for O
biosynthesis O
of O
actinorhodin B
and O
related O
streptomyces O
antibiotics O
. O

Actinorhodin B
( O
ACT B
) O
produced O
by O
Streptomyces O
coelicolor O
A3 O
( O
2 O
) O
belongs O
to O
the O
benzoisochromanequin B
( O
BIQ B
) O
class O
of O
antibiotics O
. O

ActVA O
- O
ORF5 O
, O
a O
flavin B
- O
dependent O
monooxygenase O
( O
FMO O
) O
essential O
for O
ACT O
biosynthesis O
, O
forms O
a O
two O
- O
component O
enzyme O
system O
in O
combination O
with O
a O
flavin B
: O
NADH B
oxidoreductase O
, O
ActVB O
. O

The O
genes O
for O
homologous O
two O
- O
component O
FMOs O
are O
found O
in O
the O
biosynthetic O
gene O
clusters O
for O
two O
other O
BIQs O
, O
granaticin B
( O
GRA B
) O
and O
medermycin B
( O
MED B
) O
, O
and O
a O
closely O
related O
antibiotic O
, O
alnumycin B
( O
ALN B
) O
. O

Our O
functional O
analysis O
of O
these O
FMOs O
( O
ActVA O
- O
ORF5 O
, O
Gra O
- O
ORF21 O
, O
Med O
- O
ORF7 O
, O
and O
AlnT O
) O
in O
S O
. O
coelicolor O
unambiguously O
demonstrated O
that O
ActVA O
- O
ORF5 O
and O
Gra O
- O
ORF21 O
are O
bifunctional O
and O
capable O
of O
both O
p B
- I
quinone I
formation O
at O
C O
- O
6 O
in O
the O
central O
ring O
and O
C O
- O
8 O
hydroxylation O
in O
the O
lateral O
ring O
, O
whereas O
Med O
- O
ORF7 O
catalyzes O
only O
p B
- I
quinone I
formation O
. O

No O
p B
- I
quinone I
formation O
on O
a O
BIQ O
substrate O
was O
observed O
for O
AlnT O
, O
which O
is O
involved O
in O
lateral O
p B
- I
quinone I
formation O
in O
ALN B
. O

2 I
- I
( I
1H I
- I
Pyrazol I
- I
4 I
- I
yl I
) I
acetic I
acids I
as O
CRTh2 O
antagonists O
. O

High O
throughput O
screening O
identified O
the O
pyrazole B
- I
4 I
- I
acetic I
acid I
substructure O
as O
CRTh2 O
receptor O
antagonists O
. O

Optimisation O
of O
the O
compounds O
uncovered O
a O
tight O
SAR O
but O
also O
identified O
some O
low O
nanomolar O
inhibitors O
. O

Genome O
- O
wide O
Analysis O
Reveals O
TET B
- O
and O
TDG B
- O
Dependent O
5 B
- I
Methylcytosine I
Oxidation O
Dynamics O
. O

TET O
dioxygenases O
successively O
oxidize O
5 B
- I
methylcytosine I
( O
5mC B
) O
in O
mammalian O
genomes O
to O
5 B
- I
hydroxymethylcytosin I
( O
5hmC B
) O
, O
5 B
- I
formylcytosine I
( O
5fC B
) O
, O
and O
5 B
- I
carboxylcytosine I
( O
5caC B
) O
. O

5fC B
/ O
5caC B
can O
be O
excised O
and O
repaired O
to O
regenerate O
unmodified O
cytosines B
by O
thymine B
- O
DNA O
glycosylase O
( O
TDG O
) O
and O
base O
excision O
repair O
( O
BER O
) O
pathway O
, O
but O
it O
is O
unclear O
to O
what O
extent O
and O
at O
which O
part O
of O
the O
genome O
this O
active O
demethylation O
process O
takes O
place O
. O

Here O
, O
we O
have O
generated O
genome O
- O
wide O
distribution O
maps O
of O
5hmC B
/ O
5fC B
/ O
5caC B
using O
modification O
- O
specific O
antibodies O
in O
wild O
- O
type O
and O
Tdg O
- O
deficient O
mouse O
embryonic O
stem O
cells O
( O
ESCs O
) O
. O

In O
wild O
- O
type O
mouse O
ESCs O
, O
5fC O
/ O
5caC O
accumulates O
to O
detectable O
levels O
at O
major O
satellite O
repeats O
but O
not O
at O
nonrepetitive O
loci O
. O

In O
contrast O
, O
Tdg B
depletion O
in O
mouse O
ESCs O
causes O
marked O
accumulation O
of O
5fC O
and O
5caC O
at O
a O
large O
number O
of O
proximal O
and O
distal O
gene O
regulatory O
elements O
. O

Thus O
, O
these O
results O
reveal O
the O
genome O
- O
wide O
view O
of O
iterative O
5mC O
oxidation O
dynamics O
and O
indicate O
that O
TET O
/ O
TDG B
- O
dependent O
active O
DNA O
demethylation O
process O
occurs O
extensively O
in O
the O
mammalian O
genome O
. O

Synthesis O
and O
antiproliferative O
evaluation O
of O
piperazine B
- I
1 I
- I
carbothiohydrazide I
derivatives O
of O
indolin B
- I
2 I
- I
one I
. O

By O
varying O
the O
substituents O
( O
R O
( O
1 O
) O
) O
at O
the O
indolin B
- I
2 I
- I
one I
scaffold O
, O
a O
series O
of O
indolin B
- I
2 I
- I
one I
derivatives O
bearing O
4 B
- I
phenylpiperazine I
- I
1 I
- I
carbothiohydrazide I
moiety O
at O
the O
C3 O
- O
position O
were O
synthesized O
and O
evaluated O
for O
their O
antiproliferative O
activity O
against O
three O
human O
cancer O
cell O
lines O
. O

We O
further O
selected O
the O
5 B
- I
chloroindolin I
- I
2 I
- I
one I
moiety O
for O
the O
extension O
to O
another O
series O
of O
compounds O
by O
varying O
the O
substituents O
( O
R O
( O
2 O
) O
) O
at O
the O
phenyl B
group O
connected O
with O
the O
piperazine B
ring O
. O

Among O
all O
the O
compounds O
synthesized O
, O
6d O
and O
6l O
were O
most O
potent O
with O
IC50 O
values O
of O
3 O
. O
59 O
and O
5 O
. O
58 O
mu O
M O
, O
respectively O
against O
A549 O
lung O
cancer O
cells O
, O
while O
5f O
and O
6l O
possessed O
IC50 O
values O
of O
3 O
. O
49 O
and O
4 O
. O
57 O
mu O
M O
, O
respectively O
against O
HCT O
- O
116 O
colon O
cancer O
cells O
which O
were O
comparable O
to O
that O
of O
Sunitinib B
, O
an O
indolin B
- I
2 I
- I
one I
derivative O
in O
cancer O
therapy O
. O

BDNF O
- O
induced O
local O
protein O
synthesis O
and O
synaptic O
plasticity O
. O

Brain O
- O
derived O
neurotrophic O
factor O
( O
BDNF O
) O
is O
an O
important O
regulator O
of O
synaptic O
transmission O
and O
long O
- O
term O
potentiation O
( O
LTP O
) O
in O
the O
hippocampus O
and O
in O
other O
brain O
regions O
, O
playing O
a O
role O
in O
the O
formation O
of O
certain O
forms O
of O
memory O
. O

The O
effects O
of O
BDNF O
in O
LTP O
are O
mediated O
by O
TrkB O
( O
tropomyosin O
- O
related O
kinase O
B O
) O
receptors O
, O
which O
are O
known O
to O
be O
coupled O
to O
the O
activation O
of O
the O
Ras O
/ O
ERK O
, O
phosphatidylinositol B
3 O
- O
kinase O
/ O
Akt O
and O
phospholipase O
C O
- O
gamma O
( O
PLC O
- O
gamma O
) O
pathways O
. O

The O
role O
of O
BDNF O
in O
LTP O
is O
best O
studied O
in O
the O
hippocampus O
, O
where O
the O
neurotrophin O
is O
thought O
to O
act O
at O
pre O
- O
and O
post O
- O
synaptic O
levels O
. O

Recent O
studies O
have O
shown O
that O
BDNF O
regulates O
the O
transport O
of O
mRNAs O
along O
dendrites O
and O
their O
translation O
at O
the O
synapse O
, O
by O
modulating O
the O
initiation O
and O
elongation O
phases O
of O
protein O
synthesis O
, O
and O
by O
acting O
on O
specific O
miRNAs O
. O

Furthermore O
, O
the O
effect O
of O
BDNF O
on O
transcription O
regulation O
may O
further O
contribute O
to O
long O
- O
term O
changes O
in O
the O
synaptic O
proteome O
. O

In O
this O
review O
we O
discuss O
the O
recent O
progress O
in O
understanding O
the O
mechanisms O
contributing O
to O
the O
short O
- O
and O
long O
- O
term O
regulation O
of O
the O
synaptic O
proteome O
by O
BDNF O
, O
and O
the O
role O
in O
synaptic O
plasticity O
, O
which O
is O
likely O
to O
influence O
learning O
and O
memory O
formation O
. O

This O
article O
is O
part O
of O
a O
Special O
Issue O
entitled O
' O
BDNF O
' O
. O

Protective O
effects O
of O
naringin B
against O
paraquat B
- O
induced O
acute O
lung O
injury O
and O
pulmonary O
fibrosis O
in O
mice O
. O

The O
present O
study O
evaluates O
protective O
effects O
of O
naringin B
against O
paraquat B
( O
PQ O
) O
- O
induced O
acute O
lung O
injury O
( O
ALI O
) O
and O
pulmonary O
fibrosis O
in O
mice O
. O

Survival O
probability O
against O
PQ O
intoxication O
was O
tested O
by O
a O
single O
intraperitoneal O
injection O
of O
PQ O
. O

Results O
showed O
that O
survival O
rates O
of O
mice O
exposed O
to O
PQ O
only O
( O
50mg O
/ O
kg O
within O
7days O
) O
were O
much O
lower O
than O
that O
in O
mice O
daily O
treatment O
with O
NAC B
or O
naringin B
. O

Moreover O
, O
protection O
against O
PQ O
- O
induced O
ALI O
was O
tested O
by O
daily O
pretreatment O
mice O
with O
saline O
, O
NAC B
or O
naringin B
for O
3days O
before O
PQ O
( O
30mg O
/ O
kg O
, O
i O
. O
p O
. O
) O
. O

Results O
showed O
that O
increase O
in O
leukocytes O
infiltration O
and O
overexpressions O
of O
TNF O
- O
alpha O
and O
TGF O
- O
beta O
1 O
caused O
by O
8h O
of O
PQ O
exposure O
were O
dose O
- O
dependently O
ameliorated O
by O
naringin B
. O

Furthermore O
, O
protection O
against O
PQ O
- O
induced O
pulmonary O
fibrosis O
was O
tested O
by O
pretreatment O
mice O
with O
PQ O
( O
20mg O
/ O
kg O
, O
i O
. O
p O
. O
) O
, O
and O
then O
daily O
administration O
with O
saline O
, O
NAC B
or O
naringin B
for O
prolonged O
21days O
. O

Results O
showed O
that O
naringin B
of O
60 O
and O
120mg O
/ O
kg O
significantly O
reduced O
PQ O
- O
induced O
upregulations O
of O
TNF O
- O
alpha O
, O
TGF O
- O
beta O
1 O
, O
MMP O
- O
9 O
and O
TIMP O
- O
1 O
, O
levels O
of O
pulmonary O
malonaldehyde B
and O
hydroxyproline B
, O
as O
well O
as O
pulmonary O
fibrosis O
deposition O
, O
while O
increased O
activities O
of O
SOD O
, O
GSH B
- O
Px O
and O
HO O
- O
1 O
. O

These O
results O
indicated O
that O
naringin B
had O
effective O
protection O
against O
PQ O
- O
induced O
ALI O
and O
pulmonary O
fibrosis O
. O

Immunotoxicological O
effects O
of O
inorganic O
arsenic B
on O
gilthead O
seabream O
( O
Sparus O
aurata O
L O
. O
) O
. O

Arsenic B
( O
As B
) O
has O
been O
associated O
with O
multitude O
of O
animal O
and O
human O
health O
problems O
; O
however O
, O
its O
impact O
on O
host O
immune O
system O
has O
not O
been O
extensively O
investigated O
. O

In O
fish O
, O
there O
are O
very O
few O
works O
on O
the O
potential O
risks O
or O
problems O
associated O
to O
the O
presence O
of O
arsenic B
. O

In O
the O
present O
study O
we O
have O
evaluated O
the O
effects O
of O
exposure O
( O
30 O
days O
) O
to O
sub O
- O
lethal O
concentrations O
of O
arsenic B
( O
5 O
mu O
M O
As2O3 B
) O
in O
the O
teleost O
fish O
gilthead O
seabream O
( O
Sparus O
aurata O
) O
, O
with O
special O
emphasis O
in O
the O
innate O
immune O
response O
. O

The O
arsenic B
concentration O
was O
determined O
using O
atomic O
fluorescence O
spectrometry O
( O
AFS O
) O
in O
liver O
and O
muscle O
of O
exposed O
fish O
showing O
As B
accumulation O
in O
the O
liver O
after O
30 O
days O
of O
exposure O
. O

The O
hepatosomatic O
index O
was O
increased O
at O
significant O
extent O
after O
10 O
days O
but O
returned O
to O
control O
values O
after O
30 O
days O
of O
exposure O
. O

Histological O
alterations O
in O
the O
liver O
were O
observed O
including O
hypertrophy O
, O
vacuolization O
and O
cell O
- O
death O
processes O
. O

Focusing O
on O
the O
immunological O
response O
, O
the O
humoral O
immune O
parameters O
( O
seric O
IgM O
, O
complement O
and O
peroxidase O
activities O
) O
were O
no O
affected O
to O
a O
statistically O
significant O
extent O
. O

Regarding O
the O
cellular O
innate O
parameters O
, O
head O
- O
kidney O
leucocyte O
peroxidase O
, O
respiratory O
burst O
and O
phagocytic O
activities O
were O
significantly O
increased O
after O
10 O
days O
of O
exposition O
compared O
to O
the O
control O
fish O
. O

Overall O
, O
As B
- O
exposure O
in O
the O
seabream O
affects O
the O
immune O
system O
. O

How O
this O
might O
interfere O
with O
fish O
biology O
, O
aquaculture O
management O
or O
human O
consumers O
warrants O
further O
investigations O
. O

This O
paper O
describes O
, O
for O
the O
first O
time O
, O
the O
immunotoxicological O
effects O
of O
arsenic B
exposure O
in O
the O
gilthead O
seabream O
, O
which O
is O
a O
species O
with O
the O
largest O
production O
in O
Mediterranean O
aquaculture O
. O

Evaluation O
of O
mechanisms O
involved O
in O
the O
antinociception O
of O
the O
ethanol B
extract O
from O
the O
inner O
bark O
of O
Caesalpinia O
pyramidalis O
in O
mice O
. O

ETHNOPHARMACOLOGICAL O
RELEVANCE O
: O
Caesalpinia O
pyramidalis O
Tul O
. O

( O
Fabaceae O
) O
is O
an O
endemic O
tree O
of O
the O
Northeast O
region O
of O
Brazil O
, O
mainly O
in O
the O
Caatinga O
region O
. O

More O
commonly O
, O
inner O
bark O
or O
flowers O
are O
traditionally O
used O
to O
treat O
many O
painful O
and O
inflammatory O
processes O
. O

A O
common O
use O
of O
this O
plant O
is O
made O
by O
macerating O
a O
handful O
of O
its O
stem O
bark O
in O
a O
liter O
of O
wine O
or O
sugarcane O
brandy O
. O

It O
is O
drunk O
against O
stomachache O
, O
dysenteries O
, O
and O
diarrheas O
. O

MATERIALS O
AND O
METHODS O
: O
The O
ethanol B
extract O
of O
Caesalpinia O
pyramidalis O
inner O
bark O
was O
used O
in O
mice O
via O
oral O
route O
, O
at O
the O
doses O
of O
10 O
, O
30 O
, O
and O
100mg O
/ O
kg O
, O
in O
behavioral O
models O
of O
nociception O
and O
investigates O
some O
of O
the O
mechanisms O
underlying O
this O
effect O
. O

RESULTS O
: O
The O
ethanol B
extract O
( O
30 O
and O
100mg O
/ O
kg O
, O
P O
< O
0 O
. O
001 O
) O
, O
given O
orally O
, O
produced O
dose O
dependent O
inhibition O
of O
acetic B
acid I
- O
induced O
visceral O
pain O
. O

The O
ethanol B
extract O
also O
caused O
significant O
and O
dose O
- O
dependent O
inhibition O
of O
capsaicin B
- O
( O
100mg O
/ O
kg O
, O
P O
< O
0 O
. O
001 O
) O
and O
glutamate B
- O
( O
10 O
, O
30 O
, O
and O
100mg O
/ O
kg O
, O
P O
< O
0 O
. O
01 O
) O
induced O
pain O
. O

The O
antinociception O
caused O
by O
the O
ethanol B
extract O
( O
30mg O
/ O
kg O
) O
in O
the O
abdominal O
constriction O
test O
was O
significantly O
attenuated O
( O
P O
< O
0 O
. O
001 O
) O
by O
intraperitoneal O
treatment O
of O
mice O
with O
l B
- I
arginine I
( O
600mg O
/ O
kg O
) O
. O

CONCLUSIONS O
: O
Collectively O
, O
the O
present O
results O
suggest O
that O
the O
ethanol B
extract O
of O
Caesalpinia O
pyramidalis O
produced O
dose O
- O
related O
antinociception O
in O
several O
models O
of O
pain O
through O
mechanisms O
that O
involved O
both O
glutamatergic O
system O
and O
/ O
or O
the O
l B
- I
arginine I
- O
nitric B
oxide I
pathway O
, O
supporting O
the O
folkloric O
usage O
of O
the O
plant O
to O
treat O
various O
painful O
processes O
. O

The O
PERICLES O
research O
program O
: O
An O
integrated O
approach O
to O
characterize O
the O
combined O
effects O
of O
mixtures O
of O
pesticide O
residues O
to O
which O
the O
French O
population O
is O
exposed O
. O

Due O
to O
the O
broad O
spectrum O
of O
pesticide O
usages O
, O
consumers O
are O
exposed O
to O
mixtures O
of O
residues O
, O
which O
may O
have O
combined O
effects O
on O
human O
health O
. O

The O
PERICLES O
research O
program O
aims O
to O
test O
the O
potential O
combined O
effects O
of O
pesticide O
mixtures O
, O
which O
are O
likely O
to O
occur O
through O
dietary O
exposure O
. O

The O
co O
- O
exposure O
of O
the O
French O
general O
population O
to O
79 O
pesticide O
residues O
present O
in O
the O
diet O
was O
first O
assessed O
. O

A O
Bayesian O
non O
- O
parametric O
model O
was O
then O
applied O
to O
define O
the O
main O
mixtures O
to O
which O
the O
French O
general O
population O
is O
simultaneously O
and O
most O
heavily O
exposed O
. O

Seven O
mixtures O
made O
of O
two O
to O
six O
pesticides O
were O
identified O
from O
the O
exposure O
assessment O
. O

An O
in O
vitro O
approach O
was O
used O
for O
investigating O
the O
toxicological O
effects O
of O
these O
mixtures O
and O
their O
corresponding O
individual O
compounds O
, O
using O
a O
panel O
of O
cellular O
models O
, O
i O
. O
e O
. O
primary O
rat O
and O
human O
hepatocytes O
, O
liver O
, O
intestine O
, O
kidney O
, O
colon O
and O
brain O
human O
cell O
lines O
. O

A O
set O
of O
cell O
functions O
and O
corresponding O
end O
- O
points O
were O
monitored O
such O
as O
cytotoxicity O
, O
real O
- O
time O
cell O
impedance O
, O
genotoxicity O
, O
oxidative O
stress O
, O
apoptosis O
and O
PXR O
nuclear O
receptor O
transactivation O
. O

The O
mixtures O
were O
tested O
in O
equimolar O
concentrations O
. O

Among O
the O
seven O
mixtures O
, O
two O
appeared O
highly O
cytotoxic O
, O
five O
activated O
PXR O
and O
depending O
on O
the O
assay O
one O
or O
two O
were O
genotoxic O
. O

In O
some O
experiments O
, O
the O
mixture O
effect O
was O
quantitatively O
different O
from O
the O
effect O
expected O
from O
the O
addition O
concept O
. O

The O
PERICLES O
program O
shows O
that O
, O
for O
the O
most O
pesticides O
mixtures O
to O
which O
the O
French O
general O
population O
is O
exposed O
, O
the O
toxic O
effects O
observed O
on O
human O
cells O
cannot O
be O
easily O
predicted O
based O
on O
the O
toxic O
potential O
of O
each O
compound O
. O

Consequently O
, O
additional O
studies O
should O
be O
carried O
on O
in O
order O
to O
more O
accurately O
define O
the O
mixtures O
of O
chemicals O
to O
which O
the O
consumers O
are O
exposed O
, O
as O
well O
as O
to O
improve O
the O
investigation O
, O
prediction O
and O
monitoring O
of O
their O
potential O
human O
health O
effects O
. O

Adult O
siRNA O
- O
induced O
knockdown O
of O
mGlu7 O
receptors O
reduces O
anxiety O
in O
the O
mouse O
. O

Our O
knowledge O
regarding O
the O
molecular O
pathophysiology O
underlying O
anxiety O
disorders O
remains O
incomplete O
. O

Increasing O
evidence O
points O
to O
a O
role O
of O
glutamate B
in O
anxiety O
. O

The O
group O
III O
metabotropic O
glutamate B
receptors O
( O
mGlu4 O
, O
mGlu6 O
, O
mGlu7 O
and O
mGlu8 O
receptors O
) O
remain O
the O
least O
investigated O
glutamate B
receptor O
subtypes O
partially O
due O
to O
a O
delay O
in O
the O
development O
of O
specific O
pharmacological O
tools O
. O

Early O
work O
using O
knockout O
animals O
and O
pharmacological O
tools O
aimed O
at O
investigating O
the O
role O
of O
mGlu7 O
receptor O
in O
the O
pathophysiology O
of O
anxiety O
disorders O
has O
yielded O
exciting O
yet O
not O
always O
consistent O
results O
. O

To O
further O
investigate O
the O
role O
this O
receptor O
plays O
in O
anxiety O
- O
like O
behaviour O
, O
we O
knocked O
down O
mGlu7 O
receptor O
mRNA O
levels O
in O
the O
adult O
mouse O
brain O
using O
siRNA O
delivered O
via O
an O
osmotic O
minipump O
. O

This O
reduced O
anxiety O
- O
like O
behaviour O
in O
the O
light O
- O
dark O
box O
coupled O
with O
an O
attenuation O
of O
stress O
- O
induced O
hyperthermia O
( O
SIH O
) O
and O
a O
reduction O
of O
the O
acoustic O
startle O
response O
( O
ASRs O
) O
in O
the O
fear O
- O
potentiated O
startle O
paradigm O
( O
FPS O
) O
. O

These O
effects O
on O
anxiety O
- O
like O
behaviour O
were O
independent O
of O
any O
impairment O
of O
locomotor O
activity O
and O
surprisingly O
, O
no O
behavioural O
changes O
were O
observed O
in O
the O
forced O
swim O
test O
( O
FST O
) O
, O
which O
is O
in O
contrast O
to O
mGlu7 O
receptor O
knockout O
animals O
. O

Furthermore O
, O
the O
previously O
reported O
epilepsy O
- O
prone O
phenotype O
seen O
in O
mGlu7 O
receptor O
knockout O
animals O
was O
not O
observed O
following O
siRNA O
- O
induced O
knockdown O
of O
the O
receptor O
. O

These O
data O
suggest O
targeting O
mGlu7 O
receptors O
with O
selective O
antagonist O
drugs O
may O
be O
an O
effective O
and O
safe O
strategy O
for O
the O
treatment O
of O
anxiety O
disorders O
. O

Infliximab O
counteracts O
tumor O
necrosis O
factor O
- O
alpha O
- O
enhanced O
induction O
of O
matrix O
metalloproteinases O
that O
degrade O
claudin O
and O
occludin O
in O
non O
- O
pigmented O
ciliary O
epithelium O
. O

Infliximab O
, O
a O
monoclonal O
antibody O
directed O
against O
human O
tumor O
necrosis O
factor O
- O
alpha O
( O
TNF O
- O
alpha O
) O
, O
effectively O
treats O
anterior O
uveitis O
, O
which O
can O
accompany O
Beh O
c O
et O
' O
s O
disease O
. O

Here O
, O
we O
investigated O
the O
underlying O
mechanism O
of O
this O
action O
. O

We O
examined O
human O
, O
non O
- O
pigmented O
ciliary O
epithelial O
cells O
( O
HNPCECs O
) O
, O
which O
make O
up O
the O
blood O
- O
aqueous O
barrier O
( O
BAB O
) O
in O
the O
uvea O
. O

We O
measured O
the O
expression O
levels O
of O
matrix O
metalloproteinases O
( O
MMPs O
) O
and O
tissue O
inhibitors O
of O
MMPs O
in O
the O
presence O
or O
absence O
of O
TNF O
- O
alpha O
using O
quantitative O
, O
real O
- O
time O
polymerase O
chain O
reaction O
and O
enzyme O
- O
linked O
immunosorbent O
assays O
. O

The O
expression O
of O
MMP O
- O
1 O
, O
MMP O
- O
3 O
, O
and O
MMP O
- O
9 O
increased O
in O
the O
presence O
of O
TNF O
- O
alpha O
, O
and O
the O
addition O
of O
infliximab O
reversed O
the O
increase O
. O

The O
TNF O
- O
alpha O
effects O
were O
more O
attenuated O
when O
infliximab O
was O
added O
before O
than O
when O
it O
was O
added O
after O
TNF O
- O
alpha O
exposure O
. O

Gelatin O
zymography O
demonstrated O
that O
the O
protease O
activity O
of O
these O
MMPs O
was O
also O
increased O
in O
the O
presence O
of O
TNF O
- O
alpha O
and O
attenuated O
with O
infliximab O
. O

Immunostaining O
showed O
that O
MMP O
- O
1 O
, O
MMP O
- O
3 O
, O
and O
MMP O
- O
9 O
degraded O
claudin O
- O
1 O
and O
occludin O
in O
HNPCECs O
and O
in O
non O
- O
pigmented O
ciliary O
epithelial O
cells O
of O
the O
swine O
ciliary O
body O
. O

In O
a O
monolayer O
of O
HNPCECs O
, O
we O
found O
that O
permeability O
was O
significantly O
increased O
with O
MMP O
treatment O
. O

Thus O
, O
TNF O
- O
alpha O
increased O
levels O
of O
MMPs O
in O
cells O
that O
form O
the O
BAB O
, O
and O
MMPs O
degraded O
components O
of O
the O
tight O
junctions O
in O
the O
BAB O
, O
which O
increased O
permeability O
through O
the O
cellular O
barrier O
. O

Furthermore O
, O
infliximab O
effectively O
attenuated O
the O
TNF O
- O
alpha O
- O
induced O
increases O
in O
MMP O
expression O
in O
cells O
that O
make O
up O
the O
BAB O
. O

These O
findings O
might O
suggest O
a O
basis O
for O
the O
clinical O
prevention O
of O
anterior O
uveitis O
. O

Protective O
effects O
of O
selenium B
on O
oxidative O
damage O
and O
oxidative O
stress O
related O
gene O
expression O
in O
rat O
liver O
under O
chronic O
poisoning O
of O
arsenic B
. O

Arsenic B
( O
As B
) O
is O
a O
toxic O
metalloid O
existing O
widely O
in O
the O
environment O
, O
and O
chronic O
exposure O
to O
it O
through O
contaminated O
drinking O
water O
has O
become O
a O
global O
problem O
of O
public O
health O
. O

The O
present O
study O
focused O
on O
the O
protective O
effects O
of O
selenium B
on O
oxidative O
damage O
of O
chronic O
arsenic B
poisoning O
in O
rat O
liver O
. O

Rats O
were O
divided O
into O
four O
groups O
at O
random O
and O
given O
designed O
treatments O
for O
20weeks O
. O

The O
oxidative O
damage O
of O
liver O
tissue O
was O
evaluated O
by O
lipid O
peroxidation O
and O
antioxidant O
enzymes O
. O

Oxidative O
stress O
related O
genes O
were O
detected O
to O
reflect O
the O
liver O
stress O
state O
at O
the O
molecular O
level O
. O

Compared O
to O
the O
control O
and O
Na2SeO3 B
groups O
, O
the O
MDA B
content O
in O
liver O
tissue O
was O
decreased O
and O
the O
activities O
of O
antioxidant O
enzymes O
were O
increased O
in O
the O
Na2SeO3 B
intervention O
group O
. O

The O
mRNA O
levels O
of O
SOD1 O
, O
CAT O
, O
GPx O
and O
Txnrd1 O
were O
increased O
significantly O
( O
P O
< O
0 O
. O
05 O
) O
in O
the O
combined O
Na2SeO3 B
+ O
NaAsO2 B
treatment O
group O
. O

The O
expressions O
of O
HSP70 O
and O
HO O
- O
1 O
were O
significantly O
( O
P O
< O
0 O
. O
05 O
) O
increased O
in O
the O
NaAsO2 B
group O
and O
reduced O
in O
the O
combined O
treatment O
group O
. O

The O
results O
indicate O
that O
long O
- O
term O
intake O
of O
NaAsO2 B
causes O
oxidative O
damage O
in O
the O
rat O
liver O
, O
and O
Na2SeO3 B
protects O
liver O
cells O
by O
adjusting O
the O
expression O
of O
oxidative O
stress O
related O
genes O
to O
improve O
the O
activities O
of O
antioxidant O
enzymes O
. O

Juniperus O
oxycedrus O
L O
. O
subsp O
. O

oxycedrus O
and O
Juniperus O
oxycedrus O
L O
. O
subsp O
. O

macrocarpa O
( O
Sibth O
. O
& O
Sm O
. O
) O
Ball O
. O

" O
berries O
" O
from O
Turkey O
: O
Comparative O
evaluation O
of O
phenolic O
profile O
, O
antioxidant O
, O
cytotoxic O
and O
antimicrobial O
activities O
. O

This O
work O
aimed O
to O
evaluate O
and O
compare O
the O
phenolic O
profile O
and O
some O
biological O
properties O
of O
the O
ripe O
" O
berries O
" O
methanol B
extracts O
of O
Juniperus O
oxycedrus O
L O
. O
subsp O
. O

oxycedrus O
( O
Joo O
) O
and O
Juniperus O
oxycedrus O
L O
. O
subsp O
. O

macrocarpa O
( O
Sibth O
. O
& O
Sm O
. O
) O
Ball O
. O

( O
Jom O
) O
from O
Turkey O
. O

The O
total O
phenolic O
content O
resulted O
about O
3 O
- O
fold O
higher O
in O
Jom O
( O
17 O
. O
89 O
+ O
/ O
- O
0 O
. O
23mg O
GAE O
/ O
g O
extract O
) O
than O
in O
Joo O
( O
5 O
. O
14 O
+ O
/ O
- O
0 O
. O
06mg O
GAE O
/ O
g O
extract O
) O
. O

The O
HPLC O
- O
DAD O
- O
ESI O
- O
MS O
analysis O
revealed O
a O
similar O
flavonoid B
fingerprint O
in O
Joo O
and O
Jom O
, O
whereas O
a O
difference O
in O
their O
quantitative O
content O
was O
found O
( O
4632 O
mu O
g O
/ O
g O
extract O
and O
12 O
, O
644 O
mu O
g O
/ O
g O
extract O
) O
. O

In O
addition O
, O
three O
phenolic B
acids I
were O
detected O
in O
Jom O
only O
( O
5765 O
mu O
g O
/ O
g O
extract O
) O
, O
and O
protocatechuic B
acid I
was O
the O
most O
abundant O
one O
. O

The O
antioxidant O
capacity O
of O
the O
extracts O
was O
evaluated O
by O
different O
in O
vitro O
assays O
: O
in O
the O
DPPH B
and O
in O
the O
TBA B
tests O
a O
stronger O
activity O
in O
Jom O
was O
highlighted O
, O
while O
Joo O
exhibited O
higher O
reducing O
power O
and O
metal O
chelating O
activity O
. O

Joo O
and O
Jom O
did O
not O
affect O
HepG2 O
cell O
viability O
and O
both O
extracts O
resulted O
virtually O
non O
- O
toxic O
against O
Artemia O
salina O
. O

The O
extracts O
were O
also O
studied O
for O
their O
antimicrobial O
potential O
, O
displaying O
efficacy O
against O
Gram O
- O
positive O
bacteria O
. O

The O
molecular O
basis O
of O
simple O
relationships O
between O
exposure O
concentration O
and O
toxic O
effects O
with O
time O
. O

Understanding O
the O
toxicity O
of O
chemicals O
to O
organisms O
requires O
considering O
the O
molecular O
mechanisms O
involved O
as O
well O
as O
the O
relationships O
between O
exposure O
concentration O
and O
toxic O
effects O
with O
time O
. O

Our O
current O
knowledge O
about O
such O
relationships O
is O
mainly O
explained O
from O
a O
toxicodynamic O
and O
toxicokinetic O
perspective O
. O

This O
paper O
re O
- O
introduces O
an O
old O
approach O
that O
takes O
into O
account O
the O
biochemical O
mode O
of O
action O
and O
their O
resulting O
biological O
effects O
over O
time O
of O
exposure O
. O

Empirical O
evidence O
demonstrates O
that O
the O
Druckrey O
- O
K O
u O
pfm O
u O
ller O
toxicity O
model O
, O
which O
was O
validated O
for O
chemical O
carcinogens O
in O
the O
early O
1960s O
, O
is O
also O
applicable O
to O
a O
wide O
range O
of O
toxic O
compounds O
in O
ecotoxicology O
. O

According O
to O
this O
model O
, O
the O
character O
of O
a O
poison O
is O
primarily O
determined O
by O
the O
reversibility O
of O
critical O
receptor O
binding O
. O

Chemicals O
showing O
irreversible O
or O
slowly O
reversible O
binding O
to O
specific O
receptors O
will O
produce O
cumulative O
effects O
with O
time O
of O
exposure O
, O
and O
whenever O
the O
effects O
are O
also O
irreversible O
( O
e O
. O
g O
. O
death O
) O
they O
are O
reinforced O
over O
time O
; O
these O
chemical O
have O
time O
- O
cumulative O
toxicity O
. O

Compounds O
having O
non O
- O
specific O
receptor O
binding O
, O
or O
involving O
slowly O
reversible O
binding O
to O
some O
receptors O
that O
do O
not O
contribute O
to O
toxicity O
, O
may O
also O
be O
time O
- O
dependent O
; O
however O
, O
their O
effects O
depend O
primarily O
on O
the O
exposure O
concentration O
, O
with O
time O
playing O
a O
minor O
role O
. O

Consequently O
, O
the O
mechanism O
of O
toxic O
action O
has O
important O
implications O
for O
risk O
assessment O
. O

Traditional O
risk O
approaches O
cannot O
predict O
the O
impacts O
of O
toxicants O
with O
time O
- O
cumulative O
toxicity O
in O
the O
environment O
. O

New O
assessment O
procedures O
are O
needed O
to O
evaluate O
the O
risk O
that O
the O
latter O
chemicals O
pose O
on O
humans O
and O
the O
environment O
. O

An O
example O
is O
shown O
to O
explain O
how O
the O
risk O
of O
time O
- O
dependent O
toxicants O
is O
underestimated O
when O
using O
current O
risk O
assessment O
protocols O
. O

Cognitive O
effects O
of O
variations O
in O
pubertal O
timing O
: O
Is O
puberty O
a O
period O
of O
brain O
organization O
for O
human O
sex O
- O
typed O
cognition O
? O

There O
is O
considerable O
interest O
in O
the O
organizational O
effects O
of O
pubertal O
sex O
hormones O
on O
human O
sex O
- O
related O
characteristics O
. O

Recent O
evidence O
from O
rodents O
suggests O
that O
there O
is O
a O
decreasing O
window O
of O
sensitivity O
to O
sex O
hormones O
throughout O
adolescence O
. O

If O
adolescence O
also O
represents O
a O
period O
of O
brain O
organization O
in O
human O
beings O
, O
then O
the O
timing O
of O
exposure O
to O
sex O
- O
typical O
hormones O
at O
puberty O
should O
have O
long O
- O
term O
effects O
on O
sex O
- O
typed O
characteristics O
: O
individuals O
with O
early O
timing O
should O
be O
more O
sex O
- O
typed O
than O
individuals O
with O
late O
timing O
. O

We O
tested O
this O
hypothesis O
in O
320 O
young O
adults O
by O
relating O
their O
pubertal O
timing O
( O
retrospective O
comparison O
to O
peers O
) O
to O
cognitive O
abilities O
that O
show O
sex O
differences O
. O

Results O
provide O
partial O
support O
for O
the O
hypothesis O
. O

For O
men O
, O
pubertal O
timing O
was O
inversely O
related O
to O
scores O
on O
a O
test O
of O
three O
- O
dimensional O
mental O
rotations O
. O

Effects O
do O
not O
appear O
to O
be O
due O
to O
duration O
of O
hormone O
exposure O
( O
time O
since O
puberty O
) O
, O
but O
other O
potential O
influences O
need O
further O
study O
. O

New O
anticancer O
active O
and O
selective O
phenylene B
- I
bisbenzothiazoles I
: O
Synthesis O
, O
antiproliferative O
evaluation O
and O
DNA O
binding O
. O

Novel O
amidino B
- O
derivatives O
of O
phenylene B
- I
bisbenzothiazoles I
were O
synthesized O
and O
tested O
for O
their O
antiproliferative O
activity O
against O
several O
human O
cancer O
cell O
lines O
, O
as O
well O
as O
DNA O
- O
binding O
properties O
. O

The O
synthetic O
approach O
used O
for O
preparation O
of O
isomeric O
amidino B
substituted I
- I
phenylene I
- I
bis I
- I
benzothyazoles I
3a O
- O
3f O
was O
achieved O
by O
condensation O
reaction O
of O
isophthaloyl B
dichloride I
1a O
and O
terephthaloyl B
dichloride I
1b O
or O
with O
phthalic B
acid I
1c O
with O
5 B
- I
amidinium I
- I
2 I
- I
aminobenzothiolate I
2a O
and O
5 B
- I
( I
imidazolinium I
- I
2 I
- I
yl I
) I
- I
2 I
- I
aminobenzothiolate I
2b O
in O
good O
yields O
. O

The O
targeted O
compounds O
were O
converted O
in O
the O
desired O
water O
soluble O
dihydrochloride B
salts O
by O
reaction O
of O
appropriate O
free O
base O
with O
concd O
HCl B
in O
ethanol B
or O
acetic B
acid I
. O

All O
tested O
compounds O
( O
3a O
- O
3f O
) O
showed O
antiproliferative O
effects O
on O
tumour O
cells O
in O
a O
concentration O
- O
dependant O
manner O
. O

The O
strongest O
activity O
and O
cytotoxicity O
was O
observed O
for O
diimidazolinyl B
substituted O
phenylene B
- I
bisbenzothiazole I
compound O
3b O
. O

These O
effects O
were O
shown O
to O
be O
related O
to O
DNA O
- O
binding O
properties O
, O
topoisomerase O
I O
and O
II O
poisoning O
effects O
and O
apoptosis O
induction O
. O

The O
highest O
tested O
selectivity O
towards O
tumour O
cells O
was O
observed O
for O
the O
imidazolyl B
substituted O
phenylene B
- I
benzothiazole I
3d O
that O
showed O
no O
cytotoxic O
effects O
on O
normal O
fibroblasts O
making O
it O
an O
excellent O
candidate O
for O
further O
chemical O
optimization O
and O
preclinical O
evaluation O
. O

A O
Bioluminescent O
Assay O
System O
for O
Whole O
- O
Cell O
Determination O
of O
Hormones O
. O

A O
bioluminescent O
- O
assay O
system O
was O
fabricated O
for O
an O
efficient O
determination O
of O
bioactive O
small O
molecules O
in O
physiological O
samples O
. O

The O
following O
three O
components O
were O
newly O
created O
for O
this O
assay O
system O
: O
( O
i O
) O
a O
single O
- O
chain O
probe O
exerting O
a O
7 O
. O
2 O
- O
times O
stronger O
optical O
intensity O
than O
conventional O
ones O
, O
( O
ii O
) O
a O
high O
throughput O
assay O
device O
uniquely O
designed O
for O
the O
assay O
system O
with O
ca O
. O
one O
- O
fourth O
smaller O
standard O
deviation O
( O
SD O
) O
to O
samples O
than O
without O
the O
device O
, O
( O
iii O
) O
a O
buffer O
cocktail O
optimized O
for O
the O
assay O
system O
. O

The O
advantages O
of O
the O
assay O
system O
were O
evaluated O
by O
determining O
( O
i O
) O
the O
stress O
hormone O
levels O
in O
human O
saliva O
and O
( O
ii O
) O
multicolor O
imaging O
of O
genomic O
and O
nongenomic O
effects O
of O
woman O
sex O
hormones O
. O

This O
study O
guides O
on O
how O
to O
fabricate O
an O
efficient O
assay O
system O
for O
bioactive O
small O
molecules O
with O
convenience O
and O
high O
precision O
. O

Large O
networks O
of O
vertical O
multi O
- O
layer O
graphenes B
with O
morphology O
- O
tunable O
magnetoresistance O
. O

We O
report O
on O
the O
comparative O
study O
of O
magnetotransport O
properties O
of O
large O
- O
area O
vertical O
few O
- O
layer O
graphene B
networks O
with O
different O
morphologies O
, O
measured O
in O
a O
strong O
( O
up O
to O
10 O
T O
) O
magnetic O
field O
over O
a O
wide O
temperature O
range O
. O

The O
petal O
- O
like O
and O
tree O
- O
like O
graphene B
networks O
grown O
by O
a O
plasma O
enhanced O
CVD O
process O
on O
a O
thin O
( O
500 O
nm O
) O
silicon B
oxide I
layer O
supported O
by O
a O
silicon B
wafer O
demonstrate O
a O
significant O
difference O
in O
the O
resistance O
- O
magnetic O
field O
dependencies O
at O
temperatures O
ranging O
from O
2 O
to O
200 O
K O
. O

This O
behaviour O
is O
explained O
in O
terms O
of O
the O
effect O
of O
electron O
scattering O
at O
ultra O
- O
long O
reactive O
edges O
and O
ultra O
- O
dense O
boundaries O
of O
the O
graphene B
nanowalls O
. O

Our O
results O
pave O
a O
way O
towards O
three O
- O
dimensional O
vertical O
graphene B
- O
based O
magnetoelectronic O
nanodevices O
with O
morphology O
- O
tuneable O
anisotropic O
magnetic O
properties O
. O

The O
structure O
of O
the O
biliverdin B
cofactor O
in O
the O
Pfr O
state O
of O
bathy O
and O
prototypical O
phytochromes O
. O

The O
structures O
of O
the O
chromophore O
binding O
pockets O
in O
the O
Pfr O
states O
of O
various O
bathy O
and O
prototypical O
biliverdin B
- O
binding O
phytochromes O
were O
analysed O
by O
using O
a O
combined O
spectroscopic O
- O
theoretical O
approach O
. O

For O
the O
Pfr O
state O
of O
the O
bathy O
phytochrome O
from O
Pseudomonas O
aeruginosa O
( O
PaBphP O
) O
the O
very O
good O
agreement O
between O
calculated O
Raman O
spectra O
of O
the O
tetrapyrrole B
cofactor O
, O
obtained O
by O
quantum O
- O
mechanical O
/ O
molecular O
- O
mechanical O
hybrid O
methods O
, O
and O
the O
experimental O
resonance O
Raman O
( O
RR O
) O
spectra O
confirms O
important O
conclusions O
derived O
from O
the O
previous O
crystallographic O
analyses O
, O
particularly O
the O
ZZEssa O
configuration O
of O
the O
chromophore O
and O
its O
attachment O
to O
the O
thiol B
side O
chain O
of O
Cys12 B
via O
the O
exocyclic O
vinyl I
group O
of O
ring O

A O
. O

The O
match O
between O
the O
RR O
spectra O
of O
the O
Pfr O
states O
of O
PaBphP O
and O
the O
bathy O
phytochrome O
Agp2 O
from O
Agrobacterium O
tumefaciens O
indicates O
very O
similar O
structures O
of O
the O
chromophore O
binding O
pockets O
. O

The O
homogeneous O
chromophore O
conformation O
in O
bathy O
phytochromes O
is O
in O
sharp O
contrast O
to O
the O
Pfr O
states O
of O
prototypical O
phytochromes O
as O
demonstrated O
by O
comparative O
RR O
spectroscopic O
analyses O
. O

The O
Pfr O
states O
of O
prototypical O
phytochromes O
, O
thoroughly O
studied O
for O
Agp1 O
( O
A O
. O
tumefaciens O
) O
, O
display O
conformational O
equilibria O
between O
two O
sub O
- O
states O
differing O
with O
respect O
to O
the O
CD O
methine B
bridge O
torsional O
angle O
and O
the O
AB O
methine B
bridge O
geometry O
. O

These O
differences O
may O
mainly O
root O
in O
the O
interactions O
of O
the O
cofactor O
with O
the O
highly O
conserved O
Asp194 B
( O
PaBphP O
) O
that O
occur O
via O
its O
carboxylate B
function O
in O
bathy O
phytochromes O
. O

The O
weaker O
interactions O
via O
the O
carbonyl B
function O
in O
prototypical O
phytochromes O
may O
lead O
to O
a O
higher O
structural O
flexibility O
of O
the O
chromophore O
binding O
pocket O
that O
opens O
the O
reaction O
channel O
for O
the O
thermal O
( O
ZZE O
- O
- O
> O
ZZZ O
) O
Pfr O
- O
to O
- O
Pr O
back O
- O
conversion O
. O

Genetic O
Information O
and O
the O
Prediction O
of O
Incident O
Type O
2 O
Diabetes O
in O
a O
High O
- O
Risk O
Multi O
- O
Ethnic O
Population O
: O
The O
EpiDREAM O
Genetic O
Study O
. O

OBJECTIVESTo O
determine O
if O
16 O
single O
nucleotide O
polymorphisms O
( O
SNPs O
) O
associated O
with O
type O
2 O
diabetes O
( O
T2DM O
) O
in O
Europeans O
are O
also O
associated O
with O
T2DM O
in O
South O
Asians O
and O
Latinos O
, O
and O
if O
they O
can O
add O
to O
the O
prediction O
of O
incident O
T2DM O
in O
a O
high O
- O
risk O
population O
. O
RESEARCH O
DESIGN O
AND O
METHODSIn O
the O
EpiDREAM O
prospective O
cohort O
study O
, O
physical O
measures O
, O
questionnaires O
, O
and O
blood O
samples O
were O
collected O
from O
25 O
, O
063 O
individuals O
at O
risk O
for O
dysglycemia O

. O

Sixteen O
SNPs O
that O
have O
been O
robustly O
associated O
with O
T2DM O
in O
Europeans O
were O
genotyped O
. O

Among O
15 O
, O
466 O
European O
, O
South O
Asian O
, O
and O
Latino O
subjects O
, O
we O
examined O
the O
association O
of O
these O
16 O
SNPs O
alone O
and O
combined O
in O
a O
gene O
score O
with O
incident O
cases O
of O
T2DM O
( O
n O
= O
1 O
, O
016 O
) O
that O
developed O
during O
3 O
. O
3 O
years O
of O
follow O
- O
up O
. O
RESULTSNine O
of O
the O
16 O
SNPs O
were O
significantly O
associated O
with O
T2DM O
, O
and O
their O
direction O
of O
effect O
was O
consistent O
across O
the O
three O
ethnic O
groups O
. O

The O
gene O
score O
was O
significantly O
higher O
among O
subjects O
who O
developed O
incident O
T2DM O
( O
cases O
vs O
. O
noncases O
: O
16 O
. O
47 O
[ O
2 O
. O
50 O
] O
vs O
. O
15 O
. O
99 O
[ O
2 O
. O
56 O
] O
; O
P O
= O
0 O
. O
00001 O
) O
. O

The O
gene O
score O
remained O
an O
independent O
predictor O
of O
incident O
T2DM O
with O
an O
odds O
ratio O
of O
1 O
. O
08 O
( O
95 O
% O
CI O
, O
1 O
. O
05 O
- O
1 O
. O
11 O
) O
per O
additional O
risk O
allele O
after O
adjustment O
for O
T2DM O
risk O
factors O
. O

The O
gene O
score O
in O
those O
with O
no O
family O
history O
of O
T2DM O
was O
16 O
. O
02 O
, O
whereas O
it O
was O
16 O
. O
19 O
in O
those O
with O
one O
parent O
with O
T2DM O
and O
it O
was O
16 O
. O
32 O
in O
those O
with O
two O
parents O
with O
T2DM O
( O
P O
trend O
= O
0 O
. O
0004 O
) O
. O

The O
C O
statistic O
of O
T2DM O
risk O
factors O
was O
0 O
. O
708 O
( O
0 O
. O
691 O
- O
0 O
. O
725 O
) O
and O
increased O
only O
marginally O
to O
0 O
. O
714 O
( O
0 O
. O
698 O
- O
0 O
. O
731 O
) O
with O
the O
addition O
of O
the O
gene O
score O
( O
P O
for O
C O
statistic O
change O
= O
0 O
. O
0052 O
) O
. O
CONCLUSIONT2DM O
genetic O
associations O
are O
generally O
consistent O
across O
ethnic O
groups O
, O
and O
a O
gene O
score O
only O
adds O
marginal O
information O
to O
clinical O
factors O
for O
T2DM O
prediction O
. O

Strain O
- O
induced O
Dirac O
cone O
- O
like O
electronic O
structures O
and O
semiconductor O
- O
semimetal O
transition O
in O
graphdiyne B
. O

By O
means O
of O
first O
- O
principles O
calculations O
combined O
with O
the O
tight O
- O
binding O
approximation O
, O
the O
strain O
- O
induced O
semiconductor O
- O
semimetal O
transition O
in O
graphdiyne B
is O
discovered O
. O

It O
is O
shown O
that O
the O
band O
gap O
of O
graphdiyne B
increases O
from O
0 O
. O
47 O
eV O
to O
1 O
. O
39 O
eV O
with O
increasing O
the O
biaxial O
tensile O
strain O
, O
while O
the O
band O
gap O
decreases O
from O
0 O
. O
47 O
eV O
to O
nearly O
zero O
with O
increasing O
the O
uniaxial O
tensile O
strain O
, O
and O
Dirac O
cone O
- O
like O
electronic O
structures O
are O
observed O
. O

The O
uniaxial O
strain O
- O
induced O
changes O
of O
the O
electronic O
structures O
of O
graphdiyne B
come O
from O
the O
breaking O
of O
geometrical O
symmetry O
that O
lifts O
the O
degeneracy O
of O
energy O
bands O
. O

The O
properties O
of O
graphdiyne B
under O
strains O
are O
found O
to O
differ O
remarkably O
from O
that O
of O
graphene B
. O

The O
nascent O
polypeptide O
- O
associated O
complex O
is O
a O
key O
regulator O
of O
proteostasis O
. O

The O
adaptation O
of O
protein O
synthesis O
to O
environmental O
and O
physiological O
challenges O
is O
essential O
for O
cell O
viability O
. O

Here O
, O
we O
show O
that O
translation O
is O
tightly O
linked O
to O
the O
protein O
- O
folding O
environment O
of O
the O
cell O
through O
the O
functional O
properties O
of O
the O
ribosome O
bound O
chaperone O
NAC O
( O
nascent O
polypeptide O
- O
associated O
complex O
) O
. O

Under O
non O
- O
stress O
conditions O
, O
NAC O
associates O
with O
ribosomes O
to O
promote O
translation O
and O
protein O
folding O
. O

When O
proteostasis O
is O
imbalanced O
, O
NAC O
relocalizes O
from O
a O
ribosome O
- O
associated O
state O
to O
protein O
aggregates O
in O
its O
role O
as O
a O
chaperone O
. O

This O
results O
in O
a O
functional O
depletion O
of O
NAC O
from O
the O
ribosome O
that O
diminishes O
translational O
capacity O
and O
the O
flux O
of O
nascent O
proteins O
. O

Depletion O
of O
NAC O
from O
polysomes O
and O
re O
- O
localisation O
to O
protein O
aggregates O
is O
observed O
during O
ageing O
, O
in O
response O
to O
heat O
shock O
and O
upon O
expression O
of O
the O
highly O
aggregation O
- O
prone O
polyglutamine B
- O
expansion O
proteins O
and O
A O
beta O
- O
peptide O
. O

These O
results O
demonstrate O
that O
NAC O
has O
a O
central O
role O
as O
a O
proteostasis O
sensor O
to O
provide O
the O
cell O
with O
a O
regulatory O
feedback O
mechanism O
in O
which O
translational O
activity O
is O
also O
controlled O
by O
the O
folding O
state O
of O
the O
cellular O
proteome O
and O
the O
cellular O
response O
to O
stress O
. O

Antifungal O
Azoles B
: O
Structural O
Insights O
into O
Undesired O
Tight O
Binding O
to O
Cholesterol B
- O
Metabolizing O
CYP46A1 O
. O

Although O
there O
are O
currently O
three O
generations O
of O
antifungal O
azoles B
on O
the O
market O
, O
even O
the O
third O
generation O
agents O
show O
undesired O
interactions O
with O
human O
cytochrome O
P450 O
enzymes O
. O

CYP46A1 O
is O
a O
cholesterol B
- O
metabolizing O
P450 O
in O
the O
brain O
tightly O
binding O
a O
number O
of O
structurally O
distinct O
azoles B
. O

Previously O
, O
we O
determined O
the O
crystal O
structures O
of O
CYP46A1 O
in O
complex O
with O
voriconazole B
and O
clotrimazole B
, O
and O
in O
the O
present O
work O
we O
co O
- O
crystallized O
the O
P450 O
with O
posaconazole B
at O
2 O
. O
5 O
A O
resolution O
. O

This O
long O
antifungal O
drug O
coordinates O
the O
P450 O
heme B
iron B
with O
the O
nitrogen B
atom O
of O
its O
terminal O
azole B
ring O
and O
adopts O
a O
linear O
configuration O
occupying O
the O
whole O
length O
of O
the O
substrate O
access O
channel O
and O
extending O
beyond O
the O
protein O
surface O
. O

Numerous O
drug O
- O
protein O
interactions O
determine O
the O
submicromolar O
Kd O
of O
posaconazole B
for O
CYP46A1 O
. O

We O
compared O
the O
crystal O
structure O
of O
posaconazole B
- O
bound O
CYP46A1 O
with O
those O
of O
the O
P450 O
in O
complex O
with O
other O
drugs O
including O
the O
antifungal O
voriconazole B
and O
clotrimazole B
. O

We O
also O
analyzed O
the O
accommodation O
of O
posaconazole B
in O
the O
active O
site O
of O
the O
target O
enzymes O
, O
CYPs O
51 O
, O
from O
several O
pathogenic O
species O
. O

These O
and O
the O
solution O
studies O
with O
different O
marketed O
azoles B
, O
collectively O
, O
allowed O
us O
to O
identify O
the O
determinants O
of O
tight O
azole B
binding O
to O
CYP46A1 O
and O
generate O
an O
overall O
picture O
of O
azole B
binding O
to O
this O
important O
P450 O
. O

The O
data O
obtained O
suggest O
that O
development O
of O
CYP51 O
- O
specific O
antifungal O
agents O
will O
continue O
to O
be O
a O
challenge O
. O

Therefore O
, O
structural O
understanding O
of O
the O
azole B
binding O
not O
only O
to O
CYPs O
51 O
from O
the O
pathogenic O
species O
but O
also O
to O
different O
human O
P450s O
is O
required O
to O
deal O
efficiently O
with O
this O
challenge O
. O

Pharmacological O
activation O
of O
kappa O
opioid O
receptors O
: O
aversive O
effects O
in O
adolescent O
and O
adult O
male O
rats O
. O

RATIONALE O
: O
The O
dynorphin O
( O
DYN O
) O
/ O
kappa O
opioid O
receptor O
( O
KOR O
) O
system O
is O
involved O
in O
the O
dysphoric O
properties O
of O
drugs O
of O
abuse O
. O

Given O
that O
adolescents O
show O
reduced O
sensitivity O
to O
aversive O
effects O
of O
many O
drugs O
, O
alterations O
in O
the O
DYN O
/ O
KOR O
system O
may O
contribute O
to O
the O
prevalence O
of O
drug O
use O
during O
adolescence O
. O

OBJECTIVES O
: O
The O
present O
study O
was O
designed O
to O
assess O
dysphoric O
properties O
of O
a O
selective O
kappa O
agonist O
, O
U62 B
, I
066 I
, O
in O
adolescent O
and O
adult O
rats O
using O
both O
conditioned O
taste O
aversion O
( O
CTA O
) O
and O
conditioned O
place O
aversion O
( O
CPA O
) O
paradigms O
. O

METHODS O
: O
For O
CTA O
, O
water O
- O
restricted O
rats O
were O
administered O
U62 B
, I
066 I
following O
30 O
min O
access O
to O
a O
saccharin B
solution O
, O
with O
subsequent O
saccharin B
consumption O
used O
to O
index O
aversion O
. O

For O
CPA O
, O
animals O
were O
allowed O
access O
to O
both O
compartments O
of O
a O
two O
- O
compartment O
chamber O
for O
a O
15 O
- O
min O
pre O
- O
and O
post O
- O
conditioning O
test O
. O

For O
conditioning O
, O
subjects O
were O
administered O
U62 B
, I
066 I
prior O
to O
confinement O
to O
one O
side O
of O
the O
chamber O
and O
saline O
prior O
to O
confinement O
to O
the O
other O
side O
for O
a O
total O
of O
four O
pairings O
. O

RESULTS O
: O
Overall O
, O
adolescents O
displayed O
reduced O
sensitivity O
to O
the O
kappa O
agonist O
relative O
to O
adults O
. O

Adults O
demonstrated O
taste O
aversions O
to O
the O
0 O
. O
2 O
and O
0 O
. O
3 O
mg O
/ O
kg O
doses O
of O
U62 B
, I
066 I
, O
whereas O
adolescents O
did O
not O
display O
aversions O
to O
any O
tested O
doses O
. O

Adults O
demonstrated O
a O
place O
aversion O
to O
the O
0 O
. O
1 O
and O
0 O
. O
2 O
mg O
/ O
kg O
dose O
of O
U62 B
, I
066 I
when O
paired O
with O
the O
preferred O
side O
of O
the O
conditioning O
chamber O
. O

Adolescents O
did O
not O
display O
aversions O
to O
any O
of O
the O
doses O
tested O
. O

CONCLUSIONS O
: O
Reduced O
sensitivity O
to O
DYN O
/ O
KOR O
system O
activation O
during O
adolescence O
may O
be O
a O
contributing O
factor O
to O
the O
age O
- O
typical O
insensitivity O
to O
aversive O
properties O
of O
drugs O
commonly O
abused O
by O
adolescents O
. O

Automatic O
approach O
bias O
towards O
smoking O
cues O
is O
present O
in O
smokers O
but O
not O
in O
ex O
- O
smokers O
. O

RATIONALE O
: O
Drug O
- O
addicted O
individuals O
show O
automatic O
approach O
tendencies O
towards O
drug O
- O
related O
cues O
, O
i O
. O
e O
. O
, O
an O
approach O
bias O
( O
ApB O
) O
. O

Nevertheless O
, O
little O
is O
known O
about O
ApB O
in O
tobacco O
smokers O
and O
about O
the O
presence O
of O
ApB O
after O
smoking O
abstinence O
. O

OBJECTIVES O
: O
We O
investigated O
ApB O
to O
smoking O
cues O
in O
heavy O
tobacco O
smokers O
versus O
never O
- O
smokers O
and O
studied O
its O
relation O
to O
smoking O
characteristics O
and O
craving O
. O

Second O
, O
we O
compared O
ApBs O
of O
heavy O
smokers O
with O
biases O
of O
abstinent O
heavy O
smokers O
. O

METHOD O
: O
A O
group O
of O
current O
heavy O
smokers O
( O
n O
= O
24 O
) O
, O
ex O
- O
smokers O
who O
were O
abstinent O
for O
at O
least O
5 O
years O
( O
n O
= O
20 O
) O
, O
and O
never O
- O
smokers O
( O
n O
= O
20 O
) O
took O
part O
in O
the O
experiment O
. O

An O
indirect O
smoking O
approach O
avoidance O
task O
was O
performed O
, O
in O
which O
participants O
were O
required O
to O
respond O
to O
pictures O
of O
smoking O
and O
neutral O
cues O
by O
pulling O
( O
approach O
) O
or O
pushing O
( O
avoid O
) O
on O
a O
joystick O
, O
according O
to O
the O
content O
- O
irrelevant O
format O
of O
the O
picture O
( O
landscape O
or O
portrait O
) O
. O

Craving O
scores O
were O
examined O
using O
the O
Questionnaire O
of O
Smoking O
Urges O
. O

RESULTS O
: O
Heavy O
smokers O
showed O
an O
ApB O
for O
smoking O
cues O
compared O
to O
ex O
- O
smokers O
and O
never O
- O
smokers O
, O
which O
correlated O
positively O
to O
craving O
scores O
. O

There O
were O
no O
group O
differences O
in O
ApB O
scores O
for O
ex O
- O
smokers O
and O
never O
- O
smokers O
. O

CONCLUSION O
: O
These O
results O
suggest O
that O
ApBs O
for O
smoking O
cues O
are O
present O
in O
heavy O
smokers O
and O
decrease O
after O
long O
- O
term O
successful O
smoking O
cessation O
. O

Methylphenidate B
reduces O
functional O
connectivity O
of O
nucleus O
accumbens O
in O
brain O
reward O
circuit O
. O

Release O
of O
dopamine B
in O
the O
nucleus O
accumbens O
( O
NAcc O
) O
is O
essential O
for O
acute O
drug O
reward O
. O

The O
present O
study O
was O
designed O
to O
trace O
the O
reinforcing O
effect O
of O
dopamine B
release O
by O
measuring O
the O
functional O
connectivity O
( O
FC O
) O
between O
the O
NAcc O
and O
brain O
regions O
involved O
in O
a O
limbic O
cortical O
- O
subcortical O
circuit O
during O
a O
dopaminergic O
challenge O
. O

Twenty O
healthy O
volunteers O
received O
single O
doses O
of O
methylphenidate B
( O
40 O
mg O
) O
and O
placebo O
on O
separate O
test O
days O
according O
to O
a O
double O
- O
blind O
, O
cross O
- O
over O
study O
design O
. O

Resting O
state O
functional O
magnetic O
resonance O
imaging O
( O
fMRI O
) O
was O
measured O
between O
1 O
. O
5 O
and O
2 O
h O
postdosing O
. O

FC O
between O
regions O
of O
interest O
( O
ROI O
) O
in O
the O
NAcc O
, O
the O
medial O
dorsal O
nucleus O
( O
MDN O
) O
of O
the O
thalamus O
and O
remote O
areas O
within O
the O
limbic O
circuit O
was O
explored O
. O

Methylphenidate B
significantly O
reduced O
FC O
between O
the O
NAcc O
and O
the O
basal O
ganglia O
( O
i O
. O
e O
. O
, O
subthalamic O
nucleus O
and O
ventral O
pallidum O
( O
VP O
) O
) O
, O
relative O
to O
placebo O
. O

Methylphenidate B
also O
decreased O
FC O
between O
the O
NAcc O
and O
the O
medial O
prefrontal O
cortex O
( O
mPFC O
) O
as O
well O
as O
the O
temporal O
cortex O
. O

Methylphenidate B
did O
not O
affect O
FC O
between O
MDN O
and O
the O
limbic O
circuit O
. O

It O
is O
concluded O
that O
methylphenidate B
directly O
affects O
the O
limbic O
reward O
circuit O
. O

Drug O
- O
induced O
changes O
in O
FC O
of O
the O
NAcc O
may O
serve O
as O
a O
useful O
marker O
of O
drug O
activity O
in O
in O
the O
brain O
reward O
circuit O
. O

Balancing O
power O
density O
based O
quantum O
yield O
characterization O
of O
upconverting O
nanoparticles O
for O
arbitrary O
excitation O
intensities O
. O

Upconverting O
nanoparticles O
( O
UCNPs O
) O
have O
recently O
shown O
great O
potential O
as O
contrast O
agents O
in O
biological O
applications O
. O

In O
developing O
different O
UCNPs O
, O
the O
characterization O
of O
their O
quantum O
yield O
( O
QY O
) O
is O
a O
crucial O
issue O
, O
as O
the O
typically O
drastic O
decrease O
in O
QY O
for O
low O
excitation O
power O
densities O
can O
either O
impose O
a O
severe O
limitation O
or O
provide O
an O
opportunity O
in O
many O
applications O
. O

The O
power O
density O
dependence O
of O
the O
QY O
is O
governed O
by O
the O
competition O
between O
the O
energy O
transfer O
upconversion O
( O
ETU O
) O
rate O
and O
the O
linear O
decay O
rate O
in O
the O
depopulation O
of O
the O
intermediate O
state O
of O
the O
involved O
activator O
in O
the O
upconversion O
process O
. O

Here O
we O
show O
that O
the O
QYs O
of O
Yb B
( I
3 I
+ I
) I
sensitized O
two O
- O
photon O
upconversion O
emissions O
can O
be O
well O
characterized O
by O
the O
balancing O
power O
density O
, O
at O
which O
the O
ETU O
rate O
and O
the O
linear O
decay O
rate O
have O
equal O
contributions O
, O
and O
its O
corresponding O
QY O
. O

The O
results O
in O
this O
paper O
provide O
a O
method O
to O
fully O
describe O
the O
QY O
of O
upconverting O
nanoparticles O
for O
arbitrary O
excitation O
power O
densities O
, O
and O
is O
a O
fast O
and O
simple O
approach O
for O
assessing O
the O
applicability O
of O
UCNPs O
from O
the O
perspective O
of O
energy O
conversion O
. O

Sparstolonin B
B I
suppresses O
lipopolysaccharide O
- O
induced O
inflammation O
in O
human O
umbilical O
vein O
endothelial O
cells O
. O

Sparstolonin B
B I
( O
SsnB B
) O
is O
an O
isocoumarin B
compound O
isolated O
from O
the O
tubers O
of O
both O
Sparganium O
stoloniferum O
and O
Scirpus O
yagara O
. O

We O
previously O
demonstrated O
that O
SsnB O
blocked O
the O
Toll O
- O
like O
receptor O
( O
TLR O
) O
2 O
- O
and O
TLR4 O
- O
triggered O
inflammatory O
signaling O
in O
macrophages O
by O
inhibiting O
the O
recruitment O
of O
MyD88 O
to O
the O
TIR O
domains O
of O
TLR2 O
and O
TLR4 O
. O

The O
present O
study O
was O
designed O
to O
examine O
the O
effects O
of O
SsnB O
on O
vascular O
inflammatory O
responses O
in O
human O
umbilical O
vein O
endothelial O
cells O
( O
HUVECs O
) O
challenged O
by O
lipopolysaccharide O
( O
LPS O
, O
a O
TLR4 O
ligand O
) O
. O

We O
found O
that O
SsnB O
dose O
- O
dependently O
attenuated O
the O
LPS O
- O
induced O
expression O
of O
interleukin O
( O
IL O
) O
- O
1 O
beta O
and O
monocyte O
chemoattractant O
protein O
1 O
both O
at O
the O
transcription O
and O
translation O
levels O
in O
HUVEC O
. O

LPS O
- O
induced O
endothelial O
cell O
adhesion O
molecules O
, O
intercellular O
adhesion O
molecular O
- O
1 O
and O
vascular O
cell O
adhesion O
molecule O
- O
1 O
expressions O
were O
also O
reduced O
by O
treatment O
with O
SsnB O
. O

In O
addition O
, O
co O
- O
incubation O
with O
SsnB O
attenuated O
THP O
- O
1 O
monocyte O
adhesion O
to O
LPS O
- O
activated O
HUVECs O
. O

Furthermore O
, O
SsnB O
efficiently O
suppressed O
LPS O
- O
induced O
phosphorylation O
of O
extracellular O
- O
signal O
- O
regulated O
kinase O
( O
Erk1 O
/ O
2 O
) O
and O
Akt O
in O
HUVECs O
. O

These O
findings O
show O
that O
SsnB O
can O
suppress O
endothelial O
cell O
inflammation O
, O
suggesting O
that O
SsnB O
might O
be O
suitable O
for O
development O
as O
a O
therapeutic O
agent O
for O
inflammatory O
cardiovascular O
disease O
. O

Cytochrome O
p450 O
- O
mediated O
changes O
in O
oxycodone B
pharmacokinetics O
/ O
pharmacodynamics O
and O
their O
clinical O
implications O
. O

In O
recent O
years O
the O
use O
of O
the O
opioid O
oxycodone B
has O
increased O
markedly O
and O
replacing O
morphine B
as O
the O
first O
- O
line O
choice O
of O
opioid O
in O
several O
countries O
. O

There O
are O
formulations O
for O
oral O
immediate O
, O
oral O
extended O
release O
and O
intravenous O
use O
. O

The O
bioavailability O
is O
higher O
than O
for O
morphine B
and O
less O
variable O
. O

Oxycodone B
is O
primarily O
metabolized O
in O
the O
liver O
by O
the O
cytochrome O
P450 O
( O
CYP O
) O
enzymes O
with O
CYP3A O
as O
the O
major O
metabolic O
pathway O
and O
CYP2D6 O
as O
the O
minor O
metabolic O
pathway O
to O
noroxycodone B
, O
oxymorphone B
and O
noroxymorphone B
. O

Oxycodone B
exerts O
its O
analgesic O
effect O
via O
the O
micro O
- O
opioid O
receptor O
. O

The O
metabolism O
of O
CYP2D6 O
substrates O
varies O
to O
a O
large O
degree O
between O
individuals O
as O
a O
result O
of O
allele O
functionality O
. O

Poor O
metabolizers O
( O
PM O
) O
have O
two O
non O
- O
functional O
alleles O
, O
extensive O
metabolizers O
( O
EM O
) O
are O
homozygous O
with O
two O
functional O
alleles O
or O
heterozygous O
with O
one O
functional O
allele O
and O
ultrarapid O
metabolizers O
( O
UM O
) O
have O
more O
than O
two O
functional O
alleles O
. O

There O
are O
pronounced O
interethnic O
differences O
in O
the O
allele O
distribution O
. O

On O
the O
basis O
of O
studies O
performed O
thus O
far O
, O
oxycodone B
concentrations O
in O
comparison O
with O
EM O
are O
similar O
in O
PM O
and O
reduced O
in O
UM O
. O

The O
pharmacokinetics O
in O
UM O
are O
insufficiently O
investigated O
. O

Simultaneous O
inhibition O
of O
both O
CYP3A O
and O
CYP2D6 O
results O
in O
increased O
oxycodone B
concentrations O
and O
such O
a O
combination O
should O
be O
avoided O
. O

A O
similar O
effect O
is O
to O
be O
expected O
with O
use O
of O
a O
CYP3A O
inhibitor O
in O
CYP2D6 O
PM O
. O

Concomitant O
use O
of O
enzyme O
inducers O
such O
as O
rifampicin B
, O
St O
John O
' O
s O
wort O
and O
carbamazepine B
should O
be O
avoided O
because O
of O
the O
risk O
of O
subtherapeutic O
concentrations O
of O
oxycodone B
. O

When O
the O
dosage O
of O
morphine B
may O
result O
in O
unpredictable O
bioavailability O
, O
like O
in O
patients O
with O
severe O
hepatic O
cirrhosis O
, O
oxycodone B
might O
be O
beneficial O
because O
it O
has O
higher O
and O
less O
variability O
in O
bioavailability O
between O
patients O
than O
morphine B
. O

Using O
multiple O
targeted O
therapies O
in O
oncology O
: O
considerations O
for O
use O
, O
and O
progress O
to O
date O
in O
breast O
cancer O
. O

There O
has O
been O
significant O
progress O
in O
our O
basic O
understanding O
of O
drugs O
and O
targets O
in O
the O
management O
of O
breast O
cancer O
. O

Recent O
breast O
cancer O
clinical O
trials O
have O
examined O
whether O
combinations O
of O
drugs O
targeting O
transmembrane O
receptors O
or O
their O
downstream O
effectors O
involved O
in O
cell O
signal O
transduction O
can O
increase O
response O
rates O
and O
overcome O
acquired O
and O
/ O
or O
de O
novo O
drug O
resistance O
compared O
to O
a O
single O
targeted O
agent O
with O
or O
without O
systemic O
chemotherapy O
. O

We O
reviewed O
published O
clinical O
trials O
and O
conference O
proceedings O
examining O
combinations O
of O
targeted O
therapies O
across O
different O
breast O
cancer O
subtypes O
. O

Improvements O
in O
pathological O
complete O
response O
( O
pCR O
) O
rates O
and O
progression O
free O
survival O
( O
PFS O
) O
in O
preoperatively O
treated O
and O
metastatic O
human O
epidermal O
growth O
factor O
2 O
( O
HER2 O
) O
- O
positive O
breast O
cancer O
, O
respectively O
, O
have O
been O
observed O
with O
combinations O
of O
anti O
- O
HER2 O
therapies O
given O
concomitantly O
. O

Promising O
results O
were O
also O
observed O
in O
estrogen B
receptor O
( O
ER O
) O
- O
positive O
, O
HER2 O
- O
negative O
breast O
cancer O
using O
a O
mammalian O
target O
of O
rapamycin B
inhibitor O
with O
tamoxifen B
or O
an O
aromatase O
inhibitor O
( O
AI O
) O
in O
the O
preoperative O
setting O
and O
for O
patients O
with O
metastatic O
breast O
cancer O
that O
had O
previously O
progressed O
on O
endocrine O
therapy O
alone O
. O

A O
recent O
phase O
II O
trial O
reported O
a O
statistically O
significant O
improvement O
in O
PFS O
with O
the O
addition O
of O
an O
oral O
inhibitor O
of O
cyclin O
- O
dependent O
kinase O
4 O
/ O
6 O
to O
letrozole B
compared O
to O
letrozole B
alone O
( O
26 O
. O
1 O
versus O
7 O
. O
5 O
months O
) O
. O

A O
phase O
III O
study O
is O
planned O
for O
early O
2013 O
. O

On O
the O
basis O
of O
preclinical O
data O
, O
clinical O
trials O
have O
examined O
combinations O
of O
hormonal O
agents O
such O
as O
fulvestrant B
with O
an O
AI O
. O

However O
, O
the O
results O
are O
conflicting O
. O

Early O
data O
indicated O
that O
poly B
( I
ADP I
- I
ribose I
) I
polymerase O
( O
PARP O
) O
inhibitors O
exploiting O
the O
concept O
of O
synthetic O
lethality O
would O
offer O
improved O
outcomes O
for O
patients O
with O
ER O
- O
negative O
, O
progesterone B
receptor O
( O
PR O
) O
- O
negative O
, O
HER2 O
- O
negative O
breast O
cancer O
often O
referred O
to O
as O
triple O
negative O
breast O
cancer O
( O
TNBC O
) O
; O
however O
, O
data O
in O
the O
phase O
III O
setting O
failed O
to O
confirm O
these O
findings O
but O
this O
may O
be O
because O
the O
drug O
was O
not O
a O
true O
PARP O
inhibitor O
. O

Chemotherapy O
continues O
to O
be O
the O
mainstay O
of O
treatment O
for O
TNBC O
until O
specific O
drugs O
and O
their O
associated O
targets O
are O
identified O
. O

As O
advances O
in O
medical O
technologies O
continue O
to O
identify O
multiple O
molecularly O
distinct O
breast O
cancer O
subgroups O
that O
are O
predicted O
to O
respond O
to O
combinations O
of O
targeted O
agents O
new O
challenges O
have O
arisen O
. O

In O
particular O
, O
how O
do O
we O
evaluate O
the O
safety O
and O
efficacy O
of O
these O
new O
drug O
combinations O
in O
relatively O
small O
subgroups O
of O
patients O
? O

Novel O
clinical O
trial O
designs O
will O
be O
required O
and O
increasingly O
regulatory O
agencies O
will O
require O
companion O
diagnostic O
tests O
that O
can O
identify O
the O
subgroups O
likely O
to O
respond O
to O
these O
therapies O
. O

The O
US O
Food O
and O
Drug O
Administration O
is O
assessing O
the O
role O
of O
pCR O
in O
breast O
cancer O
studies O
as O
a O
surrogate O
endpoint O
to O
predict O
clinical O
benefit O
in O
the O
accelerated O
drug O
approval O
process O
. O

Hedgehog O
Signaling O
Pathway O
and O
Cancer O
Therapeutics O
: O
Progress O
to O
Date O
. O

The O
Hedgehog O
( O
Hh O
) O
pathway O
is O
a O
developmental O
signaling O
pathway O
involved O
in O
numerous O
developmental O
processes O
, O
including O
determination O
of O
cell O
fate O
, O
patterning O
, O
proliferation O
, O
survival O
, O
and O
differentiation O
. O

While O
this O
pathway O
is O
silenced O
in O
most O
adult O
tissues O
, O
aberrant O
activation O
of O
it O
has O
been O
documented O
in O
a O
variety O
of O
malignancies O
. O

In O
cancers O
such O
as O
basal O
cell O
carcinoma O
( O
BCC O
) O
, O
ligand O
- O
independent O
mechanisms O
lead O
to O
constitutive O
Hh O
pathway O
activation O
through O
mutations O
in O
components O
of O
the O
pathway O
, O
including O
patched O
- O
1 O
( O
PTCH1 O
) O
or O
smoothened O
( O
SMO O
) O
. O

On O
the O
contrary O
, O
numerous O
other O
solid O
and O
hematologic O
tumors O
have O
been O
shown O
to O
harbor O
ligand O
- O
dependent O
activation O
of O
the O
Hh O
pathway O
by O
autocrine O
or O
paracrine O
mechanisms O
. O

Given O
that O
aberrant O
Hh O
pathway O
signaling O
has O
been O
seen O
in O
a O
number O
of O
malignancies O
, O
this O
pathway O
has O
been O
an O
attractive O
target O
for O
drug O
development O
. O

While O
the O
best O
- O
characterized O
approach O
is O
to O
target O
the O
SMO O
receptor O
, O
other O
rational O
approaches O
for O
inhibiting O
the O
Hh O
pathway O
include O
inhibiting O
downstream O
components O
or O
directly O
binding O
Hh O
ligands O
. O

In O
January O
of O
2012 O
, O
vismodegib B
, O
a O
SMO O
antagonist O
, O
became O
the O
first O
agent O
to O
target O
the O
Hh O
pathway O
to O
receive O
approval O
by O
the O
United O
States O
Food O
and O
Drug O
Administration O
( O
FDA O
) O
after O
this O
agent O
showed O
remarkable O
activity O
in O
phase O
I O
and O
II O
trials O
for O
the O
treatment O
of O
BCC O
. O

Despite O
promising O
preclinical O
studies O
with O
Hh O
pathway O
inhibitors O
in O
other O
malignancies O
that O
have O
suggested O
a O
potential O
role O
for O
these O
agents O
, O
attempts O
to O
translate O
this O
potential O
to O
clinical O
benefit O
has O
been O
disappointing O
. O

Future O
efforts O
will O
require O
further O
careful O
interpretation O
and O
analysis O
to O
determine O
the O
potential O
determinants O
and O
predictors O
of O
efficacy O
. O

Currently O
, O
several O
phase O
I O
and O
II O
trials O
evaluating O
Hh O
inhibitors O
in O
a O
variety O
of O
tumor O
settings O
are O
underway O
. O

Morphological O
Change O
and O
Mobility O
Enhancement O
in O
PEDOT B
: O
PSS B
by O
Adding O
Co O
- O
solvents O
. O

Adding O
ethylene B
glycol I
( O
EG O
) O
to O
poly B
( I
3 I
, I
4 I
- I
ethylenedioxythiophe I
) I
: O
poly B
( I
styrenesulfonate I
) I
( O
PEDOT B
: O
PSS B
) O
solution O
improves O
the O
crystallinity O
of O
the O
PEDOT B
and O
the O
ordering O
of O
the O
PEDOT B
nanocrystals O
in O
solid O
films O
. O

The O
carrier O
- O
mobility O
enhancement O
is O
confirmed O
by O
using O
ion O
- O
gel O
transistors O
combined O
with O
in O
situ O
UV O
- O
vis O
- O
NIR O
spectroscopy O
. O

A O
Generic O
Micropatterning O
Platform O
to O
Direct O
Human O
Mesenchymal O
Stem O
Cells O
from O
Different O
Origins O
Towards O
Myogenic O
Differentiation O
. O

Human O
mesenchymal O
stem O
cells O
( O
MSCs O
) O
derived O
from O
various O
origins O
show O
varied O
differentiation O
capability O
. O

Recent O
work O
shows O
that O
cell O
shape O
manipulation O
via O
micropatterning O
can O
modulate O
the O
differentiation O
of O
bone O
- O
marrow O
- O
derived O
MSCs O
. O

Herein O
, O
the O
effect O
of O
micropatterning O
on O
the O
myogenesis O
of O
MSCs O
isolated O
from O
three O
different O
sources O
( O
bone O
marrow O
, O
fetal O
tissue O
, O
and O
adipose O
) O
is O
reported O
. O

All O
the O
well O
- O
aligned O
cells O
, O
regardless O
of O
source O
, O
predominantly O
commit O
to O
myogenic O
lineage O
, O
as O
shown O
by O
the O
significant O
upregulation O
of O
myogenic O
gene O
markers O
and O
positive O
myosin O
heavy O
chain O
staining O
. O

It O
is O
demonstrated O
that O
our O
novel O
micropattern O
can O
be O
used O
as O
a O
generic O
platform O
for O
inducing O
myogenesis O
of O
MSCs O
from O
different O
sources O
and O
may O
also O
have O
the O
potential O
to O
be O
extended O
to O
induce O
other O
lineage O
commitment O
. O

3D O
Graphene B
Foams O
Cross O
- O
linked O
with O
Pre O
- O
encapsulated O
Fe3 B
O4 I
Nanospheres O
for O
Enhanced O
Lithium B
Storage O
. O

Electrostatic O
assembly O
between O
Fe3 B
O4 I
nanospheres O
and O
graphene B
oxide I
, O
and O
subsequent O
hydrothermal O
assembly O
with O
additional O
graphene B
sheets O
, O
leads O
to O
Fe3 B
O4 I
nanospheres O
encapsulated O
in O
the O
graphene B
shells O
and O
interconnected O
by O
the O
graphene B
networks O
. O

Such O
3D O
Fe3 B
O4 I
/ O
graphene B
foams O
exhibit O
enhanced O
lithium B
storage O
with O
excellent O
cycling O
performance O
and O
rate O
capability O
. O

Morphometric O
and O
Functional O
Changes O
of O
Salivary O
Gland O
Dysfunction O
after O
Radioiodine B
Ablation O
in O
a O
Murine O
Model O
. O

Background O
: O
Ablation O
of O
the O
thyroid O
tissue O
using O
radioiodine B
( O
RI O
) O
after O
the O
surgical O
removal O
of O
well O
- O
differentiated O
thyroid O
cancer O
( O
WDTC O
) O
can O
induce O
radiation O
- O
related O
salivary O
gland O
( O
SG O
) O
dysfunction O
. O

However O
, O
in O
vivo O
changes O
of O
SGs O
following O
RI O
administration O
in O
appropriate O
animal O
models O
are O
not O
well O
described O
in O
the O
literature O
. O

This O
study O
was O
undertaken O
to O
document O
morphometric O
and O
functional O
changes O
during O
the O
12 O
months O
following O
RI O
administration O
in O
a O
murine O
model O
of O
RI O
- O
induced O
SG O
dysfunction O
. O

Methods O
: O
Female O
C57BL O
/ O
6 O
, O
4 O
- O
week O
- O
old O
mice O
( O
n O
= O
60 O
) O
were O
divided O
into O
a O
RI O
- O
treated O
group O
( O
n O
= O
30 O
) O
that O
received O
RI O
orally O
( O
0 O
. O
01 O
mCi O
/ O
g O
body O
weight O
) O
or O
an O
unexposed O
control O
group O
( O
n O
= O
30 O
) O
. O

Mice O
in O
both O
groups O
were O
divided O
into O
five O
subgroups O
( O
n O
= O
6 O
per O
subgroup O
) O
and O
sacrificed O
at O
1 O
, O
2 O
, O
3 O
, O
6 O
, O
and O
12 O
months O
post O
- O
RI O
administration O
. O

Salivary O
flow O
rates O
( O
SFR O
) O
and O
salivary O
lag O
times O
were O
measured O
at O
1 O
, O
2 O
, O
3 O
, O
6 O
, O
and O
12 O
months O
after O
RI O
administration O
. O

Morphological O
and O
histological O
examinations O
and O
terminal O
deoxynucleotidyl O
transferase O
dUTP B
nick O
end O
labeling O
( O
TUNEL O
) O
assays O
were O
performed O
. O

In O
addition O
, O
changes O
in O
salivary O
99m B
Tc I
pertechnetate I
uptake O
and O
excretion O
were O
observed O
by O
single O
- O
photon O
emission O
computed O
tomography O
( O
SPECT O
) O
. O

Results O
: O
In O
RI O
- O
treated O
mice O
, O
the O
SGs O
were O
significantly O
lighter O
compared O
to O
unexposed O
controls O
at O
all O
study O
time O
points O
. O

Lag O
times O
to O
salivation O
in O
the O
RI O
- O
treated O
group O
were O
greater O
than O
in O
the O
unexposed O
controls O
, O
but O
mean O
SFR O
were O
lower O
. O

Histologic O
examinations O
of O
SGs O
in O
the O
RI O
- O
group O
showed O
pale O
cytoplasm O
, O
atypical O
ductal O
configuration O
, O
septal O
widening O
, O
cytoplasmic O
vacuolization O
with O
pleomorphism O
, O
lymphocyte O
infiltration O
, O
and O
increased O
fibrosis O
. O

Furthermore O
, O
more O
apoptotic O
cells O
were O
observed O
in O
acini O
and O
ducts O
in O
the O
RI O
group O
. O

In O
addition O
, O
patterns O
of O
99m B
Tc I
pertechnetate I
uptake O
and O
excretion O
in O
the O
RI O
- O
group O
were O
quite O
different O
from O
those O
observed O
in O
controls O
at O
1 O
and O
12 O
months O
post O
- O
RI O
. O

Conclusion O
: O
Various O
histological O
alterations O
were O
observed O
in O
mice O
exposed O
to O
radioiodine B
, O
that O
is O
, O
an O
increase O
in O
apoptotic O
acini O
and O
ductal O
cells O
and O
functional O
SG O
deterioration O
. O

The O
murine O
model O
of O
RI O
- O
induced O
SG O
dysfunction O
used O
in O
the O
present O
study O
appears O
to O
be O
applicable O
to O
preclinical O
research O
on O
RI O
- O
induced O
sialadenitis O
in O
patients O
with O
WDTC O
. O

Recommendations O
for O
the O
Use O
of O
Prolonged O
- O
Release O
Fampridine B
in O
Patients O
with O
Multiple O
Sclerosis O
( O
MS O
) O
. O

Prolonged O
- O
release O
fampridine B
( O
fampridine B
PR I
) O
is O
a O
potassium B
channel O
blocker O
that O
improves O
conductivity O
of O
signal O
on O
demyelinated O
axons O
in O
central O
nervous O
system O
. O

Fampridine B
PR I
has O
been O
approved O
to O
improve O
speed O
of O
walking O
in O
patients O
with O
multiple O
sclerosis O
. O

This O
statement O
provides O
a O
brief O
summary O
of O
data O
on O
fampridine B
PR O
and O
recommendations O
on O
practical O
use O
of O
the O
medication O
in O
clinical O
practice O
, O
prediction O
, O
and O
evaluation O
of O
response O
to O
treatment O
and O
patient O
management O
. O

Synaptotagmin O
1 O
is O
required O
for O
vesicular O
Ca B
( I
2 I
+ I
) I
/ O
H B
( I
+ I
) I
- O
antiport O
activity O
. O

A O
low O
- O
affinity O
Ca B
( I
2 I
+ I
) I
/ O
H B
( I
+ I
) I
- O
antiport O
was O
described O
in O
the O
membrane O
of O
mammalian O
brain O
synaptic O
vesicles O
. O

Electrophysiological O
studies O
showed O
that O
this O
antiport O
contributes O
to O
the O
extreme O
brevity O
of O
excitation O
- O
release O
coupling O
in O
rapid O
synapses O
. O

Synaptotagmin O
- O
1 O
, O
a O
vesicular O
protein O
interacting O
with O
membranes O
upon O
low O
- O
affinity O
Ca B
( I
2 I
+ I
) I
- O
binding O
, O
plays O
a O
major O
role O
in O
excitation O
- O
release O
coupling O
, O
by O
synchronizing O
calcium B
entry O
with O
fast O
neurotransmitter O
release O
. O

Here O
, O
we O
report O
that O
synaptotagmin O
- O
1 O
is O
necessary O
for O
expression O
of O
the O
vesicular O
Ca B
( I
2 I
+ I
) I
/ O
H B
( I
+ I
) I
- O
antiport O
. O

We O
measured O
Ca B
( I
2 I
+ I
) I
/ O
H B
( I
+ I
) I
- O
antiport O
activity O
in O
vesicles O
and O
granules O
of O
pheochromocytoma O
PC12 O
cells O
by O
three O
methods O
: O
( O
1 O
) O
Ca B
( I
2 I
+ I
) I
- O
induced O
dissipation O
of O
the O
vesicular O
H B
( I
+ I
) I
- O
gradient O
; O
( O
2 O
) O
bafilomycin B
- O
sensitive O
calcium B
accumulation O
and O
( O
3 O
) O
pH O
- O
jump O
- O
induced O
calcium O
accumulation O
. O

The O
results O
were O
congruent O
and O
highly O
significant O
: O
Ca B
( I
2 I
+ I
) I
/ O
H B
( I
+ I
) I
- O
antiport O
activity O
is O
detectable O
only O
in O
acidic O
organelles O
expressing O
functional O
synaptotagmin O
- O
1 O
. O

In O
contrast O
, O
synaptotagmin O
- O
1 O
- O
deficient O
cells O
- O
and O
cells O
where O
transgenically O
encoded O
synaptotagmin O
- O
1 O
was O
acutely O
photo O
- O
inactivated O
- O
were O
devoid O
of O
any O
Ca B
( I
2 I
+ I
) I
/ O
H B
( I
+ I
) I
- O
antiport O
activity O
. O

Therefore O
, O
in O
addition O
to O
its O
previously O
described O
functions O
, O
synaptotagmin O
- O
1 O
is O
involved O
in O
a O
rapid O
vesicular O
Ca B
( I
2 I
+ I
) I
sequestration O
through O
a O
Ca B
( I
2 I
+ I
) I
/ O
H B
( I
+ I
) I
antiport O
. O

This O
article O
is O
protected O
by O
copyright O
. O

All O
rights O
reserved O
. O

Cell O
- O
Cycle O
Changes O
and O
Oxidative O
Stress O
Response O
to O
Magnetite B
in O
A549 O
Human O
Lung O
Cells O
. O

In O
a O
recent O
study O
, O
magnetite B
was O
investigated O
for O
its O
potential O
to O
induce O
toxic O
effects O
and O
influence O
signaling O
pathways O
. O

It O
was O
clearly O
demonstrated O
that O
ROS O
formation O
leads O
to O
mitochondrial O
damage O
and O
genotoxic O
effects O
in O
A549 O
cells O
. O

On O
the O
basis O
of O
these O
findings O
, O
we O
wanted O
to O
elucidate O
the O
origin O
of O
magnetite B
- O
mediated O
ROS O
formation O
and O
its O
influence O
on O
the O
cell O
cycle O
of O
A549 O
and O
H1299 O
human O
lung O
epithelial O
cells O
. O

Concentration O
- O
and O
size O
- O
dependent O
superoxide B
formation O
, O
measured O
by O
electron O
paramagnetic O
resonance O
( O
EPR O
) O
, O
was O
observed O
. O

Furthermore O
, O
we O
could O
show O
that O
the O
GSH B
level O
decreased O
significantly O
after O
exposure O
to O
magnetite B
particles O
, O
while O
catalase O
( O
CAT O
) O
activity O
was O
increased O
. O

These O
effects O
were O
also O
dependent O
on O
particle O
size O
, O
albeit O
less O
pronounced O
than O
those O
observed O
with O
EPR O
. O

We O
were O
able O
to O
show O
that O
incubation O
of O
A549 O
cells O
prior O
to O
particle O
treatment O
with O
diphenyleneiodonium B
( O
DPI B
) O
, O
a O
NADPH B
- O
oxidase O
( O
NOX O
) O
inhibitor O
, O
leads O
to O
decreased O
ROS O
formation O
, O
but O
this O
effect O
was O
not O
observed O
for O
the O
NOX O
inhibitor O
apocynin B
. O

Soluble O
iron B
does O
not O
contribute O
considerably O
to O
ROS O
production O
. O

Analysis O
of O
cell O
- O
cycle O
distribution O
revealed O
a O
pronounced O
sub O
- O
G1 O
peak O
, O
which O
cannot O
be O
linked O
to O
increased O
cell O
death O
. O

Western O
blot O
analysis O
did O
not O
show O
activation O
of O
p53 O
but O
upregulation O
of O
p21 O
in O
A549 O
. O

Here O
, O
we O
were O
unexpectedly O
able O
to O
demonstrate O
that O
exposure O
to O
magnetite B
leads O
to O
p21 O
- O
mediated O
G1 O
- O
like O
arrest O
. O

This O
has O
been O
reported O
previously O
only O
for O
low O
concentrations O
of O
microtubule O
stabilization O
drugs O
. O

Importantly O
, O
the O
arrested O
sub O
- O
G1 O
cells O
were O
viable O
and O
showed O
no O
caspase O
3 O
/ O
7 O
activation O
. O

Antimicrobial O
and O
demelanizing O
activity O
of O
Ganoderma O
lucidum O
extract O
, O
p B
- I
hydroxybenzoic I
and I
cinnamic I
acids I
and O
their O
synthetic O
acetylated B
glucuronide I
methyl I
esters I
. O

Mushroom O
extracts O
or O
isolated O
compounds O
may O
be O
useful O
in O
the O
search O
of O
new O
potent O
antimicrobial O
agents O
. O

Herein O
, O
it O
is O
described O
the O
synthesis O
of O
protected O
( B
acetylated O
) I
glucuronide O
derivatives O
of O
p B
- I
hydroxybenzoic I
and I
cinnamic I
acids I
, O
two O
compounds O
identified O
in O
the O
medicinal O
mushroom O
Ganoderma O
lucidum O
. O

Their O
antimicrobial O
and O
demelanizing O
activities O
were O
evaluated O
and O
compared O
to O
the O
parent O
acids O
and O
G O
. O
lucidum O
extract O
. O

p B
- I
Hydroxybenzoic I
and I
cinnamic I
acids I
, O
as O
also O
their O
protected O
glucuronide O
derivatives O
revealed O
high O
antimicrobial O
( O
antibacterial O
and O
antifungal O
) O
activity O
, O
even O
better O
than O
the O
one O
showed O
by O
commercial O
standards O
. O

Despite O
the O
variation O
in O
the O
order O
of O
parent O
acids O
and O
the O
protected O
glucuronide O
derivatives O
, O
their O
antimicrobial O
activity O
was O
always O
higher O
than O
the O
one O
revealed O
by O
the O
extract O
. O

Nevertheless O
, O
the O
extract O
was O
the O
only O
one O
with O
demelanizing O
activity O
against O
Aspergillus O
niger O
. O

The O
acetylated O
glucuronide O
derivatives O
could O
be O
deprotected O
to O
obtain O
glucuronide O
metabolites O
, O
which O
circulate O
in O
the O
human O
organism O
as O
products O
of O
the O
metabolism O
of O
the O
parent O
compounds O
. O

Synthesis O
and O
antiprogestational O
properties O
of O
novel O
17 B
- I
fluorinated I
steroids I
. O

Progesterone B
receptor O
( O
PR O
) O
plays O
a O
key O
role O
in O
reproductive O
functions O
, O
and O
compounds O
that O
inhibit O
progesterone B
action O
( O
antiprogestins O
) O
have O
potential O
use O
in O
the O
treatment O
of O
estrogen B
- O
and O
progesterone B
- O
dependent O
diseases O
, O
including O
uterine O
leiomyomas O
and O
breast O
cancer O
. O

In O
the O
present O
study O
, O
we O
chemically O
synthesized O
novel O
17 B
- I
fluorinated I
steroids I
and O
evaluated O
the O
cytotoxicity O
profiles O
of O
these O
compounds O
in O
T47D O
breast O
cancer O
cells O
compared O
to O
the O
activity O
of O
known O
antiprogestins O
, O
including O
ZK230 B
211 I
, O
RU B
- I
486 I
, O
CDB2914 B
, O
CDB4124 B
and O
ORG33628 B
. O

We O
analyzed O
in O
vitro O
receptor O
- O
binding O
assays O
and O
PR O
- O
transactivation O
assays O
to O
establish O
the O
antiprogestational O
activity O
of O
these O
molecules O
. O

The O
representative O
antiprogestin O
EC304 O
was O
found O
to O
inhibit O
in O
vitro O
tumorigenicity O
in O
a O
dose O
- O
dependent O
fashion O
in O
T47D O
cells O
by O
a O
colony O
formation O
assay O
at O
1 O
and O
10nM O
concentrations O
. O

The O
potent O
in O
vivo O
antiprogestational O
activity O
of O
EC304 O
was O
also O
demonstrated O
in O
an O
antinidation O
assay O
for O
the O
interruption O
of O
early O
pregnancy O
in O
rats O
. O

The O
strong O
antiprogestational O
activity O
and O
absence O
of O
antiglucocorticoid O
activity O
in O
EC O
compounds O
may O
demonstrate O
their O
utility O
in O
the O
treatment O
of O
leiomyoma O
, O
endometriosis O
and O
breast O
cancer O
. O

Renal O
accumulation O
and O
effects O
of O
intraperitoneal O
injection O
of O
extracted O
microcystins B
in O
omnivorous O
crucian O
carp O
( O
Carassius O
auratus O
) O
. O

An O
acute O
toxicological O
experiment O
was O
designed O
to O
characterize O
the O
sequence O
of O
renal O
ultrastructural O
changes O
with O
accumulated O
MCs O
in O
crucian O
carp O
injected O
intraperitoneally O
( O
i O
. O
p O
. O
) O
with O
extracted O
microcystins B
( O
mainly O
MC B
- I
RR I
and I
- I
LR I
) O
at O
two O
doses O
, O
50 O
and O
200 O
mu O
g O
MC B
- I
LReq I
. O
kg O
( O
- O
1 O
) O
body O
weight O
. O

Quantitative O
and O
qualitative O
determinations O
of O
MCs O
in O
the O
kidney O
were O
conducted O
by O
HPLC O
and O
LC O
- O
MS O
, O
respectively O
. O

MC B
- I
RR I
content O
in O
kidney O
of O
crucian O
carp O
showed O
a O
time O
dose O
- O
dependent O
increase O
within O
48 O
h O
post O
- O
injection O
, O
followed O
by O
a O
sharp O
decline O
afterward O
, O
while O
no O
MC B
- I
LR I
in O
kidney O
was O
detectable O
throughout O
the O
experiment O
. O

Ultrastructural O
changes O
in O
the O
kidney O
of O
crucian O
carp O
progressed O
with O
increasing O
accumulated O
MCs O
and O
exposure O
times O
within O
48 O
h O
post O
- O
injection O
, O
whereas O
renal O
ultrastructural O
recovery O
of O
crucian O
carp O
in O
the O
50 O
mu O
g O
MC B
- I
LReq I
. O
kg O
( O
- O
1 O
) O
dose O
group O
was O
evident O
at O
168 O
h O
post O
- O
injection O
. O

Our O
ultrastructural O
observation O
suggests O
that O
the O
membranous O
structure O
is O
the O
main O
action O
site O
of O
MCs O
in O
the O
kidney O
, O
among O
which O
mitochondria O
damage O
in O
the O
tubules O
is O
clearly O
an O
early O
, O
and O
presumably O
a O
critically O
important O
effect O
of O
MCs O
. O

The O
increases O
in O
blood O
urea B
nitrogen B
( O
BUN O
) O
and O
creatinine B
( O
CR B
) O
in O
both O
dose O
groups O
further O
revealed O
severe O
impairment O
occurred O
in O
the O
kidney O
of O
crucian O
carp O
. O

Cephalic O
phase O
insulin O
secretion O
is O
KATP O
channel O
- O
independent O
. O

Glucose B
- O
induced O
insulin O
secretion O
from O
pancreatic O
beta O
- O
cells O
depends O
critically O
on O
activity O
of O
ATP O
- O
sensitive O
K B
+ I
channels O
( O
KATP O
channel O
) O
. O

We O
previously O
generated O
mice O
lacking O
Kir6 O
. O
2 O
, O
the O
pore O
subunit O
of O
the O
beta O
- O
cell O
KATP O
channel O
( O
Kir6 O
. O
2 O
- O
/ O
- O
) O
, O
that O
show O
almost O
no O
insulin O
secretion O
in O
response O
to O
glucose B
in O
vitro O
. O

In O
the O
present O
study O
, O
we O
compared O
insulin O
secretion O
by O
voluntary O
feeding O
( O
self O
- O
motivated O
, O
oral O
nutrient O
ingestion O
) O
and O
by O
forced O
feeding O
( O
intra O
- O
gastric O
nutrient O
injection O
via O
gavage O
) O
in O
wild O
- O
type O
( O
Kir6 O
. O
2 O
+ O
/ O
+ O
) O
and O
Kir6 O
. O
2 O
- O
/ O
- O
mice O
. O

Under O
ad O
libitum O
feeding O
or O
during O
voluntary O
feeding O
of O
standard O
chow O
, O
blood O
glucose B
levels O
and O
plasma O
insulin O
levels O
were O
similar O
in O
Kir6 O
. O
2 O
+ O
/ O
+ O
and O
Kir6 O
. O
2 O
- O
/ O
- O
mice O
. O

By O
voluntary O
feeding O
of O
carbohydrate B
alone O
, O
insulin O
secretion O
was O
induced O
significantly O
in O
Kir6 O
. O
2 O
- O
/ O
- O
mice O
, O
but O
was O
markedly O
attenuated O
compared O
to O
that O
in O
Kir6 O
. O
2 O
+ O
/ O
+ O
mice O
. O

On O
forced O
feeding O
of O
standard O
chow O
or O
carbohydrate B
alone O
, O
the O
insulin O
secretory O
response O
was O
markedly O
impaired O
or O
completely O
absent O
in O
Kir6 O
. O
2 O
- O
/ O
- O
mice O
. O

Pre O
- O
treatment O
of O
a O
muscarine O
receptor O
antagonist O
, O
atropine B
methyl I
nitrate I
, O
which O
does O
not O
cross O
the O
blood O
- O
brain O
barrier O
, O
almost O
completely O
blocked O
insulin O
secretion O
induced O
by O
voluntary O
feeding O
of O
standard O
chow O
or O
carbohydrate B
in O
Kir6 O
. O
2 O
- O
/ O
- O
mice O
. O

Substantial O
glucose B
- O
induced O
insulin O
secretion O
was O
induced O
in O
pancreas O
perfusion O
study O
of O
Kir6 O
. O
2 O
- O
/ O
- O
mice O
only O
in O
the O
presence O
of O
carbamylcholine B
. O

These O
results O
suggest O
that O
a O
KATP O
channel O
- O
independent O
mechanism O
mediated O
by O
the O
vagal O
nerve O
plays O
a O
critical O
role O
in O
insulin O
secretion O
in O
response O
to O
nutrients O
in O
vivo O
. O

MAPKAPK2 O
/ O
3 O
Regulate O
SERCA2a O
Expression O
and O
Fiber O
Type O
Composition O
to O
Modulate O
Skeletal O
Muscle O
and O
Cardiomyocyte O
Function O
. O

The O
MAPK O
- O
activated O
protein O
kinases O
2 O
and O
3 O
( O
MAPKAPK2 O
/ O
3 O
, O
MK2 O
/ O
3 O
) O
represent O
protein O
kinases O
downstream O
of O
the O
p38 O
mitogen O
- O
activated O
protein O
kinase O
( O
MAPK O
) O
. O

Using O
MK2 O
/ O
3 O
double O
knockout O
mice O
( O
MK2 O
/ O
3 O
( O
- O
/ O
- O
) O
) O
, O
we O
analyzed O
the O
role O
of O
MK2 O
/ O
3 O
in O
cross O
- O
striated O
muscle O
by O
transcriptome O
and O
proteome O
analyses O
, O
and O
by O
histology O
. O

We O
demonstrated O
enhanced O
expression O
of O
the O
slow O
oxidative O
skeletal O
muscle O
myofiber O
gene O
program O
, O
including O
the O
PPAR O
gamma O
coactivator O
1 O
alpha O
( O
PGC O
- O
1 O
alpha O
) O
. O

Using O
reporter O
gene O
and O
electrophoretic O
gel O
mobility O
shift O
assays O
we O
demonstrated O
that O
MK2 O
catalytic O
activity O
directly O
regulated O
the O
promoters O
of O
the O
fast O
fiber O
- O
specific O
myosin O
heavy O
chain O
IId O
/ O
x O
and O
the O
slow O
fiber O
- O
specific O
sarco O
/ O
endoplasmic O
reticulum O
Ca B
( I
2 I
+ I
) I
- O
ATPase O
( O
SERCA O
) O
2 O
gene O
. O

Elevated O
SERCA2a O
gene O
expression O
caused O
by O
a O
decreased O
transcription O
factor O
Egr O
- O
1 O
to O
Sp1 O
ratio O
was O
associated O
with O
accelerated O
relaxation O
and O
enhanced O
contractility O
in O
MK2 O
/ O
3 O
( O
- O
/ O
- O
) O
cardiomyocytes O
, O
concomitant O
with O
improved O
force O
parameters O
in O
MK2 O
/ O
3 O
( O
- O
/ O
- O
) O
soleus O
muscle O
. O

These O
results O
link O
MK2 O
/ O
3 O
to O
the O
regulation O
of O
calcium B
dynamics O
and O
identify O
enzymatic O
activity O
of O
MK2 O
/ O
3 O
as O
a O
critical O
factor O
for O
modulating O
cross O
- O
striated O
muscle O
function O
by O
generating O
a O
unique O
muscle O
phenotype O
exhibiting O
both O
, O
reduced O
fatigability O
and O
enhanced O
force O
in O
MK2 O
/ O
3 O
( O
- O
/ O
- O
) O
mice O
. O

Hence O
, O
the O
p38 O
- O
MK2 O
/ O
3 O
axis O
may O
represent O
a O
novel O
target O
for O
the O
design O
of O
therapeutic O
strategies O
for O
diseases O
related O
to O
fiber O
type O
changes O
or O
impaired O
SERCA2 O
function O
. O

N B
- O
alkylation O
of O
highly O
quaternized O
chitosan O
derivatives O
affects O
the O
paracellular O
permeation O
enhancement O
in O
bronchial O
epithelia O
in O
vitro O
. O

This O
study O
describes O
the O
structure O
- O
activity O
relationship O
for O
carefully O
characterized O
N B
- I
alkyl I
- I
N I
- I
quaternary I
chitosan O
derivatives O
as O
permeation O
enhancers O
for O
drugs O
that O
are O
mainly O
absorbed O
through O
the O
paracellular O
pathway O
, O
such O
as O
macromolecular O
drugs O
and O
hydrophilic O
drugs O
, O
in O
a O
well O
defined O
bronchial O
epithelial O
cell O
line O
. O

The O
O B
- I
methyl I
free O
derivatives O
used O
in O
the O
study O
were O
fully O
trimethylated O
( O
100 O
% O
) O
N B
, I
N I
, I
N I
- I
trimethyl I
chitosan O
( O
TMC O
) O
and O
N B
- I
propyl I
- O
( O
QuatPropyl B
) O
, O
N B
- I
butyl I
- O
( O
QuatButyl B
) O
and O
N B
- I
hexyl I
( I
QuatHexyl I
) I
- I
N I
, I
N I
- I
dimethyl I
chitosan O
, O
with O
85 O
- O
91 O
% O
degree O
of O
quaternization O
. O

The O
fully O
trimethylated O
TMC O
, O
from O
0 O
. O
25mg O
/ O
ml O
, O
decreased O
transepithelial O
electrical O
resistance O
( O
TER O
) O
in O
a O
reversible O
manner O
and O
enhanced O
the O
permeation O
of O
the O
macromolecule O
FITC B
- O
dextran O
4kDa O
( O
FD4 O
) O
2 O
- O
5 O
fold O
. O

TMC O
did O
not O
cause O
any O
alterations O
in O
the O
tight O
junction O
( O
TJ O
) O
protein O
claudin O
- O
4 O
or O
in O
F O
- O
actin O
architecture O
. O

QuatHexyl B
was O
the O
most O
effective O
polymer O
to O
produce O
enhanced O
permeation O
and O
decreased O
TER O
from O
0 O
. O
016mg O
/ O
ml O
. O

Nevertheless O
, O
this O
enhanced O
permeation O
was O
accompanied O
by O
reduced O
viability O
and O
dissociation O
of O
F O
- O
actin O
and O
claudin O
- O
4 O
proteins O
. O

The O
structure O
- O
activity O
relationship O
suggests O
that O
more O
lipophilic O
derivatives O
show O
more O
permeation O
enhancement O
, O
TJ O
disassembly O
, O
and O
less O
viability O
in O
the O
order O
of O
hexyl B
= O
~ O
butyl B
> O
propyl B
> O
methyl B
and O
demonstrates O
that O
the O
permeation O
effect O
is O
not O
only O
mediated O
by O
permanent O
positive O
charge O
but O
also O
through O
by O
the O
extent O
of O
N B
- O
alkylation O
. O

These O
results O
are O
relevant O
to O
elucidate O
the O
structural O
factors O
contributing O
to O
the O
permeation O
enhancement O
of O
chitosan O
derivatives O
and O
for O
potential O
use O
in O
pulmonary O
applications O
. O

Association O
of O
PON1 O
genotype O
and O
haplotype O
with O
susceptibility O
to O
coronary O
artery O
disease O
and O
clinical O
outcomes O
in O
dual O
antiplatelet O
- O
treated O
Han O
Chinese O
patients O
. O

PURPOSE O
: O
The O
aim O
of O
this O
study O
was O
to O
evaluate O
the O
association O
of O
PON1 O
genetic O
variants O
with O
the O
susceptibility O
to O
coronary O
artery O
disease O
( O
CAD O
) O
and O
with O
the O
clinical O
endpoints O
in O
aspirin B
and O
clopidogrel B
( O
dual O
antiplatelet O
therapy O
) O
- O
treated O
Han O
Chinese O
patients O
with O
CAD O
after O
percutaneous O
coronary O
intervention O
( O
PCI O
) O
. O

METHODS O
: O
A O
total O
of O
538 O
Han O
Chinese O
patients O
undergoing O
PCI O
and O
receiving O
dual O
- O
antiplatelet O
therapy O
were O
sequentially O
recruited O
to O
the O
study O
and O
followed O
for O
up O
to O
1 O
year O
. O

Healthy O
controls O
( O
n O
= O
539 O
) O
were O
enrolled O
during O
the O
same O
period O
. O

All O
study O
participants O
were O
genotyped O
for O
five O
genetic O
variants O
in O
PON1 O
and O
the O
cytochrome O
P450 O
2C19 O
* O
2 O
mutation O
( O
CYP2C19 O
* O
2 O
) O
. O

The O
effect O
of O
genetic O
variants O
on O
disease O
risk O
and O
clinical O
outcome O
of O
major O
adverse O
cardiac O
events O
( O
MACE O
) O
within O
1 O
year O
or O
bleeding O
within O
6 O
months O
was O
assessed O
. O

RESULTS O
: O
CYP2C19 O
* O
2 O
was O
associated O
with O
a O
higher O
risk O
of O
MACE O
( O
adjusted O
P O
= O
0 O
. O
0098 O
) O
, O
but O
a O
lower O
risk O
of O
bleeding O
events O
( O
adjusted O
P O
= O
0 O
. O
0016 O
) O
. O

The O
PON1 O
Q192R O
polymorphism O
was O
significantly O
associated O
with O
a O
lower O
risk O
of O
bleeding O
events O
[ O
odds O
ratio O
( O
OR O
) O
0 O
. O
61 O
, O
95 O
% O
confidence O
interval O
( O
CI O
) O
0 O
. O
43 O
- O
0 O
. O
87 O
, O
adjusted O
P O
= O
0 O
. O
0066 O
) O
. O

The O
haplotype O
bearing O
the O
PON1 O
- O
126C O
allele O
was O
associated O
with O
a O
higher O
risk O
to O
CAD O
( O
OR O
1 O
. O
48 O
, O
95 O
% O
CI O
1 O
. O
04 O
- O
2 O
. O
09 O
, O
P O
= O
0 O
. O
029 O
) O
and O
a O
higher O
risk O
of O
bleeding O
events O
( O
OR O
1 O
. O
68 O
, O
95 O
% O
CI O
1 O
. O
10 O
- O
2 O
. O
56 O
, O
P O
= O
0 O
. O
017 O
) O
compared O
to O
the O
most O
frequent O
haplotype O
. O

The O
transcription O
activity O
of O
haplotype O
p O
- O
162A O
- O
126C O
- O
108C O
in O
the O
PON1 O
promoter O
was O
2 O
. O
6 O
- O
fold O
higher O
than O
that O
of O
the O
most O
frequent O
haplotype O
( O
p O
- O
162G O
- O
126G O
- O
108T O
) O
. O

CONCLUSIONS O
: O
Based O
on O
these O
results O
, O
we O
suggest O
that O
the O
haplotype O
- O
bearing O
PON1 O
- O
126C O
allele O
contributes O
to O
the O
disease O
risk O
and O
the O
risk O
of O
bleeding O
events O
in O
dual O
antiplatelet O
- O
treated O
CAD O
patients O
after O
PCI O
. O

Structural O
transitions O
in O
mixed O
ternary O
noble O
gas O
clusters O
. O

The O
properties O
of O
noble O
gas O
systems O
can O
be O
greatly O
extended O
by O
heterogeneous O
mixtures O
of O
elements O
. O

The O
geometrical O
structures O
and O
energies O
of O
mixed O
Ar B
- I
Kr I
- I
Xe I
clusters O
were O
investigated O
using O
ternary O
Lennard O
- O
Jones O
( O
TLJ O
) O
potential O
. O

For O
the O
Ar19Kr B
n I
Xe19 I
, O
Ar19Kr19Xe B
n I
, O
and O
Ar B
n I
Kr19Xe19 I
( O
n O
= O
0 O
- O
17 O
) O
clusters O
investigated O
, O
the O
results O
show O
that O
only O
two O
minimum O
energy O
configurations O
exist O
, O
i O
. O
e O
. O
, O
polytetrahedron O
and O
six O
- O
fold O
pancake O
. O

The O
inner O
core O
of O
all O
these O
clusters O
is O
composed O
mainly O
of O
Ar B
atoms O
, O
and O
Kr B
and O
Xe B
atoms O
are O
distributed O
on O
the O
surface O
with O
well O
mixed O
pattern O
for O
polytetrahedral O
and O
segregate O
pattern O
for O
six O
- O
fold O
pancake O
configurations O
. O

The O
relative O
stability O
property O
of O
Ar B
- I
Kr I
- I
Xe I
clusters O
with O
a O
certain O
composition O
is O
discussed O
. O

Moreover O
, O
the O
role O
of O
heterogeneity O
on O
the O
strain O
was O
investigated O
, O
and O
reduced O
strain O
energies O
in O
Ar B
- I
Kr I
- I
Xe I
clusters O
were O
studied O
to O
find O
possible O
ways O
of O
reducing O
strain O
. O

The O
results O
showed O
that O
the O
strain O
energies O
were O
affected O
mainly O
by O
Ar B
- I
Ar I
, O
Ar B
- I
Kr I
, O
and O
Xe B
- I
Xe I
bonds O
. O

Blood O
- O
brain O
barrier O
structure O
and O
function O
and O
the O
challenges O
for O
CNS O
drug O
delivery O
. O

The O
neurons O
of O
the O
central O
nervous O
system O
( O
CNS O
) O
require O
precise O
control O
of O
their O
bathing O
microenvironment O
for O
optimal O
function O
, O
and O
an O
important O
element O
in O
this O
control O
is O
the O
blood O
- O
brain O
barrier O
( O
BBB O
) O
. O

The O
BBB O
is O
formed O
by O
the O
endothelial O
cells O
lining O
the O
brain O
microvessels O
, O
under O
the O
inductive O
influence O
of O
neighbouring O
cell O
types O
within O
the O
' O
neurovascular O
unit O
' O
( O
NVU O
) O
including O
astrocytes O
and O
pericytes O
. O

The O
endothelium O
forms O
the O
major O
interface O
between O
the O
blood O
and O
the O
CNS O
, O
and O
by O
a O
combination O
of O
low O
passive O
permeability O
and O
presence O
of O
specific O
transport O
systems O
, O
enzymes O
and O
receptors O
regulates O
molecular O
and O
cellular O
traffic O
across O
the O
barrier O
layer O
. O

A O
number O
of O
methods O
and O
models O
are O
available O
for O
examining O
BBB O
permeation O
in O
vivo O
and O
in O
vitro O
, O
and O
can O
give O
valuable O
information O
on O
the O
mechanisms O
by O
which O
therapeutic O
agents O
and O
constructs O
permeate O
, O
ways O
to O
optimize O
permeation O
, O
and O
implications O
for O
drug O
discovery O
, O
delivery O
and O
toxicity O
. O

For O
treating O
lysosomal O
storage O
diseases O
( O
LSDs O
) O
, O
models O
can O
be O
included O
that O
mimic O
aspects O
of O
the O
disease O
, O
including O
genetically O
- O
modified O
animals O
, O
and O
in O
vitro O
models O
can O
be O
used O
to O
examine O
the O
effects O
of O
cells O
of O
the O
NVU B
on O
the O
BBB O
under O
pathological O
conditions O
. O

For O
testing O
CNS O
drug O
delivery O
, O
several O
in O
vitro O
models O
now O
provide O
reliable O
prediction O
of O
penetration O
of O
drugs O
including O
large O
molecules O
and O
artificial O
constructs O
with O
promising O
potential O
in O
treating O
LSDs O
. O

For O
many O
of O
these O
diseases O
it O
is O
still O
not O
clear O
how O
best O
to O
deliver O
appropriate O
drugs O
to O
the O
CNS O
, O
and O
a O
concerted O
approach O
using O
a O
variety O
of O
models O
and O
methods O
can O
give O
critical O
insights O
and O
indicate O
practical O
solutions O
. O

Region O
- O
specific O
regulation O
of O
5 O
- O
HT1B O
receptors O
in O
the O
rat O
brain O
by O
chronic O
venlafaxine B
treatment O
. O

RATIONALE O
: O
Venlafaxine B
is O
a O
non O
- O
selective O
serotonin B
and O
noradrenaline B
reuptake O
inhibitor O
antidepressant O
drug O
for O
which O
clinical O
studies O
have O
suggested O
a O
high O
level O
efficacy O
and O
a O
possible O
early O
action O
onset O
compared O
to O
the O
classical O
antidepressants O
. O

Its O
therapeutic O
effects O
might O
be O
due O
, O
at O
least O
in O
part O
, O
to O
adaptive O
changes O
in O
serotonergic O
neurotransmission O
, O
through O
the O
activation O
of O
the O
different O
5 B
- I
HT I
receptor O
subtypes O
. O

5 O
- O
HT1B O
receptors O
are O
located O
in O
the O
axon O
terminals O
of O
both O
serotonergic O
and O
non O
- O
serotonergic O
neurons O
, O
where O
they O
act O
as O
inhibitory O
autoreceptors O
or O
heteroreceptors O
, O
respectively O
. O

However O
, O
the O
information O
about O
the O
involvement O
of O
this O
subtype O
in O
the O
mechanism O
of O
action O
of O
antidepressants O
is O
limited O
and O
quite O
controversial O
. O

OBJECTIVES O
: O
The O
aim O
of O
this O
study O
was O
to O
evaluate O
the O
effect O
of O
venlafaxine B
( O
10 O
mg O
kg O
( O
- O
1 O
) O
day O
( O
- O
1 O
) O
, O
p O
. O
o O
. O
) O
after O
21 O
days O
of O
treatment O
on O
the O
density O
of O
5 O
- O
HT1B O
receptors O
and O
their O
functionality O
in O
rat O
brain O
. O

METHODS O
: O
Effects O
of O
chronic O
venlafaxine B
were O
evaluated O
at O
different O
levels O
of O
5 O
- O
HT1B O
receptor O
by O
using O
receptor O
autoradiography O
, O
[ B
( I
35 I
) I
S I
] I
GTP I
gamma I
S I
binding O
, O
and O
the O
regulation O
of O
body O
temperature O
induced O
by O
selective O
5 O
- O
HT1B O
agonist O
. O

RESULTS O
: O
Our O
results O
show O
that O
venlafaxine B
induced O
an O
increase O
in O
sensitivity O
of O
5 O
- O
HT1B O
receptors O
in O
hypothalamus O
both O
at O
G O
- O
protein O
level O
and O
the O
control O
of O
core O
temperature O
without O
affecting O
the O
receptor O
density O
. O

CONCLUSIONS O
: O
These O
results O
demonstrate O
that O
adaptive O
changes O
on O
5 O
- O
HT1B O
receptors O
induced O
by O
chronic O
administration O
of O
venlafaxine B
exhibit O
regional O
differences O
suggesting O
that O
the O
hypothalamus O
might O
be O
an O
important O
site O
of O
drug O
action O
. O

Design O
, O
synthesis O
and O
spectroscopic O
characterisation O
of O
a O
focused O
library O
based O
on O
the O
polyandrocarpamine B
natural O
product O
scaffold O
. O

A O
focused O
library O
based O
on O
the O
marine O
natural O
products O
polyandrocarpamines B
A I
( I
1 I
) I
and I
B I
( O
2 O
) O
has O
been O
designed O
and O
synthesised O
using O
parallel O
solution O
- O
phase O
chemistry O
. O

In O
silico O
physicochemical O
property O
calculations O
were O
performed O
on O
synthetic O
candidates O
in O
order O
to O
optimise O
the O
library O
for O
drug O
discovery O
and O
chemical O
biology O
. O

A O
library O
of O
ten O
2 B
- I
aminoimidazolone I
products O
( O
3 O
- O
12 O
) O
was O
prepared O
by O
coupling O
glycocyamidine B
and O
a O
variety O
of O
aldehydes B
using O
a O
one O
- O
step O
stereoselective O
aldol O
condensation O
reaction O
under O
microwave O
conditions O
. O

All O
analogues O
were O
characterised O
by O
NMR O
, O
UV O
, O
IR O
and O
MS O
. O

The O
library O
was O
evaluated O
for O
cytotoxicity O
towards O
the O
prostate O
cancer O
cell O
lines O
, O
LNCaP O
, O
PC O
- O
3 O
and O
22Rv1 O
. O

Copyright O
( O
c O
) O
2013 O
John O
Wiley O
& O
Sons O
, O
Ltd O
. O

Suppression O
of O
Epithelial O
to O
Mesenchymal O
Transitioning O
( O
EMT O
) O
Enhances O
Ex O
Vivo O
Reprogramming O
of O
Human O
Exocrine O
Pancreatic O
Tissue O
towards O
Functional O
Insulin O
Producing O
beta O
- O
Like O
Cells O
. O

Due O
to O
the O
lack O
of O
tissue O
available O
for O
islet O
transplantation O
, O
new O
sources O
of O
beta O
- O
cells O
have O
been O
sought O
for O
the O
treatment O
of O
type O
1 O
diabetes O
. O

The O
aim O
of O
this O
study O
was O
to O
determine O
whether O
the O
human O
exocrid O
fraction O
from O
the O
islet O
isolation O
procedure O
could O
be O
reprogrammed O
to O
provide O
additional O
islet O
tissue O
for O
transplantation O
. O

The O
exocrine O
enriched O
cells O
rapidly O
dedifferentiated O
in O
culture O
and O
grew O
as O
a O
mesenchymal O
monolayer O
. O

Genetic O
lineage O
tracing O
confirmed O
that O
these O
mesenchymal O
cells O
arose O
in O
part O
through O
a O
process O
of O
epithelial O
to O
mesenchymal O
transitioning O
( O
EMT O
) O
. O

A O
protocol O
was O
developed O
whereby O
transduction O
of O
these O
mesenchymal O
cells O
with O
adenoviruses O
containing O
Pdx1 O
, O
Ngn3 O
, O
MafA O
and O
Pax4 O
generated O
a O
population O
of O
cells O
that O
were O
enriched O
in O
glucagon O
- O
secreting O
alpha O
- O
like O
cells O
. O

Transdifferentiation O
or O
reprogramming O
towards O
insulin O
secreting O
beta O
- O
cells O
was O
enhanced O
, O
however O
, O
when O
using O
unpassaged O
cells O
in O
combination O
with O
inhibition O
of O
EMT O
by O
inclusion O
of O
ROCK O
and O
TGF O
- O
beta O
1 O
inhibitors O
. O

Resultant O
cells O
were O
able O
to O
secrete O
insulin O
in O
response O
to O
glucose B
and O
on O
transplantation O
, O
to O
normalise O
blood O
glucose B
levels O
in O
streptozotocin B
diabetic O
NOD O
/ O
Scid O
mice O
. O

In O
conclusion O
, O
reprogramming O
of O
human O
exocrine O
enriched O
tissue O
can O
best O
be O
achieved O
using O
fresh O
material O
under O
conditions O
whereby O
EMT O
is O
inhibited O
. O

. O
rather O
than O
allowing O
the O
culture O
to O
expand O
as O
a O
mesenchymal O
monolayer O
. O

Factors O
Associated O
With O
Microalbuminuria O
in O
7 O
, O
549 O
Children O
and O
Adolescents O
With O
Type O
1 O
Diabetes O
in O
the O
T1D O
Exchange O
Clinic O
Registry O
. O

OBJECTIVETo O
examine O
factors O
associated O
with O
clinical O
microalbuminuria O
( O
MA O
) O
diagnosis O
in O
children O
and O
adolescents O
in O
the O
T1D O
Exchange O
clinic O
registry O
. O
RESEARCH O
DESIGN O
AND O
METHODST1D O
Exchange O
participants O
< O
20 O
years O
of O
age O
with O
type O
1 O
diabetes O
> O
= O
1 O
year O
and O
urinary O
albumin O
- O
to O
- O
creatinine O
ratio O
( O
ACR O
) O
measured O
within O
the O
prior O
2 O
years O
were O
included O
in O
the O
analysis O
. O

MA O
diagnosis O
required O
all O
of O
the O
following O
: O
1 O
) O
a O
clinical O
diagnosis O
of O
sustained O
MA O
or O
macroalbuminuria O
, O
2 O
) O
confirmation O
of O
MA O
diagnosis O
by O
either O
the O
most O
recent O
ACR O
being O
> O
= O
30 O
mg O
/ O
g O
or O
current O
treatment O
with O
an O
ACE O
inhibitor O
( O
ACEI O
) O
or O
angiotensin O
receptor O
blocker O
( O
ARB O
) O
, O
and O
3 O
) O
no O
known O
cause O
for O
nephropathy O
other O
than O
diabetes O
. O

Logistic O
regression O
was O
used O
to O
assess O
factors O
associated O
with O
MA O
. O
RESULTSMA O
was O
present O
in O
329 O
of O
7 O
, O
549 O
( O
4 O
. O
4 O
% O
) O
participants O
, O
with O
a O
higher O
frequency O
associated O
with O
longer O
diabetes O
duration O
, O
higher O
mean O
glycosylated O
hemoglobin O
( O
HbA1c O
) O
level O
, O
older O
age O
, O
female O
sex O
, O
higher O
diastolic O
blood O
pressure O
( O
BP O
) O
, O
and O
lower O
BMI O
( O
P O
< O
= O
0 O
. O
01 O
for O
each O
in O
multivariate O
analysis O
) O
. O

Older O
age O
was O
most O
strongly O
associated O
with O
MA O
among O
participants O
with O
HbA1c O
> O
= O
9 O
. O
5 O
% O
( O
> O
= O
80 O
mmol O
/ O
mol O
) O
. O

MA O
was O
uncommon O
( O
< O
2 O
% O
) O
among O
participants O
with O
HbA1c O
< O
7 O
. O
5 O
% O
( O
< O
58 O
mmol O
/ O
mol O
) O
. O

Of O
those O
with O
MA O
, O
only O
36 O
% O
were O
receiving O
ACEI O
/ O
ARB O
treatment O
. O
CONCLUSIONSOur O
results O
emphasize O
the O
importance O
of O
good O
glycemic O
and O
BP O
control O
, O
particularly O
as O
diabetes O
duration O
increases O
, O
in O
order O
to O
reduce O
the O
risk O
of O
nephropathy O
. O

Since O
age O
and O
diabetes O
duration O
are O
important O
nonmodifiable O
factors O
associated O
with O
MA O
, O
the O
importance O
of O
routine O
screening O
is O
underscored O
to O
ensure O
early O
diagnosis O
and O
timely O
treatment O
of O
MA O
. O

Patent O
indicators O
: O
a O
window O
to O
pharmaceutical O
market O
success O
. O

Pharmaceutical O
success O
in O
the O
market O
is O
the O
best O
reward O
for O
pharmaceutical O
investors O
undergoing O
the O
lengthy O
, O
costly O
and O
risky O
process O
of O
pharmaceutical O
Research O
and O
Development O
( O
R O
& O
D O
) O
. O

Drugs O
with O
high O
market O
revenues O
trigger O
fierce O
competition O
between O
pharmaceutical O
enterprises O
, O
as O
is O
demonstrated O
by O
the O
increasing O
Mergers O
& O
Acquisitions O
( O
M O
& O
A O
) O
cases O
focusing O
on O
seizing O
the O
best O
- O
selling O
products O
. O

On O
the O
other O
hand O
, O
patents O
, O
as O
the O
best O
shield O
for O
innovative O
drugs O
against O
generic O
drugs O
, O
become O
a O
powerful O
weapon O
for O
pharmaceutical O
enterprises O
to O
win O
the O
substantial O
returns O
generated O
by O
market O
exclusivity O
. O

Patents O
seem O
to O
be O
directly O
responsible O
for O
the O
commercial O
success O
of O
new O
medicines O
. O

In O
this O
context O
, O
it O
is O
of O
great O
significance O
to O
find O
out O
the O
empirical O
associations O
between O
pharmaceutical O
commercial O
success O
and O
patents O
. O

By O
comprehensively O
analysing O
127 O
drugs O
marketed O
in O
the O
USA O
and O
their O
621 O
American O
patents O
, O
this O
article O
identifies O
the O
evidence O
to O
link O
various O
patent O
indicators O
with O
pharmaceutical O
sales O
in O
actual O
market O
. O

Diversity O
in O
Structural O
Consequences O
of O
MexZ O
Mutations O
in O
Pseudomonas O
aeruginosa O
. O

Pseudomonas O
aeruginosa O
is O
the O
major O
cause O
of O
morbidity O
and O
mortality O
in O
patients O
with O
cystic O
fibrosis O
. O

The O
high O
level O
of O
intrinsic O
and O
acquired O
antibiotic O
resistance O
of O
P O
. O
aeruginosa O
is O
attributable O
to O
the O
low O
permeability O
of O
its O
outer O
membrane O
in O
combination O
with O
the O
expression O
of O
several O
multidrug O
resistance O
efflux O
systems O
. O

MexZ O
, O
the O
negative O
regulator O
of O
the O
MexXY O
efflux O
pump O
, O
is O
found O
to O
be O
the O
most O
frequently O
mutated O
gene O
in O
P O
. O
aeruginosa O
isolated O
from O
cystic O
fibrosis O
patient O
lungs O
, O
confirming O
its O
importance O
in O
multidrug O
resistance O
. O

Structural O
consequences O
of O
four O
MexZ O
mutations O
, O
including O
L25P O
, O
G46V O
, O
P151L O
, O
and O
S202F O
, O
have O
been O
explored O
based O
on O
the O
known O
structure O
of O
MexZ O
using O
both O
molecular O
modeling O
and O
molecular O
dynamics O
methods O
. O

According O
to O
obtained O
results O
, O
G46V O
mutation O
, O
which O
completely O
abolishes O
the O
ability O
of O
MexZ O
binding O
to O
DNA O
, O
occurs O
in O
a O
specific O
evolutionary O
conserved O
region O
of O
MexZ O
. O

In O
addition O
, O
the O
most O
fluctuation O
values O
occur O
in O
DNA O
- O
binding O
domain O
and O
Helix4 O
. O

The O
obtained O
results O
explore O
details O
of O
diversity O
in O
structural O
consequences O
of O
MexZ O
mutations O
in O
P O
. O
aeruginosa O
. O

Profiling O
976 O
ToxCast O
chemicals O
across O
331 O
enzymatic O
and O
receptor O
signaling O
assays O
. O

Understanding O
potential O
health O
risks O
is O
a O
significant O
challenge O
due O
to O
large O
numbers O
of O
diverse O
chemicals O
with O
poorly O
characterized O
exposures O
and O
mechanisms O
of O
toxicities O
. O

The O
present O
study O
analyzes O
976 O
chemicals O
( O
including O
failed O
pharmaceuticals O
, O
alternative O
plasticizers O
, O
food O
additives O
, O
and O
pesticides O
) O
in O
Phase O
I O
and O
II O
of O
the O
U O
. O
S O
. O

EPA O
' O
s O
ToxCast O
( O
TM O
) O
project O
across O
331 O
cell O
- O
free O
enzymatic O
and O
ligand O
- O
binding O
high O
- O
throughput O
screening O
( O
HTS O
) O
assays O
. O

Half O
- O
maximal O
activity O
concentrations O
( O
AC50 O
) O
were O
identified O
for O
729 O
chemicals O
in O
256 O
assays O
( O
7 O
, O
135 O
chemical O
- O
assay O
pairs O
) O
. O

Some O
of O
the O
most O
commonly O
affected O
assays O
were O
CYPs O
( O
CYP2C9 O
, O
CYP2C19 O
) O
, O
transporters O
( O
mitochondrial O
TSPO O
, O
norepinephrine B
, O
dopaminergic O
) O
, O
and O
GPCRs O
( O
aminergic O
) O
. O

Heavy O
metals O
, O
surfactants O
, O
and O
dithiocarbamate B
fungicides O
showed O
promiscuous O
, O
but O
distinctly O
different O
patterns O
of O
activity O
whereas O
many O
of O
the O
pharma O
compounds O
showed O
promiscuous O
activity O
across O
GPCRs O
. O

Literature O
analysis O
confirmed O
> O
50 O
% O
of O
the O
activities O
for O
the O
most O
potent O
chemical O
- O
assay O
pairs O
( O
56 O
) O
, O
but O
also O
revealed O
10 O
missed O
interactions O
. O

Twenty O
- O
two O
chemicals O
with O
known O
estrogenic O
activity O
were O
correctly O
identified O
for O
the O
majority O
( O
77 O
% O
) O
, O
missing O
only O
the O
weaker O
interactions O
. O

In O
many O
cases O
, O
novel O
findings O
for O
previously O
unreported O
chemical O
- O
target O
combinations O
clustered O
with O
known O
chemical O
- O
target O
interactions O
. O

Results O
from O
this O
large O
inventory O
of O
chemical O
- O
biological O
interactions O
can O
inform O
read O
- O
across O
methods O
as O
well O
as O
to O
link O
potential O
targets O
to O
molecular O
initiating O
events O
in O
adverse O
outcome O
pathways O
for O
diverse O
toxicities O
. O

This O
abstract O
does O
not O
necessarily O
reflect O
U O
. O
S O
. O

EPA O
policy O
. O

Ultrasensitive O
Polarized O
Up O
- O
Conversion O
of O
Tm B
( I
3 I
+ I
) I
- O
Yb B
( I
3 I
+ I
) I
Doped O
beta O
- O
NaYF4 B
Single O
Nanorod O
. O

Up O
- O
conversion O
luminescence O
in O
rare O
earth O
ions O
( O
REs B
) O
doped O
nanoparticles O
has O
attracted O
considerable O
research O
attention O
for O
the O
promising O
applications O
in O
solid O
- O
state O
lasers O
, O
three O
- O
dimensional O
displays O
, O
solar O
cells O
, O
biological O
imaging O
, O
and O
so O
forth O
. O

However O
, O
there O
have O
been O
no O
reports O
on O
REs B
doped O
nanoparticles O
to O
investigate O
their O
polarized O
energy O
transfer O
up O
- O
conversion O
, O
especially O
for O
single O
particle O
. O

Herein O
, O
the O
polarized O
energy O
transfer O
up O
- O
conversion O
from O
REs B
doped O
fluoride B
nanorods O
is O
demonstrated O
in O
a O
single O
particle O
spectroscopy O
mode O
for O
the O
first O
time O
. O

Unique O
luminescent O
phenomena O
, O
for O
example O
, O
sharp O
energy O
level O
split O
and O
singlet O
- O
to O
- O
triplet O
transitions O
at O
room O
temperature O
, O
multiple O
discrete O
luminescence O
intensity O
periodic O
variation O
with O
polarization O
direction O
, O
are O
observed O
upon O
excitation O
with O
980 O
nm O
linearly O
polarized O
laser O
. O

Furthermore O
, O
nanorods O
with O
the O
controllable O
aspect O
ratio O
and O
symmetry O
are O
fabricated O
for O
analysis O
of O
the O
mechanism O
of O
polarization O
anisotropy O
. O

The O
comparative O
experiments O
suggest O
that O
intraions O
transition O
properties O
and O
crystal O
local O
symmetry O
dominate O
the O
polarization O
anisotropy O
, O
which O
is O
also O
confirmed O
by O
density O
functional O
theory O
calculations O
. O

Taking O
advantage O
of O
the O
REs B
based O
up O
- O
conversion O
, O
potential O
application O
in O
polarized O
microscopic O
multi O
- O
information O
transportation O
is O
suggested O
for O
the O
polarization O
anisotropy O
from O
REs B
doped O
fluoride B
single O
nanorod O
or O
nanorod O
array O
. O

Stability O
of O
sulforaphane B
for O
topical O
formulation O
. O

Abstract O
Context O
: O
Sulforaphane B
( O
SFN B
) O
is O
a O
natural O
compound O
that O
has O
been O
investigated O
as O
a O
chemopreventive O
agent O
. O

SFN B
has O
been O
shown O
to O
inhibit O
the O
activator O
- O
protein O
- O
1 O
( O
AP O
- O
1 O
) O
transcription O
factor O
and O
may O
be O
effective O
for O
inhibition O
of O
ultraviolet O
( O
UV O
) O
induced O
skin O
carcinogenesis O
. O

This O
study O
was O
designed O
to O
investigate O
the O
stability O
of O
SFN B
as O
a O
function O
of O
pH O
, O
temperature O
and O
in O
various O
solvents O
and O
formulations O
. O

Materials O
and O
methods O
: O
Stability O
was O
analyzed O
using O
high O
- O
performance O
liquid O
chromatography O
. O

A O
potential O
lead O
formulation O
was O
identified O
and O
evaluated O
in O
vivo O
. O

Results O
: O
SFN B
was O
determined O
to O
undergo O
apparent O
first O
- O
order O
degradation O
kinetics O
for O
the O
conditions O
explored O
. O

It O
was O
observed O
that O
SFN B
undergoes O
base O
catalyzed O
degradation O
. O

Buffer O
species O
and O
solvent O
type O
impacts O
stability O
as O
well O
. O

SFN B
was O
found O
to O
be O
very O
sensitive O
to O
temperature O
with O
degradation O
rate O
changing O
by O
a O
factor O
of O
nearly O
3 O
. O
1 O
for O
every O
10 O
degrees O
C O
change O
in O
temperature O
( O
at O
pH O
4 O
. O
0 O
) O
. O

SFN B
completely O
degraded O
after O
30 O
days O
in O
a O
conventional O
pharmaceutical O
cream O
formulation O
. O

Improved O
stability O
was O
observed O
in O
organic O
formulation O
components O
. O

Stability O
studies O
were O
conducted O
on O
two O
nonaqueous O
topical O
formulations O
: O
a O
polyethylene B
glycol I
( O
PEG B
) O
ointment O
base O
and O
an O
organic O
oleaginous O
base O
. O

Conclusion O
: O
Topically O
applied O
SFN B
in O
the O
PEG B
base O
formulation O
significantly O
reduced O
AP O
- O
1 O
activation O
after O
UV O
stimulation O
in O
the O
skin O
of O
a O
transgenic O
mouse O
model O
, O
indicating O
that O
SFN B
in O
this O
formulation O
retains O
efficacy O
in O
vivo O
. O

DNA O
Interactions O
in O
Crowded O
Nanopores O
. O

The O
motion O
of O
DNA O
in O
crowded O
environments O
is O
a O
common O
theme O
in O
physics O
and O
biology O
. O

Examples O
include O
gel O
electrophoresis O
and O
the O
self O
- O
interaction O
of O
DNA O
within O
cells O
and O
viral O
capsids O
. O

Here O
we O
study O
the O
interaction O
of O
multiple O
DNA O
molecules O
within O
a O
nanopore O
by O
tethering O
the O
DNA O
to O
a O
bead O
held O
in O
a O
laser O
optical O
trap O
to O
produce O
a O
" O
molecular O
tug O
- O
of O
- O
war O
" O
. O

We O
measure O
this O
tether O
force O
as O
a O
function O
of O
the O
number O
of O
DNA O
molecules O
in O
the O
pore O
and O
show O
that O
the O
force O
per O
molecule O
decreases O
with O
the O
number O
of O
molecules O
. O

A O
simple O
scaling O
argument O
based O
on O
a O
mean O
field O
theory O
of O
the O
hydrodynamic O
interactions O
between O
multiple O
DNA O
strands O
explains O
our O
observations O
. O

At O
high O
salt O
concentrations O
, O
when O
the O
Debye O
length O
approaches O
the O
size O
of O
the O
counterions O
, O
the O
force O
per O
molecule O
becomes O
essentially O
independent O
of O
the O
number O
of O
molecules O
. O

We O
attribute O
this O
to O
a O
sharp O
decrease O
in O
electroosmotic O
flow O
which O
makes O
the O
hydrodynamic O
interactions O
ineffective O
. O

Spontaneous O
partition O
of O
carbon B
nanotubes O
in O
polymer O
- O
modified O
aqueous O
phases O
. O

The O
distribution O
of O
nanoparticles O
in O
different O
aqueous O
environments O
is O
a O
fundamental O
problem O
underlying O
a O
number O
of O
processes O
, O
ranging O
from O
biomedical O
applications O
of O
nanoparticles O
to O
their O
effects O
on O
the O
environment O
, O
health O
, O
and O
safety O
. O

Here O
, O
we O
study O
distribution O
of O
carbon B
nanotubes O
( O
CNTs O
) O
in O
two O
immiscible O
aqueous O
phases O
formed O
by O
the O
addition O
of O
polyethylene B
glycol I
( O
PEG B
) O
and O
dextran O
. O

This O
well O
- O
defined O
model O
system O
exhibits O
a O
strikingly O
robust O
phenomenon O
: O
CNTs O
spontaneously O
partition O
between O
the O
PEG B
- O
and O
the O
dextran O
- O
rich O
phases O
according O
to O
nanotube O
' O
s O
diameter O
and O
metallicity O
. O

Thermodynamic O
analysis O
suggests O
that O
this O
chirality O
- O
dependent O
partition O
is O
determined O
by O
nanotube O
' O
s O
intrinsic O
hydrophobicity O
and O
reveals O
two O
distinct O
regimes O
in O
hydrophobicity O
- O
chirality O
relation O
: O
a O
small O
diameter O
( O
< O
1 O
nm O
) O
regime O
, O
where O
curvature O
effect O
makes O
larger O
diameter O
tubes O
more O
hydrophobic O
than O
small O
diameter O
ones O
, O
and O
a O
large O
diameter O
( O
> O
1 O
. O
2 O
nm O
) O
regime O
, O
where O
nanotube O
' O
s O
polarizability O
renders O
semiconducting O
tubes O
more O
hydrophobic O
than O
metallic O
ones O
. O

These O
findings O
reveal O
a O
general O
rule O
governing O
CNT O
behaviors O
in O
aqueous O
phase O
and O
provide O
an O
extremely O
simple O
way O
to O
achieve O
spatial O
separation O
of O
CNTs O
by O
their O
electronic O
structures O
. O

Protein O
kinase O
inhibitor O
design O
by O
targeting O
the O
Asp B
- I
Phe I
- I
Gly I
( O
DFG O
) O
motif O
: O
the O
role O
of O
the O
DFG O
motif O
in O
the O
design O
of O
epidermal O
growth O
factor O
receptor O
inhibitors O
. O

The O
Asp B
- I
Phe I
- I
Gly I
( O
DFG O
) O
motif O
plays O
an O
important O
role O
in O
the O
regulation O
of O
kinase O
activity O
. O

Structure O
- O
based O
drug O
design O
was O
performed O
to O
design O
compounds O
able O
to O
interact O
with O
the O
DFG O
motif O
; O
epidermal O
growth O
factor O
receptor O
( O
EGFR O
) O
was O
selected O
as O
an O
example O
. O

Structural O
insights O
obtained O
from O
the O
EGFR O
/ O
2a O
complex O
suggested O
that O
an O
extension O
from O
the O
meta O
- O
position O
on O
the O
phenyl B
group O
( O
ring O
- O
5 O
) O
would O
improve O
interactions O
with O
the O
DFG O
motif O
. O

Indeed O
, O
introduction O
of O
an O
N B
, I
N I
- I
dimethylamino I
tail O
resulted O
in O
4b O
, O
which O
showed O
almost O
50 O
- O
fold O
improvement O
in O
inhibition O
compared O
to O
2a O
. O

Structural O
studies O
confirmed O
this O
N B
, I
N I
- I
dimethylamino I
tail O
moved O
towards O
the O
DFG O
motif O
to O
form O
a O
salt O
bridge O
with O
the O
side O
chain O
of O
Asp831 B
. O

That O
the O
interactions O
with O
the O
DFG O
motif O
greatly O
contribute O
to O
the O
potency O
of O
4b O
is O
strongly O
evidenced O
by O
synthesizing O
and O
testing O
compounds O
2a O
, O
3g O
and O
4f O
: O
when O
the O
charge O
interactions O
are O
absent O
, O
the O
inhibitory O
activity O
decreased O
significantly O
. O

Quantitative O
analysis O
of O
global O
phosphorylation O
changes O
with O
high O
- O
resolution O
tandem O
mass O
spectrometry O
and O
stable O
isotopic O
labeling O
. O

Quantitative O
measurement O
of O
specific O
protein O
phosphorylation O
sites O
is O
a O
primary O
interest O
of O
biologists O
, O
as O
site O
- O
specific O
phosphorylation O
information O
provides O
insights O
into O
cell O
signaling O
networks O
and O
cellular O
dynamics O
at O
a O
system O
level O
. O

Over O
the O
last O
decade O
, O
selective O
phosphopeptide O
enrichment O
methods O
including O
IMAC O
and O
metal B
oxides I
( O
TiO2 B
and O
ZrO2 B
) O
have O
been O
developed O
and O
greatly O
facilitate O
large O
scale O
phosphoproteome O
analysis O
of O
various O
cells O
, O
tissues O
and O
living O
organisms O
, O
in O
combination O
with O
modern O
mass O
spectrometers O
featuring O
high O
mass O
accuracy O
and O
high O
mass O
resolution O
. O

Various O
quantification O
strategies O
have O
been O
applied O
to O
detecting O
relative O
changes O
in O
expression O
of O
proteins O
, O
peptides O
, O
and O
specific O
modifications O
between O
samples O
. O

The O
combination O
of O
mass O
spectrometry O
- O
based O
phosphoproteome O
analysis O
with O
quantification O
strategies O
provides O
a O
straightforward O
and O
unbiased O
method O
to O
identify O
and O
quantify O
site O
- O
specific O
phosphorylation O
. O

We O
describe O
common O
strategies O
for O
mass O
spectrometric O
analysis O
of O
stable O
isotope O
labeled O
samples O
, O
as O
well O
as O
two O
widely O
applied O
phosphopeptide O
enrichment O
methods O
based O
on O
IMAC O
( O
NTA B
- I
Fe I
( I
3 I
+ I
) I
) O
and O
metal B
oxide I
( O
ZrO2 B
) O
. O

Instrumental O
configurations O
for O
on O
- O
line O
LC O
- O
tandem O
mass O
spectrometric O
analysis O
and O
parameters O
of O
conventional O
bioinformatic O
analysis O
of O
large O
data O
sets O
are O
also O
considered O
for O
confident O
identification O
, O
localization O
, O
and O
reliable O
quantification O
of O
site O
- O
specific O
phosphorylation O
. O

Molecular O
Mechanisms O
of O
the O
antitumor O
activity O
of O
SB225002 B
: O
A O
novel O
microtubule O
inhibitor O
. O

SB225002 B
( O
SB O
) O
is O
an O
IL O
- O
8 O
receptor O
B O
( O
IL O
- O
8RB O
) O
antagonist O
that O
has O
previously O
been O
shown O
to O
inhibit O
IL O
- O
8 O
- O
based O
cancer O
cell O
invasion O
, O
and O
to O
possess O
in O
vivo O
anti O
- O
inflammatory O
and O
anti O
- O
nociceptive O
effects O
. O

The O
present O
study O
presented O
an O
evidence O
for O
the O
cell O
cycle O
- O
targeting O
activity O
of O
SB O
in O
a O
panel O
of O
p53 O
- O
mutant O
human O
cancer O
cell O
lines O
of O
different O
origin O
, O
and O
investigated O
the O
underlying O
molecular O
mechanisms O
. O

A O
combination O
of O
cell O
cycle O
analysis O
, O
immunocytometry O
, O
immunoblotting O
, O
and O
RNA O
interference O
revealed O
that O
SB O
induced O
a O
BubR1 O
- O
dependent O
mitotic O
arrest O
. O

Mechanistically O
, O
SB O
was O
shown O
to O
possess O
a O
microtubule O
destabilizing O
activity O
evidenced O
by O
hyperphosphorylation O
of O
Bcl2 O
and O
BclxL O
, O
suppression O
of O
microtubule O
polymerization O
and O
induction O
of O
a O
prometaphase O
arrest O
. O

Molecular O
docking O
studies O
suggested O
that O
SB O
has O
a O
good O
affinity O
towards O
vinblastine B
- O
binding O
site O
on O
beta O
- O
tubulin O
subunit O
. O

Of O
note O
, O
SB265610 B
which O
is O
a O
close O
structural O
analogue O
of O
SB225002 B
with O
a O
potent O
IL O
- O
8RB O
antagonistic O
activity O
did O
not O
exhibit O
a O
similar O
antimitotic O
activity O
. O

Importantly O
, O
in O
P O
- O
glycoprotein O
overexpressing O
NCI O
/ O
Adr O
- O
Res O
cells O
the O
antitumor O
activity O
of O
SB O
was O
unaffected O
by O
multidrug O
resistance O
. O

Interestingly O
, O
the O
mechanisms O
of O
SB O
- O
induced O
cell O
death O
were O
cell O
- O
line O
dependent O
, O
where O
in O
invasive O
hepatocellular O
carcinoma O
HLE O
cells O
the O
significant O
contribution O
of O
BAK O
- O
dependent O
mitochondrial O
apoptosis O
was O
demonstrated O
. O

Conversely O
, O
SB O
activated O
p38 O
MAPK O
signaling O
in O
colorectal O
adenocarcinoma O
cells O
SW480 O
, O
and O
pharmacologic O
inhibition O
of O
p38 O
MAPK O
activity O
revealed O
its O
key O
role O
in O
mediating O
SB O
- O
induced O
caspase O
- O
independent O
cell O
death O
. O

In O
summary O
, O
the O
present O
study O
introduced O
SB O
as O
a O
promising O
antitumor O
agent O
which O
has O
the O
potential O
to O
exert O
its O
activity O
through O
dual O
mechanisms O
involving O
microtubules O
targeting O
and O
interference O
with O
IL O
- O
8 O
- O
drivin O
cancer O
progression O
. O

Wogonoside B
displays O
anti O
- O
inflammatory O
effects O
through O
modulating O
inflammatory O
mediator O
expression O
using O
RAW264 O
. O
7 O
cells O
. O

ETHNOPHARMACOLOGICAL O
RELEVANCE O
: O
The O
root O
of O
Scutellaria O
baicalensis O
Georgi O
, O
also O
called O
Huangqin O
in O
China O
, O
is O
an O
herbal O
- O
based O
nutraceutical O
which O
is O
usually O
used O
in O
Chinese O
medicated O
diet O
( O
CMD O
) O
. O

As O
an O
abundant O
ingredient O
in O
Huangqin O
, O
wogonoside B
is O
a O
flavonoid B
glycoside I
. O

The O
present O
work O
investigated O
the O
anti O
- O
inflammatory O
activities O
of O
wogonoside B
in O
lipopolysaccharides O
( O
LPS O
) O
- O
induced O
RAW264 O
. O
7 O
cells O
. O

MATERIALS O
AND O
METHODS O
: O
RAW264 O
. O
7 O
cells O
were O
used O
. O

The O
inhibition O
of O
wogonoside B
against O
nitric B
oxide I
( O
NO B
) O
, O
prostaglandin B
E2 I
( O
PGE2 B
) O
, O
tumor O
necrosis O
factor O
- O
alpha O
( O
TNF O
- O
alpha O
) O
and O
interleukin O
- O
6 O
( O
IL O
- O
6 O
) O
in O
LPS O
- O
induced O
RAW264 O
. O
7 O
cells O
were O
measured O
. O

Additionally O
, O
the O
effects O
of O
wogonoside B
on O
mRNA O
expression O
of O
inducible O
nitric B
oxide I
synthase O
( O
iNOS O
) O
, O
cyclooxygenase O
2 O
( O
COX2 O
) O
, O
TNF O
- O
alpha O
and O
IL O
- O
6 O
were O
also O
investigated O
. O

RESULTS O
AND O
DISCUSSION O
: O
Wogonoside B
not O
only O
dose O
- O
dependently O
decreased O
the O
production O
of O
inflammatory O
mediators O
including O
NO B
and O
PGE2 B
but O
also O
inhibited O
the O
release O
of O
pro O
- O
inflammatory O
cytokines O
including O
TNF O
- O
alpha O
and O
IL O
- O
6 O
in O
LPS O
- O
induced O
RAW264 O
. O
7 O
cells O
. O

Furthermore O
, O
wogonoside B
possessed O
significantly O
in O
vitro O
inhibitory O
effects O
on O
the O
gene O
expression O
of O
iNOS O
, O
COX2 O
, O
TNF O
- O
alpha O
and O
IL O
- O
6 O
. O

CONCLUSION O
: O
These O
results O
suggest O
that O
wogonoside B
may O
be O
used O
as O
a O
functional O
food O
component O
for O
prevention O
and O
treatment O
of O
inflammation O
. O

Assuring O
Safety O
Without O
Animal O
Testing O
: O
The O
Case O
for O
the O
Human O
Testis O
In O
Vitro O
. O

From O
15 O
- O
17 O
June O
2011 O
, O
a O
dedicated O
workhop O
was O
held O
on O
the O
subject O
of O
in O
vitro O
models O
for O
mammalian O
spermatogenesis O
and O
their O
applications O
in O
toxicological O
hazard O
and O
risk O
assessment O
. O

The O
workshop O
was O
sponsored O
by O
the O
Dutch O
ASAT O
initiative O
( O
Assuring O
Safety O
without O
Animal O
Testing O
) O
, O
which O
aims O
at O
promoting O
innovative O
approaches O
towards O
toxicological O
hazard O
and O
risk O
assessment O
on O
the O
basis O
of O
human O
and O
in O
vitro O
data O
, O
and O
replacement O
of O
animal O
studies O
. O

Participants O
addressed O
the O
state O
of O
the O
art O
regarding O
human O
and O
animal O
evidence O
for O
compound O
mediated O
testicular O
toxicity O
, O
reviewed O
existing O
alternative O
assay O
models O
, O
and O
brainstormed O
about O
future O
approaches O
, O
specifically O
considering O
tissue O
engineering O
. O

The O
workshop O
recognized O
the O
specific O
complexity O
of O
testicular O
function O
exemplified O
by O
dedicated O
cell O
types O
with O
distinct O
functionalities O
, O
as O
well O
as O
different O
cell O
compartments O
in O
terms O
of O
microenvironment O
and O
extracellular O
matrix O
components O
. O

This O
complexity O
hampers O
quick O
results O
in O
the O
realm O
of O
alternative O
models O
. O

Nevertheless O
, O
progress O
has O
been O
achieved O
in O
recent O
years O
, O
and O
innovative O
approaches O
in O
tissue O
engineering O
may O
open O
new O
avenues O
for O
mimicking O
testicular O
function O
in O
vitro O
. O

Although O
feasible O
, O
significant O
investment O
is O
deemed O
essential O
to O
be O
able O
to O
bring O
new O
ideas O
into O
practice O
in O
the O
laboratory O
. O

For O
the O
advancement O
of O
in O
vitro O
testicular O
toxicity O
testing O
, O
one O
of O
the O
most O
sensitive O
end O
points O
in O
regulatory O
reproductive O
toxicity O
testing O
, O
such O
an O
investment O
is O
highly O
desirable O
. O

Relations O
between O
stimulation O
of O
mesolimbic O
dopamine B
and O
place O
conditioning O
in O
rats O
produced O
by O
cocaine B
or O
drugs O
that O
are O
tolerant O
to O
dopamine B
transporter O
conformational O
change O
. O

RATIONALE O
: O
Dopamine B
transporter O
( O
DAT O
) O
conformation O
plays O
a O
role O
in O
the O
effectiveness O
of O
cocaine B
- O
like O
and O
other O
DAT O
inhibitors O
. O

Cocaine B
- O
like O
stimulants O
are O
intolerant O
to O
DAT O
conformation O
changes O
having O
decreased O
potency O
in O
cells O
transfected O
with O
DAT O
constructs O
that O
face O
the O
cytosol O
compared O
to O
wild O
- O
type O
DAT O
. O

In O
contrast O
, O
analogs O
of O
benztropine B
( O
BZT B
) O
are O
among O
compounds O
that O
are O
less O
affected O
by O
DAT O
conformational O
change O
. O

METHODS O
: O
We O
compared O
the O
displacement O
of O
radioligand O
binding O
to O
various O
mammalian O
CNS O
sites O
, O
acute O
stimulation O
of O
accumbens O
shell O
dopamine B
levels O
, O
and O
place O
conditioning O
in O
rats O
among O
cocaine B
and O
four O
BZT B
analogs O
with O
Cl B
substitutions O
on O
the O
diphenyl B
- I
ether I
system O
including O
two O
with O
carboalkoxy B
substitutions O
at O
the O
2 O
- O
position O
of O
the O
tropane B
ring O
. O

RESULTS O
: O
Binding O
assays O
confirmed O
high O
- O
affinity O
and O
selectivity O
for O
the O
DAT O
with O
the O
BZT B
analogs O
which O
also O
produced O
significant O
stimulation O
of O
mesolimbic O
dopamine B
efflux O
. O

Because O
BZT B
analogs O
produced O
temporal O
patterns O
of O
extracellular O
dopamine B
levels O
different O
from O
those O
by O
cocaine B
( O
3 O
- O
10 O
mg O
/ O
kg O
, O
i O
. O
p O
. O
) O
, O
the O
place O
conditioning O
produced O
by O
BZT B
analogs O
and O
cocaine B
was O
compared O
at O
doses O
and O
times O
at O
which O
both O
the O
increase O
in O
dopamine B
levels O
and O
rates O
of O
increase O
were O
similar O
to O
those O
produced O
by O
an O
effective O
dose O
of O
cocaine B
. O

Despite O
this O
equilibration O
, O
none O
of O
the O
BZT B
analogs O
tested O
produced O
significant O
place O
conditioning O
. O

CONCLUSIONS O
: O
The O
present O
results O
extend O
previous O
findings O
suggesting O
that O
cocaine B
- O
like O
actions O
are O
dependent O
on O
a O
binding O
equilibrium O
that O
favors O
the O
outward O
conformational O
state O
of O
the O
DAT O
. O

In O
contrast O
, O
BZT B
analogs O
with O
reduced O
dependence O
on O
DAT O
conformation O
have O
reduced O
cocaine B
- O
like O
behavioral O
effects O
and O
may O
prove O
useful O
in O
development O
of O
medications O
for O
stimulant O
abuse O
. O

The O
von O
Hippel O
- O
Lindau O
Protein O
pVHL O
Inhibits O
Ribosome O
Biogenesis O
and O
Protein O
Synthesis O
. O

pVHL O
, O
product O
of O
von O
Hippel O
- O
Lindau O
( O
VHL O
) O
tumor O
suppressor O
gene O
, O
functions O
as O
the O
substrate O
recognition O
component O
of O
an O
E3 O
- O
ubiquitin O
ligase O
complex O
that O
targets O
hypoxia O
inducible O
factor O
alpha O
( O
HIFalpha O
) O
for O
ubiquitination O
and O
degradation O
. O

Besides O
HIFalpha O
, O
pVHL O
also O
interacts O
with O
other O
proteins O
and O
has O
multiple O
functions O
. O

Here O
, O
we O
report O
that O
pVHL O
inhibits O
ribosome O
biogenesis O
and O
protein O
synthesis O
. O

We O
find O
that O
pVHL O
associates O
with O
the O
40S O
ribosomal O
protein O
S3 O
( O
RPS3 O
) O
but O
does O
not O
target O
it O
for O
destruction O
. O

Rather O
, O
the O
pVHL O
- O
RPS3 O
association O
interferes O
with O
the O
interaction O
between O
RPS3 O
and O
RPS2 O
. O

Expression O
of O
pVHL O
also O
leads O
to O
nuclear O
retention O
of O
pre O
- O
40S O
ribosomal O
subunits O
, O
diminishing O
polysomes O
and O
18S O
rRNA O
levels O
. O

We O
also O
demonstrate O
that O
pVHL O
suppresses O
both O
cap O
- O
dependent O
and O
cap O
- O
independent O
protein O
synthesis O
. O

Our O
findings O
unravel O
a O
novel O
function O
of O
pVHL O
and O
provide O
insight O
into O
the O
regulation O
of O
ribosome O
biogenesis O
by O
the O
tumor O
suppressor O
pVHL O
. O

Decreased O
Permeability O
Surface O
Area O
for O
Glucose B
in O
Obese O
Women O
with O
Postprandial O
Hyperglycemia O
: O
No O
Effect O
of O
Phosphodiesterase O
- O
5 O
( O
PDE O
- O
5 O
) O
Inhibition O
. O

Insulin O
- O
mediated O
microvascular O
recruitment O
is O
recognized O
as O
a O
potential O
mechanism O
contributing O
to O
insulin O
resistance O
. O

In O
this O
study O
, O
we O
compared O
a O
marker O
of O
microvascular O
function O
, O
the O
permeability O
surface O
area O
for O
glucose B
( O
PSglu O
) O
, O
and O
forearm O
glucose B
uptake O
after O
an O
OGTT O
in O
obese O
women O
with O
impaired O
glucose B
metabolism O
and O
healthy O
lean O
nondiabetic O
women O
, O
with O
the O
aim O
to O
characterize O
whether O
decreased O
permeability O
surface O
area O
for O
glucose B
or O
decreased O
glucose B
uptake O
may O
contribute O
to O
postprandial O
hyperglycemia O
in O
the O
obese O
group O
. O

In O
addition O
, O
we O
evaluated O
whether O
the O
phosphodiesterase O
- O
5 O
( O
PDE O
- O
5 O
) O
inhibitor O
tadalafil B
, O
in O
a O
randomized O
double O
blind O
placebo O
controlled O
design O
, O
might O
attenuate O
postprandial O
glucose B
levels O
in O
obese O
women O
. O

For O
these O
purposes O
, O
intramuscular O
microdialysis O
, O
blood O
sampling O
from O
arterial O
and O
venous O
blood O
of O
the O
forearm O
, O
and O
measurements O
of O
forearm O
blood O
flow O
were O
performed O
. O

The O
results O
showed O
an O
impaired O
permeability O
surface O
area O
for O
glucose B
( O
IAUC O
PSglu O
31 O
+ O
/ O
- O
13 O
vs O
. O
124 O
+ O
/ O
- O
31 O
; O
p O
< O
0 O
. O
05 O
) O
in O
obese O
when O
compared O
with O
lean O
participants O
, O
but O
no O
differences O
in O
forearm O
glucose B
uptake O
appeared O
between O
the O
groups O
. O

Furthermore O
, O
a O
single O
dose O
of O
tadalafil B
10 O
mg O
showed O
no O
improvement O
of O
the O
permeability O
surface O
area O
for O
glucose B
, O
glucose B
uptake O
, O
or O
circulating O
glucose B
levels O
in O
obese O
participants O
. O

In O
conclusion O
, O
the O
postprandial O
PSglu O
response O
was O
impaired O
in O
obese O
women O
showing O
postprandial O
hyperglycemia O
, O
indicating O
a O
compromised O
microcirculation O
. O

However O
, O
we O
were O
unable O
to O
demonstrate O
any O
acute O
effect O
on O
either O
vascular O
function O
or O
glucose B
uptake O
of O
the O
phosphodiesterase O
- O
5 O
( O
PDE O
- O
5 O
) O
inhibitor O
tadalafil B
. O

Dietary O
Flaxseed O
Oil O
Supplementation O
Mitigates O
the O
Effect O
of O
Lead O
on O
the O
Enzymes O
of O
Carbohydrate B
Metabolism O
, O
Brush O
Border O
Membrane O
, O
and O
Oxidative O
Stress O
in O
Rat O
Kidney O
Tissues O
. O

Lead O
is O
a O
heavy O
metal O
widely O
distributed O
in O
the O
environment O
. O

Lead O
is O
a O
ubiquitous O
environmental O
toxin O
that O
is O
capable O
of O
causing O
numerous O
acute O
and O
chronic O
illnesses O
. O

Human O
and O
animal O
exposure O
demonstrates O
that O
lead O
is O
nephrotoxic O
. O

However O
, O
attempts O
to O
reduce O
lead O
- O
induced O
nephrotoxicity O
were O
not O
found O
suitable O
for O
clinical O
use O
. O

Recently O
, O
flaxseed O
oil O
( O
FXO O
) O
, O
a O
rich O
source O
of O
omega B
- I
3 I
fatty I
acids I
and O
lignans B
, O
has O
been O
shown O
to O
prevent O
/ O
reduce O
the O
progression O
of O
certain O
types O
of O
cardiovascular O
and O
renal O
disorders O
. O

In O
view O
of O
this O
, O
the O
present O
study O
investigates O
the O
protective O
effect O
of O
FXO O
on O
lead B
acetate I
( O
PbAc B
) O
- O
induced O
renal O
damage O
. O

Rats O
were O
pre O
- O
fed O
normal O
diet O
and O
the O
diet O
rich O
in O
FXO O
for O
14 O
days O
, O
and O
then O
, O
four O
doses O
of O
lead B
acetate I
( O
25 O
mg O
/ O
kg O
body O
weight O
) O
were O
administered O
intraperitoneally O
while O
still O
on O
diet O
. O

Various O
serum O
parameters O
, O
enzymes O
of O
carbohydrate B
metabolism O
, O
brush O
border O
membrane O
( O
BBM O
) O
, O
and O
oxidative O
stress O
were O
analyzed O
in O
rat O
kidney O
. O

PbAc B
nephrotoxicity O
was O
characterized O
by O
increased O
serum O
creatinine B
and O
blood O
urea B
nitrogen B
. O

PbAc O
increased O
the O
activities O
of O
lactate B
dehydrogenase O
and O
NADP B
- O
malic O
enzyme O
, O
whereas O
it O
decreased O
malate B
and O
glucose B
- I
6 I
- I
phosphate I
dehydrogenase O
, O
glucose B
- O
6 O
- O
phosphatase O
, O
fructose B
- O
1 O
, O
6 O
- O
bisphosphatase O
, O
and O
BBM O
enzyme O
activities O
. O

PbAc B
caused O
oxidant O
/ O
antioxidant O
imbalances O
as O
reflected O
by O
increased O
lipid O
peroxidation O
and O
decreased O
activities O
of O
superoxide B
dismutase O
, O
glutathione B
peroxidase O
, O
and O
catalase O
. O

In O
contrast O
, O
FXO O
alone O
enhanced O
the O
enzyme O
activities O
of O
carbohydrate B
metabolism O
, O
BBM O
, O
and O
antioxidant O
defense O
system O
. O

FXO O
feeding O
to O
PbAc B
- O
treated O
rats O
markedly O
enhanced O
resistance O
to O
PbAc B
- O
elicited O
deleterious O
effects O
. O

In O
conclusion O
, O
dietary O
FXO O
supplementation O
ameliorated O
PbAc O
- O
induced O
specific O
metabolic O
alterations O
and O
oxidative O
damage O
by O
empowering O
antioxidant O
defense O
mechanism O
and O
improving O
BBM O
integrity O
and O
energy O
metabolism O
. O

Topological O
Dangling O
Bonds O
with O
Large O
Spin O
Splitting O
and O
Enhanced O
Spin O
Polarization O
on O
the O
Surfaces O
of O
Bi2Se3 B
. O

We O
investigate O
the O
topological O
surface O
state O
properties O
at O
various O
surface O
cleaves O
in O
the O
topological O
insulator O
Bi2Se3 B
, O
via O
first O
principles O
calculations O
and O
scanning O
tunneling O
microscopy O
/ O
spectroscopy O
( O
STM O
/ O
STS O
) O
. O

While O
the O
typical O
surface O
termination O
occurs O
between O
two O
quintuple O
layers O
, O
we O
report O
the O
existence O
of O
a O
surface O
termination O
within O
a O
single O
quintuple O
layer O
where O
dangling O
bonds O
form O
with O
giant O
spin O
splitting O
owing O
to O
strong O
spin O
- O
orbit O
coupling O
. O

Unlike O
Rashba O
split O
states O
in O
a O
2D O
electron O
gas O
, O
these O
states O
are O
constrained O
by O
the O
band O
topology O
of O
the O
host O
insulator O
with O
topological O
properties O
similar O
to O
the O
typical O
topological O
surface O
state O
, O
and O
thereby O
offer O
an O
alternative O
candidate O
for O
spintronics O
usage O
. O

We O
name O
these O
new O
states O
" O
topological O
dangling O
- O
bond O
states O
" O
. O

The O
degree O
of O
the O
spin O
polarization O
of O
these O
states O
is O
greatly O
enhanced O
. O

Since O
dangling O
bonds O
are O
more O
chemically O
reactive O
, O
the O
observed O
topological O
dangling O
- O
bond O
states O
provide O
a O
new O
avenue O
for O
manipulating O
band O
dispersions O
and O
spin O
- O
textures O
by O
adsorbed O
atoms O
or O
molecules O
. O

Efficient O
cell O
and O
cell O
- O
sheet O
harvesting O
based O
on O
smart O
surfaces O
coated O
with O
a O
multifunctional O
and O
self O
- O
organizing O
Elastin O
- O
Like O
Recombinamer O
. O

A O
wide O
range O
of O
smart O
surfaces O
with O
novel O
properties O
relevant O
for O
biomedical O
applications O
have O
been O
developed O
recently O
. O

Herein O
we O
focus O
on O
thermoresponsive O
surfaces O
that O
switch O
between O
cell O
- O
adherent O
and O
non O
- O
adherent O
states O
, O
and O
their O
applications O
for O
cell O
harvesting O
. O

These O
smart O
surfaces O
are O
obtained O
by O
covalently O
coupling O
a O
tailored O
Elastin O
- O
Like O
Recombinamer O
onto O
glass O
surfaces O
by O
means O
of O
the O
well O
- O
known O
and O
widely O
applied O
Click O
Chemistry O
methodology O
. O

The O
resulting O
recombinamer O
- O
functionalized O
surfaces O
have O
been O
characterized O
by O
means O
of O
water O
contact O
angle O
measurements O
, O
XPS O
and O
TOF O
- O
SIMS O
. O

A O
cell O
- O
based O
analysis O
of O
these O
surfaces O
with O
human O
fibroblasts O
showed O
a O
high O
degree O
of O
adhesion O
to O
the O
surface O
in O
its O
adherent O
state O
( O
37 O
( O
o O
) O
C O
) O
, O
thus O
promoting O
cell O
viability O
and O
proliferation O
. O

A O
temperature O
decrease O
triggers O
reorganization O
of O
the O
recombinamer O
, O
thus O
markedly O
increasing O
the O
number O
of O
non O
- O
adherent O
domains O
and O
masking O
the O
adherent O
ones O
. O

This O
process O
allows O
a O
specific O
and O
efficient O
temporal O
control O
of O
cell O
adhesion O
and O
cell O
detachment O
. O

After O
determination O
of O
the O
properties O
required O
for O
a O
suitable O
cell O
- O
harvesting O
system O
, O
optimization O
of O
the O
process O
allows O
single O
cells O
or O
cell O
sheets O
from O
at O
least O
two O
types O
of O
cells O
( O
HFF O
- O
1 O
and O
ADSCs O
) O
to O
be O
rapidly O
harvested O
. O

Aromatic B
glycosides I
from O
the O
flower O
buds O
of O
Lonicera O
japonica O
. O

Six O
new O
glycosides O
( O
1 O
- O
6 O
) O
have O
been O
isolated O
from O
the O
flower O
buds O
of O
Lonicera O
japonica O
. O

Their O
structures O
including O
the O
absolute O
configurations O
were O
determined O
by O
spectroscopic O
and O
chemical O
methods O
as O
( B
- I
) I
- I
2 I
- I
hydroxy I
- I
5 I
- I
methoxybenzoic I
acid I
2 I
- I
O I
- I
beta I
- I
d I
- I
( I
6 I
- I
O I
- I
benzoyl I
) I
- I
glucopyranoside I
( O
1 O
) O
, O
( B
- I
) I
- I
4 I
- I
hydroxy I
- I
3 I
, I
5 I
- I
dimethoxybenzoic I
acid I
4 I
- I
O I
- I
beta I
- I
d I
- I
( I
6 I
- I
O I
- I
benzoyl I
) I
- I
glucopyranoside I
( O
2 O
) O
, O
( B
- I
) I
- I
( I
E I
) I
- I
3 I
, I
5 I
- I

dimethoxyphenylprope I
acid I
4 I
- I
O I
- I
beta I
- I
d I
- I
( I
6 I
- I
O I
- I
benzoyl I
) I
- I
glucopyranoside I
( O
3 O
) O
, O
( B
- I
) I
- I
( I
7S I
, I
8R I
) I
- I
( I
4 I
- I
hydroxyphenylglycero I
9 I
- I
O I
- I
beta I
- I
d I
- I
[ I
6 I
- I
O I
- I
( I
E I
) I
- I
4 I
- I
hydroxy I
- I
3 I
, I
5 I
- I
dimethoxyphenylprope I
] I
- I
glucopyranoside I
( O
4 O
) O
, O
( B
- I
) I
- I
( I
7S I
, I
8R I
) I
- I
( I
4 I
- I

hydroxy I
- I
3 I
- I
methoxyphenylglycero I
9 I
- I
O I
- I
beta I
- I
d I
- I
[ I
6 I
- I
O I
- I
( I
E I
) I
- I
4 I
- I
hydroxy I
- I
3 I
, I
5 I
- I
dimethoxyphenylprope I
] I
- I
glucopyranoside I
( O
5 O
) O
, O
and O
( B
- I
) I
- I
4 I
- I
hydroxy I
- I
3 I
- I
methoxyphenol I
beta I
- I
d I
- I
{ I
6 I
- I
O I
- I
[ I
4 I
- I
O I
- I
( I
7S I
, I
8R I
) I
- I
( I
4 I
- I
hydroxy I
- I
3 I
- I
methoxyphenylglycero I
- I
8 I
- I

yl I
) I
- I
3 I
- I
methoxybenzoyl I
] I
} I
- I
glucopyranoside I
( O
6 O
) O
, O
respectively O
. O

Sub O
- O
nanomolar O
Detection O
of O
Prostate O
Specific O
Membrane O
Antigen O
in O
Synthetic O
Urine O
by O
Synergistic O
, O
Dual O
Ligand O
Phage O
. O

The O
sensitive O
detection O
of O
cancer O
biomarkers O
in O
urine O
could O
revolutionize O
cancer O
diagnosis O
and O
treatment O
. O

Such O
detectors O
must O
be O
inexpensive O
, O
easy O
to O
interpret O
, O
and O
sensitive O
. O

This O
report O
describes O
a O
bioaffinity O
matrix O
of O
viruses O
integrated O
into O
PEDOT O
films O
for O
electrochemical O
sensing O
of O
prostate O
specific O
membrane O
antigen O
( O
PSMA O
) O
, O
a O
prostate O
cancer O
biomarker O
. O

High O
sensitivity O
to O
PSMA O
resulted O
from O
synergistic O
action O
by O
two O
different O
ligands O
to O
PSMA O
on O
the O
same O
phage O
particle O
. O

One O
ligand O
was O
chemically O
synthesized O
and O
wrapped O
around O
the O
phage O
, O
and O
the O
second O
was O
genetically O
encoded O
. O

The O
dual O
ligands O
result O
in O
a O
bidentate O
binder O
with O
high O
copy O
, O
dense O
ligand O
display O
for O
enhanced O
PSMA O
detection O
through O
a O
chelate O
- O
based O
, O
avidity O
effect O
. O

Biosensing O
with O
virus O
- O
PEDOT O
films O
provides O
a O
100 O
pM O
limit O
of O
detection O
for O
PSMA O
in O
synthetic O
urine O
without O
requiring O
enzymatic O
or O
other O
amplification O
. O

Oxidative O
damage O
and O
genotoxic O
effect O
in O
mice O
caused O
by O
sub O
- O
chronic O
exposure O
to O
low O
- O
dose O
volatile O
organic O
compounds O
. O

Abstract O
Volatile O
organic O
compounds O
( O
VOCs O
) O
are O
widely O
used O
as O
constituents O
of O
household O
chemicals O
. O

Although O
adverse O
health O
effects O
have O
been O
reported O
, O
long O
- O
term O
exposure O
to O
low O
- O
level O
VOCs O
mixture O
has O
not O
been O
studied O
. O

Especially O
, O
there O
is O
a O
lack O
of O
substantial O
information O
on O
the O
sensitive O
biomarkers O
and O
carcinogenic O
markers O
. O

In O
the O
present O
study O
, O
we O
examined O
oxidative O
stress O
and O
genotoxic O
effects O
of O
sub O
- O
chronic O
low O
- O
dose O
VOCs O
mixture O
( O
formaldehyde B
, O
benzene B
, O
toluene B
and O
xylene B
) O
. O

Male O
Kunming O
mice O
were O
exposed O
to O
0 O
( O
control O
) O
and O
three O
different O
doses O
of O
VOCs O
mixture O
( O
group O
1S O
, O
5S O
and O
10S O
) O
for O
90 O
d O
( O
2 O
h O
/ O
d O
) O
. O

Group O
1S O
is O
0 O
. O
10 O
, O
0 O
. O
11 O
, O
0 O
. O
20 O
and O
0 O
. O
20 O
mg O
/ O
m O
( O
3 O
) O
, O
group O
5S O
is O
0 O
. O
50 O
, O
0 O
. O
55 O
, O
1 O
. O
00 O
and O
1 O
. O
00 O
mg O
/ O
m O
( O
3 O
) O
, O
group O
10S O
is O
1 O
. O
00 O
, O
1 O
. O
10 O
, O
2 O
. O
00 O
and O
2 O
. O
00 O
mg O
/ O
m O
( O
3 O
) O
, O
which O
, O
respectively O
, O
corresponded O
to O
1 O
, O
5 O
and O
10 O
times O
of O
indoor O
air O
quality O
standard O
( O
IAQS O
) O
in O
China O
. O

One O
day O
following O
VOCs O
exposure O
, O
oxidative O
stress O
markers O
in O
lung O
, O
8 B
- I
hydroxy I
- I
2 I
' I
- I
deoxyguanosine I
in O
bronchoalveolar O
lavage O
fluid O
and O
genotoxicity O
( O
DNA O
damage O
) O
in O
liver O
were O
examined O
. O

Results O
showed O
that O
exposure O
to O
VOCs O
( O
IAQS O
dose O
) O
resulted O
in O
oxidative O
damages O
of O
lung O
, O
which O
were O
supported O
by O
the O
significant O
changes O
on O
reactive O
oxygen B
species O
, O
reduced B
glutathione I
( O
GSH B
) O
, O
GSH B
S B
- O
transferase O
, O
total O
antioxidative O
capacity O
, O
malondialdehyde B
, O
protein O
carbonyl B
and O
nitric B
oxide I
( O
NO B
) O
. O

Moreover O
, O
oxidative O
stress O
markers O
in O
group O
5S O
and O
10S O
( O
except O
NO B
) O
in O
lung O
were O
affected O
significantly O
. O

In O
addition O
, O
VOCs O
exposure O
also O
induced O
significantly O
DNA O
damage O
in O
liver O
. O

Our O
study O
suggested O
long O
- O
term O
VOCs O
inhalation O
at O
low O
levels O
caused O
oxidative O
stress O
and O
genotoxicity O
response O
in O
mice O
. O

Since O
effects O
were O
seen O
at O
the O
current O
IAQS O
level O
, O
further O
studies O
below O
this O
level O
are O
necessary O
. O

Surgical O
resection O
of O
brain O
metastases O
- O
impact O
on O
neurological O
outcome O
. O

Brain O
metastases O
( O
BM O
) O
develop O
in O
about O
30 O
% O
of O
all O
cancer O
patients O
. O

Surgery O
plays O
an O
important O
role O
in O
confirming O
neuropathological O
diagnosis O
, O
relieving O
mass O
effects O
and O
improving O
the O
neurological O
status O
. O

To O
select O
patients O
with O
the O
highest O
benefit O
from O
surgical O
resection O
, O
prognostic O
indices O
( O
RPA O
, O
GPA O
) O
have O
been O
formulated O
which O
are O
solely O
focused O
on O
survival O
without O
considering O
neurological O
improvement O
. O

In O
this O
study O
we O
analyzed O
the O
impact O
of O
surgical O
resection O
on O
the O
neurological O
status O
in O
addition O
to O
overall O
survival O
in O
206 O
BM O
patients O
. O

Surgical O
mortality O
and O
morbidity O
was O
0 O
. O
0 O
% O
and O
10 O
. O
3 O
% O
respectively O
. O

New O
neurologic O
deficits O
occurred O
in O
6 O
. O
3 O
% O
of O
all O
patients O
. O

The O
median O
overall O
survival O
was O
6 O
. O
3 O
months O
. O

Poor O
RPA O
class O
and O
short O
time O
interval O
between O
diagnosis O
of O
cancer O
and O
the O
occurrence O
of O
BM O
were O
independent O
factors O
predictive O
for O
poor O
survival O
. O

Improvement O
of O
neurological O
performance O
was O
achieved O
in O
56 O
. O
8 O
% O
of O
all O
patients O
, O
with O
the O
highest O
improvement O
rate O
seen O
in O
patients O
presenting O
with O
increased O
intracranial O
pressure O
and O
hemiparesis O
. O

Notably O
, O
the O
neurological O
benefits O
were O
independent O
from O
RPA O
class O
. O

In O
conclusion O
, O
surgical O
resection O
leads O
to O
significant O
neurological O
improvement O
despite O
poor O
RPA O
class O
and O
short O
overall O
survival O
. O

Considering O
the O
low O
mortality O
and O
morbidity O
rates O
, O
resection O
should O
be O
considered O
as O
a O
valid O
option O
to O
increase O
neurological O
function O
and O
quality O
of O
life O
for O
patients O
with O
BM O
. O

Molecular O
sensing O
: O
modulating O
molecular O
conduction O
through O
intermolecular O
interactions O
. O

We O
observe O
changes O
in O
the O
molecular O
conductivity O
of O
individual O
oligophenylene B
- I
vinylene I
( O
OPV B
) O
molecules O
due O
to O
interactions O
with O
small O
aromatic O
molecules O
. O

Fluorescence O
experiments O
were O
correlated O
with O
scanning O
tunneling O
microscopy O
measurements O
in O
order O
to O
determine O
the O
origin O
of O
the O
observed O
effect O
. O

Both O
nitrobenzene B
and O
1 B
, I
4 I
- I
dinitrobenzene I
decreased O
fluorescence O
intensity O
and O
molecular O
conductivity O
, O
while O
toluene B
had O
no O
effect O
. O

The O
observed O
changes O
in O
the O
fluorescence O
and O
conduction O
of O
OPV B
correlate O
well O
with O
the O
electron O
withdrawing O
ability O
of O
the O
interacting O
aromatic O
molecules O
. O

These O
results O
demonstrate O
the O
potential O
usefulness O
of O
OPV O
as O
a O
sensor O
for O
aromatic O
compounds O
containing O
electron O
withdrawing O
groups O
. O

In O
vitro O
effect O
of O
N B
- I
acetylcysteine I
on O
hepatocyte O
injury O
caused O
by O
dichlorodiphenyltric B
and O
its O
metabolites O
. O

The O
organochlorine B
pesticide O
, O
dichlorodiphenyltric B
( O
DDT B
) O
, O
is O
still O
used O
to O
combat O
the O
spread O
of O
malaria O
in O
several O
developing O
countries O
despite O
its O
accumulation O
and O
known O
hepatotoxic O
effects O
that O
have O
been O
demonstrated O
both O
in O
vitro O
and O
in O
vivo O
. O

N B
- I
Acetylcysteine I
( O
NAC B
) O
is O
a O
recognized O
hepatoprotective O
agent O
that O
has O
been O
reported O
to O
reduce O
hepatotoxicity O
initiated O
by O
many O
different O
compounds O
. O

The O
aim O
of O
this O
study O
was O
to O
determine O
whether O
NAC B
could O
counter O
in O
vitro O
hepatocyte O
injury O
induced O
by O
DDT B
or O
its O
two O
major O
metabolites O
, O
dichlorodiphenyldich B
and O
dichlorodiphenyldich B
. O

HepG2 O
cell O
cultures O
were O
used O
to O
assess O
the O
following O
parameters O
of O
toxicity O
: O
cellular O
viability O
, O
intracellular O
levels O
of O
reactive O
oxygen B
species O
( O
ROS O
) O
, O
mitochondrial O
membrane O
potential O
and O
initiation O
of O
apoptosis O
. O

None O
of O
the O
three O
test O
compounds O
induced O
ROS O
generation O
, O
yet O
exposure O
to O
any O
of O
the O
three O
compounds O
produced O
mitochondrial O
hyperpolarization O
, O
which O
was O
countered O
by O
NAC B
pretreatment O
. O

All O
three O
test O
compounds O
also O
induced O
apoptotic O
cell O
death O
, O
which O
was O
inhibited O
by O
NAC B
. O

Despite O
NAC B
counteracting O
some O
adverse O
intracellular O
changes O
due O
to O
organochlorine B
exposure O
, O
it O
appeared O
to O
aggravate O
the O
cytotoxic O
effects O
of O
the O
organochlorine B
compounds O
at O
low O
test O
concentrations O
. O

As O
the O
same O
outcome O
may O
also O
occur O
in O
vivo O
, O
results O
from O
the O
present O
study O
raise O
concern O
about O
the O
use O
of O
NAC B
as O
treatment O
for O
DDT B
- O
induced O
hepatotoxicity O
. O

Improving O
the O
default O
data O
analysis O
workflow O
for O
large O
autoimmune O
biomarker O
discovery O
studies O
with O
protoarrays O
. O

Contemporary O
protein O
microarrays O
like O
the O
ProtoArray O
( O
R O
) O
are O
used O
for O
autoimmune O
antibody O
screening O
studies O
to O
discover O
biomarker O
panels O
. O

For O
ProtoArray O
data O
analysis O
the O
software O
Prospector O
and O
a O
default O
workflow O
are O
suggested O
by O
the O
manufacturer O
. O

While O
analyzing O
a O
large O
data O
set O
of O
a O
discovery O
study O
for O
diagnostic O
biomarkers O
of O
the O
Parkinson O
' O
s O
Disease O
( O
" O
ParkCHIP O
" O
) O
we O
have O
revealed O
the O
need O
for O
distinct O
improvements O
of O
the O
suggested O
workflow O
concerning O
raw O
data O
acquisition O
, O
normalization O
and O
pre O
- O
selection O
method O
availability O
, O
batch O
effects O
, O
feature O
selection O
, O
and O
feature O
validation O
. O

In O
this O
work O
appropriate O
improvements O
of O
the O
default O
workflow O
are O
proposed O
and O
it O
is O
shown O
that O
completely O
automatic O
data O
acquisition O
as O
a O
batch O
, O
a O
re O
- O
implementation O
of O
Prospector O
' O
s O
pre O
- O
selection O
method O
, O
multivariate O
or O
hybrid O
feature O
selection O
, O
and O
validation O
of O
the O
selected O
protein O
panel O
using O
an O
independent O
test O
set O
define O
in O
combination O
an O
improved O
workflow O
for O
large O
studies O
. O

This O
article O
is O
protected O
by O
copyright O
. O

All O
rights O
reserved O
. O

Elucidation O
of O
in O
situ O
polycyclic B
aromatic I
hydrocarbon I
degradation O
by O
functional O
metaproteomics O
( O
protein O
- O
SIP O
) O
. O

Current O
knowledge O
of O
the O
physiology O
and O
phylogeny O
of O
polycyclic B
aromatic I
hydrocarbon I
( O
PAH B
) O
degrading O
bacteria O
often O
relies O
on O
laboratory O
enrichments O
and O
isolations O
. O

In O
the O
present O
study O
, O
in O
situ O
microcosms O
consisting O
of O
activated O
carbon B
pellets O
( O
BACTRAP O
( O
R O
) O
s O
) O
were O
loaded O
with O
either O
( B
13 I
) I
C I
- I
naphthalene I
or O
( B
13 I
) I
C I
- I
fluorene I
and O
were O
subsequently O
exposed O
in O
the O
contaminant O
source O
and O
plume O
fringe O
region O
of O
an O
PAH O
contaminated O
aquifer O
. O

Metaproteomic O
analysis O
and O
protein O
- O
SIP O
revealed O
Burkholderiales O
, O
Actinomycetales O
and O
Rhizobiales O
as O
the O
most O
active O
microorganisms O
in O
the O
groundwater O
communities O
. O

Proteins O
identified O
of O
the O
naphthalene B
degradation O
pathway O
showed O
a O
relative O
( B
13 I
) I
C I
isotope O
abundance O
of O
approximately O
50 O
atom O
% O
demonstrating O
that O
the O
identified O
naphthalene B
degrading O
bacteria O
gained O
at O
least O
80 O
% O
of O
their O
carbon B
by O
PAH B
degradation O
. O

Although O
the O
microbial O
community O
grown O
on O
the O
fluorene B
- O
BACTRAPs O
showed O
a O
structure O
similar O
to O
the O
naphthalene B
- O
BACTRAPs O
, O
the O
identification O
of O
fluorene B
degraders O
and O
degradation O
pathways O
failed O
in O
situ O
. O

In O
complementary O
laboratory O
microcosms O
, O
a O
clear O
enrichment O
in O
proteins O
related O
to O
Rhodococcus O
and O
possible O
fluorene B
degradation O
enzymes O
was O
observed O
. O

This O
result O
demonstrates O
the O
impact O
of O
laboratory O
conditions O
on O
microbial O
community O
structure O
and O
activity O
of O
certain O
species O
and O
underlines O
the O
need O
on O
in O
situ O
exploration O
of O
microbial O
community O
functions O
. O

In O
situ O
microcosms O
in O
combination O
with O
protein O
- O
SIP O
may O
be O
a O
significant O
tool O
for O
in O
situ O
identification O
of O
metabolic O
key O
players O
as O
well O
as O
degradation O
pathways O
. O

This O
article O
is O
protected O
by O
copyright O
. O

All O
rights O
reserved O
. O

Folate B
- O
Conjugated O
PEG B
on O
Single O
Walled O
Carbon B
Nanotubes O
for O
Targeting O
Delivery O
of O
Doxorubicin B
to O
Cancer O
Cells O
. O

A O
highly O
effective O
drug O
carrier O
is O
constructed O
by O
coating O
folic B
acid I
- O
terminated O
poly B
( I
ethylene I
glycol I
) I
( O
PEG B
- I
FA I
) O
on O
single O
walled O
carbon B
nanotubes O
( O
SWNTs O
) O
in O
a O
facile O
non O
- O
covalent O
method O
. O

The O
anti O
- O
cancer O
drug O
, O
doxorubicin B
( O
DOX B
) O
, O
is O
further O
loaded O
on O
the O
surface O
of O
SWNTs O
at O
a O
very O
high O
loading O
efficiency O
, O
149 O
. O
3 O
+ O
/ O
- O
4 O
. O
1 O
% O
. O

The O
drug O
system O
( O
DOX B
/ O
PEG B
- I
FA I
/ O
SWNTs O
) O
exhibits O
excellent O
stability O
under O
neutral O
pH O
conditions O
such O
as O
serum O
, O
but O
dramatically O
releases O
DOX B
at O
reduced O
pH O
typical O
of O
the O
tumour O
environment O
and O
intracellular O
lysosomes O
and O
endosomes O
. O

With O
the O
help O
of O
FA O
, O
DOX B
/ O
PEG B
- I
FA I
/ O
SWNTs O
tend O
to O
selectively O
attach O
onto O
cancer O
cells O
and O
enter O
the O
lysosomes O
or O
endosomes O
by O
clathrin O
- O
mediated O
endocytosis O
. O

This O
can O
greatly O
improve O
the O
pharmaceutical O
efficiency O
and O
reduce O
potential O
side O
effects O
. O

Physiotherapeutic O
approach O
in O
early O
and O
late O
post O
- O
menopausal O
Brazilian O
women O
. O

Abstract O
To O
evaluate O
changes O
in O
joints O
after O
physiotherapy O
in O
post O
- O
menopausal O
women O
, O
specifically O
to O
identify O
clinical O
responses O
to O
the O
measurements O
of O
flexibility O
, O
functional O
capacity O
and O
joint O
pain O
in O
early O
and O
late O
post O
- O
menopausal O
women O
at O
a O
multi O
- O
disciplinary O
health O
education O
programme O
. O

A O
total O
of O
69 O
women O
participated O
in O
the O
Integral O
Program O
for O
the O
Attention O
to O
Climacteric O
Women O
at O
the O
Department O
of O
Gynecology O
- O
Federal O
University O
of O
Sao O
Paulo O
and O
were O
sorted O
into O
two O
groups O
of O
early O
( O
n O
= O
32 O
) O
and O
late O
( O
n O
= O
37 O
) O
post O
- O
menopause O
. O

The O
average O
age O
of O
menopause O
was O
47 O
. O
9 O
+ O
/ O
- O
5 O
. O
6 O
years O
. O

The O
Blatt O
Kupperman O
Menopausal O
Index O
scores O
for O
the O
early O
( O
baseline O
= O
12 O
. O
8 O
+ O
/ O
- O
6 O
. O
1 O
) O
and O
late O
( O
baseline O
= O
14 O
. O
1 O
+ O
/ O
- O
7 O
. O
7 O
) O
post O
- O
menopausal O
groups O
after O
the O
programme O
were O
8 O
. O
4 O
+ O
/ O
- O
7 O
. O
1 O
and O
9 O
. O
4 O
+ O
/ O
- O
8 O
. O
1 O
, O
respectively O
. O

Both O
groups O
presented O
improvements O
regarding O
functional O
capacity O
( O
p O
< O
0 O
. O
01 O
) O
and O
complaints O
of O
pain O
( O
p O
< O
0 O
. O
001 O
) O
after O
the O
intervention O
. O

The O
group O
of O
early O
post O
- O
menopausal O
women O
had O
better O
flexibility O
for O
hip O
flexion O
( O
p O
< O
0 O
. O
001 O
) O
, O
and O
the O
late O
post O
- O
menopausal O
group O
showed O
greater O
improvement O
in O
shoulder O
flexion O
( O
p O
< O
0 O
. O
001 O
) O
, O
extension O
( O
p O
< O
0 O
. O
001 O
) O
and O
elbow O
flexion O
( O
p O
< O
0 O
. O
001 O
) O
. O

After O
multi O
- O
disciplinary O
approach O
, O
both O
early O
and O
late O
post O
- O
menopausal O
groups O
experienced O
decrease O
in O
intensity O
of O
climacteric O
symptoms O
, O
reduction O
in O
pain O
intensity O
and O
improvement O
in O
functional O
capacity O
, O
but O
the O
flexibility O
was O
different O
between O
both O
the O
groups O
. O

Structural O
identification O
of O
( O
1 O
- O
- O
> O
6 O
) O
- O
alpha O
- O
D O
- O
glucan O
, O
a O
key O
responsible O
for O
the O
health O
benefits O
of O
longan O
, O
and O
evaluation O
of O
anticancer O
activity O
. O

Longan O
is O
a O
delicious O
subtropical O
fruit O
with O
great O
health O
- O
beneficial O
effects O
. O

It O
has O
been O
utilised O
for O
disease O
prevention O
and O
health O
care O
since O
ancient O
age O
. O

To O
explore O
the O
chemicals O
responsible O
for O
the O
health O
benefits O
, O
water O
- O
soluble O
polysaccharides O
were O
extracted O
from O
longan O
flesh O
in O
this O
work O
. O

A O
pure O
polysaccharide O
( O
LPS1 O
) O
was O
obtained O
through O
column O
purification O
. O

Analysis O
by O
gas O
chromatography O
showed O
LPS1 O
was O
a O
homopolysaccharide O
of O
glucose B
with O
glycosidic O
linkage O
of O
- I
- I
> I
6 I
) I
- I
D I
- I
Glc I
- I
( I
1 I
- I
- I
> I
. O

Nuclear O
magnetic O
resonance O
( O
NMR O
) O
spectra O
indicated O
that O
the O
con O
fi O
guration O
of O
anomeric O
carbon B
in O
glucose B
residual O
was O
alpha O
- O
form O
. O

The O
polysaccharide O
structure O
was O
further O
confirmed O
to O
be O
( O
1 O
- O
- O
> O
6 O
) O
- O
alpha O
- O
D O
- O
glucan O
by O
chemcial O
shift O
of O
C6 O
. O

The O
molecular O
weight O
of O
LPS1 O
was O
calculated O
to O
be O
108 O
kDa O
, O
which O
had O
661 O
glucose B
residuals O
. O

Anticancer O
assay O
showed O
that O
LPS1 O
had O
anticancer O
activity O
against O
the O
growth O
of O
HepG2 O
cells O
to O
a O
certain O
extent O
. O

However O
, O
it O
did O
not O
show O
any O
cytotoxicity O
against O
MCF O
- O
7 O
breast O
cancer O
cells O
. O

Hybrid O
Molecule O
from O
O B
( I
2 I
) I
- I
( I
2 I
, I
4 I
- I
Dinitrophenyl I
) I
diazeniumdiolate I
and O
Oleanolic B
Acid I
: O
a O
GST O
pi O
Activated O
Nitric B
Oxide I
Prodrug O
with O
Selective O
Anti O
- O
human O
Hepatocellular O
Carcinoma O
Activity O
and O
Improved O
Stability O
. O

A O
series O
of O
hybrids O
from O
O B
( I
2 I
) I
- O
( B
2 I
, I
4 I
- I
dinitrophenyl I
) I
diazeniumdiolate I
and O
oleanolic B
acid I
( O
OA O
) O
were O
designed O
, O
synthesized O
, O
and O
biologically O
evaluated O
as O
novel O
nitric B
oxide I
( O
NO B
) O
releasing O
prodrugs O
which O
could O
be O
activated O
by O
glutathione B
S B
- O
transferase O
pi O
( O
GST O
pi O
) O
overexpressed O
in O
a O
number O
of O
cancer O
cells O
. O

It O
was O
discovered O
that O
the O
most O
active O
compound O
21 O
released O
high O
levels O
of O
NO B
selectively O
in O
HCC O
cells O
but O
not O
in O
the O
normal O
cells O
, O
and O
exhibited O
potent O
antiproliferative O
activity O
in O
vitro O
as O
well O
as O
remarkable O
tumor O
- O
retarding O
effects O
in O
vivo O
. O

Compared O
with O
the O
reported O
GST O
pi O
- O
activated O
prodrugs O
JS O
- I
K I
and O
PABA B
/ O
NO O
, O
21 O
exhibited O
remarkably O
improved O
stability O
in O
the O
absence O
of O
GST O
pi O
. O

Importantly O
, O
the O
decomposition O
of O
21 O
occurred O
in O
the O
presence O
of O
GST O
pi O
, O
and O
was O
much O
more O
effective O
than O
in O
GST O
alpha O
. O

Additionally O
, O
21 O
induced O
HepG2 O
cells O
apoptosis O
by O
arresting O
cell O
cycle O
at O
G2 O
/ O
M O
phase O
, O
activating O
both O
the O
mitochondria O
- O
mediated O
pathway O
and O
the O
MAPKs O
pathway O
, O
as O
well O
as O
enhancing O
the O
intracellular O
production O
of O
ROS O
. O

Rationale O
for O
the O
higher O
reactivity O
of O
interfacial O
sites O
in O
methanol B
decomposition O
on O
Au13 B
/ O
TiO2 B
( O
110 O
) O
. O

Interfacial O
and O
perimeter O
sites O
have O
been O
known O
for O
their O
high O
activity O
in O
various O
reactions O
on O
supported O
gold O
nanoparticles O
. O

We O
find O
that O
the O
higher O
activity O
of O
interfacial O
sites O
in O
Au13 B
/ O
TiO2 B
( O
110 O
) O
towards O
methanol B
decomposition O
originates O
from O
charge O
- O
transfer O
- O
induced O
Coulomb O
interaction O
among O
the O
gold O
, O
reactant O
, O
and O
reducible O
TiO2 B
support O
, O
brought O
about O
through O
the O
formation O
of O
an O
ionic O
O B
- I
Au I
bond O
between O
gold O
and O
methoxy B
in O
such O
sites O
, O
which O
turns O
the O
participating O
perimeter O
gold O
atom O
cationic O
. O

A O
direct O
result O
of O
such O
charge O
- O
transfer O
- O
induced O
repulsive O
interaction O
between O
cationic O
gold O
and O
positively O
charged O
C B
moiety O
of O
methoxy B
is O
activation O
of O
the O
positively O
charged O
C B
moiety O
of O
methoxy B
, O
as O
manifested O
by O
the O
pronounced O
elongation O
of O
O B
- I
C I
bond O
length O
and O
the O
tilting O
of O
the O
methoxy B
axis O
, O
which O
facilitate O
reaction O
of O
methoxy B
through O
C B
- I
H I
scission O
with O
the O
bridge O
oxygen B
atoms O
that O
are O
readily O
available O
from O
the O
reducible O
support O
. O

More O
generally O
, O
our O
proposed O
mechanism O
for O
the O
reactivity O
of O
the O
gold O
/ O
TiO2 B
interface O
should O
hold O
for O
oxidation O
of O
organic O
molecules O
with O
the O
structure O
of O
R B
- I
O I
- I
R I
' I
, O
where O
R O
and O
R O
' O
are O
( B
saturated I
) I
hydrocarbons I
. O

Cadmium B
- O
Based O
Quantum O
Dot O
Induced O
Autophagy O
Formation O
for O
Cell O
Survival O
via O
Oxidative O
Stress O
. O

Quantum O
dots O
( O
QDs O
) O
are O
one O
of O
most O
utilized O
nanomaterials O
in O
nanocrystalline O
semiconductors O
. O

QDs O
emit O
near O
- O
infrared O
fluorescence O
and O
can O
be O
applied O
as O
probes O
for O
detecting O
vasculature O
and O
imaging O
in O
biological O
systems O
. O

Since O
QDs O
have O
potential O
in O
clinical O
application O
, O
the O
toxicity O
of O
QDs O
needs O
to O
be O
carefully O
evaluated O
. O

In O
our O
present O
study O
, O
we O
elucidate O
the O
cytotoxic O
mechanisms O
of O
QDs O
using O
a O
mouse O
renal O
adenocarcinoma O
( O
RAG O
) O
cell O
line O
. O

QDs O
in O
RAG O
cells O
increased O
intracellular O
reactive O
oxygen B
species O
( O
ROS O
) O
levels O
and O
induced O
autophagy O
at O
6 O
h O
, O
leading O
to O
subsequent O
apoptosis O
at O
24 O
h O
. O

QDs O
entered O
the O
cells O
and O
were O
located O
within O
the O
endoplasmic O
reticulum O
( O
ER O
) O
, O
endosome O
, O
and O
lysosome O
at O
6 O
h O
and O
endosome O
, O
lysosome O
, O
and O
mitochondria O
at O
24 O
h O
. O

However O
, O
QDs O
only O
affected O
mitochondrial O
function O
and O
did O
not O
induce O
ER O
stress O
. O

N B
- I
Acetylcysteine I
, O
an O
antioxidant O
agent O
, O
reduced O
intracellular O
ROS O
levels O
and O
decreased O
QD O
- O
induced O
autophagy O
but O
enhanced O
QD O
- O
induced O
cell O
death O
. O

Moreover O
, O
3 B
- I
methylamphetamine I
( O
an O
autophagy O
inhibitor O
) O
also O
reduced O
the O
cell O
viability O
in O
QD O
- O
treated O
cells O
. O

These O
findings O
suggest O
that O
ROS O
plays O
an O
essential O
role O
in O
the O
regulation O
of O
QD O
- O
induced O
autophagy O
, O
which O
subsequently O
enhances O
cell O
survival O
. O

Taken O
together O
, O
these O
results O
suggest O
that O
oxidative O
stress O
- O
induced O
autophagy O
is O
a O
defense O
/ O
survival O
mechanism O
against O
the O
cytotoxicity O
of O
QD O
. O

MicroRNA O
- O
32 O
( O
miR O
- O
32 O
) O
regulates O
phosphatase O
and O
tensin O
homologue O
( O
PTEN O
) O
expression O
and O
promotes O
growth O
, O
migration O
, O
and O
invasion O
in O
colorectal O
carcinoma O
cells O
. O

BACKGROUND O
: O
Colorectal O
carcinoma O
( O
CRC O
) O
is O
one O
of O
the O
leading O
causes O
of O
cancer O
- O
related O
mortality O
worldwide O
. O

MicroRNAs O
( O
miRNAs O
, O
miRs O
) O
play O
important O
roles O
in O
carcinogenesis O
. O

MiR O
- O
32 O
has O
been O
shown O
to O
be O
upregulated O
in O
CRC O
. O

In O
this O
study O
, O
we O
identified O
the O
potential O
effects O
of O
miR O
- O
32 O
on O
some O
important O
biological O
properties O
of O
CRC O
cells O
, O
and O
clarified O
the O
regulation O
of O
PTEN O
by O
miR O
- O
32 O
. O

METHODS O
: O
The O
effect O
of O
miR O
- O
32 O
on O
PTEN O
expression O
was O
assessed O
in O
CRC O
cell O
lines O
with O
miR O
- O
32 O
mimics O
/ O
inhibitor O
to O
increase O
/ O
decrease O
miR O
- O
32 O
expression O
. O

Furthermore O
, O
the O
roles O
of O
miR O
- O
32 O
in O
regulating O
CRC O
cells O
biological O
properties O
were O
analyzed O
with O
miR O
- O
32 O
mimics O
/ O
inhibitor O
- O
transfected O
cells O
. O

The O
3 O
[ O
prime O
] O
- O
untranslated O
region O
( O
3 O
[ O
prime O
] O
- O
UTR O
) O
of O
PTEN O
combined O
with O
miR O
- O
32 O
was O
verified O
by O
dual O
- O
luciferase O
reporter O
assay O
. O

RESULTS O
: O
Gain O
- O
of O
- O
function O
and O
loss O
- O
of O
- O
function O
studies O
showed O
that O
overexpression O
of O
miR O
- O
32 O
promoted O
SW480 O
cell O
proliferation O
, O
migration O
, O
and O
invasion O
, O
reduced O
apoptosis O
, O
and O
resulted O
in O
downregulation O
of O
PTEN O
at O
a O
posttranscriptional O
level O
. O

However O
, O
miR O
- O
32 O
knock O
- O
down O
inhibited O
these O
processes O
in O
HCT O
- O
116 O
cells O
and O
enhanced O
the O
expression O
of O
PTEN O
protein O
. O

In O
addition O
, O
we O
further O
identified O
PTEN O
as O
the O
functional O
downstream O
target O
of O
miR O
- O
32 O
by O
directly O
targeting O
the O
3 O
[ O
prime O
] O
- O
UTR O
of O
PTEN O
. O

CONCLUSIONS O
: O
Our O
results O
demonstrated O
that O
miR O
- O
32 O
was O
involved O
in O
tumorigenesis O
of O
CRC O
at O
least O
in O
part O
by O
suppression O
of O
PTEN O
. O

Structure O
- O
- O
activity O
relationships O
and O
in O
silico O
models O
of O
P O
- O
glycoprotein O
( O
ABCB1 O
) O
inhibitors O
. O

Abstract O
1 O
. O

The O
efflux O
pump O
p O
- O
glycoprotein O
( O
P O
- O
gp O
/ O
ABCB1 O
) O
has O
received O
enormous O
attention O
in O
drug O
( O
xenobiotic O
) O
disposition O
due O
to O
its O
role O
in O
modulation O
of O
the O
drug O
availability O
and O
in O
protection O
of O
sensitive O
organs O
. O

2 O
. O

P O
- O
gp O
mediated O
efflux O
is O
one O
of O
main O
mechanisms O
for O
multidrug O
resistance O
in O
cancer O
cells O
. O

A O
main O
approach O
to O
reverse O
the O
resistance O
and O
restore O
the O
drug O
efficacy O
is O
to O
use O
specific O
inhibitors O
of O
P O
- O
gp O
that O
suppress O
the O
efflux O
activity O
. O

3 O
. O

This O
review O
summarizes O
the O
binding O
capabilities O
of O
known O
chemical O
inhibitors O
based O
on O
the O
analyses O
of O
structure O
- O
activity O
relationships O
, O
and O
computational O
modeling O
of O
the O
inhibitors O
as O
well O
as O
the O
binding O
site O
of O
P O
- O
gp O
protein O
. O

4 O
. O

The O
molecular O
models O
will O
facilitate O
the O
design O
of O
lead O
inhibitors O
as O
drug O
candidates O
. O

Also O
, O
it O
helps O
scientists O
in O
early O
drug O
discovery O
phase O
to O
synthesize O
chemical O
series O
with O
better O
understanding O
of O
their O
P O
- O
gp O
binding O
liabilities O
. O

Nasal O
dosimetry O
of O
inspired O
naphthalene B
vapor O
in O
the O
male O
and O
female O
B6C3F1 O
mouse O
. O

Naphthalene B
vapor O
is O
a O
nasal O
cytotoxicant O
in O
the O
rat O
and O
mouse O
but O
is O
a O
nasal O
carcinogen O
in O
only O
the O
rat O
. O

Inhalation O
dosimetry O
is O
a O
critical O
aspect O
of O
the O
inhalation O
toxicology O
of O
inspired O
vapors O
and O
may O
contribute O
to O
the O
species O
differences O
in O
the O
nasal O
response O
. O

To O
define O
the O
nasal O
dosimetry O
of O
naphthalene B
in O
the O
B6C3F1 O
male O
and O
female O
mouse O
, O
uptake O
of O
naphthalene B
vapor O
was O
measured O
in O
the O
surgically O
isolated O
upper O
respiratory O
tract O
( O
URT O
) O
at O
inspiratory O
flow O
rates O
of O
25 O
or O
50ml O
/ O
min O
. O

Uptake O
was O
measured O
at O
multiple O
concentrations O
( O
0 O
. O
5 O
, O
3 O
, O
10 O
, O
30ppm O
) O
in O
controls O
and O
mice O
treated O
with O
the O
cytochrome O
P450 O
inhibitor O
5 B
- I
phenyl I
- I
1 I
- I
pentyne I
. O

In O
both O
sexes O
, O
URT O
uptake O
efficiency O
was O
strongly O
concentration O
dependent O
averaging O
90 O
% O
at O
0 O
. O
5ppm O
compared O
to O
50 O
% O
at O
30ppm O
( O
25ml O
/ O
min O
flow O
rate O
) O
, O
indicating O
saturable O
processes O
were O
involved O
. O

Both O
uptake O
efficiency O
and O
the O
concentration O
dependence O
of O
uptake O
were O
significantly O
diminished O
by O
5 B
- I
phenyl I
- I
1 I
- I
pentyne I
indicating O
inspired O
naphthalene B
vapor O
is O
extensively O
metabolized O
in O
the O
mouse O
nose O
with O
saturation O
of O
metabolism O
occurring O
at O
the O
higher O
concentrations O
. O

A O
hybrid O
computational O
fluid O
dynamic O
physiologically O
based O
pharmacokinetic O
model O
was O
developed O
for O
nasal O
dosimetry O
. O

This O
model O
accurately O
predicted O
the O
observed O
URT O
uptake O
efficiencies O
. O

Overall O
, O
the O
high O
URT O
uptake O
efficiency O
of O
naphthalene B
in O
the O
mouse O
nose O
indicates O
the O
absence O
of O
a O
tumorigenic O
response O
is O
not O
attributable O
to O
low O
delivered O
dose O
rates O
in O
this O
species O
. O

Exposure O
to O
DEHP B
decreased O
four O
fatty B
acid I
levels O
in O
plasma O
of O
prepartum O
mice O
. O

Maternal O
exposure O
to O
di B
( I
2 I
- I
ethylhexyl I
) I
phthalate I
( O
DEHP B
) O
decreased O
the O
plasma O
triglyceride B
in O
prepartum O
mice O
. O

To O
identify O
the O
fatty B
acid I
( O
FA O
) O
species O
involved O
and O
to O
understand O
the O
underlying O
mechanisms O
, O
pregnant O
Sv O
/ O
129 O
wild O
- O
type O
( O
mPPAR O
alpha O
) O
, O
peroxisome O
proliferator O
- O
activated O
receptor O
alpha O
- O
null O
( O
Ppar O
alpha O
- O
null O
) O
and O
humanized O
PPAR O
alpha O
( O
hPPAR O
alpha O
) O
mice O
were O
treated O
with O
diets O
containing O
0 O
% O
, O
0 O
. O
01 O
% O
, O
0 O
. O
05 O
% O
or O
0 O
. O
1 O
% O
DEHP B
. O

Dams O
were O
dissected O
on O
gestational O
day O
18 O
together O
with O
fetuses O
, O
and O
on O
postnatal O
day O
2 O
together O
with O
newborns O
. O

n O
- O
3 O
/ O
n O
- O
6 O
polyunsaturated B
, I
saturated I
, I
and I
monounsaturated I
FAs I
in O
maternal O
plasma O
and O
in O
liver O
of O
wild O
- O
type O
offspring O
, O
and O
representative O
enzymes O
for O
FA O
desaturation O
and O
elongation O
in O
maternal O
liver O
, O
were O
measured O
. O

The O
plasma O
levels O
of O
linoleic B
acid I
, O
alpha B
- I
linolenic I
acid I
, O
palmitic B
acid I
and O
oleic B
acid I
were O
higher O
in O
the O
pregnant O
control O
mPPARa O
mice O
than O
in O
Ppara O
- O
null O
and O
hPPARa O
mice O
. O

DEHP B
exposure O
significantly O
decreased O
the O
levels O
of O
these O
four O
FAs B
only O
in O
pregnant O
mPPAR O
alpha O
mice O
. O

Plasma O
levels O
of O
many O
FAs O
were O
higher O
in O
pregnant O
mice O
than O
in O
postpartum O
ones O
in O
a O
genotype O
- O
independent O
manner O
, O
while O
it O
was O
lower O
in O
the O
livers O
of O
fetuses O
than O
pups O
. O

DEHP B
exposure O
slightly O
increased O
hepatic O
arachidonic B
acid I
, O
alpha B
- I
linolenic I
acid I
, O
palmitoleic B
acid I
and O
oleic B
acid I
in O
fetuses O
, O
but O
not O
in O
pups O
. O

However O
, O
DEHP B
exposure O
did O
not O
clearly O
influence O
FA O
desaturase O
1 O
and O
2 O
nor O
elongase O
2 O
and O
5 O
expressions O
in O
the O
liver O
of O
all O
maternal O
mice O
. O

Taken O
together O
, O
the O
levels O
of O
plasma O
four O
FAs B
with O
shorter O
carbon B
chains O
were O
higher O
in O
pregnant O
mPPAR O
alpha O
mice O
than O
in O
other O
genotypes O
, O
and O
DEHP B
exposure O
decreased O
these O
specific O
FA O
concentrations O
only O
in O
mPPAR O
alpha O
mice O
, O
similarly O
to O
triglyceride B
levels O
. O

The O
role O
of O
methyl B
- O
CpG B
binding O
protein O
2 O
in O
liver O
fibrosis O
. O

Liver O
injure O
is O
induced O
by O
various O
insults O
such O
as O
alcohol B
abuse O
, O
if O
insults O
persistent O
, O
may O
result O
in O
the O
formation O
of O
liver O
fibrosis O
. O

Hepatic O
stellate O
cell O
( O
HSC O
) O
activation O
and O
transdifferentiation O
into O
hepatic O
myofibroblast O
, O
accompanied O
with O
potent O
pro O
- O
inflammatory O
and O
pro O
- O
fibrogenic O
activities O
and O
the O
down O
- O
regulation O
of O
anti O
- O
inflammatory O
anti O
- O
fibrogenic O
in O
gene O
expression O
in O
coordination O
with O
epigenetic O
modifications O
at O
the O
level O
of O
the O
chromatin O
structure O
, O
are O
pivotal O
events O
in O
liver O
fibrogenesis O
. O

In O
this O
review O
we O
focus O
on O
the O
role O
of O
the O
methyl B
- O
CpG O
binding O
protein O
2 O
( O
MeCP2 O
) O
transcriptional O
regulation O
of O
different O
target O
genes O
and O
the O
interaction O
MeCP2 O
with O
microRNAs O
( O
miRNAs O
) O
during O
liver O
fibrosis O
. O

In O
addition O
, O
we O
address O
different O
signaling O
pathways O
interacted O
with O
MeCP2 O
regulated O
HSC O
activation O
. O

Such O
approaches O
provide O
valuable O
insights O
into O
the O
potential O
targets O
of O
liver O
fibrosis O
, O
and O
are O
useful O
pointers O
for O
the O
development O
of O
future O
therapeutic O
strategies O
. O

Dabigatran B
for O
the O
Prevention O
of O
Stroke O
and O
Systemic O
Embolism O
in O
Atrial O
Fibrillation O
: O
A O
NICE O
Single O
Technology O
Appraisal O
. O

The O
National O
Institute O
for O
Health O
and O
Clinical O
Excellence O
( O
NICE O
) O
invited O
the O
manufacturer O
of O
dabigatran B
etexilate I
( O
Boehringer O
Ingelheim O
Ltd O
, O
UK O
) O
to O
submit O
evidence O
for O
the O
clinical O
and O
cost O
- O
effectiveness O
of O
this O
drug O
for O
the O
prevention O
of O
stroke O
and O
systemic O
embolism O
in O
patients O
with O
non O
- O
valvular O
atrial O
fibrillation O
( O
AF O
) O
as O
part O
of O
the O
NICE O
single O
technology O
appraisal O
process O
. O

The O
Centre O
for O
Reviews O
and O
Dissemination O
and O
the O
Centre O
for O
Health O
Economics O
at O
the O
University O
of O
York O
were O
commissioned O
to O
act O
as O
the O
evidence O
review O
group O
( O
ERG O
) O
. O

This O
article O
presents O
a O
summary O
of O
the O
manufacturer O
' O
s O
submission O
, O
the O
ERG O
report O
and O
the O
subsequent O
development O
of O
NICE O
guidance O
for O
the O
use O
of O
dabigatran B
within O
the O
UK O
National O
Health O
Service O
. O

Dabigatran B
was O
granted O
marketing O
authorisation O
by O
the O
European O
Medicines O
Agency O
for O
a O
sequential O
dosing O
regimen O
( O
DBG O
sequential O
) O
, O
in O
which O
patients O
under O
80 O
years O
are O
treated O
with O
dabigatran B
150 O
mg O
twice O
daily O
( O
DBG150 O
) O
and O
patients O
80 O
years O
and O
over O
are O
given O
dabigatran B
110 O
mg O
twice O
daily O
( O
DBG110 O
) O
. O

NICE O
decisions O
are O
bound O
by O
the O
marketing O
authorisation O
; O
therefore O
, O
the O
decision O
problem O
faced O
by O
the O
committee O
was O
whether O
the O
DBG O
sequential O
regimen O
was O
effective O
and O
cost O
- O
effective O
compared O
with O
warfarin B
or O
aspirin B
for O
patients O
with O
non O
- O
valvular O
AF O
and O
one O
or O
more O
risk O
factors O
. O

The O
RE O
- O
LY O
trial O
, O
a O
large O
multi O
- O
centre O
non O
- O
inferiority O
randomised O
clinical O
trial O
, O
was O
the O
primary O
source O
of O
clinical O
evidence O
. O

DBG150 O
was O
shown O
to O
be O
non O
- O
inferior O
, O
and O
subsequently O
superior O
to O
warfarin B
, O
for O
the O
primary O
outcome O
of O
all O
stroke O
/ O
systemic O
embolism O
. O

DBG110 O
was O
found O
to O
be O
non O
- O
inferior O
to O
warfarin B
. O

Results O
were O
presented O
for O
a O
post O
hoc O
subgroup O
analysis O
for O
patients O
under O
and O
over O
80 O
years O
of O
age O
, O
where O
DBG110 O
showed O
a O
statistically O
significant O
reduction O
of O
haemorrhagic O
stroke O
and O
intracranial O
haemorrhage O
in O
comparison O
to O
warfarin B
in O
patients O
over O
80 O
years O
of O
age O
. O

This O
post O
hoc O
subgroup O
analysis O
by O
age O
was O
the O
basis O
for O
the O
licensed O
DBG B
sequential O
regimen O
. O

The O
economic O
evaluation O
compared O
the O
costs O
and O
outcomes O
of O
DBG110 O
, O
DBG150 O
and O
DBG O
sequential O
against O
warfarin B
, O
aspirin B
, O
and O
aspirin B
plus O
clopidogrel B
. O

Across O
the O
three O
dosing O
regimens O
, O
dabigatran B
was O
associated O
with O
greater O
costs O
and O
better O
health O
outcomes O
than O
warfarin B
; O
however O
, O
DBG150 O
offered O
the O
most O
benefits O
and O
dominated O
DBG110 O
and O
DBG O
sequential O
( O
i O
. O
e O
. O
less O
costly O
and O
more O
effective O
) O
. O

The O
cost O
- O
effectiveness O
of O
DBG150 O
was O
less O
favourable O
for O
patients O
well O
controlled O
on O
warfarin B
. O

In O
the O
first O
appraisal O
meeting O
, O
the O
committee O
issued O
a O
' O
minded O
no O
' O
decision O
until O
additional O
analyses O
on O
the O
licensed O
DBG B
sequential O
regimen O
were O
presented O
by O
the O
manufacturer O
. O

These O
additional O
analyses O
indicated O
that O
the O
incremental O
cost O
- O
effectiveness O
ratio O
( O
ICER O
) O
of O
the O
DBG O
sequential O
regimen O
compared O
with O
warfarin B
ranged O
from O
pound O
8 O
, O
388 O
to O
pound O
18 O
, O
987 O
per O
quality O
- O
adjusted O
life O
year O
( O
QALY O
) O
gained O
depending O
on O
the O
level O
of O
monitoring O
costs O
assumed O
for O
warfarin B
. O

Patients O
on O
warfarin B
would O
need O
to O
be O
within O
therapeutic O
range O
83 O
- O
85 O
% O
of O
the O
time O
for O
the O
ICER O
to O
exceed O
pound O
30 O
, O
000 O
per O
additional O
QALY O
. O

Following O
consideration O
of O
the O
additional O
evidence O
and O
the O
responses O
from O
a O
large O
number O
of O
consultees O
and O
commentators O
, O
the O
committee O
recommended O
dabigatran B
as O
DBG O
sequential O
as O
an O
option O
for O
the O
prevention O
of O
stroke O
and O
systemic O
embolism O
in O
people O
with O
non O
- O
valvular O
AF O
with O
one O
or O
more O
risk O
factors O
for O
ischaemic O
stroke O
. O

Asymmetric O
zinc B
- O
catalyzed O
hydrosilylation O
of O
ketones B
and O
the O
effect O
of O
carboxylate B
on O
the O
enantioselectivity O
. O

Several O
chiral O
ligands O
containing O
( B
R I
, I
R I
) I
- I
diaminocyclohexane I
moieties O
and O
pyrrole B
, O
furan B
, O
or O
benzene B
have O
been O
synthesized O
. O

These O
ligands O
were O
tested O
in O
enantioselective O
zinc B
- O
catalyzed O
hydrosilylation O
reactions O
; O
excellent O
enantioselectivities O
were O
obtained O
when O
the O
ligands O
containing O
( B
R I
, I
R I
) I
- I
diaminocyclohexane I
moieties O
and O
furan O
rings O
were O
used O
. O

For O
comparison O
, O
zinc B
chloride I
combined O
with O
different O
potassium B
carboxylate I
salts O
and O
ligands O
were O
also O
tested O
for O
catalytic O
hydrosilylation O
reactions O
. O

Chirality O
25 O
: O
275 O
- O
280 O
, O
2013 O
. O

( O
c O
) O
2013 O
Wiley O
Periodicals O
, O
Inc O
. O

Variability O
in O
P O
- O
Glycoprotein O
Inhibitory O
Potency O
( O
IC50 O
) O
Using O
Various O
In O
Vitro O
Experimental O
Systems O
: O
Implications O
for O
Universal O
Digoxin B
DDI O
Risk O
Assessment O
Decision O
Criteria O
. O

A O
P O
- O
glycoprotein O
( O
P O
- O
gp O
) O
IC50 O
working O
group O
was O
established O
with O
twenty O
- O
three O
participating O
pharmaceutical O
and O
contract O
research O
laboratories O
and O
one O
academic O
institution O
to O
assess O
inter O
- O
laboratory O
variability O
in O
P O
- O
gp O
IC50 O
determinations O
. O

Each O
lab O
followed O
their O
in O
- O
house O
protocol O
to O
determine O
in O
vitro O
IC50 O
values O
for O
sixteen O
inhibitors O
using O
four O
different O
test O
systems O
: O
Caco O
- O
2 O
( O
11 O
labs O
) O
, O
MDCKII O
- O
MDR1 O
( O
6 O
labs O
) O
and O
LLC O
- O
PK1 O
- O
MDR1 O
( O
4 O
labs O
) O
cells O
, O
and O
membrane O
vesicles O
containing O
human O
P O
- O
gp O
( O
5 O
labs O
) O
. O

For O
cell O
models O
, O
various O
equations O
to O
calculate O
remaining O
transport O
activity O
( O
e O
. O
g O
. O
efflux O
ratio O
, O
unidirectional O
flux O
, O
net O
secretory O
flux O
) O
were O
also O
evaluated O
. O

The O
difference O
in O
IC50 O
values O
for O
each O
of O
the O
inhibitors O
across O
all O
test O
systems O
and O
equations O
ranged O
from O
a O
minimum O
of O
20 O
- O
and O
24 O
- O
fold O
between O
lowest O
and O
highest O
IC50 O
values O
for O
sertraline B
and O
isradipine B
, O
to O
a O
maximum O
of O
407 O
- O
and O
796 O
- O
fold O
for O
telmisartan B
and O
verapamil B
, O
respectively O
. O

For O
telmisartan B
and O
verapamil B
, O
variability O
was O
greatly O
influenced O
by O
data O
from O
one O
laboratory O
in O
each O
case O
. O

Excluding O
these O
two O
data O
sets O
brings O
the O
range O
in O
IC50 O
values O
for O
telmisartan B
and O
verapamil B
down O
to O
69 O
- O
and O
159 O
- O
fold O
. O

The O
efflux O
ratio O
based O
- O
equation O
generally O
resulted O
in O
several O
fold O
lower O
IC50 O
values O
compared O
to O
unidirectional O
or O
net O
- O
secretory O
flux O
equations O
. O

Statistical O
analysis O
indicated O
that O
variability O
in O
IC50 O
values O
was O
mainly O
due O
to O
inter O
- O
laboratory O
variability O
, O
rather O
than O
an O
implicit O
systematic O
difference O
between O
test O
systems O
. O

Potential O
reasons O
for O
variability O
are O
discussed O
and O
the O
simplest O
, O
most O
robust O
experimental O
design O
for O
P O
- O
gp O
IC50 O
determination O
proposed O
. O

The O
impact O
of O
these O
findings O
on O
drug O
- O
drug O
interaction O
risk O
assessment O
is O
discussed O
in O
the O
companion O
paper O
and O
recommendations O
are O
provided O
. O

Mechanism O
of O
Fibrinogen O
Adsorption O
at O
Solid O
Substrates O
at O
lower O
pH O
. O

Adsorption O
of O
fibrinogen O
was O
theoretically O
studied O
using O
the O
three O
dimensional O
( O
3D O
) O
random O
sequential O
adsorption O
( O
RSA O
) O
model O
. O

Fibrinogen O
molecule O
shape O
was O
approximated O
by O
the O
bead O
model O
considering O
the O
presence O
of O
flexible O
side O
arms O
. O

Various O
cases O
were O
considered O
inter O
alia O
, O
the O
side O
- O
on O
adsorption O
mechanisms O
and O
the O
3D O
side O
- O
on O
/ O
end O
- O
on O
simultaneous O
adsorption O
mechanism O
. O

The O
latter O
mechanisms O
is O
pertinent O
to O
fibrinogen O
adsorption O
at O
lower O
pH O
where O
the O
entire O
molecule O
is O
positively O
charged O
. O

Extensive O
calculations O
enabled O
one O
to O
determine O
the O
jamming O
surface O
concentration O
( O
coverage O
) O
of O
molecules O
adsorbed O
under O
the O
side O
- O
on O
and O
end O
- O
on O
orientations O
as O
well O
as O
the O
total O
coverage O
. O

For O
the O
3D O
model O
the O
maximum O
surface O
concentration O
was O
7 O
. O
29x103 O
mu O
m O
- O
2 O
corresponding O
to O
the O
protein O
coverage O
of O
4 O
. O
12 O
mg O
m O
- O
2 O
( O
without O
considering O
hydration O
) O
. O

Additionally O
, O
the O
surface O
blocking O
functions O
for O
the O
side O
- O
on O
and O
the O
3D O
adsorption O
regimes O
were O
determined O
and O
analytically O
approximated O
for O
the O
entire O
range O
of O
coverage O
by O
the O
interpolating O
polynomials O
. O

Using O
these O
blocking O
functions O
, O
fibrinogen O
adsorption O
kinetics O
for O
diffusion O
controlled O
transport O
conditions O
was O
evaluated O
. O

Comparison O
of O
these O
theoretical O
results O
with O
experimental O
data O
was O
made O
. O

It O
was O
demonstrated O
that O
the O
3D O
model O
properly O
reflects O
the O
maximum O
coverage O
of O
fibrinogen O
adsorbed O
on O
latex O
particles O
determined O
via O
the O
electrokinetic O
( O
electrophoretic O
mobility O
) O
and O
AFM O
measurements O
. O

Also O
, O
streaming O
potential O
measurements O
of O
fibrinogen O
adsorption O
kinetics O
on O
mica O
were O
successfully O
interpreted O
in O
terms O
of O
the O
3D O
adsorption O
model O
. O

The O
theoretical O
results O
derived O
in O
this O
work O
have O
implications O
for O
basic O
science O
providing O
information O
on O
mechanisms O
of O
anisotropic O
protein O
adsorption O
. O

Key O
words O
: O
adsorption O
of O
fibrinogen O
, O
fibrinogen O
adsorption O
at O
lower O
pH O
, O
irreversible O
adsorption O
of O
fibrinogen O
, O
jamming O
coverage O
of O
fibrinogen O
, O
kinetics O
of O
fibrinogen O
adsorption O
, O
random O
sequential O
adsorption O
modeling O
of O
fibrinogen O
adsorption O
. O

Aggregation O
- O
Mediated O
Macromolecular O
Uptake O
by O
a O
Molecular O
Transporter O
. O

Endocytosis O
is O
a O
key O
process O
in O
cellular O
delivery O
of O
macromolecules O
by O
molecular O
transporters O
, O
although O
the O
mechanism O
of O
internalization O
remains O
unclear O
. O

Here O
, O
we O
probe O
the O
cellular O
uptake O
of O
streptavidin O
using O
biotinylated B
guanidinoneomycin I
( O
biotinGNeo B
) O
, O
a O
low O
molecular O
weight O
guanidinium B
- O
rich O
molecular O
transporter O
. O

Two O
distinct O
modes O
were O
explored O
: O
( O
i O
) O
incubation O
of O
cells O
with O
a O
preformed O
tetravalent O
streptavidin O
- O
( B
biotinGNeo I
) I
4 I
conjugate O
and O
( O
ii O
) O
preincubation O
of O
cells O
with O
the O
biotinGNeo B
before O
exposure O
to O
streptavidin O
. O

A O
significant O
enhancement O
in O
uptake O
was O
observed O
after O
preincubation O
with O
biotinGNeo B
. O

FRET O
studies O
showed O
that O
the O
enhanced O
uptake O
was O
accompanied O
by O
extensive O
aggregation O
of O
streptavidin O
on O
the O
cell O
surface O
. O

Because O
guanidinylated B
neomycin I
was O
previously O
found O
to O
exclusively O
bind O
to O
heparan O
sulfate B
, O
our O
observations O
suggest O
that O
heparan O
sulfate B
proteoglycan O
aggregation O
is O
a O
pivotal O
step O
for O
endocytic O
entry O
into O
cells O
by O
guanidinoglycosides B
. O

These O
observations O
put O
forward O
a O
practical O
and O
general O
pathway O
for O
the O
cellular O
delivery O
of O
diverse O
macromolecules O
. O

Study O
of O
Charge O
- O
Dependent O
Transport O
and O
Toxicity O
of O
Peptide O
- O
Functionalized O
Silver B
Nanoparticles O
Using O
Zebrafish O
Embryos O
and O
Single O
Nanoparticle O
Plasmonic O
Spectroscopy O
. O

Nanomaterials O
possess O
unusually O
high O
surface O
area O
- O
to O
- O
volume O
ratios O
, O
and O
surface O
- O
determined O
physicochemical O
properties O
. O

It O
is O
essential O
to O
understand O
their O
surface O
- O
dependent O
toxicity O
in O
order O
to O
rationally O
design O
biocompatible O
nanomaterials O
for O
a O
wide O
variety O
of O
applications O
. O

In O
this O
study O
, O
we O
have O
functionalized O
the O
surfaces O
of O
silver B
nanoparticles O
( O
Ag B
NPs O
, O
11 O
. O
7 O
+ O
/ O
- O
2 O
. O
7 O
nm O
in O
diameters O
) O
with O
three O
biocompatible O
peptides O
( O
CALNNK O
, O
CALNNS O
, O
CALNNE O
) O
to O
prepare O
positively O
( O
Ag B
- O
CALNNK O
NPs O
+ O
zeta O
) O
, O
negatively O
( O
Ag B
- O
CALNNS O
NPs O
- O
2 O
zeta O
) O
, O
and O
more O
negatively O
charged O
NPs O
( O
Ag B
- O
CALNNE O
NPs O
- O
4 O
zeta O
) O
, O
respectively O
. O

Each O
peptide O
differs O
in O
a O
single O
amino B
acid I
at O
its O
C B
- O
terminus O
, O
which O
minimizes O
the O
effects O
of O
peptide O
sequences O
and O
serves O
as O
a O
model O
molecule O
to O
create O
positive O
, O
neutral O
and O
negative O
charges O
on O
the O
surface O
of O
the O
NPs O
at O
pH O
4 O
- O
10 O
. O

We O
have O
studied O
their O
charge O
- O
dependent O
transport O
into O
early O
- O
developing O
( O
cleavage O
- O
stage O
) O
zebrafish O
embryos O
and O
their O
effects O
on O
embryonic O
development O
using O
dark O
- O
field O
optical O
microscopy O
and O
spectroscopy O
( O
DFOMS O
) O
. O

We O
found O
that O
all O
three O
Ag B
- O
peptide O
NPs O
passively O
diffused O
into O
the O
embryos O
via O
their O
chorionic O
pore O
canals O
, O
and O
stayed O
inside O
the O
embryos O
throughout O
their O
entire O
development O
( O
120 O
h O
) O
, O
showing O
charge O
- O
independent O
diffusion O
modes O
and O
charge O
- O
dependent O
diffusion O
coefficients O
. O

Notably O
, O
the O
NPs O
create O
charge O
- O
dependent O
toxic O
effects O
on O
embryonic O
development O
, O
showing O
that O
the O
Ag B
- O
CALNNK O
NPs O
+ O
zeta O
( O
positively O
charged O
) O
are O
the O
most O
biocompatible O
while O
the O
Ag B
- O
CALNNE O
NPs O
- O
4 O
zeta O
( O
more O
negatively O
charged O
) O
are O
the O
most O
toxic O
. O

By O
comparing O
with O
our O
previous O
studies O
of O
the O
same O
sized O
citrated O
Ag B
and O
Au B
NPs O
, O
the O
Ag B
- O
peptide O
NPs O
are O
much O
more O
biocompatible O
than O
the O
citrated O
Ag B
NPs O
, O
and O
nearly O
as O
biocompatible O
as O
the O
Au B
NPs O
, O
showing O
the O
dependence O
of O
nanotoxicity O
upon O
the O
surface O
charges O
, O
surface O
functional O
groups O
and O
chemical O
compositions O
of O
the O
NPs O
. O

This O
study O
also O
demonstrates O
powerful O
applications O
of O
single O
NP O
plasmonic O
spectroscopy O
for O
quantitative O
analysis O
of O
single O
NPs O
in O
vivo O
and O
in O
tissues O
, O
and O
reveals O
the O
possibility O
of O
rational O
design O
of O
biocompatible O
NPs O
. O

Small O
molecule O
mediated O
proliferation O
of O
primary O
retinal O
pigment O
epithelial O
cells O
. O

Retinal O
pigment O
epithelial O
( O
RPE O
) O
cells O
form O
a O
monolayer O
adjacent O
to O
the O
retina O
and O
play O
a O
critical O
role O
in O
the O
visual O
light O
cycle O
. O

Degeneration O
of O
this O
layer O
results O
in O
vision O
loss O
, O
causing O
retinal O
disorders O
such O
as O
age O
- O
related O
macular O
degeneration O
. O

Cell O
transplant O
therapies O
exist O
to O
restore O
vision O
loss O
; O
however O
, O
risks O
associated O
with O
and O
an O
inadequate O
supply O
of O
donor O
cells O
have O
limited O
their O
therapeutic O
success O
. O

The O
identification O
of O
factors O
that O
proliferate O
RPE O
cells O
ex O
vivo O
could O
provide O
a O
renewable O
source O
of O
cells O
for O
the O
treatment O
of O
such O
disorders O
. O

We O
show O
that O
a O
small O
molecule O
( O
WS3 O
) O
can O
reversibly O
proliferate O
primary O
RPE O
cells O
isolated O
from O
fetal O
and O
adult O
human O
donors O
. O

Following O
withdrawal O
of O
WS3 O
, O
RPE O
cells O
differentiate O
into O
a O
functional O
monolayer O
, O
as O
exhibited O
by O
their O
expression O
of O
mature O
RPE O
genes O
and O
phagocytosis O
of O
photoreceptor O
outer O
segments O
. O

Furthermore O
, O
chemically O
expanded O
RPE O
cells O
preserve O
vision O
when O
transplanted O
into O
dystrophic O
Royal O
College O
of O
Surgeons O
( O
RCS O
) O
rats O
, O
a O
well O
- O
established O
model O
of O
retinal O
degeneration O
. O

Two O
new O
vinblastine B
- O
type O
N B
- I
oxide I
alkaloids I
from O
Catharanthus O
roseus O
. O

Two O
new O
vinblastine B
- O
type O
N B
- I
oxide I
alkaloids I
, O
17 B
- I
desacetoxyvinblastin I
[ I
Formula I
: I
see I
text I
] I
- I
oxide I
( O
1 O
) O
and O
20 B
' I
- I
deoxyvinblastine I
[ I
Formula I
: I
see I
text I
] I
- I
oxide I
( O
2 O
) O
, O
were O
isolated O
from O
the O
leaves O
of O
Catharanthus O
roseus O
. O

The O
structures O
of O
1 O
and O
2 O
were O
established O
by O
the O
analysis O
of O
their O
nuclear O
magnetic O
resonance O
and O
HR O
- O
ESI O
- O
MS O
spectroscopic O
data O
. O

All O
alkaloids O
were O
evaluated O
for O
their O
cytotoxic O
activities O
against O
the O
human O
hepatocellular O
carcinoma O
( O
HepG2 O
) O
cell O
line O
, O
human O
colorectal O
carcinoma O
( O
Lovo O
) O
cell O
line O
and O
human O
breast O
carcinoma O
( O
MCF O
- O
7 O
) O
cell O
line O
by O
the O
MTT B
method O
in O
vitro O
, O
respectively O
. O

The O
results O
showed O
that O
cytotoxic O
activities O
of O
alkaloids O
1 O
and O
2 O
exhibited O
moderate O
inhibitory O
activity O
on O
the O
proliferation O
of O
three O
cancer O
cells O
. O

Mechanism O
- O
based O
design O
of O
a O
photo O
- O
activatable O
firefly O
Luciferase O
. O

We O
developed O
a O
photo O
- O
activatable O
firefly O
luciferase O
( O
fLuc O
) O
whose O
activation O
can O
be O
controlled O
by O
light O
. O

A O
photocaged O
lysine B
analogue O
was O
site O
- O
specifically O
incorporated O
into O
fLuc O
to O
replace O
its O
key O
catalytic O
lysine B
residue O
- O
Lys529 B
, O
rendering O
fLuc O
inactive O
until O
light O
- O
triggered O
removal O
of O
the O
caging O
group O
. O

This O
photo O
- O
induced O
gain O
- O
of O
- O
luminescence O
provides O
a O
facile O
approach O
for O
assessing O
the O
photolysis O
efficiency O
of O
this O
valuable O
photosensitive O
lysine B
analogue O
within O
the O
context O
of O
its O
carrier O
protein O
in O
vitro O
and O
in O
living O
cells O
. O

We O
further O
took O
advantage O
of O
the O
spatial O
and O
temporal O
activation O
feature O
of O
pfLuc B
for O
intracellular O
measurement O
of O
labile O
ATP B
levels O
without O
impairment O
of O
a O
cell O
' O
s O
physiology O
. O

The O
Histone O
Mark O
H3K36me3 O
Regulates O
Human O
DNA O
Mismatch O
Repair O
through O
Its O
Interaction O
with O
MutS O
alpha O
. O

DNA O
mismatch O
repair O
( O
MMR O
) O
ensures O
replication O
fidelity O
by O
correcting O
mismatches O
generated O
during O
DNA O
replication O
. O

Although O
human O
MMR O
has O
been O
reconstituted O
in O
vitro O
, O
how O
MMR O
occurs O
in O
vivo O
is O
unknown O
. O

Here O
, O
we O
show O
that O
an O
epigenetic O
histone O
mark O
, O
H3K36me3 O
, O
is O
required O
in O
vivo O
to O
recruit O
the O
mismatch O
recognition O
protein O
hMutS O
alpha O
( O
hMSH2 O
- O
hMSH6 O
) O
onto O
chromatin O
through O
direct O
interactions O
with O
the O
hMSH6 O
PWWP O
domain O
. O

The O
abundance O
of O
H3K36me3 O
in O
G1 O
and O
early O
S O
phases O
ensures O
that O
hMutS O
alpha O
is O
enriched O
on O
chromatin O
before O
mispairs O
are O
introduced O
during O
DNA O
replication O
. O

Cells O
lacking O
the O
H3K36 O
trimethyltransferase O
SETD2 O
display O
microsatellite O
instability O
( O
MSI O
) O
and O
an O
elevated O
spontaneous O
mutation O
frequency O
, O
characteristic O
of O
MMR O
- O
deficient O
cells O
. O

This O
work O
reveals O
that O
a O
histone O
mark O
regulates O
MMR O
in O
human O
cells O
and O
explains O
the O
long O
- O
standing O
puzzle O
of O
MSI O
- O
positive O
cancer O
cells O
that O
lack O
detectable O
mutations O
in O
known O
MMR O
genes O
. O

Antiproliferative O
activity O
of O
2 B
, I
3 I
- I
disubstituted I
indoles I
toward O
apoptosis O
- O
resistant O
cancers O
cells O
. O

Many O
types O
of O
cancer O
, O
including O
glioma O
, O
melanoma O
, O
NSCLC O
, O
among O
others O
, O
are O
resistant O
to O
apoptosis O
induction O
and O
poorly O
responsive O
to O
current O
therapies O
with O
propaptotic O
agents O
. O

We O
describe O
a O
series O
of O
2 B
, I
3 I
- I
disubstituted I
indoles I
, O
which O
display O
cytostatic O
rather O
than O
cytotoxic O
effects O
in O
cancer O
cells O
, O
and O
serve O
as O
a O
new O
chemical O
scaffold O
to O
develop O
anticancer O
agents O
capable O
of O
combating O
apoptosis O
- O
resistant O
cancers O
associated O
with O
dismal O
prognoses O
. O

Synthesis O
and O
evaluation O
of O
Janus O
type O
nucleosides B
as O
potential O
HCV O
NS5B O
polymerase O
inhibitors O
. O

The O
synthesis O
of O
new O
ribo B
and I
2 I
' I
- I
beta I
- I
C I
- I
methyl I
ribo I
Janus O
type O
nucleosides B
J O
- O
AA O
, O
J O
- O
AG O
and O
J O
- O
AU O
is O
reported O
along O
with O
their O
ability O
to O
block O
HCV O
and O
HIV O
replication O
. O

Their O
toxicity O
was O
also O
assessed O
in O
Huh7 O
, O
human O
lymphocytes O
, O
CEM O
and O
Vero O
cells O
. O

The O
Demographic O
Transition O
Influences O
Variance O
in O
Fitness O
and O
Selection O
on O
Height O
and O
BMI O
in O
Rural O
Gambia O
. O

Recent O
human O
history O
is O
marked O
by O
demographic O
transitions O
characterized O
by O
declines O
in O
mortality O
and O
fertility O
[ O
1 O
] O
. O

By O
influencing O
the O
variance O
in O
those O
fitness O
components O
, O
demographic O
transitions O
can O
affect O
selection O
on O
other O
traits O
[ O
2 O
] O
. O

Parallel O
to O
changes O
in O
selection O
triggered O
by O
demography O
per O
se O
, O
relationships O
between O
fitness O
and O
anthropometric O
traits O
are O
also O
expected O
to O
change O
due O
to O
modification O
of O
the O
environment O
. O

Here O
we O
explore O
for O
the O
first O
time O
these O
two O
main O
evolutionary O
consequences O
of O
demographic O
transitions O
using O
a O
unique O
data O
set O
containing O
survival O
, O
fertility O
, O
and O
anthropometric O
data O
for O
thousands O
of O
women O
in O
rural O
Gambia O
from O
1956 O
- O
2010 O
[ O
3 O
] O
. O

We O
show O
how O
the O
demographic O
transition O
influenced O
directional O
selection O
on O
height O
and O
body O
mass O
index O
( O
BMI O
) O
. O

We O
observed O
a O
change O
in O
selection O
for O
both O
traits O
mediated O
by O
variation O
in O
fertility O
: O
selection O
initially O
favored O
short O
females O
with O
high O
BMI O
values O
but O
shifted O
across O
the O
demographic O
transition O
to O
favor O
tall O
females O
with O
low O
BMI O
values O
. O

We O
demonstrate O
that O
these O
differences O
resulted O
both O
from O
changes O
in O
fitness O
variance O
that O
shape O
the O
strength O
of O
selection O
and O
from O
shifts O
in O
selective O
pressures O
triggered O
by O
environmental O
changes O
. O

These O
results O
suggest O
that O
demographic O
and O
environmental O
trends O
encountered O
by O
current O
human O
populations O
worldwide O
are O
likely O
to O
modify O
, O
but O
not O
stop O
, O
natural O
selection O
in O
humans O
. O

First O
demonstration O
that O
brain O
CYP2D O
- O
mediated O
opiate O
metabolic O
activation O
alters O
analgesia O
in O
vivo O
. O

The O
response O
to O
centrally O
- O
acting O
drugs O
is O
highly O
variable O
between O
individuals O
and O
does O
not O
always O
correlate O
with O
plasma O
drug O
levels O
. O

Drug O
- O
metabolizing O
CYP O
enzymes O
in O
the O
brain O
may O
contribute O
to O
this O
variability O
by O
affecting O
local O
drug O
and O
metabolite O
concentrations O
. O

CYP2D O
metabolizes O
codeine B
to O
the O
active O
morphine B
metabolite O
. O

We O
investigate O
the O
effect O
of O
inhibiting O
brain O
, O
and O
not O
liver O
, O
CYP2D O
activity O
on O
codeine B
- O
induced O
analgesia O
. O

Rats O
received O
intracerebroventricu O
injections O
of O
CYP2D O
inhibitors O
( O
20 O
mu O
g O
propranolol B
or O
40 O
mu O
g O
propafenone B
) O
or O
vehicle O
controls O
. O

Compared O
to O
vehicle O
- O
pretreated O
rats O
, O
inhibitor O
- O
pretreated O
rats O
had O
: O
a O
) O
lower O
analgesia O
in O
the O
tail O
- O
flick O
test O
( O
p O
< O
0 O
. O
05 O
) O
and O
lower O
areas O
under O
the O
analgesia O
- O
time O
curve O
( O
p O
< O
0 O
. O
02 O
) O
within O
the O
first O
hour O
after O
30mg O
/ O
kg O
subcutaneous O
codeine B
, O
b O
) O
lower O
morphine B
concentrations O
and O
morphine B
to O
codeine B
ratios O
in O
the O
brain O
( O
p O
< O
0 O
. O
02 O
and O
p O
< O
0 O
. O
05 O
, O
respectively O
) O
, O
but O
not O
in O
plasma O
( O
p O
> O
0 O
. O
6 O
and O
p O
> O
0 O
. O
7 O
, O
respectively O
) O
, O
tested O
at O

30min O
after O
30mg O
/ O
kg O
subcutaneous O
codeine B
, O
and O
c O
) O
lower O
morphine B
formation O
from O
codeine B
ex O
vivo O
by O
brain O
membranes O
( O
p O
< O
0 O
. O
04 O
) O
, O
but O
not O
by O
liver O
microsomes O
( O
p O
> O
0 O
. O
9 O
) O
. O

Analgesia O
trended O
toward O
a O
correlation O
with O
brain O
morphine B
concentrations O
( O
p O
= O
0 O
. O
07 O
) O
and O
correlated O
with O
brain O
morphine B
to O
codeine B
ratios O
( O
p O
< O
0 O
. O
005 O
) O
, O
but O
not O
with O
plasma O
morphine B
concentrations O
( O
p O
> O
0 O
. O
8 O
) O
or O
plasma O
morphine B
to O
codeine B
ratios O
( O
p O
> O
0 O
. O
8 O
) O
. O

Our O
findings O
suggest O
that O
brain O
CYP2D O
affects O
brain O
morphine B
levels O
after O
peripheral O
codeine B
administration O
, O
and O
may O
thereby O
alter O
codeine B
' O
s O
therapeutic O
efficacy O
, O
side O
- O
effect O
profile O
and O
abuse O
liability O
. O

Brain O
CYPs O
are O
highly O
variable O
due O
to O
genetics O
, O
environmental O
factors O
and O
age O
, O
and O
may O
therefore O
contribute O
to O
interindividual O
variation O
in O
the O
response O
to O
centrally O
- O
acting O
drugs O
. O

Ethnopharmacological O
and O
bioactivity O
guided O
investigation O
of O
five O
TCM O
anticancer O
herbs O
. O

ETHNOPHARMACOLOGICAL O
RELEVANCE O
: O
Five O
herbs O
, O
Curcuma O
longa O
L O
. O

( O
CL O
) O
, O
Scutellaria O
baicalensis O
Georgi O
( O
SBC O
) O
, O
Scutellaria O
barbata O
D O
. O

Don B
( O
SBB O
) O
, O
Hedyotis O
diffusa O
Willd O
. O

( O
HD O
) O
and O
Solanum O
nigrum O
L O
. O

( O
SN O
) O
, O
are O
often O
prescribed O
in O
the O
polyherbal O
formulas O
for O
cancer O
treatment O
by O
traditional O
Chinese O
medicine O
( O
TCM O
) O
practitioners O
. O

The O
purpose O
of O
the O
present O
study O
was O
to O
identify O
important O
anticancer O
herbs O
used O
in O
TCM O
and O
carry O
out O
bioactivity O
- O
directed O
fractionation O
and O
isolation O
( O
BDFI O
) O
using O
six O
cancer O
cell O
lines O
as O
well O
as O
peripheral O
blood O
mononuclear O
cells O
( O
PBMCs O
) O
, O
to O
identify O
constituents O
with O
anticancer O
activity O
but O
devoid O
of O
toxic O
effects O
against O
healthy O
immune O
cells O
. O

MATERIALS O
AND O
METHODS O
: O
Of O
243 O
document O
anticancer O
TCM O
treatments O
, O
199 O
anticancer O
TCM O
herbs O
were O
ranked O
by O
the O
number O
of O
literature O
reports O
for O
each O
herb O
. O

Five O
herbs O
were O
identified O
from O
the O
top O
50 O
ranked O
herbs O
by O
at O
least O
two O
out O
of O
three O
TCM O
practitioners O
as O
frequently O
used O
in O
the O
TCM O
treatment O
of O
cancer O
. O

BDFI O
using O
MTS B
assay O
was O
applied O
to O
determine O
the O
active O
anticancer O
extracts O
, O
fractions O
, O
and O
finally O
discrete O
compounds O
. O

RESULTS O
: O
Five O
herbs O
were O
selected O
for O
study O
of O
their O
anticancer O
activities O
. O

The O
extracts O
of O
Curcuma O
longa O
L O
. O
, O
Scutellaria O
barbata O
D O
. O

Don B
, O
and O
Hedyotis O
diffusa O
showed O
antiproliferative O
activity O
to O
various O
extents O
, O
extracts O
of O
Scutellaria O
baicalensis O
Georgi O
and O
Solanum O
nigrum O
L O
. O
showed O
little O
anticancer O
activity O
. O

Seven O
out O
of O
the O
21 O
fractions O
obtained O
from O
Hedyotis O
diffusa O
showed O
anticancer O
activity O
. O

One O
new O
compound O
, O
ethyl B
13 I
( I
2 I
) I
( I
S I
) I
- I
hydroxy I
- I
chlorophyllide I
a I
( O
1 O
) O
, O
along O
with O
10 O
known O
compounds O
, O
i O
. O
e O
. O
2 B
- I
methyl I
- I
3 I
- I
methoxyanthraquinone I
( O
2 O
) O
, O
2 B
- I
hydroxymethylanthraq I
( O
3 O
) O
, O
2 B
- I
hydroxy I
- I
3 I
- I
methylanthraquinone I
( O
4 O
) O
, O
2 B
- I
hydroxymethy I
- I
1 I
- I
hydroxyanthraquinone I
( O
5 O
) O
, O
1 B
- I
methoxy I
- I
2 I
- I
hydroxyanthraquinone I
( O
6 O

) O
, O
2 B
- I
hydroxy I
- I
3 I
- I
methyl I
- I
1 I
- I
methoxyanthraquinone I
( O
7 O
) O
, O
oleanolic B
acid I
( O
8 O
) O
, O
ursolic B
acid I
( O
9 O
) O
, O
stigmasterol B
( O
10 O
) O
and O
docosanoic B
acid I
( O
11 O
) O
, O
were O
isolated O
and O
identified O
. O

Compounds O
2 O
- O
6 O
, O
8 O
and O
9 O
dose O
- O
dependently O
inhibited O
the O
cell O
viability O
of O
cancer O
cells O
within O
a O
concentration O
range O
of O
1 O
- O
200 O
micro O
M O
. O

Furthermore O
, O
compounds O
2 O
, O
3 O
, O
5 O
and O
9 O
showed O
significantly O
stronger O
inhibition O
of O
tested O
cancer O
cell O
lines O
than O
on O
that O
of O
PBMCs O
. O

CONCLUSION O
: O
This O
study O
identified O
anticancer O
herbs O
, O
extracts O
, O
fractions O
and O
eventually O
compounds O
from O
the O
documented O
anticancer O
TCM O
herbs O
by O
using O
BDFI O
. O

It O
also O
determined O
the O
antiproliferative O
activity O
in O
cancer O
and O
healthy O
immune O
cells O
of O
the O
isolated O
compounds O
from O
Hedyotis O
diffusa O
. O

The O
results O
will O
be O
useful O
in O
the O
validation O
of O
the O
clinical O
application O
of O
these O
herbs O
and O
the O
development O
of O
novel O
anticancer O
therapeutics O
. O

Production O
of O
Cyr61 O
protein O
is O
modulated O
by O
extracellular O
acidification O
and O
PI3K O
/ O
Akt O
signaling O
in O
prostate O
carcinoma O
PC O
- O
3 O
cells O
. O

High O
expression O
of O
Cyr61 O
, O
an O
extracellular O
cysteine B
- O
rich O
heparin O
- O
binding O
protein O
, O
has O
been O
associated O
with O
a O
malignant O
cell O
phenotype O
and O
poor O
outcome O
in O
prostate O
cancers O
. O

Although O
Cyr61 O
was O
found O
by O
us O
to O
be O
overproduced O
in O
androgen B
- O
independent O
PC O
- O
3 O
cells O
treated O
with O
N B
- I
acetylcysteine I
( O
NAC B
) O
, O
its O
significance O
is O
still O
unclear O
. O

We O
therefore O
aimed O
to O
determine O
how O
and O
why O
Cyr61 O
protein O
is O
overexpressed O
in O
NAC B
- O
treated O
cells O
. O

Here O
, O
we O
found O
that O
Cyr61 O
protein O
level O
markedly O
increased O
in O
cells O
treated O
with O
NAC B
at O
high O
cell O
seeding O
density O
. O

Silencing O
of O
Cyr61 O
by O
siRNA O
induced O
enhanced O
activity O
of O
caspase O
- O
3 O
/ O
7 O
, O
upregulation O
of O
the O
proapototic O
Bok O
, O
BimL O
and O
BimS O
, O
cleavage O
of O
apoptosis O
hallmarkers O
such O
as O
Bax O
, O
PARP O
and O
caspase O
- O
3 O
, O
and O
downregulation O
of O
antiapoptotic O
Bcl2 O
, O
Bcl O
- O
xL O
and O
Mcl O
- O
1 O
proteins O
. O

NAC B
treatment O
caused O
a O
reduction O
of O
extracellular O
medium O
pH O
to O
acidic O
and O
an O
increase O
in O
Akt O
phosphorylation O
, O
after O
which O
the O
replacement O
with O
NAC B
- O
free O
medium O
returned O
them O
to O
control O
levels O
within O
24h O
. O

Acid O
stimulation O
increased O
the O
levels O
of O
Cyr61 O
and O
p O
- O
Akt O
proteins O
, O
whereas O
it O
suppressed O
the O
induction O
of O
proapoptotic O
and O
antiapoptotic O
proteins O
. O

Overall O
, O
our O
data O
indicate O
that O
PC O
- O
3 O
cells O
overproduce O
Cyr61 O
protein O
via O
activation O
of O
the O
PI3K O
/ O
Akt O
signaling O
as O
a O
part O
of O
the O
survival O
mechanisms O
under O
the O
conditions O
causing O
extracellular O
acidity O
and O
further O
cytotoxicity O
. O

Comparative O
evaluation O
of O
oral O
and O
dermal O
cypermethrin B
exposure O
on O
antioxidant O
profile O
in O
Bubalus O
bubalis O
. O

Cypermethrin B
, O
a O
type O
II O
synthetic O
pyrethroid B
insecticide O
, O
@ O
0 O
. O
5mg O
/ O
kg O
/ O
day O
for O
14 O
consecutive O
weeks O
produced O
mild O
signs O
of O
toxicity O
in O
buffalo O
calves O
. O

Significant O
changes O
were O
observed O
in O
various O
antioxidant O
parameters O
in O
blood O
. O

There O
was O
a O
marked O
increase O
in O
the O
extent O
of O
lipid O
peroxidation O
( O
33 O
. O
9 O
% O
) O
and O
enzymic O
activity O
of O
glutathione B
peroxidase O
( O
6 O
. O
7 O
% O
) O
, O
superoxide B
dismutase O
( O
35 O
. O
0 O
% O
) O
, O
catalase O
( O
43 O
. O
7 O
% O
) O
, O
glutathione B
- O
S B
- O
transferase O
( O
64 O
. O
4 O
% O
) O
, O
glutathione B
reductase O
( O
36 O
. O
7 O
% O
) O
and O
glucose B
- I
6 I
- I
phosphate I
dehydrogenase O
( O
32 O
. O
1 O
% O
) O
. O

A O
significant O
decrease O
in O
blood O
glutathione B
( O
16 O
. O
7 O
% O
) O
, O
total O
antioxidant O
activity O
( O
45 O
. O
4 O
% O
) O
and O
vitamin B
E I
( O
40 O
. O
8 O
% O
) O
was O
observed O
and O
no O
significant O
effect O
was O
found O
on O
blood O
selenium B
levels O
. O

However O
, O
the O
extent O
of O
lipid O
peroxidation O
( O
42 O
% O
) O
and O
the O
depletion O
of O
glutathione B
( O
28 O
. O
8 O
% O
) O
was O
greater O
after O
dermal O
sub O
- O
acute O
toxicity O
of O
cypermethrin B
( O
0 O
. O
25 O
% O
) O
for O
14 O
consecutive O
days O
. O

Similarly O
, O
it O
was O
observed O
that O
the O
incline O
in O
the O
enzymic O
activity O
of O
glutathione B
peroxidase O
( O
29 O
. O
7 O
% O
) O
, O
superoxide B
dismutase O
( O
38 O
. O
3 O
% O
) O
and O
glutathione B
reductase O
( O
38 O
. O
3 O
% O
) O
was O
higher O
in O
dermally O
cypermethrin B
exposed O
animals O
. O

Thus O
, O
the O
present O
investigation O
contemplates O
that O
oxidative O
stress O
is O
the O
important O
mechanisms O
involved O
in O
cypermethrin B
- O
induced O
toxicity O
and O
the O
oxidative O
insult O
produced O
by O
dermal O
route O
is O
more O
severe O
as O
compared O
to O
oral O
intoxication O
. O

Biological O
effects O
induced O
by O
BSA O
- O
stabilized O
silica B
nanoparticles O
in O
mammalian O
cell O
lines O
. O

Much O
of O
the O
concerns O
regarding O
engineered O
nanoparticle O
( O
NP O
) O
toxicity O
are O
based O
on O
knowledge O
from O
previous O
studies O
on O
particles O
in O
ambient O
air O
or O
occupational O
situations O
. O

E O
. O
g O
. O
, O
the O
effects O
of O
exposure O
to O
silica B
dust O
particles O
have O
been O
studied O
intensely O
due O
to O
the O
carcinogenicity O
of O
crystalline O
silica B
. O

However O
, O
the O
increasing O
usage O
of O
engineered O
amorphous O
silica B
NPs O
has O
emphasized O
the O
need O
for O
further O
mechanistic O
insight O
to O
predict O
the O
consequences O
of O
exposure O
to O
the O
amorphous O
type O
of O
silica B
NPs O
. O

The O
present O
study O
focused O
on O
the O
in O
vitro O
biological O
effects O
following O
exposure O
to O
well O
- O
dispersed O
, O
BSA O
- O
stabilized O
, O
amorphous O
silica B
NPs O
whereas O
unmodified O
silica B
NPs O
where O
included O
for O
reasons O
of O
comparison O
. O

The O
cytotoxicity O
of O
the O
silica B
NPs O
was O
investigated O
in O
six O
different O
cell O
lines O
( O
A549 O
, O
THP O
- O
1 O
, O
CaCo O
- O
2 O
, O
ASB O
- O
XIV O
, O
J O
- O
774A O
. O
1 O
, O
and O
Colon O
- O
26 O
) O
selected O
to O
explore O
the O
significance O
of O
organ O
and O
species O
sensitivity O
in O
vitro O
. O

Viability O
data O
demonstrated O
that O
macrophages O
were O
most O
sensitive O
to O
silica B
NP O
and O
interestingly O
, O
murine O
cell O
lines O
were O
generally O
found O
to O
be O
more O
sensitive O
than O
comparable O
human O
cell O
lines O
. O

Further O
studies O
were O
conducted O
in O
the O
human O
epithelial O
lung O
cell O
line O
, O
A549 O
, O
to O
explore O
the O
molecular O
mechanism O
of O
silica B
toxicity O
. O

Generation O
of O
reactive O
oxygen B
species O
, O
one O
of O
the O
proposed O
toxicological O
mechanisms O
of O
NPs O
, O
was O
investigated O
in O
A549 O
cells O
by O
the O
dichlorofluorescin B
( O
DCF B
) O
assay O
to O
be O
significantly O
induced O
at O
NP O
concentrations O
above O
113 O
mu O
g O
/ O
mL O
. O

However O
, O
induction O
of O
oxidative O
stress O
related O
pathways O
was O
not O
found O
after O
silica B
NP O
exposure O
for O
24h O
in O
gene O
array O
studies O
conducted O
in O
A549 O
cells O
at O
a O
relatively O
low O
NP O
concentration O
( O
EC20 O
) O
. O

Up O
- O
regulated O
genes O
( O
more O
than O
2 O
- O
fold O
) O
were O
primarily O
related O
to O
lipid O
metabolism O
and O
biosynthesis O
whereas O
down O
- O
regulated O
genes O
included O
several O
processes O
such O
as O
transcription O
, O
cell O
junction O
, O
extra O
cellular O
matrix O
( O
ECM O
) O
- O
receptor O
interaction O
and O
others O
. O

Thus O
, O
gene O
expression O
data O
proposes O
that O
several O
cellular O
processes O
other O
than O
oxidative O
stress O
could O
be O
affected O
by O
exposure O
to O
silica B
NPs O
. O

Anthelmintic O
activity O
of O
Arisaema O
franchetianum O
and O
Arisaema O
lobatum O
essential O
oils O
against O
Haemonchus O
contortus O
. O

ETHNOPHARMACOLOGICAL O
RELEVANCE O
: O
Arisaema O
franchetianum O
and O
Arisaema O
lobatum O
are O
two O
perennial O
plants O
native O
to O
China O
. O

Arisaema O
franchetianum O
is O
universally O
used O
to O
promote O
the O
subsidence O
of O
induration O
and O
swelling O
, O
quicken O
blood O
and O
relieve O
pains O
, O
and O
kill O
intestinal O
parasites O
in O
humans O
and O
animals O
. O

Arisaema O
lobatum O
is O
used O
to O
treat O
malaria O
, O
intestinal O
parasites O
, O
and O
snake O
and O
insect O
bites O
in O
humans O
and O
animals O
. O

The O
aim O
of O
this O
study O
was O
to O
determine O
the O
composition O
of O
the O
essential O
oils O
from O
Arisaema O
franchetianum O
and O
Arisaema O
lobatum O
and O
evaluate O
the O
anthelmintic O
effect O
against O
Haemonchus O
contortus O
. O

MATERIALS O
AND O
METHODS O
: O
Two O
oils O
were O
investigated O
by O
GC O
and O
GC O
- O
MS O
. O

The O
anthelmintic O
bioassay O
tests O
of O
Arisaema O
franchetianum O
and O
Arisaema O
lobatum O
essential O
oil O
, O
linalool B
and O
carvacrol B
were O
performed O
using O
egg O
hatch O
assay O
( O
EHA O
) O
, O
larval O
development O
assay O
( O
LDA O
) O
and O
larval O
migration O
inhibition O
assay O
( O
LMIA O
) O
. O

RESULTS O
: O
Fifty O
six O
components O
representing O
96 O
. O
88 O
% O
of O
the O
Arisaema O
franchetianum O
oil O
and O
64 O
components O
representing O
96 O
. O
88 O
% O
of O
the O
Arisaema O
lobatum O
oil O
were O
identified O
. O

Carvacrol B
and O
linalool B
were O
found O
to O
be O
the O
major O
constituents O
of O
two O
oils O
. O

In O
the O
EHA O
, O
greater O
than O
99 O
% O
inhibition O
were O
observed O
with O
Arisaema O
franchetianum O
oil O
at O
10mg O
/ O
mL O
( O
CE50 O
1 O
. O
63mg O
/ O
mL O
) O
and O
Arisaema O
lobatum O
oil O
at O
5 O
and O
10mg O
/ O
mL O
( O
CE50 O
0 O
. O
48mg O
/ O
mL O
) O
. O

In O
the O
LDA O
, O
both O
oils O
induced O
complete O
inhibition O
at O
10mg O
/ O
mL O
, O
with O
the O
CE50 O
being O
1 O
. O
10mg O
/ O
mL O
for O
Arisaema O
franchetianum O
oil O
and O
0 O
. O
73mg O
/ O
mL O
for O
Arisaema O
lobatum O
oil O
. O

In O
the O
LMIA O
, O
the O
Arisaema O
franchetianum O
oil O
and O
Arisaema O
lobatum O
oil O
at O
best O
inhibited O
74 O
. O
1 O
% O
and O
95 O
. O
6 O
% O
of O
larval O
migration O
at O
10mg O
/ O
mL O
, O
respectively O
. O

Carvacrol B
exhibited O
similar O
activity O
to O
Arisaema O
lobatum O
essential O
oil O
and O
linalool B
did O
not O
show O
high O
activity O
in O
every O
assay O
. O

CONCLUSIONS O
: O
These O
data O
show O
for O
the O
first O
time O
that O
the O
essential O
oils O
obtained O
from O
Arisaema O
franchetianum O
or O
Arisaema O
lobatum O
had O
promising O
anthelmintic O
activity O
against O
Haemonchus O
contortus O
. O

Arisaema O
plant O
may O
offer O
an O
alternative O
source O
for O
the O
control O
of O
gastrointestinal O
nematodes O
of O
sheep O
and O
goats O
. O

Sciadopitysin B
protects O
osteoblast O
function O
via O
its O
antioxidant O
activity O
in O
MC3T3 O
- O
E1 O
cells O
. O

Age O
- O
related O
osteoblast O
dysfunction O
is O
the O
main O
cause O
of O
age O
- O
related O
bone O
loss O
in O
both O
men O
and O
women O
. O

In O
the O
present O
study O
, O
the O
effect O
of O
sciadopitysin B
, O
a O
type O
of O
biflavonoids B
, O
on O
osteoblast O
function O
was O
investigated O
in O
osteoblastic O
MC3T3 O
- O
E1 O
cells O
. O

Sciadopitysin B
caused O
a O
significant O
elevation O
of O
alkaline O
phosphatase O
activity O
, O
collagen O
synthesis O
, O
osteocalcin O
production O
, O
mineralization O
, O
and O
glutathione B
content O
in O
the O
cells O
( O
P O
< O
0 O
. O
05 O
) O
. O

Sciadopitysin B
also O
decreased O
the O
production O
of O
tumor O
necrosis O
factor O
- O
a O
( O
TNF O
- O
alpha O
) O
induced O
by O
antimycin B
A I
, O
a O
mitochondrial O
electron O
transport O
inhibitor O
. O

We O
investigated O
the O
protective O
effects O
of O
sciadopitysin B
on O
antimycin B
A I
- O
induced O
toxicity O
in O
osteoblastic O
MC3T3 O
- O
E1 O
cells O
. O

Exposure O
of O
MC3T3 O
- O
E1 O
cells O
to O
antimycin B
A I
caused O
a O
significant O
reduction O
in O
osteoblast O
dysfunction O
. O

However O
, O
pretreatment O
with O
sciadopitysin B
prior O
to O
antimycin B
A I
exposure O
significantly O
reduced O
antimycin B
A I
- O
induced O
cell O
damage O
by O
preventing O
mitochondrial O
membrane O
potential O
dissipation O
, O
adenosine B
triphosphate I
( O
ATP B
) O
loss O
, O
reactive O
oxygen B
species O
( O
ROS O
) O
release O
, O
and O
nitrotyrosine B
increase O
, O
suggesting O
that O
sciadopitysin B
may O
be O
useful O
for O
protecting O
mitochondria O
against O
a O
burst O
of O
oxidative O
stress O
. O

Moreover O
, O
sciadopitysin B
increased O
phosphorylation O
of O
cAMP B
- O
response O
element O
- O
binding O
protein O
( O
CREB O
) O
inhibited O
by O
antimycin B
A I
. O

Our O
results O
demonstrate O
that O
sciadopitysin B
may O
reduce O
or O
prevent O
osteoblasts O
degeneration O
. O

In O
vitro O
binding O
affinities O
of O
a O
series O
of O
flavonoids B
for O
mu O
- O
opioid O
receptors O
. O

Antinociceptive O
effect O
of O
the O
synthetic O
flavonoid B
3 B
, I
3 I
- I
dibromoflavanone I
in O
mice O
. O

The O
pharmacotherapy O
for O
the O
treatment O
of O
pain O
is O
an O
active O
area O
of O
investigation O
. O

There O
are O
effective O
drugs O
to O
treat O
this O
problem O
, O
but O
there O
is O
also O
a O
need O
to O
find O
alternative O
treatments O
free O
of O
undesirable O
side O
effects O
. O

In O
the O
present O
work O
the O
capacity O
of O
a O
series O
of O
flavonoids B
to O
bind O
to O
the O
mu O
opioid O
receptor O
was O
evaluated O
. O

The O
most O
active O
compound O
, O
3 B
, I
3 I
- I
dibromoflavanone I
( O
31 O
) O
, O
a O
synthetic O
flavonoid B
, O
presented O
a O
significant O
inhibition O
of O
the O
binding O
of O
the O
selective O
mu O
opioid O
ligand O
[ B
( I
3 I
) I
H I
] I
DAMGO I
, O
with O
a O
Ki O
of O
0 O
. O
846 O
+ O
/ O
- O
0 O
. O
263 O
mu O
M O
. O

Flavanone B
31 O
was O
further O
synthesized O
using O
a O
simple O
and O
cheap O
procedure O
with O
good O
yield O
. O

Its O
in O
vivo O
effects O
in O
mice O
, O
after O
acute O
treatments O
, O
were O
studied O
using O
antinociceptive O
and O
behavioral O
assays O
. O

It O
showed O
no O
sedative O
, O
anxiolytic O
, O
motor O
incoordination O
effects O
or O
inhibition O
of O
the O
gastrointestinal O
transit O
in O
mice O
at O
the O
doses O
tested O
. O

It O
evidenced O
antinociceptive O
activity O
on O
the O
acetic B
acid I
- O
induced O
nociception O
, O
hot O
plate O
and O
formalin B
tests O
( O
at O
10 O
mg O
/ O
kg O
and O
30 O
mg O
/ O
kg O
) O
. O

The O
results O
showed O
that O
the O
5 O
- O
HT2 O
receptor O
and O
the O
adrenoceptors O
seem O
unlikely O
to O
be O
involved O
in O
its O
antinociceptive O
effects O
. O

Naltrexone B
, O
a O
nonselective O
opioid O
receptors O
antagonist O
, O
totally O
blocked O
compound O
31 O
antinociceptive O
effects O
on O
the O
hot O
plate O
test O
, O
but O
naltrindole B
( O
delta O
opioid O
antagonist O
) O
and O
nor B
- I
binaltorphimine I
( O
kappa O
opioid O
antagonist O
) O
did O
not O
. O

These O
findings O
demonstrated O
that O
3 B
, I
3 I
- I
dibromoflavanone I
( O
31 O
) O
, O
at O
doses O
that O
did O
not O
interfere O
with O
the O
motor O
performance O
, O
exerted O
clear O
dose O
dependent O
antinociception O
when O
assessed O
in O
the O
chemical O
and O
thermal O
models O
of O
nociception O
in O
mice O
and O
it O
seems O
that O
its O
action O
is O
related O
to O
the O
activation O
of O
the O
mu O
opioid O
receptor O
. O

Trabecular O
bone O
adapts O
to O
long O
- O
term O
cyclic O
loading O
by O
increasing O
stiffness O
and O
normalization O
of O
dynamic O
morphometric O
rates O
. O

Bone O
has O
the O
ability O
to O
adapt O
to O
external O
loading O
conditions O
. O

Especially O
the O
beneficial O
effect O
of O
short O
- O
term O
cyclic O
loading O
has O
been O
investigated O
in O
a O
number O
of O
in O
vivo O
animal O
studies O
. O

The O
aim O
of O
this O
study O
was O
to O
assess O
the O
long O
- O
term O
effect O
( O
> O
10weeks O
) O
of O
cyclic O
mechanical O
loading O
on O
the O
bone O
microstructure O
, O
bone O
stiffness O
, O
and O
bone O
remodeling O
rates O
. O

Mice O
were O
subjected O
to O
cyclic O
mechanical O
loading O
at O
the O
sixth O
caudal O
vertebra O
with O
8N O
or O
0N O
( O
control O
) O
three O
times O
per O
week O
for O
a O
total O
period O
of O
14weeks O
. O

Structural O
bone O
parameters O
were O
determined O
from O
in O
vivo O
micro O
- O
computed O
tomography O
( O
micro O
- O
CT O
) O
scans O
performed O
at O
week O
0 O
, O
4 O
, O
6 O
, O
8 O
, O
10 O
, O
12 O
, O
and O
14 O
. O

Mechanical O
parameters O
were O
derived O
from O
micro O
- O
finite O
element O
analysis O
. O

Dynamic O
bone O
morphometry O
was O
calculated O
using O
registration O
of O
serial O
micro O
- O
CT O
scans O
. O

Bone O
volume O
fraction O
and O
trabecular O
thickness O
increased O
significantly O
more O
for O
the O
loaded O
group O
than O
for O
the O
control O
group O
( O
p O
= O
0 O
. O
006 O
and O
p O
= O
0 O
. O
002 O
respectively O
) O
. O

The O
trabecular O
bone O
microstructure O
adapted O
to O
the O
load O
of O
8N O
in O
approximately O
ten O
weeks O
, O
indicated O
by O
the O
trabecular O
bone O
volume O
fraction O
, O
which O
increased O
from O
16 O
. O
7 O
% O
at O
0weeks O
to O
21 O
. O
6 O
% O
at O
week O
10 O
and O
only O
showed O
little O
change O
afterwards O
( O
bone O
volume O
fraction O
of O
21 O
. O
5 O
% O
at O
14weeks O
) O
. O

Similarly O
bone O
stiffness O
- O
at O
the O
start O
of O
the O
experiment O
649N O
/ O
mm O
- O
reached O
846N O
/ O
mm O
at O
10weeks O
in O
the O
loaded O
group O
and O
was O
maintained O
to O
the O
end O
of O
the O
experiment O
( O
850N O
/ O
mm O
) O
. O

At O
4weeks O
the O
bone O
formation O
rate O
was O
32 O
% O
greater O
and O
the O
bone O
resorption O
rate O
22 O
% O
less O
for O
8N O
compared O
to O
0N O
. O

This O
difference O
was O
significantly O
reduced O
as O
the O
bone O
adapted O
to O
8N O
, O
with O
8N O
remodeling O
rates O
returning O
to O
the O
values O
of O
the O
0N O
group O
at O
approximately O
10weeks O
. O

Together O
these O
data O
suggest O
that O
once O
bone O
has O
adapted O
to O
a O
new O
loading O
state O
, O
the O
remodeling O
rates O
reduce O
gradually O
while O
maintaining O
bone O
volume O
fraction O
and O
stiffness O
. O

The O
extraction O
and O
analysis O
of O
cylindrospermopsin B
from O
human O
serum O
and O
urine O
. O

The O
naturally O
derived O
cyanotoxin O
, O
cylindrospermopsin B
( O
CYN B
) O
, O
has O
been O
detected O
in O
freshwater O
systems O
worldwide O
and O
poses O
a O
threat O
to O
human O
health O
. O

The O
methods O
for O
the O
extraction O
and O
detection O
of O
this O
toxin O
in O
source O
water O
are O
well O
documented O
, O
but O
methods O
for O
CYN B
determination O
in O
exposed O
individuals O
have O
not O
been O
investigated O
. O

In O
this O
study O
, O
the O
extraction O
and O
detection O
of O
CYN B
from O
two O
different O
matrices O
, O
serum O
and O
urine O
, O
was O
explored O
. O

Both O
serum O
and O
urine O
matrices O
inherently O
produce O
interference O
with O
analytical O
analyses O
and O
require O
extensive O
clean O
- O
up O
. O

Methods O
for O
extraction O
of O
CYN B
from O
both O
matrices O
were O
developed O
and O
validated O
using O
fortified O
samples O
. O

Serum O
extraction O
included O
homogenization O
followed O
by O
protein O
precipitation O
and O
solid O
phase O
extraction O
( O
SPE O
) O
. O

Urine O
samples O
were O
processed O
using O
filtration O
, O
pH O
manipulation O
, O
and O
SPE O
. O

Analyses O
using O
a O
commercially O
available O
enzyme O
- O
linked O
immunosorbent O
assay O
( O
ELISA O
) O
and O
liquid O
chromatography O
coupled O
with O
mass O
spectrometry O
( O
LC O
/ O
MS O
/ O
MS O
) O
were O
assessed O
. O

Matrix O
effects O
inhibited O
ELISA O
' O
s O
use O
as O
a O
quantitative O
tool O
for O
both O
matrices O
. O

LC O
/ O
MS O
/ O
MS O
was O
determined O
to O
be O
the O
most O
effective O
and O
reproducible O
means O
to O
detect O
and O
quantify O
CYN B
. O

The O
method O
detection O
limits O
determined O
in O
this O
study O
using O
LC O
/ O
MS O
/ O
MS O
were O
0 O
. O
25 O
and O
0 O
. O
50 O
ng O
mL O
( O
- O
1 O
) O
for O
serum O
and O
urine O
, O
respectively O
. O

This O
method O
can O
be O
used O
to O
test O
individuals O
exposed O
to O
blooms O
of O
cyanobacteria O
producing O
CYN B
. O

Developmental O
toxicity O
and O
estrogenic O
potency O
of O
zearalenone B
in O
zebrafish O
( O
Danio O
rerio O
) O
. O

Zearalenone B
( O
ZEA B
, I
F2 I
) O
is O
one O
of O
the O
most O
common O
mycotoxins O
and O
the O
only O
known O
mycoestrogen O
. O

It O
enters O
the O
food O
and O
feed O
chain O
from O
contaminated O
cereals O
and O
infiltrates O
into O
sewage O
or O
natural O
waters O
posing O
potential O
threat O
to O
exposed O
livestock O
, O
wildlife O
and O
humans O
. O

Therefore O
evaluation O
of O
its O
biological O
effects O
is O
of O
international O
importance O
. O

We O
performed O
toxicological O
tests O
on O
zebrafish O
( O
Danio O
rerio O
) O
larvae O
and O
adults O
. O

Developmental O
toxicity O
was O
assessed O
by O
an O
extended O
( O
5 O
days O
) O
fish O
embryo O
toxicity O
test O
( O
FET O
) O
. O

Effects O
of O
early O
ZEA B
exposure O
were O
concentration O
- O
dependent O
with O
LC50 O
and O
LC10 O
values O
of O
893 O
and O
335 O
mu O
g O
/ O
L O
. O

In O
larvae O
exposed O
to O
500 O
mu O
g O
/ O
L O
and O
above O
, O
ZEA B
induced O
similar O
phenotype O
to O
has O
( O
heart O
- O
and O
soul O
) O
showing O
defects O
in O
heart O
and O
eye O
development O
and O
upward O
curvature O
of O
the O
body O
axis O
. O

From O
250 O
mu O
g O
/ O
L O
at O
72hpf O
the O
gap O
in O
the O
melanophore O
streak O
at O
the O
base O
of O
the O
tail O
fin O
was O
missing O
and O
the O
fin O
fold O
was O
abnormal O
, O
suggesting O
disturbance O
in O
the O
development O
of O
the O
adult O
tail O
fin O
primordium O
. O

Estrogenic O
potency O
was O
measured O
on O
the O
basis O
of O
Vitellogenin O
( O
Vtg O
) O
protein O
( O
adults O
) O
levels O
and O
relative O
abundance O
of O
vitellogenin O
- O
1 O
mRNA O
( O
vtg O
- O
1 O
) O
( O
larvae O
and O
adults O
) O
. O

qRT O
- O
PCR O
in O
larvae O
proved O
to O
be O
sufficient O
substitute O
to O
adult O
tests O
and O
sensitive O
enough O
to O
detect O
ZEA B
in O
0 O
. O
1 O
mu O
g O
/ O
L O
concentrations O
, O
that O
is O
close O
to O
levels O
observed O
in O
wastewaters O
. O

Developmental O
defects O
reveal O
that O
besides O
direct O
estrogenic O
effects O
, O
zearalenone B
might O
interact O
with O
other O
ontogenic O
pathways O
. O

Controlled O
electrochemical O
deposition O
and O
transformation O
of O
hetero O
- O
nanoarchitectured O
electrodes O
for O
energy O
storage O
. O

A O
review O
of O
electrochemically O
synthesized O
nanomaterials O
with O
different O
controllable O
architectures O
for O
electrochemical O
energy O
storage O
devices O
is O
shown O
. O

It O
is O
demonstrated O
that O
these O
nano O
- O
architectures O
can O
be O
created O
either O
by O
electrodeposition O
or O
by O
the O
electrochemical O
transformation O
of O
materials O
. O

Electrochemical O
synthesis O
is O
presented O
here O
as O
it O
provides O
intimate O
contact O
between O
the O
electrode O
and O
current O
collector O
and O
also O
promotes O
an O
electronic O
pathway O
for O
all O
materials O
to O
be O
connected O
to O
the O
circuit O
. O

Although O
still O
in O
their O
infancy O
, O
electrosynthesized O
nano O
- O
architectures O
show O
promise O
to O
be O
used O
in O
future O
electrochemical O
energy O
storage O
devices O
as O
utilization O
of O
this O
method O
bypasses O
the O
need O
for O
bulky O
conductive O
additives O
and O
electrochemically O
inactive O
binders O
. O

Furthermore O
, O
electrochemical O
transformations O
can O
be O
used O
to O
create O
additional O
architectural O
features O
or O
change O
the O
chemical O
make O
- O
up O
of O
the O
electrode O
. O

This O
review O
is O
meant O
to O
show O
the O
creativity O
of O
current O
science O
when O
it O
comes O
to O
these O
nano O
- O
architectured O
electrodes O
. O

It O
is O
organized O
by O
technique O
used O
for O
synthesis O
including O
hard O
template O
, O
soft O
template O
, O
and O
template O
- O
free O
synthesis O
along O
with O
electrochemical O
transformation O
techniques O
. O

Effects O
of O
intravenous O
nicotine B
on O
prepulse O
inhibition O
in O
smokers O
and O
non O
- O
smokers O
: O
relationship O
with O
familial O
smoking O
. O

RATIONALE O
: O
The O
reinforcing O
properties O
of O
nicotine B
may O
be O
, O
in O
part O
, O
derived O
from O
its O
ability O
to O
enhance O
certain O
forms O
of O
cognitive O
processing O
. O

Several O
animal O
and O
human O
studies O
have O
shown O
that O
nicotine B
increases O
prepulse O
inhibition O
( O
PPI O
) O
of O
the O
startle O
reflex O
. O

However O
, O
it O
remains O
unclear O
whether O
these O
effects O
are O
related O
to O
smoking O
susceptibility O
. O

OBJECTIVES O
: O
The O
current O
study O
examined O
the O
effects O
of O
intravenously O
delivered O
nicotine B
on O
PPI O
in O
smokers O
and O
non O
- O
smokers O
, O
as O
well O
as O
its O
association O
with O
a O
quantitative O
index O
of O
familial O
smoking O
. O

METHODS O
: O
The O
sample O
consisted O
of O
30 O
non O
- O
smokers O
and O
16 O
smokers O
, O
who O
completed O
an O
initial O
assessment O
, O
followed O
on O
a O
separate O
day O
by O
a O
laboratory O
assessment O
of O
PPI O
prior O
to O
and O
following O
each O
of O
two O
intravenous O
nicotine B
infusions O
. O

Separate O
doses O
were O
used O
in O
smoker O
and O
non O
- O
smoker O
samples O
. O

RESULTS O
: O
Analyses O
indicated O
that O
both O
nicotine B
infusions O
acutely O
enhanced O
PPI O
among O
non O
- O
smokers O
, O
and O
this O
enhancement O
was O
positively O
related O
to O
the O
degree O
of O
smoking O
among O
first O
and O
second O
- O
degree O
relatives O
. O

Smokers O
also O
displayed O
PPI O
enhancement O
after O
receiving O
the O
first O
infusion O
, O
but O
this O
effect O
was O
unrelated O
to O
familial O
smoking O
. O

CONCLUSIONS O
: O
These O
data O
suggest O
that O
the O
PPI O
paradigm O
may O
have O
utility O
as O
an O
endophenotype O
for O
cognitive O
processes O
which O
contribute O
to O
smoking O
risk O
. O

Ventral O
tegmental O
area O
alpha O
6 O
beta O
2 O
nicotinic O
acetylcholine B
receptors O
modulate O
phasic O
dopamine B
release O
in O
the O
nucleus O
accumbens O
core O
. O

RATIONALE O
: O
Phasic O
dopamine B
( O
DA O
) O
signaling O
underlies O
reward O
learning O
. O

Cholinergic O
and O
glutamatergic O
inputs O
into O
the O
ventral O
tegmental O
area O
( O
VTA O
) O
are O
crucial O
for O
modulating O
burst O
firing O
activity O
and O
subsequent O
phasic O
DA O
release O
in O
the O
nucleus O
accumbens O
( O
NAc O
) O
, O
but O
the O
specific O
VTA O
nicotinic O
receptor O
subtypes O
that O
regulate O
phasic O
DA O
release O
have O
not O
been O
identified O
. O

OBJECTIVE O
: O
The O
goal O
was O
to O
determine O
the O
role O
of O
VTA O
N B
- I
methyl I
- I
D I
- I
aspartate I
receptors O
( O
NMDARs O
) O
and O
specific O
subtypes O
of O
nicotinic O
acetylcholine B
receptors O
( O
nAChRs O
) O
in O
regulating O
phasic O
DA O
release O
in O
the O
NAc O
core O
. O

METHODS O
: O
Fast O
- O
scan O
cyclic O
voltammetry O
in O
anesthetized O
rats O
was O
combined O
with O
intra O
- O
VTA O
micro O
- O
infusion O
to O
evaluate O
the O
ability O
of O
glutamatergic O
and O
cholinergic O
drugs O
to O
modulate O
stimulated O
phasic O
DA O
release O
in O
the O
NAc O
core O
. O

RESULTS O
: O
VTA O
NMDAR O
blockade O
with O
AP B
- I
5 I
decreased O
, O
while O
VTA O
NMDAR O
activation O
with O
NMDA B
increased O
NAc O
peak O
phasic O
DA O
release O
. O

Intra O
- O
VTA O
administration O
of O
the O
nonspecific O
nAChR O
antagonist O
mecamylamine B
produced O
a O
persistent O
decrease O
in O
phasic O
DA O
release O
. O

Infusion O
of O
the O
alpha O
6 O
- O
selective O
antagonist O
alpha O
- O
conotoxin O
MII O
( O
alpha O
- O
ctx O
MII O
) O
produced O
a O
robust O
, O
but O
transient O
decrease O
in O
phasic O
DA O
, O
whereas O
infusion O
of O
selective O
doses O
of O
either O
the O
alpha O
4 O
beta O
2 O
- O
selective O
antagonist O
, O
dihydro B
- I
beta I
- I
erythroidine I
, O
or O
the O
alpha O
7 O
antagonist O
, O
methyllycaconitine B
, O
had O
no O
effect O
. O

Co O
- O
infusion O
of O
AP O
- O
5 O
and O
alpha O
- I
ctx O
MII O
produced O
a O
similar O
phasic O
DA O
decrease O
as O
either O
drug O
alone O
, O
with O
no O
additive O
effect O
. O

CONCLUSIONS O
: O
The O
results O
suggest O
that O
VTA O
alpha O
6 O
beta O
2 O
nAChRs O
, O
but O
not O
alpha O
4 O
beta O
2 O
or O
alpha O
7 O
nAChRs O
, O
regulate O
phasic O
DA O
release O
in O
the O
NAc O
core O
and O
that O
VTA O
alpha O
6 O
beta O
2 O
nAChRs O
and O
NMDA B
receptors O
act O
at O
a O
common O
site O
or O
target O
to O
regulate O
NAc O
phasic O
DA O
signaling O
. O

The O
Value O
of O
Expression O
of O
M2 O
- O
PK O
and O
VEGF O
in O
Patients O
with O
Advanced O
Gastric O
Cancer O
. O

Glycolytic O
pyruvate B
kinase O
isoenzyme O
type O
M2 O
( O
M2 O
- O
PK O
) O
plays O
a O
key O
role O
in O
tumor O
metabolism O
and O
energy O
production O
. O

Vascular O
endothelial O
growth O
factor O
( O
VEGF O
) O
is O
critical O
in O
regulating O
angiogenesis O
which O
is O
an O
essential O
process O
required O
for O
tumor O
growth O
and O
metastasis O
. O

These O
two O
genes O
may O
function O
in O
accordance O
with O
tumor O
development O
. O

The O
purpose O
of O
this O
study O
was O
to O
investigate O
the O
relationship O
between O
the O
expression O
of O
M2 O
- O
PK O
and O
VEGF O
, O
and O
their O
association O
with O
clinicopathological O
features O
in O
patients O
with O
advanced O
gastric O
cancer O
. O

Expression O
of O
M2 O
- O
PK O
and O
VEGF O
were O
examined O
in O
142 O
cases O
of O
paraffin O
- O
embedded O
tissue O
blocks O
from O
patients O
with O
advanced O
gastric O
cancer O
. O

M2 O
- O
PK O
expression O
was O
found O
to O
strongly O
correlate O
with O
that O
of O
VEGF O
( O
r O
= O
0 O
. O
718 O
) O
. O

In O
addition O
, O
expression O
of O
M2 O
- O
PK O
and O
VEGF O
correlates O
with O
tumor O
size O
( O
p O
= O
0 O
. O
0001 O
, O
and O
p O
= O
0 O
. O
0017 O
, O
respectively O
) O
, O
depth O
of O
invasion O
( O
p O
= O
0 O
. O
0024 O
, O
and O
p O
= O
0 O
. O
0261 O
, O
respectively O
) O
, O
and O
lymph O
node O
metastasis O
( O
p O
= O
0 O
. O
036 O
, O
and O
p O
= O
0 O
. O
028 O
, O
respectively O
) O
. O

The O
high O
expression O
levels O
of O
M2 O
- O
PK O
and O
VEGF O
may O
indicate O
poor O
prognosis O
in O
patients O
with O
advanced O
gastric O
cancer O
. O

Effects O
of O
Soil O
Trace O
Elements O
on O
Longevity O
Population O
in O
China O
. O

Based O
on O
background O
concentrations O
of O
elements O
in O
soils O
and O
the O
sixth O
population O
census O
data O
of O
China O
, O
this O
study O
discussed O
the O
distribution O
characteristics O
of O
soil O
elements O
and O
longevity O
population O
at O
province O
level O
in O
China O
. O

Percentages O
of O
the O
aging O
population O
are O
high O
in O
Southwest O
China O
and O
the O
eastern O
coastal O
region O
but O
low O
in O
western O
and O
northwestern O
regions O
. O

Provinces O
in O
South O
and O
Southwest O
China O
gain O
a O
high O
level O
of O
longevity O
, O
while O
the O
northern O
part O
of O
China O
has O
a O
low O
level O
of O
longevity O
. O

The O
background O
concentration O
of O
Se B
in O
soil O
has O
a O
significant O
positive O
correlation O
with O
longevity O
index O
, O
while O
Ba B
and O
Ni B
have O
a O
significant O
negative O
correlation O
with O
longevity O
indexes O
. O

By O
regression O
analysis O
, O
longevity O
index O
C O
/ O
100 O
, O
000 O
can O
be O
expressed O
as O
C O
/ O
100 O
, O
000 O
= O
1 O
. O
679 O
- O
0 O
. O
205 O
Ni B
+ O
0 O
. O
413 O
Co B
+ O
0 O
. O
006 O
Se B
( O
with O
R O
( O
2 O
) O
= O
0 O
. O
402 O
and O
p O
< O
0 O
. O
01 O
) O
, O
C O
/ O
65 O
+ O
can O
be O
expressed O
as O
C O
/ O
65 O
+ O
= O
3 O
. O
425 O
- O
0 O
. O
262 O
Ni B
+ O
0 O
. O
435 O
Co B
+ O
0 O
. O
006 O
Se B
( O
with O
R O
( O
2 O
) O
= O
0 O
. O
369 O
and O
p O
< O
0 O
. O
01 O
) O
. O

Glomerular O
Filtration O
Rate O
Equations O
Overestimate O
Creatinine B
Clearance O
in O
Older O
Individuals O
Enrolled O
in O
the O
Baltimore O
Longitudinal O
Study O
on O
Aging O
: O
Impact O
on O
Renal O
Drug O
Dosing O
. O

OBJECTIVES O
: O
To O
evaluate O
the O
performance O
of O
kidney O
function O
estimation O
equations O
and O
to O
determine O
the O
frequency O
of O
drug O
dose O
discordance O
in O
an O
older O
population O
. O

DESIGN O
: O
Cross O
- O
sectional O
analysis O
of O
data O
from O
community O
- O
dwelling O
volunteers O
randomly O
selected O
from O
the O
Baltimore O
Longitudinal O
Study O
of O
Aging O
from O
January O
1 O
, O
2005 O
, O
to O
December O
31 O
, O
2010 O
. O

SUBJECTS O
: O
A O
total O
of O
269 O
men O
and O
women O
with O
a O
mean O
+ O
/ O
- O
SD O
age O
of O
81 O
+ O
/ O
- O
6 O
years O
, O
mean O
serum O
creatinine B
concentration O
( O
Scr O
) O
of O
1 O
. O
1 O
+ O
/ O
- O
0 O
. O
4 O
mg O
/ O
dl O
, O
and O
mean O
24 O
- O
hour O
measured O
creatinine B
clearance O
( O
mClcr O
) O
of O
53 O
+ O
/ O
- O
13 O
ml O
/ O
minute O
. O

MEASUREMENTS O
AND O
MAIN O
RESULTS O
: O
Kidney O
function O
was O
estimated O
by O
using O
the O
following O
equations O
: O
Cockcroft O
- O
Gault O
( O
CG O
) O
, O
Modification O
of O
Diet O
in O
Renal O
Disease O
( O
MDRD O
) O
, O
and O
Chronic O
Kidney O
Disease O
Epidemiology O
Collaboration O
( O
CKD O
- O
EPI O
) O
. O

The O
performance O
of O
each O
equation O
was O
assessed O
by O
measuring O
bias O
and O
precision O
relative O
to O
mClcr O
. O

Dose O
calculation O
errors O
( O
discordance O
) O
were O
determined O
for O
10 O
drugs O
requiring O
renal O
dosage O
adjustments O
to O
avoid O
toxicity O
when O
compared O
with O
the O
dosages O
approved O
by O
the O
Food O
and O
Drug O
Administration O
. O

The O
CG O
equation O
was O
the O
least O
biased O
estimate O
of O
mClcr O
. O

The O
MDRD O
and O
CKD O
- O
EPI O
equations O
were O
significantly O
positively O
biased O
compared O
with O
CG O
( O
mean O
+ O
/ O
- O
SD O
34 O
+ O
/ O
- O
20 O
% O
and O
22 O
+ O
/ O
- O
15 O
% O
, O
respectively O
, O
p O
< O
0 O
. O
001 O
) O
and O
mClcr O
( O
29 O
+ O
/ O
- O
47 O
% O
and O
18 O
+ O
/ O
- O
40 O
% O
, O
respectively O
, O
p O
< O
0 O
. O
001 O
) O
. O

Rounding O
low O
Scr O
values O
( O
less O
than O
1 O
. O
0 O
mg O
/ O
dl O
) O
up O
to O
an O
arbitrary O
value O
of O
1 O
. O
0 O
mg O
/ O
dl O
resulted O
in O
CG O
values O
( O
44 O
+ O
/ O
- O
10 O
ml O
/ O
minute O
) O
that O
were O
significantly O
lower O
than O
mClcr O
( O
56 O
+ O
/ O
- O
12 O
ml O
/ O
minute O
, O
p O
< O
0 O
. O
001 O
) O
and O
CG O
( O
56 O
+ O
/ O
- O
15 O
ml O
/ O
minute O
, O
p O
< O
0 O
. O
001 O
) O
. O

The O
MDRD O
and O
CKD O
- O
EPI O
equations O
had O
median O
dose O
discordance O
rates O
of O
28 O
. O
6 O
% O
and O
22 O
. O
9 O
% O
, O
respectively O
. O

CONCLUSION O
: O
The O
MDRD O
and O
CKD O
- O
EPI O
equations O
significantly O
overestimated O
creatinine B
clearance O
( O
mClcr O
and O
CG O
) O
in O
elderly O
individuals O
. O

This O
leads O
to O
dose O
calculation O
errors O
for O
many O
drugs O
, O
particularly O
in O
individuals O
with O
severe O
renal O
impairment O
. O

Thus O
equations O
estimating O
glomerular O
filtration O
rate O
should O
not O
be O
substituted O
in O
place O
of O
the O
CG O
equation O
in O
older O
adults O
for O
the O
purpose O
of O
renal O
dosage O
adjustments O
. O

In O
addition O
, O
the O
common O
practice O
of O
rounding O
or O
replacing O
low O
Scr O
values O
with O
an O
arbitrary O
value O
of O
1 O
. O
0 O
mg O
/ O
dl O
for O
use O
in O
the O
CG O
equation O
should O
be O
avoided O
. O

Additional O
studies O
that O
evaluate O
alternative O
eGFR O
equations O
in O
the O
older O
populations O
that O
incorporate O
pharmacokinetic O
and O
pharmacodynamic O
outcomes O
measures O
are O
needed O
. O

Multiple O
Site O
- O
Selective O
Insertions O
of O
Noncanonical O
Amino B
Acids I
into O
Sequence O
- O
Repetitive O
Polypeptides O
. O

A O
simple O
and O
efficient O
method O
is O
described O
for O
the O
introduction O
of O
noncanonical O
amino B
acids I
at O
multiple O
, O
defined O
sites O
within O
recombinant O
polypeptide O
sequences O
. O

Escherichia O
coli O
MRA30 O
, O
a O
bacterial O
host O
strain O
with O
attenuated O
activity O
of O
release O
factor O
1 O
( O
RF1 O
) O
, O
was O
assessed O
for O
its O
ability O
to O
support O
incorporation O
of O
a O
diverse O
range O
of O
noncanonical O
amino B
acids I
in O
response O
to O
multiple O
encoded O
amber O
( O
TAG O
) O
codons O
within O
genes O
derived O
from O
superfolder O
GFP O
and O
an O
elastin O
- O
mimetic O
protein O
polymer O
. O

Suppression O
efficiency O
and O
protein O
yield O
depended O
on O
the O
identity O
of O
the O
orthogonal O
aminoacyl O
- O
tRNA O
synthetase O
/ O
tRNA O
( O
CUA O
) O
pair O
and O
the O
noncanonical O
amino B
acid I
. O

Elastin O
- O
mimetic O
protein O
polymers O
were O
prepared O
in O
which O
noncanonical O
amino B
acid I
derivatives O
were O
incorporated O
at O
up O
to O
22 O
specific O
sites O
within O
the O
polypeptide O
sequence O
with O
high O
substitution O
efficiency O
. O

The O
identities O
and O
positions O
of O
the O
variant O
residues O
were O
confirmed O
by O
mass O
spectrometric O
analysis O
of O
the O
full O
- O
length O
polypeptides O
and O
proteolytic O
cleavage O
fragments O
from O
thermolysin O
digestion O
. O

The O
data O
suggest O
that O
this O
multisite O
suppression O
approach O
permits O
the O
preparation O
of O
protein O
- O
based O
materials O
in O
which O
novel O
chemical O
functionalities O
can O
be O
introduced O
at O
precisely O
defined O
positions O
within O
the O
polypeptide O
sequence O
. O

Studying O
the O
effect O
of O
antioxidants O
on O
cytogenetic O
manifestations O
of O
solvent O
exposure O
in O
paint O
industry O
. O

OBJECTIVE O
: O
To O
investigate O
the O
antioxidant O
role O
in O
reversing O
cytogenetic O
changes O
caused O
by O
solvent O
exposure O
in O
paint O
industry O
. O
Subjects O
and O
METHODS O
: O
A O
prospective O
controlled O
clinical O
trial O
was O
performed O
on O
39 O
workers O
exposed O
to O
solvents O
and O
39 O
workers O
not O
exposed O
to O
solvents O
by O
supplying O
a O
mixture O
of O
antioxidant O
vitamins B
( I
A I
, I
C I
, I
E I
and O
selenium B
) O
and O
the O
after O
effects O
of O
such O
regimen O
were O
analyzed O
. O

Environmental O
monitoring O
was O
carried O
out O
for O
air O
concentrations O
of O
different O
solvents O
at O
workplace O
. O

Exposed O
group O
was O
cytogenetically O
tested O
before O
and O
after O
giving O
the O
mixture O
of O
antioxidant O
vitamins O
for O
1 O
month O
duration O
. O

RESULTS O
: O
Frequency O
of O
chromosomal O
aberrations O
( O
CAs O
) O
and O
the O
mean O
of O
sister O
chromatid O
exchanges O
( O
SCEs O
) O
were O
statistically O
significantly O
higher O
among O
exposed O
workers O
than O
among O
controls O
. O

After O
the O
supplementation O
of O
antioxidants O
, O
there O
was O
a O
statistically O
significant O
decrease O
in O
the O
frequency O
of O
CAs O
, O
and O
88 O
% O
abnormal O
levels O
of O
SCEs O
were O
back O
to O
normal O
levels O
. O

CONCLUSION O
: O
Antioxidant O
supplementation O
decreases O
the O
frequency O
of O
CAs O
and O
SCEs O
among O
exposed O
workers O
. O

Pirimicarb B
- O
based O
formulation O
- O
induced O
genotoxicity O
and O
cytotoxicity O
in O
the O
fresh O
water O
fish O
Cnesterodon O
decemmaculatus O
( O
Jenyns O
, O
1842 O
) O
( O
Pisces O
, O
Poeciliidae O
) O
. O

We O
analyzed O
the O
aspects O
of O
lethality O
, O
genotoxicity O
, O
and O
cytotoxicity O
in O
the O
ten O
spotted O
live O
- O
bearer O
exposed O
under O
laboratory O
conditions O
to O
the O
pirimicarb B
- O
based O
formulation O
Patton O
Flow O
( O
( O
R O
) O
) O
( O
50 O
% O
active O
ingredient O
( O
a O
. O
i O
. O
) O
) O
. O

Acute O
effects O
were O
evaluated O
using O
different O
end O
points O
for O
lethality O
, O
genotoxicity O
, O
and O
cytotoxicity O
. O

Median O
lethal O
concentration O
( O
LC50 O
) O
estimation O
was O
employed O
as O
a O
bioassay O
for O
lethality O
, O
whereas O
micronucleus O
( O
MN O
) O
induction O
and O
alterations O
in O
erythrocyte O
/ O
erythroblast O
frequency O
were O
used O
as O
end O
points O
for O
genotoxicity O
and O
cytotoxicity O
, O
respectively O
. O

Results O
demonstrated O
an O
LC5096h O
value O
of O
88 O
mg O
/ O
L O
. O

Patton O
Flow O
( O
( O
R O
) O
) O
increased O
the O
MN O
frequency O
in O
fish O
erythrocytes O
after O
48 O
h O
of O
exposure O
at O
a O
concentration O
of O
66 O
mg O
/ O
L O
, O
whereas O
a O
concentration O
range O
of O
22 O
- O
66 O
mg O
/ O
L O
was O
able O
to O
exert O
the O
same O
genotoxic O
effect O
at O
96 O
h O
of O
treatment O
. O

Furthermore O
, O
cytotoxicity O
was O
also O
observed O
by O
alterations O
in O
erythrocyte O
/ O
erythroblast O
frequencies O
within O
the O
concentration O
range O
of O
22 O
- O
66 O
mg O
/ O
L O
, O
regardless O
of O
the O
exposure O
time O
. O

Our O
current O
observations O
provide O
evidence O
that O
Patton O
Flow O
( O
( O
R O
) O
) O
( O
50 O
% O
a O
. O
i O
. O
) O
should O
be O
considered O
a O
clear O
lethal O
, O
cytotoxic O
, O
and O
genotoxic O
agent O
on O
Cnesterodon O
decemmaculatus O
. O

Thus O
, O
repeated O
applications O
of O
this O
carbamic B
insecticide O
can O
enter O
the O
aquatic O
environment O
and O
exert O
deleterious O
effects O
on O
aquatic O
organisms O
other O
than O
the O
evaluated O
species O
C O
. O
decemmaculatus O
. O

1 B
, I
1 I
- I
Diphenyl I
, I
2 I
- I
picrylhydrazyl I
free O
radical O
scavenging O
, O
bactericidal O
, O
fungicidal O
and O
leishmanicidal O
properties O
of O
Teucrium O
stocksianum O
. O

In O
the O
present O
study O
, O
we O
evaluated O
the O
pharmacological O
and O
toxicological O
effects O
of O
Teucrium O
stocksianum O
. O

The O
crude O
extract O
of O
T O
. O
stocksianum O
( O
Ts O
. O
Cr O
) O
and O
its O
subsequent O
organic O
fractions O
: O
n B
- I
hexane I
( O
Ts O
. O
Hex B
) O
, O
chloroform B
( O
Ts O
. O
CHCl3 B
) O
and O
ethyl B
acetate I
( O
Ts O
. O
EtAc B
) O
exhibited O
1 B
, I
1 I
- I
diphenyl I
, I
2 I
- I
picrylhydrazyl I
free O
radical O
scavenging O
activity O
with O
different O
potencies O
. O

Ts O
. O
EtAc B
was O
found O
to O
be O
most O
potent O
. O

Ts O
. O
Cr O
, O
Ts O
. O
Hex B
, O
Ts O
. O
CHCl3 B
and O
Ts O
. O
EtAc B
showed O
significant O
bactericidal O
activity O
against O
Escherichia O
coli O
, O
Staphylococcus O
aureus O
, O
Salmonella O
typhi O
, O
Shigella O
flexneri O
and O
Bacillus O
subtilis O
at O
their O
extent O
. O

Ts O
. O
Cr O
, O
Ts O
. O
Hex B
, O
Ts O
. O
CHCl3 B
and O
Ts O
. O
EtAc B
displayed O
fungicidal O
action O
against O
Aspergillus O
niger O
, O
Aspergillus O
flavus O
, O
Aspergillus O
fumigatus O
and O
Fusarium O
solani O
at O
various O
minimum O
inhibitory O
concentrations O
. O

Ts O
. O
Cr O
and O
Ts O
. O
EtAc O
exhibited O
marked O
inhibition O
of O
Leishmania O
tropica O
growth O
, O
observed O
after O
48 O
and O
96 O
hrs O
of O
treatment O
. O

These O
data O
indicate O
that O
the O
T O
. O
stocksianum O
methanolic O
extract O
and O
its O
resultant O
fractions O
possess O
antioxidant O
, O
antibacterial O
, O
antifungal O
and O
antileishmanial O
activities O
. O

Thus O
, O
the O
present O
research O
unearths O
the O
scientific O
base O
for O
T O
. O
stocksianum O
medicinal O
application O
as O
antioxidant O
and O
antimicrobial O
agents O
. O

Effect O
of O
paraoxonase O
1 O
192 O
Q O
/ O
R O
polymorphism O
on O
paraoxonase O
and O
acetylcholinesterase O
enzyme O
activities O
in O
Turkish O
population O
exposed O
to O
organophosphate B
. O

Organophosphate B
( O
OP O
) O
compounds O
are O
the O
most O
commonly O
used O
pesticide O
groups O
and O
they O
are O
commercially O
used O
in O
the O
market O
for O
local O
and O
industrial O
purposes O
. O

Paraoxonase O
1 O
( O
PON1 O
) O
enzyme O
plays O
an O
important O
role O
in O
biotransformation O
of O
OP O
compounds O
, O
which O
shows O
toxic O
effects O
via O
inhibiting O
the O
acetylcholinesterase O
( O
AChE O
) O
. O

The O
aim O
of O
this O
study O
was O
to O
determine O
the O
effects O
of O
PON1 O
gene O
polymorphism O
and O
its O
effects O
on O
PON O
and O
AChE O
enzyme O
activities O
in O
individuals O
who O
were O
exposed O
to O
organophosphorus B
insecticides O
due O
to O
occupational O
reasons O
, O
and O
to O
profile O
the O
probability O
of O
susceptibility O
to O
organophosphorus B
compounds O
. O

For O
this O
purpose O
, O
54 O
individuals O
who O
were O
exposed O
to O
OPs O
and O
54 O
healthy O
unrelated O
controls O
were O
studied O
. O

First O
, O
PON1 O
and O
AChE O
enzyme O
activities O
were O
measured O
. O

Second O
, O
PON1 O
192 O
Q O
/ O
R O
polymorphism O
was O
determined O
by O
standard O
polymerase O
chain O
reaction O
- O
restriction O
fragment O
length O
polymorphism O
technique O
. O

When O
the O
PON1 O
192 O
Q O
/ O
R O
polymorphism O
was O
compared O
with O
PON1 O
enzyme O
activities O
, O
statistically O
significant O
association O
was O
found O
in O
both O
OP O
- O
exposed O
and O
control O
groups O
( O
p O
< O
0 O
. O
05 O
) O
. O

PON1 O
192 O
R O
( O
+ O
) O
( O
QR O
+ O
RR O
genotypes O
) O
genotype O
carriers O
had O
higher O
PON1 O
activities O
than O
192 O
R O
( O
- O
) O
( O
QQ O
) O
genotype O
carriers O
. O

On O
the O
other O
hand O
, O
results O
were O
statistically O
analyzed O
in O
terms O
of O
AChE O
enzyme O
activities O
and O
there O
were O
statistically O
significant O
differences O
only O
in O
the O
OP O
- O
exposed O
group O
( O
p O
< O
0 O
. O
05 O
) O
. O

The O
mean O
AChE O
concentration O
in O
the O
OP O
- O
exposed O
group O
was O
determined O
as O
33 O
. O
79 O
+ O
/ O
- O
6 O
. O
84 O
U O
/ O
g O
haemoglobin O
( O
Hb O
) O
for O
PON1 O
192 O
R O
( O
+ O
) O
carriers O
and O
30 O
. O
37 O
+ O
/ O
- O
7 O
. O
62 O
U O
/ O
g O
Hb O
for O
PON1 O
192 O
R O
( O
+ O
) O
carriers O
. O

As O
a O
conclusion O
, O
PON1 O
and O
AChE O
activities O
were O
increasing O
according O
to O
the O
genotypes O
found O
in O
individuals O
having O
been O
exposed O
to O
OPs O
at O
a O
chronic O
level O
; O
192 O
R O
( O
+ O
) O
> O
192 O
R O
( O
- O
) O
, O
respectively O
. O

Structural O
Determinants O
of O
Agonist O
Efficacy O
at O
the O
Glutamate B
Binding O
Site O
of O
NMDA B
Receptors O
. O

NMDA B
receptors O
are O
ligand O
- O
gated O
ion O
channels O
assembled O
from O
GluN1 O
and O
GluN2 O
subunits O
. O

We O
utilized O
a O
series O
of O
N B
- I
hydroxypyrazole I
- I
5 I
- I
glycine I
( O
NHP5G B
) O
partial O
agonists O
at O
the O
GluN2 O
glutamate B
binding O
site O
as O
tools O
to O
study O
activation O
of O
GluN1 O
/ O
GluN2A O
and O
GluN1 O
/ O
GluN2D O
NMDA B
receptor O
subtypes O
. O

We O
show O
using O
two O
- O
electrode O
voltage O
- O
clamp O
electrophysiology O
, O
fast O
- O
application O
patch O
- O
clamp O
, O
and O
single O
channel O
recordings O
that O
propyl B
- O
and O
ethyl B
- O
substituted O
NHP5G O
agonists O
have O
a O
broad O
range O
of O
agonist O
efficacies O
relative O
to O
the O
full O
agonist O
glutamate B
( O
< O
1 O
% O
- O
72 O
% O
) O
. O

Crystal O
structures O
of O
the O
agonist O
binding O
domains O
( O
ABDs O
) O
of O
GluN2A O
and O
GluN2D O
do O
not O
reveal O
any O
differences O
in O
the O
overall O
domain O
conformation O
induced O
by O
binding O
of O
the O
full O
agonist O
glutamate B
or O
the O
partial O
agonist O
propyl B
- I
NHP5G I
, O
which O
is O
strikingly O
different O
from O
ABD O
structures O
of O
AMPA B
and O
kainate B
receptors O
bound O
to O
full O
and O
partial O
agonists O
. O

Subsequent O
evaluation O
of O
relative O
NHP5G O
agonist O
efficacy O
at O
GluN2A O
- O
GluN2D O
chimeric O
subunits O
implicates O
the O
amino B
- O
terminal O
domain O
( O
ATD O
) O
as O
a O
strong O
determinant O
of O
agonist O
efficacy O
, O
suggesting O
that O
interdomain O
interactions O
between O
the O
ABD O
and O
the O
ATD O
may O
be O
a O
central O
element O
in O
controlling O
the O
manner O
by O
which O
agonist O
binding O
leads O
to O
channel O
opening O
. O

We O
propose O
that O
variation O
in O
the O
overall O
receptor O
conformation O
, O
which O
is O
strongly O
influenced O
by O
the O
nature O
of O
interdomain O
interactions O
in O
resting O
and O
active O
states O
, O
mediates O
differences O
in O
agonist O
efficacy O
and O
partial O
agonism O
at O
the O
GluN2 O
subunits O
. O

Microfluidic O
affinity O
and O
ChIP O
- O
seq O
analyses O
converge O
on O
a O
conserved O
FOXP2 O
- O
binding O
motif O
in O
chimp O
and O
human O
, O
which O
enables O
the O
detection O
of O
evolutionarily O
novel O
targets O
. O

The O
transcription O
factor O
forkhead O
box O
P2 O
( O
FOXP2 O
) O
is O
believed O
to O
be O
important O
in O
the O
evolution O
of O
human O
speech O
. O

A O
mutation O
in O
its O
DNA O
- O
binding O
domain O
causes O
severe O
speech O
impairment O
. O

Humans O
have O
acquired O
two O
coding O
changes O
relative O
to O
the O
conserved O
mammalian O
sequence O
. O

Despite O
intense O
interest O
in O
FOXP2 O
, O
it O
has O
remained O
an O
open O
question O
whether O
the O
human O
protein O
' O
s O
DNA O
- O
binding O
specificity O
and O
chromatin O
localization O
are O
conserved O
. O

Previous O
in O
vitro O
and O
ChIP O
- O
chip O
studies O
have O
provided O
conflicting O
consensus O
sequences O
for O
the O
FOXP2 O
- O
binding O
site O
. O

Using O
MITOMI O
2 O
. O
0 O
microfluidic O
affinity O
assays O
, O
we O
describe O
the O
binding O
site O
of O
FOXP2 O
and O
its O
affinity O
profile O
in O
base O
- O
specific O
detail O
for O
all O
substitutions O
of O
the O
strongest O
binding O
site O
. O

We O
find O
that O
human O
and O
chimp O
FOXP2 O
have O
similar O
binding O
sites O
that O
are O
distinct O
from O
previously O
suggested O
consensus O
binding O
sites O
. O

Additionally O
, O
through O
analysis O
of O
FOXP2 O
ChIP O
- O
seq O
data O
from O
cultured O
neurons O
, O
we O
find O
strong O
overrepresentation O
of O
a O
motif O
that O
matches O
our O
in O
vitro O
results O
and O
identifies O
a O
set O
of O
genes O
with O
FOXP2 O
binding O
sites O
. O

The O
FOXP2 O
- O
binding O
sites O
tend O
to O
be O
conserved O
, O
yet O
we O
identified O
38 O
instances O
of O
evolutionarily O
novel O
sites O
in O
humans O
. O

Combined O
, O
these O
data O
present O
a O
comprehensive O
portrait O
of O
FOXP2 O
' O
s O
- O
binding O
properties O
and O
imply O
that O
although O
its O
sequence O
specificity O
has O
been O
conserved O
, O
some O
of O
its O
genomic O
binding O
sites O
are O
newly O
evolved O
. O

Self O
- O
Assembly O
and O
Near O
Perfect O
Macroscopic O
Alignment O
of O
Fluorescent O
Triangulenium B
Salt O
in O
Spin O
Cast O
Thin O
Films O
on O
PTFE B
. O

Highly O
fluorescent O
, O
discotic O
trioxatriangulenium B
dyes O
were O
aligned O
by O
simple O
spin O
casting O
on O
substrates O
with O
friction O
transferred O
PTFE B
layers O
. O

The O
fluorescent O
crystalline O
thin O
films O
show O
near O
perfect O
macroscopic O
alignment O
on O
centimeter O
large O
areas O
directly O
from O
spin O
casting O
. O

Gracing O
Incidence O
X O
- O
ray O
Diffraction O
( O
GIXD O
) O
unambiguously O
allowed O
to O
determine O
a O
long O
range O
order O
unit O
cell O
as O
well O
as O
its O
orientation O
with O
respect O
to O
the O
PTFE B
fibers O
. O

Further O
analysis O
of O
the O
X O
- O
ray O
data O
, O
in O
conjunction O
with O
polarized O
absorption O
spectroscopy O
, O
suggest O
a O
lamellar O
packing O
model O
with O
alternating O
layers O
of O
alkyl O
chains O
and O
ionic O
dyes O
oriented O
parallel O
to O
the O
substrate O
. O

This O
structure O
results O
in O
a O
highly O
anisotropic O
electrostatic O
potential O
around O
the O
cationic O
chromophore O
, O
causing O
significant O
shifts O
in O
energy O
and O
orientation O
of O
the O
optical O
transitions O
. O

Thus O
, O
the O
optical O
properties O
of O
the O
material O
are O
, O
to O
a O
large O
extent O
, O
controlled O
by O
the O
position O
of O
the O
otherwise O
inert O
PF6 B
- I
counter O
ions O
. O

The O
bright O
fluorescence O
from O
the O
films O
is O
also O
polarized O
parallel O
to O
the O
PTFE B
alignment O
layer O
. O

Doping O
of O
the O
thin O
films O
with O
fluorescent O
energy O
acceptor O
traps O
shows O
that O
efficient O
exciton O
migration O
takes O
place O
in O
the O
thin O
films O
. O

The O
excellent O
exciton O
transfer O
capabilities O
, O
in O
conjunction O
with O
the O
perfect O
alignment O
, O
might O
be O
of O
interest O
in O
future O
applications O
in O
solar O
energy O
harvesting O
or O
as O
thin O
film O
sensors O
. O

How O
Selective O
Are O
the O
New O
Guidelines O
for O
Treatment O
of O
Subclinical O
Hypothyroidism O
for O
Patients O
with O
Thyrotropin O
Levels O
At O
or O
Below O
10 O
mIU O
/ O
L O
? O

Background O
: O
By O
consensus O
, O
a O
thyrotropin O
( O
TSH O
) O
level O
persistently O
> O
10 O
mIU O
/ O
L O
is O
an O
indication O
for O
the O
treatment O
of O
subclinical O
hypothyroidism O
( O
SCH O
) O
. O

Controversy O
exists O
regarding O
patients O
whose O
TSH O
level O
is O
elevated O
but O
< O
10 O
mIU O
/ O
L O
. O

Recently O
, O
the O
American O
Thyroid O
Association O
( O
ATA O
) O
and O
the O
American O
Association O
of O
Clinical O
Endocrinologists O
( O
AACE O
) O
published O
their O
position O
about O
factors O
that O
should O
be O
considered O
in O
the O
decision O
on O
treating O
SCH O
. O

This O
study O
evaluated O
the O
frequency O
of O
these O
factors O
among O
adult O
( O
non O
- O
pregnant O
) O
women O
with O
SCH O
whose O
TSH O
levels O
are O
< O
= O
10 O
mIU O
/ O
L O
. O

Methods O
: O
The O
presence O
of O
the O
conditions O
that O
should O
be O
considered O
for O
the O
treatment O
of O
SCH O
according O
to O
ATA O
and O
AACE O
was O
evaluated O
in O
252 O
women O
who O
were O
diagnosed O
with O
SCH O
and O
had O
TSH O
levels O
< O
= O
10 O
mIU O
/ O
L O
. O

Pregnant O
women O
were O
excluded O
. O

Results O
: O
Antithyroperoxidase O
antibodies O
( O
TPOAbs O
) O
were O
detected O
in O
137 O
( O
54 O
. O
3 O
% O
) O
women O
. O

A O
high O
cardiovascular O
risk O
was O
observed O
in O
43 O
( O
17 O
% O
) O
women O
. O

Eighty O
( O
31 O
. O
7 O
% O
) O
women O
who O
were O
not O
at O
high O
cardiovascular O
risk O
presented O
at O
least O
one O
classical O
risk O
factor O
( O
arterial O
hypertension O
, O
elevated O
level O
of O
low O
- O
density O
lipoprotein O
- O
cholesterol B
or O
low O
level O
of O
high O
- O
density O
lipoprotein O
- O
cholesterol B
, O
smoking O
, O
or O
first O
- O
degree O
family O
history O
of O
premature O
coronary O
artery O
disease O
) O
. O

At O
least O
one O
symptom O
or O
sign O
of O
hypothyroidism O
that O
could O
not O
be O
explained O
by O
another O
condition O
was O
observed O
in O
180 O
( O
71 O
. O
4 O
% O
) O
women O
. O

Two O
hundred O
thirty O
- O
two O
( O
92 O
% O
) O
women O
had O
positive O
TPOAbs O
, O
or O
at O
least O
one O
classical O
cardiovascular O
risk O
factor O
, O
or O
at O
least O
one O
symptom O
or O
sign O
of O
hypothyroidism O
. O

Conclusions O
: O
According O
to O
the O
new O
ATA O
and O
AACE O
guidelines O
, O
L B
- I
T4 I
therapy O
would O
be O
considered O
for O
92 O
% O
of O
women O
with O
SCH O
and O
TSH O
< O
= O
10 O
mIU O
/ O
L O
. O

NMDA B
receptors O
and O
memory O
encoding O
. O

It O
is O
humbling O
to O
think O
that O
30 O
years O
have O
passed O
since O
the O
paper O
by O
Collingridge O
, O
Kehl O
and O
McLennan O
showing O
that O
one O
of O
Jeff O
Watkins O
most O
interesting O
compounds O
, O
R B
- I
2 I
- I
amino I
- I
5 I
- I
phosphonopentanoate I
( O
d B
- I
AP5 I
) O
, O
blocked O
the O
induction O
of O
long O
- O
term O
potentiation O
in O
vitro O
at O
synapses O
from O
area O
CA3 O
of O
the O
hippocampus O
to O
CA1 O
without O
apparent O
effect O
on O
baseline O
synaptic O
transmission O
( O
Collingridge O
et O
al O
. O
, O
1983 O
) O
. O

This O
dissociation O
was O
one O
of O
the O
key O
triggers O
for O
an O
explosion O
of O
interest O
in O
glutamate B
receptors O
, O
and O
much O
has O
been O
discovered O
since O
that O
collectively O
contributes O
to O
our O
contemporary O
understanding O
of O
glutamatergic O
synapses O
- O
their O
biophysics O
and O
subunit O
composition O
, O
of O
the O
agonists O
and O
antagonists O
acting O
on O
them O
, O
and O
their O
diverse O
functions O
in O
different O
networks O
of O
the O
brain O
and O
spinal O
cord O
. O

It O
can O
be O
fairly O
said O
that O
Collingridge O
et O
al O
. O
' O
s O
( O
1983 O
) O
observation O
was O
the O
stimulus O
that O
has O
led O
, O
on O
the O
one O
hand O
, O
to O
structural O
biological O
work O
at O
the O
atomic O
scale O
describing O
the O
key O
features O
of O
NMDA B
receptors O
that O
enables O
their O
coincidence O
function O
to O
happen O
; O
and O
, O
on O
the O
other O
, O
to O
work O
with O
whole O
animals O
investigating O
the O
contributions O
that O
calcium B
signalling O
via O
this O
receptor O
can O
have O
on O
rhythmical O
activities O
controlled O
by O
spinal O
circuits O
, O
memory O
encoding O
in O
the O
hippocampus O
( O
the O
topic O
of O
this O
article O
) O
, O
visual O
cortical O
plasticity O
, O
sensitization O
in O
pain O
, O
and O
other O
functions O
. O

In O
this O
article O
, O
I O
lay O
out O
how O
my O
then O
interest O
in O
long O
- O
term O
potentiation O
( O
LTP O
) O
as O
a O
model O
of O
memory O
enabled O
me O
to O
recognise O
the O
importance O
of O
Collingridge O
et O
al O
. O
' O
s O
discovery O
- O
and O
how O
I O
and O
my O
colleagues O
endeavoured O
to O
take O
things O
forward O
in O
the O
area O
of O
learning O
and O
memory O
. O

This O
is O
in O
some O
respects O
a O
personal O
story O
, O
and O
I O
tell O
it O
as O
such O
. O

The O
idea O
that O
NMDA B
receptor O
activation O
is O
essential O
for O
memory O
encoding O
, O
though O
not O
for O
storage O
, O
took O
time O
to O
develop O
and O
to O
be O
accepted O
. O

Along O
the O
way O
, O
there O
have O
been O
confusions O
, O
challenges O
, O
and O
surprises O
surrounding O
the O
idea O
that O
activation O
of O
NMDA B
receptors O
can O
trigger O
memory O
. O

Some O
of O
these O
are O
described O
and O
how O
they O
have O
been O
addressed O
and O
resolved O
. O

Last O
, O
I O
touch O
on O
some O
new O
directions O
of O
interest O
with O
respect O
to O
the O
functional O
role O
of O
the O
NMDA B
receptor O
in O
cognition O
. O

This O
article O
is O
part O
of O
a O
Special O
Issue O
entitled O
' O
GluR O
- O
dep O
synaptic O
plasticity O
' O
. O

Scientific O
evidence O
for O
traditional O
claim O
of O
antiobesity O
activity O
of O
Tecomella O
undulata O
bark O
. O

ETHNOPHARMACOLOGICAL O
RELEVANCE O
: O
The O
bark O
of O
Tecomella O
undulata O
is O
traditionally O
claimed O
in O
the O
treatment O
of O
various O
disease O
ailments O
including O
obesity O
and O
cancer O
. O

Till O
now O
there O
are O
no O
studies O
about O
anti O
obesity O
activity O
of O
Tecomella O
undulata O
bark O
. O

AIM O
OF O
THE O
STUDY O
: O
The O
present O
study O
was O
aimed O
to O
establish O
a O
scientific O
evidence O
for O
anti O
obesity O
efficiency O
of O
ethyl B
acetate I
extract O
of O
Tecomella O
undulata O
bark O
( O
EATUB O
) O
. O

Further O
to O
standardize O
the O
active O
fractions O
of O
EATUB O
using O
different O
biomarkers O
. O

MATERIALS O
AND O
METHODS O
: O
We O
investigated O
activity O
of O
EATUB O
fractions O
( O
F1 O
- O
F7 O
) O
using O
3T3 O
- O
L1 O
fibroblasts O
. O

Further O
, O
F1 O
- O
mediated O
effects O
were O
characterized O
by O
determining O
mRNA O
and O
protein O
levels O
of O
SIRT1 O
, O
one O
of O
the O
key O
targets O
for O
the O
treatment O
of O
obesity O
, O
using O
semi O
quantitative O
RT O
- O
PCR O
( O
sqRT O
- O
PCR O
) O
and O
western O
blot O
analysis O
. O

The O
consequences O
of O
modulation O
of O
SIRT1 O
on O
mRNA O
and O
protein O
levels O
of O
various O
adipogenesis O
mediators O
like O
PPAR O
gamma O
, O
C O
/ O
EBP O
alpha O
, O
E2F1 O
, O
leptin O
, O
adiponectin O
and O
LPL O
were O
also O
studied O
. O

In O
- O
vivo O
studies O
were O
performed O
using O
High O
Fat O
Diet O
( O
HFD O
) O
obese O
mice O
. O

RESULTS O
: O
Our O
data O
showed O
that O
compared O
to O
controls O
, O
preadipocytes O
and O
adipocytes O
incubated O
with O
F1 O
exhibited O
a O
significant O
decrease O
in O
adipogenesis O
and O
lipogenesis O
. O

In O
addition O
, O
sqRT O
- O
PCR O
and O
western O
blot O
analysis O
showed O
significant O
increase O
in O
SIRT1 O
and O
adiponectin O
levels O
and O
decrease O
in O
PPAR O
gamma O
, O
C O
/ O
EBP O
alpha O
, O
E2F1 O
, O
leptin O
and O
LPL O
levels O
in O
preadipocytes O
and O
adipocytes O
. O

In O
- O
vivo O
studies O
of O
F1 O
in O
HFD O
induced O
obese O
mice O
showed O
significant O
improvement O
in O
lipid O
profile O
and O
glucose B
levels O
. O

The O
bioactive O
fraction O
( O
F1 O
) O
was O
determined O
to O
possess O
4 O
. O
95 O
% O
of O
ferulic B
acid I
. O

CONCLUSION O
: O
Thus O
, O
our O
findings O
signified O
the O
beneficial O
effects O
of O
Tecomella O
undulata O
bark O
in O
pharmacologic O
interventions O
related O
to O
obesity O
and O
metabolic O
disorders O
. O

Ferulic B
acid I
and O
rutin B
are O
being O
reported O
and O
quantified O
for O
the O
first O
time O
from O
the O
bark O
of O
Tecomella O
undulata O
. O

Cytotoxic O
effects O
of O
amphetamine B
mixtures O
in O
primary O
hepatocytes O
are O
severely O
aggravated O
under O
hyperthermic O
conditions O
. O

Amphetamine B
consumers O
are O
often O
, O
deliberately O
or O
not O
, O
polydrug O
abusers O
. O

Predicting O
combination O
effects O
based O
on O
concentration O
- O
response O
analysis O
of O
individual O
components O
is O
a O
valid O
strategy O
for O
accurate O
toxicological O
assessment O
of O
mixtures O
. O

We O
previously O
reported O
that O
joint O
effects O
of O
3 B
, I
4 I
- I
methylenedioxymetham I
( O
MDMA B
, O
ecstasy B
) O
and O
three O
other O
often O
co O
- O
ingested O
amphetamines B
( O
methamphetamine B
, O
4 B
- I
methylthyoamphetamin I
and O
D B
- I
amphetamine I
) O
could O
be O
predicted O
by O
the O
concentration O
addition O
( O
CA O
) O
model O
in O
HepG2 O
cells O
. O

We O
sought O
to O
further O
evaluate O
the O
relevance O
of O
these O
findings O
by O
extending O
these O
studies O
to O
a O
cell O
model O
that O
more O
closely O
mimics O
the O
in O
vivo O
situation O
. O

Detailed O
cytotoxic O
information O
of O
the O
four O
individual O
amphetamines B
on O
primary O
rat O
hepatocytes O
was O
recorded O
by O
the O
MTT B
assay O
, O
at O
37 O
degrees O
C O
and O
40 O
. O
5 O
degrees O
C O
, O
simulating O
the O
rise O
in O
body O
temperature O
that O
could O
be O
induced O
following O
amphetamine B
intake O
. O

Mixture O
expectations O
were O
calculated O
using O
CA O
and O
independent O
action O
( O
IA O
) O
models O
. O

At O
37 O
degrees O
C O
, O
concentration O
- O
dependent O
cytotoxicity O
occurred O
for O
the O
drugs O
individually O
and O
combined O
. O

Mixture O
effects O
were O
accurately O
predicted O
by O
the O
CA O
model O
, O
while O
the O
IA O
model O
underestimated O
cytotoxicity O
. O

At O
40 O
. O
5 O
degrees O
C O
these O
cytotoxic O
effects O
were O
aggravated O
. O

Our O
findings O
provide O
evidence O
of O
the O
increased O
risks O
associated O
with O
the O
abuse O
of O
amphetamine B
mixtures O
, O
especially O
during O
hyperthermia O
, O
emphasising O
the O
need O
to O
increase O
awareness O
of O
misinformed O
users O
who O
believe O
these O
drugs O
are O
safe O
. O

Receiver O
Operating O
Characteristic O
Analysis O
of O
HLA O
, O
CTLA4 O
, O
and O
Insulin O
Genotypes O
for O
Type O
1 O
Diabetes O
. O

OBJECTIVEThis O
study O
assessed O
the O
ability O
to O
distinguish O
between O
type O
1 O
diabetes O
- O
affected O
individuals O
and O
their O
unaffected O
relatives O
using O
HLA O
and O
single O
nucleotide O
polymorphism O
( O
SNP O
) O
genotypes O
. O
RESEARCH O
DESIGN O
AND O
METHODSEight O
models O
, O
ranging O
from O
only O
the O
high O
- O
risk O
DR3 O
/ O
DR4 O
genotype O
to O
all O
significantly O
associated O
HLA O
genotypes O
and O
two O
SNPs O
mapping O
to O
the O
cytotoxic O
T O
- O
cell O
- O
associated O
antigen O
- O
4 O
gene O
( O
CTLA4 O
) O
and O
insulin O
( O
INS O
) O
genes O

, O
were O
fitted O
to O
high O
- O
resolution O
class O
I O
and O
class O
II O
HLA O
genotyping O
data O
for O
patients O
from O
the O
Type O
1 O
Diabetes O
Genetics O
Consortium O
collection O
. O

Pairs O
of O
affected O
individuals O
and O
their O
unaffected O
siblings O
were O
divided O
into O
a O
" O
discovery O
" O
( O
n O
= O
1 O
, O
015 O
pairs O
) O
and O
a O
" O
validation O
" O
set O
( O
n O
= O
318 O
pairs O
) O
. O

The O
discriminating O
performance O
of O
various O
combinations O
of O
genetic O
information O
was O
estimated O
using O
receiver O
operating O
characteristic O
( O
ROC O
) O
curve O
analysis O
. O
RESULTSThe O
use O
of O
only O
the O
presence O
or O
absence O
of O
the O
high O
- O
risk O
DR3 O
/ O
DR4 O
genotype O
achieved O
very O
modest O
discriminating O
ability O
, O
yielding O
an O
area O
under O
the O
curve O
( O
AUC O
) O
of O
0 O
. O
62 O
in O
the O
discovery O
set O
and O
0 O
. O
59 O
in O
the O
validation O
set O
. O

The O
full O
model O
, O
which O
included O
HLA O
information O
from O
the O
class O
II O
loci O
DPB1 O
, O
DRB1 O
, O
DQB1 O
, O
selected O
alleles O
from O
HLA O
class O
I O
loci O
A O
and O
B O
, O
and O
SNPs O
from O
the O
CTLA4 O
and O
INS O
genes O
, O
increased O
the O
AUC O
to O
0 O
. O
74 O
in O
the O
discovery O
set O
and O
to O
0 O
. O
71 O
in O
the O
validation O
set O
. O

A O
cost O
- O
effective O
alternative O
is O
proposed O
, O
using O
genotype O
information O
equivalent O
to O
typing O
four O
SNPs O
( O
DR3 O
, O
DR4 O
- O
DQB1 O
* O
03 O
: O
02 O
, O
CTLA O
- O
4 O
, O
and O
INS O
) O
, O
which O
achieved O
an O
AUC O
of O
0 O
. O
72 O
in O
the O
discovery O
set O
and O
0 O
. O
69 O
in O
the O
validation O
set O
. O
CONCLUSIONSGenotypin O
data O
sufficient O
to O
tag O
DR3 O
, O
DR4 O
- O
DQB1 O
* O
03 O
: O
02 O
, O
CTLA4 O
, O
and O
INS O
was O
shown O
to O
distinguish O
between O
subjects O
with O
type O
1 O
diabetes O
and O
their O
unaffected O
siblings O
adequately O
to O
achieve O
clinically O

utility O
to O
identify O
children O
in O
multiplex O
families O
to O
be O
considered O
for O
early O
intervention O
. O

Cuf2 O
boosts O
the O
transcription O
of O
APC O
/ O
C O
activator O
Fzr1 O
to O
terminate O
the O
meiotic O
division O
cycle O
. O

The O
number O
of O
nuclear O
divisions O
in O
meiosis O
is O
strictly O
limited O
to O
two O
. O

Although O
the O
precise O
mechanism O
remains O
unknown O
, O
this O
seems O
to O
be O
achieved O
by O
adjusting O
the O
anaphase O
- O
promoting O
complex O
/ O
cyclosome O
( O
APC O
/ O
C O
) O
activity O
to O
degrade O
cyclin O
. O

Here O
, O
we O
describe O
a O
fission O
yeast O
cuf2 O
mutant O
that O
enters O
into O
a O
third O
nuclear O
division O
cycle O
, O
represented O
by O
ectopic O
spindle O
assembly O
and O
abnormal O
chromosome O
segregation O
. O

Cuf2 O
is O
a O
meiotic O
transcription O
factor O
, O
and O
its O
critical O
target O
is O
fzr1 O
( O
+ O
) O
/ O
mfr1 O
( O
+ O
) O
, O
which O
encodes O
a O
meiotic O
APC O
/ O
C O
activator O
. O

fzr1 O
Delta O
also O
enters O
a O
third O
nuclear O
division O
. O

Thus O
, O
Cuf2 O
ensures O
termination O
of O
the O
M O
- O
phase O
cycle O
by O
boosting O
Fzr1 O
expression O
to O
generate O
functional O
gametes O
. O

Intracellular O
trafficking O
of O
solid O
lipid O
nanoparticles O
and O
their O
distribution O
between O
cells O
through O
tunneling O
nanotubes O
. O

The O
intracellular O
fate O
of O
nanosized O
drug O
delivery O
systems O
is O
still O
not O
well O
understood O
. O

Various O
internalization O
pathways O
have O
been O
discovered O
, O
but O
knowledge O
of O
their O
intracellular O
trafficking O
is O
still O
incomplete O
. O

The O
aim O
of O
this O
study O
was O
to O
examine O
the O
internalization O
, O
pathways O
, O
and O
positioning O
taken O
by O
solid O
lipid O
nanoparticles O
( O
SLNs O
) O
in O
cells O
. O

SLNs O
were O
fluorescence O
labeled O
with O
a O
newly O
synthesized O
fluorescent O
probe O
, O
14 B
- I
DACA I
. O

The O
probe O
was O
strongly O
incorporated O
into O
the O
nanoparticle O
core O
under O
the O
influence O
of O
its O
long O
lipophilic O
chain O
, O
enabling O
superior O
visualization O
of O
SLNs O
under O
complex O
and O
dynamic O
intracellular O
conditions O
. O

The O
intracellular O
distribution O
of O
SLNs O
was O
studied O
qualitatively O
using O
a O
co O
- O
localization O
technique O
and O
quantitatively O
using O
fluorescence O
intensity O
profiles O
. O

SLNs O
were O
seen O
inside O
the O
cells O
as O
distinct O
bright O
blue O
dots O
that O
underwent O
dynamic O
movement O
and O
were O
finally O
positioned O
in O
the O
proximity O
of O
the O
nucleus O
. O

A O
few O
SLNs O
were O
shown O
to O
be O
present O
in O
mitochondria O
and O
between O
actin O
filaments O
, O
but O
none O
in O
the O
cell O
nucleus O
or O
lysosomes O
. O

SLNs O
are O
here O
reported O
to O
be O
present O
in O
tunneling O
nanotubes O
( O
TNTs O
) O
, O
which O
could O
be O
a O
new O
route O
of O
SLN O
transfer O
between O
cells O
. O

More O
TNTs O
were O
observed O
in O
cells O
treated O
with O
SLNs O
. O

The O
presence O
of O
TNTs O
was O
additionally O
confirmed O
by O
atomic O
force O
microscopy O
analysis O
, O
which O
indicated O
that O
treated O
cells O
were O
more O
rough O
than O
control O
cells O
. O

Detailed O
investigation O
of O
the O
subcellular O
localization O
of O
SLNs O
and O
the O
evidence O
for O
their O
transfer O
and O
distribution O
via O
TNTs O
to O
the O
cells O
, O
which O
are O
not O
in O
direct O
contact O
with O
the O
source O
of O
SLNs O
, O
are O
important O
for O
understanding O
the O
mechanism O
of O
targeted O
drug O
delivery O
. O

Understanding O
the O
possible O
intercellular O
distribution O
of O
SLNs O
via O
TNTs O
can O
significantly O
influence O
approaches O
to O
treating O
organelle O
- O
specific O
diseases O
. O

Ubiquitous O
trisulfur B
radical O
anion O
: O
fundamentals O
and O
applications O
in O
materials O
science O
, O
electrochemistry O
, O
analytical O
chemistry O
and O
geochemistry O
. O

The O
trisulfur B
radical O
anion O
[ B
S3 I
] I
. I
( I
- I
) I
is O
well O
- O
known O
from O
inorganic O
chemistry O
textbooks O
as O
the O
blue O
chromophore O
in O
ultramarine O
blues O
in O
which O
this O
highly O
reactive O
species O
is O
trapped O
in O
a O
zeolitic O
framework O
. O

Recent O
findings O
have O
revealed O
that O
[ B
S3 I
] I
. I
( I
- I
) I
has O
a O
multi O
- O
faceted O
role O
in O
a O
variety O
of O
media O
, O
including O
alkali B
metal I
- O
sulfur B
batteries O
, O
aqueous O
solutions O
at O
high O
temperatures O
and O
pressures O
, O
and O
ionic O
liquids O
; O
it O
has O
also O
been O
used O
to O
detect O
trace O
amounts O
of O
water O
in O
organic O
solvents O
. O

This O
tutorial O
review O
illustrates O
how O
various O
physical O
techniques O
are O
used O
to O
identify O
a O
reactive O
species O
in O
solution O
and O
shows O
how O
elucidation O
of O
electronic O
structures O
can O
be O
used O
to O
explain O
spectroscopic O
and O
structural O
properties O
. O

Examples O
of O
the O
function O
of O
[ B
S3 I
] I
. I
( I
- I
) I
in O
materials O
science O
, O
electrochemistry O
, O
analytical O
chemistry O
and O
geochemistry O
are O
used O
to O
illustrate O
the O
widespread O
influence O
of O
this O
fundamentally O
important O
triatomic O
sulfur B
species O
. O

COMPLETE O
ARTIFICIAL O
SALIVA O
ALTERS O
EXPRESSION O
OF O
PROINFLAMMATORY O
CYTOKINES O
IN O
HUMAN O
DERMAL O
FIBROBLASTS O
. O

Complete O
artificial O
saliva O
( O
CAS O
) O
is O
a O
saliva O
substitute O
often O
used O
as O
a O
vehicle O
for O
test O
articles O
, O
including O
smokeless O
tobacco O
products O
. O

In O
the O
course O
of O
a O
study O
employing O
normal O
adult O
human O
dermal O
fibroblasts O
( O
HDFa O
) O
as O
a O
model O
in O
vitro O
, O
we O
discovered O
that O
CAS O
as O
a O
vehicle O
introduced O
a O
significant O
change O
in O
the O
expression O
of O
proinflammatory O
cytokines O
. O

To O
determine O
the O
effects O
of O
CAS O
on O
gene O
expression O
, O
real O
- O
time O
quantitative O
reverse O
- O
transcriptase O
polymerase O
chain O
reaction O
( O
qRT O
- O
PCR O
) O
gene O
array O
analysis O
was O
used O
. O

Results O
indicate O
that O
robust O
changes O
in O
the O
expression O
of O
the O
proinflammatory O
cytokine O
interleukin O
8 O
( O
IL8 O
) O
and O
the O
vascular O
cell O
adhesion O
molecule O
1 O
( O
VCAM1 O
) O
occur O
within O
5 O
hours O
of O
exposure O
to O
CAS O
. O

To O
determine O
whether O
CAS O
also O
alters O
cytokine O
release O
into O
the O
culture O
media O
, O
cytometric O
bead O
array O
( O
CBA O
) O
assays O
for O
human O
inflammatory O
cytokines O
were O
performed O
. O

Analysis O
shows O
that O
CAS O
induced O
the O
release O
of O
IL8 O
and O
interleukin O
6 O
( O
IL6 O
) O
. O

This O
study O
focused O
on O
determining O
which O
components O
in O
CAS O
were O
responsible O
for O
the O
proinflammatory O
response O
in O
HDFa O
. O

The O
following O
components O
were O
investigated O
: O
alpha O
- O
amylase O
, O
lysozyme O
, O
acid O
phosphatase O
, O
and O
urea B
. O

Results O
demonstrated O
that O
enzymatically O
active O
alpha O
- O
amylase O
induced O
gene O
expression O
for O
proinflammatory O
cytokines O
IL8 O
, O
IL6 O
, O
tumor O
necrosis O
factor O
- O
alpha O
( O
TNF O
alpha O
) O
, O
and O
interleukin O
1 O
alpha O
( O
IL1 O
alpha O
) O
, O
and O
for O
VCAM1 O
. O

Therefore O
, O
it O
is O
important O
to O
carefully O
evaluate O
the O
" O
vehicle O
effects O
" O
of O
CAS O
and O
its O
components O
in O
in O
vitro O
toxicology O
research O
. O

Simple O
and O
Rapid O
Synthesis O
of O
Magnetite B
/ O
Hydroxyapatite B
Composites O
for O
Hyperthermia O
Treatments O
via O
a O
Mechanochemical O
Route O
. O

This O
paper O
presents O
a O
simple O
method O
for O
the O
rapid O
synthesis O
of O
magnetite B
/ O
hydroxyapatite B
composite O
particles O
. O

In O
this O
method O
, O
superparamagnetic O
magnetite O
nanoparticles O
are O
first O
synthesized O
by O
coprecipitation O
using O
ferrous B
chloride I
and O
ferric B
chloride I
. O

Immediately O
following O
the O
synthesis O
, O
carbonate B
- O
substituted O
( O
B O
- O
type O
) O
hydroxyapatite B
particles O
are O
mechanochemically O
synthesized O
by O
wet O
milling O
dicalcium B
phosphate I
dihydrate I
and O
calcium B
carbonate I
in O
a O
dispersed O
suspension O
of O
magnetite B
nanoparticles O
, O
during O
which O
the O
magnetite B
nanoparticles O
are O
incorporated O
into O
the O
hydroxyapatite B
matrix O
. O

We O
observed O
that O
the O
resultant O
magnetite B
/ O
hydroxyapatite B
composites O
possessed O
a O
homogeneous O
dispersion O
of O
magnetite B
nanoparticles O
, O
characterized O
by O
an O
absence O
of O
large O
aggregates O
. O

When O
this O
material O
was O
subjected O
to O
an O
alternating O
magnetic O
field O
, O
the O
heat O
generated O
increased O
with O
increasing O
magnetite B
concentration O
. O

For O
a O
magnetite O
concentration O
of O
30 O
mass O
% O
, O
a O
temperature O
increase O
greater O
than O
20 O
K O
was O
achieved O
in O
less O
than O
50 O
s O
. O

These O
results O
suggest O
that O
our O
composites O
exhibit O
good O
hyperthermia O
properties O
and O
are O
promising O
candidates O
for O
hyperthermia O
treatments O
. O

A O
Detailed O
Experimental O
and O
Theoretical O
Study O
into O
the O
Properties O
of O
C60 B
Dumbbell O
Junctions O
. O

A O
combined O
experimental O
and O
theoretical O
investigation O
is O
carried O
out O
into O
the O
electrical O
transport O
across O
a O
fullerene B
dumbbell O
one O
- O
molecule O
junction O
. O

The O
newly O
designed O
molecule O
comprises O
two O
C60 B
s I
connected O
to O
a O
fluorene B
backbone O
via O
cyclopropyl B
groups O
. O

It O
is O
wired O
between O
gold O
electrodes O
under O
ambient O
conditions O
by O
pressing O
the O
tip O
of O
a O
scanning O
tunnelling O
microscope O
( O
STM O
) O
onto O
one O
of O
the O
C60 B
groups O
. O

The O
STM O
allows O
us O
to O
identify O
a O
single O
molecule O
before O
the O
junction O
is O
formed O
through O
imaging O
, O
which O
means O
unambiguously O
that O
only O
one O
molecule O
is O
wired O
. O

Once O
lifted O
, O
the O
same O
molecule O
could O
be O
wired O
many O
times O
as O
it O
was O
strongly O
fixed O
to O
the O
tip O
, O
and O
a O
high O
conductance O
state O
close O
to O
10 O
( O
- O
2 O
) O
G0 O
is O
found O
. O

The O
results O
also O
suggest O
that O
the O
relative O
conductance O
fluctuations O
are O
low O
as O
a O
result O
of O
the O
low O
mobility O
of O
the O
molecule O
. O

Theoretical O
analysis O
indicates O
that O
the O
molecule O
is O
connected O
directly O
to O
one O
electrode O
through O
the O
central O
fluorene B
, O
and O
that O
to O
bind O
it O
to O
the O
gold O
fully O
it O
has O
to O
be O
pushed O
through O
a O
layer O
of O
adsorbates O
naturally O
present O
in O
the O
experiment O
. O

Extracellular O
Electron O
Transfer O
across O
Bacterial O
Cell O
Membranes O
via O
a O
Cytocompatible O
Redox O
- O
Active O
Polymer O
. O

A O
redox O
- O
active O
phospholipid O
polymer O
with O
a O
phospholipid O
- O
mimicking O
structure O
( O
2 B
- I
methacryloyloxyethyl I
phosphorylcholine I
; O
MPC B
) O
was O
synthesized O
to O
construct O
a O
biocompatible O
electron O
mediator O
between O
bacteria O
and O
an O
electrode O
. O

In O
this O
study O
, O
a O
copolymer O
of O
MPC B
and O
vinylferrocene B
[ O
VF O
; O
poly B
( I
MPC I
- I
co I
- I
VF I
) I
] O
( O
PMF B
) O
is O
synthesized O
. O

When O
PMF B
is O
added O
to O
cultures O
of O
the O
bacterial O
species O
Escherichia O
coli O
( O
Gram O
negative O
) O
and O
Lactobacillus O
plantarum O
( O
Gram O
positive O
) O
, O
which O
have O
different O
cell O
wall O
structures O
, O
a O
catalytic O
current O
mediated O
by O
PMF B
is O
observed O
. O

In O
addition O
, O
growth O
curves O
and O
live O
/ O
dead O
assays O
indicate O
that O
PMF B
does O
not O
decrease O
metabolic O
activity O
or O
cell O
viability O
. O

These O
results O
indicate O
that O
PMF O
mediates O
extracellular O
electron O
transfer O
across O
bacterial O
cell O
membranes O
without O
associated O
cytotoxicity O
. O

PICK1 O
Deficiency O
Impairs O
Secretory O
Vesicle O
Biogenesis O
and O
Leads O
to O
Growth O
Retardation O
and O
Decreased O
Glucose B
Tolerance O
. O

Secretory O
vesicles O
in O
endocrine O
cells O
store O
hormones O
such O
as O
growth O
hormone O
( O
GH O
) O
and O
insulin O
before O
their O
release O
into O
the O
bloodstream O
. O

The O
molecular O
mechanisms O
governing O
budding O
of O
immature O
secretory O
vesicles O
from O
the O
trans O
- O
Golgi O
network O
( O
TGN O
) O
and O
their O
subsequent O
maturation O
remain O
unclear O
. O

Here O
, O
we O
identify O
the O
lipid O
binding O
BAR O
( O
Bin O
/ O
amphiphysin O
/ O
Rvs O
) O
domain O
protein O
PICK1 O
( O
protein O
interacting O
with O
C O
kinase O
1 O
) O
as O
a O
key O
component O
early O
in O
the O
biogenesis O
of O
secretory O
vesicles O
in O
GH O
- O
producing O
cells O
. O

Both O
PICK1 O
- O
deficient O
Drosophila O
and O
mice O
displayed O
somatic O
growth O
retardation O
. O

Growth O
retardation O
was O
rescued O
in O
flies O
by O
reintroducing O
PICK1 O
in O
neurosecretory O
cells O
producing O
somatotropic O
peptides O
. O

PICK1 O
- O
deficient O
mice O
were O
characterized O
by O
decreased O
body O
weight O
and O
length O
, O
increased O
fat O
accumulation O
, O
impaired O
GH O
secretion O
, O
and O
decreased O
storage O
of O
GH O
in O
the O
pituitary O
. O

Decreased O
GH O
storage O
was O
supported O
by O
electron O
microscopy O
showing O
prominent O
reduction O
in O
secretory O
vesicle O
number O
. O

Evidence O
was O
also O
obtained O
for O
impaired O
insulin O
secretion O
associated O
with O
decreased O
glucose B
tolerance O
. O

PICK1 O
localized O
in O
cells O
to O
immature O
secretory O
vesicles O
, O
and O
the O
PICK1 O
BAR O
domain O
was O
shown O
by O
live O
imaging O
to O
associate O
with O
vesicles O
budding O
from O
the O
TGN O
and O
to O
possess O
membrane O
- O
sculpting O
properties O
in O
vitro O
. O

In O
mouse O
pituitary O
, O
PICK1 O
co O
- O
localized O
with O
the O
BAR O
domain O
protein O
ICA69 O
, O
and O
PICK1 O
deficiency O
abolished O
ICA69 O
protein O
expression O
. O

In O
the O
Drosophila O
brain O
, O
PICK1 O
and O
ICA69 O
co O
- O
immunoprecipitated O
and O
showed O
mutually O
dependent O
expression O
. O

Finally O
, O
both O
in O
a O
Drosophila O
model O
of O
type O
2 O
diabetes O
and O
in O
high O
- O
fat O
- O
diet O
- O
induced O
obese O
mice O
, O
we O
observed O
up O
- O
regulation O
of O
PICK1 O
mRNA O
expression O
. O

Our O
findings O
suggest O
that O
PICK1 O
, O
together O
with O
ICA69 O
, O
is O
critical O
during O
budding O
of O
immature O
secretory O
vesicles O
from O
the O
TGN O
and O
thus O
for O
vesicular O
storage O
of O
GH O
and O
possibly O
other O
hormones O
. O

The O
data O
link O
two O
BAR O
domain O
proteins O
to O
membrane O
remodeling O
processes O
in O
the O
secretory O
pathway O
of O
peptidergic O
endocrine O
cells O
and O
support O
an O
important O
role O
of O
PICK1 O
/ O
ICA69 O
in O
maintenance O
of O
metabolic O
homeostasis O
. O

X O
- O
ray O
structure O
analysis O
of O
a O
solid O
solution O
of O
milbemycins B
A3 I
and I
A4 I
. O

Milbemycins B
A3 I
and I
A4 I
are O
pharmaceutically O
and O
agriculturally O
useful O
macrolides O
isolated O
from O
Streptomyces O
species O
. O

The O
molecular O
structures O
of O
the O
title O
compounds O
were O
unambiguously O
established O
by O
a O
single O
crystal O
X O
- O
ray O
analysis O
of O
the O
solid O
solution O
of O
both O
compounds O
. O

The O
crystals O
present O
trigonal O
system O
, O
space O
group O
P32 O
with O
Z O
= O
3 O
, O
unit O
cell O
dimensions O
: O
a O
= O
12 O
. O
2211 O
( O
4 O
) O
, O
c O
= O
17 O
. O
5372 O
( O
7 O
) O
A O
; O
V O
= O
2268 O
. O
4 O
( O
1 O
) O
A O
( O
3 O
) O
, O
mu O
= O
0 O
. O
082 O
mm O
( O
- O
1 O
) O
; O
d O
= O
1 O
. O
183 O
g O
cm O
( O
- O
3 O
) O
. O

An O
interesting O
system O
of O
intramolecular O
hydrogen B
bonds O
and O
weak O
intermolecular O
CH B
. O
. O
. O
O B
type O
hydrogen B
bond O
was O
observed O
in O
the O
solid O
state O
. O

Site O
- O
specific O
and O
Far O
- O
Red O
Light O
- O
Activatable O
Prodrug O
of O
Combretastain B
A I
- I
4 I
Using O
Photo O
- O
Unclick O
Chemistry O
. O

Although O
tissue O
- O
penetrable O
light O
( O
red O
and O
NIR O
) O
has O
a O
great O
potential O
for O
spatiotemporally O
controlled O
release O
of O
therapeutic O
agents O
, O
it O
has O
been O
hampered O
because O
of O
the O
lack O
of O
chemistry O
translating O
the O
photonic O
energy O
to O
a O
cleavage O
of O
a O
chemical O
bond O
. O

Recently O
, O
we O
discovered O
that O
an O
aminoacrylate B
group O
could O
be O
cleaved O
to O
release O
parent O
drugs O
after O
oxidation O
by O
SO O
, O
and O
have O
called O
this O
" O
photo O
- O
unclick O
chemistry O
" O
. O

We O
demonstrate O
its O
application O
to O
far O
- O
red O
light O
- O
activated O
prodrugs O
. O

A O
prodrug O
of O
combretastatin B
A I
- I
4 I
( O
CA4 B
) O
was O
prepared O
, O
CMP B
- I
L I
- I
CA4 I
: O
CMP B
( O
dithiaporphyrin B
, O
a O
photosensitizer O
) O
and O
L B
( I
aminoacrylate I
linker O
) O
. O

Upon O
irradiation O
with O
690 O
nm O
diode O
laser O
, O
the O
aminoacrylate B
linker O
of O
the O
prodrug O
was O
cleaved O
rapidly O
releasing O
CA4 O
( O
> O
80 O
% O
in O
10 O
min O
) O
in O
CDCl3 B
. O

In O
the O
tissue O
culture O
, O
it O
showed O
about O
a O
6 O
- O
fold O
increase O
in O
its O
IC50 O
in O
MCF O
- O
7 O
after O
the O
irradiation O
, O
most O
likely O
, O
because O
of O
the O
released O
CA4 O
. O

Most O
significantly O
, O
CMP B
- I
L I
- I
CA4 I
had O
better O
antitumor O
efficacy O
in O
vivo O
than O
its O
non O
- O
cleavable O
( O
NC O
) O
analog O
, O
CMP B
- O
NCL I
- I
CA4 I
. O

This O
is O
the O
first O
demonstration O
of O
the O
in O
vivo O
efficacy O
of O
the O
novel O
low O
- O
energy O
light O
- O
activatable O
prodrug O
using O
the O
photo O
- O
unclick O
chemistry O
. O

" O
Strange O
Kinetics O
" O
in O
the O
Temperature O
Dependence O
of O
Methionine B
Ligand O
Rebinding O
Dynamics O
in O
Cytochrome O
c O
. O

Temperature O
dependence O
of O
methionine B
ligand O
dissociation O
and O
rebinding O
dynamics O
in O
cytochrome O
c O
in O
aqueous O
solution O
has O
been O
studied O
using O
classical O
molecular O
dynamics O
simulation O
. O

Results O
are O
compared O
with O
previous O
study O
of O
rebinding O
dynamics O
at O
300K O
in O
water O
in O
order O
to O
understand O
how O
the O
change O
of O
protein O
environment O
and O
the O
underlying O
protein O
energy O
landscape O
influence O
the O
dynamics O
. O

Rebinding O
dynamics O
at O
77K O
, O
180K O
, O
and O
300K O
exhibits O
changes O
in O
both O
timescale O
and O
mechanism O
as O
the O
protein O
and O
solvent O
undergo O
a O
dynamic O
" O
glass O
transition O
. O
" O
At O
each O
temperature O
, O
the O
rebinding O
dynamics O
yields O
a O
subset O
of O
trajectories O
that O
undergo O
fast O
rebinding O
as O
well O
as O
a O
subset O
of O
trajectories O
that O
undergo O
slower O
rebinding O
. O

At O
300K O
in O
water O
, O
both O
a O
fast O
( O
4 O
. O
0 O
ps O
) O
and O
slow O
( O
14 O
. O
6 O
ps O
) O
rebinding O
is O
observed O
. O

While O
fast O
rebinding O
occurs O
from O
a O
" O
downward O
" O
( O
heme B
pointing O
) O
substate O
of O
the O
methionine B
, O
the O
slow O
rebinding O
involves O
interconversion O
between O
an O
" O
upward O
" O
substate O
, O
from O
which O
rebinding O
cannot O
occur O
, O
and O
the O
downward O
substate O
. O

At O
lower O
temperatures O
( O
77K O
and O
180K O
) O
the O
upward O
dissociated O
substate O
was O
not O
observed O
due O
to O
the O
high O
barrier O
imposed O
by O
the O
" O
frozen O
" O
protein O
structure O
. O

However O
, O
a O
slow O
rebinding O
phase O
is O
observed O
at O
both O
77K O
and O
180K O
and O
is O
associated O
with O
a O
process O
of O
trapping O
in O
downward O
but O
" O
binding O
forbidden O
" O
substates O
with O
subsequent O
slow O
dynamical O
conversion O
to O
" O
binding O
competent O
" O
substates O
from O
which O
rebinding O
is O
relatively O
rapid O
. O

Distinctive O
rebinding O
dynamics O
at O
77K O
and O
180K O
suggest O
that O
different O
rebinding O
time O
scales O
are O
predetermined O
by O
the O
protein O
and O
solvent O
structural O
arrangement O
prior O
to O
photodissociation O
, O
which O
causes O
either O
fast O
rebinding O
( O
about O
2ps O
) O
or O
slow O
( O
> O
50ps O
) O
rebinding O
. O

Suggestions O
for O
future O
experiments O
to O
further O
probe O
the O
role O
of O
dynamic O
heterogeneity O
in O
the O
kinetics O
of O
methionine B
ligand O
binding O
in O
cytochrome O
c O
protein O
are O
proposed O
. O

( O
De O
) O
Lithiation O
Mechanism O
of O
Li B
/ O
SeSx B
( O
x O
= O
0 O
- O
7 O
) O
Batteries O
Determined O
by O
In O
- O
situ O
Synchrotron O
X O
- O
ray O
Diffraction O
and O
X O
- O
ray O
Absorption O
Spectroscopy O
. O

Electrical O
energy O
storage O
for O
transportation O
has O
going O
beyond O
the O
limit O
of O
converntional O
lithium B
- O
ion O
batteries O
currently O
. O

New O
material O
or O
new O
battery O
system O
development O
is O
an O
alternative O
approach O
to O
achieve O
the O
goal O
of O
new O
high O
energy O
storage O
system O
with O
energy O
densities O
five O
times O
or O
more O
greater O
. O

A O
series O
of O
SeSx O
- O
carbon B
( O
x O
= O
0 O
- O
7 O
) O
composite O
materials O
has O
been O
prepared O
and O
evaluated O
as O
the O
positive O
electrodes O
in O
secondary O
lithium B
cells O
with O
ether B
- O
based O
electrolyte O
. O

In O
- O
situ O
synchrotron O
high O
energy O
X O
- O
ray O
diffraction O
was O
utilized O
to O
investigate O
the O
crystalline O
phase O
transition O
during O
cell O
cycling O
. O

Complementary O
, O
in O
- O
situ O
Se O
K O
- O
edge O
X O
- O
ray O
absorption O
near O
edge O
structure O
analysis O
was O
used O
to O
track O
the O
evolution O
of O
the O
Se O
valence O
state O
for O
both O
crystalline O
and O
non O
- O
crystalline O
phases O
, O
including O
amorphous O
and O
electrolyte O
- O
dissolved O
phases O
in O
the O
( O
de O
) O
lithiation O
process O
. O

On O
the O
basis O
of O
these O
reuslts O
, O
a O
mechanism O
for O
the O
( O
de O
) O
lithiation O
process O
is O
proposed O
, O
where O
Se B
is O
reduced O
to O
the O
polyselenides B
, O
Li2Sen B
( O
n O
> O
= O
4 O
) O
, O
Li2Se2 B
, O
and O
Li2Se B
sequentially O
during O
the O
lithiation O
, O
and O
Li2Se B
is O
oxidized O
to O
Se B
through O
Li2Sen B
( O
n O
> O
= O
4 O
) O
during O
the O
delithiation O
. O

In O
addition O
, O
X O
- O
ray O
photoelectron O
spectroscopy O
and O
electrochemical O
impedance O
spectroscopy O
demonstrated O
the O
reversibility O
of O
the O
Li B
/ O
Se O
system O
in O
ether B
- O
based O
electrolyte O
and O
the O
presence O
of O
side O
products O
in O
the O
carbonate B
- O
based O
electrolytes O
. O

For O
Li B
/ O
SeS2 B
and O
Li B
/ O
SeS7 B
cells O
, O
Li2Se B
and O
Li2S B
are O
the O
discharged O
products O
with O
the O
presence O
of O
Se B
only O
as O
the O
crystalline O
phase O
in O
the O
end O
of O
charge O
. O

The O
Governing O
Role O
of O
Surface O
Hydration O
in O
Ion O
Specific O
Adsorption O
to O
Silica B
- O
an O
AFM O
Based O
Account O
of O
the O
Hofmeister O
Universality O
and O
its O
Reversal O
. O

AFM O
measurements O
of O
the O
force O
acting O
between O
silica B
surfaces O
in O
the O
presence O
of O
varied O
alkali B
- I
chloride I
salts O
and O
pH O
' O
s O
elucidate O
the O
origin O
of O
the O
Hofmeister O
adsorption O
series O
and O
its O
reversal O
. O

At O
low O
pH O
, O
electrostatics O
is O
shown O
to O
be O
insignificant O
. O

The O
preferential O
adsorption O
of O
Cs B
+ I
to O
the O
silica B
surface O
is O
traced O
to O
the O
weak O
hydration O
of O
neutral O
silanols B
and O
the O
resulting O
hydrophobic O
expulsion O
of O
weakly O
hydrated O
ions O
from O
bulk O
solution O
to O
the O
interface O
. O

The O
same O
interactions O
keep O
the O
strongly O
hydrated B
Li I
+ I
and O
Na B
+ I
in O
solution O
. O

As O
pH O
is O
increased O
, O
a O
tightly O
bound O
hydration O
layer O
forms O
on O
deprotonating O
silanols B
. O

Cs B
+ I
is O
correspondingly O
expelled O
from O
the O
surface O
and O
adsorption O
of O
small O
ions O
is O
encouraged O
. O

The O
deduced O
role O
of O
surface O
hydration O
is O
corroborated O
by O
hydration O
repulsion O
observed O
at O
high O
pH O
, O
surface O
over O
- O
charging O
at O
low O
pH O
, O
and O
data O
in O
other O
oxides B
. O

Fungal O
ABC O
Transporter O
- O
Associated O
Activity O
of O
Isoflavonoids B
from O
the O
Root O
Extract O
of O
Dalea O
formosa O
. O

New O
potential O
treatments O
for O
disseminated O
fungal O
infections O
are O
needed O
, O
especially O
for O
infections O
caused O
by O
the O
commonly O
drug O
- O
resistant O
pathogens O
Candida O
albicans O
and O
C O
. O
glabrata O
. O

These O
pathogens O
cause O
systemic O
candidiasis O
, O
a O
significant O
cause O
of O
mortality O
in O
immune O
- O
compromised O
patients O
. O

ABC O
transporters O
of O
the O
pleiotropic O
drug O
resistance O
subfamily O
, O
such O
as O
Cdr1p O
of O
C O
. O
albicans O
, O
play O
an O
important O
role O
in O
antifungal O
resistance O
and O
are O
potential O
bioassay O
targets O
for O
antifungal O
therapies O
against O
drug O
- O
resistant O
pathogens O
. O

We O
observed O
strong O
antifungal O
growth O
inhibitory O
activity O
in O
the O
methanol B
extract O
of O
Dalea O
formosa O
roots O
. O

This O
extract O
afforded O
six O
new O
isoflavonoids B
, O
sedonans B
A I
- I
F I
( O
1 O
- O
6 O
) O
, O
a O
new O
but B
- I
2 I
- I
enolide I
, O
4 B
' I
- I
O I
- I
methylpuerol I
A I
( O
7 O
) O
, O
and O
the O
new O
pterocarpan B
ent B
- I
sandwicensin I
( O
8 O
) O
. O

The O
structures O
and O
absolute O
configurations O
of O
these O
compounds O
were O
assigned O
using O
spectroscopic O
and O
chiroptical O
techniques O
. O

The O
direct O
antifungal O
activity O
of O
1 O
against O
C O
. O
glabrata O
( O
MIC O
= O
20 O
mu O
M O
) O
was O
higher O
than O
that O
of O
fluconazole B
. O

Sedonans B
A I
- I
F I
and O
ent B
- I
sandwicensin I
were O
also O
active O
against O
Saccharomyces O
cerevisiae O
strains O
that O
express O
differing O
ABC O
transporter O
- O
associated O
resistance O
mechanisms O
but O
differed O
in O
their O
susceptibility O
to O
Cdr1p O
- O
mediated O
detoxification O
. O

A O
sedonan B
A I
( O
1 O
) O
/ O
ent B
- I
sandwicensin I
( O
8 O
) O
combination O
exhibited O
synergistic O
growth O
inhibition O
. O

The O
results O
demonstrate O
that O
multiple O
crude O
extract O
compounds O
are O
differentially O
affected O
by O
efflux O
- O
mediated O
resistance O
and O
are O
collectively O
responsible O
for O
the O
observed O
bioactivity O
. O

A O
Chemometric O
Approach O
to O
Distribution O
of O
Selenium B
in O
Medicinal O
Plants O
Cultivated O
in O
Poland O
. O

Abstract O
The O
aim O
of O
this O
study O
was O
to O
evaluate O
the O
level O
of O
selenium B
( O
Se B
) O
in O
common O
raw O
plant O
materials O
( O
herbs O
, O
leaves O
, O
flowers O
, O
fruits O
, O
and O
roots O
) O
obtained O
from O
medicinal O
plants O
cultivated O
in O
Poland O
. O

Furthermore O
, O
the O
relationship O
between O
the O
morphological O
part O
of O
a O
plant O
and O
its O
species O
was O
examined O
, O
and O
the O
concentration O
of O
Se B
in O
it O
was O
measured O
. O

Spectrofluorimetric O
determination O
of O
Se B
in O
148 O
samples O
of O
44 O
plant O
species O
revealed O
that O
the O
majority O
of O
the O
plants O
contained O
Se B
at O
a O
level O
from O
several O
to O
several O
tens O
of O
mu O
g O
/ O
kg O
dry O
weight O
( O
d O
. O
w O
. O
) O
. O

A O
relatively O
high O
Se B
concentration O
, O
in O
the O
order O
of O
50 O
mu O
g O
/ O
kg O
d O
. O
w O
. O
, O
was O
found O
in O
Majoranae O
herba O
, O
Crataegi O
fructus O
, O
and O
Lini O
semen O
. O

An O
especially O
high O
Se B
level O
, O
> O
100 O
mu O
g O
/ O
kg O
d O
. O
w O
. O
, O
was O
found O
in O
only O
three O
plants O
- O
Equiseti O
herba O
, O
Farfarae O
folium O
, O
and O
Cichorii O
radix O
. O

Application O
of O
a O
nonparametric O
Kruskal O
- O
Wallis O
analysis O
of O
variance O
test O
indicates O
that O
the O
morphological O
variable O
influences O
the O
level O
of O
Se B
in O
the O
studied O
groups O
of O
raw O
plant O
materials O
. O

The O
mean O
concentration O
of O
Se B
in O
fruits O
differs O
significantly O
from O
that O
found O
in O
flowers O
and O
roots O
. O

However O
, O
there O
was O
no O
statistically O
significant O
difference O
between O
the O
Se B
content O
in O
herbs O
and O
leaves O
and O
its O
levels O
in O
fruits O
, O
flowers O
, O
and O
roots O
. O

Cluster O
analysis O
and O
principal O
component O
analysis O
calculations O
show O
that O
it O
is O
possible O
to O
relate O
the O
Se B
concentration O
in O
plant O
material O
to O
the O
plant O
species O
and O
botanical O
family O
of O
the O
medicinal O
plant O
in O
only O
a O
few O
cases O
. O

Analysis O
of O
average O
Se B
levels O
in O
the O
plant O
species O
showed O
that O
the O
plants O
belonging O
to O
the O
Apiaceae O
and O
Labiatae O
are O
more O
Se B
- O
rich O
than O
those O
belonging O
to O
Rosaceae O
botanical O
families O
. O

Non O
- O
destructive O
monitoring O
of O
creaming O
of O
oil O
- O
in O
- O
water O
emulsion O
- O
based O
formulations O
using O
magnetic O
resonance O
imaging O
. O

Abstract O
A O
non O
- O
destructive O
method O
for O
monitoring O
creaming O
of O
emulsion O
- O
based O
formulations O
is O
in O
great O
demand O
because O
it O
allows O
us O
to O
understand O
fully O
their O
instability O
mechanisms O
. O

This O
study O
was O
aimed O
at O
demonstrating O
the O
usefulness O
of O
magnetic O
resonance O
( O
MR O
) O
techniques O
, O
including O
MR O
imaging O
( O
MRI O
) O
and O
MR O
spectroscopy O
( O
MRS O
) O
, O
for O
evaluating O
the O
physicochemical O
stability O
of O
emulsion O
- O
based O
formulations O
. O

Emulsions O
that O
are O
applicable O
as O
the O
base O
of O
practical O
skin O
creams O
were O
used O
as O
test O
samples O
. O

Substantial O
creaming O
was O
developed O
by O
centrifugation O
, O
which O
was O
then O
monitored O
by O
MRI O
. O

The O
creaming O
oil O
droplet O
layer O
and O
aqueous O
phase O
were O
clearly O
distinguished O
by O
quantitative O
MRI O
by O
measuring O
T1 O
and O
the O
apparent O
diffusion O
coefficient O
. O

Components O
in O
a O
selected O
volume O
in O
the O
emulsions O
could O
be O
analyzed O
using O
MRS O
. O

Then O
, O
model O
emulsions O
having O
different O
hydrophilic O
- O
lipophilic O
balance O
( O
HLB O
) O
values O
were O
tested O
, O
and O
the O
optimal O
HLB O
value O
for O
a O
stable O
dispersion O
was O
determined O
. O

In O
addition O
, O
the O
MRI O
examination O
enables O
the O
detection O
of O
creaming O
occurring O
in O
a O
polyethylene B
tube O
, O
which O
is O
commonly O
used O
for O
commercial O
products O
, O
without O
losing O
any O
image O
quality O
. O

These O
findings O
strongly O
indicate O
that O
MR O
techniques O
are O
powerful O
tools O
to O
evaluate O
the O
physicochemical O
stability O
of O
emulsion O
- O
based O
formulations O
. O

This O
study O
will O
make O
a O
great O
contribution O
to O
the O
development O
and O
quality O
control O
of O
emulsion O
- O
based O
formulations O
. O

Spectroscopic O
Study O
of O
the O
Light O
- O
Harvesting O
CP29 O
Antenna O
Complex O
of O
Photosystem O
II O
- O
Part O
I O
. O

Recent O
structural O
data O
revealed O
that O
the O
CP29 O
protein O
of O
higher O
plant O
Photosystem O
II O
( O
PSII O
) O
contains O
13 O
chlorophylls B
( O
Chls B
) O
per O
complex O
[ O
Pan O
et O
al O
. O
, O
Nat O
. O
Struct O
. O
Mol O
. O
Biol O
. O
2011 O
, O
18 O
, O
309 O
] O
, O
i O
. O
e O
. O
, O
five O
Chls B
more O
than O
in O
the O
predicted O
CP29 O
homology O
- O
based O
structure O
model O
[ O
Bassi O
et O
al O
. O
, O
Proc O
. O
Natl O
. O
Acad O
. O
Sci O
. O
USA O
1999 O
, O
96 O
, O
10056 O
] O
. O

This O
lack O
of O
consensus O
presents O
a O
constraint O
on O
the O
interpretation O
of O
CP29 O
optical O
spectra O
and O
their O
underlying O
electronic O
structure O
. O

To O
address O
this O
problem O
, O
we O
present O
new O
low O
- O
temperature O
( O
5 O
K O
) O
absorption O
, O
fluorescence O
, O
and O
hole O
- O
burned O
( O
HB O
) O
spectra O
for O
CP29 O
proteins O
from O
spinach O
, O
which O
are O
compared O
with O
the O
previously O
reported O
data O
. O

We O
focus O
on O
excitation O
energy O
transfer O
( O
EET O
) O
and O
the O
nature O
of O
the O
lowest O
- O
energy O
state O
( O
s O
) O
. O

We O
argue O
that O
CP29 O
proteins O
previously O
studied O
by O
HB O
spectroscopy O
lacked O
at O
least O
one O
Chl B
a I
molecule O
( O
i O
. O
e O
. O
, O
a615 O
or O
a611 O
) O
, O
which O
along O
with O
Chl B
a612 I
contribute O
to O
the O
lowest O
energy O
state O
in O
more O
intact O
CP29 O
, O
and O
one O
Chl B
b I
( O
most O
likely O
b607 O
) O
. O

This O
is O
why O
the O
low O
- O
energy O
state O
and O
fluorescence O
maxima O
reported O
by O
Pieper O
et O
al O
. O

[ O
Photochem O
. O
Photobiol O
. O
2000 O
, O
71 O
, O
574 O
] O
were O
blueshifted O
by O
~ O
1 O
nm O
, O
the O
low O
- O
energy O
state O
appeared O
to O
be O
highly O
localized O
on O
a O
single O
Chl B
a I
molecule O
, O
and O
the O
position O
of O
the O
low O
- O
energy O
state O
was O
independent O
of O
burning O
fluence O
. O

In O
contrast O
, O
the O
position O
of O
the O
nonresonant O
HB O
spectrum O
shifts O
blue O
with O
increasing O
fluence O
in O
intact O
CP29 O
, O
as O
this O
state O
is O
strongly O
contributed O
to O
by O
several O
pigments O
( O
i O
. O
e O
. O
, O
a611 O
, O
a612 O
, O
a615 O
and O
a610 O
) O
. O

Zero O
- O
phonon O
hole O
widths O
obtained O
for O
the O
Chl B
b I
band O
at O
638 O
. O
5 O
nm O
( O
5 O
K O
) O
revealed O
two O
independent O
Chl B
b I
- O
- O
> O
Chl B
a I
EET O
times O
, O
i O
. O
e O
. O
, O
4 O
+ O
/ O
- O
0 O
. O
5 O
ps O
and O
0 O
. O
4 O
+ O
/ O
- O
0 O
. O
1 O
ps O
. O

The O
latter O
value O
is O
a O
factor O
of O
two O
faster O
than O
previously O
observed O
by O
HB O
spectroscopy O
and O
very O
similar O
to O
the O
one O
observed O
by O
Gradinaru O
et O
al O
. O

[ O
J O
. O
Phys O
. O
Chem O
. O
B O
2000 O
, O
104 O
, O
9330 O
] O
in O
pump O
- O
probe O
experiments O
. O

EET O
time O
from O
650 O
nm O
Chl B
b I
- O
- O
> O
Chl B
a I
and O
downward O
EET O
from O
Chl B
( O
s O
) O
a O
state O
( O
s O
) O
at O
665 O
nm O
occurs O
in O
4 O
. O
9 O
+ O
/ O
- O
0 O
. O
7 O
ps O
. O

These O
findings O
provide O
important O
constraints O
for O
excitonic O
calculations O
that O
are O
discussed O
in O
the O
accompanying O
paper O
( O
Part O
II O
) O
. O

Group O
B O
Streptococcus O
pilus O
sortase O
regulation O
: O
a O
single O
mutation O
in O
the O
lid O
region O
induces O
pilin O
protein O
polymerization O
in O
vitro O
. O

Gram O
- O
positive O
bacteria O
build O
pili O
on O
their O
cell O
surface O
via O
a O
class O
C O
sortase O
- O
catalyzed O
transpeptidation O
mechanism O
from O
pilin O
protein O
substrates O
. O

Despite O
the O
availability O
of O
several O
crystal O
structures O
, O
pilus O
- O
related O
C O
sortases O
remain O
poorly O
characterized O
to O
date O
, O
and O
their O
mechanisms O
of O
transpeptidation O
and O
regulation O
need O
to O
be O
further O
investigated O
. O

The O
available O
3 O
- O
dimensional O
structures O
of O
these O
enzymes O
reveal O
a O
typical O
sortase O
fold O
, O
except O
for O
the O
presence O
of O
a O
unique O
feature O
represented O
by O
an O
N B
- O
terminal O
highly O
flexible O
loop O
known O
as O
the O
" O
lid O
. O
" O
This O
region O
interacts O
with O
the O
residues O
composing O
the O
catalytic O
triad O
and O
covers O
the O
active O
site O
, O
thus O
maintaining O
the O
enzyme O
in O
an O
autoinhibited O
state O
and O
preventing O
the O
accessibility O
to O
the O
substrate O
. O

It O
is O
believed O
that O
enzyme O
activation O
may O
occur O
only O
after O
lid O
displacement O
from O
the O
catalytic O
domain O
. O

In O
this O
work O
, O
we O
provide O
the O
first O
direct O
evidence O
of O
the O
regulatory O
role O
of O
the O
lid O
, O
demonstrating O
that O
it O
is O
possible O
to O
obtain O
in O
vitro O
an O
efficient O
polymerization O
of O
pilin O
subunits O
using O
an O
active O
C O
sortase O
lid O
mutant O
carrying O
a O
single O
residue O
mutation O
in O
the O
lid O
region O
. O

Moreover O
, O
biochemical O
analyses O
of O
this O
recombinant O
mutant O
reveal O
that O
the O
lid O
confers O
thermodynamic O
and O
proteolytic O
stability O
to O
the O
enzyme O
. O
- O
Cozzi O
, O
R O
. O
, O
Zerbini O
, O
F O
. O
, O
Assfalg O
, O
M O
. O
, O
D O
' O
Onofrio O
, O
M O
. O
, O
Biagini O
, O
M O
. O
, O
Martinelli O
, O
M O
. O
, O
Nuccitelli O
, O
A O
. O
, O
Norais O
, O
N O
. O
, O
Telford O
, O
J O
. O

L O
. O
, O
Maione O
, O
D O
. O
, O
Rinaudo O
, O
C O
. O

D O
. O

Group O
B O
Streptococcus O
pilus O
sortase O
regulation O
: O
a O
single O
mutation O
in O
the O
lid O
region O
induces O
pilin O
protein O
polymerization O
in O
vitro O
. O

Anti O
- O
allergic O
actions O
of O
rottlerin B
from O
Mallotus O
philippinensis O
in O
experimental O
mast O
cell O
- O
mediated O
anaphylactic O
models O
. O

Allergy O
is O
an O
acquired O
hypersensitivity O
reaction O
of O
the O
immune O
system O
mediated O
by O
cross O
- O
linking O
of O
the O
allergen O
- O
specific O
IgE O
- O
bound O
high O
- O
affinity O
IgE O
receptors O
, O
leading O
to O
immediate O
mast O
cell O
degranulation O
. O

Rottlerin B
is O
an O
active O
molecule O
isolated O
from O
Mallotus O
philippinensis O
, O
a O
medicinal O
plant O
used O
in O
Ayurvedic O
Medicine O
System O
for O
anti O
- O
allergic O
and O
anti O
- O
helminthic O
treatments O
. O

The O
present O
study O
investigated O
potential O
anti O
- O
allergic O
effects O
of O
rottlerin B
in O
animal O
models O
of O
IgE O
- O
dependent O
anaphylaxis O
and O
the O
anti O
- O
allergic O
mechanisms O
of O
action O
of O
rottlerin B
in O
mast O
cells O
. O

Anti O
- O
allergic O
actions O
of O
rottlerin B
were O
evaluated O
in O
passive O
cutaneous O
anaphylaxis O
and O
passive O
systemic O
anaphylaxis O
mouse O
models O
, O
and O
in O
anaphylactic O
contraction O
of O
bronchial O
rings O
isolated O
from O
sensitized O
guinea O
pigs O
. O

Direct O
mast O
cell O
- O
stabilizing O
effect O
of O
rottlerin B
was O
examined O
in O
RBL O
- O
2H3 O
mast O
cell O
line O
. O

Anti O
- O
allergic O
signaling O
mechanisms O
of O
action O
of O
rottlerin B
in O
mast O
cells O
were O
also O
examined O
. O

Rottlerin B
prevented O
IgE O
- O
mediated O
cutaneous O
vascular O
extravasation O
, O
hypothermia O
, O
elevation O
in O
plasma O
histamine B
level O
and O
tracheal O
tissue O
mast O
cell O
degranulation O
in O
mice O
in O
a O
dose O
- O
dependent O
manner O
. O

In O
addition O
, O
rottlerin B
suppressed O
ovalbumin O
- O
induced O
guinea O
pig O
bronchial O
smooth O
muscle O
contraction O
. O

Furthermore O
, O
rottlerin B
concentration O
- O
dependently O
blocked O
IgE O
- O
mediated O
immediate O
release O
of O
beta O
- O
hexosaminidase O
from O
RBL O
- O
2H3 O
mast O
cells O
. O

Rottlerin B
was O
found O
to O
inhibit O
IgE O
- O
induced O
PLC O
gamma O
1 O
and O
Akt O
phosphorylation O
, O
production O
of O
IP3 O
and O
rise O
in O
cytosolic O
Ca B
( I
2 I
+ I
) I
level O
in O
mast O
cells O
. O

We O
report O
here O
for O
the O
first O
time O
that O
rottlerin B
possesses O
anti O
- O
allergic O
activity O
by O
blocking O
IgE O
- O
induced O
mast O
cell O
degranulation O
, O
providing O
a O
foundation O
for O
developing O
rottlerin B
for O
the O
treatment O
of O
allergic O
asthma O
and O
other O
mast O
cell O
- O
mediated O
allergic O
disorders O
. O

Clock O
Gene O
Expression O
in O
the O
Liver O
of O
Streptozotocin B
- O
induced O
and O
Spontaneous O
Type O
1 O
Diabetic O
Rats O
. O

Several O
investigations O
have O
shown O
a O
relation O
between O
diabetes O
and O
alterations O
of O
the O
liver O
circadian O
clock O
. O

We O
investigated O
the O
diurnal O
expression O
of O
clock O
genes O
and O
clock O
- O
controlled O
genes O
( O
CCGs O
) O
in O
3 O
- O
hour O
intervals O
for O
a O
24 O
- O
h O
period O
in O
the O
livers O
of O
male O
streptozotocin B
( O
STZ B
) O
- O
treated O
rats O
, O
male O
spontaneous O
type O
1 O
diabetic O
LEW O
. O
1AR1 O
- O
iddm O
( O
Iddm O
) O
rats O
, O
and O
Iddm O
rats O
treated O
for O
10 O
days O
with O
insulin O
. O

Hepatic O
mRNA O
was O
extracted O
, O
and O
the O
relative O
expression O
of O
clock O
genes O
( O
Per1 O
, O
Per2 O
, O
Bmal1 O
, O
Clock O
, O
Cry1 O
) O
, O
as O
well O
as O
CCGs O
( O
Dbp O
, O
E4bp4 O
, O
RevErb O
alpha O
, O
Ror O
alpha O
, O
Ppar O
gamma O
) O
, O
was O
analyzed O
by O
reverse O
transcription O
followed O
by O
real O
- O
time O
polymerase O
chain O
reaction O
. O

Diabetic O
STZ B
and O
Iddm O
rats O
, O
as O
well O
as O
insulin O
- O
substituted O
Iddm O
rats O
, O
exhibited O
a O
significant O
diurnal O
expression O
pattern O
of O
clock O
genes O
as O
determined O
by O
Cosinor O
analysis O
; O
however O
, O
the O
MESOR O
( O
midline O
estimating O
statistic O
of O
rhythm O
) O
of O
Bmal1 O
, O
Per2 O
, O
and O
Clock O
transcript O
expression O
was O
altered O
in O
Iddm O
and O
insulin O
- O
substituted O
Iddm O
rats O
. O

The O
hepatic O
expression O
of O
the O
CCGs O
Dbp O
and O
RevErb O
alpha O
revealed O
a O
diurnal O
rhythm O
in O
all O
investigated O
groups O
. O

Insulin O
administration O
to O
Iddm O
rats O
normalized O
the O
enhanced O
MESOR O
in O
the O
expression O
of O
Dbp O
, O
RevErb O
alpha O
, O
and O
E4bp4 O
to O
the O
levels O
of O
normoglycemic O
controls O
. O

Cosinor O
analysis O
indicated O
no O
diurnal O
rhythm O
of O
Ppar O
gamma O
expression O
in O
the O
livers O
of O
diabetic O
STZ B
or O
Iddm O
rats O
or O
in O
those O
of O
insulin O
- O
substituted O
Iddm O
rats O
. O

Also O
, O
insulin O
substitution O
could O
not O
reverse O
the O
decreased O
MESOR O
of O
Ppar O
gamma O
expression O
in O
Iddm O
rats O
. O

In O
consequence O
of O
the O
diabetic O
disease O
, O
changes O
in O
the O
expression O
of O
clock O
genes O
and O
CCGs O
suggest O
alterations O
in O
the O
hepatic O
peripheral O
clock O
mechanism O
. O

Studies O
on O
the O
Himbert O
Intramolecular O
Arene B
/ O
Allene B
Diels O
- O
Alder O
Cycloaddition O
. O

Mechanistic O
Studies O
and O
Expansion O
of O
Scope O
to O
All B
- I
Carbon I
Tethers O
. O

The O
unusual O
intramolecular O
arene B
/ O
allene B
cycloaddition O
described O
30 O
years O
ago O
by O
Himbert O
permits O
rapid O
access O
to O
strained O
polycyclic O
compounds O
that O
offer O
great O
potential O
for O
the O
synthesis O
of O
complex O
scaffolds O
. O

To O
more O
fully O
understand O
the O
mechanism O
of O
this O
cycloaddition O
reaction O
, O
and O
to O
guide O
efforts O
to O
extend O
its O
scope O
to O
new O
substrates O
, O
quantum O
mechanical O
computational O
methods O
were O
employed O
in O
concert O
with O
laboratory O
experiments O
. O

These O
studies O
indicated O
that O
the O
cycloadditions O
likely O
proceed O
via O
concerted O
processes O
; O
a O
stepwise O
biradical O
mechanism O
was O
shown O
to O
be O
higher O
in O
energy O
in O
the O
cases O
studied O
. O

The O
original O
Himbert O
cycloaddition O
chemistry O
is O
also O
extended O
from O
heterocyclic O
to O
carbocyclic B
systems O
, O
with O
computational O
guidance O
used O
to O
predict O
thermodynamically O
favorable O
cases O
. O

Complex O
polycyclic O
scaffolds O
result O
from O
the O
combination O
of O
the O
cycloaddition O
and O
subsequent O
ring O
- O
rearrangement O
metathesis O
reactions O
. O

Reversible O
Sliding O
in O
Networks O
of O
Nanowires O
. O

This O
work O
demonstrates O
that O
metal O
nanowires O
in O
a O
percolating O
network O
can O
reversibly O
slide O
across O
one O
another O
. O

Reversible O
sliding O
allows O
networks O
of O
metal O
nanowires O
to O
maintain O
electrical O
contact O
while O
being O
stretched O
to O
strains O
greater O
than O
the O
fracture O
strain O
for O
individual O
nanowires O
. O

This O
phenomenon O
was O
demonstrated O
by O
using O
networks O
of O
nanowires O
as O
compliant O
electrodes O
for O
a O
dielectric O
elastomer O
actuator O
. O

Reversible O
nanowire O
sliding O
enabled O
actuation O
to O
a O
maximum O
area O
strain O
of O
200 O
% O
, O
and O
repetitive O
cycling O
of O
the O
actuator O
to O
an O
area O
strain O
of O
25 O
% O
over O
150 O
times O
. O

During O
actuation O
, O
the O
transmittance O
of O
the O
network O
increased O
4 O
. O
5 O
times O
, O
from O
13 O
% O
to O
58 O
% O
. O

Compared O
to O
carbon B
- O
based O
compliant O
electrodes O
, O
networks O
of O
metal O
nanowires O
can O
actuate O
across O
a O
broader O
range O
of O
optical O
transmittance O
. O

The O
widely O
tunable O
transmittance O
of O
nanowire O
- O
based O
actuators O
allows O
for O
their O
use O
as O
a O
light O
valve O
. O

Piezotronic O
Effect O
in O
Solution O
- O
Grown O
p O
- O
Type O
ZnO B
Nanowires O
and O
Films O
. O

Investigating O
the O
piezotronic O
effect O
in O
p O
- O
type O
piezoelectric O
semiconductor O
is O
critical O
for O
developing O
a O
complete O
piezotronic O
theory O
and O
designing O
/ O
fabricating O
novel O
piezotronic O
applications O
with O
more O
complex O
functionality O
. O

Using O
a O
low O
temperature O
solution O
method O
, O
we O
were O
able O
to O
produce O
ultralong O
( O
up O
to O
60 O
mu O
m O
in O
length O
) O
Sb B
doped O
p O
- O
type O
ZnO B
nanowires O
on O
both O
rigid O
and O
flexible O
substrates O
. O

For O
the O
p O
- O
type O
nanowire O
field O
effect O
transistor O
, O
the O
on O
/ O
off O
ratio O
, O
threshold O
voltage O
, O
mobility O
, O
and O
carrier O
concentration O
of O
0 O
. O
2 O
% O
Sb B
- O
doped O
sample O
are O
found O
to O
be O
10 O
( O
5 O
) O
, O
2 O
. O
1 O
V O
, O
0 O
. O
82 O
cm O
( O
2 O
) O
. O
V O
( O
- O
1 O
) O
. O
s O
( O
- O
1 O
) O
, O
and O
2 O
. O
6 O
x O
10 O
( O
17 O
) O
cm O
( O
- O
3 O
) O
, O
respectively O
, O
and O
the O
corresponding O
values O
for O
1 O
% O
Sb B
doped O
samples O
are O
10 O
( O
4 O
) O
, O
2 O
. O
0 O
V O
, O
1 O
. O
24 O
cm O
( O
2 O
) O
. O
V O
( O
- O
1 O
) O

. O
s O
( O
- O
1 O
) O
, O
and O
3 O
. O
8 O
x O
10 O
( O
17 O
) O
cm O
( O
- O
3 O
) O
. O

We O
further O
investigated O
the O
universality O
of O
piezotronic O
effect O
in O
the O
as O
- O
synthesized O
Sb B
- O
doped O
p O
- O
type O
ZnO B
NWs O
and O
reported O
for O
the O
first O
time O
strain O
- O
gated O
piezotronic O
transistors O
as O
well O
as O
piezopotential O
- O
driven O
mechanical O
energy O
harvesting O
based O
on O
solution O
- O
grown O
p O
- O
type O
ZnO B
NWs O
. O

The O
results O
presented O
here O
broaden O
the O
scope O
of O
piezotronics O
and O
extend O
the O
framework O
for O
its O
potential O
applications O
in O
electronics O
, O
optoelectronics O
, O
smart O
MEMS O
/ O
NEMS O
, O
and O
human O
- O
machine O
interfacing O
. O

Topographically O
- O
patterned O
porous O
membranes O
in O
a O
microfluidic O
device O
as O
an O
in O
vitro O
model O
of O
renal O
reabsorptive O
barriers O
. O

Models O
of O
reabsorptive O
barriers O
require O
both O
a O
means O
to O
provide O
realistic O
physiologic O
cues O
to O
and O
quantify O
transport O
across O
a O
layer O
of O
cells O
forming O
the O
barrier O
. O

Here O
we O
have O
topographically O
- O
patterned O
porous O
membranes O
with O
several O
user O
- O
defined O
pattern O
types O
. O

To O
demonstrate O
the O
utility O
of O
the O
patterned O
membranes O
, O
we O
selected O
one O
type O
of O
pattern O
and O
applied O
it O
to O
a O
membrane O
to O
serve O
as O
a O
cell O
culture O
support O
in O
a O
microfluidic O
model O
of O
a O
renal O
reabsorptive O
barrier O
. O

The O
topographic O
cues O
in O
the O
model O
resemble O
physiological O
cues O
found O
in O
vivo O
while O
the O
porous O
structure O
allows O
quantification O
of O
transport O
across O
the O
cell O
layer O
. O

Sub O
- O
micron O
surface O
topography O
generated O
via O
hot O
- O
embossing O
onto O
a O
track O
- O
etched O
polycarbonate B
membrane O
, O
fully O
replicated O
topographical O
features O
and O
preserved O
porous O
architecture O
. O

Pore O
size O
and O
shape O
were O
analyzed O
with O
SEM O
and O
image O
analysis O
to O
determine O
the O
effect O
of O
hot O
embossing O
on O
pore O
morphology O
. O

The O
membrane O
was O
assembled O
into O
a O
bilayer O
microfluidic O
device O
and O
a O
human O
kidney O
proximal O
tubule O
epithelial O
cell O
line O
( O
HK O
- O
2 O
) O
and O
primary O
renal O
proximal O
tubule O
epithelial O
cells O
( O
RPTEC O
) O
were O
cultured O
to O
confluency O
on O
the O
membrane O
. O

Immunofluorescent O
staining O
of O
both O
cell O
types O
revealed O
protein O
expression O
indicative O
of O
the O
formation O
of O
a O
reabsorptive O
barrier O
responsive O
to O
mechanical O
stimulation O
: O
ZO O
- O
1 O
( O
tight O
junction O
) O
, O
paxillin O
( O
focal O
adhesions O
) O
and O
acetylated O
alpha O
- O
tubulin O
( O
primary O
cilia O
) O
. O

HK O
- O
2 O
and O
RPTEC O
aligned O
in O
the O
direction O
of O
ridge O
/ O
groove O
topography O
of O
the O
membrane O
in O
the O
device O
, O
evidence O
that O
the O
device O
has O
mechanical O
control O
over O
cell O
response O
. O

This O
topographically O
- O
patterned O
porous O
membrane O
provides O
an O
in O
vitro O
platform O
on O
which O
to O
model O
reabsorptive O
barriers O
with O
meaningful O
applications O
for O
understanding O
biological O
transport O
phenomenon O
, O
underlying O
disease O
mechanisms O
, O
and O
drug O
toxicity O
. O

Rapeseed O
oil O
- O
rich O
diet O
alters O
hepatic O
mitochondrial O
membrane O
lipid O
composition O
and O
disrupts O
bioenergetics O
. O

Diet O
is O
directly O
related O
with O
physiological O
alterations O
occurring O
at O
a O
cell O
and O
subcellular O
level O
. O

However O
, O
the O
role O
of O
diet O
manipulation O
on O
mitochondrial O
physiology O
is O
still O
largely O
unexplored O
. O

Aiming O
at O
correlating O
diet O
with O
alterations O
of O
mitochondrial O
membrane O
composition O
and O
bioenergetics O
, O
Wistar O
- O
Han O
male O
rats O
were O
fed O
for O
11 O
, O
22 O
and O
33 O
days O
with O
a O
rapeseed O
oil O
- O
based O
diet O
and O
mitochondrial O
bioenergetics O
, O
and O
membrane O
composition O
were O
compared O
at O
each O
time O
point O
with O
a O
standard O
diet O
group O
. O

Considerable O
differences O
were O
noticed O
in O
mitochondrial O
membrane O
lipid O
composition O
, O
namely O
in O
terms O
of O
fatty B
acyl I
chains O
and O
relative O
proportions O
of O
phospholipid O
classes O
, O
the O
modified O
diet O
inducing O
a O
decrease O
in O
the O
saturated O
to O
unsaturated O
molar O
ratio O
and O
an O
increase O
in O
the O
phosphatidylcholine B
to O
phosphatidylethanola B
molar O
ratio O
. O

Mass O
spectrometry O
lipid O
analysis O
showed O
significant O
differences O
in O
the O
major O
species O
of O
cardiolipin B
, O
with O
an O
apparent O
increased O
incorporation O
of O
oleic B
acid I
as O
a O
result O
of O
exposure O
to O
the O
modified O
diet O
. O

Rats O
fed O
the O
modified O
diet O
during O
22 O
days O
showed O
decreased O
hepatic O
mitochondrial O
state O
3 O
respiration O
and O
were O
more O
susceptible O
to O
Ca B
( I
2 I
+ I
) I
- O
induced O
transition O
pore O
opening O
. O

Rapeseed O
oil O
- O
enriched O
diet O
also O
appeared O
to O
promote O
a O
decrease O
in O
hydroperoxide B
production O
by O
the O
respiratory O
chain O
, O
although O
a O
simultaneous O
decrease O
in O
vitamin B
E I
content O
was O
detected O
. O

In O
conclusion O
, O
our O
data O
indicate O
that O
the O
rapeseed O
oil O
diet O
causes O
negative O
alterations O
on O
hepatic O
mitochondrial O
bioenergetics O
, O
which O
may O
result O
from O
membrane O
remodeling O
. O

Such O
alterations O
may O
have O
an O
impact O
not O
only O
on O
energy O
supply O
to O
the O
cell O
, O
but O
also O
on O
drug O
- O
induced O
hepatic O
mitochondrial O
liabilities O
. O

Individual O
multi O
- O
locus O
heterozygosity O
is O
associated O
with O
lower O
morning O
plasma O
cortisol B
concentration O
. O

OBJECTIVE O
. O

STRESS O
IS O
IMPLICATED O
AS O
A O
RISK O
FACTOR O
FOR O
NUMEROUS O
ILLNESSES O
IN O
HUMANS O
, O
PUTATIVELY O
IN O
PART O
MEDIATED O
BY O
BIOLOGICAL O
RESPONSES O
TO O
STRESS O
, O
SUCH O
AS O
ELEVATED O
CORTISOL B
. O

THE O
THEORY O
OF O
GENETIC O
HOMEOSTASIS O
SUGGESTS O
THAT O
INDIVIDUAL O
HETEROZYGOSITY O
FACILITATES O
COMPENSATION O
FOR O
ENVIRONMENTAL O
STRESSES O
. O

WE O
HYPOTHESIZED O
THAT O
HETEROZYGOSITY O
AMELIORATES O
THE O
BIOLOGICAL O
RESPONSE O
TO O
A O
GIVEN O
LEVEL O
OF O
PERCEIVED O
STRESS O
, O
REFLECTED O
IN O
LOWER O
PLASMA O
CORTISOL B
CONCENTRATIONS O
. O
DESIGN O
. O

WE O
EXAMINE O
THE O
ROLE O
OF O
HETEROZYGOSITY O
ON O
THE O
ASSOCIATION O
BETWEEN O
PERCEIVED O
PSYCHOLOGICAL O
STRESS O
AND O
MORNING O
CORTISOL B
CONCENTRATIONS O
IN O
854 O
INDIVIDUALS O
FROM O
THE O
ISOLATED O
ISLAND O
OF O
VIS O
, O
CROATIA O
. O
METHODS O
. O

CORTISOL B
WAS O
MEASURED O
IN O
MORNING O
PLASMA O
SAMPLES O
. O

1184 O
AUTOSOMAL O
MICROSATELLITE O
MARKERS O
WERE O
GENOTYPED O
AND O
INDIVIDUAL O
MULTI O
- O
LOCUS O
HETEROZYGOSITY O
WAS O
CALCULATED O
AS O
THE O
PROPORTION O
OF O
HETEROZYGOUS O
MARKERS O
. O

GENERAL O
HEALTH O
QUESTIONNAIRE O
( O
GHQ O
- O
30 O
) O
WAS O
USED O
TO O
ASSESS O
THE O
DEGREE O
OF O
PSYCHOLOGICAL O
DISTRESS O
. O
RESULTS O
. O

MEAN O
MULTI O
- O
LOCUS O
HETEROZYGOSITY O
WAS O
34 O
. O
850 O
. O
45 O
% O
( O
RANGE O
: O
31 O
. O
97 O
- O
36 O
. O
22 O
% O
) O
. O

Psychological O
distress O
( O
GHQ O
Likert O
score O
> O
31 O
) O
was O
more O
prevalent O
in O
women O
( O
37 O
% O
versus O
18 O
% O
in O
men O
, O
p O
< O
0 O
. O
0001 O
) O
, O
in O
less O
educated O
people O
( O
beta O
= O
- O
0 O
. O
35 O
per O
year O
in O
school O
, O
p O
< O
0 O
. O
001 O
) O
and O
in O
lower O
socio O
- O
economic O
classes O
( O
beta O
= O
- O
3 O
. O
59 O
, O
p O
< O
0 O
. O
0001 O
) O
. O

Cortisol B
was O
positively O
associated O
with O
psychological O
distress O
( O
beta O
= O
2 O
. O
20 O
, O
p O
= O
0 O
. O
01 O
) O
. O

In O
a O
regression O
model O
adjusting O
for O
age O
, O
BMI O
, O
education O
and O
GHQ O
- O
30 O
score O
, O
multi O
- O
locus O
heterozygosity O
was O
independently O
and O
inversely O
associated O
with O
morning O
plasma O
cortisol B
( O
p O
= O
0 O
. O
005 O
) O
. O
Conclusion O
. O

More O
heterozygous O
individuals O
, O
as O
measured O
by O
microsatellite O
markers O
, O
had O
lower O
morning O
plasma O
cortisol B
concentrations O
for O
a O
given O
level O
of O
perceived O
psychological O
stress O
. O

This O
may O
be O
important O
, O
as O
higher O
cortisol B
concentrations O
may O
increase O
allostatic O
load O
and O
be O
associated O
with O
higher O
risk O
of O
stress O
- O
related O
illness O
. O

Efficient O
Light O
Harvesting O
with O
Micropatterned O
3D O
Pyramidal O
Photoanodes O
in O
Dye O
- O
Sensitized O
Solar O
Cells O
. O

3D O
TiO2 B
photoanodes O
in O
dye O
- O
sensitized O
solar O
cells O
( O
DSCs O
) O
are O
fabricated O
by O
the O
soft O
lithographic O
technique O
for O
efficient O
light O
trapping O
. O

An O
extended O
strategy O
to O
the O
construction O
of O
randomized O
pyramid O
structure O
is O
developed O
by O
the O
conventional O
wet O
- O
etching O
of O
a O
silicon B
wafer O
for O
low O
- O
cost O
fabrication O
. O

Moreover O
, O
the O
futher O
enhancement O
of O
light O
absorption O
resulting O
in O
photocurrent O
increase O
is O
achieved O
by O
combining O
the O
3D O
photoanode O
with O
a O
conventional O
scattering O
layer O
. O

Buckling O
- O
Induced O
Reversible O
Symmetry O
Breaking O
and O
Amplification O
of O
Chirality O
Using O
Supported O
Cellular O
Structures O
. O

Buckling O
- O
induced O
reversible O
symmetry O
breaking O
and O
amplification O
of O
chirality O
using O
macro O
- O
and O
microscale O
supported O
cellular O
structures O
is O
described O
. O

Guided O
by O
extensive O
theoretical O
analysis O
, O
cellular O
structures O
are O
rationally O
designed O
, O
in O
which O
buckling O
induces O
a O
reversible O
switching O
between O
achiral O
and O
chiral O
configurations O
. O

Additionally O
, O
it O
is O
demonstrated O
that O
the O
proposed O
mechanism O
can O
be O
generalized O
over O
a O
wide O
range O
of O
length O
scales O
, O
geometries O
, O
materials O
, O
and O
stimuli O
. O

Upgraded O
Silicon B
Nanowires O
by O
Metal O
- O
Assisted O
Etching O
of O
Metallurgical O
Silicon B
: O
A O
New O
Route O
to O
Nanostructured O
Solar O
- O
Grade O
Silicon B
. O

Through O
metal O
assisted O
chemical O
etching O
( O
MaCE O
) O
, O
superior O
purification O
of O
dirty O
Si B
was O
observed O
, O
from O
99 O
. O
74 O
to O
99 O
. O
9884 O
% O
for O
metallurgical O
Si B
and O
from O
99 O
. O
999772 O
to O
99 O
. O
999899 O
% O
for O
upgraded O
metallurgical O
Si B
. O

Meanwhile O
, O
large O
area O
of O
silicon B
nanowires O
( O
SiNW O
) O
was O
fabricated O
. O

The O
purification O
effect O
induced O
~ O
35 O
% O
increase O
in O
photocurrent O
for O
SiNW O
based O
photoelectrochemical O
cell O
. O

High O
- O
Performance O
Vertical O
Organic O
Transistors O
. O

Vertical O
organic O
thin O
- O
film O
transistors O
( O
VOTFTs O
) O
are O
promising O
devices O
to O
overcome O
the O
transconductance O
and O
cut O
- O
off O
frequency O
restrictions O
of O
horizontal O
organic O
thin O
- O
film O
transistors O
. O

The O
basic O
physical O
mechanisms O
of O
VOTFT O
operation O
, O
however O
, O
are O
not O
well O
understood O
and O
VOTFTs O
often O
require O
complex O
patterning O
techniques O
using O
self O
- O
assembly O
processes O
which O
impedes O
a O
future O
large O
- O
area O
production O
. O

In O
this O
contribution O
, O
high O
- O
performance O
vertical O
organic O
transistors O
comprising O
pentacene B
for O
p O
- O
type O
operation O
and O
C60 B
for O
n O
- O
type O
operation O
are O
presented O
. O

The O
static O
current O
- O
voltage O
behavior O
as O
well O
as O
the O
fundamental O
scaling O
laws O
of O
such O
transistors O
are O
studied O
, O
disclosing O
a O
remarkable O
transistor O
operation O
with O
a O
behavior O
limited O
by O
injection O
of O
charge O
carriers O
. O

The O
transistors O
are O
manufactured O
by O
photolithography O
, O
in O
contrast O
to O
other O
VOTFT O
concepts O
using O
self O
- O
assembled O
source O
electrodes O
. O

Fluorinated O
photoresist O
and O
solvent O
compounds O
allow O
for O
photolithographical O
patterning O
directly O
and O
strongly O
onto O
the O
organic O
materials O
, O
simplifying O
the O
fabrication O
protocol O
and O
making O
VOTFTs O
a O
prospective O
candidate O
for O
future O
high O
- O
performance O
applications O
of O
organic O
transistors O
. O

Protective O
Role O
of O
( B
RS I
) I
- I
glucoraphanin I
Bioactivated O
with O
Myrosinase O
in O
an O
Experimental O
Model O
of O
Multiple O
Sclerosis O
. O

AIM O
: O
The O
discovery O
of O
new O
natural O
compounds O
with O
pharmacological O
properties O
is O
a O
field O
of O
interest O
widely O
growing O
. O

Recent O
literature O
shows O
that O
Brassica O
vegetables O
( O
Cruciferae O
) O
possess O
therapeutic O
effects O
particularly O
ascribed O
due O
to O
their O
content O
in O
glucosinolates B
, O
which O
upon O
myrosinase O
hydrolysis O
release O
the O
corresponding O
isothiocyanates B
. O

This O
study O
examines O
the O
potential O
neuroprotective O
and O
immunomodulatory O
effects O
of O
( B
RS I
) I
- I
glucoraphanin I
from O
Tuscan O
black O
kale O
( O
Brassica O
oleracea O
L O
. O
var O
. O
acephala O
sabellica O
) O
bioactivated O
with O
myrosinase O
( O
bioactive O
RS B
- I
GRA I
) O
( O
10 O
mg O
/ O
kg O
/ O
day O
intraperitoneally O
) O
, O
in O
an O
experimental O
autoimmune O
encephalomyelitis O
( O
EAE O
) O
, O
a O
model O
of O
multiple O
sclerosis O
. O

METHODS O
: O
EAE O
was O
induced O
by O
immunization O
with O
myelin O
oligodendroglial O
glycoprotein O
peptide O
( O
MOG35 O
- O
55 O
) O
in O
mice O
. O

After O
immunization O
, O
mice O
were O
observed O
daily O
for O
signs O
of O
EAE O
and O
weight O
loss O
. O

Clinical O
score O
was O
evaluated O
using O
a O
standardized O
scoring O
system O
. O

RESULTS O
: O
By O
Western O
blot O
analysis O
of O
spinal O
cord O
tissues O
, O
we O
have O
demonstrated O
that O
treatment O
with O
bioactive O
RS O
- O
GRA O
significantly O
decreased O
nuclear O
factor O
( O
NF O
) O
- O
kB O
translocation O
, O
pro O
- O
inflammatory O
cytokine O
production O
such O
as O
interleukin O
- O
1 O
beta O
( O
IL O
- O
1 O
beta O
) O
, O
and O
apoptosis O
( O
Bax O
and O
caspase O
3 O
expression O
) O
. O

CONCLUSION O
: O
Our O
results O
clearly O
demonstrate O
that O
bioactive O
RS O
- O
GRA O
treatment O
may O
represent O
a O
useful O
therapeutic O
perspective O
in O
the O
treatment O
of O
this O
disease O
. O

Anti O
- O
HIV O
and O
NO B
production O
inhibition O
activities O
of O
epi B
- I
aleuritolic I
acid I
derivatives O
. O

Fifteen O
epi B
- I
aleuritolic I
acid I
derivatives O
were O
synthesized O
and O
evaluated O
for O
anti O
- O
HIV O
activity O
in O
293 O
T O
cells O
and O
NO B
production O
inhibition O
activity O
. O

Of O
the O
derivatives O
, O
1 O
, O
2 O
, O
3 O
, O
4 O
, O
11 O
, O
and O
13 O
showed O
relatively O
potent O
anti O
- O
HIV O
activity O
with O
EC50 O
values O
ranging O
from O
5 O
. O
80 O
to O
13 O
. O
30 O
mu O
M O
. O

The O
most O
potent O
compound O
, O
3 B
alpha I
- I
2 I
' I
, I
2 I
' I
- I
dimethylsuccinic I
acyl I
epi I
- I
aleuritolic I
acid I
( O
11 O
) O
, O
displayed O
significant O
anti O
- O
HIV O
activity O
with O
an O
EC50 O
value O
of O
5 O
. O
80 O
mu O
M O
. O

Compounds O
1 O
, O
3 O
, O
4 O
, O
and O
11 O
showed O
NO B
inhibition O
activity O
, O
with O
IC50 O
values O
ranging O
from O
3 O
. O
40 O
to O
7 O
. O
10 O
mu O
M O
and O
compound O
1 O
inhibited O
NO B
production O
with O
an O
IC50 O
value O
of O
3 O
. O
40 O
mu O
M O
. O

Phytochemical O
investigation O
on O
Atriplex O
halimus O
L O
. O
from O
Sardinia O
. O

In O
this O
study O
, O
we O
reported O
the O
phytochemical O
composition O
of O
the O
aerial O
parts O
of O
Atriplex O
halimus O
L O
. O
collected O
from O
Sardinia O
. O

This O
species O
is O
a O
halophytic O
shrub O
, O
typical O
of O
the O
Mediterranean O
Basin O
. O

Four O
new O
glycosylated B
flavonoids I
were O
isolated O
and O
their O
structures O
were O
elucidated O
on O
the O
basis O
of O
1D O
, O
2D O
NMR O
and O
MS O
spectra O
as O
3 B
' I
, I
5 I
' I
- I
dimethoxymyricetin I
- I
3 I
- I
O I
- I
beta I
- I
d I
- I
xylopyranosyl I
- I
7 I
- I
O I
- I
fucopyranosyl I
- I
( I
1 I
- I
- I
> I
3 I
) I
- I
beta I
- I
d I
- I
glucopyranoside I
( O
1 O
) O
, O
3 B
' I
- I
methoxyquercetin I
- I
7 I
- I
O I
- I
beta I
- I
d I
- I
fucopyranosyl I
- I
( I
1 I
- I
- I

> I
3 I
) I
- I
beta I
- I
d I
- I
glucopyranosyl I
- I
3 I
- I
O I
- I
beta I
- I
xylopyranosyl I
- I
( I
1 I
- I
- I
> I
4 I
) I
- I
beta I
- I
xylopyranoside I
( O
2 O
) O
, O
3 B
' I
- I
methoxyquercetin I
- I
7 I
- I
O I
- I
alpha I
- I
l I
- I
rhamnopyranosyl I
- I
3 I
- I
O I
- I
alpha I
- I
arabinofuranosyl I
- I
( I
1 I
- I
- I
> I
6 I
) I
- I
beta I
- I
d I
- I
glucopyranoside I
( O
3 O
) O
and O
3 B
' I
, I
5 I
' I
- I
dimethoxymyricetin I
- I
7 I
- I
O I
- I

fucopyranosyl I
- I
( I
1 I
- I
- I
> I
3 I
) I
- I
beta I
- I
d I
- I
glucopyranoside I
( O
4 O
) O
. O

LC O
- O
MS O
( O
n O
) O
analysis O
on O
the O
extract O
revealed O
the O
presence O
of O
other O
myricetin B
, O
quercetin B
, O
isorhamnetin B
glycosides I
, O
simple O
phenolic B
acids I
and I
esters B
. O

Indanomycin B
- O
related O
antibiotics O
from O
marine O
Streptomyces O
antibioticus O
PTZ0016 O
. O

Four O
indanomycin B
- O
related O
antibiotics O
2 O
- O
5 O
were O
isolated O
from O
the O
cultured O
broth O
of O
marine O
Streptomyces O
antibioticus O
strain O
PTZ0016 O
. O

Their O
structures O
were O
characterised O
as O
16 B
- I
deethylindanomycin I
( O
2 O
) O
, O
iso B
- I
16 I
- I
deethylindanomycin I
( O
3 O
) O
, O
16 B
- I
deethylindanomycin I
methyl I
ester I
( O
4 O
) O
and O
iso B
- I
16 I
- I
deethylindanomycin I
methyl I
ester I
( O
5 O
) O
on O
the O
basis O
of O
NMR O
, O
HR O
- O
ESI O
- O
MS O
and O
CD O
evidences O
. O

Compounds O
3 O
- O
5 O
are O
new O
additions O
to O
the O
class O
of O
indanomycin B
antibiotics O
. O

All O
isolated O
compounds O
showed O
in O
vitro O
activity O
against O
Staphylococcus O
aureus O
with O
minimal O
inhibitory O
concentration O
at O
4 O
. O
0 O
- O
8 O
. O
0 O
mu O
g O
/ O
ml O
. O

Amelioration O
of O
palmitate B
- O
induced O
insulin O
resistance O
in O
C2C12 O
muscle O
cells O
by O
rooibos O
( O
Aspalathus O
linearis O
) O
. O

Increased O
levels O
of O
free O
fatty B
acids I
( O
FFAs O
) O
, O
specifically O
saturated O
free O
fatty B
acids I
such O
as O
palmitate B
are O
associated O
with O
insulin O
resistance O
of O
muscle O
, O
fat O
and O
liver O
. O

Skeletal O
muscle O
, O
responsible O
for O
up O
to O
80 O
% O
of O
the O
glucose B
disposal O
from O
the O
peripheral O
circulation O
, O
is O
particularly O
vulnerable O
to O
increased O
levels O
of O
saturated O
FFAs O
. O

Rooibos O
( O
Aspalathus O
linearis O
) O
and O
its O
unique O
dihydrochalcone B
C I
- I
glucoside I
, O
aspalathin B
, O
shown O
to O
reduce O
hyperglycemia O
in O
diabetic O
rats O
, O
could O
play O
a O
role O
in O
preventing O
or O
ameliorating O
the O
development O
of O
insulin O
resistance O
. O

This O
study O
aims O
to O
establish O
whether O
rooibos O
can O
ameliorate O
experimentally O
- O
induced O
insulin O
- O
resistance O
in O
C2C12 O
skeletal O
muscle O
cells O
. O

Palmitate B
- O
induced O
insulin O
resistant O
C2C12 O
cells O
were O
treated O
with O
an O
aspalathin B
- O
enriched O
green O
( O
unfermented O
) O
rooibos O
extract O
( O
GRE O
) O
, O
previously O
shown O
for O
its O
blood O
glucose B
lowering O
effect O
in O
vitro O
and O
in O
vivo O
or O
an O
aqueous O
extract O
of O
fermented O
rooibos O
( O
FRE O
) O
. O

Glucose B
uptake O
and O
mitochondrial O
activity O
were O
measured O
using O
2 B
- I
deoxy I
- I
[ I
( I
3 I
) I
H I
] I
- I
d I
- I
glucose I
, O
MTT B
and O
ATP B
assays O
, O
respectively O
. O

Expression O
of O
proteins O
relevant O
to O
glucose B
metabolism O
was O
analysed O
by O
Western O
blot O
. O

GRE O
contained O
higher O
levels O
of O
all O
compounds O
, O
except O
the O
enolic B
phenylpyruvic I
acid I
- I
2 I
- I
O I
- I
glucoside I
and O
luteolin B
- I
7 I
- I
O I
- I
glucoside I
. O

Both O
rooibos O
extracts O
increased O
glucose B
uptake O
, O
mitochondrial O
activity O
and O
ATP B
production O
. O

Compared O
to O
FRE O
, O
GRE O
was O
more O
effective O
at O
increasing O
glucose B
uptake O
and O
ATP B
production O
. O

At O
a O
mechanistic O
level O
both O
extracts O
down O
- O
regulated O
PKC O
theta O
activation O
, O
which O
is O
associated O
with O
palmitate B
- O
induced O
insulin O
resistance O
. O

Furthermore O
, O
the O
extracts O
increased O
activation O
of O
key O
regulatory O
proteins O
( O
AKT O
and O
AMPK O
) O
involved O
in O
insulin O
- O
dependent O
and O
non O
- O
insulin O
regulated O
signalling O
pathways O
. O

Protein O
levels O
of O
the O
glucose B
transporter O
( O
GLUT4 O
) O
involved O
in O
glucose B
transport O
via O
these O
two O
pathways O
were O
also O
increased O
. O

This O
in O
vitro O
study O
therefore O
confirms O
that O
rooibos O
can O
ameliorate O
palmitate B
- O
induced O
insulin O
resistance O
in O
C2C12 O
skeletal O
muscle O
cells O
. O

Inhibition O
of O
PKC O
theta O
activation O
and O
increased O
activation O
of O
AMPK O
and O
AKT O
offer O
a O
plausible O
mechanistic O
explanation O
for O
this O
ameliorative O
effect O
. O

Mikania O
laevigata O
: O
Chemical O
characterization O
and O
selective O
cytotoxic O
activity O
of O
extracts O
on O
tumor O
cell O
lines O
. O

Cancer O
is O
the O
second O
major O
cause O
of O
mortality O
worldwide O
, O
losing O
only O
to O
cardiovascular O
disease O
. O

Nowadays O
, O
around O
50 O
% O
of O
antineoplastic O
drugs O
were O
discovered O
and O
isolated O
by O
indications O
of O
plants O
in O
folk O
medicine O
. O

In O
Brazilian O
flora O
there O
are O
many O
species O
of O
plants O
which O
have O
great O
therapeutic O
importance O
, O
highlighting O
the O
Mikania O
laevigata O
( O
Asteraceae O
) O
that O
has O
been O
used O
for O
their O
valuable O
properties O
, O
especially O
in O
the O
respiratory O
tract O
. O

In O
the O
present O
study O
, O
the O
compounds O
of O
M O
. O
laevigata O
extracts O
were O
characterized O
by O
High O
Resolution O
Mass O
Spectrometry O
( O
HRMS O
) O
and O
Gas O
Chromatography O
with O
Mass O
analysis O
( O
GC O
/ O
MS O
- O
EI O
) O
. O

Therefore O
, O
the O
presence O
of O
some O
compounds O
with O
promising O
biological O
properties O
as O
antitumor O
activity O
was O
detected O
. O

Coumarin B
( O
1 B
, I
2 I
- I
benzopyrone I
) O
was O
previously O
reported O
as O
responsible O
for O
some O
biological O
activities O
of O
this O
plant O
species O
. O

Here O
, O
the O
extracts O
were O
evaluated O
by O
their O
cytotoxic O
activity O
against O
tumor O
( O
Hep O
- O
2 O
, O
HeLa O
) O
and O
non O
tumor O
( O
MRC O
- O
5 O
) O
cell O
lines O
, O
presenting O
significant O
inhibitory O
activity O
of O
cell O
growth O
in O
all O
extracts O
analyzed O
, O
chloroform B
, O
ethyl B
acetate I
, O
hexane B
, O
ethanol B
, O
which O
is O
related O
to O
its O
chemical O
composition O
. O

From O
the O
four O
different O
extracts O
here O
tested O
, O
two O
of O
them O
, O
hexane B
and O
ethanol B
, O
presented O
a O
clear O
selectivity O
against O
both O
tumor O
cells O
lines O
investigated O
. O

This O
can O
be O
explained O
by O
variances O
and O
increase O
of O
phenolic B
compounds O
in O
the O
ethanol B
fraction O
and O
an O
association O
of O
molecules O
with O
coumarin B
found O
in O
the O
hexane B
fraction O
. O

Rokumi O
- O
jio O
- O
gan O
- O
containing O
prescriptions O
regulate O
oxidative O
stress O
through O
improving O
dyslipidemia O
in O
a O
subtotal O
nephrectomized O
rat O
model O
. O

ETHNOPHARMACOLOGICAL O
RELEVANCE O
: O
Rokumi O
- O
jio O
- O
gan O
- O
containing O
prescriptions O
, O
traditional O
medicine O
, O
are O
widely O
used O
to O
treat O
renal O
dysfunction O
in O
Japan O
. O

AIM O
OF O
THE O
STUDY O
: O
The O
present O
study O
was O
conducted O
to O
examine O
whether O
two O
Rokumi O
- O
jio O
- O
gan O
- O
containing O
prescriptions O
( O
Hachimi O
- O
jio O
- O
gan O
and O
Bakumi O
- O
jio O
- O
gan O
) O
have O
an O
ameliorative O
effect O
on O
dyslipidemia O
in O
nephrectomized O
rats O
. O

MATERIALS O
AND O
METHODS O
: O
Each O
prescription O
was O
orally O
administered O
to O
nephrectomized O
rats O
at O
150mg O
/ O
kg O
body O
weight O
per O
day O
for O
10 O
weeks O
, O
and O
its O
effect O
was O
compared O
with O
vehicle O
- O
treated O
nephrectomized O
rats O
. O

RESULTS O
: O
Rats O
given O
Hachimi O
- O
jio O
- O
gan O
and O
Bakumi O
- O
jio O
- O
gan O
showed O
an O
improvement O
of O
renal O
functional O
parameters O
such O
as O
serum O
urea B
nitrogen B
, O
creatinine B
, O
creatinine B
clearance O
, O
and O
urinary O
protein O
. O

The O
increased O
triglyceride B
, O
total O
cholesterol B
, O
non O
- O
esterified O
fatty B
acid I
, O
high O
- O
density O
lipoprotein O
cholesterol B
, O
and O
very O
low O
- O
density O
lipoprotein O
cholesterol B
/ O
low O
- O
density O
lipoprotein O
cholesterol B
levels O
in O
serum O
, O
and O
triglyceride B
and O
total O
cholesterol B
contents O
in O
the O
kidney O
of O
nephrectomized O
rats O
were O
significantly O
decreased O
by O
Hachimi O
- O
jio O
- O
gan O
and O
Bakumi O
- O
jio O
- O
gan O
administration O
. O

Furthermore O
, O
Hachimi O
- O
jio O
- O
gan O
acts O
as O
a O
regulator O
of O
peroxisome O
proliferator O
- O
activated O
receptor O
alpha O
, O
sterol B
regulatory O
element O
binding O
protein O
( O
SREBP O
) O
- O
1 O
, O
and O
SREBP O
- O
2 O
. O

On O
the O
contrary O
, O
the O
increased O
reactive O
oxygen B
species O
and O
thiobarbituric B
acid I
- O
reactive O
substance O
were O
decreased O
, O
while O
superoxide B
dismutase O
and O
the O
reduced O
glutathione B
/ O
oxidized O
glutathione B
ratio O
were O
augmented O
by O
Hachimi O
- O
jio O
- O
gan O
rather O
than O
Bakumi O
- O
jio O
- O
gan O
. O

The O
improvement O
of O
nuclear O
factor O
- O
kappa O
Bp65 O
, O
cyclooxygenase O
- O
2 O
, O
inducible O
nitric B
oxide I
synthase O
, O
NF O
- O
E2 O
- O
related O
factor O
2 O
, O
and O
heme B
oxygenase O
- O
1 O
was O
marked O
in O
the O
group O
administered O
Bakumi O
- O
jio O
- O
gan O
. O

However O
, O
oil O
red O
O O
staining O
showed O
that O
the O
increased O
lipid O
deposition O
in O
the O
kidney O
of O
nephrectomized O
rats O
improved O
on O
Hachimi O
- O
jio O
- O
gan O
and O
Bakumi O
- O
jio O
- O
gan O
administration O
. O

CONCLUSION O
: O
This O
study O
provides O
scientific O
evidence O
that O
two O
Rokumi O
- O
jio O
- O
gan O
- O
containing O
prescriptions O
( O
Hachimi O
- O
jio O
- O
gan O
and O
Bakumi O
- O
jio O
- O
gan O
) O
improves O
oxidative O
stress O
via O
dyslipidemia O
in O
the O
remnant O
kidney O
of O
nephrectomized O
rats O
. O

Cyperi O
Rhizoma O
inhibits O
the O
1 B
- I
methyl I
- I
4 I
- I
phenyl I
- I
1 I
, I
2 I
, I
3 I
, I
6 I
- I
tetrahydropyridine I
- O
induced O
reduction O
in O
nigrostriatal O
dopaminergenic O
neurons O
in O
estrogen B
- O
deprived O
mice O
. O

ETHNOPHARMACOLOGICAL O
RELEVANCE O
: O
Cyperi O
Rhizoma O
has O
commonly O
been O
used O
for O
the O
treatment O
of O
gynecological O
and O
neuropsychiatric O
disorders O
in O
traditional O
medicine O
. O

The O
aim O
of O
this O
study O
was O
to O
evaluate O
the O
estrogenic O
properties O
and O
neuroprotective O
effects O
of O
Cyperi O
Rhizoma O
under O
estrogen B
- O
deprived O
condition O
in O
female O
mice O
. O

MATERIALS O
AND O
METHODS O
: O
To O
determine O
the O
estrogen B
- O
like O
effect O
of O
Cyperi O
Rhizoma O
extract O
( O
CRE O
) O
, O
we O
measured O
luciferase O
expression O
after O
transfection O
of O
a O
promoter O
construct O
containing O
an O
estrogen B
response O
element O
( O
ERE O
) O
and O
treatment O
of O
CRE O
. O

To O
evaluate O
the O
neuroprotective O
effect O
of O
CRE O
, O
we O
measured O
striatal O
dopamine B
, O
movement O
ability O
, O
tyrosine B
hydroxylase O
( O
TH O
) O
immunoreactivity O
, O
and O
apoptosis O
- O
related O
protein O
expression O
levels O
after O
treatment O
of O
CRE B
either O
with O
or O
without O
1 B
- I
methyl I
- I
4 I
- I
phenyl I
- I
1 I
, I
2 I
, I
3 I
, I
6 I
- I
tetrahydropyridine I
( O
MPTP B
) O
in O
ovariectomized O
female O
mice O
. O

RESULTS O
: O
CRE O
significantly O
induced O
the O
luciferase O
expression O
driven O
by O
an O
ERE O
in O
PC12 O
cells O
, O
a O
dopaminergic O
cell O
line O
, O
in O
a O
dose O
- O
dependent O
manner O
. O

In O
mice O
, O
MPTP B
significantly O
decreased O
the O
levels O
of O
dopamine B
in O
the O
striatum O
and O
behavior O
performance O
; O
in O
contrast O
, O
both O
CRE B
and O
17 B
beta I
- I
estradiol I
benzoate I
( O
EB O
) O
recovered O
these O
parameters O
to O
normal O
levels O
. O

CRE O
and O
EB O
treatment O
also O
recovered O
TH O
immunopositive O
fibers O
and O
cells O
, O
respectively O
, O
from O
MPTP B
toxicity O
. O

Additionally O
, O
MPTP B
significantly O
down O
- O
regulated O
Bcl O
- O
2 O
expression O
in O
the O
mitochondria O
of O
dopaminergic O
cells O
in O
the O
SN O
, O
followed O
by O
an O
increase O
in O
Bax O
expression O
, O
cytochrome O
C O
translocation O
to O
the O
cytosol O
, O
andcleaved O
- O
caspase O
- O
3 O
expression O
, O
whereas O
these O
were O
inhibited O
by O
CRE B
or O
EB O
treatment O
. O

CONCLUSIONS O
: O
These O
findings O
provide O
the O
first O
evidence O
that O
CRE O
has O
estrogen B
- O
like O
and O
neuroprotective O
effects O
on O
dopaminergic O
neurons O
in O
estrogen B
- O
deprived O
mice O
treated O
with O
MPTP B
- O
toxin O
. O

Antecedents O
and O
consequences O
of O
drug O
abuse O
in O
rats O
selectively O
bred O
for O
high O
and O
low O
response O
to O
novelty O
. O

Human O
genetic O
and O
epidemiological O
studies O
provide O
evidence O
that O
only O
a O
subset O
of O
individuals O
who O
experiment O
with O
potentially O
addictive O
drugs O
become O
addicts O
. O

What O
renders O
some O
individuals O
susceptible O
to O
addiction O
remains O
to O
be O
determined O
, O
but O
most O
would O
agree O
that O
there O
is O
no O
single O
trait O
underlying O
the O
disorder O
. O

However O
, O
there O
is O
evidence O
in O
humans O
that O
addiction O
liability O
has O
a O
genetic O
component O
, O
and O
that O
certain O
personality O
characteristics O
related O
to O
temperament O
( O
e O
. O
g O
. O
the O
sensation O
- O
seeking O
trait O
) O
are O
associated O
with O
individual O
differences O
in O
addiction O
liability O
. O

Consequently O
, O
we O
have O
used O
a O
selective O
breeding O
strategy O
based O
on O
locomotor O
response O
to O
a O
novel O
environment O
to O
generate O
two O
lines O
of O
rats O
with O
distinct O
behavioral O
characteristics O
. O

We O
have O
found O
that O
the O
resulting O
phenotypes O
differ O
on O
a O
number O
of O
neurobehavioral O
dimensions O
relevant O
to O
addiction O
. O

Relative O
to O
bred O
low O
- O
responder O
( O
bLR O
) O
rats O
, O
bred O
high O
- O
responder O
( O
bHR O
) O
rats O
exhibit O
increased O
exploratory O
behavior O
, O
are O
more O
impulsive O
, O
more O
aggressive O
, O
seek O
stimuli O
associated O
with O
rewards O
, O
and O
show O
a O
greater O
tendency O
to O
relapse O
. O

We O
therefore O
utilize O
this O
unique O
animal O
model O
to O
parse O
the O
genetic O
, O
neural O
and O
environmental O
factors O
that O
contribute O
to O
addiction O
liability O
. O

Our O
work O
shows O
that O
the O
glucocorticoid O
receptor O
( O
GR O
) O
, O
dopaminergic O
molecules O
, O
and O
members O
of O
the O
fibroblast O
growth O
factor O
family O
are O
among O
the O
neurotransmitters O
and O
neuromodulators O
that O
play O
a O
role O
in O
both O
the O
initial O
susceptibility O
to O
addiction O
as O
well O
as O
the O
altered O
neural O
responses O
that O
follow O
chronic O
drug O
exposure O
. O

Moreover O
, O
our O
findings O
suggest O
that O
the O
hippocampus O
plays O
a O
major O
role O
in O
mediating O
vulnerability O
to O
addiction O
. O

It O
is O
hoped O
that O
this O
work O
will O
emphasize O
the O
importance O
of O
personalized O
treatment O
strategies O
and O
identify O
novel O
therapeutic O
targets O
for O
humans O
suffering O
from O
addictive O
disorders O
. O

This O
article O
is O
part O
of O
a O
Special O
Issue O
entitled O
' O
NIDA O
40th O
Anniversary O
Issue O
' O
. O

Fusidic B
acid I
and O
rifampicin B
co O
- O
loaded O
PLGA B
nanofibers O
for O
the O
prevention O
of O
orthopedic O
implant O
associated O
infections O
. O

Implant O
- O
associated O
infections O
following O
invasive O
orthopedic O
surgery O
are O
a O
major O
clinical O
problem O
, O
and O
are O
one O
of O
the O
primary O
causes O
of O
joint O
failure O
following O
total O
joint O
arthroplasty O
. O

Current O
strategies O
using O
perioperative O
antibiotics O
have O
been O
met O
with O
little O
clinical O
success O
and O
have O
resulted O
in O
various O
systemic O
toxicities O
and O
the O
promotion O
of O
antibiotic O
resistant O
microorganisms O
. O

Here O
we O
report O
the O
development O
of O
a O
biodegradable O
localized O
delivery O
system O
using O
poly B
( I
D I
, I
L I
- I
lactic I
acid I
- I
co I
- I
glycolic I
acid I
) I
( O
PLGA B
) O
for O
the O
combinatorial O
release O
of O
fusidic B
acid I
( O
FA O
) O
( O
or O
its O
sodium B
salt O
; O
SF O
) O
and O
rifampicin B
( O
RIF B
) O
using O
electrospinning O
. O

The O
drug O
- O
loaded O
formulations O
showed O
good O
antibiotic O
encapsulation O
( O
~ O
75 O
% O
- O
100 O
% O
) O
, O
and O
a O
biphasic O
drug O
release O
profile O
. O

All O
dual O
- O
loaded O
formulations O
showed O
direct O
antimicrobial O
activity O
in O
vitro O
against O
Staphylococcus O
epidermidis O
, O
and O
two O
strains O
of O
methicillin B
- O
resistant O
Staphylococcus O
aureus O
( O
MRSA O
) O
. O

Furthermore O
, O
lead O
formulations O
containing O
10 O
% O
( O
w O
/ O
w O
) O
FA O
/ O
SF O
and O
5 O
% O
( O
w O
/ O
w O
) O
RIF O
were O
able O
to O
prevent O
the O
adherence O
of O
MRSA O
to O
a O
titanium B
implant O
in O
an O
in O
vivo O
rodent O
model O
of O
subcutaneous O
implant O
- O
associated O
infection O
. O

Immune O
circuits O
in O
asthma O
. O

Asthma O
is O
an O
inflammatory O
disorder O
of O
the O
conducting O
airways O
that O
has O
traditionally O
been O
classified O
according O
to O
severity O
. O

While O
this O
has O
been O
helpful O
in O
guiding O
treatment O
with O
drugs O
that O
are O
currently O
available O
such O
as O
beta O
2 O
- O
adrenoceptor O
agonists O
and O
corticosteroids B
, O
it O
takes O
little O
account O
of O
disease O
heterogeneity O
and O
causal O
pathways O
. O

This O
review O
draws O
attention O
to O
subphenotypes O
of O
asthma O
involving O
different O
mechanisms O
and O
moves O
the O
focus O
away O
from O
the O
adaptive O
immune O
response O
more O
towards O
innate O
immune O
mechanisms O
. O

This O
mandates O
a O
new O
view O
of O
the O
disease O
in O
which O
causal O
pathways O
linked O
to O
biomarkers O
are O
found O
and O
treatments O
targeted O
to O
these O
pathways O
as O
described O
in O
a O
more O
personalised O
approach O
to O
medicine O
. O

Synthesis O
, O
spectral O
and O
antimicrobial O
evaluation O
of O
some O
novel O
1 B
- I
methyl I
- I
3 I
- I
alkyl I
- I
2 I
, I
6 I
- I
diphenylpiperidin I
- I
4 I
- I
one I
oxime I
carbonates I
. O

Synthesis O
of O
some O
novel O
biologically O
active O
piperidin B
- I
4 I
- I
one I
oxime I
carbonates I
from O
1 B
- I
methyl I
- I
3alkyl I
- I
2 I
, I
6 I
- I
diphenylpiperidin I
- I
4 I
- I
one I
oximes I
and O
substituted O
chloroformates B
was O
carried O
out O
in O
the O
presence O
of O
potassium B
carbonate I
as O
base O
and O
tetrabutylammonium B
bromide I
( O
TBAB B
) O
as O
catalyst O
. O

The O
newly O
synthesized O
compounds O
were O
characterized O
by O
IR O
, O
( B
1 I
) I
H I
, O
( B
13 I
) I
C I
NMR O
and O
LC O
- O
mass O
spectra O
. O

Based O
on O
the O
( B
1 I
) I
H I
NMR O
analysis O
, O
all O
the O
compounds O
were O
found O
to O
adopt O
normal O
chair O
conformation O
with O
equatorial O
orientation O
of O
all O
the O
substituents O
. O

For O
all O
the O
synthesized O
compounds O
( O
5a O
- O
5l O
) O
antimicrobial O
activity O
has O
been O
tested O
against O
bacterial O
and O
fungal O
strains O
using O
Streptomycin B
and O
Amphotericin B
B I
as O
standards O
. O

Synthesis O
of O
proline B
analogues O
as O
potent O
and O
selective O
cathepsin O
S O
inhibitors O
. O

Cathepsin O
S O
is O
a O
potential O
target O
of O
autoimmune O
disease O
. O

A O
series O
of O
proline B
derived O
compounds O
were O
synthesized O
and O
evaluated O
as O
cathepsin O
S O
inhibitors O
. O

We O
discovered O
potent O
cathepsin O
S O
inhibitors O
through O
structure O
- O
activity O
relationship O
studies O
of O
proline B
analogues O
. O

In O
particular O
, O
compound O
19 O
- O
( O
S O
) O
showed O
promising O
in O
vitro O
/ O
vivo O
pharmacological O
activities O
and O
properties O
as O
a O
selective O
cathepsin O
S O
inhibitor O
. O

The O
preventive O
effect O
of O
uncarboxylated O
osteocalcin O
against O
free O
fatty B
acid I
- O
induced O
endothelial O
apoptosis O
through O
the O
activation O
of O
phosphatidylinositol B
3 O
- O
kinase O
/ O
Akt O
signaling O
pathway O
: O
Uncarboxylated O
osteocalcin O
and O
endothelial O
apoptosis O
. O

OBJECTIVE O
: O
Increasing O
evidence O
suggests O
that O
osteocalcin O
( O
OC O
) O
, O
one O
of O
the O
osteoblast O
- O
specific O
proteins O
, O
has O
been O
associated O
with O
atherosclerosis O
, O
but O
results O
are O
conflicting O
. O

The O
aim O
of O
this O
study O
was O
to O
elucidate O
the O
independent O
effect O
of O
uncarboxylated O
osteocalcin O
( O
ucOC O
) O
, O
an O
active O
form O
of O
osteocalcin O
which O
has O
been O
suggested O
to O
have O
an O
insulin O
sensitizing O
effect O
, O
on O
vascular O
endothelial O
cells O
. O

MATERIALS O
AND O
METHODS O
: O
We O
used O
human O
aortic O
endothelial O
cells O
and O
treated O
them O
with O
ucOC O
. O

Linoleic B
acid I
( O
LA O
) O
was O
used O
as O
a O
representative O
free O
fatty B
acid I
. O

Apoptosis O
was O
evaluated O
using O
various O
methods O
including O
a O
terminal O
deoxyribonucleotide B
transferase O
- O
mediated O
deoxyuridine B
triphosphate I
nick O
- O
end O
labeling O
analysis O
kit O
and O
Western O
blotting O
for O
cleaved O
caspase O
3 O
, O
cleaved O
poly B
( I
ADP I
- I
ribose I
) I
polymerase O
and O
Bcl O
- O
xL O
. O

The O
phosphorylations O
of O
Akt O
and O
endothelial O
nitric B
oxide I
synthase O
( O
eNOS O
) O
as O
well O
as O
the O
level O
of O
NO B
were O
measured O
to O
confirm O
the O
effect O
of O
ucOC O
on O
insulin O
signaling O
pathway O
. O

RESULTS O
: O
Pretreatment O
of O
ucOC O
( O
30ng O
/ O
ml O
) O
prevented O
LA O
- O
induced O
apoptosis O
in O
insulin O
- O
stimulated O
endothelial O
cells O
; O
effects O
were O
abolished O
by O
pretreatment O
with O
the O
phosphatidylinositol B
3 O
- O
kinase O
( O
PI3 O
- O
kinase O
) O
inhibitor O
, O
wortmannin B
. O

Treatment O
of O
ucOC O
( O
ranged O
from O
0 O
. O
3 O
to O
30ng O
/ O
ml O
) O
significantly O
increased O
the O
phosphorylation O
of O
Akt O
and O
eNOS O
and O
nitric B
oxide I
secretion O
from O
endothelial O
cells O
in O
a O
PI3 O
- O
kinase O
dependent O
manner O
. O

CONCLUSIONS O
: O
Our O
study O
is O
the O
first O
to O
demonstrate O
the O
independent O
effect O
of O
ucOC O
on O
vascular O
endothelial O
cells O
. O

Our O
results O
further O
suggest O
that O
ucOC O
could O
have O
beneficial O
effects O
on O
atherosclerosis O
. O

Gene O
expression O
profiling O
and O
pathway O
analysis O
of O
hepatotoxicity O
induced O
by O
triptolide B
in O
Wistar O
rats O
. O

Triptolide B
( O
TP O
) O
, O
a O
major O
component O
of O
TWHF O
, O
is O
widely O
used O
to O
treat O
rheumatoid O
arthritis O
, O
systemic O
lupus O
erythematosus O
, O
nephritis O
and O
leprosy O
. O

However O
, O
its O
clinical O
use O
is O
limited O
by O
hepatotoxicity O
. O

To O
further O
elucidate O
the O
underlying O
mechanism O
of O
its O
hepatotoxic O
effects O
, O
hepatic O
gene O
expression O
profiles O
were O
analyzed O
. O

TP O
( O
1000 O
and O
300 O
mu O
g O
/ O
kg O
) O
was O
orally O
administered O
to O
Wistar O
rats O
for O
14days O
. O

Current O
study O
indicated O
that O
female O
rats O
were O
more O
sensitive O
to O
TP O
- O
induced O
hepatotoxicity O
than O
males O
. O

Genome O
- O
wide O
microarray O
analyses O
identified O
3329 O
differentially O
expressed O
genes O
in O
liver O
of O
female O
rats O
. O

Analyses O
of O
these O
genes O
identified O
over O
- O
represented O
functions O
associated O
with O
insulin O
signaling O
pathway O
, O
glucose B
metabolism O
, O
cell O
cycle O
, O
oxidative O
stress O
and O
apoptosis O
, O
which O
were O
consistent O
with O
the O
results O
of O
significant O
increase O
of O
Caspase O
- O
3 O
activity O
and O
reduction O
of O
serum O
glucose B
, O
GSH B
/ O
GSSG B
ratio O
, O
glucose B
- O
6 O
- O
phosphatase O
and O
phosphoenolpyruvate B
carboxykinase O
activities O
, O
liver O
glycogen O
. O

In O
addition O
, O
it O
was O
observed O
for O
the O
first O
time O
that O
glucocorticoids O
and O
IGF1 O
might O
get O
involved O
in O
TP O
- O
induced O
hepatotoxicity O
. O

These O
data O
suggest O
that O
TP O
treatment O
could O
alter O
the O
hepatic O
redox O
status O
, O
reduce O
serum O
glucose B
and O
induce O
hepatocyte O
apoptosis O
, O
consistent O
with O
the O
differential O
expression O
of O
genes O
involved O
in O
insulin O
signaling O
pathway O
, O
glucose B
metabolism O
pathway O
and O
cell O
stress O
pathway O
, O
all O
of O
which O
might O
contribute O
to O
the O
overall O
TP O
- O
induced O
hepatotoxicity O
. O

TCDD B
induces O
the O
expression O
of O
insulin O
- O
like O
growth O
factor O
binding O
protein O
4 O
in O
5L O
rat O
hepatoma O
cells O
: O
a O
cautionary O
tale O
of O
the O
use O
of O
this O
cell O
line O
in O
studies O
on O
dioxin B
toxicity O
. O

Previous O
quantitative O
proteomic O
studies O
on O
the O
actions O
of O
2 B
, I
3 I
, I
7 I
, I
8 I
- I
tetrachlorodibenzo I
- I
p I
- I
dioxin I
( O
TCDD B
) O
in O
5L O
rat O
hepatoma O
cells O
, O
a O
cell O
model O
frequently O
used O
for O
investigating O
the O
mechanisms O
of O
TCDD B
toxicity O
, O
had O
indicated O
that O
dioxin B
exposure O
reduced O
the O
abundance O
of O
numerous O
proteins O
which O
are O
regulated O
at O
the O
level O
of O
protein O
synthesis O
initiation O
. O

In O
the O
present O
study O
, O
we O
have O
analysed O
the O
mechanism O
mediating O
this O
inhibition O
. O

TCDD B
treatment O
of O
the O
cells O
largely O
prevented O
the O
activation O
of O
eukaryotic O
translation O
initiation O
factor O
4E O
- O
binding O
protein O
1 O
, O
a O
regulator O
of O
translation O
initiation O
and O
substrate O
of O
the O
mammalian O
target O
of O
rapamycin B
( O
mTOR O
) O
. O

By O
" O
working O
upwards O
" O
from O
mTOR O
, O
we O
observed O
that O
TCDD B
inhibited O
endogenous O
and O
IGF O
- O
I O
- O
induced O
AKT O
and O
ERK O
activation O
by O
interfering O
with O
tyrosine B
phosphorylation O
of O
insulin O
receptor O
substrate O
1 O
. O

This O
inhibition O
was O
mediated O
by O
a O
TCDD B
- O
induced O
secreted O
factor O
which O
was O
identified O
as O
insulin O
- O
like O
growth O
factor O
binding O
protein O
4 O
( O
IGFBP O
- O
4 O
) O
. O

The O
induction O
of O
IGFBP O
- O
4 O
protein O
was O
dependent O
on O
a O
functional O
aryl B
hydrocarbon I
receptor O
and O
was O
preceded O
by O
a O
rapid O
increase O
in O
the O
level O
of O
IGFBP O
- O
4 O
mRNA O
indicating O
that O
IGFBP O
- O
4 O
is O
a O
previously O
unknown O
transcriptional O
target O
of O
TCDD B
in O
5L O
cells O
. O

IGFBP O
- O
4 O
was O
not O
induced O
by O
TCDD B
in O
the O
parental O
cell O
line O
of O
5L O
cells O
, O
Fao O
, O
and O
in O
various O
closely O
related O
rat O
hepatoma O
cell O
lines O
as O
well O
as O
in O
other O
unrelated O
cell O
types O
. O

Analysis O
of O
5L O
cell O
chromosomes O
by O
multicolour O
spectral O
karyotyping O
( O
SKY O
) O
revealed O
that O
the O
cells O
carry O
several O
hitherto O
uncharacterised O
chromosomal O
translocations O
. O

The O
observations O
suggest O
that O
in O
5L O
cells O
the O
Igfbp O
- O
4 O
gene O
may O
have O
got O
under O
the O
control O
of O
a O
promoter O
containing O
dioxin B
responsive O
element O
( O
s O
) O
leading O
to O
the O
induction O
of O
IGFBP O
- O
4 O
by O
TCDD B
. O

These O
findings O
emphasise O
a O
particular O
caution O
when O
interpreting O
and O
extrapolating O
results O
on O
the O
action O
mechanisms O
of O
TCDD B
obtained O
in O
studies O
using O
5L O
cells O
as O
a O
model O
system O
. O

Pyrazole B
derivatives O
as O
inhibitors O
of O
arachidonic B
acid I
- O
induced O
platelet O
aggregation O
. O

Antiplatelet O
drugs O
are O
promising O
therapeutics O
to O
intervene O
with O
platelet O
aggregation O
in O
arterial O
thrombosis O
, O
most O
prominently O
in O
myocardial O
infarction O
and O
ischemic O
stroke O
. O

Here O
, O
we O
describe O
the O
synthesis O
and O
structure O
- O
activity O
relationships O
of O
potent O
inhibitors O
of O
platelet O
aggregation O
based O
on O
the O
1 B
, I
5 I
- I
diarylpyrazol I
- I
3 I
- I
carboxamide I
scaffold O
. O

Analogs O
from O
this O
series O
demonstrated O
potent O
anti O
- O
aggregatory O
activities O
against O
arachidonic B
acid I
- O
induced O
platelet O
aggregation O
, O
as O
measured O
by O
turbidimetric O
method O
of O
Born O
. O

1 B
, I
5 I
- I
Diarylpyrazole I
- I
3 I
- I
carboxamides I
obtained O
with O
small O
- O
basic O
amines B
( O
7 O
, O
8 O
, O
50 O
, O
51 O
, O
61 O
, O
62 O
) O
displayed O
the O
strongest O
activity O
with O
IC50 O
values O
in O
low O
nanomolar O
range O
( O
5 O
. O
7 O
- O
83 O
nM O
) O
. O

On O
the O
basis O
of O
their O
high O
potency O
in O
cellular O
environment O
, O
these O
straightforward O
pyrazole B
derivatives O
may O
possess O
potential O
in O
the O
design O
of O
more O
potent O
compounds O
for O
intervention O
with O
cardiovascular O
diseases O
. O

A O
selective O
antagonist O
reveals O
a O
potential O
role O
of O
G O
protein O
- O
coupled O
receptor O
55 O
in O
platelet O
and O
endothelial O
cell O
function O
. O

The O
G O
protein O
coupled O
receptor O
55 O
( O
GPR55 O
) O
is O
a O
lysophosphatidylinos B
( O
LPI O
) O
receptor O
that O
is O
also O
responsive O
to O
certain O
cannabinoids B
. O

Although O
GPR55 O
has O
been O
implicated O
in O
several O
( O
patho O
) O
physiological O
functions O
, O
its O
role O
is O
still O
enigmatic O
mainly O
owing O
to O
the O
lack O
of O
selective O
GPR55 O
antagonists O
. O

Here O
we O
show O
that O
the O
compound O
CID16020046 B
( O
( B
4 I
- I
[ I
4 I
- I
( I
3 I
- I
hydroxyphenyl I
) I
- I
3 I
- I
( I
4 I
- I
methylphenyl I
) I
- I
6 I
- I
oxo I
- I
1H I
, I
4H I
, I
5H I
, I
6H I
- I
pyrrolo I
[ I
3 I
, I
4 I
- I
c I
] I
pyrazol I
- I
5 I
- I
yl I
] I
benzoic I
acid I
) O
is O
a O
selective O
GPR55 O
antagonist O
. O

In O
yeast O
cells O
expressing O
human O
GPR55 O
, O
CID16020046 B
antagonized O
agonist O
- O
induced O
receptor O
activation O
. O

In O
HEK293 O
cells O
stably O
expressing O
human O
GPR55 O
( O
HEK O
- O
GPR55 O
) O
, O
the O
compound O
behaved O
as O
an O
antagonist O
on O
LPI O
- O
mediated O
Ca2 B
+ I
release O
and O
extracellular O
signal O
- O
regulated O
kinases O
( O
ERK1 O
/ O
2 O
) O
activation O
, O
but O
not O
in O
HEK293 O
cells O
expressing O
cannabinoid O
receptor O
1 O
or O
2 O
( O
CB1 O
or O
CB2 O
) O
. O

CID16020046 B
concentration O
- O
dependently O
inhibited O
LPI O
- O
induced O
activation O
of O
nuclear O
factor O
of O
activated O
T O
- O
cells O
( O
NFAT O
) O
, O
nuclear O
factor O
kappa O
of O
activated O
B O
cells O
( O
NF O
- O
kappa O
B O
) O
and O
serum O
response O
element O
( O
SRE O
) O
, O
translocation O
of O
NFAT O
and O
NF O
- O
kappa O
B O
, O
and O
GPR55 O
internalization O
. O

It O
reduced O
LPI O
- O
induced O
wound O
healing O
in O
primary O
human O
lung O
microvascular O
endothelial O
cells O
( O
HMVEC O
- O
L O
) O
and O
reversed O
LPI O
- O
inhibited O
platelet O
aggregation O
, O
suggesting O
a O
novel O
role O
for O
GPR55 O
in O
platelet O
and O
endothelial O
cell O
function O
. O

CID16020046 B
is O
therefore O
a O
valuable O
tool O
to O
study O
GPR55 O
- O
mediated O
mechanisms O
in O
primary O
cells O
and O
tissues O
. O

Method O
for O
quantitative O
measurements O
of O
the O
elastic O
modulus O
of O
biological O
cells O
in O
AFM O
indentation O
experiments O
. O

Here O
we O
overview O
and O
further O
develop O
a O
quantitative O
method O
to O
measure O
mechanics O
of O
biological O
cells O
in O
indentation O
experiments O
, O
which O
is O
based O
on O
the O
use O
of O
atomic O
force O
microscopy O
( O
AFM O
) O
. O

We O
demonstrate O
how O
the O
elastic O
modulus O
of O
the O
cell O
body O
should O
be O
measured O
when O
the O
cellular O
brush O
is O
taken O
into O
account O
. O

The O
brush O
is O
an O
essential O
inelastic O
part O
of O
the O
cell O
, O
which O
surrounds O
all O
eukaryotic O
( O
the O
brush O
is O
mostly O
microvilli O
and O
glycocalyx O
) O
and O
gram O
- O
negative O
prokaryotic O
cells O
( O
the O
brush O
is O
polysaccharides O
) O
. O

The O
other O
main O
feature O
of O
the O
described O
method O
is O
the O
use O
of O
a O
relatively O
dull O
AFM O
probe O
to O
stay O
in O
the O
linear O
stress O
- O
strain O
regime O
. O

In O
particular O
, O
we O
show O
that O
the O
elastic O
modulus O
( O
aka O
the O
Young O
' O
s O
modulus O
) O
of O
cells O
is O
independent O
of O
the O
indentation O
depth O
up O
to O
10 O
- O
20 O
% O
deformation O
for O
the O
eukaryotic O
cells O
studied O
here O
. O

Besides O
the O
elastic O
modulus O
, O
the O
method O
presented O
allows O
obtaining O
the O
parameters O
of O
cellular O
brush O
, O
such O
as O
the O
effective O
length O
and O
grafting O
density O
of O
the O
brush O
. O

Although O
the O
method O
is O
demonstrated O
on O
eukaryotic O
cells O
, O
it O
is O
directly O
applicable O
for O
all O
types O
of O
cells O
, O
and O
even O
non O
- O
biological O
soft O
materials O
surrounded O
by O
either O
a O
brush O
or O
any O
field O
of O
long O
- O
range O
forces O
. O

Prostaglandin B
E2 I
acts O
via O
bone O
marrow O
macrophages O
to O
block O
PTH O
- O
stimulated O
osteoblast O
differentiation O
in O
vitro O
. O

Intermittent O
PTH O
is O
the O
major O
anabolic O
therapy O
for O
osteoporosis O
while O
continuous O
PTH O
causes O
bone O
loss O
. O

PTH O
acts O
on O
the O
osteoblast O
( O
OB O
) O
lineage O
to O
regulate O
bone O
resorption O
and O
formation O
. O

PTH O
also O
induces O
cyclooxygenase O
- O
2 O
( O
COX O
- O
2 O
) O
, O
producing O
prostaglandin B
E2 I
( O
PGE2 B
) O
, O
that O
can O
act O
on O
both O
OBs O
and O
osteoclasts O
( O
OCs O
) O
. O

Because O
intermittent O
PTH O
is O
more O
anabolic O
in O
Cox O
- O
2 O
knockout O
( O
KO O
) O
than O
wild O
type O
( O
WT O
) O
mice O
, O
we O
hypothesized O
COX O
- O
2 O
might O
contribute O
to O
the O
effects O
of O
continuous O
PTH O
by O
suppressing O
PTH O
- O
stimulated O
differentiation O
of O
mesenchymal O
stem O
cells O
into O
OBs O
. O

We O
compared O
effects O
of O
continuous O
PTH O
on O
bone O
marrow O
stromal O
cells O
( O
BMSCs O
) O
and O
primary O
OBs O
( O
POBs O
) O
from O
Cox O
- O
2 O
KO O
mice O
, O
mice O
with O
deletion O
of O
PGE2 B
receptors O
( O
Ptger4 O
and O
Ptger2 O
KO O
mice O
) O
, O
and O
WT O
controls O
. O

PTH O
increased O
OB O
differentiation O
in O
BMSCs O
only O
in O
the O
absence O
of O
COX O
- O
2 O
expression O
or O
activity O
. O

In O
the O
absence O
of O
COX O
- O
2 O
, O
PTH O
stimulated O
differentiation O
if O
added O
during O
the O
first O
week O
of O
culture O
. O

In O
Cox O
- O
2 O
KO O
BMSCs O
, O
PTH O
- O
stimulated O
differentiation O
was O
prevented O
by O
adding O
PGE2 B
to O
cultures O
. O

Co O
- O
culture O
of O
POBs O
with O
M O
- O
CSF O
- O
expanded O
bone O
marrow O
macrophages O
( O
BMMs O
) O
showed O
that O
the O
inhibition O
of O
PTH O
- O
stimulated O
OB O
differentiation O
required O
not O
only O
COX O
- O
2 O
or O
PGE2 B
but O
also O
BMMs O
. O

Sufficient O
PGE2 B
to O
mediate O
the O
inhibitory O
effect O
was O
made O
by O
either O
WT O
POBs O
or O
WT O
BMMs O
. O

The O
inhibitory O
effect O
mediated O
by O
COX O
- O
2 O
/ O
PGE2 O
was O
transferred O
by O
conditioned O
media O
from O
RANKL O
- O
treated O
BMMs O
and O
could O
be O
blocked O
by O
osteoprotegerin O
, O
which O
interferes O
with O
RANKL O
binding O
to O
its O
receptor O
on O
OC O
lineage O
cells O
. O

Deletion O
of O
Ptger4 O
, O
but O
not O
Ptger2 O
, O
in O
BMMs O
prevented O
the O
inhibition O
of O
PTH O
- O
stimulated O
OB O
differentiation O
. O

As O
expected O
, O
PGE2 B
also O
stimulated O
OB O
differentiation O
, O
but O
when O
given O
in O
combination O
with O
PTH O
, O
the O
stimulatory O
effects O
of O
both O
were O
abrogated O
. O

These O
data O
suggest O
that O
PGE2 B
, O
acting O
via O
EP4R O
on O
BMMs O
committed O
to O
the O
OC O
lineage O
, O
stimulated O
secretion O
of O
a O
factor O
or O
factors O
that O
acted O
to O
suppress O
PTH O
- O
stimulated O
OB O
differentiation O
. O

This O
suppression O
of O
OB O
differentiation O
could O
contribute O
to O
the O
bone O
loss O
seen O
with O
continuous O
PTH O
in O
vivo O
. O

Zno B
nanoparticle O
based O
highly O
efficient O
CdS B
/ O
CdSe B
quantum O
dot O
- O
sensitized O
solar O
cells O
. O

20 O
nm O
ZnO B
nanoparticles O
are O
used O
to O
fabricate O
the O
mesoporous O
photoanode O
of O
the O
CdS B
/ O
CdSe B
quantum O
dot O
- O
sensitized O
solar O
cells O
by O
the O
simple O
doctor O
blade O
method O
. O

A O
maximum O
power O
conversion O
efficiency O
of O
4 O
. O
46 O
% O
has O
been O
achieved O
, O
which O
indicated O
exciting O
prospects O
for O
ZnO B
nanoparticle O
based O
quantum O
dot O
- O
sensitized O
solar O
cells O
. O

A O
randomized O
, O
double O
- O
blind O
, O
placebo O
- O
controlled O
crossover O
study O
of O
alpha O
4 O
beta O
2 O
* O
nicotinic O
acetylcholine B
receptor O
agonist O
AZD1446 B
( O
TC B
- I
6683 I
) O
in O
adults O
with O
attention O
- O
deficit O
/ O
hyperactivity O
disorder O
. O

RATIONALE O
: O
Stimulation O
of O
nicotinic O
cholinergic O
systems O
has O
been O
shown O
to O
alleviate O
ADHD O
symptoms O
and O
to O
improve O
cognitive O
performance O
. O

AZD1446 B
is O
a O
selective O
alpha O
4 O
beta O
2 O
* O
nicotinic O
acetylcholine B
receptor O
agonist O
with O
potential O
effect O
on O
the O
symptoms O
of O
ADHD O
. O

OBJECTIVES O
: O
The O
purpose O
of O
this O
study O
is O
to O
evaluate O
the O
efficacy O
, O
safety O
, O
and O
pharmacokinetics O
of O
AZD1446 B
in O
adults O
with O
ADHD O
treated O
for O
2 O
weeks O
. O

METHOD O
: O
This O
was O
a O
randomized O
, O
double O
- O
blind O
, O
placebo O
- O
controlled O
crossover O
trial O
. O

Participants O
were O
79 O
adults O
with O
ADHD O
, O
grouped O
according O
to O
their O
use O
of O
nicotine B
- O
containing O
products O
. O

Nicotine B
non O
- O
users O
received O
placebo O
and O
two O
of O
three O
AZD1446 B
treatment O
regimens O
( O
80 O
mg O
tid O
, O
80 O
mg O
qd O
, O
10 O
mg O
tid O
) O
. O

Nicotine B
users O
received O
placebo O
, O
AZD1446 B
80 O
mg O
tid O
and O
80 O
mg O
qd O
. O

Efficacy O
measures O
included O
the O
Conners O
' O
Adult O
ADHD O
Rating O
Scale O
and O
cognitive O
measures O
of O
immediate O
and O
delayed O
verbal O
episodic O
memory O
, O
learning O
, O
attention O
, O
working O
memory O
, O
executive O
functioning O
, O
and O
spatial O
problem O
solving O
( O
CogState O
computerized O
test O
battery O
) O
. O

RESULTS O
: O
There O
was O
no O
significant O
effect O
of O
AZD1446 B
on O
any O
of O
the O
clinical O
scores O
irrespective O
of O
dose O
, O
schedule O
, O
or O
concomitant O
use O
of O
nicotine B
products O
. O

A O
statistically O
significant O
improvement O
was O
seen O
on O
the O
Groton O
Maze O
Learning O
Task O
, O
a O
measure O
of O
executive O
functioning O
, O
in O
nicotine B
non O
- O
users O
after O
treatment O
with O
AZD1446 B
80 O
mg O
qd O
. O

CONCLUSIONS O
: O
AZD1446 B
was O
well O
tolerated O
, O
but O
did O
not O
significantly O
improve O
ADHD O
symptoms O
after O
2 O
weeks O
of O
treatment O
compared O
to O
placebo O
. O

While O
the O
present O
study O
does O
not O
support O
the O
therapeutic O
utility O
of O
AZD1446 B
in O
ADHD O
, O
its O
potential O
pro O
- O
cognitive O
effects O
remain O
to O
be O
explored O
in O
other O
neuropsychiatric O
disorders O
. O

Modelling O
the O
Cost O
Effectiveness O
of O
Disease O
- O
Modifying O
Treatments O
for O
Multiple O
Sclerosis O
: O
Issues O
to O
Consider O
. O

Several O
cost O
- O
effectiveness O
models O
of O
disease O
- O
modifying O
treatments O
( O
DMTs O
) O
for O
multiple O
sclerosis O
( O
MS O
) O
have O
been O
developed O
for O
different O
populations O
and O
different O
countries O
. O

Vast O
differences O
in O
the O
approaches O
and O
discrepancies O
in O
the O
results O
give O
rise O
to O
heated O
discussions O
and O
limit O
the O
use O
of O
these O
models O
. O

Our O
main O
objective O
is O
to O
discuss O
the O
methodological O
challenges O
in O
modelling O
the O
cost O
effectiveness O
of O
treatments O
for O
MS O
. O

We O
conducted O
a O
review O
of O
published O
models O
to O
describe O
the O
approaches O
taken O
to O
date O
, O
to O
identify O
the O
key O
parameters O
that O
influence O
the O
cost O
effectiveness O
of O
DMTs O
, O
and O
to O
point O
out O
major O
areas O
of O
weakness O
and O
uncertainty O
. O

Thirty O
- O
six O
published O
models O
and O
analyses O
were O
identified O
. O

The O
greatest O
source O
of O
uncertainty O
is O
the O
absence O
of O
head O
- O
to O
- O
head O
randomized O
clinical O
trials O
. O

Modellers O
have O
used O
various O
techniques O
to O
compensate O
, O
including O
utilizing O
extension O
trials O
. O

The O
use O
of O
large O
observational O
cohorts O
in O
recent O
studies O
aids O
in O
identifying O
population O
- O
based O
, O
' O
real O
- O
world O
' O
treatment O
effects O
. O

Major O
drivers O
of O
results O
include O
the O
time O
horizon O
modelled O
and O
DMT O
acquisition O
costs O
. O

Model O
endpoints O
must O
target O
either O
policy O
makers O
( O
using O
cost O
- O
utility O
analysis O
) O
or O
clinicians O
( O
conducting O
cost O
- O
effectiveness O
analyses O
) O
. O

Lastly O
, O
the O
cost O
effectiveness O
of O
DMTs B
outside O
North O
America O
and O
Europe O
is O
currently O
unknown O
, O
with O
the O
lack O
of O
country O
- O
specific O
data O
as O
the O
major O
limiting O
factor O
. O

We O
suggest O
that O
limited O
data O
should O
not O
preclude O
analyses O
, O
as O
models O
may O
be O
built O
and O
updated O
in O
the O
future O
as O
data O
become O
available O
. O

Disclosure O
of O
modelling O
methods O
and O
assumptions O
could O
improve O
the O
transferability O
and O
applicability O
of O
models O
designed O
to O
reflect O
different O
healthcare O
systems O
. O

Three O
Ubiquitination O
Sites O
of O
Organic O
Anion O
Transporter O
- O
1 O
Synergistically O
Mediate O
Protein O
Kinase O
C O
- O
dependent O
Endocytosis O
of O
the O
Transporter O
. O

Organic O
anion O
transporter O
- O
1 O
( O
OAT1 O
) O
mediates O
the O
body O
disposition O
of O
a O
diverse O
array O
of O
clinically O
important O
drugs O
, O
including O
anti O
- O
HIV O
therapeutics O
, O
anti O
- O
tumor O
drugs O
, O
antibiotics O
, O
anti O
- O
hypertensives O
, O
and O
anti O
- O
inflammatories O
. O

Therefore O
, O
understanding O
the O
regulation O
of O
OAT1 O
has O
profound O
clinical O
significance O
. O

We O
previously O
established O
that O
OAT1 O
constitutively O
internalizes O
from O
and O
recycles O
back O
to O
cell O
surface O
, O
and O
that O
activation O
of O
protein O
kinase O
C O
( O
PKC O
) O
inhibits O
OAT1 O
activity O
by O
promoting O
ubiquitination O
of O
the O
transporter O
, O
which O
then O
leads O
to O
an O
accelerated O
internalization O
of O
the O
transporter O
from O
cell O
surface O
to O
intracellular O
compartments O
. O

In O
the O
current O
study O
, O
we O
demonstrated O
that O
PKC O
isoform O
PKC O
- O
alpha O
was O
responsible O
for O
OAT1 O
ubiquitination O
. O

To O
directly O
address O
the O
role O
of O
OAT1 O
ubiquitination O
, O
we O
then O
generated O
two O
OAT1 O
mutants O
, O
each O
having O
multiple O
lysines B
( O
K O
) O
simultaneously O
mutated O
to O
arginine B
( O
R O
) O
. O

One O
mutant O
K163 O
/ O
297 O
/ O
303 O
/ O
315 O
/ O
321R O
lost O
sensitivities O
to O
PKC O
- O
induced O
inhibition O
of O
transport O
activity O
, O
to O
PKC O
- O
induced O
ubiquitination O
, O
and O
to O
PKC O
- O
induced O
acceleration O
of O
transporter O
internalization O
. O

Further O
dissecting O
each O
lysine B
within O
this O
mutant O
, O
we O
identified O
Lys297 B
, O
Lys303 B
and O
Lys315 B
being O
the O
ubiquitin O
- O
conjugation O
sites O
. O

Interestingly O
, O
mutating O
any O
one O
of O
the O
three O
lysines B
prevented O
the O
ubiquitin O
- O
conjugation O
to O
the O
other O
two O
lysines B
, O
suggesting O
that O
Lys297 B
, O
Lys303 B
and O
Lys315 B
may O
form O
an O
optimal O
structure O
to O
interact O
with O
ubiquitination O
machineries O
. O

This O
is O
the O
first O
demonstration O
that O
Lys297 B
, O
Lys303 B
and O
Lys315 B
play O
synergistic O
role O
in O
PKC O
- O
regulated O
OAT1 O
ubiquitination O
, O
trafficking O
and O
transport O
activity O
. O

Progesterone B
receptor O
induces O
bcl O
- O
x O
expression O
through O
intragenic O
binding O
sites O
favoring O
RNA O
polymerase O
II O
elongation O
. O

Steroid B
receptors O
were O
classically O
described O
for O
regulating O
transcription O
by O
binding O
to O
target O
gene O
promoters O
. O

However O
, O
genome O
- O
wide O
studies O
reveal O
that O
steroid B
receptors O
- O
binding O
sites O
are O
mainly O
located O
at O
intragenic O
regions O
. O

To O
determine O
the O
role O
of O
these O
sites O
, O
we O
examined O
the O
effect O
of O
progestins B
on O
the O
transcription O
of O
the O
bcl O
- O
x O
gene O
, O
where O
only O
intragenic O
progesterone B
receptor O
- O
binding O
sites O
( O
PRbs O
) O
were O
identified O
. O

We O
found O
that O
in O
response O
to O
hormone O
treatment O
, O
the O
PR O
is O
recruited O
to O
these O
sites O
along O
with O
two O
histone O
acetyltransferases O
CREB O
- O
binding O
protein O
( O
CBP O
) O
and O
GCN5 O
, O
leading O
to O
an O
increase O
in O
histone O
H3 O
and O
H4 O
acetylation O
and O
to O
the O
binding O
of O
the O
SWI O
/ O
SNF O
complex O
. O

Concomitant O
, O
a O
more O
relaxed O
chromatin O
was O
detected O
along O
bcl O
- O
x O
gene O
mainly O
in O
the O
regions O
surrounding O
the O
intragenic O
PRbs O
. O

PR O
also O
mediated O
the O
recruitment O
of O
the O
positive O
elongation O
factor O
pTEFb O
, O
favoring O
RNA O
polymerase O
II O
( O
Pol O
II O
) O
elongation O
activity O
. O

Together O
these O
events O
promoted O
the O
re O
- O
distribution O
of O
the O
active O
Pol O
II O
toward O
the O
3 O
' O
- O
end O
of O
the O
gene O
and O
a O
decrease O
in O
the O
ratio O
between O
proximal O
and O
distal O
transcription O
. O

These O
results O
suggest O
a O
novel O
mechanism O
by O
which O
PR O
regulates O
gene O
expression O
by O
facilitating O
the O
proper O
passage O
of O
the O
polymerase O
along O
hormone O
- O
dependent O
genes O
. O

Seawater O
- O
driven O
magnesium B
based O
Janus O
micromotors O
for O
environmental O
remediation O
. O

We O
describe O
the O
use O
of O
seawater O
as O
fuel O
to O
propel O
Janus O
micromotors O
. O

The O
new O
micromotors O
consist O
of O
biodegradable O
and O
environmentally O
friendly O
magnesium B
microparticles O
and O
a O
nickel B
- O
gold O
bilayer O
patch O
for O
magnetic O
guidance O
and O
surface O
modification O
. O

Such O
seawater O
- O
driven O
micromotors O
, O
which O
utilize O
macrogalvanic O
corrosion O
and O
chloride B
pitting O
corrosion O
processes O
, O
eliminate O
the O
need O
for O
external O
fuels O
to O
offer O
efficient O
and O
prolonged O
propulsion O
towards O
diverse O
applications O
in O
aquatic O
environments O
. O

Electrically O
driven O
ultraviolet O
random O
lasing O
from O
an O
n O
- O
MgZnO B
/ O
i B
- O
ZnO B
/ O
SiO2 B
/ O
p B
- O
Si B
asymmetric O
double O
heterojunction O
. O

Electrically O
pumped O
lasing O
action O
has O
been O
realized O
in O
ZnO B
from O
an O
n O
- O
MgZnO B
/ O
i O
- O
ZnO B
/ O
SiO2 B
/ O
p O
- O
Si B
asymmetric O
double O
heterostructure O
, O
an O
ultralow O
threshold O
of O
3 O
. O
9 O
mA O
was O
obtained O
. O

The O
mechanism O
of O
the O
laser O
is O
associated O
with O
the O
in O
- O
plane O
random O
resonator O
cavities O
formed O
in O
the O
ZnO B
films O
and O
the O
elaborate O
hollow O
- O
shaped O
SiO2 B
cladding O
pattern O
, O
which O
prevent O
the O
lateral O
diffusion O
of O
injection O
current O
and O
ultimately O
lower O
the O
threshold O
current O
of O
the O
laser O
diode O
. O

In O
addition O
, O
a O
waveguide O
mechanism O
due O
to O
different O
refractive O
indices O
of O
three O
epilayers O
enhances O
the O
guided O
optical O
field O
on O
the O
ZnO B
side O
, O
resulting O
in O
an O
improved O
light O
extraction O
efficiency O
. O

Drug O
- O
Induced O
Macular O
Edema O
. O

Macular O
edema O
constitutes O
a O
serious O
pathologic O
entity O
of O
ophthalmology O
resulting O
in O
vision O
loss O
with O
a O
remarkable O
impact O
on O
the O
quality O
of O
life O
of O
patients O
. O

It O
is O
the O
final O
common O
pathway O
of O
various O
systemic O
diseases O
and O
underlying O
intraocular O
conditions O
, O
with O
diabetes O
mellitus O
being O
the O
most O
frequent O
cause O
. O

Other O
causes O
include O
venous O
occlusive O
disease O
, O
intraocular O
surgery O
, O
and O
inflammatory O
conditions O
of O
the O
posterior O
segment O
of O
the O
eye O
. O

Macular O
edema O
is O
a O
recognized O
side O
effect O
of O
various O
systemic O
and O
local O
medications O
and O
requires O
special O
consideration O
among O
ophthalmologists O
and O
other O
clinicians O
. O

Recently O
, O
antidiabetic O
thiazolidinediones B
have O
been O
implicated O
in O
the O
development O
of O
macular O
edema O
, O
and O
a O
review O
of O
the O
English O
literature O
revealed O
that O
other O
systemically O
administered O
drugs O
like O
fingolimod B
, O
recently O
approved O
for O
relapsing O
forms O
of O
multiple O
sclerosis O
, O
the O
anticancer O
agents O
tamoxifen B
and O
the O
taxanes B
, O
as O
well O
as O
niacin B
and O
interferons O
have O
been O
reported O
to O
cause O
macular O
edema O
. O

Ophthalmologic O
pharmaceutical O
agents O
, O
like O
prostaglandin B
analogs O
, O
epinephrine B
, O
timolol B
, O
and O
ophthalmic O
preparation O
preservatives O
have O
also O
been O
reported O
to O
cause O
macular O
edema O
as O
an O
adverse O
event O
. O

The O
purpose O
of O
this O
article O
is O
to O
provide O
a O
short O
, O
balanced O
overview O
of O
the O
available O
evidence O
in O
this O
regard O
. O

The O
available O
data O
and O
the O
possible O
pathophysiologic O
mechanisms O
leading O
to O
the O
development O
of O
macular O
edema O
are O
discussed O
. O

Possible O
therapeutic O
strategies O
for O
drug O
- O
induced O
macular O
edema O
are O
also O
proposed O
. O

A O
Highly O
Crystalline O
Manganese B
- I
Doped I
Iron I
Oxide I
Nanocontainer O
with O
Predesigned O
Void O
Volume O
and O
Shape O
for O
Theranostic O
Applications O
. O

Hollow O
Mn B
- I
doped I
iron I
oxide I
nanocontainers O
, O
formed O
by O
a O
novel O
one O
- O
pot O
synthetic O
process O
, O
fulfill O
the O
dual O
requirements O
of O
delivering O
an O
effective O
dose O
of O
an O
anticancer O
drug O
to O
tumor O
tissue O
and O
enabling O
image O
- O
contrast O
monitoring O
of O
the O
nanocontainer O
fate O
through O
T2 O
- O
weighted O
magnetic O
resonance O
imaging O
, O
thereby O
determining O
the O
optimal O
balance O
between O
diagnostic O
and O
therapeutic O
moieties O
in O
an O
all O
- O
in O
- O
one O
theranostic O
nanoplatform O
. O

Oxygen B
- O
functionalized O
few O
- O
layer O
graphene B
sheets O
as O
active O
catalysts O
for O
oxidative O
dehydrogenation O
reactions O
. O

Invited O
for O
this O
month O
' O
s O
cover O
is O
the O
group O
from O
the O
Center O
for O
Nanophase O
Materials O
Sciences O
( O
CNMS O
) O
at O
the O
Oak O
Ridge O
National O
Laboratory O
. O

The O
illustration O
is O
of O
the O
catalytic O
activity O
of O
the O
reported O
oxygen B
- O
functionalized O
few O
- O
layer O
graphenes B
, O
whereas O
the O
micrograph O
background O
image O
is O
of O
the O
same O
graphenes B
recorded O
by O
the O
authors O
using O
a O
new O
helium B
- O
ion O
microscope O
at O
the O
CNMS O
. O

Read O
the O
full O
text O
of O
the O
article O
at O
10 O
. O
1002 O
/ O
cssc O
. O
201200756 O
. O

NUCLEOSIDE B
REVERSE O
TRANSCRIPTASE O
INHIBITORS O
INDUCE O
A O
MITOPHAGY O
- O
ASSOCIATED O
ENDOTHELIAL O
DYSFUNCTION O
THAT O
IS O
REVERSED O
BY O
COENZYME B
Q10 I
CO O
- O
TREATMENT O
. O

Cardiovascular O
complications O
have O
been O
documented O
in O
HIV O
- O
1 O
infected O
populations O
, O
and O
antiretroviral O
therapy O
may O
play O
a O
role O
. O

Nucleoside B
reverse O
transcriptase O
inhibitors O
( O
NRTI O
) O
are O
antiretrovirals O
known O
to O
induce O
mitochondrial O
damage O
in O
endothelial O
cells O
, O
culminating O
in O
endothelial O
dysfunction O
, O
an O
initiating O
event O
in O
atherogenesis O
. O

Though O
the O
mechanism O
for O
NRTI O
- O
induced O
endothelial O
toxicity O
is O
not O
yet O
clear O
, O
our O
prior O
work O
suggested O
that O
a O
mitochondrial O
oxidative O
stress O
may O
be O
involved O
. O

To O
further O
delineate O
the O
mechanism O
of O
toxicity O
, O
endothelial O
cells O
were O
treated O
with O
NRTI O
of O
varying O
subclasses O
, O
and O
the O
level O
of O
reactive O
oxygen B
species O
( O
ROS O
) O
and O
mitochondrial O
function O
were O
assessed O
. O

To O
test O
whether O
rescue O
of O
mitochondrial O
electron O
transport O
attenuated O
NRTI O
- O
induced O
endothelial O
dysfunction O
, O
in O
some O
cases O
, O
cells O
were O
co O
- O
treated O
with O
the O
electron O
transport O
cofactor O
coenzyme B
Q10 I
( O
Q10 B
) O
. O

At O
4 O
- O
6h O
, O
NRTI O
increased O
levels O
of O
ROS O
but O
decreased O
the O
activities O
of O
electron O
transport O
chain O
complexes O
I O
- O
IV O
, O
levels O
of O
ATP B
and O
the O
NAD B
/ O
NADH B
ratio O
. O

Moreover O
, O
nitric B
oxide I
levels O
were O
decreased O
, O
while O
endothelin O
- O
1 O
release O
was O
increased O
. O

Q10 B
abolished O
NRTI O
- O
induced O
mitochondria O
injury O
and O
effects O
on O
endothelial O
agonist O
production O
. O

Interestingly O
, O
in O
cells O
treated O
with O
NRTI O
only O
, O
markers O
for O
mitochondrial O
toxicity O
returned O
to O
baseline O
levels O
by O
18 O
- O
24h O
, O
suggesting O
a O
compensatory O
mechanism O
for O
clearing O
damaged O
mitochondria O
. O

Using O
confocal O
microscopy O
, O
with O
confirmation O
utilizing O
the O
autophagy O
and O
mitophagy O
markers O
LC O
- O
3 O
and O
NIX O
, O
respectively O
, O
we O
observed O
autophagy O
of O
mitochondria O
at O
8 O
- O
10 O
h O
after O
treatment O
. O

Q10 B
prevented O
NRTI O
- O
mediated O
increase O
in O
LC O
- O
3 O
. O

These O
findings O
suggest O
that O
NRTI O
- O
induced O
mitophagy O
may O
be O
involved O
in O
NRTI O
- O
induced O
endothelial O
dysfunction O
and O
that O
this O
damage O
likely O
results O
from O
oxidant O
injury O
. O

Further O
, O
Q10 B
supplementation O
could O
potentially O
prevent O
NRTI O
- O
induced O
endothelial O
dysfunction O
. O

X O
- O
ray O
structure O
analysis O
and O
characterization O
of O
AFUEI O
, O
an O
elastase O
inhibitor O
from O
Aspergillus O
fumigatus O
. O

Elastase O
from O
Aspergillus O
sp O
. O

is O
an O
important O
factor O
for O
aspergillosis O
. O

AFUEI O
is O
an O
inhibitor O
of O
the O
elastase O
derived O
from O
Aspergillus O
fumigatus O
. O

AFUEI O
is O
a O
member O
of O
the O
I78 O
inhibitor O
family O
, O
and O
has O
a O
high O
inhibitory O
activity O
against O
elastases O
of O
Aspergillus O
fumigatus O
and O
Aspergillus O
flavus O
, O
human O
neutrophil O
elastase O
and O
bovine O
chymotrypsin O
, O
but O
does O
not O
inhibit O
bovine O
trypsin O
. O

Here O
we O
report O
the O
crystal O
structure O
of O
AFUEI O
in O
two O
crystal O
forms O
. O

AFUEI O
is O
a O
wedge O
- O
shaped O
protein O
composed O
of O
an O
extended O
loop O
and O
a O
scaffold O
protein O
core O
. O

The O
structure O
of O
AFUEI O
shows O
remarkable O
similarity O
to O
serine B
protease O
inhibitors O
of O
the O
potato O
inhibitor O
I O
family O
, O
although O
they O
are O
classified O
into O
different O
inhibitor O
families O
. O

A O
structural O
comparison O
with O
the O
potato O
I O
family O
inhibitors O
suggests O
that O
the O
extended O
loop O
of O
AFUEI O
corresponds O
to O
the O
binding O
loop O
of O
the O
potato O
inhibitor O
I O
family O
and O
AFUEI O
inhibits O
its O
cognate O
proteases O
through O
the O
same O
mechanism O
as O
the O
Potato O
I O
family O
inhibitors O
. O

Copolymerization O
of O
2 B
- I
methylene I
- I
1 I
, I
3 I
- I
dioxepane I
and O
glycidyl B
methacrylate I
, O
a O
well O
- O
defined O
and O
efficient O
process O
for O
achieving O
functionalized O
polyesters B
for O
covalent O
binding O
of O
bioactive O
molecules O
. O

The O
understanding O
of O
cell O
- O
material O
interactions O
is O
important O
for O
creating O
personalized O
implants O
for O
tissue O
engineering O
. O

This O
has O
resulted O
in O
an O
interest O
in O
developing O
polymers O
with O
functional O
groups O
with O
the O
possibility O
of O
controlling O
the O
macromolecular O
surface O
. O

We O
have O
in O
a O
one O
- O
pot O
reaction O
synthesized O
a O
series O
of O
amorphous O
and O
degradable O
polyester B
- O
based O
copolymers O
with O
active O
functional O
groups O
by O
copolymerization O
of O
2 B
- I
methylene I
- I
1 I
, I
3 I
- I
dioxepane I
and O
glycidyl B
methacrylate I
. O

The O
properties O
of O
the O
final O
polymers O
were O
varied O
by O
varying O
the O
feed O
ratios O
of O
the O
monomers O
and O
it O
was O
seen O
that O
it O
was O
possible O
to O
control O
the O
amount O
of O
active O
functional O
groups O
. O

The O
resulting O
epoxy B
- O
functionalized O
polyester B
was O
further O
modified O
by O
covalent O
immobilization O
of O
heparin O
. O

The O
heparinization O
was O
done O
in O
order O
, O
in O
a O
future O
aspect O
, O
to O
enhance O
the O
osteogenic O
differentiation O
of O
mesenchymal O
stem O
cells O
. O

Heparin O
binds O
directly O
with O
the O
growth O
factor O
bone O
morphogenetic O
protein O
- O
2 O
and O
helps O
to O
retain O
its O
activity O
. O

The O
molecular O
structure O
of O
the O
copolymers O
was O
characterized O
by O
nuclear O
magnetic O
resonance O
, O
size O
exclusion O
chromatography O
, O
and O
fourier O
transform O
infrared O
spectroscopy O
. O

Differential O
scanning O
calorimetry O
and O
tensile O
testing O
showed O
that O
the O
monomer O
feed O
ratio O
had O
a O
great O
influence O
on O
the O
properties O
of O
the O
final O
polymer O
and O
that O
it O
thus O
was O
possible O
to O
control O
the O
mechanical O
properties O
to O
suit O
an O
intended O
application O
. O

The O
presence O
of O
heparin O
was O
verified O
by O
toluidine B
blue I
staining O
and O
all O
the O
films O
tested O
showed O
positive O
signals O
for O
heparin O
. O

Influence O
of O
histidine B
incorporation O
on O
buffer O
capacity O
and O
gene O
transfection O
efficiency O
of O
HPMA B
- O
co O
- O
oligolysine O
brush O
polymers O
. O

One O
of O
the O
major O
intracellular O
barriers O
to O
non O
- O
viral O
gene O
delivery O
is O
efficient O
endosomal O
escape O
. O

The O
incorporation O
of O
histidine B
residues O
into O
polymeric O
constructs O
has O
been O
found O
to O
increase O
endosomal O
escape O
via O
the O
proton O
sponge O
effect O
. O

Statistical O
and O
diblock O
copolymers O
of O
N B
- I
( I
2 I
- I
hydroxypropyl I
) I
methacrylamide I
( O
HPMA B
) O
, O
oligolysine O
, O
and O
oligohistidine O
were O
synthesized O
via O
reversible O
- O
addition O
fragmentation O
chain O
transfer O
( O
RAFT O
) O
polymerization O
, O
and O
tested O
for O
in O
vitro O
transfection O
efficiency O
, O
buffering O
ability O
, O
and O
polyplex O
uptake O
mechanism O
via O
the O
use O
of O
chemical O
endocytic O
inhibitors O
. O

Interestingly O
, O
histidine B
- O
containing O
statistical O
and O
diblock O
polymers O
exhibited O
increased O
buffer O
capacity O
in O
different O
endosomal O
pH O
ranges O
. O

Statistical O
copolymers O
transfected O
better O
than O
block O
copolymers O
that O
contained O
similar O
amounts O
of O
histidine B
. O

In O
addition O
, O
only O
the O
polymer O
containing O
the O
highest O
incorporation O
of O
oligohistidine B
residues O
led O
to O
increases O
in O
transfection O
efficiency O
over O
the O
HPMA B
- O
oligolysine O
base O
polymer O
. O

Thus O
, O
for O
these O
polymer O
architectures O
, O
high O
histidine B
incorporation O
may O
be O
required O
for O
efficient O
endosomal O
escape O
. O

Furthermore O
, O
uptake O
studies O
indicate O
that O
non O
- O
acidified O
caveolae O
- O
mediated O
endocytosis O
may O
be O
the O
primary O
route O
of O
transfection O
for O
these O
copolymers O
, O
suggesting O
that O
alternative O
approaches O
for O
increasing O
endosomal O
escape O
may O
be O
beneficial O
for O
enhancing O
transfection O
efficiency O
with O
these O
HPMA B
- O
oligolysine O
copolymers O
. O

Surface O
- O
sensitive O
two O
- O
dimensional O
magneto O
- O
fingerprint O
in O
mesoscopic O
Bi2Se3 B
channels O
. O

Periodic O
Aharonov O
- O
Bohm O
and O
Altshuler O
- O
Aronov O
- O
Spivak O
oscillations O
have O
traditionally O
been O
observed O
in O
lateral O
transport O
through O
patterned O
mesoscopic O
loops O
of O
diffusive O
conductors O
. O

However O
, O
our O
studies O
of O
perpendicular O
- O
to O
- O
plane O
magnetotransport O
in O
straight O
- O
channel O
, O
diffusive O
devices O
of O
epitaxial O
Bi2Se3 B
surprisingly O
reveal O
signatures O
of O
Aharonov O
- O
Bohm O
orbits O
- O
- O
periodic O
conductance O
fluctuation O
magneto O
- O
fingerprints O
- O
- O
even O
though O
the O
devices O
are O
not O
explicitly O
patterned O
into O
loops O
. O

We O
show O
that O
the O
length O
scale O
of O
these O
orbits O
corresponds O
to O
the O
typical O
perimeter O
of O
triangular O
terraces O
found O
on O
the O
surface O
of O
these O
thin O
film O
devices O
, O
strongly O
suggesting O
that O
the O
periodic O
magneto O
- O
fingerprint O
arises O
from O
coherent O
scattering O
of O
electron O
waves O
from O
the O
step O
- O
edges O
. O

Our O
interpretation O
is O
bolstered O
by O
control O
measurements O
in O
devices O
without O
such O
surface O
morphology O
which O
only O
show O
a O
conventional O
, O
aperiodic O
magneto O
- O
fingerprint O
. O

These O
results O
show O
that O
lithographically O
patterned O
Bi2Se3 B
devices O
provide O
a O
novel O
class O
of O
mesoscopic O
physical O
systems O
for O
systematic O
studies O
of O
coherent O
surface O
sensitive O
transport O
. O

Simulations O
of O
droplet O
coalescence O
in O
simple O
shear O
flow O
. O

Simulating O
droplet O
coalescence O
is O
challenging O
because O
small O
- O
scale O
( O
tens O
of O
nanometers O
) O
phenomena O
determine O
the O
behaviour O
of O
much O
larger O
( O
micron O
- O
to O
millimetre O
- O
scale O
) O
droplets O
. O

In O
general O
, O
liquid O
droplets O
colliding O
in O
a O
liquid O
medium O
coalesce O
when O
the O
capillary O
number O
is O
less O
than O
a O
critical O
value O
. O

We O
present O
simulations O
of O
droplet O
collisions O
and O
coalescence O
in O
simple O
shear O
flow O
using O
the O
free O
- O
energy O
binary O
- O
liquid O
lattice O
Boltzmann O
method O
. O

In O
previous O
simulations O
of O
low O
- O
speed O
collisions O
, O
droplets O
coalesced O
at O
unrealistically O
high O
capillary O
numbers O
. O

Simulations O
of O
non O
- O
coalescing O
droplets O
have O
not O
been O
reported O
, O
and O
therefore O
the O
critical O
capillary O
number O
for O
simulated O
collisions O
was O
unknown O
. O

By O
simulating O
droplets O
with O
radii O
up O
to O
100 O
lattice O
nodes O
, O
we O
determine O
the O
critical O
capillary O
number O
for O
coalescence O
and O
quantify O
the O
effects O
of O
several O
numerical O
and O
geometric O
parameters O
. O

The O
simulations O
were O
performed O
with O
a O
well O
- O
resolved O
interface O
, O
a O
Reynolds O
number O
of O
one O
, O
and O
capillary O
numbers O
from O
0 O
. O
01 O
to O
0 O
. O
2 O
. O

The O
ratio O
of O
the O
droplet O
radius O
and O
interface O
thickness O
has O
the O
greatest O
effect O
on O
the O
critical O
capillary O
number O
. O

As O
in O
experiments O
, O
the O
critical O
capillary O
number O
decreases O
with O
increasing O
droplet O
size O
. O

A O
second O
numerical O
parameter O
, O
the O
interface O
diffusivity O
( O
Peclet O
number O
) O
also O
influences O
the O
conditions O
for O
coalescence O
: O
coalescence O
occurs O
at O
higher O
capillary O
numbers O
with O
lower O
Peclet O
numbers O
( O
higher O
diffusivity O
) O
. O

The O
effects O
of O
the O
vertical O
offset O
between O
the O
droplets O
and O
the O
confinement O
of O
the O
droplets O
were O
also O
studied O
. O

Physically O
reasonable O
results O
were O
obtained O
and O
provide O
insight O
into O
the O
conditions O
for O
coalescence O
. O

Simulations O
that O
match O
the O
conditions O
of O
experiments O
reported O
in O
the O
literature O
remain O
computationally O
impractical O
. O

However O
, O
the O
scale O
of O
the O
simulations O
is O
now O
sufficiently O
large O
that O
a O
comparison O
with O
experiments O
involving O
smaller O
droplets O
( O
~ O
10 O
mu O
m O
) O
and O
lower O
viscosities O
( O
10 O
( O
- O
6 O
) O
m O
( O
2 O
) O
/ O
s O
, O
the O
viscosity O
of O
water O
) O
may O
be O
possible O
. O

Experiments O
at O
these O
conditions O
are O
therefore O
needed O
to O
determine O
the O
interface O
thickness O
and O
Peclet O
number O
that O
should O
be O
used O
for O
predictive O
simulations O
of O
coalescence O
phenomena O
. O

Carbonic O
anhydrase O
inhibitors O
. O

Benzenesulfonamides B
incorporating O
cyanoacrylamide B
moieties O
strongly O
inhibit O
Saccharomyces O
cerevisiae O
beta O
- O
carbonic O
anhydrase O
. O

A O
series O
of O
benzenesulfonamides B
incorporating O
cyanoacrylamide B
moieties O
( O
tyrphostine B
analogs O
) O
were O
assayed O
as O
inhibitors O
of O
the O
beta O
- O
carbonic O
anhydrase O
( O
CA O
, O
EC O
4 O
. O
2 O
. O
1 O
. O
1 O
) O
from O
Saccharomyces O
cerevisiae O
, O
ScCA O
. O

Some O
of O
these O
compounds O
were O
low O
nanomolar O
or O
subnanomolar O
ScCA O
inhibitors O
and O
showed O
selectivity O
ratios O
in O
the O
range O
of O
4 O
. O
91 O
- O
69 O
. O
86 O
for O
inhibiting O
the O
yeast O
enzyme O
over O
the O
offtarget O
human O
( O
h O
) O
isoforms O
hCA O
I O
and O
of O
6 O
. O
46 O
- O
13 O
. O
52 O
for O
inhibiting O
ScCA O
over O
hCA O
II O
. O

The O
model O
organism O
S O
. O
cerevisiae O
and O
this O
particular O
enzyme O
may O
be O
useful O
for O
detecting O
antifungals O
with O
a O
novel O
mechanism O
of O
action O
compared O
to O
the O
classical O
azole B
drugs O
to O
which O
significant O
drug O
resistance O
emerged O
. O

Indeed O
, O
some O
of O
these O
sulfonamides B
inhibited O
the O
growth O
of O
the O
yeast O
with O
CC50 O
- O
s O
in O
the O
range O
of O
0 O
. O
73 O
- O
6 O
. O
54 O
mu O
M O
. O

Apoptosis O
inducing O
activity O
of O
benzophenanthridine B
- O
type O
alkaloids O
and O
2 B
- I
arylbenzofuran I
neolignans I
in O
HCT116 O
colon O
carcinoma O
cells O
. O

Thirteen O
compounds O
belonging O
to O
different O
classes O
of O
alkaloids O
( O
1 O
- O
9 O
) O
and O
lignans B
( O
10 O
- O
13 O
) O
, O
isolated O
from O
the O
methanol B
extract O
of O
roots O
of O
the O
African O
medicinal O
plant O
Zanthoxylum O
capense O
, O
were O
assayed O
for O
their O
ability O
as O
apoptosis O
inducers O
in O
HCT116 O
colon O
carcinoma O
cells O
. O

The O
cytotoxicity O
of O
these O
compounds O
was O
evaluated O
in O
HCT116 O
colon O
carcinoma O
cells O
by O
the O
MTS B
assay O
. O

Out O
of O
the O
tested O
compounds O
, O
three O
benzophenanthridine B
alkaloids I
( O
1 O
, O
4 O
, O
and O
7 O
) O
, O
a O
dibenzyl B
butyrolactone I
lignan I
( O
10 O
) O
, O
and O
two O
2 B
- I
arylbenzofuran I
neolignans I
( O
12 O
and O
13 O
) O
displayed O
significant O
cytotoxicity O
to O
HCT116 O
cells O
, O
confirmed O
by O
the O
Guava O
ViaCount O
viability O
assay O
. O

The O
selected O
compounds O
( O
1 O
, O
4 O
, O
7 O
, O
10 O
, O
12 O
, O
and O
13 O
) O
were O
further O
tested O
for O
apoptosis O
induction O
activity O
in O
HCT116 O
cells O
, O
by O
evaluation O
of O
nuclear O
morphology O
following O
Hoechst B
staining O
, O
and O
by O
caspase O
- O
3 O
like O
activity O
assays O
. O

Morphologic O
evaluation O
of O
HCT116 O
nuclei O
following O
Hoechst B
staining O
and O
fluorescence O
microscopy O
revealed O
that O
compounds O
1 O
, O
4 O
, O
7 O
, O
10 O
, O
12 O
, O
and O
13 O
induced O
apoptosis O
in O
HCT116 O
colon O
carcinoma O
cells O
, O
producing O
similar O
, O
or O
higher O
, O
apoptosis O
levels O
when O
compared O
with O
5 B
- I
fluorouracil I
( O
5 B
- I
FU I
) O
, O
the O
cornerstone O
cytotoxic O
used O
in O
colon O
cancer O
treatment O
for O
several O
decades O
. O

In O
fact O
, O
HCT116 O
cells O
developed O
morphological O
changes O
characteristic O
of O
apoptosis O
, O
including O
chromatin O
condensation O
, O
nuclear O
fragmentation O
and O
formation O
of O
apoptotic O
bodies O
. O

Importantly O
, O
compounds O
4 O
and O
13 O
at O
20 O
mu O
M O
were O
the O
most O
promising O
in O
this O
study O
, O
inducing O
respectively O
~ O
11 O
- O
and O
7 O
- O
fold O
increases O
in O
apoptotic O
cells O
as O
compared O
to O
vehicle O
control O
, O
whereas O
5 B
- I
FU I
increased O
apoptosis O
by O
~ O
2 O
- O
fold O
. O

Apoptosis O
induction O
for O
compounds O
4 O
and O
13 O
was O
further O
confirmed O
by O
caspase O
- O
3 O
- O
like O
activity O
assays O
, O
which O
showed O
respectively O
~ O
2 O
- O
and O
1 O
. O
5 O
- O
fold O
increases O
in O
caspase O
- O
3 O
- O
like O
activity O
compared O
to O
vehicle O
control O
. O

These O
results O
suggested O
that O
specific O
benzophenanthridine B
alkaloids I
and O
2 B
- I
arylbenzofuran I
neolignans I
isolated O
from O
Zanthoxylum O
capense O
show O
strong O
anticancer O
activity O
in O
HCT116 O
colon O
carcinoma O
cells O
. O

Nordihydroguaiaretic B
acid I
induces O
Nrf2 O
nuclear O
translocation O
in O
vivo O
and O
attenuates O
renal O
damage O
and O
apoptosis O
in O
the O
ischemia O
and O
reperfusion O
model O
. O

It O
has O
been O
shown O
that O
the O
pretreatment O
with O
nordihydroguaiaretic B
acid I
( O
NDGA B
) O
, O
a O
lignan B
with O
direct O
and O
indirect O
antioxidant O
properties O
, O
protects O
against O
the O
ischemia O
- O
reperfusion O
( O
I O
/ O
R O
) O
- O
induced O
renal O
oxidant O
damage O
. O

Although O
it O
has O
been O
shown O
that O
NDGA B
induces O
Nrf2 O
nuclear O
translocation O
in O
renal O
epithelial O
LLC O
- O
PK1 O
cells O
in O
culture O
, O
it O
is O
unknown O
if O
NDGA B
may O
induce O
Nrf2 O
translocation O
in O
vivo O
. O

In O
this O
work O
was O
explored O
if O
NDGA B
is O
able O
to O
induce O
in O
vivo O
Nrf2 O
nuclear O
translocation O
in O
kidneys O
of O
rats O
submitted O
to O
uni O
- O
nephrectomy O
( O
U O
- O
NX O
) O
or O
I O
/ O
R O
injury O
. O

Four O
groups O
of O
male O
Wistar O
rats O
were O
used O
: O
U O
- O
NX O
, O
NDGA B
, O
I O
/ O
R O
, O
and O
I O
/ O
R O
+ O
NDGA B
. O

NDGA B
was O
injected O
i O
. O
p O
. O

( O
10mg O
/ O
kg O
/ O
day O
) O
starting O
48h O
before O
I O
/ O
R O
. O

Kidney O
samples O
were O
obtained O
at O
3h O
of O
reperfusion O
after O
to O
measure O
Nrf2 O
translocation O
. O

Additional O
groups O
of O
rats O
were O
studied O
at O
24h O
of O
reperfusion O
to O
measure O
histological O
damage O
and O
apoptosis O
. O

NDGA B
was O
able O
to O
induce O
Nrf2 O
translocation O
in O
vivo O
in O
kidneys O
of O
rats O
submitted O
to O
both O
U O
- O
NX O
and O
I O
/ O
R O
injury O
and O
to O
protect O
against O
renal O
histological O
damage O
and O
apoptosis O
. O

It O
is O
concluded O
that O
the O
pretreatment O
of O
NDGA B
is O
able O
to O
induce O
in O
vivo O
nuclear O
Nrf2 O
translocation O
in O
kidney O
of O
rats O
suggesting O
that O
this O
may O
be O
involved O
in O
the O
renoprotection O
against O
I O
/ O
R O
. O

Cytokine O
targets O
in O
airway O
inflammation O
. O

Asthma O
is O
an O
inflammatory O
disease O
of O
the O
airway O
wall O
that O
leads O
to O
bronchial O
hyper O
- O
reactivity O
and O
airway O
obstruction O
, O
caused O
by O
inflammation O
, O
mucus O
hyper O
- O
production O
and O
airway O
wall O
remodelling O
. O

Central O
to O
pathogenesis O
, O
Th2 O
and O
Th17 O
lymphocytes O
of O
the O
adaptive O
immune O
system O
control O
many O
aspects O
of O
the O
disease O
by O
producing O
cytokines O
such O
as O
IL O
- O
4 O
, O
IL O
- O
5 O
, O
IL O
- O
13 O
, O
and O
IL O
- O
17 O
. O

In O
addition O
, O
many O
cells O
of O
the O
innate O
immune O
system O
such O
as O
mast O
cells O
, O
basophils O
, O
neutrophils O
, O
eosinophils O
, O
dendritic O
cells O
( O
DCs O
) O
, O
and O
innate O
lymphoid O
cells O
( O
ILCs O
) O
play O
an O
important O
role O
in O
the O
initiation O
or O
maintenance O
of O
disease O
. O

Epithelial O
cells O
are O
ever O
more O
implicated O
in O
disease O
pathogenesis O
, O
as O
they O
are O
able O
to O
sense O
exposure O
to O
pathogens O
via O
pattern O
recognition O
receptors O
( O
PRRs O
) O
and O
can O
activate O
DCs O
. O

This O
review O
article O
will O
deal O
with O
the O
role O
of O
cytokines O
that O
are O
considered O
essential O
controllers O
of O
the O
inflammatory O
, O
immune O
and O
regenerative O
response O
to O
allergens O
, O
viruses O
and O
environmental O
pollutants O
. O

Emerging O
Th2 O
cytokines O
such O
as O
thymic O
stromal O
lymphopoietin O
, O
GM O
- O
CSF O
, O
IL O
- O
1 O
, O
IL O
- O
33 O
, O
IL O
- O
25 O
mediate O
the O
crosstalk O
between O
epithelial O
cells O
, O
DCs O
, O
and O
ILCs O
. O

Understanding O
the O
crosstalk O
between O
structural O
cells O
, O
innate O
and O
adaptive O
immune O
cells O
that O
is O
mediated O
by O
cytokines O
provides O
important O
mechanistic O
insights O
into O
how O
asthma O
develops O
and O
perpetuates O
itself O
. O

It O
could O
also O
provide O
the O
framework O
on O
which O
we O
will O
select O
new O
therapeutic O
strategies O
that O
prevent O
exacerbations O
and O
alter O
the O
natural O
course O
of O
the O
disease O
. O

Pharmacokinetic O
study O
of O
four O
flavones B
of O
Glycyrrhiza O
in O
rat O
plasma O
using O
HPLC O
- O
MS O
. O

AIM O
OF O
THE O
STUDY O
: O
This O
study O
aimed O
to O
develop O
a O
specific O
HPLC O
- O
MS O
method O
for O
simultaneous O
quantification O
of O
four O
flavones B
of O
Glycyrrhiza O
in O
rat O
plasma O
after O
oral O
administration O
and O
to O
describe O
the O
pharmacokinetics O
of O
four O
flavones B
in O
rat O
plasma O
. O

MATERIALS O
AND O
METHODS O
: O
A O
simple O
, O
sensitive O
and O
selective O
method O
for O
simultaneous O
determination O
of O
four O
flavones B
of O
Glycyrrhiza O
in O
rat O
plasma O
, O
i O
. O
e O
. O
, O
liquiritin B
, O
isoliquiritin B
, O
liquiritigenin B
, O
isoliquiritigenin B
, O
by O
high O
performance O
liquid O
chromato O
- O
graphy O
- O
tandem O
mass O
spectrometry O
( O
HPLC O
- O
MS O
) O
with O
negative O
electrospray O
ionization O
mode O
, O
was O
developed O
and O
validated O
. O

The O
method O
was O
applied O
to O
investigate O
the O
pharmacokinetics O
of O
four O
flavones B
in O
rat O
plasma O
after O
oral O
administration O
of O
Glycyrrhiza B
flavones I
. O

Chromatographic O
separation O
was O
accomplished O
on O
an O
Agilent O
TC O
- O
C18 O
column O
( O
4 O
. O
6mm O
x O
250mm O
, O
5 O
mu O
m O
) O
, O
with O
gradient O
elution O
by O
using O
a O
mixture O
of O
methanoic B
acid I
( O
A O
) O
and O
acetonitrile B
( O
B O
) O
as O
the O
mobile O
phase O
at O
a O
flow O
rate O
of O
0 O
. O
8mL O
/ O
min O
. O

RESULTS O
: O
The O
calibration O
curves O
for O
four O
flavones B
had O
good O
linearity O
in O
the O
measured O
range O
with O
higher O
than O
0 O
. O
997 O
. O

Relative O
standard O
deviations O
( O
RSDs O
) O
of O
the O
intra O
- O
and O
inter O
- O
day O
precision O
at O
different O
levels O
were O
all O
less O
than O
4 O
. O
8 O
% O
. O

The O
pharmacokinetic O
profile O
of O
four O
flavones B
in O
rat O
plasma O
was O
fitted O
with O
a O
two O
- O
compartment O
model O
detected O
by O
a O
simple O
, O
rapid O
and O
accurate O
HPLC O
- O
MS O
method O
. O

Time O
( O
h O
) O
to O
reach O
peak O
concentration O
( O
mu O
g O
/ O
mL O
) O
of O
liquiritin B
( O
2 O
. O
69 O
+ O
/ O
- O
0 O
. O
04 O
) O
, O
isoliquiritin B
( O
10 O
. O
16 O
+ O
/ O
- O
0 O
. O
02 O
) O
, O
liquiritigenin B
( O
2 O
. O
83 O
+ O
/ O
- O
0 O
. O
02 O
) O
, O
isoliquiritigenin B
( O
0 O
. O
28 O
+ O
/ O
- O
0 O
. O
01 O
) O
were O
2 O
. O
02 O
+ O
/ O
- O
0 O
. O
23 O
, O
1 O
. O
97 O
+ O
/ O
- O
0 O
. O
20 O
, O
0 O
. O
48 O
+ O
/ O
- O
0 O
. O
02 O
, O
1 O
. O
93 O
+ O
/ O
- O
0 O
. O
36 O

, O
respectively O
. O

The O
distribution O
and O
elimination O
half O
- O
life O
( O
h O
) O
and O
area O
under O
the O
concentration O
- O
time O
curve O
( O
mu O
g O
/ O
mL O
* O
h O
) O
from O
t O
= O
0 O
to O
last O
time O
of O
liquiritin B
, O
isoliquiritin B
, O
liquiritigenin B
, O
isoliquiritigenin B
were O
1 O
. O
02 O
+ O
/ O
- O
0 O
. O
48 O
/ O
2 O
. O
27 O
+ O
/ O
- O
0 O
. O
53 O
/ O
16 O
. O
97 O
+ O
/ O
- O
0 O
. O
43 O
, O
2 O
. O
04 O
+ O
/ O
- O
1 O
. O
01 O
/ O
2 O
. O
38 O
+ O
/ O
- O
0 O
. O
80 O
/ O
69 O
. O
20 O
+ O
/ O
- O
5 O
. O
24 O
, O
0 O
. O
35 O
+ O

/ O
- O
0 O
. O
10 O
/ O
4 O
. O
26 O
+ O
/ O
- O
0 O
. O
16 O
/ O
14 O
. O
83 O
+ O
/ O
- O
0 O
. O
11 O
, O
1 O
. O
18 O
+ O
/ O
- O
0 O
. O
32 O
/ O
3 O
. O
04 O
, O
+ O
/ O
- O
0 O
. O
22 O
/ O
2 O
. O
10 O
+ O
/ O
- O
0 O
. O
09 O
, O
respectively O
. O

Isoliquiritin O
presented O
the O
phenomenon O
of O
double O
peaks O
and O
the O
others O
appeared O
together O
in O
a O
single O
and O
plateau O
absorption O
phase O
. O

Isoliquiritigenin B
had O
the O
lowest O
oral O
bioavailability O
because O
of O
Cmax O
and O
AUC0 O
- O
infinity O
. O

Liquiritigenin B
had O
the O
fastest O
absorption O
and O
distribution O
rate O
and O
the O
lowest O
elimination O
rate O
according O
to O
Tmax O
, O
t1 O
/ O
2 O
alpha O
, O
t1 O
/ O
2 O
beta O
. O

CONCLUSIONS O
: O
This O
paper O
first O
reported O
on O
identification O
and O
determination O
of O
four O
flavones B
of O
Glycyrrhiza O
in O
rat O
plasma O
and O
their O
respective O
pharmacokinetic O
characteristics O
. O

The O
results O
provided O
a O
meaningful O
basis O
for O
better O
understanding O
the O
absorption O
mechanism O
of O
Glycyrrhiza O
and O
evaluating O
the O
clinical O
application O
of O
this O
medicine O
. O

Herbalists O
and O
wild O
medicinal O
plants O
in O
M O
' O
Sila O
( O
North O
Algeria O
) O
: O
An O
ethnopharmacology O
survey O
. O

AIM O
OF O
THE O
STUDY O
: O
The O
main O
aim O
of O
this O
study O
was O
to O
identify O
, O
catalogue O
and O
document O
the O
large O
number O
of O
wild O
medicinal O
plants O
used O
in O
the O
M O
' O
Sila O
region O
( O
northern O
Algeria O
) O
for O
the O
treatment O
of O
several O
human O
pathologies O
. O

Another O
more O
ambitious O
aim O
is O
to O
contribute O
to O
overcoming O
the O
limits O
of O
an O
orally O
transmitted O
pharmacopoeia O
, O
attempting O
to O
exploit O
the O
large O
ethnopharmacology O
patrimony O
of O
the O
region O
for O
further O
pharmacological O
purposes O
. O

MATERIALS O
AND O
METHODS O
: O
Our O
field O
study O
was O
carried O
out O
over O
a O
period O
of O
three O
years O
( O
2008 O
- O
2010 O
) O
. O

During O
this O
period O
, O
herbalists O
were O
interviewed O
using O
semi O
- O
structured O
questionnaires O
investigating O
the O
herbalist O
as O
a O
holder O
of O
information O
( O
gender O
, O
age O
and O
educational O
level O
) O
and O
about O
wild O
medicinal O
plants O
( O
local O
name O
, O
uses O
and O
part O
used O
) O
. O

In O
addition O
, O
the O
relative O
importance O
value O
of O
the O
species O
was O
determined O
and O
informant O
consensus O
factor O
( O
ICF O
) O
was O
calculated O
for O
the O
medicinal O
plants O
included O
in O
the O
study O
. O

RESULTS O
: O
A O
total O
of O
83 O
herbalists O
were O
interviewed O
, O
men O
dominate O
the O
practice O
of O
traditional O
medicine O
in O
the O
region O
. O

About O
41 O
% O
of O
them O
are O
between O
31 O
- O
40 O
years O
, O
and O
about O
a O
third O
( O
34 O
% O
) O
is O
illiterate O
. O

The O
traditional O
herbal O
knowledge O
is O
passed O
from O
generation O
to O
generation O
in O
the O
verbal O
form O
, O
being O
almost O
totally O
absent O
a O
writing O
tradition O
. O

The O
interviewed O
herbalists O
identified O
and O
recorded O
58 O
plants O
species O
and O
50 O
genera O
belonging O
to O
27 O
plant O
families O
. O

Lamiaceae O
and O
Asteraceae O
were O
the O
most O
represented O
plant O
families O
. O

The O
aerial O
parts O
were O
the O
most O
commonly O
used O
plant O
part O
, O
while O
infusion O
and O
decoction O
were O
the O
most O
common O
method O
of O
traditional O
drug O
preparation O
. O

CONCLUSIONS O
: O
The O
survey O
provides O
a O
veritable O
source O
of O
information O
on O
the O
herbalists O
and O
wild O
medicinal O
plants O
. O

Plants O
which O
are O
used O
in O
different O
parts O
of O
the O
world O
for O
the O
treatment O
of O
similar O
diseases O
may O
be O
deemed O
to O
be O
effective O
in O
pharmacological O
terms O
. O

These O
medicinal O
plants O
may O
be O
incorporated O
into O
the O
healthcare O
delivery O
system O
of O
the O
country O
. O

Epidemiology O
of O
Paget O
' O
s O
disease O
of O
Bone O
: O
A O
systematic O
review O
and O
meta O
- O
analysis O
of O
secular O
changes O
. O

CONTEXT O
: O
Several O
studies O
have O
suggested O
that O
the O
prevalence O
and O
severity O
of O
PDB O
have O
fallen O
in O
recent O
years O
. O

The O
magnitude O
of O
this O
trend O
and O
its O
globalization O
have O
not O
been O
well O
established O
. O

OBJECTIVE O
: O
To O
estimate O
the O
pooled O
magnitude O
of O
the O
changes O
in O
the O
prevalence O
of O
PDB O
. O

As O
a O
secondary O
objective O
, O
to O
make O
up O
a O
world O
atlas O
of O
PDB O
prevalence O
. O

METHODS O
: O
Systematic O
review O
of O
English O
and O
non O
- O
English O
articles O
using O
MEDLINE O
( O
1946 O
to O
2013 O
) O
and O
EMBASE O
( O
1980 O
to O
2013 O
) O
. O

Search O
terms O
included O
epidemiology O
, O
incidence O
, O
prevalence O
, O
cohort O
studies O
, O
osteitis O
deformans O
or O
Paget O
disease O
of O
bone O
. O

Studies O
with O
incidence O
and O
/ O
or O
prevalence O
rate O
for O
PDB O
were O
included O
. O

Two O
authors O
independently O
extracted O
the O
data O
using O
predefined O
data O
fields O
and O
quality O
assessment O
. O

A O
pooled O
analyses O
based O
on O
random O
- O
effects O
models O
was O
carried O
out O
for O
secular O
trends O
. O

RESULTS O
: O
Twenty O
- O
eight O
articles O
documented O
the O
prevalence O
of O
PDB O
; O
four O
articles O
the O
incidence O
and O
two O
articles O
the O
rate O
of O
new O
referrals O
. O

The O
prevalence O
of O
PDB O
varied O
greatly O
between O
the O
different O
countries O
, O
from O
0 O
. O
00028 O
% O
in O
Japan O
to O
5 O
. O
4 O
% O
in O
UK O
. O

There O
were O
available O
data O
on O
changes O
in O
prevalence O
from O
two O
different O
surveys O
over O
two O
different O
time O
frames O
in O
Europe O
and O
New O
Zealand O
. O

In O
all O
but O
one O
city O
( O
Turin O
) O
, O
a O
drop O
in O
the O
prevalence O
of O
PDB O
was O
recorded O
( O
pooled O
OR O
0 O
. O
64 O
: O
95 O
% O
CI O
: O
0 O
. O
45 O
- O
0 O
. O
91 O
) O
. O

CONCLUSION O
: O
The O
incidence O
and O
prevalence O
rates O
of O
PDB O
vary O
widely O
between O
populations O
but O
both O
have O
decreased O
in O
most O
regions O
over O
recent O
years O
. O

The O
changes O
are O
heterogeneous O
however O
and O
within O
countries O
, O
the O
largest O
changes O
have O
been O
in O
areas O
that O
previously O
had O
a O
high O
prevalence O
. O

The O
reasons O
for O
these O
changes O
remain O
unclear O
at O
present O
but O
are O
likely O
to O
be O
due O
to O
an O
interaction O
between O
genetic O
factors O
and O
environmental O
triggers O
which O
may O
differ O
in O
different O
regions O
. O

Diminished O
response O
to O
in O
vivo O
mechanical O
loading O
in O
trabecular O
and O
not O
cortical O
bone O
in O
adulthood O
of O
female O
C57Bl O
/ O
6 O
mice O
coincides O
with O
a O
reduction O
in O
deformation O
to O
load O
. O

Bone O
loss O
occurs O
during O
adulthood O
in O
both O
women O
and O
men O
and O
affects O
trabecular O
bone O
more O
than O
cortical O
bone O
. O

The O
mechanism O
responsible O
for O
trabecular O
bone O
loss O
during O
adulthood O
remains O
unexplained O
, O
but O
may O
be O
due O
at O
least O
in O
part O
to O
a O
reduced O
mechanoresponsivenes O
. O

We O
hypothesized O
that O
trabecular O
and O
cortical O
bone O
would O
respond O
anabolically O
to O
loading O
and O
that O
the O
bone O
response O
to O
mechanical O
loading O
would O
be O
reduced O
and O
the O
onset O
delayed O
in O
adult O
compared O
to O
postpubescent O
mice O
. O

We O
evaluated O
the O
longitudinal O
adaptive O
response O
of O
trabecular O
and O
cortical O
bone O
in O
postpubescent O
, O
young O
( O
10 O
week O
old O
) O
and O
adult O
( O
26 O
week O
old O
) O
female O
C57Bl O
/ O
6J O
mice O
to O
axial O
tibial O
compression O
using O
in O
vivo O
microCT O
( O
day O
0 O
, O
5 O
, O
10 O
, O
and O
15 O
) O
and O
dynamic O
histomorphometry O
( O
day O
15 O
) O
. O

Loading O
elicited O
an O
anabolic O
response O
in O
both O
trabecular O
and O
cortical O
bone O
in O
young O
and O
adult O
mice O
. O

As O
hypothesized O
, O
trabecular O
bone O
in O
adult O
mice O
exhibited O
a O
reduced O
and O
delayed O
response O
to O
loading O
compared O
to O
the O
young O
mice O
, O
apparent O
in O
trabecular O
bone O
volume O
fraction O
and O
architecture O
after O
10 O
days O
. O

No O
difference O
in O
mechanoresponsivenes O
of O
the O
cortical O
bone O
was O
observed O
between O
young O
and O
adult O
mice O
. O

Finite O
element O
analysis O
showed O
that O
load O
- O
induced O
strain O
was O
reduced O
with O
age O
. O

Our O
results O
suggest O
that O
trabecular O
bone O
loss O
that O
occurs O
in O
adulthood O
may O
in O
part O
be O
due O
to O
a O
reduced O
mechanoresponsivenes O
in O
this O
tissue O
and O
/ O
or O
a O
reduction O
in O
the O
induced O
tissue O
deformation O
which O
occurs O
during O
habitual O
loading O
. O

Therapeutic O
approaches O
that O
address O
the O
mechanoresponsivenes O
of O
the O
bone O
tissue O
may O
be O
a O
promising O
and O
alternate O
strategy O
to O
maintain O
trabecular O
bone O
mass O
during O
aging O
. O

Evaluation O
of O
genotoxicity O
of O
nitrile B
fragrance O
ingredients O
using O
in O
vitro O
and O
in O
vivo O
assays O
. O

Genotoxicity O
studies O
were O
conducted O
on O
a O
group O
of O
8 O
fragrance O
ingredients O
that O
belong O
to O
the O
nitrile B
family O
. O

These O
nitriles B
are O
widely O
used O
in O
consumer O
products O
however O
there O
is O
very O
limited O
data O
in O
the O
literature O
regarding O
the O
genotoxicity O
of O
these O
nitriles B
. O

The O
8 O
nitriles B
were O
assessed O
for O
genotoxicity O
using O
an O
Ames O
test O
, O
in O
- O
vitro O
chromosome O
aberration O
test O
or O
in O
- O
vitro O
micronucleus O
test O
. O

The O
positive O
results O
observed O
in O
the O
in O
- O
vitro O
tests O
were O
further O
investigated O
using O
an O
in O
- O
vivo O
micronucleus O
test O
. O

The O
results O
from O
these O
different O
tests O
were O
compared O
and O
these O
8 O
nitriles B
are O
not O
considered O
to O
be O
genotoxic O
. O

Dodecanitrile B
and O
2 B
, I
2 I
, I
3 I
- I
trimethylcyclopent I
- I
3 I
- I
enylacetonitrile I
were O
negative O
in O
the O
in O
- O
vitro O
chromosome O
aberration O
test O
and O
in O
- O
vitro O
micronucleus O
test O
, O
respectively O
. O

While O
citronellyl B
nitrile I
, O
3 B
- I
methyl I
- I
5 I
- I
phenylpentanenitrile I
, O
cinnamyl B
nitrile I
, O
and O
3 B
- I
methyl I
- I
5 I
- I
phenylpent I
- I
2 I
- I
enenitrile I
revealed O
positive O
results O
in O
the O
in O
- O
vitro O
tests O
, O
but O
confirmatory O
in O
- O
vivo O
tests O
determined O
these O
nitriles B
to O
be O
negative O
in O
the O
in O
- O
vivo O
micronucleus O
assay O
. O

The O
remaining O
two O
nitriles B
( O
benzonitrile B
and O
alpha B
- I
cyclohexylidene I
benzeneacetonitrile I
) O
were O
negative O
in O
the O
in O
- O
vivo O
micronucleus O
test O
. O

This O
study O
aims O
to O
evaluate O
the O
genotoxicity O
potential O
of O
these O
nitriles B
as O
well O
as O
enrich O
the O
literature O
with O
genotoxicity O
data O
on O
fragrance O
ingredients O
. O

Hydroxytyrosyl B
alkyl I
ether I
derivatives O
inhibit O
platelet O
activation O
after O
oral O
administration O
to O
rats O
. O

The O
low O
lipophilicity O
of O
hydroxytyrosol B
( O
HT O
) O
has O
motivated O
efforts O
to O
synthesize O
homologous O
series O
with O
better O
lipid O
solubility O
, O
such O
as O
the O
ethers B
, O
which O
are O
more O
lipophilic O
than O
HT O
. O

Because O
HT O
inhibits O
platelet O
aggregation O
, O
the O
aim O
of O
the O
study O
was O
to O
assess O
the O
possible O
anti O
- O
platelet O
effect O
of O
five O
HT B
ether I
derivatives O
( O
ethyl B
, O
butyl B
, O
hexyl B
, O
octyl B
and O
dodecyl B
) O
after O
oral O
administration O
to O
rats O
. O

Whole O
blood O
collagen O
- O
induced O
platelet O
aggregation O
and O
calcium B
- O
induced O
thromboxane B
B2 I
( O
TxB2 B
) O
, O
aortic O
6 B
- I
keto I
- I
prostaglandin I
F1 I
alpha I
( O
6 B
- I
keto I
- I
PGF1 I
alpha I
) O
and O
nitrites B
+ O
nitrates B
, O
plasma O
concentration O
of O
lipid O
peroxides B
( O
TBARS O
) O
and O
red O
blood O
cell O
content O
of O
reduced B
glutathione I
( O
GSH B
) O
were O
measured O
. O

The O
administration O
of O
20 O
mg O
/ O
kg O
/ O
day O
inhibited O
platelet O
aggregation O
, O
TxB2 O
and O
TBARS O
in O
a O
non O
- O
linear O
manner O
related O
to O
the O
length O
of O
the O
carbon B
chain O
, O
with O
a O
cut O
- O
off O
effect O
in O
the O
hexyl B
derivative O
. O

Aortic O
nitrite B
and O
red O
blood O
cell O
GSH B
production O
were O
also O
increased O
. O

The O
aortic O
production O
of O
6 B
- I
keto I
- I
PGF1 I
alpha I
was O
unaltered O
except O
in O
the O
group O
treated O
with O
the O
dodecyl B
derivative O
. O

The O
administration O
of O
50 O
mg O
/ O
kg O
/ O
day O
showed O
a O
similar O
pharmacodynamic O
profile O
but O
without O
the O
non O
- O
linear O
effect O
. O

In O
conclusion O
, O
HT B
ethers O
, O
especially O
the O
hexyl B
derivative O
, O
are O
a O
potential O
alternative O
to O
hydroxytyrosol B
, O
and O
their O
effect O
merits O
additional O
research O
to O
determine O
their O
role O
in O
the O
prophylaxis O
of O
vascular O
disease O
. O

Medicines O
Combinations O
Options O
and O
Regulatory O
Hurdles O
. O

The O
number O
of O
fixed O
dose O
combinations O
( O
FDC O
) O
on O
the O
market O
is O
increasing O
. O

However O
, O
both O
regulatory O
guidelines O
and O
the O
evidence O
for O
better O
effectiveness O
of O
fixed O
dose O
combinations O
are O
not O
established O
yet O
. O

These O
aspects O
were O
the O
topic O
for O
a O
recent O
EUFEPS O
workshop O
in O
Copenhagen O
. O

The O
discussion O
confirms O
the O
presence O
of O
hurdles O
and O
recommendations O
to O
further O
progress O
and O
alleviate O
the O
problems O
. O

The O
general O
conclusion O
was O
: O
Refinement O
of O
general O
systems O
pharmacology O
tools O
for O
identification O
of O
key O
molecular O
targets O
in O
disease O
development O
; O
Precompetitive O
methodologies O
and O
technologies O
designed O
for O
( O
co O
- O
) O
development O
of O
FDCs O
; O
Simulation O
and O
modeling O
algorithms O
applied O
on O
pharmacodynamics O
( O
synergy O
) O
, O
pharmacokinetics O
and O
safety O
; O
New O
formulations O
of O
FDCs O
of O
solid O
, O
liquid O
or O
inhalation O
forms O
; O
Prospective O
clinical O
studies O
for O
measuring O
the O
efficacy O
and O
effectiveness O
of O
use O
of O
drug O
- O
drug O
combinations O
in O
elderly O
. O

Cyclooxygenase O
activity O
contributes O
to O
the O
monoaminergic O
damage O
caused O
by O
serial O
exposure O
to O
stress O
and O
methamphetamine B
. O

Methamphetamine B
( O
Meth B
) O
is O
a O
widely O
abused O
psychostimulant O
that O
causes O
long O
- O
term O
dopamine B
( O
DA O
) O
and O
serotonin B
( O
5 B
- I
HT I
) O
depletions O
. O

Stress O
and O
Meth B
abuse O
are O
comorbid O
events O
in O
society O
and O
stress O
exacerbates O
Meth B
- O
induced O
monoaminergic O
terminal O
damage O
. O

Stress O
is O
also O
known O
to O
produce O
neuroinflammation O
. O

This O
study O
examined O
the O
role O
of O
the O
neuroinflammatory O
mediator O
, O
cyclooxygenase O
( O
COX O
) O
, O
in O
the O
depletions O
of O
monoamines B
caused O
by O
serial O
exposure O
to O
chronic O
unpredictable O
stress O
( O
CUS O
) O
and O
Meth B
. O

CUS B
produced O
an O
increase O
in O
COX O
- O
2 O
protein O
expression O
and O
enhanced O
Meth B
- O
induced O
monoaminergic O
depletions O
in O
the O
striatum O
and O
hippocampus O
. O

The O
enhanced O
DA O
and O
5 B
- I
HT I
depletions O
in O
the O
striatum O
, O
but O
not O
the O
hippocampus O
, O
were O
prevented O
by O
pretreatment O
with O
COX O
inhibitor O
, O
ketoprofen B
, O
during O
stress O
or O
during O
Meth B
; O
however O
, O
ketoprofen B
did O
not O
attenuate O
the O
monoaminergic O
damage O
caused O
by O
Meth B
alone O
. O

The O
COX O
- O
dependent O
enhancement O
by O
stress O
of O
Meth B
- O
induced O
monoaminergic O
depletions O
was O
independent O
of O
hyperthermia O
, O
as O
ketoprofen B
did O
not O
attenuate O
Meth B
- O
induced O
hyperthermia O
. O

In O
addition O
, O
the O
EP1 O
receptor O
antagonist O
, O
SC B
- I
51089 I
, O
did O
not O
attenuate O
DA O
or O
5 B
- I
HT I
depletions O
caused O
by O
stress O
and O
Meth B
. O

These O
findings O
illustrate O
that O
COX O
activity O
, O
but O
not O
activation O
of O
the O
EP1 O
receptor O
, O
is O
responsible O
for O
the O
potentiation O
of O
Meth B
- O
induced O
damage O
to O
striatal O
monoamine B
terminals O
by O
stress O
and O
suggests O
the O
use O
of O
anti O
- O
inflammatory O
drugs O
for O
mitigating O
the O
neurotoxic O
effects O
associated O
with O
the O
combination O
of O
stress O
and O
Meth B
. O

Upregulation O
of O
the O
dorsal O
raphe O
nucleus O
- O
prefrontal O
cortex O
serotonin B
system O
by O
chronic O
treatment O
with O
escitalopram B
in O
hyposerotonergic O
Wistar O
- O
Kyoto O
rats O
. O

Wistar O
- O
Kyoto O
( O
WKY O
) O
rats O
are O
sensitive O
to O
chronic O
stressors O
and O
exhibit O
depression O
- O
like O
behavior O
. O

Dorsal O
raphe O
nucleus O
( O
DRN O
) O
serotonin B
( O
5 B
- I
HT I
) O
neurons O
projecting O
to O
the O
prefrontal O
cortex O
( O
PFC O
) O
comprise O
the O
important O
neurocircuitry O
underlying O
the O
pathophysiology O
of O
depression O
. O

To O
evaluate O
the O
DRN O
- O
PFC O
5 B
- I
HT I
system O
in O
WKY O
rats O
, O
we O
examined O
the O
effects O
of O
escitalopram B
( O
ESCIT B
) O
on O
the O
extracellular O
5 B
- I
HT I
level O
in O
comparison O
with O
Wistar O
rats O
using O
dual O
- O
probe O
microdialysis O
. O

The O
basal O
levels O
of O
5 B
- I
HT I
in O
the O
DRN O
, O
but O
not O
in O
the O
PFC O
, O
in O
WKY O
rats O
was O
reduced O
as O
low O
as O
30 O
% O
of O
Wistar O
rats O
. O

Responses O
of O
5 B
- I
HT I
in O
the O
DRN O
and O
PFC O
to O
ESCIT O
administered O
systemically O
and O
locally O
were O
attenuated O
in O
WKY O
rats O
. O

Feedback O
inhibition O
of O
DRN O
5 B
- I
HT I
release O
induced O
by O
ESCIT O
into O
the O
PFC O
was O
also O
attenuated O
in O
WKY O
rats O
. O

Chronic O
ESCIT O
induced O
upregulation O
of O
the O
DRN O
- O
PFC O
5 B
- I
HT I
system O
in O
WKY O
rats O
, O
with O
increases O
in O
basal O
5 B
- I
HT I
in O
the O
DRN O
, O
responsiveness O
to O
ESCIT O
in O
the O
DRN O
and O
PFC O
, O
and O
feedback O
inhibition O
, O
whereas O
downregulation O
of O
these O
effects O
was O
induced O
in O
Wistar O
rats O
. O

Thus O
, O
the O
WKY O
rat O
is O
an O
animal O
model O
of O
depression O
with O
low O
activity O
of O
the O
DRN O
- O
PFC O
5HT B
system O
. O

The O
finding O
that O
chronic O
ESCIT O
upregulates O
the O
5 B
- I
HT I
system O
in O
hyposerotonergic O
WKY O
rats O
may O
contribute O
to O
improved O
understanding O
of O
mechanisms O
of O
action O
of O
antidepressants O
, O
especially O
in O
depression O
with O
5 B
- I
HT I
deficiency O
. O

Bioconcentration O
of O
chromium B
in O
edible O
mushrooms O
: O
influence O
of O
environmental O
and O
genetic O
factors O
. O

Chromium B
concentrations O
were O
determined O
in O
167 O
samples O
of O
wild O
edible O
mushrooms O
, O
collected O
from O
three O
different O
sites O
( O
urban O
, O
traffic O
and O
pastureland O
areas O
) O
in O
Lugo O
( O
NW O
Spain O
) O
. O

The O
hymenophore O
( O
H O
) O
and O
the O
rest O
of O
the O
fruiting O
body O
( O
RFB O
) O
were O
analysed O
separately O
. O

The O
analyses O
were O
performed O
using O
inductively O
coupled O
plasma O
optical O
emission O
spectrometry O
( O
ICP O
- O
OES O
) O
. O

The O
highest O
mean O
chromium B
levels O
( O
mg O
/ O
kg O
dry O
weight O
) O
of O
3 O
. O
5 O
and O
8 O
. O
0 O
, O
4 O
. O
5 O
and O
6 O
. O
2 O
, O
and O
6 O
. O
2 O
and O
4 O
. O
3 O
were O
found O
in O
Lycoperdon O
utriforme O
, O
Coprinus O
comatus O
and O
Agaricus O
campestris O
in O
H O
and O
RFB O
, O
respectively O
. O

The O
highest O
concentrations O
of O
chromium B
were O
observed O
in O
terrestrial O
saprophytic O
species O
in O
relation O
to O
mycorrhizal O
species O
. O

With O
respect O
to O
the O
underlying O
substrates O
, O
chromium B
concentration O
was O
lowest O
in O
the O
pastureland O
area O
( O
24 O
. O
6 O
mg O
/ O
kg O
dw O
) O
. O

All O
mushroom O
species O
were O
bioexclusors O
of O
chromium B
( O
BCF O
< O
1 O
) O
with O
statistically O
significant O
differences O
( O
p O
< O
0 O
. O
001 O
) O
. O

The O
consumption O
of O
mushrooms O
harvested O
from O
the O
areas O
investigated O
poses O
no O
toxicological O
risk O
to O
human O
health O
due O
to O
chromium B
. O

Synthetic O
pathway O
to O
22 B
, I
23 I
- I
dioxocholestanic I
chain O
derivatives O
and O
their O
usefulness O
for O
obtaining O
brassinosteroid B
analogues O
. O

Recognizing O
the O
functionality O
of O
the O
pentacyclic B
steroidal I
derivative O
7a O
as O
important O
synthon O
to O
obtain O
new O
brassinosteroid B
analogs O
, O
we O
have O
accomplished O
the O
derivatization O
of O
hecogenin B
, O
a O
sapogenin O
from O
the O
25R O
serie O
containing O
a O
carbonyl B
group O
at O
C O
- O
12 O
, O
to O
a O
22 B
, I
23 I
- I
dioxocholestanic I
chain O
derivative O
. O

Starting O
from O
hecogenin B
acetate I
( O
5a O
) O
or O
hecogenin B
tosylate I
( O
5b O
) O
, O
we O
obtained O
two O
pentacyclic O
derivatives O
( O
7a O
and O
7b O
) O
which O
were O
subjected O
to O
an O
oxidation O
reaction O
on O
the O
double O
bond O
at O
C O
- O
12 O
( O
23 O
) O
to O
obtain O
a O
22 B
, I
23 I
- I
dioxocholestanic I
chain O
, O
with O
the O
regeneration O
of O
the O
carbonyl B
group O
at O
C O
- O
12 O
. O

Reduction O
of O
the O
carbonyl B
groups O
lead O
to O
the O
20 B
- I
epi I
- I
12 I
, I
23 I
- I
dihydroxy I
- I
22 I
- I
oxo I
system O
11a O
- O
b O
. O

The O
absolute O
configuration O
of O
compound O
11a O
was O
established O
by O
X O
- O
ray O
diffraction O
analysis O
. O

Evolution O
of O
Manduca O
sexta O
hornworms O
and O
relatives O
: O
Biogeographical O
analysis O
reveals O
an O
ancestral O
center O
of O
diversification O
in O
Central O
America O
. O

The O
hawkmoth O
genus O
Manduca O
is O
a O
diverse O
group O
of O
very O
large O
, O
conspicuous O
moths O
that O
has O
served O
as O
an O
important O
model O
across O
many O
biological O
disciplines O
. O

Two O
species O
in O
particular O
, O
the O
tobacco O
hornworm O
( O
Manduca O
sexta O
) O
and O
the O
tomato O
hornworm O
( O
Manduca O
quinquemaculatus O
) O
have O
been O
researched O
extensively O
. O

Studies O
across O
biological O
fields O
have O
referred O
to O
these O
two O
species O
as O
being O
closely O
related O
or O
even O
sister O
species O
, O
but O
the O
extent O
to O
which O
these O
two O
model O
organisms O
are O
related O
remains O
largely O
unknown O
. O

We O
conducted O
a O
comprehensive O
multi O
- O
gene O
phylogenetic O
analysis O
of O
Manduca O
, O
based O
on O
both O
an O
ML O
and O
Bayesian O
framework O
, O
which O
resulted O
in O
a O
monophyletic O
Manduca O
but O
only O
when O
two O
other O
genera O
, O
Dolba O
and O
Euryglottis O
are O
included O
. O

We O
tentatively O
conclude O
that O
the O
sister O
group O
to O
Manduca O
sexta O
comprises O
the O
Caribbean O
M O
. O
afflicta O
and O
M O
. O
johanni O
, O
and O
the O
sister O
lineage O
to O
this O
clade O
includes O
M O
. O
quinquemaculatus O
and O
the O
Hawaiian O
M O
. O
blackburni O
. O

Thus O
, O
M O
. O
sexta O
and O
M O
. O
quinquemaculatus O
are O
closely O
related O
, O
but O
are O
not O
sister O
species O
. O

Biogeographical O
analyses O
reveal O
an O
ancestral O
center O
of O
diversification O
in O
Central O
America O
, O
and O
Manduca O
appears O
to O
have O
subsequently O
colonized O
North O
and O
South O
America O
. O

Our O
phylogeny O
provides O
an O
important O
foundation O
for O
comparative O
studies O
of O
two O
model O
organisms O
and O
their O
relatives O
. O

Designing O
, O
structural O
elucidation O
, O
comparison O
of O
DNA O
binding O
, O
cleavage O
, O
radical O
scavenging O
activity O
and O
anticancer O
activity O
of O
copper B
( I
I I
) I
complex O
with O
5 B
- I
dimethyl I
- I
2 I
- I
phenyl I
- I
4 I
- I
[ I
( I
pyridin I
- I
2 I
- I
ylmethylene I
) I
- I
amino I
] I
- I
1 I
, I
2 I
- I
dihydro I
- I
pyrazol I
- I
3 I
- I
one I
Schiff I
base I
ligand O
. O

A O
novel O
copper B
( I
I I
) I
Schiff I
base I
complex O
has O
been O
synthesized O
and O
fully O
characterized O
by O
spectral O
, O
analytical O
and O
structural O
modes O
. O

Single O
crystal O
X O
- O
ray O
diffraction O
studies O
revealed O
that O
the O
copper B
( I
I I
) I
complex O
[ B
CuCl I
( I
PPh3 I
) I
L I
] I
has O
a O
distorted O
tetrahedral O
geometry O
around O
the O
central O
copper B
( I
I I
) I
ion O
. O

The O
interaction O
of O
the O
ligand O
and O
the O
complex O
with O
CT O
- O
DNA O
has O
been O
explored O
by O
absorption O
titration O
method O
which O
revealed O
that O
the O
compounds O
could O
interact O
with O
CT O
- O
DNA O
through O
intercalation O
. O

A O
gel O
electrophoresis O
assay O
demonstrated O
the O
ability O
of O
the O
complex O
to O
cleave O
the O
pBR322 O
DNA O
. O

The O
antioxidative O
properties O
showed O
that O
the O
copper B
( I
I I
) I
complex O
has O
a O
strong O
radical O
- O
scavenging O
potency O
than O
ligands O
. O

Further O
the O
cytotoxic O
effect O
of O
the O
compounds O
examined O
on O
cancerous O
cell O
lines O
showed O
that O
the O
complex O
exhibited O
substantial O
anticancer O
activity O
. O

Synthesis O
and O
biological O
evaluation O
of O
novel O
phosphatidylinositol B
3 O
- O
kinase O
inhibitors O
: O
Solubilized O
4 B
- I
substituted I
benzimidazole I
analogs O
of O
2 B
- I
( I
difluoromethyl I
) I
- I
1 I
- I
[ I
4 I
, I
6 I
- I
di I
( I
4 I
- I
morpholinyl I
) I
- I
1 I
, I
3 I
, I
5 I
- I
triazin I
- I
2 I
- I
yl I
] I
- I
1H I
- I
benzimidazole I
( O
ZSTK474 B
) O
. O

A O
range O
of O
4 O
- O
substituted O
derivatives O
of O
the O
pan O
class O
I O
PI O
3 O
- O
kinase O
inhibitor O
2 B
- I
( I
difluoromethyl I
) I
- I
1 I
- I
[ I
4 I
, I
6 I
- I
di I
- I
( I
4 I
- I
morpholinyl I
) I
- I
1 I
, I
3 I
, I
5 I
- I
triazin I
- I
2 I
- I
yl I
] I
- I
1H I
- I
benzimidazole I
( O
ZSTK474 B
) O
were O
prepared O
in O
a O
search O
for O
more O
soluble O
analogs O
. O

4 B
- I
Aminoalkoxy I
substituents O
provided O
the O
most O
potent O
derivatives O
, O
with O
the O
4 B
- I
O I
( I
CH2 I
) I
3NMe2 I
analog O
( O
compound O
14 O
) O
being O
identified O
as O
displaying O
the O
best O
overall O
activity O
in O
combination O
with O
good O
aqueous O
solubility O
( O
25 O
mg O
/ O
mL O
for O
the O
hydrochloride B
salt O
) O
. O

This O
compound O
was O
tested O
in O
a O
U87MG O
xenograft O
model O
, O
but O
displayed O
less O
potency O
than O
ZSTK474 B
as O
a O
result O
of O
an O
unfavorable O
pharmacokinetic O
profile O
. O

Nitroimidazolyl B
hydrazones I
are O
better O
amoebicides O
than O
their O
cyclized B
1 I
, I
3 I
, I
4 I
- I
oxadiazoline I
analogues O
: O
In O
vitro O
studies O
and O
Lipophilic O
efficiency O
analysis O
. O

Two O
series O
of O
compounds O
with O
hydrazone B
derivatives O
( O
HZ1 B
- O
HZl2 B
, O
series O
1 O
) O
and O
oxadiazoline B
derivatives O
( O
OZ1 B
- O
OZ12 B
, O
series O
2 O
) O
of O
the O
2 B
- I
methyl I
- I
5 I
- I
nitro I
- I
1H I
- I
imidazole I
scaffold O
were O
designed O
and O
synthesized O
. O

Physicochemical O
properties O
and O
Lipophilic O
efficiency O
( O
LipE O
) O
analysis O
predicted O
higher O
intrinsic O
quality O
of O
the O
acylhydrazone B
derivatives O
( O
series O
1 O
) O
than O
their O
corresponding O
oxadiazoline B
analogues O
( O
series O
2 O
) O
. O

In O
vitro O
antiamoebic O
results O
supported O
the O
above O
findings O
and O
validated O
that O
the O
acylhydrazone B
derivatives O
( O
HZ1 O
- O
HZl2 O
) O
show O
better O
activity O
than O
the O
oxadiazoline B
derivatives O
( O
OZ1 B
- O
OZ12 B
) O
. O

MTT B
assay O
, O
using O
HepG2 O
cell O
line O
, O
revealed O
noncytotoxic O
nature O
of O
the O
compounds O
. O

The O
most O
promising O
results O
were O
observed O
for O
compounds O
HZ5 O
( O
IC50 O
= O
0 O
. O
96 O
mu O
M O
) O
and O
HZ9 O
( O
IC50 O
= O
0 O
. O
81 O
mu O
M O
) O
both O
in O
silico O
and O
in O
vitro O
. O

Analysis O
of O
the O
Lipophilic O
efficiency O
( O
LipE O
) O
of O
the O
compounds O
provided O
new O
insight O
for O
the O
design O
of O
potent O
and O
selective O
amoebicides O
. O

Enmein B
- O
type O
diterpenoid B
analogs O
from O
natural O
kaurene B
- O
type O
oridonin B
: O
Synthesis O
and O
their O
antitumor O
biological O
evaluation O
. O

A O
series O
of O
enmein B
- O
type O
diterpenoid B
analogs O
( O
11 O
- O
20 O
) O
derived O
from O
natural O
kaurene B
- O
type O
diterpenoid B
oridonin B
were O
synthesized O
and O
biologically O
evaluated O
. O

All O
target O
compounds O
showed O
improved O
anti O
- O
proliferative O
activities O
against O
four O
human O
cancer O
cell O
lines O
compared O
with O
natural O
oridonin B
and O
parent O
compound O
10 O
. O

Some O
compounds O
were O
more O
potent O
than O
positive O
control O
Taxol B
. O

Furthermore O
, O
mechanistic O
investigation O
showed O
that O
the O
representative O
compound O
17 O
affected O
cell O
cycle O
and O
induced O
apoptosis O
at O
low O
micro O
- O
molar O
level O
in O
human O
hepatoma O
Bel O
- O
7402 O
cells O
, O
via O
an O
oxidative O
stress O
triggered O
mitochondria O
- O
related O
caspase O
- O
dependent O
pathway O
. O

Siah2 O
regulates O
tight O
junction O
integrity O
and O
cell O
polarity O
through O
control O
of O
ASPP2 O
stability O
. O

Changes O
in O
cell O
adhesion O
and O
polarity O
are O
closely O
associated O
with O
epithelial O
cell O
transformation O
and O
metastatic O
capacity O
. O

The O
tumor O
suppressor O
protein O
ASPP O
( O
Apoptosis O
- O
Stimulating O
Proteins O
of O
p53 O
) O
2 O
has O
been O
implicated O
in O
control O
of O
cell O
adhesion O
and O
polarity O
through O
its O
effect O
on O
the O
PAR O
complex O
. O

Here O
we O
demonstrate O
that O
under O
hypoxic O
conditions O
, O
the O
ubiquitin O
ligase O
Siah O
( O
seven O
in O
absentia O
homolog O
) O
2 O
controls O
ASPP2 O
availability O
, O
with O
concomitant O
effect O
on O
epithelial O
cell O
polarity O
. O

LC O
- O
MS O
/ O
MS O
analysis O
identified O
ASPP2 O
and O
ASPP1 O
as O
Siah2 O
- O
interacting O
proteins O
. O

Biochemical O
analysis O
confirmed O
this O
interaction O
and O
mapped O
degron O
motifs O
within O
ASPP2 O
, O
which O
are O
required O
for O
Siah2 O
- O
mediated O
ubiquitination O
and O
proteasomal O
- O
dependent O
degradation O
. O

Inhibition O
of O
Siah2 O
expression O
increases O
ASPP2 O
levels O
and O
enhances O
ASPP2 O
- O
dependent O
maintenance O
of O
tight O
junction O
( O
TJ O
) O
integrity O
, O
and O
polarized O
architecture O
in O
three O
dimensional O
( O
3D O
) O
organotypic O
culture O
. O

Conversely O
, O
increase O
of O
Siah2 O
expression O
under O
hypoxia O
decreases O
ASPP2 O
levels O
and O
the O
formation O
of O
apical O
polarity O
in O
3D O
culture O
. O

In O
all O
, O
our O
studies O
demonstrate O
the O
role O
of O
Siah2 O
in O
regulation O
of O
TJ O
integrity O
and O
cell O
polarity O
under O
hypoxia O
, O
through O
its O
regulation O
of O
ASPP2 O
stability O
. O
Oncogene O
advance O
online O
publication O
, O
6 O
May O
2013 O
; O
doi O
: O
10 O
. O
1038 O
/ O
onc O
. O
2013 O
. O
149 O
. O

The O
effect O
of O
intranasal O
oxytocin B
treatment O
on O
conditioned O
fear O
extinction O
and O
recall O
in O
a O
healthy O
human O
sample O
. O

RATIONALE O
: O
To O
improve O
outcomes O
for O
patients O
undergoing O
extinction O
- O
based O
therapies O
( O
e O
. O
g O
. O
, O
exposure O
therapy O
) O
for O
anxiety O
disorders O
such O
as O
post O
- O
traumatic O
stress O
disorder O
( O
PTSD O
) O
, O
there O
has O
been O
interest O
in O
identifying O
pharmaceutical O
compounds O
that O
might O
facilitate O
fear O
extinction O
learning O
and O
recall O
. O

Oxytocin B
( O
OT O
) O
is O
a O
mammalian O
neuropeptide O
that O
modulates O
activation O
of O
fear O
extinction O
- O
based O
neural O
circuits O
and O
fear O
responses O
. O

Little O
is O
known O
, O
however O
, O
about O
the O
effects O
of O
OT O
treatment O
on O
conditioned O
fear O
responding O
and O
extinction O
in O
humans O
. O

OBJECTIVES O
: O
The O
purpose O
of O
the O
present O
study O
was O
to O
assess O
the O
effects O
of O
OT O
in O
a O
fear O
- O
potentiated O
startle O
task O
of O
fear O
conditioning O
and O
extinction O
. O

METHODS O
: O
A O
double O
- O
blind O
, O
placebo O
- O
controlled O
study O
of O
44 O
healthy O
human O
participants O
was O
conducted O
. O

Participants O
underwent O
a O
conditioned O
fear O
acquisition O
procedure O
, O
after O
which O
they O
were O
randomized O
to O
treatment O
group O
and O
delivered O
OT O
( O
24 O
IU O
) O
or O
placebo O
via O
intranasal O
( O
IN O
) O
spray O
. O

Forty O
- O
five O
minutes O
after O
treatment O
, O
participants O
underwent O
extinction O
training O
. O

Twenty O
- O
four O
hours O
later O
, O
subjects O
were O
tested O
for O
extinction O
recall O
. O

RESULTS O
: O
Relative O
to O
placebo O
, O
the O
OT O
group O
showed O
increased O
fear O
- O
potentiated O
startle O
responding O
during O
the O
earliest O
stage O
of O
extinction O
training O
relative O
to O
placebo O
; O
however O
, O
all O
treatment O
groups O
showed O
the O
same O
level O
of O
reduced O
responding O
by O
the O
end O
of O
extinction O
training O
. O

Twenty O
- O
four O
hours O
later O
, O
the O
OT O
group O
showed O
significantly O
higher O
recall O
of O
extinction O
relative O
to O
placebo O
. O

CONCLUSIONS O
: O
The O
current O
study O
provides O
preliminary O
evidence O
that O
OT O
may O
facilitate O
fear O
extinction O
recall O
in O
humans O
. O

These O
results O
support O
further O
study O
of O
OT O
as O
a O
potential O
adjunctive O
treatment O
for O
extinction O
- O
based O
therapies O
in O
fear O
- O
related O
disorders O
. O

Greater O
risk O
sensitivity O
of O
dorsolateral O
prefrontal O
cortex O
in O
young O
smokers O
than O
in O
nonsmokers O
. O

RATIONALE O
: O
Despite O
a O
national O
reduction O
in O
the O
prevalence O
of O
cigarette O
smoking O
, O
~ O
19 O
% O
of O
the O
adult O
US O
population O
persists O
in O
this O
behavior O
, O
with O
the O
highest O
prevalence O
among O
18 O
- O
25 O
- O
year O
- O
olds O
. O

Given O
that O
the O
choice O
to O
smoke O
imposes O
a O
known O
health O
risk O
, O
clarification O
of O
brain O
function O
related O
to O
decision O
- O
making O
, O
particularly O
involving O
risk O
- O
taking O
, O
in O
smokers O
may O
inform O
prevention O
and O
smoking O
cessation O
strategies O
. O

OBJECTIVES O
: O
This O
study O
aimed O
to O
compare O
brain O
function O
related O
to O
decision O
- O
making O
in O
young O
smokers O
and O
nonsmokers O
. O

METHODS O
: O
The O
Balloon O
Analogue O
Risk O
Task O
( O
BART O
) O
is O
a O
computerized O
risky O
decision O
- O
making O
task O
in O
which O
participants O
pump O
virtual O
balloons O
, O
each O
pump O
associated O
with O
an O
incremental O
increase O
in O
potential O
payoff O
on O
a O
given O
trial O
but O
also O
with O
greater O
risk O
of O
balloon O
explosion O
and O
loss O
of O
payoff O
. O

We O
used O
this O
task O
to O
compare O
brain O
activation O
associated O
with O
risky O
decision O
- O
making O
in O
smokers O
( O
n O
= O
18 O
) O
and O
nonsmokers O
( O
n O
= O
25 O
) O
, O
while O
they O
performed O
the O
BART O
during O
functional O
magnetic O
resonance O
imaging O
( O
fMRI O
) O
. O

The O
participants O
were O
young O
men O
and O
women O
, O
17 O
- O
21 O
years O
of O
age O
. O

RESULTS O
: O
Risk O
level O
( O
number O
of O
pumps O
) O
modulated O
brain O
activation O
in O
the O
right O
dorsolateral O
and O
ventrolateral O
prefrontal O
cortices O
more O
in O
smokers O
than O
in O
nonsmokers O
, O
and O
smoking O
severity O
( O
Heaviness O
of O
Smoking O
Index O
) O
was O
positively O
related O
to O
this O
modulation O
in O
an O
adjacent O
frontal O
region O
. O

CONCLUSIONS O
: O
Given O
evidence O
for O
involvement O
of O
the O
right O
dorsolateral O
and O
ventrolateral O
prefrontal O
cortices O
in O
inhibitory O
control O
, O
these O
findings O
suggest O
that O
young O
smokers O
have O
a O
different O
contribution O
of O
prefrontal O
cortical O
substrates O
to O
risky O
decision O
- O
making O
than O
nonsmokers O
. O

Future O
studies O
are O
warranted O
to O
determine O
whether O
the O
observed O
neurobiological O
differences O
precede O
or O
result O
from O
smoking O
. O

Measuring O
nanoparticle O
flow O
with O
the O
image O
structure O
function O
. O

We O
present O
a O
technique O
to O
measure O
the O
velocity O
and O
flow O
profiles O
of O
a O
nanofluid O
in O
a O
microfluidic O
channel O
. O

Importantly O
, O
we O
extract O
the O
flow O
velocity O
from O
a O
series O
of O
standard O
brightfield O
images O
without O
employing O
particle O
tracking O
or O
laser O
- O
enhanced O
methods O
. O

Our O
analysis O
retrieves O
the O
flow O
information O
from O
the O
image O
structure O
function O
of O
sub O
- O
diffraction O
limited O
nanoparticles O
in O
suspension O
. O

We O
are O
able O
to O
spatially O
resolve O
the O
flow O
velocity O
and O
map O
out O
the O
parabolic O
flow O
profile O
across O
the O
width O
of O
a O
microfluidic O
channel O
. O

Role O
of O
quercetin B
in O
cadmium B
- O
induced O
oxidative O
stress O
, O
neuronal O
damage O
, O
and O
apoptosis O
in O
rats O
. O

The O
present O
study O
was O
carried O
out O
to O
evaluate O
the O
neuroprotective O
effect O
of O
quercetin B
( O
QE O
) O
in O
protecting O
the O
cadmium B
( O
Cd B
) O
- O
induced O
neuronal O
injury O
in O
frontal O
cortex O
of O
rats O
. O

A O
total O
of O
30 O
adult O
male O
Sprague O
- O
Dawley O
rats O
were O
randomly O
divided O
into O
three O
groups O
of O
10 O
animals O
each O
: O
control O
, O
Cd O
treated O
and O
Cd O
treated O
with O
QE O
. O

The O
Cd B
- O
treated O
group O
was O
injected O
subcutaneously O
with O
cadmium B
chloride I
( O
CdCl2 B
) O
dissolved O
in O
saline O
at O
a O
dose O
of O
2 O
ml O
/ O
kg O
/ O
day O
for O
30 O
days O
, O
resulting O
in O
a O
dosage O
of O
1 O
mg O
/ O
kg O
Cd B
. O

The O
rats O
in O
QE O
- O
treated O
groups O
were O
given O
QE O
( O
15 O
mg O
/ O
kg O
body O
weight O
) O
once O
a O
day O
intraperitoneally O
starting O
2 O
days O
prior O
to O
Cd O
injection O
, O
during O
the O
study O
period O
. O

Rats O
were O
sacrificed O
at O
the O
end O
of O
the O
study O
and O
the O
frontal O
cortex O
tissues O
were O
removed O
for O
biochemical O
and O
histopathological O
investigation O
. O

To O
date O
, O
there O
is O
no O
available O
information O
on O
the O
effect O
of O
QE O
on O
neuronal O
injury O
after O
Cd B
exposure O
. O

Rats O
intoxicated O
with O
Cd B
for O
30 O
days O
, O
significantly O
increased O
tissue O
malondialdehyde B
( O
MDA B
) O
levels O
and O
significantly O
decreased O
enzymatic O
antioxidants O
superoxide B
dismutase O
, O
glutathione B
peroxidase O
and O
catalase O
in O
the O
frontal O
cortex O
tissue O
. O

Administration O
of O
QE O
with O
Cd B
significantly O
diminished O
the O
levels O
of O
MDA B
and O
significantly O
elevated O
the O
levels O
of O
enzymatic O
antioxidants O
in O
the O
frontal O
cortex O
tissue O
. O

The O
histopathological O
studies O
in O
the O
brain O
of O
rats O
also O
supported O
that O
QE O
markedly O
reduced O
the O
Cd B
- O
induced O
histopathological O
changes O
and O
well O
preserved O
the O
normal O
histological O
architecture O
of O
the O
frontal O
cortex O
tissue O
. O

The O
caspase O
- O
3 O
immunopositivity O
was O
increased O
in O
degenerating O
neurons O
of O
the O
Cd O
group O
. O

Treatment O
with O
QE O
markedly O
reduced O
the O
immunoreactivity O
of O
degenerating O
neurons O
. O

In O
conclusion O
, O
the O
results O
of O
the O
current O
study O
suggest O
that O
QE O
may O
be O
beneficial O
in O
combating O
the O
Cd B
- O
induced O
neurotoxicity O
in O
the O
brain O
of O
rats O
. O

We O
believe O
that O
further O
preclinical O
research O
into O
the O
utility O
of O
QE O
may O
indicate O
its O
usefulness O
as O
a O
potential O
treatment O
for O
neurodegeneration O
after O
Cd B
exposure O
in O
rats O
. O

Differential O
regulation O
of O
Arabidopsis O
plastid O
gene O
expression O
and O
RNA O
editing O
in O
non O
- O
photosynthetic O
tissues O
. O

RNA O
editing O
is O
one O
of O
the O
post O
- O
transcriptional O
processes O
that O
commonly O
occur O
in O
plant O
plastids O
and O
mitochondria O
. O

In O
Arabidopsis O
, O
34 O
C O
- O
to O
- O
U O
RNA O
editing O
events O
, O
affecting O
transcripts O
of O
18 O
plastid O
genes O
, O
have O
been O
identified O
. O

Here O
, O
we O
examined O
the O
editing O
and O
expression O
of O
these O
transcripts O
in O
different O
organs O
, O
and O
in O
green O
and O
non O
- O
green O
seedlings O
( O
etiolated O
, O
cia5 O
- O
2 O
, O
ispF O
and O
ispG O
albino O
mutants O
, O
lincomycin B
- O
, O
and O
norflurazon B
- O
treated O
) O
. O

The O
editing O
efficiency O
of O
Arabidopsis O
plastid O
transcripts O
varies O
from O
site O
to O
site O
, O
and O
may O
be O
specifically O
regulated O
in O
different O
tissues O
. O

Steady O
state O
levels O
of O
plastid O
transcripts O
are O
low O
or O
undetectable O
in O
etiolated O
seedlings O
, O
but O
most O
editing O
sites O
are O
edited O
with O
efficiencies O
similar O
to O
those O
observed O
in O
green O
seedlings O
. O

By O
contrast O
, O
the O
editing O
of O
some O
sites O
is O
completely O
lost O
or O
significantly O
reduced O
in O
other O
non O
- O
green O
tissues O
; O
for O
instance O
, O
the O
editing O
of O
ndhB O
- O
149 O
, O
ndhB O
- O
1255 O
, O
and O
ndhD O
- O
2 O
is O
completely O
lost O
in O
roots O
and O
in O
lincomycin B
- O
treated O
seedlings O
. O

The O
editing O
of O
ndhD O
- O
2 O
is O
also O
completely O
lost O
in O
albino O
mutants O
and O
norflurazon B
- O
treated O
seedlings O
. O

However O
, O
matK O
- O
640 O
is O
completely O
edited O
, O
and O
accD O
- O
794 O
, O
atpF O
- O
92 O
, O
psbE O
- O
214 O
, O
psbF O
- O
77 O
, O
psbZ O
- O
50 O
, O
and O
rps14 O
- O
50 O
are O
completely O
or O
highly O
edited O
in O
both O
green O
and O
non O
- O
green O
tissues O
. O

In O
addition O
, O
the O
expression O
of O
nucleus O
- O
encoded O
RNA O
polymerase O
dependent O
transcripts O
is O
specifically O
induced O
by O
lincomycin B
, O
and O
the O
splicing O
of O
ndhB O
transcripts O
is O
significantly O
reduced O
in O
the O
albino O
mutants O
and O
inhibitor O
- O
treated O
seedlings O
. O

Our O
results O
indicate O
that O
plastid O
gene O
expression O
, O
and O
the O
splicing O
and O
editing O
of O
plastid O
transcripts O
are O
specifically O
and O
differentially O
regulated O
in O
various O
types O
of O
non O
- O
green O
tissues O
. O

Analysis O
of O
the O
inhibitory O
activity O
of O
Abeliophyllum O
distichum O
leaf O
constituents O
against O
aldose B
reductase O
by O
using O
high O
- O
speed O
counter O
current O
chromatography O
. O

We O
isolated O
five O
phenolic B
glycosides I
( O
acteoside B
, O
eutigoside B
B I
, O
isoacteoside B
, O
rutin B
and O
cornoside B
) O
from O
Abeliophyllum O
distichum O
leaves O
by O
high O
- O
speed O
counter O
current O
chromatography O
( O
HSCCC O
) O
using O
a O
solvent O
system O
of O
ethyl B
acetate I
: O
n B
- I
butanol I
: O
water O
( O
8 O
: O
0 O
. O
7 O
: O
5 O
) O
. O

We O
determined O
the O
purity O
of O
the O
5 O
compounds O
by O
high O
- O
performance O
liquid O
chromatography O
, O
and O
confirmed O
their O
chemical O
structures O
by O
using O
nuclear O
magnetic O
resonance O
data O
. O

We O
examined O
the O
inhibitory O
effect O
of O
these O
compounds O
on O
rat O
lens O
aldose B
reductase O
. O

Among O
these O
compounds O
, O
acteoside B
( O
1 O
) O
showed O
the O
most O
potent O
inhibitory O
effect O
, O
with O
an O
IC50 O
value O
of O
1 O
. O
39 O
mu O
M O
. O

The O
inhibitory O
effect O
of O
1 O
was O
5 O
. O
0 O
times O
greater O
than O
that O
of O
quercetin B
( O
7 O
. O
05 O
mu O
M O
) O
, O
which O
was O
used O
as O
a O
positive O
control O
. O

These O
results O
suggest O
that O
acteoside B
may O
be O
a O
promising O
agent O
for O
the O
prevention O
or O
treatment O
of O
diabetic O
complications O
. O

Moreover O
, O
HSCCC O
is O
a O
promising O
method O
for O
the O
isolation O
and O
purification O
of O
biologically O
active O
compounds O
from O
natural O
products O
. O

Understanding O
the O
Cost O
- O
Effectiveness O
of O
Influenza O
Vaccination O
in O
Children O
: O
Methodological O
Choices O
and O
Seasonal O
Variability O
. O

BACKGROUND O
: O
The O
universal O
vaccination O
of O
children O
for O
influenza O
has O
recently O
been O
recommended O
in O
the O
UK O
and O
is O
being O
considered O
in O
other O
developed O
countries O
. O

OBJECTIVES O
: O
The O
aim O
of O
this O
study O
was O
to O
explore O
the O
potential O
costs O
and O
benefits O
of O
childhood O
influenza O
vaccination O
to O
gain O
a O
better O
understanding O
of O
the O
key O
drivers O
of O
cost O
- O
effectiveness O
. O

METHODS O
: O
As O
our O
case O
study O
we O
examined O
the O
cost O
- O
effectiveness O
of O
vaccination O
in O
Australian O
schoolchildren O
using O
an O
age O
- O
stratified O
Susceptible O
Exposed O
Infectious O
Recovered O
model O
. O

RESULTS O
: O
The O
results O
of O
this O
study O
highlight O
the O
critical O
role O
that O
methodological O
choices O
play O
in O
determining O
the O
cost O
- O
effectiveness O
of O
influenza O
vaccination O
. O

These O
choices O
include O
decisions O
about O
the O
structure O
of O
the O
model O
( O
including O
/ O
excluding O
herd O
immunity O
) O
and O
what O
costs O
and O
benefits O
to O
include O
in O
the O
analysis O
. O

In O
scenarios O
where O
herd O
protection O
was O
included O
we O
estimated O
that O
the O
program O
was O
likely O
to O
be O
cost O
- O
effective O
. O

The O
study O
also O
illustrates O
the O
importance O
of O
the O
inherent O
seasonal O
variability O
of O
influenza O
, O
which O
can O
produce O
counter O
- O
intuitive O
results O
, O
with O
low O
transmission O
seasons O
being O
easier O
to O
control O
by O
vaccination O
but O
resulting O
in O
fewer O
benefits O
. O

CONCLUSIONS O
: O
Universal O
childhood O
influenza O
vaccination O
is O
likely O
to O
be O
cost O
- O
effective O
if O
a O
substantial O
herd O
protection O
effect O
can O
be O
achieved O
by O
the O
program O
. O

However O
, O
it O
is O
important O
that O
decision O
makers O
understand O
the O
role O
of O
seasonal O
variability O
and O
the O
impact O
of O
alternative O
methodological O
choices O
in O
economic O
evaluations O
of O
influenza O
vaccination O
. O

The O
bacterial O
translocon O
SecYEG O
opens O
upon O
ribosome O
binding O
. O

In O
cotranslational O
translocation O
, O
the O
ribosome O
funnel O
and O
the O
channel O
of O
the O
protein O
translocation O
complex O
SecYEG O
are O
aligned O
. O

For O
the O
nascent O
chain O
to O
enter O
the O
channel O
immediately O
after O
synthesis O
, O
a O
yet O
unidentified O
signal O
triggers O
displacement O
of O
the O
SecYEG O
sealing O
plug O
from O
the O
pore O
. O

Here O
we O
show O
that O
ribosome O
binding O
to O
the O
resting O
SecYEG O
channel O
triggers O
this O
conformational O
transition O
. O

The O
purified O
and O
reconstituted O
SecYEG O
channel O
opens O
to O
form O
a O
large O
ion O
- O
conducting O
channel O
which O
has O
the O
conductivity O
of O
the O
plug O
deletion O
mutant O
. O

The O
number O
of O
ion O
conducting O
channels O
inserted O
into O
the O
planar O
bilayer O
per O
fusion O
event O
roughly O
equals O
the O
number O
of O
SecYEG O
channels O
counted O
by O
fluorescence O
correlation O
spectroscopy O
in O
a O
single O
proteoliposome O
. O

Thus O
, O
the O
open O
probability O
of O
the O
channel O
must O
be O
close O
to O
unity O
. O

To O
prevent O
the O
otherwise O
lethal O
proton O
leak O
, O
a O
closed O
post O
- O
translational O
conformation O
of O
the O
SecYEG O
complex O
bound O
to O
a O
ribosome O
must O
exist O
. O

Gain O
- O
of O
- O
function O
mutations O
in O
transient O
receptor O
potential O
C6 O
( O
TRPC6 O
) O
activate O
extracellular O
- O
signal O
- O
regulated O
kinases O
Erk1 O
/ O
2 O
. O

Gain O
- O
of O
- O
function O
mutations O
in O
the O
canonical O
transient O
receptor O
potential O
6 O
( O
TRPC6 O
) O
gene O
are O
a O
cause O
of O
autosomal O
dominant O
focal O
segmental O
glomerulosclerosis O
( O
FSGS4 O
) O
. O

The O
mechanisms O
whereby O
abnormal O
TRPC6 O
activity O
results O
in O
proteinuria O
remain O
unknown O
. O

The O
Erk1 O
/ O
2 O
MAP O
kinases O
are O
activated O
in O
glomeruli O
and O
podocytes O
in O
several O
proteinuric O
disease O
models O
. O

We O
therefore O
examined O
whether O
FSGS O
- O
associated O
mutations O
in O
TRPC6 O
result O
in O
activation O
of O
these O
kinases O
. O

In O
293T O
cells O
and O
cultured O
podocytes O
, O
overexpression O
of O
gain O
- O
of O
- O
function O
TRPC6 O
mutants O
resulted O
in O
increased O
Erk1 O
/ O
2 O
phosphorylation O
, O
an O
effect O
dependent O
upon O
channel O
function O
. O

Pharmacologic O
inhibitor O
studies O
implicated O
several O
signaling O
mediators O
, O
including O
calmodulin O
and O
calcineurin O
, O
supporting O
the O
importance O
of O
TRPC6 O
- O
mediated O
calcium B
influx O
in O
this O
process O
. O

Through O
media O
transfer O
experiments O
, O
we O
uncovered O
two O
distinct O
mechanisms O
for O
Erk O
activation O
by O
mutant O
TRPC6 O
, O
a O
cell O
autonomous O
, O
EGFR O
- O
independent O
mechanism O
and O
a O
cell O
non O
- O
autonomous O
mechanism O
involving O
metalloprotease O
- O
mediated O
release O
of O
a O
presumed O
EGFR O
ligand O
. O

The O
inhibitors O
KN B
- I
92 I
and O
H89 B
were O
able O
to O
block O
both O
pathways O
in O
mutant O
TRPC6 O
expressing O
cells O
, O
as O
well O
as O
the O
prolonged O
elevation O
of O
intracellular O
calcium B
levels O
upon O
carbachol B
stimulation O
seen O
in O
these O
cells O
. O

However O
, O
these O
effects O
appear O
independent O
of O
their O
effects O
on O
CaMKII O
and O
PKA O
, O
respectively O
. O

Phosphorylation O
of O
T70 O
, O
S282 O
and O
Y31 O
/ O
Y285 O
were O
not O
necessary O
for O
Erk O
activation O
by O
mutant O
TRPC6 O
, O
though O
a O
phosphomimetic O
TRPC6 O
S282E O
mutant O
was O
capable O
of O
Erk O
activation O
. O

Taken O
together O
, O
these O
results O
identify O
two O
pathways O
downstream O
of O
mutant O
TRPC6 O
leading O
to O
Erk O
activation O
that O
may O
play O
a O
role O
in O
the O
development O
of O
FSGS O
. O